Retina 2015
Upping the Ante
Program Directors
Pravin U Dugel MD and Jennifer I Lim MD
In conjunction with the American Society of Retina Specialists,
the Macula Society, the Retina Society, and Club Jules Gonin
Sands Expo/Venetian
Las Vegas, Nevada
Friday, Nov. 13 – Saturday, Nov. 14, 2015
Presented by:
The American Academy of Ophthalmology
Sponsored in part by an unrestricted educational grant from
Genentech
Retina 2015 Planning Group
Pravin U Dugel MD
Program Director
Jennifer I Lim MD
Program Director
Carl D Regillo MD
Richard F Spaide MD
Former Program Directors
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
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
John T Thompson MD
M Gilbert Grand MD
Emily Y Chew MD
John T Thompson MD
Michael T Trese MD
Emily Y Chew MD
William F Mieler MD
Michael T Trese MD
Kirk H Packo MD
William F Mieler MD
Mark S Blumenkranz MD
Kirk H Packo MD
George A Williams MD
Mark S Blumenkranz MD
Julia A Haller MD
George A Williams MD
Stanley Chang MD
Julia A Haller MD
Harry W Flynn Jr MD
Stanley Chang MD
H MacKenzie Freeman MD
Harry W Flynn Jr MD
H MacKenzie Freeman MD
Thomas M Aaberg Sr MD
Paul Sternberg Jr MD
Subspecialty Day Advisory Committee
William F Mieler MD
Associate Secretary
Donald L Budenz MD MPH
Daniel S Durrie MD
Francis S Mah MD
R Michael Siatkowski MD
Nicolas J Volpe MD
Jonathan B Rubenstein MD
Secretary for Annual Meeting
Staff
Melanie R Rafaty CMP, Director, Scientific
Meetings
Ann L’Estrange, Scientific Meetings Specialist
Christa Fernandez, Presenter Coordinator
Debra Rosencrance CMP CAE, Vice
President, Meetings & Exhibits
Patricia Heinicke Jr, Copyeditor
Mark Ong, Designer
Gina Comaduran, Cover Design
©2015 American Academy of Ophthalmology. All rights reserved. No portion may be reproduced without express written consent of the American Academy of Ophthalmology.
ii
2015 Subspecialty Day | Retina
2015 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
Las Vegas and Retina 2015: Upping the Ante.
Pravin U Dugel MD
Jennifer Irene Lim MD
Abbott Medical Optics: C
Acucela: C
Alcon Laboratories, Inc.: C
Alimera Sciences, Inc.: C,O
Allergan: C | Digisight: O
Genentech: C
Novartis Pharmaceuticals Corp.: C
Ophthotech: C,O
Ora: C | Regeneron: C
ThromboGenics: C
Alcon Laboratories, Inc.: C
Alexion: C
Genentech: C,L,S
ICON Bioscience: C,S
Lumenis, Inc.: C
Pfizer, Inc.: S
Regeneron Pharmaceuticals, Inc.: C,L,S
Santen, Inc.: C
Carl D Regillo MD FACS
Richard F Spaide MD
Program Director
Acucela: C,S
Advanced Cell
Technology: S
Alcon Laboratories, Inc.:
C,S
Alimera Sciences, Inc.:
C,S
Allergan: C,S
Bausch + Lomb: C
Genentech: C,S
NotalVision, Ltd.: C,S
Novartis Pharmaceuticals
Corp.: C
Pfizer, Inc. C
Regeneron
Pharmaceuticals, Inc.:
C,S
Santen, Inc.: S
Second Sight Medical
Products, Inc.: S
ThromboGenics, Inc.: C,S
Program Director
Genentech: C
Topcon Medical Systems, Inc.: P,C
2015 Subspecialty Day | Retina
Retina 2015 Contents
2015 Retina Subspecialty Day Planning Group ii
CME iv
The Charles L Schepens MD Lecture vi
Faculty Listing vii
Program Schedule xxvii
Section I:
Masters of Surgery 1
Section II:
Vitreoretinal Surgery, Part I 12
Advocating for Patients 35
The Charles L Schepens MD Lecture 37
Section III:
The Business of Retina 38
Section IV:
Late Breaking Developments, Part I 44
Section V:
My Coolest Surgical Video 45
Section VI: Pediatric Retina 46
Section VII: Retinal Vein Occlusion 49
Section VIII:
Diabetic Retinopathy Clinical Research Network (DRCRnet) Protocols 54
Section IX:
First-time Results of Clinical Trials, Part I 58
Section X:
Neovascular AMD 62
Section XI:
Imaging 81
Section XII:
Late Breaking Developments, Part II 110
Section XIII:
Oncology Panel 111
Section XIV:
Diabetes 112
Section XV:
First-time Results of Clinical Trials, Part II 126
Section XVI:
Uveitis 137
Section XVII: Non-neovascular AMD 138
Section XVIII: Vitreoretinal Surgery, Part II 159
Section XIX: Video Surgical Complications—What Would You Do? 174
Faculty Financial Disclosure 175
Retina Exhibitors 184
Presenter Index 186
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iv
2015 Subspecialty Day | Retina
CME Credit
Academy’s CME Mission Statement
The purpose of the American Academy of Ophthalmology’s
Continuing Medical Education (CME) program is to 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.
2015 Retina Subspecialty Day Meeting Learning
Objectives
Upon completion of this activity, participants should be able to:
• Explain the current management of macular edema
secondary to retinal occlusive disease and diabetic
­retinopathy
• Explain the pathobiology and management of atrophic
and exudative AMD and other causes of CNV
• Identify emerging developments in retinal imaging
• Describe new vitreoretinal surgical techniques and instrumentation
• Identify new developments in hereditary retinal degenerations, pediatric retinal diseases, and ocular oncology
• Summarize current and new clinical trial data for retinal
diseases such as AMD, diabetic retinopathy, and retinal
vein occlusion
2015 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.
2015 Retina Subspecialty Day Meeting CME Credit
The American Academy of Ophthalmology is accredited by the
Accreditation Council for Continuing Medical Education to provide CME 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.
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
interest. 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.
Attendance Verification for CME Reporting
Before processing your requests for CME credit, the Academy
must verify your attendance at Subspecialty Day and/or at AAO
2015. In order to be verified for CME or auditing purposes, you
must either:
• Register in advance, receive materials in the mail, and turn
in the Final Program and/or Subspecialty Day Syllabus
exchange voucher(s) onsite;
• Register in advance and pick up your badge onsite if
­materials did not arrive before you traveled to the meeting;
• Register onsite; or
• Scan the barcode on your badge as you enter an AAO
2015 course or session room.
CME Credit Reporting
Level 2 Lobby and Academy Resource Center, Hall B – Booth
2632
Attendees whose attendance has been verified (see above) at
AAO 2015 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 2015 at the CME Credit Reporting booth.
Academy Members: The CME credit reporting receipt is not a
CME transcript. CME transcripts that include AAO 2015 credits entered onsite will be available to Academy members on the
Academy’s website beginning Dec. 10, 2015.
NOTE: CME credits must be reported by Jan. 13, 2016.
After AAO 2015, credits can be claimed at www.aao.org.
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 2015.
Nonmembers: The Academy will provide nonmembers with
verification of credits earned and reported for a single Academysponsored CME activity, but it does not provide CME credit
transcripts. To obtain a printed record of your credits, you must
2015 Subspecialty Day | Retina
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 2015 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 for detailed CME reporting information.
CME Credit
v
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2015 Subspecialty Day | Retina
The Charles L Schepens MD Lecture
Digital Medicine: Implications for Retina and Beyond
Friday, Nov. 13, 2015
10:07 AM – 10:27 AM
Mark S Blumenkranz MD
Mark S Blumenkranz MD MMS is H. J. Smead Professor of
Ophthalmology in the Department of Ophthalmology at Stanford University. He received his undergraduate degree, a graduate
degree in biochemical pharmacology, and his medical education
at Brown University. He completed his internship in surgery and
his ophthalmic residency training at Stanford, and in 1980 a fellowship in vitreoretinal diseases at the Bascom Palmer Eye Institute, where he subsequently served on the faculty for five years.
After leaving Bascom Palmer Dr. Blumenkranz joined Associated
Retinal Consultants in Royal Oak, Michigan, and became the
founding director of the vitreoretinal fellowship program at William Beaumont Hospital, before returning to Stanford in 1992 to
lead the retinal service and then the department as chairman from
1997 until 2015. He spearheaded the development of the Byers
Eye Institute at Stanford and served as its founding director from
the time of its opening in 2010 until 2015.
Dr. Blumenkranz was an early innovator in vitrectomy
techniques to treat complex forms of retinal detachment, and
he helped to usher in the modern era of intravitreal, gene, and
surgical adjuvant drug therapy. He has also published extensively in the area of new lasers and laser tissue interactions. He
has published more than 150 papers in peer-reviewed journals
and multiple book chapters, abstracts, and patents in the field.
Dr. Blumenkranz has a long-standing interest and expertise in
university corporate technology transfer and early stage biomedical company development, having either founded or served on
the boards of directors of a number of successful medical drug
and device companies.
Dr. Blumenkranz has served on the editorial boards of the
American Journal of Ophthalmology, Retina, Ophthalmology,
and Graefe’s Archives for Ophthalmology. He is a past recipient
of the Heed Award, the Rosenthal Award in Visual Sciences, the
American Academy of Ophthalmology Lifetime Achievement
Award, the Alcon Research Institute Award, ARVO Fellows
designation, and the Gertrude Pyron Award from the American Society of Retina Specialists for lifetime contributions in
vitreoretinal surgery. He has delivered multiple named award
lectures over the past thirty-five years, including most recently
the Jackson Memorial Lecture at the Academy’s Annual Meeting
in 2013. He is a past president of the American University Professors of Ophthalmology (AUPO), the Retina Society, and the
Macula Society. He is a member of the Steering Committee of the
Audacious Goals Initiative of the NEI, and he is a Fellow of the
Corporation of Brown University, where he is the long-serving
chair of the Medical School Committee.
Dr. Blumenkranz and his wife, Recia Kott Blumenkranz MD,
are the parents of three children, Carla, Scott, and Erik, and live
in Portola Valley, California.
2015 Subspecialty Day | Retina
vii
Faculty
Thomas M Aaberg Jr MD
Jayakrishna Ambati MD
Marcos P Avila MD
Ada, MI
Founder and President
Retina Specialists of Michigan
Assistant Clinical Professor of
Ophthalmology
Michigan State University
Lexington, KY
Professor and Vice Chair
Ophthalmology and Visual Sciences
University of Kentucky
Professor of Physiology
University of Kentucky
Goiania, GO, Brazil
Professor of Ophthalmology
Head of the Ophthalmology Department
Universidade Federal de Goiás
No photo
available
Carl C Awh MD
Anita Agarwal MD
J Fernando Arevalo MD FACS
Nashville, TN
Professor of Ophthalmology
Vanderbilt Eye Institute
Vanderbilt University School of
Medicine
Riyadh, Saudi Arabia
Edmund F and Virginia Ball Professor of
Ophthalmology
Wilmer Eye Institute and Johns Hopkins
University School of Medicine
Chief of Vitreoretina Division
The King Khaled Eye Specialist Hospital,
Riyadh
Nashville, TN
President, Tennessee Retina, PC
Sophie J Bakri MD
Rochester, MN
Professor of Ophthalmology
Mayo Clinic
Thomas A Albini MD
Miami, FL
Associate Professor of Clinical
Ophthalmology
Bascom Palmer Eye Institute
Robert L Avery MD
Santa Barbara, CA
Codirector, California Retina Research
Foundation
Founder, California Retina Consultants
viii
Faculty Listing
2015 Subspecialty Day | Retina
Francesco M Bandello MD FEBO
Audina M Berrocal MD
Mark S Blumenkranz MD
Milano, Italy
Full Professor and Chairman
Department of Ophthalmology
University Scientific Institute San
Raffaele
Miami, FL
Professor of Clinical Ophthalmology
Bascom Palmer Eye Institute
University of Miami
Staff Physician
Miami Children’s Hospital
Palo Alto, CA
H J Smead Professor and Chairman
Stanford University School of Medicine
Director, Byers Eye Institute at Stanford
Caroline R Baumal MD
Boston, MA
Associate Professor
Tufts University School of Medicine
Vitreoretinal Surgeon
New England Eye Center
Francesco Boscia MD
Maria H Berrocal MD
San Juan, PR
Faculty, Department of Ophthalmology
University of Puerto Rico
Director, Berrocal & Associates
Bari, Italy
Associate Professor and Chairman
Department of Ophthalmology
University of Sassari
David S Boyer MD
Paul S Bernstein MD PhD
Susanne Binder MD
Salt Lake City, UT
Professor of Ophthalmology and Visual
Sciences
Moran Eye Center
University of Utah
Vienna, Austria
Professor, Department of
Ophthalmology
Rudolf Foundation Clinic
Professor of Ophthalmology
The Ludwig Boltzmann Institute for
Retinology and Biomicroscopic Laser
Surgery
Los Angeles, CA
Clinical Professor of Ophthalmology
University of Southern California / Keck
School of Medicine
Partner, Retina Vitreous Associates
Medical Group
Faculty Listing
2015 Subspecialty Day | Retina
Neil M Bressler MD
Gary C Brown MD
Antonio Capone Jr MD
Baltimore, MD
Chief, Retina Division
The James P Gills Professor of
Ophthalmology
Wilmer Eye Institute
Johns Hopkins University School of
Medicine
Editor-in-Chief
JAMA Ophthalmology
Plymouth Meeting, PA
Professor of Ophthalmology
Director Emeritus, Retina Service
Wills Eye Hospital, Jefferson Medical
College
Chief Medical Officer and Director of
Pharmacoeconomics
Center for Value-Based Medicine
Royal Oak, MI
Professor of Ophthalmology
William Beaumont Hospital / Oakland
University School of Medicine
Copresident, Partner, Owner
Associated Retinal Consultants
ix
Usha Chakravarthy MBBS PhD
Susan B Bressler MD
Baltimore, MD
The Julia G Levy PhD Professor of
Ophthalmology
Wilmer Eye Institute
Johns Hopkins University School of
Medicine
David J Browning MD PhD
Charlotte, NC
Retina Service
Charlotte Eye, Ear, Nose, and Throat
Associates
Belfast, Northern Ireland
Professor of Ophthalmology and Vision
Science
Queen’s University of Belfast
Wiley Andrew Chambers MD
Peter A Campochiaro MD
David M Brown MD
Houston, TX
Clinical Professor of Ophthalmology
Baylor College of Medicine
Director of Clinical Research
Retina Consultants of Houston
Baltimore, MD
Eccles Professor of Ophthalmology and
Neuroscience
John Hopkins University School of
Medicine
McLean, VA
Clinical Professor of Ophthalmology
The George Washington University
x
Faculty Listing
2015 Subspecialty Day | Retina
R V Paul Chan MD
Emily Y Chew MD
Carl C Claes MD
New York, NY
St. Giles Associate Professor of Pediatric
Retina
Weill Cornell Medical College
Bethesda, MD
Deputy Director
Division of Epidemiology and Clinical
Applications
National Eye Institute / National
Institutes of Health
Schilde, Belgium
Head of Vitreoretinal Surgery
Saint Augustinus Hospital (Wilrijk/
Antwerp)
Director, Ophthalmology Medical
Center
Vlaamse Kaai 29 Antwerp/ Belgium
Stanley Chang MD
New York, NY
KK Tse and KT Ying Professor of
Ophthalmology
Columbia University
David R Chow MD
North York, ON, Canada
Assistant Professor of Ophthalmology
University of Toronto
Codirector, Toronto Retina Institute
Borja F Corcóstegui MD
Barcelona, Spain
Professor of Ophthalmology
University Autònoma of Barcelona
Institut de Microcirurgía Ocular
Steven T Charles MD
Memphis, TN
Clinical Professor of Ophthalmology
University of Tennesee, Memphis
No photo
available
Nauman A Chaudhry MBBS
New London, CT
Clinical Professor
Yale New Haven Hospital
Thomas A Ciulla MD
Indianapolis, IN
Retina Service
Midwest Eye Institute
Scott W Cousins MD
Durham, NC
Vice Chair for Research
Professor of Ophthalmology and
Immunology
Duke University
Faculty Listing
2015 Subspecialty Day | Retina
Karl G Csaky MD
Christine Curcio PhD
Lucian V Del Priore MD PhD
Dallas, TX
Senior Scientist
Retina Foundation of the Southwest
Partner, Texas Retina Associates
Birmingham, AL
Professor of Ophthalmology
University of Alabama at Birmingham
Charleston, SC
Professor and Chairman
Storm Eye Institute
Medical University of South Carolina
Professor of Regenerative Medicine
Medical University of South Carolina
xi
No photo
available
Catherine A Cukras MD PhD
Bethesda, MD
Donald J D’Amico MD
New York, NY
Professor and Chairman
Department of Ophthalmology
Weill Cornell Medical College
Ophthalmologist-in-Chief
New York-Presbyterian
Diana V Do MD
Omaha, NE
Associate Professor of Ophthalmology
Vice Chair for Education
Director, Carl Camras Center for
Innovative Research
Truhlsen Eye Institute
University of Nebraska Medical Center
Emmett T Cunningham Jr MD
PhD MPH
Hillsborough, CA
Director, The Uveitis Service
California Pacific Medical Center
Adjunct Clinical Professor of
Ophthalmology
Stanford University School of Medicine
Janet Louise Davis MD
Miami, FL
Leach Distinguished Professor of
Ophthalmology
University of Miami Miller School of
Medicine
Director, Uveitis Service
Member, Retina Service
Bascom Palmer Eye Institute
Kimberly A Drenser MD PhD
Royal Oak, MI
Vitreoretinal Surgeon
Associated Retinal Consultants
Professor, William Beaumont Oakland
University School of Medicine
xii
Faculty Listing
2015 Subspecialty Day | Retina
Didier H Ducournau MD
Jacque L Duncan MD
Ehab N El Rayes MD PhD
Nantes, France
CEO, European VitreoRetinal Services
Company
European VitreoRetinal Society (EVRS)
Vitreoretinal Surgeon
Clinique Sourdille, Nantes
San Francisco, CA
Professor, Clinical Ophthalmology
University of California, San Francisco
Cairo, Egypt
Professor of Ophthalmlogy
Retina Department
Institute of Ophthalmology
Vitreoretinal Consultant
The Retina Clinic, Cairo
Claus Eckardt MD
Pravin U Dugel MD
Frankfurt, Germany
Professor of Ophthalmology
Klinikum Frankfurt Höchst
Phoenix, AZ
Managing Partner
Retinal Consultants of Arizona
Clinical Professor of Ophthalmology
USC Eye Institute, Keck School of
Medicine
University of Southern California, Los
Angeles, CA
Dean Eliott MD
Boston, MA
Associate Director of Retina Service
Associate Professor of Ophthalmology
Massachusetts Eye & Ear Infirmary,
Harvard Medical School
Justis P Ehlers MD
Shaker Heights, OH
Assistant Professor of Ophthalmology
Cole Eye Institute
Cleveland Clinic
Jay S Duker MD
Boston, MA
Director, New England Eye Center
Tufts Medical Center
Professor and Chairman
Department of Ophthalmology
Tufts University School of Medicine
Michel Eid Farah MD
São Paulo, SP, Brazil
Professor of Ophthalmology
Federal University of São Paulo
Faculty Listing
2015 Subspecialty Day | Retina
xiii
No photo
available
Philip J Ferrone MD
Harry W Flynn Jr MD
Martin Friedlander MD
Great Neck, NY
Partner, Long Island Vitreoretinal
Consultants
Assistant Professor of Ophthalmology
Columbia University
Miami, FL
Professor of Ophthalmology
The J Donald M Gass Chair in
Ophthalmology
Bascom Palmer Eye Institute
University of Miami Miller School of
Medicine
La Jolla, CA
Professor of Cell and Molecular Biology
The Scripps Research Institute
Chief, Retina Service
Division of Ophthalmology
Scripps Clinic
No photo
available
Marta Figueroa MD
Madrid, Spain
Medical Director
Vissum Madrid
Professor of Ophthalmology
University of Alcalá de Henares
David Fonseca Martins MD
Setubal, Portugal
Sunir J Garg MD FACS
Philadelphia, PA
Associate Professor of Ophthalmology
The Retina Service of Wills Eye Hospital
Partner, MidAtlantic Retina
K Bailey Freund MD
Gerald A Fishman MD
Chicago, IL
Professor of Ophthalmology
Ophthalmology and Visual Science
University of Illinois at Chicago
Director, The Pangere Center for
Inherited Retinal Diseases
The Chicago Lighthouse for People Who
Are Blind or Visually Impaired
New York, NY
Clinical Professor of Ophthalmology
New York University
Partner, Vitreous Retina Macula
Consultants of New York
Alain Gaudric MD
Paris, France
Emeritus Professor of Ophthalmology
Université Paris-Diderot
Hopital Lariboisiere, AP-HP
xiv
Faculty Listing
2015 Subspecialty Day | Retina
No photo
available
Ronald C Gentile MD
Julia A Haller MD
Tarek S Hassan MD
Manhasset, NY
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
Thomas Jefferson University
Royal Oak, MI
Professor of Ophthalmology
Oakland University William Beaumont
School of Medicine
Partner and Director, Vitreoretinal
Training Program
Associated Retinal Consultants
Mark C Gillies MD PhD
Sydney, Australia
Professor of Ophthalmology
Save Sight Institute, University of Sydney
Dennis P Han MD
Milwaukee, WI
Jack A and Elaine D Klieger Professor of
Ophthalmology
Medical College of Wisconsin
Vitreoretinal Section Head
The Froedert & Medical College Eye
Institute
Jeffrey S Heier MD
Boston, MA
Director, Vitreoretinal Service
Ophthalmic Consultants of Boston
Codirector, Vitreoretinal Fellowship
Ophthalmic Consultants of Boston /
Tufts University School of Medicine
Evangelos S Gragoudas MD
Boston, MA
Professor of Ophthalmology
Harvard Medical School
Director, Retina Service
Massachusetts Eye and Ear Infirmary
No photo
available
Akito Hirakata MD
J William Harbour MD
Jeffrey G Gross MD
Columbia, SC
Founder and Managing Partner
Carolina Retina Center, PA
Miami, FL
Professor and Vice Chairman
Dr. Mark J Daily Endowed Chair
Bascom Palmer Eye Institute
Director of Ocular Oncology
Bascom Palmer Eye Institute and
Sylvester Comprehensive Cancer
Center
Tokyo, Japan
Professor and Chairman
Department of Ophthalmology
Kyorin University School of Medicine
Faculty Listing
2015 Subspecialty Day | Retina
Allen C Ho MD
Suber S Huang MD MBA
Michael S Ip MD
Philadelphia, PA
Director of Retina Research
Mid Atlantic Retina and Wills Eye
Hospital
Professor of Ophthalmology
Thomas Jefferson University
South Euclid, OH
Director, Center for Retina and Macular
Disease
University Hospitals Eye Institute
Searle Professor and Vice Chair
Department of Ophthalmology and
Visual Sciences
Case Western Reserve University School
of Medicine
Madison, WI
Associate Professor of Ophthalmology
and Visual Sciences
University of Wisconsin, Madison
No photo
available
Tatsuro Ishibashi MD
Fukuoka, Japan
Nancy M Holekamp MD
Chesterfield, MO
Director, Retina Service
Pepose Vision Institute
Professor of Clinical Ophthalmology
Washington University School of
Medicine
Mark S Humayun MD PhD
Los Angeles, CA
Professor of Ophthalmology
University of Southern California
No photo
available
Frank G Holz MD
Raymond Iezzi MD
Bonn, Germany
Professor of Ophthalmology
University of Bonn, Germany
Rochester, MN
Associate Professor of Ophthalmology
Mayo Clinic
Timothy L Jackson MBChB
London, England
Consultant Ophthalmic Surgeon
King’s College London
Glenn J Jaffe MD
Durham, NC
Professor of Ophthalmology
Director, Duke Reading Center
Duke University
xv
xvi
Faculty Listing
2015 Subspecialty Day | Retina
Lee M Jampol MD
Peter K Kaiser MD
Szilard Kiss MD
Chicago, IL
Feinberg Professor of Ophthalmology
Northwestern University
Chair, DRCRnet
Cleveland, OH
Professor of Ophthalmology
Cleveland Clinic Lerner College of
Medicine
New York, NY
Director of Clinical Research
Associate Professor of Ophthalmology
Weill Cornell Medical College
Mark W Johnson MD
Richard S Kaiser MD
John W Kitchens MD
Ann Arbor, MI
Professor of Ophthalmology and Visual
Sciences
University of Michigan
Director, Retina Service
W K Kellogg Eye Center
Cherry Hill, NJ
Associate Surgeon
Retina Service of Wills Eye Institute
Associate Clinical Professor
Thomas Jefferson University
Lexington, KY
Physician, Retina Associates of Kentucky
Voluntary Faculty
University of Kentucky
Kazuaki Kadonosono MD
Yokohama, Kanagawa, Japan
Professor and Chair
Ophthalmology & Microtechnology
Yokohama City University, School of
Medicine
Judy E Kim MD
Milwaukee, WI
Professor of Ophthalmology
Medical College of Wisconsin
Derek Y Kunimoto MD JD
Paradise Valley, AZ
Co-Managing Partner
Retinal Consultants of AZ
Director, Scottsdale Eye Surgery Center
Faculty Listing
2015 Subspecialty Day | Retina
xvii
No photo
available
Baruch D Kuppermann MD PhD
Gerardo Ledesma-Gil MD
Jennifer Irene Lim MD
Irvine, CA
Professor and Chief
Retina Service
Gavin Herbert Eye Institute
University of California, Irvine
Mexico City, Mexico
Resident
Instituto de Oftalmologia Conde de
Valenciana
Chicago, IL
Professor of Ophthalmology
University of Illinois at Chicago, Illinois
Eye and Ear Infirmary
Director of the Retina Service
Marion H Schenk Esq. Chair in
Ophthalmology
Illinois Eye and Ear Infirmary
University of Illinois at Chicago
No photo
available
Yasuo Kurimoto MD PhD
Kobe, Japan
Director, Department of Ophthalmology
Kobe City Medical Center General
Hospital
Director, Department of Ophthalmology
Institute of Biomedical Research and
Innovation Hospital
Thomas C Lee MD
Los Angeles, CA
Associate Professor of Ophthalmology
University of Southern California
Director, Vision Center
Children’s Hospital Los Angeles
Anat Loewenstein MD
Tel Aviv, Israel
Director, Department of Ophthalmology
Tel Aviv Medical Center
Professor of Ophthalmology
Vice Dean, Sackler Faculty of Medicine
Tel Aviv University
No photo
available
Xiaoxin Li MD
Michael Larsen MD
Glostrup, Denmark
Beijing, BJ, China
Professor of Ophthalmology
People’s Eye Center of Peking University
Chair of Eye Center
Eye Center of International Hospital of
Peking University
No photo
available
Zhizhong Ma MD
Beijing, China
Professor
Peking University Third Hospital
xviii
Faculty Listing
2015 Subspecialty Day | Retina
Mathew W MacCumber MD PhD
Albert M Maguire MD
Daniel F Martin MD
Chicago, IL
Professor of Ophthalmology
Rush University Medical Center
Retina Specialist
Illinois Retina Associates, SC
Bryn Mawr, PA
Professor of Ophthalmology
University of Pennsylvania
Clinical Associate
Children’s Hospital of Philadelphia
Cleveland, OH
Chairman, Cole Eye Institute
Cleveland Clinic
Carlos Mateo MD
Yumiko Machida MD
Tamer Mahmoud MD
Tokyo, Japan
Durham, NC
Associate Professor of Ophthalmology
Program Director, Vitreoretinal
Fellowship
Duke University Eye Center
Robert E MacLaren MBChB
Oxford, England
Professor of Ophthalmology and
Consultant Vitreoretinal Surgeon
University of Oxford and Oxford Eye
Hospital UK
Honorary Consultant
Moorfields Eye Hospital, London UK
Barcelona, Spain
Associate Professor of Ophthalmology
Instituto de Microcirugía Ocular of
Barcelona
Miguel A Materin MD
Brian P Marr MD
New York, NY
Associate Attending
Memorial Sloan Kettering Cancer Center
New Haven, CT
Director, Ophthalmic Oncology
Smilow Cancer Hospital at Yale-New
Haven
Faculty Listing
2015 Subspecialty Day | Retina
xix
H Richard McDonald MD
Andrew A Moshfeghi MD MBA
Timothy G Murray MD MBA
San Francisco, CA
Clinical Professor of Ophthalmology
Director, Vitreoretinal Fellowship
Program
California Pacific Medical Center
Los Angeles, CA
Associate Professor, Director
Clinical Trials Unit
University of Southern California
South Miami, FL
Founding Director
Ocular Oncology and Retina (MOOR)
Professor Emeritus of Ophthalmology
and Radiation Oncology
Bascom Palmer Eye Institute
William F Mieler MD
Evanston, IL
Interim Head, Professor and Vice
Chairman of Ophthalmology
Department of Ophthalmology & Visual
Sciences
Interim Head, Professor and Vice
Chairman
Department of Ophthalmology
University of Illinois at Chicago
Joan W Miller MD
Boston, MA
Henry Willard Williams Professor of
Ophthalmology
Harvard Medical School
Chief and Chair of Ophthalmology
Massachusetts Eye & Ear Infirmary,
Massachusetts General Hospital,
Harvard Medical School
Darius M Moshfeghi MD
Palo Alto, CA
Associate Professor of Ophthalmology
Director of Telemedicine
Director of Pediatric Vitreoretinal
Surgery
Byers Eye Institute
Stanford University School of Medicine
Quan Dong Nguyen MD
Omaha, NE
Chairman and Inaugural Director
McGaw Professor of Ophthalmology
Truhlsen Eye Institute
University of Nebraska Medical Center
Robert F Mullins PhD MS
Yuichiro Ogura MD PhD
Iowa City, IA
Professor
Department of Ophthalmology and
Visual Sciences, The University of
Iowa
Investigator
Stephen A Wynn Institute for Vision
Research, The University of Iowa
Nagoya, Japan
Professor and Chairman
Department of Ophthalmology and
Visual Science
Nagoya City University Graduate School
of Medical Sciences
xx
Faculty Listing
2015 Subspecialty Day | Retina
Masahito Ohji MD
Yusuke Oshima MD
Grazia Pertile MD
Otsu, Shiga, Japan
Professor and Chairman
Department of Ophthalmology
Shiga University of Medical Science
Takatsuki-City, Osaka, Japan
Founder and Director
Oshima Eye Clinic
Vitreoretina & Cataract Surgery Center,
Osaka
Adviser, Consultant Ophthalmologist,
and Vitreoretinal Surgeon
Nishikasai Inouye Eye Hospital, Tokyo
Negrar, VR, Italy
Director, Department of Ophthalmology
Sacro Cuore Hospital
Dante Pieramici MD
Kyoko Ohno-Matsui MD
Tokyo, Japan
Professor of Ophthalmology
Tokyo Medical and Dental University
Kirk H Packo MD
Santa Barbara, CA
Partner, California Retina Consultants
President, California Retina Research
Foundation
Chicago, IL
Professor and Chairman
Department of Ophthalmology
Rush University Medical Center
Partner, Illinois Retina Associates
Annabelle A Okada MD
Eric A Pierce MD PhD
Tokyo, Japan
Professor of Ophthalmology
Kyorin University School of Medicine
Boston, MA
Director, Ocular Genomics Institute
Massachusetts Eye and Ear Infirmary
David W Parke II MD
San Francisco, CA
CEO
American Academy of Ophthalmology
Timothy W Olsen MD
John S Pollack MD
Atlanta, GA
F Phinizy Calhoun Sr. Professor
Chairman of Ophthalmology
Emory University
Joliet, IL
Assistant Professor of Ophthalmology
Rush University Medical Center
Partner, Illinois Retina Associates
Faculty Listing
2015 Subspecialty Day | Retina
xxi
Jonathan L Prenner MD
Carl D Regillo MD FACS
William L Rich III MD FACS
Princeton, NJ
Associate Clinical Professor
Rutgers Robert Wood Johnson Medical
School, University of Medicine and
Dentistry of New Jersey, NJ Retina
Partner, NJ Retina
Bryn Mawr, PA
Professor of Ophthalmology
Thomas Jefferson University
Director, Retina Services
Wills Eye Institute
Falls Church, VA
Medical Director for Health Policy
American Academy of Ophthalmology
Clinical Instructor
Department of Ophthalmology
Georgetown University
No photo
available
Carmen A Puliafito MD MBA
Los Angeles, CA
Dean, John and Mary Hooval Dean’s
Chair in Medicine
Keck School, University of Southern
California
Professor of Ophthalmology and Health
Management
USC Eye Institute
University of Southern California
Elias Reichel MD
Boston, MA
Professor of Ophthalmology
Tufts University School of Medicine
Vice Chairman
New England Eye Center
No photo
available
Christopher D Riemann MD
Cincinnati, OH
Director, Vitreoretinal Fellowship
Cincinnati Eye Institute and University
of Cincinnati
Member, Board of Directors
Cincinnati Eye Institute
Kourous Rezaei MD
P Kumar Rao MD
Saint Louis, MO
Associate Professor
Ophthalmology and Visual Sciences
Washington University in St. Louis
Harvey, IL
Associate Professor of Ophthalmology
Rush University Medical Center
Partner, Illinois Retina Associates
Stanislao Rizzo MD
Lucca, Italy
Director, SOD Oculistica
Azienda Ospedaliero-Universitaria
Careggi, Firenze, Italy
xxii
Faculty Listing
2015 Subspecialty Day | Retina
Philip J Rosenfeld MD PhD
Taiji Sakamoto MD PhD
Ursula M Schmidt-Erfurth MD
Miami, FL
Professor of Ophthalmology
Bascom Palmer Eye Institute
University of Miami Miller School of
Medicine
Kagoshima, Japan
Professor and Chair of Ophthalmology
Kagoshima University
Vienna, Austria
Professor of Ophthalmology
Chair, Department of Ophthalmology
and Optometry
Medical University of Vienna
No photo
available
David Sarraf MD
Edina, MN
Partner, VitreoRetinal Surgery, PA
Los Angeles, CA
Clinical Professor of Ophthalmology
Stein Eye Institute
University of California, Los Angeles
Srinivas R Sadda MD
Andrew P Schachat MD
Los Angeles, CA
Professor of Ophthalmology
University of California, Los Angeles
(UCLA)
Director, Doheny Image Reading Center
Doheny Eye Institute
Cleveland, OH
Vice Chairman for Clinical Affairs
Cole Eye Institute, Cleveland Clinic
Professor of Ophthalmology
Lerner College of Medicine
Edwin Hurlbut Ryan Jr MD
Hendrik P Scholl MD
Baltimore, MD
Professor of Ophthalmology
Wilmer Eye Institute
Johns Hopkins University
Steven D Schwartz MD
Los Angeles, CA
Ahmanson Professor of Ophthalmology
Chief, Retina Division
Jules Stein Eye Institute
University of California, Los Angeles
Professor of Ophthalmology
David Geffen School of Medicine at
UCLA
Faculty Listing
2015 Subspecialty Day | Retina
xxiii
Ingrid U Scott MD MPH
Jerry A Shields MD
Rishi P Singh MD
Hershey, PA
Professor of Ophthalmology and Public
Health Sciences
Penn State College of Medicine
Philadelphia, PA
Director, Oncology Service
Wills Eye Hospital
Professor of Ophthalmology
Thomas Jefferson University
Cleveland, OH
Staff Physician
Cole Eye Institute, Cleveland Clinic
Foundation
Assistant Professor of Ophthalmology
Cleveland Clinic Lerner College of
Medicine
No photo
available
Gaurav K Shah MD
Town and Country, MO
Clinical Professor of Ophthalmology &
Visual Sciences
The Retina Institute
Fumio Shiraga MD
Okayama, Japan
Professor and Chairman
Okayama University
Wendy M Smith MD
Rochester, MN
Assistant Professor of Ophthalmology
Mayo Clinic
No photo
available
Carol L Shields MD
Paul A Sieving MD PhD
Philadelphia, PA
Codirector, Ocular Oncology Service
Wills Eye Hospital
Professor of Ophthalmology
Thomas Jefferson University Hospital
Bethesda, MD
Director, National Eye Institute
Eric H Souied MD PhD
Creteil, France
Head of Department
CHIC Creteil, University Paris-Est
xxiv
Faculty Listing
2015 Subspecialty Day | Retina
Richard F Spaide MD
Peter W Stalmans MD PhD
Edwin M Stone MD PhD
New York, NY
Ophthalmologist
Vitreous, Retina and Macula
Consultants of New York
Leuven, Belgium
Clinical Professor
Department of Ophthalmology
UZLeuven
Iowa City, IA
Professor of Ophthalmology
University of Iowa Hospital and Clinics
Janet R Sparrow PhD
Giovanni Staurenghi MD
New York, NY
Anthony Donn Professor
Columbia University
Milan, Italy
Professor of Ophthalmology
Department of Biomedical and Clinical
Science
“Luigi Sacco” University of Milan
No photo
available
J Timothy Stout MD PhD MBA
Houston, TX
Professor and Chairman
Cullen Eye Institute
Director, Clayton Gene Therapy
Laboratory
Baylor College of Medicine
No photo
available
Sunil K Srivastava MD
Cleveland, OH
Staff Physician
Cole Eye Institute, Cleveland Clinic
Foundation
Jay M Stewart MD
Jennifer K Sun MD
Brisbane, CA
Boston, MA
Assistant Professor of Ophthalmology
Harvard Medical School
Chief, Center for Clinical Eye Research
and Trials
Beetham Eye Institute, Joslin Diabetes
Center
Michael W Stewart MD
Jacksonville, FL
Professor and Chairman
Department of Ophthalmology
Mayo Clinic Florida
Faculty Listing
2015 Subspecialty Day | Retina
No photo
available
No photo
available
Ramin Tadayoni MD PhD
Paul E Tornambe MD
Laurent Velasque MD
Paris, France
Professor of Ophthalmology
Paris 7 University - Sorbonne Paris Cité
Chairman, Ophthalmology Department
Saint-Louis, Lariboisière, Fernand-Widal
University Hospitals, AP-HP
Poway, CA
Director, Retina Research Foundation of
San Diego
President, Retina Consultants, San Diego
Bordeaux, France
No photo
available
Nadia Khalida Waheed MD
Cynthia A Toth MD
Hiroko Terasaki MD
Nagoya, Japan
Chairman and Professor
Department of Ophthalmology
Nagoya University, Graduate School of
Medicine
xxv
Durham, NC
Professor of Ophthalmology
Duke University Medical Center
Professor of Biomedical Engineering
Pratt School of Engineering
Duke University
Cambridge, MA
Assistant Professor in Ophthalmology
Tufts University School of Medicine
No photo
available
Yu Wakatsuki MD
Tokyo, Japan
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 of Ophthalmology
Eye Research Institute
Oakland University
Chief, Pediatric & Adult Vitreoretinal
Surgery
Beaumont Eye Institute, William
Beaumont Hospital
John A Wells III MD
West Columbia, SC
Partner, Palmetto Retina Center, LLC
Chairman, Department of
Ophthalmology
Palmetto Health / University of South
Carolina School of Medicine,
Columbia, SC
xxvi
Faculty Listing
2015 Subspecialty Day | Retina
David F Williams MD
Sebastian Wolf MD PhD
Lihteh Wu MD
Minneapolis, MN
Partner, VitreoRetinal Surgery, PA
Assistant Clinical Professor of
Ophthalmology
University of Minnesota
Bern, Switzerland
Professor of Ophthalmology
University Bern, Switzerland
San José, San José, Costa Rica
Associate Surgeon
Asociados de Macula Vitreo y Retina de
Costa Rica
Associate Professor
University of Costa Rica
No photo
available
Thomas J Wolfensberger MD
George A Williams MD
Lausanne, Switzerland
Lawrence A Yannuzzi MD
Royal Oak, MI
Professor and Chair
Department of Ophthalmology
Oakland University William Beaumont
School of Medicine
New York, NY
President and Founder
The Macula Foundation, Inc.
Manhattan Eye, Ear and Throat
Hospital / North Shore Hospital
Professor of Clinical Ophthalmology
College of Physicians and Surgeons
Columbia University Medical School
Tien Yin Wong MBBS
David J Wilson MD
Portland, OR
Director, Chair, and Professor
Casey Eye Institute
Oregon Health and Science University
Singapore, Singapore
Professor of Ophthalmology and
Medical Director
Singapore Eye Research Institute
Singapore National Eye Center
Vice Dean, Office of Clinical Sciences
Duke-NUS Graduate Medical School
National University of Singapore
Marco A Zarbin MD PhD FACS
No photo
available
Charles C Wykoff MD PhD
Houston, TX
Chatham, NJ
Professor and Chair
Institute of Ophthalmology and Visual
Science
Rutgers-New Jersey Medical School
2015 Subspecialty Day | Retina
Program Schedule
xxvii
Retina 2015: Upping the Ante
In conjunction with the American Society of Retina Specialists,
the Macula Society, the Retina Society, and Club Jules Gonin
Friday, Nov. 13
7:00 AM
CONTINENTAL BREAKFAST
8:00 AM
Opening Remarks
Section I: Masters of Surgery
Moderators: Michael T Trese MD*, Thomas J Wolfensberger MD
8:05 AM
New Instruments
David R Chow MD*
1
8:12 AM
Retinal Detachment
Didier H Ducournau MD
2
8:17 AM
27-gauge Diabetic Traction Retinal Detachment
Yusuke Oshima MD*
3
8:22 AM
Intraocular Lens
Jonathan L Prenner MD*
5
8:27 AM
Giant Retinal Tear
María H Berrocal MD*
7
8:32 AM
Proliferative Vitreoretinopathy
Stanley Chang MD*
9
8:37 AM
Trauma
Carl C Claes MD*
10
8:42 AM
Wound Construction
Kirk H Packo MD*
11
Section II: Vitreoretinal Surgery, Part I
Moderators: Suber S Huang MD MBA, Marcos P Avila MD
8:47 AM
Internal Limiting Membrane Peeling for All Macular Holes: Pro
John T Thompson MD*
12
8:50 AM
Internal Limiting Membrane Peeling for All Macular Holes: Con
Dante Pieramici MD*
13
8:53 AM
Audience Vote
8:54 AM
Routine Intraoperative OCT Is Useful for Macular Surgery: Pro
Justis P Ehlers MD*
14
8:57 AM
Routine Intraoperative OCT Is Useful for Macular Surgery: Con
Dennis P Han MD*
15
9:00 AM
Audience Vote
9:01 AM
27-gauge Vitrectomy Will Be the New Standard for Pars Plana Vitrectomy: Pro
Christopher D Riemann MD*
16
9:04 AM
27-gauge Vitrectomy Will Be the New Standard for Pars Plana Vitrectomy: Con
Edwin Hurlbut Ryan Jr MD*
17
9:07 AM
Audience Vote
9:08 AM
Scleral Buckle Is Preferred in Young, Phakic Retinal Detachment Patients: Gaurav K Shah MD*
Pro
18
9:11 AM
Scleral Buckle Is Preferred in Young, Phakic Retinal Detachment Patients: Philip J Ferrone MD*
Con
20
9:14 AM
Audience Vote
9:15 AM
Indocyanine Green Is Safe for Internal Limiting Membrane Peeling: Pro
Mathew W MacCumber MD PhD*
21
9:18 AM
Indocyanine Green Is Safe for Internal Limiting Membrane Peeling: Con
22
9:21 AM
Audience Vote
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
Pravin U Dugel MD*
Jennifer Irene Lim MD*
Julia A Haller MD*
xxviii
Program Schedule
2015 Subspecialty Day | Retina
9:22 AM
Face-down Position Is Not Necessary for Macular Holes: Pro
Ehab N El Rayes MD PhD*
23
9:25 AM
Face-down Position Is Not Necessary for Macular Holes: Con
John S Pollack MD*
25
9:28 AM
Audience Vote
9:29 AM
Pars Plana Vitrectomy Should be Combined With Cataract Extraction / IOL for All Cases: Pro
Timothy G Murray MD MBA* 26
9:32 AM
Pars Plana Vitrectomy Should be Combined With Cataract Extraction / IOL for All Cases: Con
Sunir J Garg MD FACS*
28
9:35 AM
Audience Vote
9:36 AM
Heads Up – No Microscope Is the Future of Vitreoretinal Surgery: Pro
Claus Eckardt MD*
29
9:39 AM
Heads Up – No Microscope Is the Future of Vitreoretinal Surgery: Con
Steven T Charles MD*
30
9:42 AM
Audience Vote
9:43 AM
The Timing of Vitrectomy for Retained Lens Material Is Critical: Pro
Michael W Stewart MD*
31
9:46 AM
The Timing of Vitrectomy for Retained Lens Material Is Critical: Con
Caroline R Baumal MD*
32
9:49 AM
Audience Vote
9:50 AM
Pars Plana Vitrectomy for Diabetic Macular Edema Without Vitreomacular Traction Is Useful: Pro
David F Williams MD*
33
9:53 AM
Pars Plana Vitrectomy for Diabetic Macular Edema Without Vitreomacular Traction Is Useful: Con
Darius M Moshfeghi MD*
34
9:56 AM
Audience Vote
9:57 AM
Advocating for Patients
John A Wells III MD*
35
The Charles L Schepens MD Lecture
10:02 AM
Introduction of the 2015 Charles L Schepens MD Lecturer
David W Parke II MD*
10:07 AM
Digital Medicine: Implications for Retina and Beyond
Mark S Blumenkranz MD*
10:27 AM
REFRESHMENT BREAK and RETINA EXHIBITS
Section III: The Business of Retina
Moderators: Emmett T Cunningham Jr MD PhD MPH, Thomas C Lee MD*
11:07 AM
Retinal Outcome Measures
William L Rich III MD FACS
38
11:14 AM
How Drugs and Devices Get Approved
Wiley Andrew Chambers MD
39
11:21 AM
The Gap in Global Heath Care Delivery
David W Parke II MD*
41
11:28 AM
Can It Be Less? Strategies for Reducing the Cost of Health Care
George A Williams MD*
43
Section IV: Late Breaking Developments, Part I
Moderator: Daniel F Martin MD
11:35 AM
Long-term Response to Anti-VEGF Therapy for Diabetic Macular Edema Can Be Predicted After 3 Injections: An Analysis of
Protocol I Data
Pravin U Dugel MD
44
11:41 AM
AKB-9778 In the Treatment of Diabetic Macular Edema: Results From the TIME-2 Study
Peter A Campochiaro MD
44
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
37
Program Schedule
2015 Subspecialty Day | Retina
Section V: My Coolest Surgical Video
Moderators: Tarek S Hassan MD*, Carl C Awh MD*
Virtual Moderator: Donald J D’Amico MD
Panelists: Sophie J Bakri MD*, Susanne Binder MD*, Marta Figueroa MD*,
Kazuaki Kadonosono MD, Grazia Pertile MD, Stanislao Rizzo MD
11:49 AM
“Street View” of Macular Surgery
11:52 AM
Discussion
11:57 AM
Silicone Oil Retention Sutures in Traumatic Aniridia
12:00 PM
Discussion
12:05 PM
Cystectomy for Chronic Cystoid Macular Edema
12:08 PM
Discussion
12:13 PM
Homemade Chandelier
12:16 PM
Discussion
12:21 PM
Large-Scaled Simple Layer Retinal Pigment Epithelium Transplantation for Hemorrhagic Polypoidal Choroidal Vasculopathy
12:24 PM
Discussion
12:29 PM
Vote for Winner
Section VI: Pediatric Retina
Moderators: R V Paul Chan MD*, Audina M Berrocal MD
12:31 PM
xxix
Cynthia A Toth MD*
45
Ronald C Gentile MD*
45
Yu Wakatsuki MD
45
Laurent Velasque MD
45
Zhizhong Ma MD
45
Diagnoses You Cannot Afford to Miss: Retinal Diseases With Systemic Implications
Gerald A Fishman MD
46
12:38 PM
What, When, and Why to Test for Retinal Degenerations
Kimberly A Drenser MD PhD* 48
12:43 PM
Inherited Diseases Panel
Panel Moderator: Hendrik P Scholl MD*
Panelists: Robert E MacLaren MBChB*, Albert M Maguire MD*, Eric A Pierce MD PhD,
Paul A Sieving MD PhD, J Timothy Stout MD PhD MBA
12:58 PM
LUNCH and RETINA EXHIBITS
Section VII: Retinal Vein Occlusion
Moderators: Hiroko Terasaki MD*, Carl D Regillo MD*
2:13 PM
Overview of Current Treatment Options and Evidence-Based Data
2:20 PM
Retinal Vein Occlusion Panel
Panel Moderator: Andrew P Schachat MD*
Panelists: Diana V Do MD*, Nancy M Holekamp MD*, Szilard Kiss MD*,
Ingrid U Scott MD MPH*, Eric H Souied MD PhD*, Lihteh Wu MD*
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
Peter A Campochiaro MD*
49
xxx
Program Schedule
2015 Subspecialty Day | Retina
Section VIII: Diabetic Retinopathy Clinical Research Network (DRCRnet) Protocols
Moderators: Jennifer K Sun MD, Lee M Jampol MD*
Panel Moderator: H Richard McDonald MD
Panelists: Neil M Bressler MD*, Susan B Bressler MD*, Gary C Brown MD*, David J Browning MD PhD*
2:35 PM
DRCRnet Protocol T
2:42 PM
Panel Discussion
2:49 PM
DRCRnet Protocol S
2:56 PM
Panel Discussion
3:03 PM
REFRESHMENT BREAK and RETINA EXHIBITS
Section IX: First-time Results of Clinical Trials, Part I
Moderators: Joan W Miller MD*, Mark S Humayun MD PhD*
3:43 PM
Squalamine Eye Drops in Retinal Vascular Diseases
John A Wells III MD*
54
Jeffrey G Gross MD*
56
David S Boyer MD*
58
3:48 PM
AVA-101 Gene Therapy for Neovascular AMD: Fifty-Two-Week Results Jeffrey S Heier MD*
From the Phase 2a Clinical Trial
60
3:53 PM
Anti-Platelet Derived Growth Factor Pretreatment in Neovascular AMD: Pravin U Dugel MD*
Results of a Pilot Study Evaluating VEGF/PDGF Crosstalk
61
3:58 PM
Discussion
Section X: Neovascular AMD
Moderators: Timothy W Olsen MD*, Sebastian Wolf MD PhD*
4:08 PM
Progression of AMD Following Cataract Surgery
Emily Y Chew MD*
62
4:15 PM
Long-term Anti-VEGF Monotherapy: Do Patients Improve?
Michael Larsen MD*
64
4:22 PM
Genetics of AMD: Now and the Future
Edwin M Stone MD PhD*
65
4:29 PM
Polypoidal Choroidal Vasculopathy: Anti-VEGF or Photodynamic Therapy?
Tien Yin Wong MBBS*
66
Rapid Fire: AMD Pipeline Update
4:36 PM
Beta-Amyloid Monoclonal Antibody Scott W Cousins MD
67
4:41 PM
Conbercept
Xiaoxin Li MD
68
4:46 PM
Intravitreal Ziv-Aflibercept
Michel Eid Farah MD
71
4:51 PM
Radiation for Wet AMD: Highs, Lows, and Next Steps
Timothy L Jackson MBChB*
72
4:56 PM
MacTel Project
Martin Friedlander MD
75
5:01 PM
Oral VEGF Receptor/PDGF Receptor Inhibitor X-82
Nauman A Chaudhry MBBS
77
5:06 PM
Sustained Drug Delivery Strategies in AMD
Peter K Kaiser MD*
79
5:11 PM
Panel: Treatment of Neovascular AMD Today: Data or Delusion?
Panel Moderator: Carmen A Puliafito MD MBA
Panelists: Frank G Holz MD*, Glenn J Jaffe MD*, Jennifer Irene Lim MD*,
Elias Reichel MD*, Nadia Khalida Waheed MD*, Lawrence A Yannuzzi MD*
5:31 PM
Closing Remarks
5:33 PM
ADJOURN
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
Pravin U Dugel MD*
Jennifer Irene Lim MD*
2015 Subspecialty Day | Retina
Program Schedule
xxxi
Saturday, Nov. 14
7:00 AM
CONTINENTAL BREAKFAST
8:00 AM
Opening Remarks
Section XI: Imaging
Moderators: Richard F Spaide MD*, Tatsuro Ishibashi MD
8:05 AM
Adaptive Optics
Judy E Kim MD*
81
8:09 AM
En Face OCT
Philip J Rosenfeld MD PhD
82
8:13 AM
Adaptive Optics Scanning Laser Ophthalmoscopy
Jacque L Duncan MD
84
8:17 AM
Multimodal Imaging
Alain Gaudric MD*
86
8:21 AM
Swept Source OCT
Kyoko Ohno-Matsui MD
89
8:25 AM
Choroidal OCT in Inflammation
Anita Agarwal MD
90
8:29 AM
Autofluorescence
David Sarraf MD*
95
8:33 AM
Wide-Angle Imaging
Srinivas R Sadda MD*
97
8:37 AM
Spectral Domain OCT of Foveal Disorders
Anat Loewenstein MD*
98
8:41 AM
OCT Angiography
Jay S Duker MD*
99
8:45 AM
Volume-Rendering OCT Angiography
Richard F Spaide MD*
102
8:49 AM
What Tumor, What Imaging Modality?
Carol L Shields MD
103
8:53 AM
Prediction of Disease Progression and Therapeutic Response Using Computational Analysis
Ursula M Schmidt-Erfurth
MD*
105
Pravin U Dugel MD*
Jennifer Irene Lim MD*
Section XII: Late Breaking Developments, Part II
Moderators: Yuichiro Ogura MD PhD*, William F Mieler MD*
8:57 AM
Phase 3 Trial of AAV2-hRPE65v2 (SPK-RPE65) to Treat RPE65 Mutation-Associated Inherited Retinal Dystrophies
Albert M Maguire MD*
110
9:03 AM
2-Year Results of Dexamethasone Implant vs, Bevacizumab for Diabetic Macular Edema
Mark C Gillies, MD PhD*
110
9:09 AM
Long-Term Effect of Intensive Glucose Control In Type 2 Diabetes: The ACCORDION Eye Study
Emily Y Chew MD
110
9:15 AM
The OASIS Study Evaluating Ocriplasmin for the Treatment of Symptomatic VMA/(VMT) Including Macular Hole over 2 years
Peter K Kaiser MD*
110
9:21 AM
Analysis of Diabetic Retinopathy Progression in Patients Treated With
0.2 μg/day Fluocinolone Acetonide Over 36 Months
Charles C Wykoff, MD, PhD
110
9:27 AM
Prospective, Multicenter Investigation of Aflibercept Treat and Extend Therapy for Neovascular Age-related Macular Degeneration
(ATLAS Study): Two Year Results
Carl D Regillo MD FACS*
110
9:33 AM
Mitochondrial Protection—A Novel Approach to Mitochondrial Dysfunction in Retinal Disease: Results of a Phase 1/2 Open-Label,
Dose-Escalation Study of MTP-131 in Subjects with Diabetic Macular
Edema and Intermediate Age-Related Macular Degeneration
Jeffrey S Heier, MD*
110
9:39 AM
Cost-Effectiveness of Intravitreous Aflibercept, Repackaged
Bevacizumab, and Ranibizumab for Diabetic Macular Edema
Neil M Bressler MD*
110
9:45 AM
Vision Loss Consequent to Intravitreal Stem Cell Injection
Thomas A Albini MD
110
9:51 AM
REFRESHMENT BREAK and AAO 2015 EXHIBITS
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
xxxii
Program Schedule
2015 Subspecialty Day | Retina
Section XIII: Oncology Panel
10:24 – 10:44 AM
Panel Moderators: Jerry A Shields MD, J William Harbour MD*
Panelists: Thomas M Aaberg Jr MD*, Janet Louise Davis MD*, Evangelos S Gragoudas MD*,
Brian P Marr MD, Miguel A Materin MD, David J Wilson MD 111
Section XIV: Diabetes
Moderators: Francesco M Bandello MD FEBO*, J Fernando Arevalo MD FACS*
10:44 AM
Laser for Diabetic Macular Edema Is Dead: Pro
Andrew A Moshfeghi MD
MBA*112
10:47 AM
Laser for Diabetic Macular Edema Is Dead: Con
Harry W Flynn Jr MD
10:50 AM
Audience Vote
10:51 AM
There Is a Role for Steroids in Diabetic Macular Edema: Pro
Baruch D Kuppermann MD
PhD*116
10:54 AM
There Is a Role for Steroids in Diabetic Macular Edema: Con
Allen C Ho MD*
117
10:57 AM
Audience Vote
10:58 AM
Chronic Anti-VEGF Injection Is a Systemic Risk in Diabetic Macular Edema / Diabetic Retinopathy Patients: Pro
Robert L Avery MD*
118
11:01 AM
Chronic Anti-VEGF Injection Is a Systemic Risk in Diabetic Macular Edema / Diabetic Retinopathy Patients: Con
Usha Chakravarthy MBBS
PhD*
119
114
11:04 AM
Audience Vote
11:05 AM
Anti-VEGF Injection Is the New Standard of Care for Proliferative Diabetic Retinopathy: Pro
Michael S Ip MD*
120
11:08 AM
Anti-VEGF Injection Is the New Standard of Care for Proliferative Diabetic Retinopathy: Con
Rishi P Singh MD*
121
11:11 AM
Audience Vote
11:12 AM
Ocriplasmin Is Safe and Its Indications Should Be Expanded: Pro
Peter W Stalmans MD PhD*
122
11:15 AM
Ocriplasmin Is Safe and Its Indications Should Be Expanded: Con
Mark W Johnson MD*
123
11:18 AM
Audience Vote
11:19 AM
Statistical Significance vs. Clinical Significance: What Really Matters in My Practice?
Marco A Zarbin MD PhD
FACS*
124
11:26 AM
LUNCH and AAO 2015 EXHIBITS
Section XV: First-time Results of Clinical Trials, Part II
Moderators: Mark S Blumenkranz MD*, Taiji Sakamoto MD PhD*
12:44 PM
Stem Cell-Derived Retinal Pigment Epithelium Transplantation for Atrophic Macular Degeneration and Stargardt Macular Dystrophy:
Phase 1 Results and Ongoing Trials
Steven D Schwartz MD
126
12:49 PM
Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Transplantation
Yasuo Kurimoto MD PhD*
127
12:54 PM
DAVE (Diabetic Anti-VEGF): Wide-Field Guided Panretinal Photocoagulation for Diabetic Macular Edema, One-Year Results
David M Brown MD*
129
12:59 PM
Results of the Nexus Study: An Investigation of iSONEP, A Monoclonal Thomas A Ciulla MD*
Antibody Targeting Sphingosine-1-Phosphate in Patients With Wet AMD
1:04 PM
Discussion
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
133
2015 Subspecialty Day | Retina
Program Schedule
Section XVI: Uveitis
1:14 – 1:34 PM
Panel Moderator: Sunil K Srivastava MD*
Panelists: Thomas A Albini MD, Quan Dong Nguyen MD*, Annabelle A Okada MD*,
P Kumar Rao MD*, Wendy M Smith MD
xxxiii
137
Section XVII: Non-neovascular AMD
Moderators: Ramin Tadayoni MD PhD*, Giovanni Staurenghi MD*
1:34 PM
What Is the Evidence of Complement Involvement in Retinal Pigment Epithelial Cell Loss?
Jayakrishna Ambati MD*
138
1:41 PM
Do Visual Cycle Metabolites Really Cause AMD?
Janet R Sparrow PhD
140
1:48 PM
What Causes Autofluorescence Changes at the Border of Geographic Atrophy? New Findings About GA
Christine Curcio PhD*
142
1:55 PM
Membrane Attack Complex—Is the Choroid the Real Site to Worry About?
Robert F Mullins MS PhD
145
2:02 PM
What Does Macular Pigment Do?
Paul S Bernstein MD PhD*
146
2:07 PM
Is the Problem the Bruch Membrane? Is the Future Home of Transplanted Retinal Pigment Epithelial Cells a Hostile Environment?
Lucian V Del Priore MD PhD* 148
2:12 PM
Rod Function in AMD
Catherine A Cukras MD PhD 152
2:17 PM
What Should We Be Measuring as a Geographic Atrophy Endpoint?
Karl G Csaky MD*
154
2:22 PM
A Newly Recognized Risk and Disease Modifier in AMD: Pachychoroid
K Bailey Freund MD*
157
2:27 PM
REFRESHMENT BREAK and AAO 2015 EXHIBITS
Section XVIII: Vitreoretinal Surgery, Part II
Moderators: Borja F Corcostegui MD, Fumio Shiraga MD*
3:12 PM
Optic Pit Maculopathy Management
Akito Hirakata MD
159
3:19 PM
Emerging Therapies for Proliferative Vitreoretinopathy
Richard S Kaiser MD*
162
3:26 PM
Avoiding and Managing Retinal Folds
Dean Eliott MD*
164
3:33 PM
Techniques for Managing Suprachoroidal Hemorrhages
John W Kitchens MD*
167
3:40 PM
Complications of Perfluorocarbon Liquid and How to Avoid Them
Masahito Ohji MD*
169
3:47 PM
Complications of Silicone Oil and How to Avoid Them
Derek Y Kunimoto MD JD*
171
3:54 PM
Pearls for Maximizing Outcomes of Retinal Detachment Repair by Pneumatic Retinopexy
Paul E Tornambe MD*
172
Section XIX: Video Surgical Complications—What Would You Do?
Moderators: Kourous Rezaei MD*, Donald J D’Amico MD*
Virtual Moderator: Rishi P Singh MD*
Panelists: Francesco Boscia MD*, Antonio Capone Jr MD*, Raymond Iezzi MD*,
Carlos Mateo MD, Cynthia A Toth MD*
4:01 PM
Subretinal Air Displacement of Submacular Hemorrhage
4:03 PM
Discussion
4:08 PM
What Did You Do?
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
Tamer H Mahmoud MD*
174
Tamer H Mahmoud MD*
174
xxxiv
Program Schedule
4:11 PM
Postoperative Roll Cake-Like Macular Fold After Retinal Detachment Surgery: A Case Report
4:13 PM
Discussion
4:18 PM
2015 Subspecialty Day | Retina
Hiroyuki Nakashizuka MD
174
What Did You Do?
Hiroyuki Nakashizuka MD
174
4:21 PM
Acute Intraocular Bleeding Due to Explosive Separation of Silicone Oil Injector
Jay M Stewart MD*
174
4:23 PM
Discussion
4:28 PM
What Did You Do?
Jay M Stewart MD*
174
4:31 PM
Entry Site Hemorrhage: An Unexpected Complication
David Fonseca Martins MD
174
4:33 PM
Discussion
4:38 PM
What Did You Do?
David Fonseca Martins MD
174
4:41 PM
Incidental Subfoveal Perfluorocarbon Heavy Liquids After Vitrectomy for Giant Retinal Tear
Gerardo Ledesma-Gil MD
174
4:43 PM
Discussion
4:48 PM
What Did You Do?
Gerardo Ledesma-Gil MD
174
4:51 PM
Closing Remarks
Pravin U Dugel MD*
Jennifer Irene Lim MD*
4:56 PM
ADJOURN
* Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
Section I: Masters of Surgery
2015 Subspecialty Day | Retina
New Instruments
David R Chow MD
NOTES
1
2
Section I: Masters of Surgery
2015 Subspecialty Day | Retina
Retinal Detachment
Let’s Try to Understand
Didier Ducournau MD
The author tries to explain why the European Vitreo-Retinal
Society retinal detachment study, analyzed by the French
National Institute of Statistics, concluded that vitrectomy performed with a Venturi pump machine almost triples the failure
rate compared to the use of a flow-control pump, independently
of the surgeon’s experience, age, and nationality.
Since a Venturi pump does not allow control of the quantity
of liquid entering the hand piece, a low cutting speed cannot be
used, otherwise the risk of browsing the retina is too high. To
decrease this danger, high-speed cutting is mandatory, but this
comes at the expense of both performance and effectiveness:
• For peripheral vitrectomy, it has been established that
removing the posterior hyaloid is statistically linked to a
lower failure rate. High-speed cutting only allows one to
perform a shaving, as the vitreous cortex itself does not
have the time to enter in between two cuts, leaving a mattress of vitreous adherent to the retina. The problem is that
the shaving allows the PVR to develop postoperatively,
while the cortex peeling dissection does prevent it.
• At the periphery a peeling cannot be performed, but the
issue is just the same. If we want to perform a precise
shaving, time must be allowed for the adherent vitreous to
move toward the port, but then the retina will follow. To
avoid catching the retina, one must use a low and precise
aspiration flow, between 1 and 3 cc per minute, lower
than the natural outflow of BSS induced by the infusion
pressure. To obtain such a low flow, the flow control
pump acts like a dam that reduces the flow of a river while
creating a positive upstream pressure. Such a precise dissection cannot be achieved by a Venturi pump, where
performance is limited to generating a negative pressure,
increasing the gradient of pressure and therefore the natural outflow of the BSS.
Section I: Masters of Surgery
2015 Subspecialty Day | Retina
3
27-gauge Diabetic Traction Retinal Detachment
Yusuke Oshima MD, Maria H Berrocal MD, Pravin U Dugel MD, Chi-chun Lai MD, Manish Nagpal MD,
Carl D Regillo MD FACS, and George A Williams MD
I.Introduction
This video presentation will highlight the latest
27-gauge vitrectomy setting and surgical sequences for
treating diabetic traction retinal detachment with vitreous hemorrhage and fibrotic neovascular membranes.
The surgical techniques and tips for using the 27-gauge
instruments in combination with a wide-angle viewing system and chandelier endoillumination will be
demonstrated step by step, including trocar-cannula
setting, peripheral vitreous shaving with scleral indentation, bimanual and single-hand membrane dissection,
hemostasis, inner-limiting membrane peeling underneath perfluorocarbon liquid, and panretinal endolaser
photocoagulation. The efficiency of the currently most
efficient 27-gauge vitreous cutter will be demonstrated
also. At the end of this presentation, the attendees will
not only be familiar with the 27-gauge vitrectomy system for treating diabetic traction retinal detachment,
but they will also get a glimpse of the future technological advances.
II. Course Outline
State-of-the-art techniques and technologies for microincision vitrectomy surgery to treat complex vitreoretinal diseases
III. Overview of the Latest Developments in Microincision
Vitrectomy Surgery
A. Advantages of new-generation vitrectomy machines
1. Duty-cycle control
2. IOP control
4. Advantages of the latest wide-angle viewing system
IV. Video-Oriented Demonstration of the Advanced Techniques and Technologies Used in MIVS for Treating
Challenging Vitreoretinal Pathologies
A. Video clips
1. Diabetic traction retinal detachment
2. Proliferative vitreoretinopathy
3. Myopic foveoschisis and macular hole retinal
detachment
4. Subretinal hemorrhage
5. Dislocated IOL or retained lens fragments
6. Infectious endophthalmitis
7. Traumatic cases
B. Contents of instructions
1. Instruction for appropriate setting of trocarcannula and chandelier illumination
a. How to prevent inadvertent suprachoroidal
infusion
b. Key steps and preferable location for chandelier optic fiber setting
2. Surgical techniques for membrane dissection
and/or peeling
a. Single-hand membrane dissection techniques
and tips
3. Dual pneumatic drive cutter duty-cycle control
4. Compatibilities with 23-, 25-, and 27-gauge cutters
b. Bimanual manipulation with pneumatically
controlled instruments
c. Proportional reflux hydrodissection and viscodissection
d. Perfluorocarbon liquid-assisted membrane
peeling
B. Newly designed trocar-cannula system
1. Closure valve
2. Wound adaptation and structural analysis
C. New surgical instruments
1. Pneumatically controlled forceps and scissors
2. Laser probes (multispot laser probes, directional
shaft)
D. Advances in illumination and visualizing systems
1. Wave-length characteristics of xenon and mercury vapor light sources
2. Photo-toxicity and retinal threshold time
3. Variations and utilities of chandelier endoillumination
3. Intraocular hemostasis
a. Direct compression technique
b. Bimanual hemostasis
4. Appropriate timing, dosage, and efficacy of surgical adjuncts
a.Bevacizumab
b. Triamcinolone acetonide
c. Trypan blue
d. Brilliant blue G
e.Microplasmin?
4
Section I: Masters of Surgery
5. Peripheral manipulations
2015 Subspecialty Day | Retina
V. Panel Discussion
a. Tips for visualizing the far peripheral area
A. Intra- and postoperative complications
b. How to perform extensive peripheral vitreous
shaving
B. Prevention and management of complications
c. Bimanual techniques for peripheral membrane removal
C. Future technological advances (“Get a head start on
what is around the corner!”)
d.Retinotomy/retinectomy
6. Appropriate choice of tamponade substances
a. Perfluorocarbon liquid
b. Air, SF6, or C3F8
c. Silicone oil (What is the appropriate timing
for removal?)
7. Wound construction and sealing techniques
a. Tips for massage and compression
b. Air tamponade
c.Diathermy
d. Suture placement
Selected Readings
1. Oshima Y, Shima C, Wakabayashi T, et al. Microincision vitrectomy surgery and intravitreal bevacizumab as a surgical adjunct to
treat diabetic traction retinal detachment. Ophthalmology 2009;
116:927-938.
2. Oshima Y, Wakabayashi T, Sato T, et al. A 27-gauge instrument
system for transconjunctival sutureless microincision vitrectomy
surgery. Ophthalmology 2010; 117:93-102.
3. Wakabayashi T, Oshima Y. Microincision vitrectomy surgery for
diabetic retinopathy. Retinal Physician, October 1, 2011: 66-70.
4. Berrocal M. A minimalist approach to surgery for diabetic retinal
detachment. Retina Today, April 2014: 65-68.
5. Osawa S, Oshima Y. Innovations in 27-gauge vitrectomy for
sutureless microincision vitrectomy surgery. Retina Today, July/
August 2014: 42-45.
Section I: Masters of Surgery
2015 Subspecialty Day | Retina
Intraocular Lens
A Novel Approach for Rescuing and Scleral Fixating a Posterior Dislocated
IOL/Bag Complex Without Conjunctival Opening
Jonathan L Prenner MD
Introduction
Eyes in which a posterior chamber IOL completely dislocates
into the posterior segment, while remaining within the capsular
bag, present a unique surgical challenge. Traditionally, two
techniques have been employed to fix this problem. One method
involves removing the lens/bag complex and replacing it with a
secondary anterior chamber or posterior chamber IOL. Alternatively, the second method entails explanting the lens from the bag
complex, followed by repositioning the dislocated lens with iris
or scleral fixation. A report from the American Academy of Ophthalmology Ophthalmic Technology Assessment group (OTA)
reviewed the standard approaches to secondary IOL placement
in the absence of adequate capsular support—anterior chamber
IOL (AC-IOL), scleral sutured posterior chamber IOL (PC-IOL),
and iris fixated PC-IOL—and did not identify compelling data to
recommend one technique over another.1,2 I here present a novel
procedure that allows for repositioning and suture fixation of the
lens/bag complex without the need for manipulating the conjunctiva or creating large scleral incisions.
The approach utilizes a number of anterior segment techniques that have been previously described. Those techniques are
combined with maneuvers that take advantage of the surgical
instrumentation and skill set of the posterior segment surgeon.
By combining these approaches, we have been able to design a
reliable and reproducible operation that allows for rescue of a
posteriorly dislocated lens/bag complex with permanent scleral
fixation in the ciliary sulcus.
Figure 1.
Technique
A standard, 25-gauge, 3-port vitrectomy setup is placed into
position. A reverse scleral tunnel, as described by Hoffman et
al,3 is then created at 3 o’clock. This is accomplished by using a
guarded (0.5 mm) blade to create a 2-mm long, partial thickness
clear corneal incision at the corneal limbus (see Figure 1). An
angled crescent blade is then used to dissect the groove posteriorly into the sclera, remaining at 50% of the scleral depth. The
crescent blade is bent approximately 30 degrees, to straightening
the angle of the blade, which improves visualization and prevents
the blade from contacting the operating microscope (see Figure 2). The tunnel is carried posteriorly for 3.5 mm and is kept
perpendicular to the limbus. A second pocket is then made 180
degrees away at 9 o’clock. A 15-degree blade is then used to create a paracentesis 1 clock hour above each pocket.
Figure 2.
5
6
Section I: Masters of Surgery
2015 Subspecialty Day | Retina
Attention is paid posteriorly to where the 25-gauge vitrectomy is then completed. The vitreous base is shaved and the IOL,
within the capsular bag, is allowed to fall posteriorly onto the
retinal surface. The peripheral retina is examined with scleral
depression to rule out any peripheral pathology that may have
developed. The lens-bag complex is then carefully approached.
A 25-gauge soft tipped cannula or forceps is used to engage
the IOL/bag complex at the haptic / optic junction (see Figure
3). Once grasped, the lens/bag complex is elevated into the iris
plane.
Figure 4.
The needles are then cut off, and a Sinskey hook is utilized to
externalize both suture ends from each pocket. A 3-knot is tied
on each side, and each knot is tightened down and slid under
the protective roof of each pocket to achieve perfect centration.
Once centered, the knots are made permanent with two 1-1
throws on each side. The 25-gauge trochars are then removed,
and typically can be left unsutured.
Discussion
Figure 3.
A needle docking technique is then utilized to suture the lens.4
A 25-gauge needle is passed 2 mm from the limbus through
the bed of the pocket opposite to the hand holding the lens/bag
complex. The 25-gauge needle is passed transconjunctivally into
the globe and then between the lens haptic and optic, close to
the haptic near the apex of its curvature. A double-armed 9-0
prolene is passed through the opposing paracentesis, backwards,
so that corneal fibers are not engaged in a false track. The needle
is docked into the opening of the 25-gauge needle and removed
(see Figure 4). The 25-gauge needle is then passed through the
same pocket again, now 1.5 mm from the limbus, and placed
above the lens/bag complex. The needle from the second half of
the prolene suture is passed backwards through the same paracentesis and is docked into the 25-gauge needle and removed.
This effectively lassoes the haptic/bag complex. The process
needs to be repeated on the opposite side, but the lens/bag complex cannot effectively be grasped while floating in the midvitreous and hinged by the first suture. To combat this problem, the
light pipe is used to reposition the lens/bag complex back onto
the surface of the retina. This allows one to repeat the initial process and adequately grasp the IOL/bag complex at the opposing
optic haptic junction. Once the lens is engaged and brought into
the iris plane, the lassoing process is repeated on the second side.
This technique allows for the lens/bag complex to be rescued
without cutting down the conjunctiva, cauterizing, and creating
scleral flaps. Many eyes that have complete lens/bag dislocation
have coexisting pseudoexfoliation.5 Preserving the conjunctiva
for potential subsequent trabeculectomy, or if a trabeculectomy
is already present, is advantageous. The lenses are exceptionally
well centered and are stable immediately after fixation. The procedure allows for a reliable and reproducible operation.
References
1. Wagner M, Cox T, Ariyasu R, et al. Intraocular lens implantation
in absence of capsular support. Ophthalmology 2003; (110):840859.
2. Dick HB, Augustin AJ. Lens implant selection with absence of capsular support. Curr Opin Ophthalmol. 2001; 12:47-57.
3. Hoffman RS, Fine H, Packer M. Scleral fixation without conjunctival dissection. J Cataract Refract Surg. 2006; 32:1907-1912.
4. Chan CC, Crandall AS, Ahmed II. Ab externo scleral suture loop
fixation for posterior chamber intraocular lens decentration: clinical
results. J Cataract Refract Surg. 2006; 32(1):121-128.
5. Jehan FS, Mamalis N, Crandall AS. Spontaneous late dislocation
of intraocular lens within the capsular bag in pseudoexfoliation
patients. Ophthalmology 2001; 108:1727-1731.
Section I: Masters of Surgery
2015 Subspecialty Day | Retina
7
Giant Retinal Tear
María H Berrocal MD
I.Definition
A. Circumferential tear of more than 90 degrees
B. Posterior hyaloid remains attached to the anterior
retina.
B. Lens preservation of clear lens (to allow for correct
IOL biometry in future)
C. Remove all the vitreous posteriorly.
D. Inject perfluoro-octane slowly with dual bore cannulas to avoid increases in IOP, keep infusion pressure low during this maneuver.
E. Unroll retina with heavy liquid, fill eye to cover the
edge of the tear, keep perfluorocarbon liquid (PFCL)
level below infusion to avoid fish eggs.
F. Remove anterior flap of retina with vitrectomy
probe thoroughly, trim vitreous attachments from
corners of the tear. (This is the area where residual
vitreous traction can cause new breaks. Chandelier
and scleral depression useful in phakic eyes in particular.
G. If epiretinal membrane, star folds, or macular hole
are present, peel membranes/internal limiting membrane through the PFCL. (Staining with indocyanine
green, Trypan blue, or Brilliant Blue can be done
prior to PFCL injection if deemed useful.)
H. Laser corners and edge of tear 2-3 rows up to the
ora-curved laser.
II.Incidence
1.5% of rhegmatogenous detachments
III.Etiology
A. Idiopathic: 54%
B. Trauma: 16%
C. Hereditary: 14% (Marfan, Stickler-Wagner, EhlersDanlos)
D. High myopia: 10%
E.Coloboma
F.Iatrogenic
G. Bilateral giant retinal tears (GRT): 12.8%
IV.Pathogenesis
A. Liquefaction of central vitreous with peripheral vitreous condensation
B. Traction in the region posterior to the vitreous base
C. Vitreous adherent to anterior edge of tear
I. Inspect the rest of the retina as small breaks in areas
of attached retina can be present and should be
treated.
D. Posterior retina has no adhesions and inverts
J. Perform fluid-air exchange with aspiration with
soft-tip needle on edge of the GRT. Imperative to
remove all the fluid anterior to the PFCL edge to
prevent slippage of the retina and folds. Aspirate
PFCL over the optic nerve.
K. Flush the eye with minimally expanding concentration of perfluoropropane or perfluoroethane gas.
L. If using silicone oil tamponade, perform a direct silicone oil/PFCL exchange with simultaneous injection
of silicone oil and aspiration of PFCL.
V.Management
A.Laser
1. If retina is attached, laser photocoagulation
effective.
2. 2-3 rows to edge of the tear with 3-4 rows of
laser around the corners to the ora serrata (The
ends of the tear are areas of traction.)
B. Scleral buckle
1. Can be effective if edge is not inverted
2. Good option in children to preserve lens, positioning issues
C. Primary vitrectomy with perfluorocarbon liquids to
unroll and reposition the folded retina. Long-acting
gas or silicone oil tamponade.
D. Vitrectomy with scleral buckle if proliferative vitreoretinopathy (PVR) present
E. Combined phaco/vitrectomy if significant cataract
VI. Preferred Surgical Technique
A. 25-gauge or 23-gauge, 3-port vitrectomy with
valved cannulas ± chandelier
M. If PVR, place a #41 or #42 band as a scleral buckle
prior to the vitrectomy.
VII.Complications
A. Retina slippage during PFCL removal
B. Retinal folds (slippage, with scleral buckle, high
myopia)
C. Residual PFCL
D. Cataract progression
E. Recurrent retinal detachment/PVR
8
Section I: Masters of Surgery
2015 Subspecialty Day | Retina
VIII. Causes of Redetachment
References
A. Anterior traction on the corners
B. Missed breaks away from the tear
1. Chang S. Low viscosity liquid fluorochemicals in vitreous surgery.
Am J Ophthalmol. 1987; 103(1):38-43.
C. Concomitant macular holes
D. PVR: More common if blood and pigment are present and in old detachments
IX.Results
A. 80%-90% reattachment rate with 1 procedure
B. 94%-100% final reattachment rate
C. If PVR is present, visual prognosis is poor.
X. Management of the Other Eye
A. High-risk characteristics
1. Myopia over 10 D
2. White without pressure
3. Vitreous condensation
B. Treat peripheral pathology with laser
C. Prophylactic buckle is controversial.
2. Chang S, Lincoff H. Zimmerman NJ, Fuchs W. Giant retinal tears:
surgical techniques and results using perfluorocarbon liquids. Arch
Ophthalmol. 1989; 107(5):761-766.
3. Freeman HM. The vitreous in idiopathic giant retinal breaks. Bull
Soc Belge Ophtalmol. 1987; 223(pt 1):229-240.
4. 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(1):17-20.
5. Scott IU, Murray TG, Flynn HW, Feuer WJ, Schiffman JC; Perfluoron Study Group. Ophthalmology 2002; 109(10):1828-1833.
6. Ang A, Poulson AV, Goodburn SF, Richards AJ, Scott JD, Snead
MP. Retinal detachment and prophylaxis in type 1 Sticklers syndrome. Ophthalmology 2008; 115(1):164-168.
7. Ang GS, Townsend J, Lois N. Epidemiology of giant tears in the
United Kingdom: The British Giant Retinal Tear Epidemiology Eye
Study (BGEES). Invest Ophthalmol Vis Sci. 2010; 51(9):2781-2787.
8. 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(3):232-237.
9. Gonzalez MA, Flynn HW Jr, Smiddy WE, Albini TA, Berrocal AM,
Tenzel P. Giant retinal tears after prior pars plana vitrectomy: management strategies and outcomes. Clin Ophthalmol. 2013; 7:16871691.
Section I: Masters of Surgery
2015 Subspecialty Day | Retina
9
Proliferative Vitreoretinopathy
Stanley Chang MD
The surgical approach begins with careful preoperative examination where the location of retinal breaks and the extent of epiretinal membranes and traction are noted. An increased anterior
chamber flare, representing breakdown of the blood-retinal barrier, may be a poorer prognostic sign. If there is clinically significant cataract or anterior proliferative vitreoretinopathy (PVR),
the lens should be removed or phacoemulsification with IOL
implantation can be done. A low IOP may reflect retinal detachment or a tendency for postoperative hypotony.
An encircling scleral buckle (usually 2.5-mm band) is placed
to support the width of the vitreous base. I prefer vitrectomy
using 23-gauge instruments with the ability to use a 27-gauge
cutter for more delicate maneuvers such as relaxing retinotomies.
A chandelier light is often helpful, and an illuminated 23-gauge
retinal pick with ILM forceps or endgripping forceps are the
main instruments used for bimanual epiretinal membrane peeling. Panoramic viewing is essential for viewing the peripheral
retina without distorting the shape of the eye.
The approach to the epiretinal proliferation starts from a
posterior to anterior direction. If there is a closed funnel configuration, a viscoelastic may be injected within the funnel to open
the preretinal space and allow access for removal of peripapillary
membranes. Once the funnel is opened, perfluoro-n-octane (Perfluoron, Alcon) is injected to flatten the posterior retina. Epiretinal proliferation located in the midperipheral retina can then
be removed, with gradual addition of perfluorocarbon liquid to
stabilize the retina. Often these membranes are single or multiple
star folds that may be connected in thin sheets of surface proliferation. I do not use any dyes to stain the internal limiting membrane (ILM) because it is more difficult to peel ILM when the
retina is detached and there is a low incidence of reoperation for
macular pucker. Anterior PVR can also be addressed by opening
the peripheral trough and shaving the basal vitreous. Relaxing
retinotomies are necessary if there is continued traction that cannot be relieved by peeling. Retinotomies are often necessary in
areas of extensive laser photocoagulation, areas of peripheral
vitreous or retinal incarceration near old sclerotomy sites, and
for marked subretinal proliferation. I find the use of the 27-gauge
vitreous cutter very efficient for making these retinotomies with
precision. When the retina appears smoothly flattened on the
retinal pigment epithelium (RPE) under perfluorocarbon liquid,
the endpoint is reached.
Endolaser photocoagulation is often placed around any retinal breaks. I prefer to complete as much laser treatment under
the perfluorocarbon liquid, adding any additional peripheral
laser after exchange with the long-term tamponade. Posteriorly
I prefer only 1-2 rows of photocoagulation, and on the scleral
buckle only 2-3 rows. The laser should be done to preserve as
much peripheral retina as possible to preserve the peripheral
vision and spare as much retina in case reoperation is necessary.
The choice of long-term tamponade—C3F8 gas or silicone
oil—varies. I tend to choose gas (14% C3F8 gas:air concentration) for patients undergoing the first operation for PVR. Silicone
oil (5000 cs) is preferred for children, patients who have undergone multiple surgeries previously, if air travel is required, in eyes
with severe open globe injury and retinal detachment, or if there
are signs of corneal decompensation or long-term hypotony.
When silicone oil is used I prefer a direct perfluorocarbon liquid
to silicone oil exchange, which provides a more complete fill. I
do not have any experience with the “heavy” oils that should be
removed within 3 months.
In eyes with silicone oil, I usually suggest removal of the oil in
6-12 months postoperatively if possible. The most favorable eyes
are those with an IOP more than 6 mmHg and if there are no
signs of reproliferation or detachment. When removing silicone
oil, I always examine the patient carefully preoperatively to look
for potential areas of reproliferation of epiretinal membranes.
Frequently I use triamcinolone suspension to stain and remove
epiretinal membranes that have reproliferated under oil.
10
Section I: Masters of Surgery
2015 Subspecialty Day | Retina
Trauma
Carl C Claes MD
NOTES
Section I: Masters of Surgery
2015 Subspecialty Day | Retina
Wound Construction
Kirk H Packo MD
NOTES
11
12
Section II: Vitreoretinal Surgery, Part I
2015 Subspecialty Day | Retina
Internal Limiting Membrane Peeling for All Macular
Holes: Pro
John T Thompson MD
Extensive published literature has shown the effectiveness of
internal limiting membrane (ILM) peeling in helping to improve
the closure rate of macular holes. The recent trend toward using
shorter-acting gas bubbles and decreased duration of prone
positioning has made it even more important to achieve rapid
macular hole closure in the first few days following surgery. The
mechanism by which ILM peeling helps to close macular holes is
unknown, but it probably promotes formation of the small glial
plug that reapposes the edges of the macular hole after successful
macular hole closure. Another important benefit of ILM peeling
is that it helps to ensure that all tangential traction around the
macular hole has been eliminated. A Cochrane meta-analysis of
all published randomized trials comparing ILM peeling to no
ILM peeling for macular holes confirmed that ILM peeling was
associated with a higher percentage of closed macular holes after
one surgery (at P < .00001) and better visual acuity (at P = .02,)
with no increased risk of intraoperative complications.1 ILM
peeling was also found to be more cost-effective due to lower
reoperation costs.1 Many macular holes can be successfully
closed without ILM peeling, but it is difficult to predict preoperatively which ones won’t close. The best success occurs when the
ILM is routinely peeled in eyes with macular holes.
Reference
1. Cornish KS, Lois N, Scott NW, et al. Vitrectomy with internal limiting membrane peeling versus no peeling for idiopathic full-thickness
macular holes. Ophthalmology 2014; 121:649-655.
2015 Subspecialty Day | Retina
Section II: Vitreoretinal Surgery, Part I
Internal Limiting Membrane Peeling for All Macular
Holes: Con
Dante J Pieramici MD
Is internal limiting membrane (ILM) peeling recommend for all
macular holes? To address this question we must first ask, is it
necessary to remove the ILM in all cases of macular hole surgery,
so as to achieve successful closure and visual improvement?
There are a number of lines of evidence suggesting that this
conclusion is not true. First there are cases that resolve spontaneously, even stage 3 full-thickness holes. Secondly, the use of ocriplasmin demonstrates that simply alleviating the vitreomacular
adhesion (VMA) component is enough in nearly half of cases
with macular holes less than 400 microns in size. Finally, prior
to the popularity of ILM removal for cases of idiopathic macular
hole, surgeons simply aimed to remove the posterior hyaloid and
closed most holes. Finally, removal of the ILM does not come
about without potential risk of iatrogenic injury. The enemy of
good can be better.
13
14
Section II: Vitreoretinal Surgery, Part I
2015 Subspecialty Day | Retina
Routine Intraoperative OCT Is Useful for Macular
Surgery: Pro
Justis P Ehlers MD
In the last 10-15 years, OCT has transformed the clinical management of vitreoretinal diseases. The high-resolution anatomic
information provided by OCT is a natural complement to the
operating room. OCT has given clinicians the ability to visualize
vitreomacular traction, macular holes, or epiretinal membranes
in ways not previously possible. In that same way, applying
intraoperative OCT to ophthalmic surgery has the potential to
transform the surgical approach to macular surgery through the
visualization of residual membranes, confirmation of surgical
objectives, and identification of architectural alterations resulting from surgical manipulations. Intraoperative OCT may be the
next paradigm shift in vitreoretinal surgery.
Selected Readings
1. 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 e1001.
2. Ehlers JP, Kaiser PK, Srivastava SK. Intraoperative optical coherence tomography using the RESCAN 700: preliminary results from
the DISCOVER study. Br J Ophthalmol. 2014; 98(10):1329-1332.
3. 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.
4. Ehlers JP, Ohr MP, Kaiser PK, Srivastava SK. Novel microarchitectural dynamics in rhegmatogenous retinal detachments identified
with intraoperative optical coherence tomography. Retina 2013;
33(7):1428-1434.
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. Ehlers JP, Tam T, Kaiser PK, Martin DF, Smith GM, Srivastava SK.
Utility of intraoperative optical coherence tomography during vitrectomy surgery for vitreomacular traction syndrome. Retina 2014;
34(7):1341-1346.
7. Ehlers JP, Xu D, Kaiser PK, Singh RP, Srivastava SK. Intrasurgical dynamics of macular hole surgery: an assessment of surgeryinduced ultrastructural alterations with intraoperative optical
coherence tomography. Retina 2014; 34(2):213-221.
8. Pichi F, Alkabes M, Nucci P, Ciardella AP. Intraoperative SD-OCT
in macular surgery. Ophthalmic Surg Lasers Imaging. 2012; 43(6
suppl):S54-60.
9. Ray R, Baranano 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.
10. 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.
11. 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.
12. Ehlers JP, Tao YK, Srivastava SK. The value of intraoperative optical coherence tomography imaging in vitreoretinal surgery. Curr
Opin Ophthalmol. 2014; 25(3):221-227.
13. Hahn P, Migacz J, O’Donnell 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.
14. 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 Optics Express.
2014; 5(6):1877-1885.
15. Ehlers JP, Itoh Y, Xu L, Kaiser PK, Singh RP, Srivastava SK. Factors
associated with persistent subfoveal fluid and complete macular
hole closure in the PIONEER Study. Invest Ophthalmol Vis Sci.
2014; 56(2):1141-1146.
2015 Subspecialty Day | Retina
Section II: Vitreoretinal Surgery, Part I
15
Routine Intraoperative OCT Is Useful for Macular
Surgery: Con
Dennis P Han MD
Introduction
The goal of this presentation is to introduce potential caveats
in the implementation of intraoperative OCT for vitreoretinal
surgery. The acceptance of this technology will depend on how
it addresses stated problems. The final arbiter will be whether it
can improve visual outcome and do it in a cost-effective way.
To understand whether intraoperative OCT solves our
problems, we must first know the nature of the problems. These
might be considered legitimate problems:
1. We have difficulty identifying epiretinal membranes
(ERM) or internal limiting membranes (ILM) that are significant enough to affect visual outcome.
2. We have difficulty with technical aspects of removing
membranes, and an easier and safer removal technique is
needed.
3. We must balance any improvement resulting from new
technology with its cost.
Problem #1: Identifying Visually Significant
Membranes
Fact: Residual epiretinal membranes after conventional ERM
peeling have little impact on visual function.
Chang et al,1 in a large series of epiretinal membranes removed
with single peeling (ERM only) or double peeling (ERM and
ILM both removed to achieve more complete removal), found
that residual ERM in the fovea was present at 1 month postoperatively in 52% of single-peeled cases vs. 2.5% of double-peeled
cases. Yet there was no difference in visual outcome between the
2 groups, in spite of many more residual membranes in the single-peeled group. Although within the single-peeled group, eyes
with residual ERMS were associated with slightly less final acuity
(approximately 1 line of VA difference), the baseline acuity was
not reported in this comparison, and, even if an actual difference
existed in VA change within this small subgroup, it is not clear
that added surgical manipulations to remove the ERMs would
have made a difference.
Fact: Skilled graders of the presence or absence of a residual
ERM cannot agree in 25% of cases.
Difficulty interpreting postoperative OCT after ERM stripping
occurred in 25% of patients in the Chang series; a third person
was required to adjudicate. This may be even more problematic
because the resolution of OCT images in the operating room
may be affected by surgically induced changes in media clarity.
Fact: With current technology, we can close macular holes at an
extremely high rate (90%-100% in recent surgical series).2
Problem #2: We have difficulty with technical
aspects of removing membranes, and an easier and
safer removal technique is needed.
Fact: We already have multiple modalities to assist in
the surgical visualization of ERM or ILM for surgical
manipulation; the utility of intraoperative OCT must prove
itself in an environment that incorporates them.
A target state for intraoperative OCT is to view membranes in
a real-time way that exceeds or complements the conventional
microscope view in not just locating membranes but also safely
manipulating the “working” end of instruments used for membrane peeling. Shadowing effects may inhibit viewing. Having
multiple simultaneous viewing platforms carries risks of user
distraction and ocular injury. A period of learning would be
expected, and frequent use is possibly needed to maintain expertise.
Our current state is that we have the capability to stain ILM
dyes, “dust” ERMs with triamcinolone acetonide, identify ERMs
preoperatively with OCT, and view them in a 3-dimensional,
stereoscopic, real-time fashion through a conventional operating
microscope. The utility of intraoperative OCT, whether image
viewing is real time or not, must be considered in light of these
factors. The ideal state would eliminate the need for extra measures of ILM or ERM staining, which carry their own risk.
Retinal light toxicity is a known complication of prolonged
attempts at membrane peeling.4 Intraoperative OCT for surgical decision making may shorten or lengthen the duration of
surgery and could affect the risk of light toxicity in a favorable
or unfavorable manner. Efficient image acquisition, proper interpretation, and an accurate assessment of the risks of additional
surgical manipulation or its omission would be needed for intraoperative OCT to have optimal impact.
Problem #3: Cost-effectiveness: Is it worth the price?
Fact: Until we know the costs of implementation and the degree
and duration of visual improvement , the cost-effectiveness of
intraoperative OCT cannot be assessed.
References
1. Chang S, Gregory-Roberts EM, Park S, Laud K, Smith SD, Hoang
QV. Double peeling during vitrectomy for macular pucker. JAMA
Ophthalmology. 2013; 131(4):525-530.
2. Chin EK, Almeida DRP, Sohn EH. Structural and functional
changes after macular hole surgery: a review. Int Ophthalmol Clin.
2014; 54(2):17-27.
3. Brown MM, Brown GC, Sharma S, Landy J. Health care economic
analyses and value-based medicine. Surv Ophthalmol. 2003;
48(2):204-223.
4. Park DW, Sipperly JO, Sneed SR, Dugel PU, Jacobsen J. Macular
hole surgery with internal limiting membrane peeling and intravitreous air. Ophthalmology 1999; 106(7):1392-1397.
16
Section II: Vitreoretinal Surgery, Part I
2015 Subspecialty Day | Retina
27-Gauge Vitrectomy Will Be the New Standard for
Pars Plana Vitrectomy: Pro
Chris Riemann MD
Next generation 27-gauge pars plana vitrectomy instrumentation has capitalized on improved understanding of the physics
and engineering principles that define vitrectomy fluidics. Cut
rate, duty cycle, and sphere of influence are optimized to achieve
superb safety, excellent cutter performance, and exquisite control
on the surface of the retina. Even smaller incisions result in quiet,
cosmetically appealing postop eyes with little inflammation,
fast healing, and happy patients. Aside from performing most
surgical tasks as well as larger gauge instrumentation, 27-gauge
vitrectomy expands the degrees of freedom available to the operating surgeon during intraoperative manipulations, especially in
close proximity to the retina.
2015 Subspecialty Day | Retina
Section II: Vitreoretinal Surgery, Part I
17
27-Gauge Vitrectomy Will Be the New Standard for
Pars Plana Vitrectomy: Con
Edwin Hurlbut Ryan Jr MD
Minimally invasive vitrectomy, introduced by DeJuan in
2002,1 has now replaced 20-gauge surgery in the hands of most
surgeons. In 2014, 96% of vitrectomies in the United States
were reportedly done using 23- or 25-gauge instruments, with
25-gauge more popular, with 52%, vs. 44% for 23-gauge.2
Oshima introduced 27-gauge vitrectomy in 2010,3 and while this
method is gaining in popularity, it still represents a tiny share of
the market.
Should 27-gauge be the standard platform for vitrectomy? At
this point in time, my answer is “not yet.”
My preference for microincisional vitrectomy is 25-gauge.
The advantages of 25-gauge vitrectomy over 20-gauge vitrectomy are multiple. Faster wound healing, less discomfort, less
inflammation, less vitreous incarceration, potentially fewer
retinal tears, and more rapid visual recovery are a few of the benefits, among others. What does 27-gauge add to this? Theoretically with a 0.4-mm wound 27-gauge has a greater likelihood of
self-sealing than does the 0.5-mm wound created with 25-gauge.
Also, some surgeons argue that the 27-gauge wound allows the
surgeon to fashion a perpendicular incision rather than a beveled
incision, as is most commonly employed using 23- or 25-gauge.
Other arguments favoring 27-gauge include the smaller “sphere
of influence,” which would theoretically make removal of vitreous adjacent to the retina safer since the tissue is less likely to
jump into the cutting instrument.4 Also the very tiny size of the
27-gauge vitrectomy probe is said to allow access to tissue planes
that might be inaccessible with larger tools.5 In reality, all of
these theoretical benefits now exist with the current 25-gauge
instrumentation.
The downsides of 27-gauge are three: First, the instruments,
while stiffer than the original 25-gauge instruments, are still too
flexible. The original 25-gauge instruments were much too flex-
ible, and delicate maneuvers on the surface of the retina were
very anxiety provoking. 27-gauge stiffness is better than that,
but there’s still some degree of movement that is not controllable, which makes this surgeon a bit uncomfortable. Secondly,
the flow rate through the vitreous cutter is definitely slower than
what is found with 25-gauge cutters, and the suction isn’t as
robust. This is an inescapable fact of physics (specifically, Poiseuille’s law, which states that the flow is related to the radius
to the fourth power). While the increased time required for core
vitrectomy is not huge, it is definitely noticeable. Third, the cost
is greater for 27-gauge, and the quiver of available instruments is
smaller.
So: Microincisional vitrectomy? Resounding yes. 27-gauge?
Not ready for every case yet.
References
1. Fujii GY, De Juan E Jr, Humayun MS, et al. A new 25-gauge instrument system for transconjunctival sutureless vitrectomy surgery.
Ophthalmology 2002; 109(10):1807-1812.
2. Rezaei KA, Stone TW, eds. 2014 Global Trends in Retina Survey.
Chicago: American Society of Retina Specialists; 2014.
3. Oshima Y, Wakabayashi T, Sato T, Ohji M, Tano Y. A 27-gauge
instrument system for transconjunctival sutureless microincision
vitrectomy surgery. Ophthalmology 2010; 117(1):93-102.
4. Dugel PU, Abulon DJ, Dimalanta R. Comparison of attraction
capabilities associated with high-speed, dual-pneumatic vitrectomy
probes. Retina 2015; 35(5):915-920.
5. Berrocal M, Williams DF. Smaller gauge instruments are better and
safer. Retina Today, January / February 2015.
18
Section II: Vitreoretinal Surgery, Part I
2015 Subspecialty Day | Retina
Scleral Buckling Is Preferred in Young, Phakic Retinal
Detachment Patients: Pro
Gaurav K Shah MD and Harpreet S Walia MD
I.Introduction
A. Rhegmatogenous retinal detachments (RRD) in
young patients account for 3%-12% of all RRD.
1. Excluding pediatric detachments and subsequent
hereditary vitreoretinopathies, RRD in younger
patients are often attributable to nonpenetrating
ocular trauma, retinal dialyses, and high myopia.
3. In both scenarios, the buckling effect reduces the
risk of late tractional forces causing redetachment, whereas vitrectomized eyes with incomplete vitreous base dissection can have untoward
outcomes.
2. Late presentation is often encountered with high
frequencies of macular detachment and proliferative vitreoretinopathy (PVR).
3. Although often different at presentation, adolescent RRD has surgical and visual outcomes as
promising as those of senile RRD.
A. Scleral buckling remains the mainstay for repair of
retinal dialysis.
Single operation success rates (SOSR) of 87%.
B. Young patients with PVR
1. PVR grade A: Reported SOSR after scleral buckling ranges between 80% and 87.5%.
2. PVR Grade C or higher: SOSR after scleral buckling reaches 58%.
III.Advantages
A. Scleral buckling confers the distinct advantage of
avoiding excessive vitreous manipulation.
1. The elevation of the hyaloid and complete
removal of vitreous poses a challenge in this subset of patients who are often phakic.
Incomplete vitreous dissection can engender or
exacerbate PVR, causing redetachment.
2. It is easier to fix a scleral buckle failure than a
PPV failure.
A large series found that eyes that failed initial
treatment with scleral buckling required approximately 30% fewer secondary retinal procedures,
and a third less use of silicone oil, compared with
those who underwent initial PPV or PPV plus
scleral buckling.
B. Scleral buckling preserves the crystalline lens and
accommodation in adolescent patients.
C. Scleral buckling provides circumferential support of
a firmly adherent vitreous base in adolescents.
1. Highly myopic eyes: These eyes carry an
increased lifelong risk of detachment.
D. Scleral buckling may reduce positioning needs.
1. Adolescent patients may have unique rehabilitative needs (ie, early return to work, school, caring for others).
2. Less reliance on silicone oil tamponade and subsequent removal
II. Scleral buckling yields an excellent success rate in adolescent RRD.
2. Eyes that suffered nonpenetrating trauma: Subsequent retinal breaks can occur much later.
B. RRD in this population merit special attention.
E. Scleral buckling in younger patients does not induce
significant myopia and anisometropia.
1. One study found that the mean refractive change
was only −0.6 D at follow-up of up to 4 years.
2. In younger patients still in the amblyogenic
period, the myopic change after scleral buckle
was found to be less than in the subsequent nonoperated eye, indicating reduced progressive
scleral elongation.
IV.Conclusion
Despite advances in vitreoretinal surgery, scleral buckling provides an excellent method of repair for RRD in
young patients.
Selected Readings
1. Akabande N, Yamamoto S, Tsukahara I, et al. Surgical outcomes in
juvenile retinal detachment. Jpn J Ophthalmol. 2001; 45:409-411.
2. Brown GC, Tasman WS. Familial retinal dialysis. Can J Ophthalmol. 1980; 15:193-195.
3. Fivgas GD, Capone A Jr. Pediatric rhegmatogenous retinal detachment. Retina 2001; 21:101-106.
4. Gonzales CR, Singh S, Yu F, et al. Pediatric rhegmatogenous retinal
detachment: clinical features and surgical outcomes. Retina 2008;
28:847-852.
5. Mansouri A, Almony A, Shah GK, Blinder KJ, Sharma S. Recurrent
retinal detachment: does initial treatment matter? Br J Ophthalmol.
2010; 94:1344-1347.
6. Nagpal M, Nagpal K, Rishi P. Juvenile rhegmatogenous retinal
detachment. Indian J Ophthalmol. 2004; 52:297-302.
7. Shah GK, Almony A, Blinder KJ. Postoperative complications of
retinal detachment repair with scleral buckles. Paper presented at:
Retina Subspecialty Day, Annual Meeting of the American Academy of Ophthalmology; October 16, 2010; Chicago.
2015 Subspecialty Day | Retina
8. Stoffelns BM, Richard G. Is buckle surgery still the state of the art
for retinal detachments due to retinal dialysis? J Pediatr Ophthalmol Strabismus. 2010; 47:281-287.
9. Winslow RL, Tasman W. Juvenile rhegmatogenous retinal detachment. Ophthalmology 1978; 607-618.
10. Wu WC, Lai CC, See LC, et al. Unambiguous comparison of juvenile and senile rhegmatogenous retinal detachment. Ophthalmic
Surg Lasers Imaging. 2005; 36:197-204.
Section II: Vitreoretinal Surgery, Part I
19
20
Section II: Vitreoretinal Surgery, Part I
2015 Subspecialty Day | Retina
Scleral Buckle Is Preferred in Young, Phakic Retinal
Detachment Patients: Con
Philip J Ferrone MD
Pediatric retinal detachments are often complex and associated
with congenital abnormalities, ocular trauma, vitreoretinal interface abnormalities, and prior intraocular surgery. In addition,
the issues of a late presentation, predisposition to proliferative
vitreoretinopathy, and amblyopia can limit anatomical and
functional success of retinal detachment surgery in these young
patients.
Some pathology is well suited for repair by scleral buckle in
children, and these typically include retinal dialysis, simple rhegmatogenous retinal detachments, and some lattice-related retinal
detachments, both with and without subretinal strand formation.
Occasionally, a simple Stickler-related retinal detachment can be
repaired well with a scleral buckle alone also. However, significant concerns in these patients include the induced myopia that
can be associated with scleral buckling and the potential effect of
an encircling scleral buckle in a young, growing eye.
On the other hand, there are many types of retinal detachments that affect children that are often not as well addressed
with a scleral buckle alone, as opposed to a vitrectomy. These
types of retinal detachments include persistent fetal vascular syndrome-related retinal detachments, familial exudative
vitreoretinopathy-related detachments, sickle cell detachments,
and ROP retinal detachments. In addition, penetrating traumarelated detachments, most complex Stickler-related detachments,
posterior retinal tear detachments, proliferative vitreoretino­
pathy-related detachments, and giant retinal tear detachments
are all most often repaired best with vitrectomy. One must also
remember that with vitrectomy in children, cataract formation
following vitrectomy is not as much of an issue as it is in the
older adult population.
Selected Readings
1. Chen S, Jiunn-Feng H, Te-Cheng Y. Pediatric rhegmatogenous retinal detachment in Taiwan. Retina 2006; 26:410-414.
2. Gonzales C, Singh S, Yu F, Kreiger AE, Gupta A, Schwartz SD.
Pediatric rhegmatogenous retinal detachment. Retina 2008; 28:847852.
3. Soheilian M, Ramezani A, Malihi M, et al. Clinical features and
surgical outcomes of pediatric rhegmatogenous retinal detachment.
Retina 2009; 29:545-551.
4. Figas G, Capone A Jr. Pediatric rhegmatogenous retinal detachment. Retina 21:101-106, 2001.
5. Errera MH, Liyanage SE, Moya R, Wong SC, Ezra E. Primary
scleral buckling for pediatric rhegmatogenous retinal detachment.
Retina 2015; 35(7):1441-1449.
6. Ferrone PJ, Harrison C, Trese MT. Lens clarity after lens-sparing
vitrectomy in a pediatric population. Ophthalmology 1997;
104(2):273-278.
2015 Subspecialty Day | Retina
Section II: Vitreoretinal Surgery, Part I
Indocyanine Green Is Safe for Internal Limiting
Membrane Peeling: Pro
Mathew W MacCumber MD PhD
Indocyanine green is by far the most popular dye for staining
the internal limiting membrane (ILM) during vitrectomy in the
United States (62%, ASRS Preferences and Trends survey, 2013;
70%, ASRS Global Trends survey, 2014). Thousands of patients
have had successful ICG-assisted vitrectomy for macular hole
and/or epiretinal membrane since it was first introduced into the
surgical armamentarium.1,2 When considering safety, important
considerations are (1) techniques to maintain its use within a
safe and effective therapeutic window and (2) the relative risks of
employing an alternative dye or no dye at all.
References
1. Kadonosono K, Itoh N, Uchio E, et al. Staining of internal limiting membrane in macular hole surgery. Arch Ophthalmol. 2000;
118(8):1116-1118.
2. Brooks HL Jr. Macular hole surgery with and without internal
limiting membrane peeling. Ophthalmology 2000; 107(10):19391948.
21
22
Section II: Vitreoretinal Surgery, Part I
2015 Subspecialty Day | Retina
Indocyanine Green Is Safe for Internal Limiting
Membrane Peeling: Con
Julia A Haller MD
Indocyanine green dye has been shown to improve the visualization of the internal limiting membrane (ILM) and epiretinal
membranes during vitrectomy. Much research has demonstrated
that there are issues with intravitreal indocyanine green (ICG)
application, including worse functional outcomes and a higher
incidence of retinal pigment epithelial (RPE) changes and visual
field defects.
Over 100 in vitro, ex vivo, and in vivo animal investigations,
as well as clinical reports, on intravitreal ICG staining are found
in the literature. ICG-related toxicity mechanisms may include
biochemical direct injury to the ganglion cells/neuroretinal cells,
RPE cells, and superficial retinal vessels; apoptosis and gene
expression alterations to either RPE cells or neuroretinal cells;
osmolarity effect of ICG solution on the vitreoretinal interface;
light-induced injury; and mechanical cleavage effect on the ILM/
inner retina. Most animal experiments suggest a dose-dependent
toxic effect on retinal tissue. This hypothesis is supported by
clinical data from series using low dye concentrations and short
incubation times.
ICG helps with visualization of structures that are important
to address effectively in vitreoretinal surgery. Limiting its toxicity can be achieved by using as low a concentration as possible,
avoiding repeated ICG injections, injecting dye away from a
macular hole to prevent direct dye contact with the RPE, short
ICG incubation time, and minimizing light exposure.
Selected Readings
1. Tsipursky MS, Heller MA, De Souza SA, et al. Comparative evaluation of no dye assistance, indocyanine green and triamcinolone
acetonide for internal limiting membrane peeling during macular
hole surgery. Retina 2013; 33(6):1123-1131.
2. Wu Y, Zhu W, Xu D, et al. Indocyanine green-assisted internal
limiting membrane peeling in macular hole surgery: a meta-analysis.
PLoS One 2012; 7(11):e48405.
3. Farah ME, Maia M, Rodrigues EB. Dyes in ocular surgery: principles for use in chromovitrectomy. Am J Ophthalmol. 2009;
148(3):332-340.
4. Rodrigues EB, Meyer CH, Mennel S, Farah ME. Mechanisms of
intravitreal toxicity of indocyanine green dye: implications for chromovitrectomy. Retina 2007; 27(7):958-970.
5. Kampik A, Haritoglou C, Gandorfer A. What are vitreoretinal surgeons dyeing for? Retina 2006; 26(6):599-601.
6. Kusaka S, Oshita T, Ohji M, Tano Y. Reduction of the toxic effect
of indocyanine green on retinal pigment epithelium during macular
hole surgery. Retina 2003; 23(5):733-734.
7. Da Mata AP, Burk SE, Riemann CD, et al. Indocyanine greenassisted peeling of the retinal internal limiting membrane during
vitrectomy surgery for macular hole repair. Ophthalmology 2001;
108(7):1187-1192.
2015 Subspecialty Day | Retina
Section II: Vitreoretinal Surgery, Part I
23
Face-down Position Is Not Necessary for Macular
Holes: Pro
Ehab N El Rayes MD PhD
Idiopathic macular hole (MH) is a common cause of vision loss.
It is strongly associated with certain factors such as presence of
antero-posterior and tangential traction. Our goal for successful
macular hole repair is a safe, effective way with the least possible
patient suffering.
Kelly and Wendel1 first demonstrated in 1991 the possibility
of surgical MH closure and consequent improvement in visual
acuity.
The aims of successful closure of a MH are to:
I. Increase Retinal Elasticity
A. Remove vitreous and antero-posterior traction. We
know that posterior vitreous detachment or even
pharmacovitreolysis by itself can lead to closure of
lamellar or small holes.
1. Better visualization systems
2. Efficient stains and dyes for epiretinal membranes and ILM aiding complete identification
and removal
3. Intraoperative visualization of epimacular surface forces and traction with intraoperative OCT
(iOCT), aiding intraoperative judgment of traction relief
II. Temporarily Isolate the Hole From the Vitreous Fluid
B. Remove all epiretinal membranes and peel the internal limiting lamina (ILM). Over the years this has
improved with the evolution of the industry, techniques, and what we have.
A. A complete (full) gas fill of SF6 or, less frequently,
C3F8 keeps the hole edges dry in all positions except
supine for more than 7 days (no face-down position,
so no positioning needed). Depending on the nature
of concentration of gas used, up to a residual 50%
gas bubble is sufficient to close the MH in setting
position. This fulfills the goal of why we use gas
with no face-down needed.
B. OCT studies have shown retinal changes such as
healing, flattening, resorption of cystic fluid, and
approximation of the hole edges and closure within
the first 24-48 hours of surgery.2-6
III. Encourage Retinal Healing Process
This occurs as early as the first 24 hours, triggered by
surgery and ILM peeling and leading to proliferation of
glial cells, mainly Müller cells and astrocytes, helping
align the edges of the hole and close the defect. This is
followed by reorganization of the ellipsoid layers and
reorientation of photoreceptors.
Because of this understanding of how early MHs close (as
early as the first 24-48 hours), we adopt no face-down in macular hole surgery.
Several studies in the literature support the concept that
no face-down is needed in MH repair,4,7-13 and several others
showed no difference in the rate of closure with or without posturing.8,14,15
In most of these cases, we combine phacovitrectomy as the
one procedure to avoid late lens changes and better clarity.
We believe that our understanding of:
• how early wound healing occurs,
• seeing how efficiently we removed epiretinal traction and
even seeing the hole edges start to flatten on the table
(iOCT), and
• the dynamics of the gas in relation to the hole
changes and decreases our concerns about closure delay, or need
for any face-down posturing. So adequate removal of epiretinal
traction together with complete fluid/gas exchange (bubble closing the hole without face-down) achieves our goals in MH repair
without the agony of keeping our patients in a face-down position as an unnecessary step, especially when dealing with elderly
patients with coexisting health problems. This makes the procedure more accepted by our patients.
References
1. Kelly NE, Wendel RT. Vitreous surgery for idiopathic macular
holes. Arch Ophthalmol. 1991; 109:654-659.
2. Ehlers JP, McNutt SA, Kaiser PK, Srivastava SK. Contrastenhanced intraoperative optical coherence tomography. Br J Ophthalmol. 2013; 97:1384-1386.
3. Kasuga Y, Arai J, Akimoto M, Yoshimura N. Optical coherence
tomography to confirm early closure of macular holes. Am J Ophthalmol. 2000; 130:675-676.
4. Eckardt C, Eckert T, Eckardt U, et al. Macular hole surgery with air
tamponade and optical coherence tomography-based duration of
face-down positioning. Retina 2008; 28:1087-1096.
5. Shah SP, Manjunath V, Rogers AH, et al. Optical coherence
tomography-guided facedown positioning for macular hole surgery.
Retina 2013; 33:356-362.
6. Yamashita T, Yamashita T, Kawano H, et al. Early imaging of
macular hole closure: a diagnostic technique and its quality for
gas-filled eyes with spectral domain optical coherence tomography.
Ophthalmologica 2013; 229:43-49.
7. Tornambe PE, Poliner LS, Grote K. Macular hole surgery without
face-down positioning: a pilot study. Retina 1997; 17:179-185.
8. Isomae T, Sato Y, Shimada H. Shortening the duration of prone
positioning after macular hole surgery: comparison between 1-week
and 1-day prone positioning. Jpn J Ophthalmol. 2002; 46:84-88.
9. Tranos PG, Peter NM, Nath R, et al. Macular hole surgery without
prone positioning. Eye (Lond). 2007; 21:802-806.
10. Dhawahir-Scala FE, Maino A, Saha K, et al. To posture or not to
posture after macular hole surgery. Retina 2008; 28:60-65.
24
Section II: Vitreoretinal Surgery, Part I
11. Simcock PR, Scalia S. Phacovitrectomy without prone posture for
full thickness macular holes. Br J Ophthalmol. 2001; 85:13161319.
12. Madgula IM, Costen M. Functional outcome and patient preferences following combined phaco-vitrectomy for macular hole without prone posturing. Eye (Lond). 2008; 22:1050-1053.
13. Nadel J, Delas B, Pinero A. Vitrectomy without face down posturing for idiopathic macular holes. Retina 2012; 32:918-921.
14. Krohn J. Duration of face-down positioning after macular hole surgery: a comparison between 1 week and 3 days. Acta Ophthalmol
Scand. 2005; 83:289-292.
15. Sato Y, Isomae T. Macular hole surgery with internal limiting membrane removal, air tamponade, and 1-day prone positioning. Jpn J
Ophthalmol. 2003; 47:503-506.
2015 Subspecialty Day | Retina
2015 Subspecialty Day | Retina
Section II: Vitreoretinal Surgery, Part I
Face-down Position Is Not Necessary for Macular
Holes: Con
John S Pollack MD
To suggest that face-down positioning is not necessary for macular hole surgery is misleading. That argument will become believable when studies produce approximately 95% macular hole
closure rates without postoperative instructions for patients to
look down and without rapid progression of cataract in the first
few weeks after surgery. Until then, “face-down” positioning is
still necessary for macular hole surgery; it is just a matter of the
degree and the duration of such positioning.
25
26
Section II: Vitreoretinal Surgery, Part I
2015 Subspecialty Day | Retina
Pars Plana Vitrectomy Should Be Combined With
Cataract Extraction/IOL for All Cases: Pro
Timothy G Murray MD MBA
Pars plana vitrectomy surgery is aimed at improving
best visual function via restoration of retinal anatomy.
Diagnostic evaluation, surgical techniques, and vitreoretinal instrumentation have significantly improved
over the last 5 years, enabling outstanding surgical
results, improved patient outcomes, and decreased iatrogenic complications. These improvements have been
associated with evolving surgical indications that have
demanded better visual outcomes for our patients.
VII. Surgical Approach
A. Presurgical evaluation including spectral domain
OCT, IOL calculation, and comprehensive clinical
assessment imperative.
B. Surgical set-up including combined anterior/posterior vitrectomy platform, preselected IOL, MIVS
approach
C. Transconjunctival cannula placement using valved
cannulas preferred. Small-incision torsional phacoemulsification with placement of IOL of choice
(acrylic preferred over silicone). Toric IOL placement not compromised but currently not recommending multifocal IOLs in patients with significant
macular pathology (decreased contrast sensitivity);
IOL placement and 10-nylon closure of clear corneal biplanar incision is effective but not necessary
for fluidic stability. Standard pars plana vitrectomy
management of macular pathology. Intravitreal
triamcinolone acetonide placement at conclusion
of case speeds up resolution of pre-existing macular
edema. Standard evaluation of sclerotomies and
wound stability do not require routine closure.
II. Epiretinal Membrane and/or Vitreomacular Traction
A. Surgical indications: Traditionally 20/60 or worse
BCVA with metamorphopsia; currently reports on
outcomes for visual acuity (VA) 20/30 or worse
with focus on severity of metamorphopsia
B. Expected outcomes
1. Historically: 2-line improvement of VA
2. Currently: VA outcomes of 20/40 or better
expected
III. Pre-existing age related cataract (even if not visually
significant) will significantly progress within first 12
months from macular surgery. Visual impact of progressive cataract will significantly limit post-macular
surgery typically occurring within 6 months after
surgery. Visual limitation from cataract progression is
most pronounced in patients with best VA outcomes.
IV. Patient expectations focus on VA and functional visual
improvement. Earlier visual recovery (microincisional
vitrectomy surgery, MIVS) is critical but sustained
visual recovery is expected by the patient undergoing
macular surgery. Visual compromise from progressive
cataract, particularly early, is commonly understood by
the patient as a “complication” of surgery (as is “early”
secondary cataract surgery).
V. Secondary cataract surgery after macular surgery is
associated with higher rates of complications, including zonular compromise, capsular compromise, dislocated nuclear / cortical fragments, and cystoid macular
edema. Secondary cataract surgery may be associated
with recurrent macular hole rates as high as 10%.
ment systems into a single console, ideally positioned
for combined macular surgery and cataract extraction/
IOL implantation.
I.Introduction
VI. Combined macular surgery (particularly MIVS) and
small-incision torsional phacoemulsification enable
rapid and sustained VA outcomes with minimal
incremental surgical risk. Initial concerns regarding
large-incision surgical cataract management (ECCE)
combined with larger-gauge vitrectomy surgery have
been virtually eliminated with advanced anterior segment instrumentation coupled with advanced posterior
segment surgical technologies. Recent platforms have
integrated state-of-the-art anterior and posterior seg-
VIII. Clinical Trial Data – MOOR
IX. Surgical Outcomes
A. Enhanced recovery of best and sustained VA and
function associated with single surgical procedure.
Combined vitrectomy with phacoemulsification/
IOL implantation eliminates visual loss from preexisting cataract and its associated postsurgical progression. No significant increases in endophthalmitis, hypotony, choroidal detachment. Single surgical
recovery eliminates any risk associated with planned
secondary cataract extraction.
B. Currently the routine surgical approach for most
centers providing macular surgery in patients with
pre-existing cataract when managed outside of
North America
C. Not commonly accepted for most referral programs
within North America
D. Evolving demographics and sustained health-care
cost pressures may shift surgeons within North
America to more closely emulate the combined surgical approach to managing macular pathology and
cataract of our international colleagues.
2015 Subspecialty Day | Retina
Section II: Vitreoretinal Surgery, Part I
27
Selected Readings
1. Lonngi M, Houston SK, Murray TG, et al. Microincisional vitrectomy for retinal detachment in I-125 brachytherapy-treated patients
with posterior uveal malignant melanoma. Clin Ophthalmol. 2013;
7:427-435.
2. Murray TG, Layton AJ, Tong KB, et al. Transition to a novel
advanced integrated vitrectomy platform: comparison of the surgical impact of moving from the Accurus vitrectomy platform to the
Constellation Vision System for microincisional vitrectomy surgery.
Clin Ophthalmol. 2013; 7:367-377.
3. Parke DW 3rd, Sisk RA, Murray TG. Intraoperative intravitreal triamcinolone decreases macular edema after vitrectomy with phacoemulsification. Clin Ophthalmol. 2012; 6:1347-1353.
4. Parke DW 3rd, Sisk RA, Houston SK, Murray TG. Ocular hypertension after intravitreal triamcinolone with vitrectomy and phacoemulsification. Clin Ophthalmol. 2012; 6:925-931.
5. Sisk RA, Murray TG. Combined phacoemulsification and sutureless 23-gauge pars plana vitrectomy for complex vitreoretinal diseases. Br J Ophthalmol. 2010; 94(8):1028-1032.
6. Hartley KL, Smiddy WE, Flynn HW Jr, Murray TG. Pars plana
vitrectomy with internal limiting membrane peeling for diabetic
macular edema. Retina 2008; 28(3):410-419.
7. Chaudhry NA, Flynn HW Jr, Murray TG, Belfort A, Mello M Jr.
Combined cataract surgery and vitrectomy for recurrent retinal
detachment. Retina 2000; 20(3):257-261.
8. Chaudhry NA, Flynn HW Jr, Murray TG, Nicholson D, Palmberg
PF. Pars plana vitrectomy during cataract surgery for prevention of
aqueous misdirection in high-risk fellow eyes. Am J Ophthalmol.
2000; 129(3):387-388.
9. Scott IU, Alexandrakis G, Flynn HW Jr, et al. Combined pars plana
vitrectomy and glaucoma drainage implant placement for refractory
glaucoma. Am J Ophthalmol. 2000; 129(3):334-341.
10. Alexandrakis G, Chaudhry NA, Flynn HW Jr, Murray TG. Combined cataract surgery, intraocular lens insertion, and vitrectomy in
eyes with idiopathic epiretinal membrane. Ophthalmic Surg Lasers.
1999; 30(4):327-328.
28
Section II: Vitreoretinal Surgery, Part I
2015 Subspecialty Day | Retina
Pars Plana Vitrectomy Should Be Combined With
Cataract Extraction /IOL for All Cases: Con
Sunir J Garg MD FACS
Not all vitrectomy requires cataract extraction:
•
•
•
•
•
Age dependent
Difficult for urgent cases
Difficulty coordinating care
Gas can displace lens
Corneal edema makes internal limiting membrane peel
challenging.
2015 Subspecialty Day | Retina
Section II: Vitreoretinal Surgery, Part I
Heads Up – No Microscope Is the Future of
Vitreoretinal Surgery: Pro
Claus Eckardt MD
In heads-up surgery the surgeon operates while viewing a 3-D
image on a large HD display instead of looking through the oculars of a microscope. Switching from traditional microsurgery to
heads-up surgery is quick and unproblematic. It has the advantages of excellent ergonomics and the ability to apply digital
image processing to brighten the image.
29
30
Section II: Vitreoretinal Surgery, Part I
2015 Subspecialty Day | Retina
Heads Up – No Microscope Is the Future of
Vitreoretinal Surgery: Con
“Heads-Up” Electronic Viewing vs. Optical Viewing
Steve Charles MD
“Heads-up surgery” is being marketed as providing an ergonomic benefit. Tiltable binoculars have been available from
operating microscope manufacturers for two decades to address
this issue. Shorter stack height because of thinner laser filters,
beam splitters, inverters, and zoom optics coupled with tiltable
binoculars have eliminated ergonomic problems even for the
very short or very tall surgeon. But so-called heads-up surgery
actually creates an ergonomic problem by requiring the surgeon
to view a flat panel display with a head turn unless the display
is located far away at the patient’s feet, which typically does not
allow unobstructed viewing.
So-called heads-up surgery is implemented by attaching a
pair of cameras to the operating microscope optics and displaying a stereo image on a flat panel display viewed with passive
glasses. Heads-up displays in the aircraft cockpit superimpose
forward-looking infrared images (AKA enhanced vision) and/
or a photo-realistically rendered 3-D terrain database (AKA
synthetic vision), localizer, glideslope, airspeed, altitude, altitude,
speed and angle of attack trend vectors, and autopilot modes on
a live optical view seen through the cockpit windshield. So-called
heads-up surgery requires the surgeon to view the image electronically with significantly reduced resolution and contrast. HD
TV has 1920x1080 = 2,073,600 pixels = 1.98 megapixels, and
4K UHD television has 8.29 megapixels, while the human eye
produces 575 megapixels.
The dynamic range of the human eye is 90 dB, orders of
magnitude greater than current video systems’ LCD displays.
OLED displays have a very high dynamic range but are much
more costly and not utilized in the commercially available headsup surgery system. CCD and even CMOS cameras have less
dynamic range than the human eye and produce HDR (high
dynamic range) video only by using different gains on a sequence
of frames.
The color gamut of LCD or LED displays is somewhat restrictive compared to human vision, in part because of television
recording and broadcasting bandwidth limits. In addition, LCD
displays alter color appearance based on viewing angles.
The measured depth of field with so-called heads-up surgery
is half as much as operating microscope viewing, a crucial disadvantage for vitreomacular surgery in particular.
There are other significant disadvantages of so-called headsup surgery: flat panel displays often collect dust and finger prints
on the display surface. Reflected light from monitoring and
surgical equipment displays and LEDs may also interfere with
optimal visualization of the display. Operating microscope visualization is never affected by glare or ambient lighting.
In summary, why should the surgeon trade reduced image
quality for a solution to a nonexistent ergonomic problem driven
by marketing hype?
2015 Subspecialty Day | Retina
Section II: Vitreoretinal Surgery, Part I
31
The Timing of Vitrectomy for Retained Lens Material
Is Critical: Pro
Michael W Stewart MD
The first cases of retained lens fragments (RLF) surfaced when
phacoemulsification lensectomy gained popularity in the 1980s,
and the number of subsequent reports has increased steadily.
Appropriate postoperative medical and surgical management
produces excellent anatomic and visual outcomes for most
patients, but permanent vision loss still plagues a significant
minority. Since most patients undergoing cataract surgery have
lofty expectations, unfavorable outcomes due to RLF create significant discontent and frequent medical malpractice lawsuits.
Immediate, early, delayed, and late removal of RLF has been
described, with some authors even advocating prolonged observation for eyes that appear stable. Superior visual outcomes
after immediate or early vitrectomy have been reported, whereas
large, nonrandomized, single-institution series show similar
visual outcomes regardless of the timing of vitrectomy. Much
confusion is due to varying definitions of “delayed vitrectomy,”
which range from several weeks to several years. Perhaps the
only position shared by all authors concerns the need to carefully
and frequently monitor patients, with a low threshold for secondary vitrectomy.
To better understand the wealth of reported data, a systematic review of the literature was performed with subsequent
meta-analyses. The following recommendations regarding the
optimal timing of vitrectomy were developed:
1. Immediate vitrectomy (without moving or transferring the
patient) produces excellent results and may be considered
if equipment and personnel are available.
2. Delayed same-day vitrectomy (after patient transfer), and
vitrectomy performed during the following 2 days produces poorer results.
3. Early vitrectomy performed 3-7 (and perhaps up to 14)
days after cataract surgery produces excellent results, on
par with immediate vitrectomy.
4. Delayed vitrectomy beyond 14 days is associated with
increased risks of poor vision (< 20/200), not good vision
(< 20/40), retinal detachment, glaucoma, corneal edema,
and increased intraocular inflammation. The longer the
delay to vitrectomy, the greater the likelihood of complications.
The timing of vitrectomy often matters, and to mitigate risk
surgeons should consider immediate vitrectomy or early delayed
vitrectomy (3-7 days).
32
Section II: Vitreoretinal Surgery, Part I
2015 Subspecialty Day | Retina
The Timing of Vitrectomy for Retained Lens
Fragments Is Critical: Con
Caroline Baumal MD
I will present you with the science and the practical issues to
show that timing is not critical.
B. Early PPV
1. Cornea stromal edema, poor visualization may
lead to incomplete lens removal, inadequate PPV,
more risk of peripheral tears, retinal detachment
2. Inability to put in an anterior chamber IOL or
TS-IOL
3. Intraocular inflammation
I.Background
Retained lens fragments (RLF) after cataract surgery
II.Incidence
A. ICD-10 code RLF
B. Complications of RLF: reduced vision, floaters,
inflammation, elevated IOP, cystoid macular edema,
cornea edema
VI. Strategy for RLF for Best Clinical Results
A. Quiet the eye
III. Indications for RLF Removal
IV. Timing of Pars Plana Vitrectomy (PPV) for RLF: The
Science
B. Expect inflammation and IOP rise, treat prophylactically
C. Added benefit of PVD, clear cornea, better results
D. Planned PPV
A. Numerous clinical studies on this topic
B. What have these shown??
VII. Timing of PPV for RLF Is Not Critical
1. Equivocal results
A. Not supported by the science
2. No study has definitively shown that immediate
PPV yields better results (better acuity/less complications) than planned PPV.
B. Not practical
C. Large meta-analysis
V. Timing of PPV for RLF: Practical Issues
A. Immediate PPV
1. Feasibility in the OR
2. Proximity to a retinal surgeon
3. Availability: Can you just pop over to your surgical center to perform PPV the moment a lens
drops and leave the 60 patients awaiting antiVEGF injection in your office?
4. Informed consent: under the drapes?
Selected Readings
1. Scott IU, Flynn HW Jr, Smiddy WE, et al. Clinical features and outcomes of pars plana vitrectomy in patients with retained lens fragments. Ophthalmology 2003; 110:1567.
2. Vanner EA, Stewart MW. Meta-analysis comparing same-day versus delayed vitrectomy clinical outcomes for intravitreal retained
lens fragments after age-related cataract surgery. Clin Ophthalmol.
2014; 8:2261.
2015 Subspecialty Day | Retina
Section II: Vitreoretinal Surgery, Part I
Pars Plana Vitrectomy for Diabetic Macular Edema
Without Vitreomacular Traction Is Useful: Pro
David F Williams MD
It is fortunate that today we have multiple therapeutic options
to treat diabetic macular edema, including photocoagulation,
medications, including anti-VEGF drugs and a variety of steroid preparations, and surgical approaches utilizing vitrectomy.
Individual eyes may respond variably to each of these treatments, necessitating a flexible therapeutic approach to maximize
long-term visual outcomes across a diverse patient population.
Despite the proliferation of new pharmacological therapies, a
surgical approach utilizing vitrectomy surgery still plays a valuable role in select cases.
Selected Reading
1. Bonnin S, Sandali O, Bonnel S, et al. Vitrectomy with internal limiting membrane peeling for tractional and nontractional diabetic
macular edema: long-term results of a comparative study. Retina
2015; 35:921-928.
33
34
Section II: Vitreoretinal Surgery, Part I
2015 Subspecialty Day | Retina
Pars Plana Vitrectomy for Diabetic Macular Edema
Without Vitreomacular Traction Is Useful: Con
Darius M Moshfeghi MD
NOTES
Advocating for Patients
2015 Subspecialty Day | Retina
35
2015 Advocating for Patients
John Wells III MD
Ophthalmology’s goal in protecting quality patient eye care
remains a key priority for the Academy. All ophthalmologists
should consider their contributions to the following three funds
as (a) part of their costs of doing business and (b) their individual
responsibility in advocating for patients and their profession:
• Surgical Scope Fund (SSF)
• OPHTHPAC® Fund
• State Eye PAC
Your ophthalmologist colleagues serving on Academy committees—the Surgical Scope Fund Committee and the Secretariat
for State Affairs and OPHTHPAC Committee—are committing
many hours on your behalf. The Secretariat for State Affairs is
collaborating closely with state ophthalmology society leaders
to protect Surgery by Surgeons at the state level. Meanwhile, the
OPHTHPAC Committee is hard at work identifying congressional advocates in each state to maintain close relationships with
federal legislators in order to advance ophthalmology and patient
causes. Both groups’ ultimate goals are to ensure robust funds
for both the SSF and the OPHTHPAC Fund so that they are able
to (a) protect quality patient eye care, (b) protect ophthalmology
practices from payment cuts, (c) reduce burdensome regulations,
and (d) advance the profession by promoting funding for vision
research and expanded inclusion of ophthalmology in public and
private programs.
These committed ophthalmologists serving on your behalf
have a simple message to convey:
“We also need you”!
• We need you to contribute to each of these 3 funds.
• We need you to establish relationships with state and federal legislators.
• We need you to help us protect quality patient eye care
and the profession.
Surgical Scope Fund
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
campaign—in partnership with state ophthalmology societies
and with support from the SSF—has helped 32 state/territorial
ophthalmology societies reject optometric surgery proposals.
As of July 1, 2015, the Secretariat for State Affairs, in collaboration with the California Academy of Eye Physicians and
Surgeons (CAEPS) and the California Medical Society, continues
to battle an onerous optometric surgery scope of practice bill
(SB 622) in the Golden State. The Secretariat has reached out
to all ophthalmology subspecialty society partners to help in
this effort, and several have stepped up to the plate. In addition,
ophthalmology leaders at California academic institutions have
played a critical role by voicing their concerns about the California surgery bill and the impact it would have on quality eye
care for patients. A June 24 op-ed in the San Francisco Examiner
aptly focused on these leaders’ concerns with its headline “Quality surgical eye care ensured through training.” CAEPS has benefitted from contributions to the SSF, having received significant
support from the fund.
Other state ophthalmology societies have also benefitted from
SSF distributions in 2015 and were able to successfully implement patient safety advocacy campaigns to defeat attempts by
optometry to expand its scope of practice to include surgery. The
Texas Ophthalmological Association was successful in its patient
advocacy and public education efforts to defeat three different
optometric-backed surgical scope expansion bills in the Texas
state legislature.
In addition, the Academy supported the Alaska Society of Eye
Physicians and Surgeons in opposing optometric surgery scope
legislation that posed a threat to patient surgical care. If enacted,
the optometric surgery bill would have authorized optometrists
in Alaska to perform surgery with lasers, scalpels, and needles,
and to perform other surgical procedures. The legislation would
also have allowed optometrists to perform all injections except
intravitreal and to prescribe any controlled substances. Thanks
to an effective Surgery by Surgeons advocacy campaign, with
support from the SSF, this legislation died in committee. The
Alaska state legislature adjourned for the year on April 27.
The Academy relies not only on the financial contributions
to the SSF from individual ophthalmologists and their business
practices, but also on the contributions made by ophthalmic
state, subspecialty, and specialized interest societies. The American Society of Retina Specialists (ASRS), the Macula Society,
and the Retina Society contributed to the Surgical Scope Fund in
2014, and the Academy counts on their contributions in 2015.
OPHTHPAC® Fund
OPHTHPAC is a crucial part of the Academy’s strategy to
protect and advance ophthalmology’s interests in key areas
including physician payments from Medicare, as well as to
protect 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 and is 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. Among the significant achievements of OPHTHPAC
are the following:
• Repealed the flawed Sustainable Growth Rate (SGR)
­formula
• Blocked the unbundling of the Medicare global surgery fee
period
• Removed a provision in fraud and abuse legislation that
targeted eyelid surgery
• Protected your ability to perform in-office ancillary services
36
Advocating for Patients
2015 Subspecialty Day | Retina
Surgical Scope Fund
OPHTHPAC® Fund
State Eye PAC
To derail optometric surgical scope of practice
initiatives that threaten patient eye safety and
quality of surgical care
Ophthalmology’s interests at the federal level
Support for candidates for State House and
Senate
Political grassroots activities, lobbyists and
media
Campaign contributions, legislative education
Campaign contributions, legislative education
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.
Support for candidates for U.S. Congress
No funds may be used for candidates or PACs.
Contributions: Unlimited
Individual, practice, and organization
Contributions are 100% confidential.
• Working to reduce the burdens from Medicare’s existing quality improvement programs such as the Electronic
Health Record Meaningful Use program
• Working in collaboration with subspecialty societies to
preserve access to compounded and repackaged drugs
such as bevacizumab
Leaders of the three retina societies are part of the American
Academy of Ophthalmology’s Ophthalmic Advocacy Leadership
Group (OALG), which has met for the past eight years in January in the Washington D.C. area to provide critical input and to
discuss and collaborate on the Academy’s advocacy agenda. The
topics discussed at the 2015 OALG meeting included collaborative efforts on the IRIS registry and quality reporting under Medicare. As 2015 Congressional Advocacy Day (CAD) partners,
the three retina societies ensured a strong presence of retina specialists to support ophthalmology’s priorities as nearly 400 Eye
M.D.s had scheduled CAD visits to members of Congress in conjunction with the Academy’s 2015 Mid-Year Forum in Washington, D.C. The three retina societies remain crucial partners with
the Academy in its ongoing federal and state advocacy initiatives.
State Eye PAC
It is also important for all ophthalmologists to support our
respective State Eye PACs because state ophthalmology societies cannot count on the Academy’s SSF alone. The presence of a
strong State Eye PAC providing financial support for campaign
contributions and legislative education to elect ophthalmologyfriendly candidates to the state legislature is also critical. The
Secretariat for State Affairs strategizes with state ophthalmology
societies on target goals for State Eye PAC levels.
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 should be considered the costs of doing
business. SSF contributions are completely confidential and
may be made with corporate checks or credit cards, unlike PAC
contributions, which must be made by individuals and which are
subject to reporting requirements.
Please respond to your Academy colleagues who are volunteering their time on your behalf to serve on the OPHTHPAC*
and Surgical Scope Fund** Committees, as well as your state
ophthalmology society leaders, when they call on you and your
subspecialty society to contribute. Advocate for your patients
now!
*OPHTHPAC Committee
Donald J Cinotti MD (NJ) – Chair
Janet A Betchkal MD (FL)
William S Clifford MD (KS)
Robert A Copeland Jr MD (Washington DC)
Anna Luisa Di Lorenzo MD (MI)
Sidney K Gicheru MD (TX)
Michael L Gilbert MD (WA)
Gary S Hirshfield MD (NY)
Jeff S Maltzman MD (AZ)
Thomas J McPhee MD (AZ)
Lisa Nijm MD JD (IL)
Andrew J Packer MD (CT)
Diana R Shiba MD (CA)
Woodford S Van Meter MD (KY)
John (“Jack”) A Wells III MD (SC)
Ex Officio Members
Daniel J Briceland MD (AZ)
Michael X Repka MD (MD)
Russell Van Gelder MD PhD (WA)
George A Williams MD (MI)
**Surgical Scope Fund Committee
Thomas A Graul MD (NE) – Chair
Arezo Amirikia MD (MI)
Matthew F Appenzeller MD (NC)
Ronald A Braswell MD (MS)
John P Holds MD (MO)
Cecily A Lesko MD FACS (NJ)
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)
2015 Subspecialty Day | Retina
The Charles L Schepens MD Lecture
37
Digital Medicine: Implications for Retina and Beyond
Mark S Blumenkranz MD MMS
We are entering a brave and relatively uncharted new world of
medicine in which the massive body of data enabled by digital
technologies will not only inform but also dictate decision making and payment for health-care services. It has been posited that
digital health care, enabled by biosensors and wireless communications, will be the critical factor that moves us from an era of
high-tech, high-cost, but low-access care to high-tech, low-cost,
and high-access care that is improved even further by reduction
in waste and inefficiency.
Ophthalmology is one of the subspecialties that is likely to
be most affected because of the demographics of our patients,
who tend to be elderly and to suffer from chronic conditions
that require frequent office visits for monitoring and therapeutic
intervention at unpredictable intervals. This is further exacerbated by our use of sophisticated diagnostic imaging studies,
expensive biopharmaceuticals, and precision laser-based therapies to treat those conditions. It has been estimated that although
currently annual expenditures are in the range of $100 hundred
million dollars or less in the United States, spending on remote
patient monitoring is likely to rise to greater than $14.5 billion in
the near term.
I will focus my remarks on recent developments in digital
ophthalmology, including remote monitoring of chronic diseases
such as diabetic retinopathy and macular degeneration, new
applications in public health for underserved populations, the
enablement of more cost-efficient drug development protocols,
and finally new care paradigms for other chronic diseases like
glaucoma that harness the power of big data and allow true personalized medicine to become a reality.
38
Section III: The Business of Retina
2015 Subspecialty Day | Retina
Retinal Outcome Measures: Why? How?
William L Rich III MD FACS
Why?
Why are we as a profession discussing the issue of retinal performance measures? Probably the best reason was stated by
Lord Kelvin in the nineteenth century: “If you can’t measure
it, you can’t improve.” Our profession is uniquely positioned
to improve quality, outcomes, and further research into retinal
disease. It is part of our heritage. The American Academy of
Ophthalmology was one of the first specialty organizations to
develop an evidence base, in 1985 publishing the first ophthalmic
guidelines, or Preferred Practice Patterns. In order to develop
benchmarks for performance improvement, the Academy in
1995 initiated the National Eye Outcomes Network, a national
ophthalmic surgical outcomes registry. It was paper-based, it
played havoc with office work flow, and no one wanted the
data! It was closed in 1998.
Times have changed. Enter federal regulatory programs for
quality reporting. Since early in President George W. Bush’s
administration there has been a bipartisan push to move away
from fee for service medicine and toward pay for value in federal
health-care programs, with “value” defined as the cost of providing quality care. The first quality requirement included reporting on 50% of a physician’s Medicare patients on three process
measures. Following passage of the HiTech Act in 2008 things
became much more complicated. Physicians were stimulated to
“e-prescribe,” adopt EHR, and meet onerous Meaningful Use
Criteria. The passage of the Affordable Care Act included a mandate that the Centers for Medicare and Medicaid Services (CMS)
pay all physicians on the basis of their quality and cost by 2017.
Failure to meet Meaningful Use and Physician Quality Reporting System (PQRS) requirements in 2015 will result in an 11%
reduction in Medicare fees in 2017, with ongoing penalties for at
least a decade.
How?
How do we as a profession meet these complex regulatory
requirements while continuing on our mission to improve quality
and outcomes? The profession has met this demand by developing, first, retinal process measures and, more recently, outcomes
measures, establishing the Intelligent Research in Sight (IRIS)
Registry to calculate performance and help the subspecialty
financially. In 2007 the Academy worked with ophthalmic
subspecialists to develop nine process measures (four in retina)
that were endorsed by the National Quality Forum, accepted by
CMS, and used in 2012 for the first phase of quality reporting.
Now in 2015 physicians are mandated to report on nine quality
measures, across three quality domains.
One complicating factor was the failure of the National Quality Forum in 2013 to continue endorsement of the four retinal
process measures; only new valid outcomes measures would be
approved. The move to meet this critical need was initiated by
the Academy with a successful appeal to CMS to reinstate the
removed measures and to develop new measures by the IRIS
Registry Measure Work Group.
The glide path to measure design must involve specialty
physicians knowledgeable in the arcane process of measure
development. The IRIS retinal work group members, Mathew
MacCumber MD PhD, John Thompson MD, and Suber Huang
MD, are leaders of retinal subspecialty societies and familiar
with the principles of measure development. After a review of
the evidence base, several new retinal outcomes measures were
developed over 15 months and are available for use this year in
the IRIS Registry. Like all outcome measures, they are registry
reported and all had to be electronically specified for EHR use.
For 2015 there are now six retinal PQRS measures (four process
and two outcome) and 11 IRIS outcome measures. IRIS includes
performance measures for patients with diabetic retinopathy,
exudative AMD, and retinal detachment repair. All these measures will be presented at the 2015 Retina Subspecialty Day
meeting and are available for review on the Academy website.
These new retinal measures include validated tools to capture
patient satisfaction and patient-reported outcomes.
There are painful examples of how lack of adherence to good
science, a poor understanding of the technical demands of measure design, or failure to electronically specify and field test data
for EHRs can lead to disastrous implementation. Four outcomes
measures submitted by a small group of eye teaching hospitals
failed to follow these accepted steps for developing measures,
and all were grievously flawed. PQRS measure 384 is a measure
of the percentage of rhegmatogenous detachments that remain
reattached after one procedure. The narrative says it includes
complex detachments, but the denominator lists 68113—repair
of complex detachment—as an exclusion! The IRIS Measure
Group will take over these four measures next year, but it is too
late to correct them for 2015. However, IRIS Measures 14 and
15, which are well designed and address retinal detachment outcomes, are available in 2015.
The use of these new retinal outcomes measures that are
calculated in IRIS and downloaded to the retinal specialist’s
individual dashboard will allow Eye M.D.s to compare their
performance to a national benchmark with over 8,000 ophthalmologists. As of June 15, 2015, the IRIS Registry included data
on over 30 million charts from 9.8 million patients. A powerful
data repository!
In summary, with the use of outcomes measures and a registry, retinal specialists will have the tools to measure and improve
their performance and outcomes, meet onerous regulatory
requirements, compare registry results with our international colleagues, and participate in research.
Section III: The Business of Retina
2015 Subspecialty Day | Retina
39
How Drugs and Devices Get Approved
Wiley A Chambers MD
I. What does the FDA regulate?
A. Food, Drug & Cosmetic (FD&C) Act provides for
regulation of interstate commerce and prohibits
interstate transportation of unapproved new drug
products.
1. Drugs: Section 505 of FD&C Act
2. Biologics: Public Health Service Act
3. Devices: Section 510 of FD&C Act
B. New products
1. Approval of new drug products: “New drug” is
after 1938.
2. Old drugs that were changed after 1938 are considered “new drugs.”
C. What is not regulated?
1.Procedures
2. Old drugs (drugs unchanged in manufacture or
use since 1938)
3. Practice of medicine
2. The study uses a design that permits a valid comparison with a control to provide a quantitative
assessment of drug effect.
3. The method of selection of subjects provides
adequate assurance that subjects have the disease
or condition being studied.
4. The method of assigning patients to treatment and control groups minimizes bias and is
intended to ensure comparability of the groups.
5. Adequate measures are taken to minimize bias
on the part of the subjects, observers, and analysts.
6. The methods of assessment of subjects’ response
are well defined and reliable.
7. Analysis of the study results is adequate to assess
the effects of the drug.
B. Usual expectation is that the finding will be demonstrated in more than one trial. Can be exceptions,
but the general expectation is at least two trials.
C. Finding should be unlikely to be due to chance.
a. Use of drug products in approved indications
1. Two-sided testing is commonly expected.
b. Use of drug products for unlabeled indication
when it is in the patient’s best interest
2. 95% confidence interval is commonly expected,
P < .05.
c. It is not the practice of medicine to conduct
studies for unlabeled indications.
3. Statistical adjustments are recommended to be
made for any “look” at the data, including any
safety look, whether or not the data is unmasked.
II. Needed for Approval
A. Methods used in manufacture of the product are
sufficient to ensure its identity, strength, quality,
purity, stability, and bioavailability.
B. Facilities are adherent to current good manufacturing practices.
C. Nonclinical studies to address risks not adequately
addressed in clinical studies
D. There is substantial evidence that the drug will
have the effect it is purported or represented to
have under the conditions of use prescribed, recommended, or suggested in the proposed labeling.
D. Superiority to a concurrent control is expected to be
demonstrated unless a noninferiority margin can be
supported.
IV. Potential Ophthalmic Endpoints
A.Anatomic
E. Benefits outweigh the risks when the drug product is
taken by the intended population as labeled.
F. Adequate labeling
III. Substantial Evidence
A. Adequate and well-controlled investigations / clinical trials (usually at least two)
1. There is a clear statement of the objectives of the
investigation.
1. Improvement of diabetic retinopathy (based on
photographs): Two-step change on Early Treatment Diabetic Retinopathy Study (ETDRS) Retinopathy Scale
a. Lucentis (ranibizumab) injection: Diabetic
retinopathy in patients with diabetic macular
edema (DR in DME)
b. Eylea (aflibercept) injection: Diabetic retino­
pathy in patients with diabetic macular edema
(DR in DME)
2. Prevention of diabetic retinopathy progression
(based on photographs)
3. Prevention of CMV retinitis progression (based
on photographs). Example, Cytovene (ganciclovir sodium for injection)
40
Section III: The Business of Retina
4. Prevention of retinal detachment (clinical examination)
5. Slowing the rate of progression of an area
affected by geographic atrophy (ie, slowing loss
of photoreceptors)
2015 Subspecialty Day | Retina
B. Subjective with interpretation: Visual function
1. Visual acuity: Doubling of the visual angle (eg,
20/40 to 20/20)
a. Lucentis (ranibizumab) injection: Macular
degeneration, macular edema following retinal vein occlusion, diabetic macular edema
b. Eylea (aflibercept) injection: Macular degeneration, macular edema following retinal vein
occlusion, diabetic macular edema
2. Color vision
3. Visual fields: Slow or prevent visual field loss
(measurable change in 5 or more field points)
E. Patient reported: Multiple questions and/or domains
1. Visual function questionnaire (National Eye
Institute Visual Function Questionnaire, NEI
VFQ): Not currently externally validated (qualified)
2. Ocular Surface Disease Index (OSDI): Externally
validated
F. How much is clinically important?
a. IOP: 1-mmHg change
b. Refractive power: 0.1 D change
c. Pupil size: 0.2-mm change
d. Tear production: 1-mm change on Schirmer
test
2. Examples of endpoints measured and considered
clinically important
4. Contrast sensitivity
1.IOP
a. Numerous beta-blockers
b. Numerous prostaglandin analogs
c. Numerous carbonic anhydrase inhibitors
2. Refractive power
3. Pupil size
a. Atropine ophthalmic solution
b. Phenylephrine ophthalmic solution
4. Tear production: Restasis (cyclosporine ophthalmic emulsion)
1.Pain
a. Lidocaine hydrochloride ophthalmic gel
b. Proparacaine hydrochloride ophthalmic solution
a. Multiple antihistamines
b. Multiple mast cell stabilizers
3. Ocular irritation
a. Doubling of the visual angle in best corrected
distance visual acuity, often a 3-line change
b. Maintenance of pupil size of 5-6 mm in the
presence of a light stimulus
1. An endpoint “that is reasonably likely, based on
epidemiologic, therapeutic, pathophysiologic, or
other evidence, to predict clinical benefit.”
2. Must be used for a condition that is a serious or
life-threatening illness
3. Must demonstrate a meaningful benefit over
existing treatments
4. Requirement to study the drug post-approval to
“verify and describe its clinical benefit”
V. Application Submitted Requesting Approval to Market
A. Submitted to FDA when the sponsor of the studies believes that there is adequate evidence to
support the application
B. If after review the FDA agrees, application is
approved and product can be marketed.
C. Common reason that an product is not
approved: Application never submitted.
2.Itching
G. Surrogate endpoints
D. Patient reported: Single item
C.Objective
1. Examples of endpoints may be measurable, but
not clinically important.
Section III: The Business of Retina
2015 Subspecialty Day | Retina
41
The Gap in Global Health Care Delivery
David W Parke II MD
Health care delivery is frequently viewed through simple lenses:
“Developed nations generally have good access to quality care,
and developing nations generally have poorer access to quality
care.” “U.S. healthcare is really expensive but is of very high
quality.” “Delivery of an adequate amount of quality health care
is generally a matter of economics and government or private
insurance coverage.” Similar statements are frequently made pertaining to eye care in particular.
In reality, as is frequently the case, the truth is far more complex. While developed nations generally have higher quality and
more accessible care, it is not always so. Whereas economics
plays a role, it is not the sole significant driver.
Consider the following. The U.S. health care expenditure
in 2014 was 17.4% of GDP—nearly twice as high as the average among other high-income countries. Although spending for
health care in the United States has slowed, it remains higher
than the international average. About one-half of total U.S.
health care cost is labor (physicians, nurses, administrators, etc.).
Physician pay is less than 10% of all health care expenditures,
and nursing compensation is less than 7%. “Increases in the
earnings received by physicians and nurses cannot explain much
of the increase in overall health care expenditures” (Glied et al).
From the “quality perspective,” the United States ranks
around the Organization for Cooperation in Economic Development (OECD) mean for most major health statistics in developed nations. A Commonwealth Fund survey of adults in 11
high-income countries shows that the United States ranks last
on measures of financial access to care and availability of care
on nights and weekends. This difference is income dependent.
High-income Americans rate above the average when compared
to high-income individuals in other countries with regard to care
availability and rating of physicians. However, even high-income
Americans report more financial barriers to care. Seventeen
percent of above-average income Americans report not visiting a
doctor for a problem because of cost, compared with 5% of their
international counterparts. Clearly, income-based disparities (or
gaps) in care exist even in developed nations.
Trust in physicians as leaders has dropped from 73% to 34%
between 1966 and 2012. Faith in individual physician integrity
remains high—about 70% as “high” or “very high.” Public
confidence in the U.S. health care system is low, with only 23%
expressing “a great deal or quite a lot of” confidence in the system. The United States is unique among OECD countries in that
it ranks near the bottom in public trust in country’s physicians
but near the top in patients’ satisfaction with their own medical
treatment.
Disparities in eye care in the United States still exist. Access to
high quality care in certain regions still lags behind more affluent areas. However, the biggest disparities exist among major
regions of the globe and among nations. Consider that, globally, cataract remains the cause of blindness in about one-half of
cases, or nearly 20 million people worldwide. Rates of cataract
surgery vary tremendously country to country.
Retinal diseases, particularly AMD and diabetic retinopathy,
account collectively for less than 10% of world blindness. AMD
in particular is responsible for only about 1% of global visual
impairment despite being the leading cause of irreversible vision
loss in Americans over age 65. Despite the fact that in the United
States, diabetic retinopathy causes more person-years of vision to
be lost than any other disease—and despite the fact that diabetes
mellitus prevalence is increasing worldwide—diabetic retinopathy is the identified cause of visual impairment in less than 1%
of cases worldwide. But health care is local in many respects, and
there are regions where diabetic retinopathy is a major public
health problem. On the other hand, there are areas of the globe
where infectious diseases such as onchocerciasis, trachoma, and
cytomegalovirus retinitis remain major causes of visual impairment and blindness.
The gaps to delivering better care concern us all as physicians,
in part because they have implications for all developed nations.
Consider that Botswana has one ophthalmologist per million
population. The United States has about 61 ophthalmologists per
million, and Greece has 176 per million. In some countries, ophthalmology residency lasts 5-7 years and may not even involve
significant surgical experience. To what extent is this variability
a factor in the access to and delivery of high-quality care?
Big challenges face the global ophthalmology and retina community in the near future pertaining to access, cost, and quality
of care. And all three factors are linked. For example, anti-VEGF
treatment has become a mainstay of therapy for both AMD and
diabetic retinopathy. How should this be financed, apportioned,
and delivered on a global basis? By whom and under what
criteria? How many retina surgeons are needed in developing
countries, and should their retina-specific training differ from
someone practicing in Las Vegas? How can ophthalmologists
and retina subspecialists in particular work with public health
officials and primary care physicians and other health care providers to stratify patients at highest risk and get them into care
networks? What models of retina care work best in different
regions and circumstances? How can we measure the impact of
our individual care and our programs? And (with my Academy
hat squarely in place) how can the Academy with its staff and
technology resources best play an effective role in elevating the
quality of retina care worldwide?
References
1. Glied SA, Ma S, Pearlstein I. Understanding pay differentials among
health professional, nonprofessionals, and their counterparts in
other sectors. Health Aff. 2015; 34:929-935.
2. Organization for Economic Cooperation and Development. OECD
Health Statistics 2014: How Does the United States Compare?
Paris: OECD; 2014.
3. Hartman M, Martin AB, Lassman D, Catlin A. National health
spending in 2013: growth slows, remains in step with the overall
economy. Health Aff. 2015; 34:150-160.
4. Bureau of Economic Analysis. Gross domestic product (GDP) by
industry data. Washington: BEA; 2015. Available from: http://
www/bea.gov/industry/gdpbyind_data.htm.
42
Section III: The Business of Retina
5. Blendon RJ, Benson MA, Hero JO. Public trust in physicians—
U.S. medicine in international perspective. N Engl J Med. 2014;
371:1570-1572.
6. Davis K, Ballreich J. Equitable access to care: how the United States
ranks internationally. N Engl J Med. 2014; 371:1567-1570.
7. Resnikoff S, Felch W, Gauthier TM, Spivey B. The number of ophthalmologists in practice and training worldwide: a growing gap
despite more than 200,000 practitioners. Br J Ophthalmol. 2012;
96:783-787.
8. Pascolini D, Mariotti SP. Global estimates of visual impairment:
2010. Br J Ophthalmol. 2012; 96:614-618.
2015 Subspecialty Day | Retina
2015 Subspecialty Day | Retina
Section III: The Business of Retina
43
Can It Be Less? Strategies for Reducing the Cost of
Health Care
George A Williams MD
Health care in the United States is disproportionately expensive
compared to the rest of the world. National Health Expenditures
(NHE) in 2014 were $3.1 trillion, more than the gross domestic product (GDP) of either France or Great Britain, making
American health care the fifth largest economic enterprise on the
planet.
NHE account for 17.6% of U.S. GDP, nearly 50% higher
than any other developed country. The per capita NHE is double
the average of other developed nations. Importantly, these higher
expenditures are not related to per capita income. Multiple
analyses demonstrate that the primary driver of health-care cost
is the price of individual health care services and that prices are
higher in the United States than anywhere else. There is further
consensus that the current fee for service (FFS) payment system
creates economic distortions and diminishes the value of delivered care. Therefore, both government and commercial payers
have announced payment initiatives and program to reduce costs
and increase value.
For Medicare, the U.S. Department of Health and Human
Services (HHS) has established the goal of tying 50% of FFS
Medicare payments to quality or value by the end of 2018
through alternative payment models (APMs). Under the Affordable Care Act, Medicare now categorizes payment according to
how providers are paid:
Category 1: FFS with no link to quality
Category 2: FFS with a link to quality
Category 3: APM built on FFS
Category 4: Population-based payment
In 2014, CMS estimated that 20% of payments were in categories 3 and 4. The goal is 30% by 2016 and 50% by 2018.
CMS expects less than 10% of payments to be in Category 1 by
2018. CMS recognizes that although it is the largest individual
payer, it must partner with commercial and other public payers
to create system-wide change. CMS therefore has created the
Health Care Payment Learning and Action Network to align
payment policy across sectors.
The results of these programs are increasingly apparent to
ophthalmologists in limited networks, step therapy, accountable
care organizations, and the continuing morass of the Physician
Quality Reporting System, Meaningful Use, and the Value-Based
Modifier. Already ophthalmologists are subject to significant and
increasing penalties under these programs. Although the Medicare Access and CHIP Reauthorization Act (MACRA) meritbased incentive payment system (MIPS) provides some relief in
2019, there are still substantial penalties for failure to achieve
still to-be-determined quality and cost criteria. MACRA provides
further incentives to participate in qualified APM. There is a
5% bonus on all professional services for physicians with 25%
of either revenue or patients through qualified APMs in 2019,
which increases to 75% by 2023. Qualified APMs require the
use of certified EHR, have quality measures, and bear financial
risk.
How ophthalmologists and other specialists will participate in
qualified APMs remains uncertain. The continuing development
of APMs will be framed by the triple aim of (1) improving the
experience of care, (2) improving the health of populations, and
(3) reducing per capita costs of health care.
The obvious question is, can ophthalmology succeed in the
coming reimbursement environment? I believe ophthalmology will not only succeed but thrive. Through ophthalmology’s leadership in outpatient and office-based care, continuing
technological innovations that deliver better clinical outcomes
with improved productivity, qualified clinical data registries
(IRIS), and the unsurpassed impact of ophthalmic services on
our patients’ quality of life, we are the prototype for success in a
quality- and value-based payment system. Although the transition will be difficult and the challenges many, ophthalmology’s
future has never been brighter.
44
Section IV: Late Breaking Developments, Part I
Late Breaking Developments, Part I
NOTES
2015 Subspecialty Day | Retina
2015 Subspecialty Day | Retina
Section V: My Coolest Surgical Video
45
My Coolest Surgical Videos
“Street View” of Macular Surgery
Homemade Chandelier
Cynthia A Toth MD
Laurent Velasque MD
Silicone Oil Retention Sutures in Traumatic Aniridia
Large-Scaled Simple Layer RPE Transplantation for
Hemorrhagic Polypoidal Choroidal Vasculopathy
Ronald C Gentile MD
Zhizhong Ma MD
Cystectomy for Chronic Cystoid Macular Edema
Yu Wakatsuki MD
46
Section VI: Pediatric Retina
2015 Subspecialty Day | Retina
Diagnoses You Cannot Afford to Miss: Retinal Diseases
With Systemic Implications
Gerald Allen Fishman MD
A number of retinal diseases present with systemic implications.
Four such diseases are selected for presentation.
I. Batten Disease (Juvenile-Onset Ceroid Lipofuscinosis):
Clinical Findings
A. Rare autosomal recessive disease
B. Substantial and rapid loss of vision
C. Pigmentary retinal degeneration
D. Intellectual decline
E. Mood and behavioral impairments
2. Clinical suspicion of this disease can lead to
rapid diagnosis, improved care, and avoidance of
unnecessary diagnostic tests.
IV. Angioid Streaks (AS)
A. Clinical findings
1. Angioid-like dehiscences in Bruch membrane
2. Serous and hemorrhagic detachments of the retinal pigment epithelium
3. Choroidal neovascularization (72%-86%) of
eyes
F. Loss of motor skills
4. Visual acuity loss
G. Majority with a CLN3 gene mutation
H. Average survival from symptom onset is 15 years.
5. Half of the cases were found to be associated
with a systemic disease.
6. 59%-87% of AS cases are associated with pseudoxanthoma elasticum (PXE).
7. Associated also with Paget disease and sickle cell
retinopathies, among other diseases
8. Prevalence estimated at 1/25,000 to 1/100,000.
9. When associated with pseudoxanthoma elasticum (Gronblad-Standberg syndrome), AS are
associated with coronary artery disease, peripheral vascular disease, skin changes, and gastrointestinal bleeding.
II. Kjellin Syndrome: Clinical Findings
A. Rare autosomal recessive neuro-ophthalmic syndrome
B. Retinal flecks in the macula
C. Often good visual acuity
D. Normal ERG and EOG
E. Characteristic findings on fluorescein angiography
F. Spastic paraplegia
G.Dementia
H. SPG (spastic paraplegia genes) 11 and 15 identified
1. Laser photocoagulation
III. Methylmalonic Aciduria and Homocystinuria Type C
2. Anti-VEGF intravitreal injection
A. Clinical findings
1. Autosomal recessive disease
2. Mutations in the MMACHC gene identified
3. Most common inborn error of B12 (cobalamin)
metabolism leading to increase in plasma homocysteine
4. Early onset of substantial loss of vision
5. Progressive diffuse pigmentary retinal degeneration
6.Maculopathy
7. Optic atrophy
8. Hematological, cardiovascular, respiratory,
dermatological, cognitive decline, seizure, and
psychiatric abnormalities
9. Occurs in approximately 1/100,000 live births
B.Treatment
1. Hydroxycobalamin, betaine, carnitine
B.Treatment
Selected Readings
Batten disease
1. Williams R, Mole S. New nomenclature and classification scheme
for the neuronal ceroid lipofuscinosis. Neurology 2012; 79:183191.
2. Adams HR, Mink, JW; University of Rochester Batten Center Study
Group. Neurobehavioral features and natural history of juvenile
neuronal ceroid lipofuscinosis (Baten disease). J Child Neurol.
2014; 28:1128-1136.
Kjellin syndrome
3. Kjellin K. Familial spastic paraplegia with amyotrophy, oligophrenia, and central retinal degeneration. Arch Neurol. 1959; 1:133140.
4. Farmer SG, Longstreth WT Jr, Kalina RE, Todorov AB. Fleck
retina in Kjellin’s syndrome. Am J Ophthalmol. 1985; 99:45-50.
5. Frisch IB, Haag P, Steffen H, et al. Kjellin’s syndrome. Ophthalmology 2002; 109:1484-1491.
2015 Subspecialty Day | Retina
Methylmalonic aciduria and homocystinuria type C
6. Lerner-Ellis JP, Tirone JC, Pawelek PD, et al. Identification of the
gene responsible for methylmalonic aciduria and homocystinuria
cblC type. Nat Genetics. 2006; 38:93-100.
7. Gerth C, Morel CF, Feigenbaum A, Levin AV. Ocular phenotype in
patients with methylmalonic aciduria and homocystinuria, cobalamin C type. J AAPOS. 2008; 12:591-596.
8. Gizicki R, Marie-Claude R, Gómez-López L, Orquin J, et al. Longterm visual outcome of methylmalonic aciduria and homocystinuria, cobalamin C type. Ophthalmology 2014; 121:381-386.
Angioid streaks
9. Clarkson JG, Altman RD. Angioid streaks. Surv Ophthalmol.
1982; 26:235-246.
10. Goodman RM, Smith EW, Paton D. Pseudoxanthoma elasticum: a
clinical and histopathological study. Medicine 1963; 42:297-334.
Section VI: Pediatric Retina
47
48
Section VI: Pediatric Retina
2015 Subspecialty Day | Retina
What, When, and Why to Test for Retinal
Degenerations?
Kimberly Drenser MD PhD
Retinal degenerations remain one of the most frustrating diagnoses in regard to appropriate testing and management. It is further
complicated by the lack of satisfactory treatment options available to most patients with degenerative diseases of the retina.
Gene testing can be expensive, time consuming, and, given that
it frequently does not change patient management, useless. With
the advent of viral-mediated gene replacement therapy and
new synthetic replacement molecules, there is a new horizon
for managing and treating inherited retinal degenerations. This
presentation will review the workup and current therapies available or in trials for the treatment of various retinal degenerative
diseases, and therefore, how to better manage your clinic and
these patients.
• Congenital X-linked retinoschisis: Potential gene therapy
for retinoschisin replacement
• Leber congenital amaurosis: Gene therapy for RPE65
replacement
• Wnt-associated vitreoretinopathies: Potential therapeutic
agents for management and treatment
Section VII: Retinal Vein Occlusion
2015 Subspecialty Day | Retina
49
Overview of Current Treatment Options and
Evidence-Based Data
Peter A Campochiaro MD
is reduced. This was true for 3 factors known
to cause vascular leakage.
I.Pathogenesis
A. Critical role of vascular endothelial growth factor
(VEGF)
i. Hepatocyte growth factor (HGF)
1. Macular edema: Mol Ther. 2008; 16:791-799.
ii. Endocrine gland VEGF (EG-VEGF)
2. Intraretinal hemorrhages
iii.Activin-A
a.
Ophthalmology 2011; 118:2041-2049.
These are candidates for contribution to
chronic edema that deserve further study.
b.
Ophthalmology 2011; 118:1594-1602.
3. Retinal nonperfusion: Ophthalmology 2013;
120:795-802.
II.Treatment
A. VEGF neutralizing proteins and short-term outcomes
B Role of other vasoactive proteins
1. ORVO Study
a. Twenty-three central retinal vein occlusion
(CRVO) and 17 branch RVO (BRVO) subjects with edema despite prior anti-VEGF
treatment had aqueous taps at baseline and 4
and 16 weeks after dexamethasone implant.
BCVA and center subfield thickness (CST)
were measured every 4 weeks. Aqueous vasoactive protein levels were measured by protein
array or enzyme-linked immunosorbent assay
(ELISA).
b. Substantial heterogeneity among patients:
RVO patients with macular edema have differences in levels of proteins that are present.
c. However, there are some factors that are
elevated in the majority of patients and are
reduced by dexamethasone implant as edema
1.Ranibizumab
a.BRAVO
i.
Ophthalmology 2010; 117:1102-1112.
ii.
Ophthalmology 2011; 118:2041-2049.
iii. 397 patients with macular edema following BRVO randomized 1:1:1 to monthly
intraocular injections of 0.3 mg or 0.5 mg
of ranibizumab or sham injections.
iv. Month 6 and 12 outcomes: See Tables 1
and 2.
b.CRUISE
i.
Ophthalmology 2010; 117:1124-1133.
ii.
Ophthalmology 2011; 118:1594-1602.
Table 1. BRAVO Month 6 Outcomes
0.3 mg
0.5 mg
Sham
Mean change from baseline BCVA
16.6
18.3
7.3 letters
% gained ≥15 letters in BCVA
55.2
61.1
28.8
% ≥ 20/40
67.9
64.9
41.7
% CST ≤ 250 µm
91.0
84.7
45.5
% rescue grid laser
18.7
19.8
54.5
0.3 mg
0.5 mg
Sham
Mean change from baseline BCVA
16.4
18.3
12.1 letters
% gained ≥15 letters in BCVA
56.0
60.3
43.9
% ≥ 20/40
67.9
66.4
56.8
% CFT ≤ 250 µm
83.6
86.3
78.8
Table 2. BRAVO Month 12 Outcomes
50
Section VII: Retinal Vein Occlusion
2015 Subspecialty Day | Retina
iii. 397 patients with macular edema following BRVO randomized 1:1:1 to monthly
intraocular injections of 0.3 mg or 0.5 mg
of ranibizumab or sham injections.
iv. Month 6 and 12 outcomes: See Tables 3
and 4.
Looking at the slope of change in BCVA
between Months 7 and 15, there was no significant difference between patients treated
p.r.n. and those treated with monthly injections. See Table 5.
In patients who have resolution of edema
after monthly injections for 7 months, outcomes are excellent and there is no difference
between p.r.n. and monthly injections for the
next 8 months.
c.SHORE
202 patients with macular edema secondary
to branch or central RVO received monthly
injections of 0.5-mg ranibizumab starting at
baseline through Month 6. Between Months
7 and 14, subjects were randomized at the
first study visit at which they met vision and
spectral domain OCT (SD-OCT) stability
criteria. Randomization was 1:1 to treatment
with 0.5-mg ranibizumab pro re nata (p.r.n.)
vs. continued monthly injections. Nonrandomized subjects (NR) who did not meet
visual OCT stability criteria) continued to
receive monthly injections and were re-evaluated for randomization the following month.
2.Bevacizumab
a.CRVO
i.
Ophthalmology 2012; 119:184-189.
ii. 60 patients randomized 1:1 to 1.25-mg
bevacizumab or sham (See Table 6 for outcomes.)
Table 3. CRUISE Month 6 Outcomes
0.3 mg
0.5 mg
Sham
Mean change from baseline BCVA
12.7
14.9
0.8 letters
% gained ≥15 letters in BCVA
46.2
47.7
28.8
% ≥ 20/40
43.9
46.9
20.8
% CFT ≤ 250 µm
75.0
76.9
23.1
0.3 mg
0.5 mg
Sham
Mean change from baseline BCVA
13.9
13.9
7.3 letters
% gained ≥15 letters in BCVA
47.0
50.8
33.1
% ≥ 20/40
43.2
43.1
34.6
% CFT ≤ 250 µm
75.8
77.7
70.8
p.r.n.
Monthly
NR
Mean change from baseline BCVA
21.0
18.7
14.5 letters
% gained ≥ 15 letters in BCVA
70.7
66.3
% ≥ 20/40
76.8
71.3
Residual edema
32.9
25.0
Table 4. CRUISE Month 12 Outcomes
Table 5. SHORE Month 15 Outcomes
Table 6. Month 6 Outcomes, CRVO
Bevacizumab
Sham
Mean change from baseline BCVA
14.1
−2.0 letters
% gained ≥ 15 letters in BCVA
60.0
20.0
% no residual edema
86.7
20.0
Section VII: Retinal Vein Occlusion
2015 Subspecialty Day | Retina
b.MARVEL
iv. 189 patients with CRVO randomized 3:2
to 2-mg aflibercept or sham (See Table 8
for outcomes.)
i.
Br J Ophthalmol. 2015; 99:954-959.
ii. 75 patients with BRVO randomized 1:1 to
0.5-mg ranibizumab or 1.25-mg bevacizumab p.r.n. (See Table 7 for outcomes.)
b.GALILEO
i.
Br Med J. 2013; 97:278-284.
ii.
Ophthalmology 2014; 121:202-208.
3.Aflibercept
51
iii.
Am J Ophthalmol. 2014; 158:1032-1038.
a.COPERNICUS
i.
Ophthalmology 2012; 119:1024-1032.
ii.
Am J Ophthalmol. 2013; 115:429-437.
iv. 177 patients randomized 3:2 to aflibercept
2 mg q 4 weeks or sham (See Table 9 for
outcomes.)
iii.
Ophthalmology 2014; 121:1414-1420.
Table 7. MARVEL Month 6 Outcomes
Ranibizumab
Bevacizumab
Mean change from baseline BCVA
18.1
5.6 letters
% gained ≥ 15 letters in BCVA
59.4
57.8
% ≥ 20/40
62.2
68.4
% rescue laser
10.8
21.0
Table 8. COPERNICUS Month 6, 12, and 24 Outcomes
Outcome
Dosage
Treatment Group
Month 6 outcomes
2 mg q 4 weeks
Sham
Mean change from baseline BCVA
17.3
−4.0 letters
% gained ≥ 15 letters in BCVA
56.1
12.3
Month 12 outcomes
2 mg q 4 weeks/p.r.n.
Sham/p.r.n.
Mean change from baseline BCVA
16.2
3.8 letters
% gained ≥ 15 letters in BCVA
55.3
30.1
Month 24 outcomes
2 mg q 4 weeks/p.r.n.
Sham/p.r.n.
Mean change from baseline BCVA
13.0
1.5 letters
% gained ≥ 15 letters in BCVA
49.1
23.3
Table 9. GALILEO Month 6, 12, and 18 Outcomes
Outcome
Dosage
Treatment Group
Month 6 outcomes
2 mg q 4 weeks
Sham
Mean change from baseline BCVA
18.0
3.3 letters
% gained ≥ 15 letters in BCVA
60.2
22.1
Month 12 outcomes
2 mg q 4 weeks/p.r.n.
Sham
Mean change from baseline BCVA
16.9
3.8 letters
% gained ≥ 15 letters in BCVA
60.2
32.4
Month 18 outcomes
2 mg q 4 weeks/p.r.n.
Mean change from baseline BCVA
13.0
1.5 letters
% gained ≥ 15 letters in BCVA
57.3
29.4
52
Section VII: Retinal Vein Occlusion
2015 Subspecialty Day | Retina
c.VIBRANT
i.
Ophthalmology 2015; 122:538-544.
a.
Ophthalmology 2014; 121:209-219.
ii. 183 patients with BRVO randomized 1:1
to aflibercept 2 mg q 4 weeks or grid (See
Table 10 for outcomes.)
B. VEGF neutralizing proteins and long-term outcomes
2.RETAIN
C. Scatter photocoagulation
1.HORIZON
b. Month 49 outcomes, 0.5-mg ranibizumab
p.r.n. (See Table 12 for BRVO and CRVO
outcomes.)
1.RELATE
a.
Ophthalmology 2012; 119:802-809.
a.
Ophthalmology 2015; 122:1426-1437.
b. 304 patients who completed BRAVO and
304 who completed CRUISE. Seen at least
every 3 months, 0.5-mg ranibizumab p.r.n.
Report on patients who completed at least 12
months. (See Table 11.)
b. Scatter photocoagulation did not improve
outcomes or reduce treatment burden. (See
Table 13.)
Table 10. VIBRANT Month 6 Outcomes
2 mg q 4 weeks
Grid
Mean change from baseline BCVA
17.0
6.9 letters
% gained ≥ 15 letters in BCVA
52.7
26.7
Table 11. HORIZON Month 12 Outcomes: Mean Change From Baseline BCVA
0.3/0.5 mg
0.5 mg
Sham/0.5 mg
BRVO
−2.3
−0.7
0.9 letters
CRVO
−5.2
−4.1
−4.1 letters
Table 12. RETAIN Outcomes for BRVO and CRVO
BRVO
50%: Edema Resolution
50%: Mean of 3 Injections in Year 4
Mean BCVA improvement of 22.9 letters
Mean BCVA improvement of 18.4 letters
Mean BCVA = 20/32
Mean BCVA = 20/32
BCVA ≥ 20/40 in 80%
BCVA ≥ 20/40 in 80%
CRVO
44%: Edema Resolution
56%: Mean of 6 Injections in Year 4
Mean BCVA improvement of 25.2 letters
Mean BCVA improvement of 4.3 letters
Mean BCVA = 20/40
Mean BCVA = 20/63
BCVA ≥ 20/40 in 64%
BCVA ≥ 20/40 in 28%
Table 13. RELATE Outcomes for CRVO and BRVO
Change From Randomization BCVA
Week 48
Week 96
Week 144
CRVO: laser + RBZ p.r.n.
−3.3
+0.69
+0.4
CRVO: RBZ p.r.n.
0
−1.69
−6.7
BRVO: laser + RBZ p.r.n.
−7.5
−2.0
−2.6
BRVO: RBZ p.r.n.
+2.8a
+4.8a
+3.1
aP
≤ .03
RBZ indicates ranibizumab.
Section VII: Retinal Vein Occlusion
2015 Subspecialty Day | Retina
D. Intraocular steroids
III.Recommendations
1. Triamcinolone acetonide: SCORE
Inject VEGF neutralizing protein once a month for 6
months.
a.
Arch Ophthalmol. 2009; 127:1101.
b.
Arch Ophthalmol. 2009; 127:1115.
c. Outcomes (see Table 14)
A. If edema resolved: Trial of p.r.n.; if recurrent edema,
treat and extend.
1. Trial of p.r.n. about every 6 months to see if
injections can be stopped
2. If frequent injections still needed after 2 years,
consider Dex implant, particularly if pseudophakic, but potentially even if phakic.
2. Dexamethasone (Dex) implant: GENEVA
a.
Ophthalmology 2010; 117:1134-1146.
b. 1267 patients with RVO randomized to 0.7mg Dex, 0.35-mg Dex, or Sham (see Table
15)
53
B. Persistent edema despite monthly injections:
Consider Dex implant if pseudophakic, continue
monthly anti-VEGF injections if phakic.
C. Monthly injections for 2 years in phakic patients but
edema still not eliminated: Consider Dex implant.
Table 14. SCORE Outcomes for CRVO and BRVO
CRVO
Month 12
Observation
1 mg q 4 weeks
4 mg q 4 weeks
Mean change from baseline BCVA
−12.1
−1.2
−1.2 letters
% gained ≥15 letters in BCVA
7
27
28
Month 24
Observation
1 mg q 4 weeks
4 mg q 4 weeks
Mean change from baseline BCVA
−10.7
−4.4
−2.4 letters
% gained ≥15 letters in BCVA
9
31
26
Month 12
Grid
1 mg q 4 weeks
4 mg q 4 weeks
Mean change from baseline BCVA
−12.1
−1.2
−1.2 letters
% gained ≥15 letters in BCVA
28.9
25.6
27.2
Month 24
Observation
1 mg q 4 weeks
4 mg q 4 weeks
Mean change from baseline BCVA
−10.7
−4.4
−2.4 letters
% gained ≥15 letters in BCVA
9
31
26
0.35 mg
0.7 mg
Sham
Mean change from baseline BCVA
5.2
5.2
2.5 letters
% gained ≥ 15 letters in BCVA
19
18
22
BRVO
Table 15. GENEVA Month 6 Outcomes
54
Section VIII: DRCRnet Protocols
2015 Subspecialty Day | Retina
DRCRnet Protocol T
Comparative Effectiveness Randomized Clinical Trial of Aflibercept,
Bevacizumab, or Ranibizumab for Diabetic Macular Edema (1-Year Results)
John A Wells III 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 this study.
Diabetic macular edema (DME) affects approximately 750,000
people in the United States and is a leading cause of vision loss.1
Intravitreous injections of antivascular endothelial growth
factor (anti-VEGF) agents have been shown to be superior to
laser, which has been the standard treatment for DME since the
1980s.3-9 Three commonly used anti-VEGF agents have been
shown effective in treating DME: aflibercept, bevacizumab, and
ranibizumab.3,10-13
Prior to the results of this study, the relative efficacy and
safety of these 3 agents in the treatment of DME were unknown.
In 2012, the Diabetic Retinopathy Clinical Research Network
(DRCRnet) initiated a randomized clinical trial to compare the
relative changes in visual acuity (VA) and OCT central subfield
thickness (CST) efficacy, at 1-year, of intravitreous injections of
anti-VEGF agents aflibercept, bevacizumab, or ranibizumab for
treating DME involving the center of the macula.
The study was conducted at 89 sites in the DRCRnet. One
eye of 660 adults with decreased VA from DME involving the
center of the macula, confirmed with an OCT CST time domain
equivalent ≥ 250 µm, was assigned randomly to a standardized
treatment protocol of intravitreous 2.0-mg aflibercept (n = 224),
1.25-mg bevacizumab (n = 218), or 0.3-mg ranibizumab (n =
218). Follow-up visits occurred every 4 weeks. The primary outcome was change in VA at 1 year. Secondary efficacy outcomes
included change in CST on OCT. Follow-up visits occurred every
4 weeks in the first year. Retreatment with anti-VEGF was based
on VA and/or OCT CST changes. After 6 months, if centerinvolved DME persisted and was not improving, focal/grid laser,
if feasible, was added. If the nonstudy eye needed anti-VEGF
treatment, the nonstudy eye received the same agent as the study
eye.
The mean change in VA letter score at 1 year was greater with
aflibercept (+13.3) than bevacizumab (+9.7) or ranibizumab
(+11.2) (see Figure 1). The greater overall effect was driven by
eyes with initial VA of 20/50 or worse (~50% of the cohort) (see
Figure 2). Mean VA letter score improvement in this subgroup
was +18.9 aflibercept, +11.8 bevacizumab, +14.2 ranibizumab
(P-values: aflibercept-bevacizumab < .001, aflibercept-ranibizumab = .003, ranibizumab-bevacizumab = .21). The mean
letter score difference between aflibercept and bevacizumab
was +6.5, equating on a patient level to 63% relatively more
aflibercept- than bevacizumab-treated eyes improving ≥ 15 letters (improvement 67% vs. 41%); a +4.7-letter mean difference
between aflibercept and ranibizumab equates to 34% relatively
more aflibercept- than ranibizumab-treated eyes (improvement
67% vs. 50%). For eyes with initial VA 20/32 to 20/40, mean
change was +8.0 (aflibercept), +7.5 (bevacizumab), and +8.3
(ranibizumab).
Figure 1. Mean change in visual acuity letter score, full cohort.
Figure 2. Mean change in visual acuity letter score: A. baseline BCVA
20/32 to 20/40, B. baseline BCVA 20/50 or worse.
The treatment effect on OCT CSF thickness will be presented.
Information regarding safety will be presented separately.
The median number of injections received, out of a possible
maximum of 13, was 9 in the aflibercept group and 10 in the
bevacizumab and ranibizumab groups (P = .045 for overall
comparison). Focal/grid laser photocoagulation was administered at least once (between 24 and 48 weeks) in 37% of eyes
treated with aflibercept, 56% of eyes with bevacizumab, and
2015 Subspecialty Day | Retina
46% of eyes with ranibizumab (P < .001 for overall comparison). E
­ ndophthalmitis occurred in 0.02% of injections (2 nonstudy eyes treated with study drugs) among 2 study participants
(0.3%). Two study eyes (1%) from each group reported intraocular inflammation. The study did not identify a difference in the
rates of death, hospitalization, serious adverse events, or other
prespecified systemic adverse events, including Anti-Platelet Trialists’ Collaboration (APTC)-defined cardiovascular events.
In conclusion, in eyes with decreased VA from DME, all 3
agents, on average, substantially improved VA. However, the relative effect depends on initial VA. When initial VA loss was mild,
there were no apparent differences, on average, between the 3
treatment groups. However, the worse the initial VA, the greater
the relative advantage of aflibercept over the other 2 agents.
References
1. Varma R, Bressler NM, Goan 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. Randomized trial
evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology
2010; 117:1064-1077 e35.
3. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for
diabetic macular edema: results from 2 Phase III randomized trials:
RISE and RIDE. Ophthalmology 2012; 119:789-801.
4. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of
the ranibizumab for edema of the macula in diabetes (READ-2)
study. Ophthalmology 2010; 117:2146-2151.
5. Scott IU, Edwards A, et al.; Diabetic Retinopathy Clinical Research
Network. A Phase II randomized clinical trial of intravitreal
bevacizumab for diabetic macular edema. Ophthalmology 2007;
114:1860-1867.
Section VIII: DRCRnet Protocols
55
6. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE
study ranibizumab monotherapy or combined with laser versus
laser monotherapy for diabetic macular edema. Ophthalmology
2011; 118:615-625.
7. Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the
management of diabetic macular edema (BOLT study) 12-month
data: report 2. Ophthalmology 2010; 117:1078-1086 e2.
8. Arevalo JF, Sanchez JG, Fromow-Guerra J, et al. Comparison of
two doses of primary intravitreal bevacizumab (Avastin) for diffuse
diabetic macular edema: results from the Pan-American Collaborative Retina Study Group (PACORES) at 12-month follow-up. Graefes Arch Clin Exp Ophthalmol. 2009; 247:735-743.
9. Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the
DA VINCI Study of VEGF Trap-Eye in eyes with diabetic macular
edema. Ophthalmology 2012; 119:1658-1665.
10. Arevalo JF, Lasave AF, Wu L, et al. Intravitreal bevacizumab plus
grid laser photocoagulation or intravitreal bevacizumab or grid
laser photocoagulation for diffuse diabetic macular edema: results
of the Pan-american Collaborative Retina Study Group at 24
months. Retina 2013; 33:403-413.
11. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal
aflibercept for diabetic macular edema. Ophthalmology 2014;
121:2247-2254.
12. Brown DM, Nguyen QD, Marcus DM, et al. Long-term outcomes
of ranibizumab therapy for diabetic macular edema: the 36-month
results from two Phase III trials: RISE and RIDE. Ophthalmology
2013; 120:2013-2022.
13. Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective
randomized controlled trial of intravitreal bevacizumab or laser
therapy (BOLT) in the management of diabetic macular edema:
24-month data: report 3. Arch Ophthalmol. 2012; 130:972-979.
56
Section VIII: DRCRnet Protocols
2015 Subspecialty Day | Retina
DRCRnet Protocol S
Panretinal Photocoagulation vs. Intravitreous Ranibizumab for Proliferative
Diabetic Retinopathy—A Randomized Trial
Jeffrey G Gross MD
I.Background
A. Proliferative diabetic retinopathy (PDR) is a leading
cause of vision loss in people with diabetes mellitus.1,2
B. Panretinal photocoagulation (PRP) has been the
standard treatment for PDR since the Diabetic Retinopathy Study demonstrated its benefit 40 years
ago.3
C. Although effective, PRP is inherently destructive.4-7
Adverse events include:
1. Peripheral visual field loss
2. Decreased night vision
3. Worsening of diabetic macular edema (DME)
C. Primary outcome of this noninferiority study was
mean change in visual acuity from baseline to 2
years (noninferiority margin of 5 letters).
D. Secondary outcomes included proportion of eyes in
the deferred PRP group requiring PRP treatment,
changes in Humphrey visual field, National Eye
Institute Visual Function Questionnaire (NEI VFQ25) assessment, need for supplemental PRP after
completion of initial PRP, need for vitrectomy, and
frequency of vitreous hemorrhage.
E. Follow-up schedule: primary outcome visit at 2
years
1. Baseline to 1 year
D. Anti-vascular endothelial growth factor agents,
when given for DME, decrease the risk of PDR
worsening.
II. Primary Objective
To compare the efficacy and safety of PRP with that
of intravitreous ranibizumab (0.5 mg in 0.05 mL) for
PDR.
i. Visits every 16 weeks
ii. Eyes with DME may be seen more frequently for DME treatment as needed.
iii. Could receive additional PRP if neovascularization (NV) worsened
III.Methods
a. PRP group
b. Ranibizumab group:
i. Visits every 4 weeks to evaluate for PDR
treatment with ranibizumab, eyes simultaneously evaluated for DME treatment.
ii. Following 4 mandatory monthly injections, the NV status was assessed at each
visit. An additional 2 injections were given
unless the NV had resolved.
iii. Subsequently, additional injections were
performed every 4 weeks if the NV was
improving and could be continually
deferred if NV was resolved or remained
stable for 3 consecutive visits.
Study design: Randomized multicenter clinical trial.
A. At 56 sites in the Diabetic Retinopathy Clinical
Research Network (DRCRnet), 394 eyes of 305
adults with PDR and no prior PRP were assigned
randomly to prompt PRP or a standardized treatment protocol of 0.5-mg intravitreous ranibizumab
with deferred PRP if needed.
B. Randomization criteria
1. At least 18 years old
2. Type 1 or type 2 diabetes
3. Study eye meeting all of the following criteria (a
participant may have 2 study eyes)
a.PDR
b. No history of PRP
c. BCVA letter score ≥ 24 (~Snellen equivalent
20/320 or better)
d. Eyes with and without central-involved DME
were eligible but could not have had intravitreous anti-vascular endothelial growth factor
within 2 months or intravitreous or peribulbar steroids within 4 months of enrollment.
2. 1 year to 2 years
a. PRP group
i. Visits every 16 weeks
ii. Eyes with DME may be seen more frequently for DME treatment as needed.
b. Ranibizumab group
i. Visits every 4 weeks to 16 weeks to evaluate for PDR treatment with ranibizumab
ii. Interval was extended if injections for
PDR (and any DME) deferred (“defer and
extend”).
Section VIII: DRCRnet Protocols
2015 Subspecialty Day | Retina
IV.Results
The results of this clinical trial will be presented; however, because of the potential public health impact of
these results, the DRCRnet requests that the results be
presented only after the 2-year primary manuscript is
published, which is expected to occur prior to the 2015
AAO Subspecialty Day Meeting.
A.Randomization
B. Baseline characteristics
1.Participant
2.Ocular
C. Treatment for PDR
D.Efficacy
1. Primary outcome: Change in visual acuity at 2
years
2. OCT central subfield thickness
3. Diabetic retinopathy
E.Safety
V.Conclusions
Conclusions will follow from the results presented.
57
References
1. Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl
J Med. 2012; 366(13):1227-1239.
2. Aiello LP. Angiogenic pathways in diabetic retinopathy. N Engl J
Med. 2005; 353:839-841.
3. Diabetic Retinopathy Study Research Group. Photocoagulation
treatment of proliferative diabetic retinopathy: DRS Report no. 8:
Clinical application of Diabetic Retinopathy Study (DRS) findings.
Ophthalmology 1981; 88(7):583-600.
4. Silva PS, Cavallerano JD, Sun JK, et al. Proliferative diabetic retinopathy. In: Ryan SJ, ed., Retina. 5th ed. Elsevier; 2013.
5. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;
103(12):1796-1806.
6. Diabetic Retinopathy Clinical Research Network. Observational
study of the development of diabetic macular edema following
panretinal (scatter) photocoagulation given in 1 or 4 sittings. Arch
Ophthalmol. 2009; 127(2):132-140.
7. Diabetic Retinopathy Clinical Research Network. Randomized trial
evaluating short-term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema following focal/grid laser for
diabetic macular edema in eyes also receiving panretinal photocoagulation. Retina 2011; 31(6):1009-10027.
58
Section IX: First-time Results of Clinical Trials, Part I
2015 Subspecialty Day | Retina
Squalamine Eye Drops in Retinal Vascular Diseases:
AMD
David S Boyer MD
Introduction
Clinical Study Results
Squalamine lactate is an inhibitor of new blood vessel formation
(angiogenesis) as demonstrated by in vitro and in vivo assays.
Since angiogenesis is implicated in the growth and maintenance
of choroidal neovascularization, squalamine lactate is potentially an attractive development candidate in the treatment of
age-related macular degeneration (AMD), in which blood vessel
proliferation has a role.
The Phase 2 IMPACT study aimed to determine whether topical OHR-102 (0.2% squalamine lactate ophthalmic solution)
administered b.i.d. in combination with ranibizumab (RBZ)
p.r.n. can safely improve visual outcomes and reduce treatment
frequency of RBZ compared to placebo + RBZ p.r.n. monotherapy in patients with treatment-naïve neovascular AMD. The
study was carried out at 23 sites in the United States and enrolled
only treatment-naïve patients with CNV due to AMD measuring
≤ 12 disc areas, OCT central subfield ≥ 300 microns with subretinal fluid or cystoid macular edema, any lesion composition,
and BCVA of 20/40 to 20/320. Patients received RBZ at baseline
and were randomized 1:1 to topical OHR-102 b.i.d. (combination group) or placebo vehicle solution b.i.d. Diabetics without
diabetic retinopathy were included. All patients were followed
monthly for 9 months with strict retreatment criteria. Retreatment with RBZ was performed if OCT demonstrated cystoid
macular edema, intraretinal / subretinal fluid, or RPE elevation.
A total of 142 patients were enrolled into the IMPACT study,
and 128 completed the assessments (modified intention to treat
[mITT] population) through the 9-month visit. Mean baseline
BCVA in all subjects was 59.1 letters (~20/63 Snellen). In the
mITT population with classic containing lesions (OHR-102: n
= 37, RBZ monotherapy: n = 28), 44% of the patients receiving
OHR-102 achieved a ≥ 3-line gain at 9 months, as compared to
29% in the Lucentis monotherapy group. Mean gains in visual
acuity were +11 letters for the OHR-102 combination arm
and +5 letters with RBZ monotherapy, a clinically meaningful
benefit of 6 letters. The mITT data in classic containing lesions
also showed a more pronounced separation between the OHR102 and the RBZ monotherapy groups for those patients who
achieved ≥ 4-line and ≥ 5-line vision gains. Of the patients receiving OHR-102, 22% and 17% achieved ≥ 4-line and ≥ 5-line
gains, respectively, at 9 months, as compared to 7% and 7% for
those who received RBZ monotherapy. The mITT overall population, comprising the patients with either classic containing or
occult only lesions (OHR-102: n = 65, Lucentis monotherapy: n
= 63), demonstrated a lesser benefit, with patients gaining +7.8
letters for the OHR-102 combination arm and +5.3 letters for
RBZ monotherapy. Additional data on visual acuity outcomes
based on lesion size and characteristics will be presented. There
was no difference in frequency of RBZ retreatment between
the groups. OHR-102 was generally well tolerated, with only 2
treatment-related discontinuations in the study.
Background
Squalamine lactate inhibits angiogenesis in tumor and in ocular
angiogenesis models by a long-lived intracellular mechanism of
action. The mechanism of action results from the specific entry of
squalamine lactate into activated endothelial cells through membrane invaginations known as “caveolae” and the subsequent
binding and chaperoning of calmodulin by squalamine to an
intracellular membrane compartment. This unique mechanism,
utilizing a unique calmodulin binding site, has 3 principal antiangiogenic effects on endothelial cells: (1) blockage of cell signals
from multiple growth factors including vascular endothelial
growth factor (VEGF), platelet-derived growth factor (PDGF),
and basic fibroblastic growth factor (bFGF), altering cellular
activation and cell division, (2) inhibition of the function of surface integrin alpha-v-beta-3, altering cell-cell interactions, and (3)
alteration of the cytoskeleton structure, decreasing motility.
Squalamine lactate administered intraperitoneally was shown
to inhibit choroidal neovascular membrane (CNVM) development in an animal model using laser-induced CNV in rats.
Additional supportive nonclinical results were seen in a mouse
model of oxygen-induced retinopathy (OIR) that is a model of
the human form of ROP. Single-dose squalamine lactate, as well
as 5-day treatment, improved retinal neovascularization and did
not appear to adversely affect the general health or retinal vascular development of neonatal mice. In another set of experiments
using the OIR model in mice, retinal neovascularization with
late squalamine lactate treatment was arrested or regressed. In
a separate arm of the study, early squalamine lactate treatment,
at all doses, inhibited retinal neovascularization in this model of
retinopathy.
Iris neovascularization was created in cynomolgus monkeys
by occluding retinal veins with an argon laser and then inducing
persistent hypotony by placement of a 4-0 central corneal suture.
Intravenous (IV) infusion of squalamine led to inhibition of the
development of iris neovascularization and partial regression of
new vessels in this experimental model of iris neovascularization.
Phase 2 data on IV squalamine lactate in wet AMD have
shown a dose-related improvement in visual acuity which in the
40-mg weekly dose groups reached clinical significance (Studies
MSI-1256F-106, -207, -208, and -209). Squalamine was administered at weekly intervals for 4 weeks, with monthly doses thereafter for 52 weeks (Studies MSI-1256F, -208, and -209).
Conclusions
The results of the IMPACT study demonstrate that topically
administered OHR-102 combination therapy may lead to
improved visual function in some patients with wet AMD where
lesions contain some component of classic CNV. Importantly,
lesion size and composition play a key role in determining outcomes for OHR-102 and other combination therapies.
2015 Subspecialty Day | Retina
Section IX: First-time Results of Clinical Trials, Part I
59
Selected Readings
1. Bonn D. Blocking angiogenesis in diabetic retinopathy. Lancet
1996; 348(9027):604.
7. Genaidy M, Kazi AA, Peyman GA, et al. Effect of squalamine on
iris neovascularization in monkeys. Retina 2002; 22(6):772-778.
2. Chen Q. Squalamine inhibition of endothelial cell function is associated with modulation of calmodulin-dependent signal transduction
events. Unpublished data. Jan. 20, 2004; A-1001:1-48.
8. Higgins RD, Sanders RJ, Yan Y, Zasloff M, Williams JI. Squalamine improves retinal neovascularization. Invest Ophthalmol Vis
Sci. 2000; 41(6):1507-1512.
3. Ciulla TA, Criswell MH, Danis RP, Williams JI, McLane MP, Holroyd KJ. Squalamine lactate reduces choroidal neovascularization
in a laser-injury mode in the rat. Retina 2003; 23(6):808-814.
9. Higgins RD, Yan Y, Geng Y, Zasloff M, Williams JI. Regression of
retinopathy by squalamine in a mouse model. Pediatr Res. 2004;
56(1):144-149.
4. Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston: Clinical applications of research on angiogenesis. N Engl J
Med. 1995; 333(26):1757-1763.
10. Li D, Williams JI, Pietras RJ. Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or without
HER-2 gene overexpression. Oncogene 2002; 21(18):2805-2814.
5. Folkman J, Kalluri R. Tumor angiogenesis. In: Kufe DW, Pollock
RE, Weichselbaum RR, et al., eds. Holland-Frei Cancer Medicine,
6th ed. Hamilton, Ontario: BC Decker; 2003:161-194.
11. McLane M. Anti-angiogenic effects of squalamine on laser-induced
choroidal or hypoxia induced retinal neovascularization in rats.
A-1002. Unpublished data. Jan. 20, 2004; A-1001:1-48.
6. Fontanini G, Lucchi M, Vignati S, et al. Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: a prospective study. J Natl Cancer Inst. 1997; 89(12):881-886.
12. O’Brien PC, Fleming TR. A multiple testing procedure for clinical
trials. Biometrics 1979; 35:549-556.
60
Section IX: First-time Results of Clinical Trials, Part I
2015 Subspecialty Day | Retina
AVA-101 Gene Therapy for Neovascular AMD:
Fifty-Two-Week Trial Results From the Phase 2a
Clinical Trial
A Phase 2a Controlled Trial to Establish the Baseline Safety and
Efficacy of a Single Subretinal Injection of rAAV.sFlt-1 Into Eyes of
Patients With Exudative AMD
Jeffrey S Heier MD
I. Overview of Gene Therapy for Retinal Disease
A. Retinal diseases are well suited for treatment with
gene-based therapies.
1. Eye is small and relatively protected / isolated.
2. Allows local delivery of gene therapy product to
desired site
III. AVA-101 Phase 2a Objectives
A. Primary objective
3. Allows high concentration with injection of a
small amount of vector
Assess the safety and tolerability of AVA-101 in subjects with exudative AMD for a period up to 3 years
4. Reduced likelihood / severity of immune
response / adverse event
B. Secondary objectives
1. Assess the efficacy of AVA-101 in maintaining or
improving vision and preventing moderate vision
loss in patients with exudative AMD
2. Assess the efficacy of AVA-101 at 52 weeks in
terms of reducing the need for ranibizumab injections
3. Assess the biodistribution of AVA-101 by laboratory testing
B. Injection sites are readily accessible.
1. Subretinal delivery
2. Intravitreal delivery
3. Two 0.5-mg ranibizumab injections (baseline
and 1 month) cover the “ramp-up” period for
sVEGFR-1 production.
C. Assessment of retinal function and structure
1. Function: BCVA
2.Structure
a.OCT
b. Fundus photography
c. Fluorescein angiography
1. 32 participants
2. Exudative AMD (naïve and previously treated)
3. Age 55 years and older
Ophthalmic complications and toxicity or systemic
complications as measured by clinical exam and
laboratory testing from 1 month following injection
B. Secondary endpoints
A. Phase 2a patient population
A. Primary endpoint
II. AVA-101 Phase 2a Study Design
IV. AVA-101 Phase 2a Endpoints
B. Single cohort
1. 21 patients in AVA-101 cohort, with ranibizumab 0.5-mg rescue therapy
2. 11 patients in control arm, with ranibizumab
0.5-mg as rescue therapy only
C. AVA-101 delivery to the eye
1. Subretinal delivery: core vitrectomy with subretinal administration of AVA-101 adjacent to
macula
2. AAV vector produces naturally occurring
sVEGFR-1
1. BCVA assessments at 52 weeks including the following calculated endpoints
a. Mean change from baseline
b. Percent gaining ≥ 15 letters from baseline
c. Percent losing ≥ 15 letters from baseline
2. Number of rescue ranibizumab injections up to
and including 52 weeks
3. Presence of AVA-101 in serum, tears, saliva,
urine, and vitreous
V. AVA-101 Phase 2a Results
A. Safety: No adverse safety signals
B. Efficacy: Biologic activity demonstrated
1. Need for ranibizumab rescue
2. Anatomic outcomes (OCT)
3. Visual acuity
2015 Subspecialty Day | Retina
Section IX: First-time Results of Clinical Trials, Part I
61
Anti-PDGF Pretreatment in Neovascular AMD: Results
of a Pilot Study Evaluating VEGF/PDGF Crosstalk
Pravin U Dugel MD
NOTES
62
Section X: Neovascular AMD
2015 Subspecialty Day | Retina
Progression of AMD Following Cataract Surgery
In the Age-Related Eye Disease Study 2 (AREDS2)
Emily Y Chew MD and the AREDS2 Research Group
Purpose
The association of progression to late AMD with cataract surgery has been controversial. The objective of this study was to
evaluate the association of cataract surgery with progression of
AMD in the Age-Related Eye Disease Study 2 (AREDS2).
Background Information
AMD and age-related cataract are two of the leading causes of
blindness in the United States. Although both diseases increase
with age and they share some common risk factors, it is not clear
if there is a direct relationship between these two ocular conditions. Clinically, the relationship between cataract surgery and
the development of advanced AMD poses an important management question: whether cataract surgery may in fact accelerate
the progression of AMD to the most severe form that threatens
vision, either the neovascular form or geographic atrophy involving the center of fovea. This has been studied in autopsy cases,
case series,1 and population-based studies.2-5 Randomized clinical trials and prospective studies have not demonstrated a harmful effect of cataract surgery on the progression to late AMD.6-10
We have published previously on the analyses of the original
AREDS,7 showing no association of progression to late AMD
following cataract surgery. AREDS2 provides yet another opportunity to evaluate the influence of cataract surgery on progression to late AMD.
Methods
We limited our analyses to eyes without late AMD at baseline.
We also eliminated eyes that had cataract surgery but had developed late AMD (either neovascular or central geographic atrophy) before the surgery. Eyes of eligible AREDS2 participants
were matched based upon cataract surgery with either the “case”
group, consisting of those who had cataract surgery, or the “control” group, who never had cataract surgery. Matching criteria
included period of follow-up, AMD status at baseline, AREDS2
treatment assignment to lutein/zeaxanthin, age group at time of
cataract surgery, gender, race, severity of AMD status just before
cataract surgery (for cases), and presence or absence of neovascular AMD in the fellow eye before cataract surgery.
Clinical evaluations for the presence of a lens or pseudophakia and ocular photographs of the fundus (3 stereoscopic fields)
and red reflex photos were conducted annually and graded
centrally for AMD status and lens presence, respectively. History of cataract surgery or treatment for neovascular AMD was
captured at the 6-month telephone call that occurred between
annual study visits. Analyses were conducted as ratio (R) = case
eyes with incident late AMD prior to matched control/control
eyes with incident late AMD prior to matched case. R > 1 suggests increased likelihood of late AMD occurring sooner among
cases (those having cataract surgery) than among the matched
controls.
We also analyzed the data for the time to late AMD, and
separately to neovascular AMD and central geographic atrophy
using the Cox proportional hazards regression models, adjusting for the following covariates: time to cataract surgery, age,
AMD severity, sex, and smoking status. We also analyzed the
data using logistic regression. We analyzed the right eyes first,
followed by the analyses for the left eyes with the Cox models.
Using logistic regression models, specifically generalized estimating equation (GEE) to account for the use of both eyes, we
analyzed each participant again for the outcome of development
of late AMD and the two components, neovascular AMD and
central geographic atrophy.
Results
There were 1390 eyes with incident cataract, and following
matching for the above variables, we had 989 cases (from 689
participants). Of these 989 case eyes, 912 (92%) were almost
matched on all criteria. 483 matched pairs (53%) did not
develop late AMD in either the case eye or the control eye. For
incident late AMD, R = 105/322 = 0.33; 95% CI, 0.11-0.55. For
incident neovascular AMD, R = 89/231 = 0.39; 95% CI, 0.140.63. For incident central geographic AMD, R = 52/120 = 0.43;
95% CI, 0.11-0.76.
For the results of the Cox models, we found the hazards ratio
(HR) to be 1.09 (95% CI, 0.85-0.40, 0.99; 95% CI, 0.75-1.28
for the right and left eyes, respectively) for the outcome of late
AMD. Similarly, there were no statistically significant findings
for the development of neovascular AMD or central geographic
atrophy for either the right or left eyes for the Cox models. Other
results from the logistic regression using the GEE method: the
odds ratio was 1.10 (95% CI, 0.76-1.60) for late AMD, and
again there were no statistically significant findings for neovascular AMD or central geographic atrophy.
Conclusions
In AREDS2, similar to the results of the original AREDS, no
statistically significant association of progression to late AMD,
either neovascular or central geographic atrophy with cataract
extraction, was found in any of the analyses conducted. It is possible that the epidemiologic studies in the past may have had difficulties with unadjusted confounding playing a role. In both the
AREDS and AREDS2, the decision for cataract extraction was
influenced heavily by the retinal specialists who were the study
investigators. The decision to conduct cataract surgery in epidemiologic studies was more likely to be determined by general
ophthalmologists who did not have the benefit of the longer-term
follow-up in AREDS and AREDS2.
The AREDS2 participants received surgery during 2006 to
2012, while the epidemiologic studies had cataract surgery conducted in the late 1980s to mid-1990s. Improvements in cataract
surgical techniques over time might have resulted in a lower likelihood of developing inflammation following surgery during the
more recent period of the AREDS2 study. AREDS2 participants
are also more likely to have received a blue-light or UV blocking
IOL implant, which have been hypothesized to reduce the risk of
progression to AMD.
2015 Subspecialty Day | Retina
Finally, the AREDS2 participants, unlike the subjects of the
epidemiologic studies, are healthy volunteers. Thus the results
of this clinical trial might be less generalizable. However, we are
now supported by a well-designed prospective study of cataract
extraction and AMD progression conducted by Wang et al in
Australia. The conclusions of this prospective study also found
no increased risk of progression to late AMD in persons following cataract surgery, again using paired analyses; the odds ratio
was 1.07 with 95% CI, 0.74-1.65, P-value. Furthermore, we
have demonstrated that persons with even the most severe AMD
may experience visual improvement following cataract surgery,
in both AREDS and AREDS2.11,12
In conclusion, persons at risk for developing late AMD
should be followed vigilantly following cataract surgery to assess
for potential of developing late AMD because of the successful
therapies with anti-VEGF therapies for those who develop neovascular AMD. There are no statistically significant differences
in the progression rates to late AMD in those with and without
cataract surgery.
References
1. Pollack A, Marcovich A, Bukelman A, Oliver M. Age-related macular degeneration after extracapsular cataract extraction with intraocular lens implantation. Ophthalmology 1996; 103:1546-1554.
2. Cugati S, de Loryn T, Pham T, Arnold J, Mitchell P, Wang JJ.
Australian prospective study of cataract surgery and age-related
macular degeneration: rationale and methodology. Ophthalmic
Epidemiol. 2007; 14:408-414.
3. Klein BE. Is the risk of incidence or progression of age-related
macular degeneration increased after cataract surgery? Arch Ophthalmol. 2009; 127:1528-1529.
4. Klein BE, Howard KP, Lee KE, Iyengar SK, Sivakumaran TA, Klein
R. The relationship of cataract and cataract extraction to agerelated macular degeneration: the Beaver Dam Eye Study. Ophthalmology 2012; 119:1628-1633.
Section X: Neovascular AMD
63
5. Klein R, Klein BE, Wong TY, Tomany SC, Cruickshanks KJ. The
association of cataract and cataract surgery with the long-term incidence of age-related maculopathy: the Beaver Dam Eye Study. Arch
Ophthalmol. 2002; 120:1551-1558.
6. Baatz H, Darawsha R, Ackermann H, et al. Phacoemulsification
does not induce neovascular age-related macular degeneration.
Invest Ophthalmol Vis Sci. 2008; 49:1079-1083.
7. Chew EY, Sperduto RD, Milton RC, et al. Risk of advanced agerelated macular degeneration after cataract surgery in the AgeRelated Eye Disease Study: AREDS report 25. Ophthalmology
2009; 116:297-303.
8. Hooper CY, Lamoureux EL, Lim L, et al. Cataract surgery in highrisk age-related macular degeneration: a randomized controlled
trial. Clin Experiment Ophthalmol. 2009;37:570-6.
9. Tabandeh H, Chaudhry NA, Boyer DS, Kon-Jara VA, Flynn HW,
Jr. Outcomes of cataract surgery in patients with neovascular agerelated macular degeneration in the era of anti-vascular endothelial
growth factor therapy. J Cataract Refract Surg. 2012;38:677-82.
10. Wang JJ, Fong CS, Rochtchina E, et al. Risk of age-related macular
degeneration 3 years after cataract surgery: paired eye comparisons.
Ophthalmology 2012;119:2298-303.
11. Forooghian F, Agron E, Clemons TE, Ferris FL, 3rd, Chew EY.
Visual acuity outcomes after cataract surgery in patients with
age-related macular degeneration: Age-Related Eye Disease Study
report no. 27. Ophthalmology 2009;116:2093-100.
12. Huynh N, Nicholson BP, Agron E, et al. Visual acuity after cataract
surgery in patients with age-related macular degeneration: AgeRelated Eye Disease Study 2 report number 5. Ophthalmology
2014;121:1229-36.
64
Section X: Neovascular AMD
2015 Subspecialty Day | Retina
Long-term Anti-VEGF Monotherapy:
Do Patients Improve?
Michael Larsen MD
NOTES
Section X: Neovascular AMD
2015 Subspecialty Day | Retina
65
Genetics of AMD: Now and the Future
Edwin M Stone MD PhD
I. Many macular diseases have a genetic component.
II. Value in Understanding Genetics of Macular Diseases
A. Mendelian maculopathies
A.Mendelian
1.Rare
1. Eludicate pathophysiology
2. Genetic variants have large effect; they “cause”
disease.
2. Genetic counseling
3. Gene augmentation/genome editing strategies
3. Mendelian maculopathies
a. AR Stargardt disease: ABCA4
b. Best disease: BEST1
c. Pattern dystrophy: PRPH2
d. AD Stargardt disease: ELOVL4
e. Sorsby fundus dystrophy: TIMP3
f. Malattia leventinese: EFEMP1
g. Pseudoxanthoma elasticum: ABCC6
h. North Carolina macular dystrophy: chromosomes 5 and 6
i. PROM1-associated macular dystrophy:
PROM1
j. Macular dystrophy with diabetes and deafness: mito 3243
B. Complex macular disease: AMD
1.Common
2. Genetic variants have smaller effect; they
increase “risk” of disease.
3. Genes associated with AMD risk
a. Complement factor H (CFH)
b.
ARMS2/HTRA1
c.
C2/CFB
d.Others
B.AMD
1. Elucidate pathophysiology
2. Intervene early in disease process (eventually)
III. Genetic Testing for Macular Diseases
A. Already very useful for Mendelian disease
B. Not indicated yet for AMD1
C. Will be key to novel treatments for both types of
disease in the future
Reference
1. Stone EM. Genetic testing for age-related macular degeneration: not
indicated now. JAMA Ophthalmol. 2015; 133(5):598-600.
66
Section X: Neovascular AMD
2015 Subspecialty Day | Retina
Polypoidal Choroidal Vasculopathy: Anti-VEGF or
Photodynamic Therapy?
Tien Y Wong MBBS
Polypoidal choroidal vasculopathy (PCV) is a subtype of wet
AMD, more common in blacks and Asians.1 While the standard
of care for traditional classic wet AMD is antivascular endothelial growth factor (VEGF) monotherapy, the optimal treatment
of PCV remains unclear.2,3
The two main modalities of PCV treatment include photodynamic therapy (PDT) and use of the anti-VEGF agents aflibercept, bevacizumab, and ranibizumab. Both PDT and anti-VEGF
therapy have been shown to be efficacious, but there are differences in their relative abilities to improve vision and achieve
polyp closure, and optimal treatment regimens have yet to be
established.
The EVEREST study4 was the first randomized controlled
trial evaluating standard fluence PDT with or without ranibizumab 0.5 mg and ranibizumab monotherapy involving 61
Asian patients, with therapy randomized into 3 groups: PDT
monotherapy, ranibizumab monotherapy, and combination
therapy with PDT and ranibizumab. The primary endpoint was
the proportion of patients with complete regression of polyps
at 6 months. The study found a higher polyp closure rate with
PDT with or without ranibizumab than with ranibizumab alone
(77.8% and 71.4% vs. 28.6%; P < .01) and thus established the
efficacy of PDT in the closure of PCV polyps. However, EVEREST was not adequately powered to assess differences in visual
acuity or central retinal thickness changes.
In the LAPTOP study,5 another randomized controlled trial,
93 patients were randomized to 2 arms: a standard fluence PDT
monotherapy arm and a ranibizumab monotherapy arm where
patients received 3 monthly injections of ranibizumab 0.5 mg.
Additional treatment was performed as needed in each arm.
At 12 months, the study found a higher proportion of patients
gaining more than 0.2 logMAR units in the ranibizumab arm
(30.4% vs. 17.0%, P = .039). In addition, the mean gain in logMAR visual acuity was also greater in the ranibizumab arm at
12 months (P = .011) and at 24 months (P = .025). Thus, these 2
trials showed that although PDT may be more effective at polyp
closure than anti-VEGF, anti-VEGF therapy seemed to be better
at improving or preventing visual loss in patients with PCV.
Anti-VEGF monotherapy, such as ranibizumab monotherapy,
has been studied in treatment-naïve eyes with PCV. The polyp
regression rates achieved by ranibizumab monotherapy at 6
months range from 25% to 33%, comparable to rates in the
EVEREST trial. More recently, a few studies have investigated
the efficacy of aflibercept in the treatment of PCV. A small noncomparative prospective study of 16 treatment-naïve eyes with
PCV saw a high rate of polyp regression (75%) at 6 months with
aflibercept monotherapy given at 2 monthly intervals after 3 initial monthly loading doses.6 This is in contrast to the low polyp
regression rate achieved by ranibizumab monotherapy in other
studies (28.6%-40%) and the EVEREST trial (28.6%).
Two large Phase 3 trials, EVEREST II and PLANET, will
release results in 2016. The optimal treatment for PCV requires
further clarification with new data from these trials.
References
1. Laude A, Cackett PD, Vithana EN, Yeo IY, Wong D, Koh AH,
Wong TY, Aung T. Polypoidal choroidal vasculopathy and neovascular age-related macular degeneration: same or different disease?
Prog Retin Eye Res. 2010; 29(1):19-29.
2. Cheung CM, Li X, Mathur R, Lee SY, Chan CM, Yeo I, Loh BK,
Williams R, Wong EY, Wong D, Wong TY. A prospective study of
treatment patterns and 1-year outcome of Asian age-related macular degeneration and polypoidal choroidal vasculopathy. PLoS
One. 2014; 9(6):e101057.
3. Wong CW, Cheung CM, Mathur R, Li X, Chan CM, Yeo I, Wong
E, Lee SY, Wong D, Wong TY. Three-year results of polypoidal
choroidal vasculopathy treated with photodynamic therapy: retrospective study and systematic review. Retina. Epub ahead of print
2015 Feb 24.
4. Koh A, Lee WK, Chen LJ, et al. Everest Study: Efficacy and safety
of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with
symptomatic macular polypoidal choroidal vasculopathy. Retina
2012; 32:1453-1464.
5. Inoue M, Arakawa A, Yamane S, Kadonosono K. Short-term
efficacy of intravitreal aflibercept in treatment-naive patients with
polypoidal choroidal vasculopathy. Retina 2014; 34:2178-2184.
6. Oishi A, Kojima H, Mandai M, et al. Comparison of the effect of
ranibizumab and verteporfin for polypoidal choroidal vasculopathy: 12-month LAPTOP study results. Am J Ophthalmol. 2013;
156:644-651.
Section X: Neovascular AMD
2015 Subspecialty Day | Retina
Beta-Amyloid Monoclonal Antibody
Scott W Cousins MD
NOTES
67
68
Section X: Neovascular AMD
2015 Subspecialty Day | Retina
Conbercept
Efficacy of Intravitreal Injection of Conbercept in Polypoidal Choroidal
Vasculopathy: Subgroup Analysis of the AURORA Study
Xiaoxin Li MD on behalf of the AURORA Study Group
Introduction and Background
Results
There is no widely accepted and effective method for treating
polypoidal choroidal vasculopathy (PCV). Various studies have
found that anti-VEGF monotherapy may reduce subretinal fluid
and cause stabilization of vision in eyes with PCV. But their
application was limited because of relatively low polyps regression rates (11%-61%) at 6 to 24 months follow-up.
Conbercept (KH902; Chengdu Kanghong Biotech Co.; Sichuan, China) is the most recent member of the anti-VEGF family
of drugs. Recently developed to provide a more potent and prolonged anti-VEGF effect, conbercept was approved by the China
Food and Drug Administration (CFDA) in November 2013.
Similar to aflibercept, conbercept consists of the VEGF binding
domains of the human VEGFR-1 and VEGFR-2 combined with
the Fc portion of the human immunoglobulin G-1. In addition
to having high affinity for all isoforms of VEGF-A, it also binds
to placental growth factor and VEGF-B. The structural difference between conbercept and aflibercept is that conbercept
also contains the fourth binding domain of VEGFR-2, which is
essential for receptor dimerization and enhances the association
rate of VEGF to the receptor. Since this domain of VEGFR-2 has
a lower isoelectric point, the addition of this domain to KH902
decreases the positive charge of the molecule and results in
decreased adhesion to the extracellular matrix.
AURORA was a 1-year, prospective, multicenter (9 sites),
randomized, double-masked, controlled study of the safety, tolerability, and efficacy of intravitreal injections of different doses
and different dosing regimens of conbercept in patients with
neovascular AMD (nAMD). It reported that multiple injections
of 0.5 mg or 2.0 mg conbercept in patients with nAMD (including PCV) resulted in continued visual acuity improvement that
was maintained throughout 12 months of follow-up. To determine the efficacy of conbercept in patients with PCV, we retrospectively compared the 12-month visual acuity and anatomic
outcomes using different conbercept doses in a subgroup of eyes
with PCV from the AURORA study.
1. Among the 32 patients in the pooled 0.5-mg group, 16
were assigned to the 3+p.r.n. group and 16 were assigned
to the monthly (Q1M) group. Among the 21 patients in
the pooled 2.0-mg group, 11 were assigned to the 3+p.r.n.
group and 10 were assigned to the Q1M group. The 2
dosage groups were well balanced for demographics and
ocular characteristics in the study eye at baseline.
2. At Month 12, mean changes in BCVA from baseline were
14.4 ± 14.1 letter scores for the 0.5-mg group and 14.2 ±
21.0 letter scores for the 2.0-mg group (see Figure 1).
Methods
Fifty-three patients (32 in the 0.5-mg group and 21 in the 2.0-mg
group) diagnosed with PCV in the AURORA study were retrospectively evaluated. Efficacy outcomes were compared between
the 2 dosage groups.
Figure 1. The mean changes in BCVA letter scores from baseline through
Month 12 in patients receiving 0.5-mg and 2.0-mg doses. The BCVA
improved significantly during the first 3-month loading phase (P < .001
for both groups) and then continued to improve through Month 12 (P <
.001 for the 0.5-mg group; P = .011 for the 2.0-mg group).
2015 Subspecialty Day | Retina
Section X: Neovascular AMD
69
3. At Month 12, mean central retinal thickness (CRT)
decreased by 104.5 ± 127.3 μm in the 0.5-mg group and
140.7 ± 127.9 μm in the 2.0-mg group; mean total macular volume (TMV) decreased by 0.9 ± 2.3 mm3 and 1.0 ±
1.2 mm3 in the 0.5-mg and 2.0-mg groups, respectively
(see Figure 2).
Figure 3. The mean changes in subretinal fluid (SRF) thickness from
baseline through Month 12 in both dosage groups. The SRF thickness
decreased during the first 3-month loading phase (P < .001 in the 0.5-mg
group; P = .003 in the 2.0-mg group) and then slightly increased through
Month 12 compared with baseline (P < .001 in the 0.5-mg group, P =
.007 in the 2.0-mg group). There was no significant difference between
the 2 dosage groups for the improvements in SRF thickness from baseline
through Month 3 (P = .639) and Month 12 (P = .320).
Figure 2. The mean changes in central retinal thickness (CRT) from
baseline through Month 12 in both dosage groups. The CRT decreased
during the first 3-month loading phase (P = .015 in the 0.5-mg group;
P = 0.003 in the 2.0-mg group) and then continued to decrease through
Month 12 compared with baseline (P < .001 in the 0.5-mg and 2.0-mg
groups). There was no significant difference between the 2 dosage groups
with respect to the improvement of CRT from baseline to Month 3 (P =
.060) and Month 12 (P = .357).
5. At Month 12, the mean pigmented epithelial detachment
(PED) height decreased by 79.3 ± 217.8 μm and 61.3 ±
161.5 μm in the 0.5-mg and 2.0-mg groups, respectively
(see Figure 4).
4. At Month 12, the mean subretinal fluid (SRF) thickness
decreased by 111.9 ± 122.5 μm and 76.3 ± 112.6 μm in
the 0.5-mg and 2.0-mg groups, respectively (see Figure 3).
Figure 4. The mean changes in retinal pigment epithelial detachment
(PED) height from baseline through Month 12 in both dosage groups.
The decreased PED height during the first 3-month loading phase was
not statistically significant in either group (P = .520 in the 0.5-mg group;
P = .778 in the 2.0-mg group). By Month 12, the continued decrease
compared with baseline was borderline statistically significant in the 0.5mg group (P = .05) and not statistically significant in the 2.0-mg group
(P = .1440). There was no significant difference between the 2 dosage
groups for the decrease in PED height from baseline at Month 3 (P =
.995) and Month 12 (P = .749).
70
Section X: Neovascular AMD
2015 Subspecialty Day | Retina
6. At Month 12, the mean total lesion area decreased by 2.51
± 5.94 mm2 (P = .088) and 4.62 ± 5.51 mm2 in the 0.5-mg
group and 2.0-mg groups, respectively (see Figure 5).
Figure 5. The mean changes in total lesion area from baseline through
Month 12 in patients in both dosage groups. At Month 3, the decrease in
lesion area compared to baseline was not statistically significant for the
0.5-mg group (P = .236) but was statistically significant for the 2.0-mg
group (P = .002). At Month 12, the decrease in lesion area compared
with baseline was still not statistically significant for the 0.5-mg group
(P = .088) but was statistically significant for the 2.0-mg group (P =
.004). There was no significant difference between the 2 dosage groups
for the reduction of total lesion area from baseline to Month 3 (P = .392)
and Month 12 (P = .264).
7. At Month 12, complete regression of polyps was observed
in 56.5% of the 0.5-mg group and 52.9% of the 2.0-mg
group, while partial regression was observed in 26.1% and
35.3% of the 0.5-mg and 2.0-mg groups, respectively (see
Figures 6 and 7).
Figures 6 and 7. Distribution of changes in polyp area from baseline to
Month 3 and Month 12 in both dosage groups.
Conclusions
Intravitreal injection of conbercept appears to significantly
improve visual acuity and anatomic outcomes of patients with
PCV.
Reference
1. Li X, Xu G, Wang Y, et al. Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month
randomized Phase 2 study: AURORA study. Ophthalmology
2014:121:1740-1747.
2015 Subspecialty Day | Retina
Section X: Neovascular AMD
71
Intravitreal Ziv-Aflibercept
Michel Eid Farah MD
In this small series, patients with wet AMD underwent intravitreal injections of ziv-aflibercept, the aflibercept used for intravenous administration in the treatment of metastatic colorectal
cancer. The main message is that we found intravitreous zivaflibercept effective and we did not observe signs of toxicity for
at least 6 months of follow-up.
The main difference between ziv-aflibercept (Zaltrap) and
aflibercept (Eylea) is the osmolarity. Eylea is an iso-osmotic
solution, whereas Zaltrap is hyper-osmolar (1000 mOsm) when
compared to the vitreous.
Before starting the Phase 1 study we performed an in vitro
study using retinal pigment epithelial cells exposed to 12.5 or
25 mg/mL ziv-aflibercept. Neither concentration reduced cell
viability.
Intravitreal injections of both drugs were performed in 18
rabbits. No changes were observed in serum, aqueous, or vitreous osmolarity. PH and full-field electroretinogram (ERG)
showed no signs of toxicity. No funduscopic or OCT alterations
were found.
The histological findings showed small areas of vacuolization
in the ganglion cell and nuclear layers. No difference was seen
between aflibercept and ziv-aflibercept eyes. Our experimental
study showed that neither aflibercept nor ziv-aflibercept caused
toxicity to the retina.
Considering the lack of toxicity found in vitro and in vivo,
a study to describe the results of patients with wet AMD, either
naive or refractory to bevacizumab, who underwent ziv-aflibercept intravitreal injections was performed. The total dose was
1.75 mg.
The injections were done every 30 days for 3 months. Retreatments were performed as needed. The primary end point is 1
year.
Patients are subjected to color fundus picture, OCT, microperimetry, and fluorescein and indocyanine green angiography, as
well as full-field ERG. Initial cases with 6-month follow-up serve
as representative examples.
All patients experienced decrease in subretinal fluid and
improvement in visual acuity, and did not show signs of toxicity.
The main message is that the initial results point out that
intravitreal ziv-aflibercept may be effective for wet AMD and not
toxic to the retina. Of course, our study will go on and others are
necessary.
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Section X: Neovascular AMD
2015 Subspecialty Day | Retina
Radiation for Wet AMD: Highs, Lows, and Next Steps
Timothy L Jackson MBChB
I. Rationale for Using Radiation to Treat Wet AMD
A. Radiation preferentially damages proliferating cells,
including fibroblasts, inflammatory cells, and endothelial cells.1
B. Mature retinal cells are less sensitive to radiation.
C. Wet AMD disease activity is driven by proliferating
cells, similar to a scarring response. Radiation can
reduce scarring.2
D. Anti-VEGF drugs suppress rather than eliminate
disease activity.
E. Radiation has the potential to kill proliferating cells
and thereby produce a more durable effect.
A. Patients undergo vitrectomy.
B. An endoscopic probe containing a strontium-90
radiation source is then held over the macula.
C. Probe emits beta radiation.
D. Macula receives 24 Gray dose over 3-4 minutes.
E. Initial uncontrolled studies showed positive results.
II. Early Radiation Treatment for Wet AMD
A. First reported in 1993 by Chakravarthy3
B. Early trials adapted external beam radiotherapy
devices designed to treat centimeter-dimension
tumors, not micron-dimension AMD lesions.
C. A Cochrane review of randomized trials failed to
establish efficacy.4
III. Radiation Revisited: Modern AMD Radiotherapy
Devices
1. A study of 34 treatment-naïve participants
reported a gain of 8.9 letters over 12 months
despite very few p.r.n. anti-VEGF injections
(maximum of 2 p.r.n. injections, with 16 patients
requiring no p.r.n. injections following 2 mandated baseline injections).6
2.The Macular Epiretinal Brachytherapy in Previously Treated Neovascular Age-Related Macular
Degeneration (MERITAGE) study enrolled 53
patients requiring frequent anti-VEGF therapy
and also suggested reduced injection frequency
following EMB.7
F. Two subsequent large randomized controlled trials
gave disappointing results:
1.The Choroidal Neovascularization Secondary
to AMD Treated with Beta Radiation Epiretinal
Therapy (CABERNET)8, 9
Two main devices:
A. Epimacular brachytherapy (EMB: NeoVista; Fremont, CA)
B. Stereotactic radiotherapy (SRT: Oraya; Newark,
CA)5
a. Enrolled 495 treatment-naïve participants
b. Failed to meet its primary endpoint (noninferior visual acuity)
c. Not designed to determine if radiation
reduced anti-VEGF therapy as the control
group had mandated injections
d. At the 2-year primary endpoint 3% had mild,
nonproliferative radiation retinopathy, but
paradoxically this group had better vision
than EMB patients without retinopathy, and
overall safety was acceptable.
IV. Epimacular Brachytherapy (see Figure 1)
Figure 1. Epimacular brachytherapy.
2.The Macular Epiretinal Brachytherapy versus
Ranibizumab (Lucentis)-Only Treatment
(MERLOT)
a. Enrolled 363 participants already receiving
anti-VEGF therapy
b. Designed to determine if radiation reduces
p.r.n. anti-VEGF therapy while maintaining
vision
c. Failed to meet either coprimary endpoint,
with vision favoring the anti-VEGF monotherapy control, and a trend for more rather
than fewer p.r.n. anti-VEGF injections following radiation
Section X: Neovascular AMD
2015 Subspecialty Day | Retina
d. Safety was acceptable at the 1-year primary
endpoint, with only 0.4% having microvascular abnormalities attributed to radiation.
Further safety review is planned.
G.
Stereotactic Radiotherapy for Age-Related Macular
Degeneration (STAR)
1. UK, randomized, double-masked, sham
controlled, National Institute of Health
Research-funded trial of SRT in previously
treated wet AMD (ClinicalTrials.gov identifier:
NCT02243878).
2. Recruits the subset of best responders identified
in INTREPID.
3. 411 participants randomized 2:1 to 16 Gray SRT
plus p.r.n. ranibizumab or p.r.n. ranibizumab
monotherapy.
4. Primary outcome is number of p.r.n. ranibizumab injections over 2 years.
5. Also powered to establish noninferiority of visual
acuity
6.Recruiting
V. Stereotactic Radiotherapy (See Figure 2)
Figure 2. Stereotactic radiotherapy.
73
VI. Possible Reasons for Differences in Clinical Response
Comparing EMB and SRT
A. Patient is positioned on a chin rest.
B. Eye is held in position using a suction-coupled contact lens.
A. EMB requires vitrectomy, which reduces drug halflife about 5-fold.
C. Eye tracking software halts treatment if the eye position deviates.
D. A robotically controlled device aims 3 highly collimated beams of radiation through the inferior sclera
to overlap at the macula.
B. EMB dose reduces exponentially with increasing
distance from the probe, so it is critical to keep the
probe positioned on the retina during treatment,
and in the area of greatest disease activity, which
may be hard to determine in some occult lesions.
E. Treatment is centered on the fovea, with the 90%
isodose extending across a 4-mm diameter. Beyond
4 mm the dose reduces steeply.
F. IRay in Conjunction With Anti-VEGF Treatment
for Patients With Wet AMD (INTREPID)10 study
1. Randomized, double masked, sham-controlled
study
2.230 participants already receiving anti-VEGF
therapy were randomized to 16 Gray, 24 Gray,
or sham SRT.
3. The study met its primary endpoint, showing a
one-third reduction in p.r.n. anti-VEGF therapy
at 1 year.
4. Subgroup analysis11
a. Identified “best responders” as eyes with
lesions smaller than the 4-mm treatment zone
at enrollment and with active leakage (defined
as a macular volume greater than the median)
b. At Year 1, these best responders had significantly better vision (5 letters superior to
control) and significantly fewer anti-VEGF
injections (55% fewer than control).
5. Extended safety follow-up found microvascular
abnormalities in Year 2, but in only 1% did these
possibly affect vision as most were outside the
fovea.12
VII.Conclusion
A. Longer follow-up is important as radiation damage
may occur late, although most changes are not visually damaging.
B. EMB use, or further studies, do not appear justified.
C. Case selection is important for SRT.
1. Lesions within treatment zone
2. Actively leaking at time of treatment
References
1. Kirwan JF, Constable PH, Murdoch IE, Khaw PT. Beta irradiation: new uses for an old treatment: a review. Eye (Lond). 2003;
17(2):207-215.
2. Nevarez JA, Parrish RK 2nd, Heuer DK, et al. The effect of beta
irradiation on monkey Tenon’s capsule fibroblasts in tissue culture.
Curr Eye Res. 1987; 6(5):719-723.
3. Chakravarthy U, Houston RF, Archer DB. Treatment of age-related
subfoveal neovascular membranes by teletherapy: a pilot study. Br J
Ophthalmol. 1993; 77(5):265-273.
4. Evans JR, Sivagnanavel V, Chong V. Radiotherapy for neovascular age-related macular degeneration (Cochrane Review). In:
Cochrane Database of Systematic Reviews, 2010, Issue 5. Art.
No.:CD004004.
5. Petrarca R, Jackson TL. Radiation therapy for neovascular agerelated macular degeneration. Clin Ophthalmol. 2011; 5:57-63.
6. Avila MP, Farah ME, Santos A, et al. Twelve-month short-term
safety and visual-acuity results from a multicentre prospective study
74
Section X: Neovascular AMD
of epiretinal strontium-90 brachytherapy with bevacizumab for
the treatment of subfoveal choroidal neovascularisation secondary to age-related macular degeneration. Br J Ophthalmol. 2009;
93(3):305-309.
7. Dugel PU, Petrarca R, Bennett M, et al. Macular epiretinal brachytherapy in treated age-related macular degeneration: MERITAGE
study: twelve-month safety and efficacy results. Ophthalmology
2012; 119(7):1425-1431.
8. Dugel PU, Bebchuk JD, Nau J, et al. Epimacular brachytherapy for
neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET). Ophthalmology 2013; 120(2):317-327.
9. Jackson TL, Dugel PU, Bebchuk JD, et al. Epimacular brachytherapy for neovascular age-related macular degeneration (CABERNET): fluorescein angiography and optical coherence tomography.
Ophthalmology 2013; 120(8):1597-1603.
10. Jackson TL, Chakravarthy U, Kaiser PK, et al. Stereotactic radiotherapy for neovascular age-related macular degeneration: 52-week
safety and efficacy results of the INTREPID study. Ophthalmology
2013; 120(9):1893-1900.
11. Jackson TL, Shusterman EM, Arnoldussen M, et al. Stereotactic radiotherapy for wet age-related macular degeneration
(INTREPID): influence of baseline characteristics on clinical
response. Retina 2015; 35(2):194-204.
12. Jackson TL, Chakravarthy U, Slakter JS, et al. Stereotactic radiotherapy for neovascular age-related macular degeneration: year 2
results of the INTREPID study. Ophthalmology 2015; 122(1):138145.
2015 Subspecialty Day | Retina
2015 Subspecialty Day | Retina
Section X: Neovascular AMD
75
MacTel Project
Martin Friedlander MD PhD
Macular telangiectasia type 2 (MacTel), a degenerative condition
of the macula that affects both eyes, may cause progressive loss
of central vision. As early as the 1960s, Gass used fundus examination and fluorescein angiography to describe patients with
macular dysfunction associated with telangiectasis of retinal vessels.1 In 1982, Gass et al published the seminal paper on macular
telangiectasis (then called juxtafoveal or parafoveal telangiectasia) and in further work, subdivided macular telangiectasis into
three groups.2 In type 1, the telangiectasia is associated with
dilated retinal capillaries, leakage on fluorescein angiography,
and retinal thickening. These patients are mostly male. The telangiectasia is unilateral in most cases and easily visible. This form
is typically not diagnosed until after age 40 years. Patients with
unilateral MacTel may be asymptomatic. Visual acuity at presentation usually ranges from 20/25 to 20/40, although 20/200 may
occur.
Figure 1.
In type 2 MacTel, leakage occurs during fluorescein angiography with manifest retinal capillary dilatation but without retinal
thickening. This is the most common form of macular telangiectasia. These people typically are diagnosed in their fifth or sixth
decade of life. Both sexes are affected. This disorder is characterized by minimal exudation, superficial retinal crystalline deposits, retinal opacification, and right-angle venules. As the disease
progresses, intraretinal pigment plaques and intraretinal and/or
subretinal neovascularization may develop. In type 3 MacTel,
capillary occlusion is suspected to cause the telangiectasia. These
patients are diagnosed with bilateral, easily visible telangiectasia,
minimal exudation, and capillary occlusion.
In 2005, in order to better understand the underlying pathophysiology of the disease and to develop a treatment, the MacTel
Project was initiated. One of the first activities of this program
was to start a prospective natural history study to define the
clinical aspects of the MacTel type 2 more clearly. Several new
features have now been described that alter our concept of the
disorder’s pathogenesis:
• One of the earliest signs is loss of luteal pigment centrally
as manifested by fundus autofluorescence imaging using a
confocal laser ophthalmoscope.
• OCT has shown abnormalities in photoreceptors early in
the disease, which is associated with significant loss of scotopic and photopic function beginning nasal to fixation.3
This gives rise to pre-fixational blindness.
• With adaptive optics imaging it has become evident that
cone loss is an early characteristic of the disease and that
photoreceptor loss may be functional rather than structural; two independent studies have shown that affected
cones may lose their outer segments but preserve inner
segments4 that go “dormant” but may be “revived”
spontaneously5 or with neurotrophic molecules. Thus,
photoreceptor loss is intrinsic to the disorder, occurs early
in the disease, may precede vascular change, and may be
functionally reversible.
• In addition (1) it has been shown that anti-VEGF treatment causes reversal of the blood vessel changes but does
not influence progression of photoreceptor cell loss or
functional loss; (2) it has also been confirmed that the
retina is thinner than normal in MacTel, unlike other
macular conditions such as diabetic retinopathy in which
edema can lead to retinal thickening; and (3) there is
leakage of dye during fluorescein angiography such as
diabetic retinopathy. It is also evident that opacification
of the retina that is not due to retinal edema occurs very
early in disease. Histopathological examination of several
postmortem eyes taken from patients with MacTel shows
the presence of subretinal deposits and an abnormality of
Müller glial.
The incidence of MacTel is now estimated to be 1:22,000.6
A recent study correlating visual field defects detected by micro­
perimetry with OCT shows that the defects are closely associated
with cavitation of the outer retina, indicating that loss of vision
in MacTel is associated with loss of photoreceptors. Current evidence implies that photoreceptor cell loss is intrinsic to the disorder rather than being consequent upon blood vessel changes.
Photoreceptor abnormality occurs early in the disorder, and
progression of photoreceptor cell loss is not influenced by modulation of blood vessel changes using anti-VEGF treatment. To
date, there is no effective treatment for MacTel.
The class of molecules called “neurotrophic factors” has
been demonstrated to reduce the rate of photoreceptor cell loss
during retinal degeneration. One of these, ciliary neurotrophic
factor (CNTF), was found to be effective in slowing vision loss
from photoreceptor cell death in 12 animal models of outer
retinal degeneration (eg, rd/rd, rds/rds, 334ter-3 rats, 334ter-4
rats, P23H-1 rats, Rdy cats, rcd1 dogs). Similarly, delivery of a
neurotrophic factor to the outer retina in a mouse model that
shares many phenotypic MacTel characteristics has shown profound functional and anatomic photoreceptor cell rescue without
correcting associated vascular abnormalities.7 In addition, there
is evidence that CNTF can cause regeneration of cone outer segment in rats with mutations in the rhodopsin gene.8 Further,
76
Section X: Neovascular AMD
encapsulated cell delivery of CNTF has been tested in 3 human
Phase 2 safety studies in the treatment of retinal dystrophies and
atrophic age-related macular disease. In these studies, there is
some evidence of therapeutic benefit.9,10 The combined evidence
from animal and human studies suggests that use of neurotrophic molecules may provide therapeutic benefit for patients
with MacTel.
One major challenge is the delivery of this potential therapeutic CNTF agent to the back of the eye and in particular to
the retina. The blood-retinal barrier prevents the penetration of
a variety of molecules to the neurosensory retina from plasma,
in a manner similar to the action of the blood-brain barrier
between the central nervous system and systemic circulation. To
overcome this challenge, Neurotech USA developed encapsulated
cell technology (ECT) to enable controlled, sustained delivery of
therapeutic agents directly into the vitreous humor, thus providing direct access to the retina while restricting exposure of the
growth factor outside the eye. ECT utilizes cells encapsulated
within a semipermeable polymer membrane that secrete therapeutic factors directly into the vitreous. Further, ECT devices
can be surgically retrieved, providing an added level of safety.
Given the convergence of changing concepts of MacTel as a neurodegenerative disease and the development of technologies that
can deliver therapeutic doses of neurotrophic molecules to the
retina, the MacTel Project has sponsored a clinical trial designed
to assess the safety and efficacy of encapsulated cell-based therapeutic delivery of CNTF to patients with MacTel. Phase 1 results
of 4 years show that the device and CNTF are well tolerated
without any significant adverse events; the Phase 2 trial has just
recently competed enrollment, and 1-year interim data will be
evaluated in the second quarter of 2016.
In 2014 the sponsors of the MacTel Project decided to accelerate the pace and scope of research through increased resources
and establishment of a research institute devoted to full-time
investigation of MacTel and related neuro / vasculo / glial degenerative disease of the retina. Named the Lowy Medical Research
Institute (LMRI; www.lmri.org ), it is located next to the campus
of the Scripps Research Institute in La Jolla, California, and
in addition to its own full-time staff, continues to support the
activities of MacTel-related research through grants to nearly a
dozen laboratories and 22 clinics worldwide. In addition to basic
preclinical basic research, there are programs in adaptive optics,
OCT, metabolomics, visual psychophysics, and genetics. Several
hundred patients with MacTel and appropriate control populations have had whole exome and genome sequencing as well as
SNP-chip analysis providing data for linkage and genome-wide
association analyses. A number of candidate genes and gene
families have been identified and are currently being validated
and explored further.
In addition to dramatically increasing studies related to this
disorder, the LMRI/MacTel Project has been put forward as
a model for productive collaboration between private philanthropy and clinical / laboratory investigators. This topic has
received increasing attention recently as government funding
has leveled off and pharmaceutical industry investments have
2015 Subspecialty Day | Retina
become more restrictive.11 While a relatively small percentage of
total research funding currently comes from private philanthropy
compared to government and industry, this investment is growing and provides flexibility and quick start-up times that can
dramatically help a project.
In the presentation, recent findings from the Natural History
Study and Clinical Trials will be presented along with data from
GWAS and WES genetic studies. Imaging (adaptive optics and
OCT) studies and laboratory advances will also be discussed.
References
1. Gass JDM. A fluorescein angiographic study of macular dysfunction secondary to retinal vascular disease. V. Retinal telangiectasia.
Arch Ophthalmol. 1968; 80:592-605.
2. Gass JD, Oyakawa RT. Idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol. 1982; 100:769-780.
3. Charbel Issa P, Troeger E, Finger R, Holz FG, Wilke R, Scholl HP.
Structure-function correlation of the human central retina. PLoS
One 2010; 5(9):e12864.
4. Scoles D, Sulai YN, Langlo CS, et al. In vivo imaging of human
cone photoreceptor inner segments. Invest Ophthalmol Vis Sci.
2014; 55(7):4244-4251.
5. Wang Q, Tuten WS, Lujan BJ, et al. Adaptive optics microperimetry and OCT images show preserved function and recovery of
cone visibility in macular telangiectasia type 2 retinal lesions. Invest
Ophthalmol Vis Sci. 2015; 56(2):778-786.
6. Lamoureux E, Maxwell R, Marella M, Dirani M, Fenwick E,
Guymer R. The longitudinal impact of macular telangiectasia (MacTel) type 2 on vision-related quality of life. Invest Ophthalmol Vis
Sci. 2011; 52(5):2520-2524.
7. Dorrell MI, Aguilar E, Jacobson R, et al. Antioxidant or neurotrophic factor treatment preserves function in a mouse model of
neovascularization-associated oxidative stress. J Clin Invest. 2009;
119:611-623.
8. McGill TJ, Prusky GT, Douglas RM, et al. Intraocular CNTF
reduces vision in normal rats in a dose-dependent manner. Invest
Ophthalmol Vis Sci. 2007; 48:5756-5766.
9. Sieving PA, Caruso RC, Tao W, et al. Ciliary neurotrophic factor
(CNTF) for human retinal degeneration: Phase I trial of CNTF
delivered by encapsulated cell intraocular implants. Proc Natl Acad
Sci USA. 2006; 103:3896-3901.
10. Talcott KE, Ratnam K, Sundquist SM, et al. Longitudinal study of
cone photoreceptors during retinal degeneration and in response to
ciliary neurotrophic factor treatment. Invest Ophthalmol Vis Sci.
2011; 52(5):2219-2226.
11. Broad WJ. Billionaires with big ideas are privatizing American science. New York Times, March 15, 2014.
12. Chew EY, Clemons TE, Peto T, et al; MacTel-CNTF Research
Group (2015). Ciliary neurotrophic factor for macular telangiectasia type 2: results from a Phase 1 safety trial. Am J Ophthalmol.
2015; 159(4):659-666.
Section X: Neovascular AMD
2015 Subspecialty Day | Retina
Oral VEGF Receptor/PDGF Receptor Inhibitor X-82
Nauman A Chaudhry MBBS
NOTES
77
NOTES
Section X: Neovascular AMD
2015 Subspecialty Day | Retina
79
Sustained Drug Delivery Strategies in AMD
Peter K Kaiser MD
I.Introduction
A. Fixed dose anti-VEGF strategies lead to the best
visual acuity results.
B. Less frequent dosing leads to less optimal efficacy
results.
3. Does not last as long as viral vectors
C. Encapsulated cell technology
1. Transfected human RPE cells are placed within
surgically implanted cylinders covered in an
immunoprotective membrane, with pores that
allow oxygen and nutrients in but protect the
transfected human RPE cells from the host’s
immune system.
2. Surface area important; current implant has 5
rods
3. Reversible by implant removal
4. NT-503: Sustained release of sFlt-1
II. Higher Affinity Anti-VEFG Agents
A. Abicipar pegol: DARPin (designed ankyrin repeat
protein) technology
B. Conbercept: Fusion protein
C. RTH258: Single chain antibody fragment
III. Gene Therapy
A. Viral vectors
1.AAV2-sFlt-01
a. Several companies are using replication deficient adenovirus vectors to deliver the soluble
VEGF receptor 1 plasmid to target cells.
Blocks VEGF and PLGF.
b. Different injection locations
i. Intravitreal: Considered more immunogenic
ii. Subretinal: Technically more difficult
2. Different promoter systems can improve specificity.
3. Different viral vectors may improve transfection
rates.
4.Advantages
a. High transfection capacity
b. Can transfect specific cells
IV. Biodegradable Implants
A. Polymer based drug delivery platforms
1. Solvent casting and compression molding
2.Extrusion
3.Microparticles
a. Emulsion methods
(a) Use oil-in-water process, where polymer is dissolved in a water-immiscible
volatile organic solvent and the drug is
dissolved or suspended into the polymer solution
(b) Resulting mixture is emulsified in a
large volume of water in the presence
of an emulsifier (eg, polyvinyl alcohol).
(c) Solvent in the emulsion is removed,
either by evaporation at elevated temperatures or extraction in large quantities of water.
(d) Double emulsion can encapsulate
hydrophilic drugs.
5.Disadvantages
a. Potential immunogenicity
b.Inflammation
c. Risk of insertional mutagenesis
d. Uncontrolled duration with no exit strategy
e. Persistence of viral particles in the brain
f. Expensive to manufacture
1. Electric pulse induces cell membrane destabilization that persists for minutes after the electric
pulse, allowing the plasmid to be injected into
the cells; cell membrane changes are reversible.
2. Only cells within electric field get transfected.
ii. Water-soluble drugs
(a) Use water-in-oil process
(b) Emulsification using high-speed
homogenizers or sonicators
B. Non-viral gene therapy: Electrogenotherapy
i. Hydrophobic drugs
iii.Disadvantages
(a) Random particle sizes
(b) Low drug load
b. Phase separation
i. Drug is dissolved in a polymer solution.
80
Section X: Neovascular AMD
ii. Organic solvent (eg, silicone oil, vegetable
oil, liquid paraffin) is added to this mixture while it is stirred continuously.
iii. Polymer solvent is gradually extracted,
creating soft coacervate droplets.
iv. Droplets are exposed to another nonsolvent (eg, hexane or heptane) to harden the
coacervate phase.
c. Spray drying
i. Drug is dissolved or dispersed in a polymer
solution. One company is using high pressure chamber with CO2 under pressure to
mix polymer and drug to improve homogeneity.
ii. Solution is sprayed through a nozzle in a
stream of heated air to produce microparticles.
iii. Size of microparticles is determined by
atomizing conditions.
iv. Not suitable for drugs sensitive to heating
and the mechanical shear of atomization
i. Template approach to prepare particles of
predefined size and shape and with homogeneous size distribution
(a) Non-erodable templates
(b) Hydrogel templates
ii. Homogenous particle sizes
iii. Higher drug loading capacities
4. Different polymers offer variable release rates.
a. Poly-lactic-co-glycolic-acid (PLGA)
i. Only ophthalmology-approved polymer
(Ozurdex)
ii.Pro-Inflammatory
i. Poly(lactide) (PLA)
ii. Poly (glycolic acid) (PGA)
iii. Polyethylene glycol (PEG)
iv. Poly(caprolactone) (PCL)
1. Preformed depots: Formulated with hydrolytically degradable synthetic poly(ethylene glycol)
hydrogels
2.Thermoresponsive
C. Lipid-based drug delivery platforms
1. Hydrolysis of phospholipid layers surrounding
drug
2. Adjusting phospholipid formulation adjusts
release rates.
D.Tethadur
1. Porous, straw-like nanostructures
2. Size of pores determines release rate of drug contained within.
V. Nonbioerodable Reservoir Implants
b. Other polymers will have longer regulatory
pathway.
B. Hydrogel platforms
d.Microfabrication
2015 Subspecialty Day | Retina
A. Port delivery system
1. Surgically implanted through 3.2-mm sclerotomy
site
2. In-office refill
B. Micropumps: Replenish intraocular pump
VI. Future Technologies
Section XI: Imaging
2015 Subspecialty Day | Retina
81
Adaptive Optics
Assessing Retinal Structures Using Split-detector Adaptive Optics Scanning
Light Ophthalmoscope
Judy E Kim MD
By correcting the monochromatic aberrations induced by the
cornea and lens of the eye, adaptive optics scanning light ophthalmoscopy (AO-SLO) allows in vivo imaging of retinal structures with improved resolution. As a result, individual rod and
cone photoreceptors as well as retinal vessels have been imaged
in normal and diseased states. However, visualization of photoreceptors, which are seen as bright spots in confocal AO-SLO,
depends on intact outer segment morphology to allow detection
of directional coupling (waveguiding) of light. In disease states,
dark spots or areas may be present at the level of photoreceptors
when imaged with AO-SLO, and it has been difficult to know
whether this is due to absence of photoreceptors or due to lack of
waveguiding from the orientation and directionality of the outer
segments.
This previous limitation of confocal AO-SLO has been overcome by the recent development of a modified imaging technique
called nonconfocal split-detector AO-SLO. In this differential
phase technique, the photoreceptor inner segments can be visualized whether the outer segments are present or absent. A recent
study has shown that the diameter of inner segments visualized in
vivo with split-detector AO is in good agreement with histology.
Confocal and split-detector imaging can be performed simultaneously on subjects, and a comparison of images from normal
subjects revealed a 1:1 correspondence between the bright spot
in the confocal image and the mound-like structures in the splitdetector image, indicating corresponding cone photoreceptors.
In addition, despite presence of dark gaps in confocal AO
images, apparently intact inner segments were identified in subjects with disease states in foveal and perifoveal regions using
split-detector AO, suggesting remnant cone inner segments
despite substantial disruption of outer segments. Therefore, splitdetector imaging provides a method to visualize cone inner segments in a manner that appears to be independent of the integrity
of the outer segment.
The significance of these findings is that cone photoreceptor
analyses based only on confocal bright signals will underestimate
the degree of residual cone numbers when compared to using
split-detector AO. In addition, direct visualization of residual
cone structures is possible even in complex retinal diseases that
affect the outer segments and retinal pigment epithelial layer such
as AMD and inherited retinal degenerations. Split-detector imaging can also provide structural insight into the repair process of
conditions such as macular holes. Finally, better understanding
of the baseline quantification of remnant cone structures in disease states may allow better selection and follow-up of subjects
for clinical trials for gene therapy and pharmacotherapy.
Selected Readings
1. Liang J, Williams DR. Aberrations and retinal image quality of the
normal human eye. J Opt Soc Am A. 1997; 14:2873-2883.
2. Dubra A, Sulai Y, Norris JL, et al. Noninvasive imaging of the
human rod photoreceptor mosaic using a confocal adaptive optics
scanning ophthalmoscope. Biomed Opt Express. 2011; 2:18641876.
3. Scoles D, Sulai YN, Langlo CS, et al. In Vivo imaging of human
cone photoreceptor inner segments. Invest Ophthalmol Vis Sci.
2014; 55:4244-4251.
4. Randerson EL, Davis D, Higgins B, et al. Assessing photoreceptor
structure in macular hole using split-detector adaptive optics scanning light ophthalmoscopy. Eur Ophthalmic Review. 2015; 9:5963.
82
Section XI: Imaging
2015 Subspecialty Day | Retina
En Face OCT
Philip J Rosenfeld MD PhD
En face optical coherence tomography (OCT) imaging has come
of age over the past 10 years. This strategy makes sense since we
typically view the fundus using an en face approach during routine examinations and when using traditional photographic and
angiographic imaging techniques. Historically, en face imaging
and C-scan imaging were synonymous, but en face OCT imaging has evolved to be so much more than typical C-scan imaging. Typically, flat OCT C-scans failed to follow any anatomic
boundary, and this never made sense when imaging a curvilinear
tissue like the eye. Consecutive C-scan slices needed to be viewed
in aggregate in order to gain any useful insights into normal and
diseased anatomy. In contrast, current en face OCT imaging
algorithms follow defined layers in the retina and choroid. In
addition, the thickness of these layers can be adjusted so that the
images follow the anatomy of the eye and the ocular layers can
be dissected throughout the entire depth of the scan, from the
vitreous to the sclera. By using boundary-specific en face imaging, we can reliably and reproducibly examine the ocular layers
just as we would histopathologically. Moreover, the ability to
extract both B-scan and en face images from a single OCT dataset provides a valuable 3-dimensional perspective. Now, with the
advent of OCT angiography, we have the ability to view these
datasets over time, thus providing a fourth dimension to our
viewing capabilities. En face OCT imaging provides a valuable
strategy for diagnosing disease, following disease progression,
and determining when therapies are effective.
En face OCT imaging became clinically useful only in the
early 2000s, with the development of spectral domain OCT
(SD-OCT) and the ability to perform high-speed, high-density
raster scans of the retina. Jiao et al1,2 at the Bascom Palmer Eye
Institute were the first to report the use of en face OCT imaging based on defined retinal boundaries, resulting in the ability
to register OCT B-scans to a defined region of the fundus. This
strategy was patented and exclusively licensed to Carl Zeiss
Meditec (Dublin, CA; patent numbers US7301644, US7505142,
US7659990, US7924429, and US8319974). The key ideas in this
strategy were the ability to identify at least one surface in a 3-D
dataset, define a subvolume based on the surface, assign a single
representative intensity value along an axis of the subvolume,
and then display an image of the single representative intensity
values in a 2-D map. These patents were the subject of litigation
between Carl Zeiss Meditec and Optovue (Fremont, CA), which
was settled by a cross-licensing agreement (See “Zeiss settles
OCT patent infringement case,” SPIE website, http://optics.org/
news/3/1/18).
In its simplest form, en face OCT imaging can generate a
fundus image that incorporates much of the light reflected back
to the detector. This is known as an OCT fundus image (OFI) or
a summed voxel projection. By identifying the retina as a layer
between the inner limiting membrane (ILM) and the retinal pigment epithelium (RPE), it is possible to generate retinal thickness
maps. Retinal thickness maps are available on almost all OCT
instruments, and these maps have been used to study retinal
thickening and thinning in diseased states. In addition, different
layers within the retina have been segmented and studied in specific diseases, such as the nerve fiber layer and ganglion cell layer
in glaucoma. However, in the study of those diseases of interest
to the retina specialist, en face imaging has been particularly useful for following patients with exudative eye diseases, dry AMD
(geographic atrophy [GA], elevations of the RPE, and subretinal
drusenoid deposits), and diseases that affect the outer photoreceptor layer, particularly diseases that disrupt the inner segment /
outer segment / ellipsoid zone (IS/OS/EZ), such as in macular
telangiectasia type 2.
Geographic Atrophy
SD-OCT imaging identifies GA based on the characteristic
hypertransmission of light into the choroid below the Bruch
membrane that occurs when the RPE is absent. This increased
penetration of light into the choroid occurs because RPE and
choriocapillaris normally scatter the light, and their absence
permits more light to penetrate.3,4 When GA is visualized on an
OFI, the atrophy appears brighter than the surrounding area
since it represents the summation of all the reflected light from
all the A-scans. The use of the OFI to detect and measure areas
of GA and its growth has been shown to correlate well with GA
detection on clinical examination, color fundus imaging, and
fundus autofluorescence imaging.5,6
Another OCT-based en face imaging strategy for GA uses
only the light that is reflected from the choroid beneath the
Bruch membrane rather than all the reflected light in a given
A-scan. This image, derived from the sub-RPE slab, is similar in
principle to the OFI, with the area of GA on the sub-RPE slab
image appearing bright, but the sub-RPE slab image has higher
contrast at the borders of GA, and the GA appears more distinct
when compared with the OFI.7 An automated algorithm (available on the Cirrus HD-OCT instrument, Carl Zeiss Meditec)
is capable of automatically segmenting the GA margins on the
sub-RPE slab images, and the measurements of GA using both
the OFI and sub-RPE slab images were found to be highly correlated, with very good agreement between manual and automated
measurements. Currently, this automated algorithm is the only
FDA-approved algorithm commercially available for GA segmentation.
Outer Retinal Pathology
When diagnosing and following GA, an additional advantage
of SD-OCT en face imaging is that it can be used to assess the
integrity of different retinal layers surrounding GA, which
can help predict the directionality of GA growth. Nunes et al8
identified photoreceptor outer segment abnormalities along the
margins of GA by using a 20-µm thick SD-OCT en face slab that
included the ellipsoid zone (IS/OS/EZ; also known as band #2),
and abnormalities in this slab were found to extend over 1000
microns from the edge of GA in some eyes. These areas of EZ
disruption were shown to be predictive of where the GA would
enlarge over the ensuing year. Disruption in this IS/OS/EZ has
been correlated with abnormal photoreceptor function in a wide
range of exudative retinal diseases, but the quantitative loss of
this zone has been studied extensively in macula telangiectasia
2015 Subspecialty Day | Retina
Section XI: Imaging
83
type 2.9-11 Outer retinal en face imaging is also ideal for identifying and following outer retinal tubulation.12
Another en face OCT imaging strategy that can be used to
evaluate structural abnormalities in the retina utilizes a minimum intensity (MI) algorithm to create an en face image that
represents the minimum intensity signal from each A-scan. In
healthy retina, the minimum intensity (darkest signal) from each
OCT A-scan localizes within the outer nuclear layer (ONL) or
Henle fiber layer (HFL). In GA, this strategy has been used to
predict the margin of GA that was most likely to enlarge.13 In the
vicinity of focal pathology associated with GA progression, the
reflectivity of these normally dark layers often increases, and this
elevated reflectivity is presumably due to some disruption of the
photoreceptors at that location and can be visualized using an en
face minimum intensity slab projection image. Minimum intensity projection images have also been used to follow neovascular
AMD patients undergoing ranibizumab therapy.14
More recently, en face imaging of the photoreceptor / RPE
interface has been shown to be useful for identifying subretinal
drusenoid deposits, also known as reticular pseudodrusen. Using
a thin layer en face OCT imaging, Spaide et al15 demonstrated
the correlation between subretinal drusenoid deposits and reticular pseudodrusen. Using another en face imaging strategy, Schaal
et al demonstrated the utility of a 20-µm thick slab positioned
55 to 35 microns above the RPE layer for detecting the presence
and distribution of subretinal drusenoid deposits.16 In this study,
they used both montaged SD-OCT en face images and widefield
swept source OCT en face images that measured 9x12 mm.
3. Bearelly S, Chau FY, Koreishi A, et al. Spectral domain optical
coherence tomography imaging of geographic atrophy margins.
Ophthalmology 2009; 116(9):1762-1769.
Summary
11. Nunes RP, Goldhardt R, de Amorim Garcia Filho CA, et al.
Spectral-domain optical coherence tomography measurements of
choroidal thickness and outer retinal disruption in macular telangiectasia type 2. Ophthalmic Surg Lasers Imaging Retina. 2015;
46(2):162-170.
With the emergence of high-speed, high-density OCT raster scanning techniques, en face OCT imaging technology has become
popular among retina specialists as shown by the exponential
increase in publications on this topic, a recently published
atlas,17 and the overflowing attendance at the annual International En-Face OCT Congress held in Rome on the second Saturday in December. As OCT scanning speeds increase, as swept
source OCT technology becomes more widespread, and as OCT
angiography spreads globally, en face OCT imaging will become
even more prevalent in the clinics. After all, why subject patients
to the discomfort, time, and cost associated with multimodal
imaging when the use of OCT can provide multidimensional,
widefield imaging of the retina and choroid that provides highquality fundus images, which are achieved quickly and with
minimal discomfort through an undilated pupil.
4. Lujan BJ, Rosenfeld PJ, Gregori G, et al. Spectral domain optical
coherence tomographic imaging of geographic atrophy. Ophthalmic Surg Lasers Imaging. 2009; 40(2):96-101.
5. Yehoshua Z, Rosenfeld PJ, Gregori G, et al. Progression of geographic atrophy in age-related macular degeneration imaged with
spectral domain optical coherence tomography. Ophthalmology
2011; 118(4):679-686.
6. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al. Comparison of geographic atrophy growth rates using different imaging
modalities in the COMPLETE Study. Ophthalmic Surg Lasers
Imaging Retina. 2015; 46(4):413-422.
7. Yehoshua Z, Garcia Filho CA, Penha FM, et al. Comparison of
geographic atrophy measurements from the OCT fundus image and
the sub-RPE slab image. Ophthalmic Surg Lasers Imaging Retina.
2013; 44(2):127-132.
8. Nunes RP, Gregori G, Yehoshua Z, et al. Predicting the progression
of geographic atrophy in age-related macular degeneration with SDOCT en face imaging of the outer retina. Ophthalmic Surg Lasers
Imaging Retina. 2013; 44(4):344-359.
9. Sallo FB, Peto T, Egan C, et al. “En face” OCT imaging of the IS/
OS junction line in type 2 idiopathic macular telangiectasia. Invest
Ophthalmol Vis Sci. 2012; 53(10):6145-6152.
10. Chew EY, Clemons TE, Peto T, et al. Ciliary neurotrophic factor
for macular telangiectasia type 2: results from a Phase 1 safety trial.
Am J Ophthalmol. 2015; 159(4):659-666 e1.
12. Jung JJ, Freund KB. Long-term follow-up of outer retinal tubulation documented by eye-tracked and en face spectral-domain optical coherence tomography. Arch Ophthalmol. 2012; 130(12):16181619.
13. Stetson PF, Yehoshua Z, Garcia Filho CA, et al. OCT minimum
intensity as a predictor of geographic atrophy enlargement. Invest
Ophthalmol Vis Sci. 2014; 55(2):792-800.
14. Nicholson BP, Nigam D, Toy B, et al. Effect of ranibizumab on
high-speed indocyanine green angiography and minimum intensity
projection optical coherence tomography findings in neovascular
age-related macular degeneration. Retina 2015; 35(1):58-68.
References
15. Spaide RF. Colocalization of pseudodrusen and subretinal
drusenoid deposits using high-density en face spectral domain optical coherence tomography. Retina 2014; 34(12):2336-2345.
1. Jiao S, Knighton R, Huang X, et al. Simultaneous acquisition of sectional and fundus ophthalmic images with spectral-domain optical
coherence tomography. Opt Express. 2005; 13(2):444-452.
16. Schaal KB, Legarreta AD, Gregori G, et al. Widefield en face optical
coherence tomography imaging of subretinal drusenoid deposits.
Ophthalmic Surg Lasers Imaging Retina. 2015; 46(5):550-559.
2. Jiao S, Wu C, Knighton RW, et al. Registration of high-density
cross sectional images to the fundus image in spectral-domain
ophthalmic optical coherence tomography. Opt Express. 2006;
14(8):3368-3376.
17. Lumbroso B, Huang D, Romano A, et al. Clinical En Face OCT
Atlas. New Dehli, India: Jaypee Brothers Medical Publishers; 2013.
84
Section XI: Imaging
2015 Subspecialty Day | Retina
Adaptive Optics Scanning Laser Ophthalmoscopy
Jacque L Duncan MD
I. Adaptive Optics Scanning Laser Ophthalmoscopy
(AO-SLO): New Noninvasive Retinal Imaging ­
Modality
A. Aberrations in light exiting the eye prevent imaging
individual photoreceptors with single-cell resolution.
B. Adaptive optics is a technique to precisely measure
and compensate for aberrations.
1. Shack-Hartmann wavefront sensor measures
aberrations emerging from pupil illuminated
with a near-infrared scanning laser ophthalmoscope.
2. Aberrations are communicated to a deformable
mirror that bends its shape to compensate for
and correct aberrations, such 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 normal eye 3 degrees nasal and 1
degree superior to fixation. Small white spots indicate light waveguided
by individual cones.
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. Correlation with cross-sectional images of retinal
structure using spectral domain OCT
Figure 2. Composite image where AO-SLO montage is precisely aligned
with images from SD-OCT using retinal vascular landmarks permits
3-dimensional assessment of retinal structure and identification of
regions of interest to follow longitudinally. Horizontal and vertical lines
indicate location of SD-OCT scans, which are translated temporally
and inferiorly from the fovea for visualization of the AO-SLO montage.
Regions of interest where individual cones are unambiguous are indicated
with boxes and named with initials and numbers indicating their position
with respect to the fovea as follows—L: left, R: right, U: upper, L: lower,
S: superior, I: inferior. Region of interest UR2 is shown in Figure 1.
Section XI: Imaging
2015 Subspecialty Day | Retina
D. AO-SLO enables observation of cone photoreceptors longitudinally over time.
1. Identify regions of interest where cones are seen
unambiguously
2. Monitor cone spacing, cone packing, and cone
density at regions of interest to provide objective,
sensitive outcome measure for clinical trials
a. Macular telangiectasia type 2
i. AO-SLO microperimetry reveals function
in areas where cones were not visible but
external limiting membrane band was preserved on SD-OCT scans.
ii. Confocal AO-SLO images require intact
inner segment / outer segment junction or
ellipsoid zone bands and outer segment /
RPE bands to be visible.
iii. Residual, partially degenerating photoreceptors may retain measurable visual function (albeit with reduced sensitivity) where
cones have lost outer segments but retain
inner segments.
E. New AO-SLO systems use non-confocal scattered
light to visualize cone inner segments and retinal
pigment epithelial (RPE) cells.
3. Uses AO-SLO microperimetry to assess function
in localized areas where cones are not visible
using confocal images
Figure 3. Cone counting at baseline (left panel) and 12 months later
(right panel) at region of interest UR2 shown in Figures 1 and 2. Cones
are marked with plus symbols.
b. Case presentation: Acute macular neuroretinopathy
i. Initially visual acuity is severely reduced
and cones are not visible within foveal
area.
ii. Three years later, visual acuity recovered
with improved visual function in regions
where cones are still not visible.
iii. AO-SLO measures of visual function provide evidence of residual cones that cannot
be seen with other imaging modalities.
F. AO-SLO microperimetry
1. Uses AO-SLO to correct aberrations and deliver
small visual stimuli precisely to individual cones
or small groups of cones
2. Combines with high-speed fundus tracking to
test cone function of individual cones or regions
where cones are not visible
85
G. In summary, AO-SLO is a novel, high-resolution
tool for retinal imaging that provides novel insights
into the structure and function of macular cones in
patients with retinal disease.
86
Section XI: Imaging
2015 Subspecialty Day | Retina
Multimodal Imaging
Alain Gaudric MD
I. What imaging modalities can be used?
The term “multimodal imaging” simply refers to the
possibility of comparing several images of a fundus
obtained from different imaging techniques or sources
and providing complementary (additional) information. The term is also used in other fields of medical
imaging. Multiplying imaging sources allows a large
possibility of multimodal combinations.
Fundus photographs were traditionally obtained
with a retinograph equipped with a charge coupled
device (CCD) camera, but scanner laser ophthalmoscope (SLO) tends to replace CCD devices, including
for color photos by combining several wavelengths.
In addition to traditional fundus color and red-free
photographs, blue reflectance images may be added
to show the macular pigment and to characterize
retinal surface anomalies.
B. Fundus autofluorescence (FAF)
FAF in blue light is commonly used to assess the
lipofuscin content of the retinal pigment epithelium
(RPE) and may show a hypo- or hyperautofluorescence.1 However, the visual pigments contained
in the photoreceptor outer segments also provide
autofluorescence, which is revealed by the bleaching
procedure.2 Lastly, FAF may be used to measure
macular pigment density.
OCT can be used along with various modalities,
including B-scans, possibly improved by enhanced
deep imaging (EDI) mode, topographic thickness
map, or en face images (C-scans) segmented at various levels. The co-recording of a detailed SLO image
of the fundus and of a B- or C-scan OCT allows us
to compare, point by point, retinal anomalies seen
on the various modalities. The OCT signal processed along with a decorrelation mode may also
display the vascular component of the retina in 3
dimensions.4,5
1. Fluorescein angiography (FA) has the potential
of showing circulation times and vascular filling,
abnormal vessel permeability, and pooling of dye
or staining of abnormal retinal structures.
1. The use of ultrawide-field images allows for the
easy visualization of the peripheral retina,6 even
if some detail is lost in the macula.
2. On the other hand, the details of retinal structures, vessels, and photoreceptors may be
observed at a higher magnification by adaptive
optics (AO) in en face mode.7-9
The correlation between all these imaging modalities
is usually not automated and should be done mentally
or, for clinical research purposes, by overlying manually the different images, with some problems related to
various magnifications or distortions of the images that
differ from one device to another.
II. What kind of multimodal imaging do we need?
A. Imaging modality combination
Comparison between fundus color (as a surrogate
for ophthalmoscopy) or monochromatic images and
B-scan OCT is the basic multimodal imaging modality and is now part of the routine clinical practice.
This information is usually sufficient to make the
diagnosis in most cases. However, other modalities
may be added if needed, according to the type of
disease.
FA is commonly used, for instance, to confirm the
diagnosis of CNV in AMD or to assess capillary
perfusion in diabetic retinopathy. Adding blue
reflectance imaging may be useful to characterize
retinal surface anomalies such as epiretinal membrane, dissociated optic nerve fiber layer after inner
limiting membrane peeling, or defects in the optic
nerve fiber layer, although all these anomalies may
also be shown by B- or C-scan OCT. However, the
macular xanthophyll pigment is specifically detected
by blue reflectance image and FAF.
The use of FAF is especially useful in assessing the
degree of outer retinal atrophy in diseases such as
hereditary retinal dystrophies, chronic central chorioretinopathy (CSC), or dry AMD, for instance.
D. Fundus angiography
So multimodal imaging is like a Swiss army knife that
allows cutting, dissecting, and opening the retinal
image in various planes.
C. Optical coherence tomography (OCT)
Lastly, the field and magnification of fundus observation have moved in two directions:
Near infrared (NIR) autofluorescence has the potential to detect melanin fluorescence3 and helps differentiate it from that of lipofuscin.
E. Wide-field and high magnification
A. Fundus photographs
2. Indocyanine green angiography (ICGA) shows
better choroidal circulation, but the information
provided by these two angiographic modalities is
partially challenged by the advances in OCT.
Section XI: Imaging
2015 Subspecialty Day | Retina
the progression of RPE atrophy,18 which may
occur after repeated anti-VEGF injections.
B.Examples
The following examples discuss the value of various imaging modalities for some common diseases.
Color fundus photograph and B-scan OCT are
the cornerstone of the diagnosis, to which various
modalities may be added. However, in order to
improve our understanding of macular diseases, a
more comprehensive multimodal imaging may be
used.
3. Diabetic retinopathy (DR)
1. Central serous chorioretinopathy (CSC)
a. Acute CSC
b. Chronic CSC
In chronic CSC, the diagnosis may be more
challenging, and differential diagnoses such
as polypoid choroidal vasculopathy (PCV) or
choroidal inflammatory or malignant infiltration should be ruled out. The comparison
between FAF, OCT in EDI mode, and ICGA
will help to make the diagnosis.10,11
The frequent presence of flat irregular pigment epithelium detachment in the macula
under the detached retina may be suggestive
of CNV12: OCT-angio appears today as a
promising technology to characterize new vessels.11 For research purposes, FAF bleaching
enables differentiating hyperautofluorescence
due to subretinal accumulation of lipofuscin
and photoreceptor outer segment atrophy.13
The diagnosis of acute CSC requires only
a minimum of imaging tests: B-scan OCT
shows the serous retinal detachment, and FA
is needed to visualize the leaking point for
diagnosis confirmation and treatment indication.
2.AMD
a. Geographic atrophy
Color fundus photo and, even more, FAF are
the best modalities to characterize and localize the atrophy with respect to the foveal center.1,14 OCT in C-mode may be a surrogate
for FAF to delineate RPE and choroidal atrophy,15 and B-scan may rule out the presence
of associated choroidal new vessels (CNV).
For a research purposes, AO may be used to
monitor thoroughly the changes at the atrophy edge.16
b. Neovascular AMD
Color fundus photo and B-scan OCT usually provide enough information to diagnose
CNV, even if FA is still frequently used at the
initial examination. However, OCT-angio
could become shortly the main diagnostic
test, as it combines in a single acquisition
the angio-flow, showing the neovascular
network,17,18 and the B-scan, showing the
impact of CNV on the underlying retina. For
a research purpose, FAF may be used to assess
87
a. Diagnosis and grading
The diagnosis and grading of DR is based on
fundus color photos and OCT to assess macular edema when present. However, the use of
ultrawide-field SLO imaging may change our
grading method, including the use of widefield FA.6,19-21
b. Treatment of macular edema
Initial workup includes FA and OCT, while
the monitoring is only based on OCT. However, OCT-angio, combined with B-scan
OCT, might provide a better assessment of
capillary density than FA and be part of the
routine examination of diabetic macular
edema. In the future, multimodal imaging of
DR might combine ultrawide-field examination of the fundus, for peripheral ischemia,
with OCT-angio, for a high-resolution assessment of the macular capillary network,5,22,17
combined with B-scan OCT to measure
macular thickness. For a research purpose,
quantifying peripheral retinal ischemia and
capillary perfusion density in the macula
might become a new prognosis indicator.6
4. Macular telangiectasia type 2 (MacTel 2)
MacTel2 is characterized by many anomalies
affecting the macula. Blue reflectance images
showing an oval-shaped whitening of the
macula, occasionally with crystals, and B-scan
OCT showing the formation of inner or outer
foveal cysts in a nonthickened retina provide
usually enough information to identify a case of
MacTel2.23,24 However, for a research purpose,
quantifying macular pigment loss, OCT-angio
assessment of outer retina capillary invasion,25
and cone density measurement on AO26 may be
used to better stage the cases.23-25
III.Conclusion
In many instances, only a few imaging modalities are
needed to make the diagnosis of retinal diseases. However, in unusual or complex diseases additional modalities may be added to better characterize the retinal
layers affected by the disease. The optimum number of
tests that should be performed to make the diagnosis
of various conditions has not been evaluated so far.
Moreover, the constant development of new imaging
techniques results in frequent paradigm shifts in the
way we diagnose retinal diseases. The reader should
also be reminded that functional tests, and especially
electrophysiology, are major determinants in various
retinal diseases, including in hereditary retinal dystrophies. Even then, multimodal imaging per se is a powerful tool to characterize most retinal diseases, but its
performance remains to be improved.
88
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2015 Subspecialty Day | Retina
References
1. Holz FG, Steinberg JS, Gobel A, Fleckenstein M, Schmitz-Valckenberg S. Fundus autofluorescence imaging in dry AMD: 2014 Jules
Gonin Lecture of the Retina Research Foundation. Graefes Arch
Clin Exp Ophthalmol. 2015; 253(1):7-16.
2. Theelen T, Berendschot TT, Boon CJ, Hoyng CB, Klevering BJ.
Analysis of visual pigment by fundus autofluorescence. Exp Eye
Res. 2008; 86(2):296-304.
3. Cideciyan AV, Swider M, Jacobson SG. Autofluorescence imaging
with near-infrared excitation:normalization by reflectance to reduce
signal from choroidal fluorophores. Invest Ophthalmol Vis Sci.
2015; 56(5):3393-3406.
4. Nagiel A, Sadda SR, Sarraf D. A promising future for optical
coherence tomography angiography. JAMA Ophthalmol. 2015;
133(6):629-630.
5. Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers
imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol. 2015; 133(1):45-50.
6. Patel M, Kiss S. Ultra-wide-field fluorescein angiography in retinal
disease. Curr Opin Ophthalmol. 2014; 25(3):213-220.
7. Carroll J, Kay DB, Scoles D, Dubra A, Lombardo M. Adaptive
optics retinal imaging--clinical opportunities and challenges. Curr
Eye Res. 2013; 38(7):709-721.
8. Kim JE, Chung M. Adaptive optics for retinal imaging: current status. Retina 2013; 33(8):1483-1486.
9. Zawadzki RJ, Capps AG, Kim DY, et al. Progress on developing
adaptive optics-optical coherence tomography for retinal imaging:
monitoring and correction of eye motion artifacts. IEEE J Sel Top
Quantum Electron. 2014; 20(2).
10. Daruich A, Matet A, Dirani A, et al. Central serous chorioretinopathy: recent findings and new physiopathology hypothesis. Prog
Retin Eye Res. Epub ahead of print 2015 May 27. doi: 10.1016/j.
preteyeres.2015.05.003.
11. Bonini Filho MA, de Carlo TE, Ferrara D, et al. Association of choroidal neovascularization and central serous chorioretinopathy with
optical coherence tomography angiography. JAMA Ophthalmol.
Epub ahead of print 2015 May 21. doi: 10.1001/jamaophthalmol.2015.1320.
12. Hage R, Mrejen S, Krivosic V, Quentel G, Tadayoni R, Gaudric A.
Flat irregular retinal pigment epithelium detachments in chronic
central serous chorioretinopathy and choroidal neovascularization.
Am J Ophthalmol. 2015; 159(5):890-903 e893.
13. Freund KB, Mrejen S, Jung J, Yannuzzi LA, Boon CJ. Increased
fundus autofluorescence related to outer retinal disruption. JAMA
Ophthalmol. 2013; 131(12):1645-1649.
14. Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren Campagne M. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology 2014; 121(5):1079-1091.
15. Stetson PF, Yehoshua Z, Garcia Filho CA, Portella Nunes R, Gregori G, Rosenfeld PJ. OCT minimum intensity as a predictor of
geographic atrophy enlargement. Invest Ophthalmol Vis Sci. 2014;
55(2):792-800.
16. Gocho K, Sarda V, Falah S, et al. Adaptive optics imaging of geographic atrophy. Invest Ophthalmol Vis Sci. 2013; 54(5):36733680.
17. Moult E, Choi W, Waheed NK, et al. Ultrahigh-speed swept-source
OCT angiography in exudative AMD. Ophthalmic Surg Lasers
Imaging Retina. 2014; 45(6):496-505.
18. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al. Comparison of geographic atrophy growth rates using different imaging
modalities in the COMPLETE Study. Ophthalmic Surg Lasers
Imaging Retina. 2015; 46(4):413-422.
19. Silva PS, Cavallerano JD, Haddad NM, et al. Peripheral lesions
identified on ultrawide field imaging predict increased risk of diabetic retinopathy progression over 4 years. Ophthalmology 2015;
122(5):949-956.
20. Price LD, Au S, Chong NV. Optomap ultrawide field imaging
identifies additional retinal abnormalities in patients with diabetic
retinopathy. Clin Ophthalmol. 2015; 9:527-531.
21. Manjunath V, Papastavrou V, Steel DH, et al. Wide-field imaging
and OCT vs clinical evaluation of patients referred from diabetic
retinopathy screening. Eye (Lond). 2015; 29(3):416-423.
22. Ishibazawa A, Nagaoka T, Takahashi A, et al. Optical coherence
tomography angiography in diabetic retinopathy: a prospective
pilot study. Am J Ophthalmol. 2015; 160(1):35-44 e31.
23. Sallo FB, Leung I, Clemons TE, Peto T, Bird AC, Pauleikhoff D.
Multimodal imaging in type 2 idiopathic macular telangiectasia.
Retina 2015; 35(4):742-749.
24. Charbel Issa P, Gillies MC, Chew EY, et al. Macular telangiectasia
type 2. Prog Retin Eye Res. 2013; 34:49-77.
25. Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers in
macular telangiectasia type 2 imaged by optical coherence tomographic angiography. JAMA Ophthalmol. 2015; 133(1):66-73.
26. Jacob J, Paques M, Krivosic V, et al. Meaning of visualizing retinal
cone mosaic on adaptive optics images. Am J Ophthalmol. 2015;
159(1):118-123 e111.
Section XI: Imaging
2015 Subspecialty Day | Retina
89
Swept Source OCT
Kyoko Ohno-Matsui MD
The recent advances in ocular imaging by different technologies
have been remarkable. Among the different techniques for ocular
imaging, OCT has attained the greatest and most rapid advancements. This has resulted in the development of the many types
of OCT instruments that are commercially available. Among
them, the swept source OCT instrument uses a light source that
is fundamentally more complex than that used by conventional
spectral domain OCT (SD-OCT) instruments.
The falloff in sensitivity within the tissue for the swept source
OCT is much less than that for SD-OCT instruments. This
is because the wavelength of the swept laser source is in the
1-micron region, and this longer wavelength is capable of penetrating deeper into tissues than are the relatively shorter wavelengths typically used in the SD-OCT instruments. In addition,
the new technique of dynamic focusing provides a greater depth
of focus.1 Thus, both the vitreous and the deeper choroid and
sclera can be imaged simultaneously by swept source OCT.2 The
imaging of very deep tissues (eg, tissues posterior to the sclera),
which is generally not possible to do with conventional SD-OCT
instruments, can be made in situ.2 This is especially true for
highly myopic eyes with thin retinas and choroids, which allows
clinicians to view structures even posterior to the eye globe.3
Observations of structures deep in the optic nerve such as the
lamina cribrosa and subarachnoid space are also possible. Such
in situ observations deep into the optic nerve and deep into the
sclera and beyond have already contributed greatly to unraveling
the pathogenesis of various ocular pathologies.
OCT angiography is a relatively new technology that can
record the movements of the erythrocytes and allows a 3-dimensional view of the perfused vasculature of the retina and choroid.
Using swept source-based OCT angiography, we can view the
deeper vascular structures such as the large choroidal and intrascleral vessels and the vasculature in the optic nerve. This is possible because of the ability of the light to penetrate deeper into
tissues than the conventional OCT instruments.
In this presentation, I shall show how to view and interpret
the images obtained by the swept source OCT instruments, and
also how such improved imaging can contribute to the clinical
management of different ocular disorders.
Imaging the Vitreous
The swept source OCT technique of dynamic focusing and windowed averaging allows a greater depth of focus than previous
methods and allows clear images of the anatomy of the vitreous
in situ.1
Imaging the Sclera and Orbit
In highly myopic eyes with thin retinas and choroids, the entire
thickness of the sclera can be observed. In addition, structures
deeper than the outer border of the sclera, the retrobulbar structures, are visible in the swept source OCT images in some individuals.
Imaging the Optic Nerve
Detailed images of the structure of the optic disc and lamina
cribrosa (eg, focal defects, optic disc pits) can be seen with enough
resolution to make diagnoses. In eyes with a large peripapillary
conus, the subarachnoid space as well as the arterial ring of ZinnHaller can be seen. In eyes with congenital optic disc anomalies,
the spatial relationship between the subarachnoid space and optic
disc pits or disc colobomas can be clearly imaged.5
Swept Source OCT Angiography
Swept source OCT angiography can obtain images of the retinal
vasculature and choriocapillaris, as well as the deeper vessels
including the large choroidal vessels and the intrascleral vessels
in some individuals. The vasculature within and around the optic
nerve can also be observed.6
In summary, swept source OCT will enable clinicians to
obtain clear images of the eye with great range of depths, from
the vitreous to the retina-choroid, and in some eyes, even deeper
to the sclera, retrobulbar orbit, and structures of the optic nerve.
Swept source OCT angiography enables clear observations of the
vasculature of such deep tissues. Thus, swept source OCT should
be a powerful tool for imaging the tissues at various depths,
which should help in the diagnosis and treatment of different diseases. It will also be useful for the clinical management of various
disorders involving the retina, choroid, sclera, retrobulbar orbit,
and optic nerve.
References
1. Spaide RF. Visualization of the posterior vitreous with dynamic
focusing and windowed averaging swept source optical coherence
tomography. Am J Ophthalmol. 2014; 158(6):1267-1274.
2. Mrejen S, Spaide RF. Optical coherence tomography: imaging of
the choroid and beyond. Surv Ophthalmol. 2013; 58(5):387-429.
3. Ohno-Matsui K, Akiba M, Modegi T, et al. Association between
shape of sclera and myopic retinochoroidal lesions in patients with
pathologic myopia. Invest Ophthalmol Vis Sci. 2012; 53:6046-6061.
Imaging the Retina-Choroid
4. Spaide RF. The choroid. In: Spaide RF, Ohno-Matsui K, Yannuzzi
LA, eds. Pathologic Myopia. New York: Springer; 2014:113-132.
In addition to a clear observation of the retinal structures,
detailed observations of the inner retinal and choroidal structures
can be obtained by swept source OCT.4 The choroidal images
obtained by swept source OCT are helpful in diagnosing and
managing choroidal tumors.
5. Ohno-Matsui K, Hirakata A, Inoue M, Akiba M, Ishibashi T.
Evaluation of congenital optic disc pits and optic disc colobomas
by swept-source optical coherence tomography. Invest Ophthalmol
Vis Sci. 2013; 54(12):7769-7778.
6. Jia Y, Wei E, Wang X, et al. Optical coherence tomography angiography of optic disc perfusion in glaucoma. Ophthalmology 2014;
121(7):1322-1332.
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2015 Subspecialty Day | Retina
Choroidal OCT in Inflammation
Anita Agarwal MD
Choroidal imaging by utilizing the extended depth imaging
(EDI) technique first described by Spaide et al1 is evolving as yet
another technique in improving our understanding of chorioretinal disorders and their pathology. This presentation will illustrate various OCT manifestations of choroidal and chorioretinal
inflammatory disorders using case examples.
I. Choroidal Disorder: Sarcoid Granuloma2,3
Sarcoid: Space occupying in choroid
Figure 3.
Figure 4.
Figure 1.
Figure 5.
Figure 6.
Figure 2.
Section XI: Imaging
2015 Subspecialty Day | Retina
II. Chorioretinal Disorders
A. Acute posterior multifocal placoid pigment epitheliopathy (APMPPE): Affects retinal pigment epithelium, photoreceptors, and choriocapillaris
Figure 9.
Figure 10.
Figure 7.
Figure 8.
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Section XI: Imaging
2015 Subspecialty Day | Retina
B. Serpiginous like
1. Affects choroid and choriocapillaris
2. Thickened choroid on OCT and focal granuloma
Figure 13.
Figure 11.
Figure 14.
Figure 12.
2015 Subspecialty Day | Retina
C. Vogt-Koyanagi-Harada (VKH) syndrome
1. Affects choroid diffusely and focally
2. Thickened choroid on OCT, subretinal fluid and
fibrin bands
Figure 15.
Figure 16.
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2015 Subspecialty Day | Retina
D. Birdshot chorioretinopathy:4-11 Affects choroid
(thickened)
Figure 17.
Figure 18.
References
1. Spaide RF. Enhanced depth imaging optical coherence tomography
of retinal pigment epithelial detachment in age-related macular
degeneration. Am J Ophthalmol. 2009; 147(4):644-652.
7. Ishihara K, Hangai M, Kita M, Yoshimura N. Acute Vogt-Koyanagi-Harada disease in enhanced spectral-domain optical coherence tomography. Ophthalmology 2009; 116(9):1799-1807.
2. Rostaqui O, Querques G, Haymann P, Fardeau C, Coscas G, Souied EH. Visualization of sarcoid choroidal granuloma by enhanced
depth imaging optical coherence tomography. Ocul Immunol
Inflamm. 2014; 22(3):239-241.
8. Gupta V, Gupta A, Gupta P, Sharma A. Spectral-domain Cirrus
optical coherence tomography of choroidal striations seen in the
acute stage of Vogt-Koyanagi-Harada disease. Am J Ophthalmol.
2009; 147(1):148-153e2.
3. Goldberg NR, Jabs DA, Busingye J. Optical coherence tomography
imaging of presumed sarcoid retinal and optic nerve nodules. Ocul
Immunol Inflamm. 2014; 1-4.
9. Sherif E. When you can have the bird without shooting it!
Extramacular enhanced depth optical coherence tomography in birdshot chorioretinopathy. JAMA Ophthalmol. 2013;
131(10):1369.
4. da Silva FT, Sakata VM, Nakashima A, et al. Enhanced depth imaging optical coherence tomography in long-standing Vogt-KoyanagiHarada disease. Br J Ophthalmol. 2013; 97(1):70-74.
5. Nakayama M, Keino H, Okada AA, et al. Enhanced depth imaging
optical coherence tomography of the choroid in Vogt-KoyanagiHarada disease. Retina 2012; 32(10):2061-2069.
6. Lee GE, Lee BW, Rao NA, Fawzi AA. Spectral domain optical
coherence tomography and autofluorescence in a case of acute posterior multifocal placoid pigment epitheliopathy mimicking VogtKoyanagi-Harada disease: case report and review of literature. Ocul
Immunol Inflamm. 2011; 19(1):42-47.
10. Keane PA, Allie M, Turner SJ, et al. Characterization of birdshot
chorioretinopathy using extramacular enhanced depth optical
coherence tomography. JAMA Ophthalmol. 2013; 131(3):341-350.
11. Witkin AJ, Duker JS, Ko TH, Fujimoto JG, Schuman JS. Ultrahigh
resolution optical coherence tomography of birdshot retinochoroidopathy. Br J Ophthalmol. 2005; 89(12):1660-1661.
Section XI: Imaging
2015 Subspecialty Day | Retina
95
Autofluorescence
Integrating Fundus Autofluorescence Into Clinical Practice
David Sarraf MD
I.Definitions
A. Fluorescence: Emission of a wavelength of light
upon stimulation by light of a different wavelength
B. Autofluorescence: Intrinsic fluorescent capability;
no need for dye administration
II. Common Ocular Fluorophores
A.Cornea
B. Crystalline lens
C. Photoreceptor metabolites (3 billion outer segments
phagocytosed by retinal pigment epithelium, RPE)
D. Lipofuscin, A2E, and other visual cycle fluorophores
E. Subretinal vitelliform material
F. Optic nerve head drusen
G. Astrocytic hamartoma
H.Sclera
1. Excitation filter (band-pass filter): 535-580 nm
2. Barrier filter (band-pass filter): 615-715 nm
3. Wavelength selection rejects unwanted autofluorescence (eg, cornea and lens).
4.Advantages
A. Confocal scanning laser ophthalmoscope (Heidelberg)
a. Less absorption of excitation light by luteal
pigment (xanthophyll)
b. More comfortable for patient
c. Color and FAF on same camera
d. FAF possible after fluorescein angiography
5.Disadvantages
a. Poor image quality with nuclear sclerosis
b. Images have less contrast, no image averaging.
D. Ultrawide-field system (Optos): SLO
1. Excitation: 532 nm
2. Emission: >540 nm
3.Advantages
1. Excitation: 488 nm
a. Widest field of view
2. Emission: > 500 nm
3. Confocal: Stimulation and emission focused at
the same optical plane
b. Less absorption of excitation light by luteal
pigment (xanthophyll)
c. Color and FAF on same camera
4.Advantages
d. FAF possible after fluorescein angiography
a. Real-time averaging: Increased signal / noise,
improved contrast
b. Confocal system eliminates nonretinal FAF
(eg, lens).
c. 20, 30, and 55 degree images
d. Macular pigment density measurements
5.Disadvantages
III. Commonly Used Fundus Autofluorescence (FAF)
Systems
C. Spaide filters adapted for Topcon fundus camera
a. Excitation wavelength (light) absorbed by
macular pigment (xanthophyll)
b. Can’t do confocal scanning laser ophthalmo­
scopy (cSLO) FAF after fluorescein angiography (FA)
c. Intense blue light is uncomfortable for
patient.
d. Possible loss of information with averaging
B. Fundus camera (Topcon, Zeiss, Canon)
4.Disadvantages
a. Image artifacts
b. No averaging, poor contrast
IV. Basic FAF Terminology
A. Hyperautofluorescence
B.Hypoautofluorescence
C.Isofluorescence
V. Causes of Reduced Autofluorescence
(Hypoautofluorescence)
A. Reduced or absent RPE lipofuscin
1. RPE atrophy (eg, geographic atrophy, central
serous chorioretinopathy, hereditary)
2. RPE tear
3. Reduced visual cycle (eg, RDH5)
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Section XI: Imaging
B. Blockage from material anterior to the RPE
1. Media opacities
2. Macular pigment (eg, lutein and zeaxanthin)
3. Intraretinal and/or subretinal hemorrhage
4. Fibrosis and scar tissue
5. Migrated melanin-containing cells (eg, spicules)
VI. Causes of Increased Autofluorescence (Hyperautofluorescence)
A. Increased RPE lipofuscin
1. Lipofuscinopathies including Stargardt, pattern
dystrophy
2. RPE tear (scrolled or retracted border)
B. Subretinal autofluorescent material
1. Best disease
2. Acquired vitelliform lesions
3. Central serous chorioretinopathy (CSCR)
C. Loss of luteal or photopigment (window defect)
1. Multiple evanescent white dot syndrome
(MEWDS), punctate inner choroidopathy, multifocal choroidopathy syndrome
2.CSCR
3. Macular telangiectasia type 2 (MacTel 2)
D. Other autofluorescent material
1. Optic disc drusen
2. Astrocytic hamartoma
VII. Fundus Autofluorescence Imaging in Clinical Practice
A. Patterns of geographic atrophy (eg, banded, trickling) predict progression.
B. AMD phenotypes (eg, reticular vs. cuticular drusen)
C. Identify and monitor progression of RPE tears
D. CSCR phenotypes, monitor course of disease
2015 Subspecialty Day | Retina
E. Drug toxicity detection (eg, hydroxychloroquine,
dideoxyinosine)
F. Diagnose and monitor white dot syndromes (eg,
MEWDS, acute zonal occult outer retinopathy …)
G. Disease signatures (eg, A3243G, ABCA4, PXE)
H. Identify and distinguish vitelliform disorders (eg,
Best, AOVMD, AEPVM)
I. Diagnose hereditary retinal diseases (eg, RDH5,
CRB1, NR2E3)
J. Surgical assessment (eg, macular hole)
Selected Readings
1. Delori FC, Dorey CK, Staurenghi G, et al. In vivo fluorescence of
the ocular fundus exhibits retinal pigment epithelium lipofuscin
characteristics. Invest Ophthalmol Vis Sci. 1995; 36:718-729.
2. Fleckenstein M, Schmitz-Valckenberg S, Lindner M, et al.; Fundus
Autofluorescence in Age-Related Macular Degeneration Study
Group. The “diffuse-trickling” fundus autofluorescence phenotype
in geographic atrophy. Invest Ophthalmol Vis Sci. 2014; 55:29112920
3. Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology 2015;
122:110-116.
4. Schmitz-Valckenberg S, Holz FG, Bird AC, Spaide RF. Fundus
autofluorescence imaging: review and perspectives. Retina 2008;
28:385-409.
5. Schmitz-Valckenberg S, Fleckenstein M, Scholl HP, Holz FG. Fundus autofluorescence and progression of age-related macular degeneration. Surv Ophthalmol. 2009; 54:96-117.
6. Spaide RF. Autofluorescence from the outer retina and subretinal
space: hypothesis and review. Retina 2008; 28:5-35.
7. Theelen T, Berendschot TT, Boon CJ, Hoyng CB, Klevering BJ.
Analysis of visual pigment by fundus autofluorescence. Exp Eye
Res. 2008; 86:296-304.
8. von Rückmann A, Fitzke FW, Bird AC. Distribution of fundus
autofluorescence with a scanning laser ophthalmoscope. Br J Ophthalmol. 1995; 79:407-412.
Section XI: Imaging
2015 Subspecialty Day | Retina
Wide-Angle Imaging
Srinivas R Sadda MD
NOTES
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Spectral Domain OCT of Foveal Disorders
Anat Loewenstein MD, Gilad Rabina MD, and Dafna Goldenberg MD
Spectral domain OCT (SD-OCT) has dramatically improved
the quality of retinal imaging and the ability to assess the severity of retinal diseases. It provides a way to visualize the retina
in extremely high definition, thus enabling extremely detailed
observations and accurate measurements to be performed. This
has contributed to detection and quantification of abnormalities
within the retina, particularly in the foveal area. It has improved
the ability to detect, diagnose, and monitor foveal disorders such
as those caused by vitreoretinal interface abnormalities with cystoid changes prior to macular hole development, photic maculopathy, laser burns, foveal atrophy, solar retinopathy, or focal
foveal atrophy from unknown etiology.
On SD-OCT, foveal atrophy appears as thickening of the
retinal pigment epithelium (RPE) with hyper-reflective band, and
deep hyper-reflectivity corresponding to the loss of outer layers and photoreceptors. Defects in the inner segment and outer
segment junction of the photoreceptors with chronic disruption
of the inner photoreceptor junction have been found to be correlated with worse vision.
We present 3 cases of focal foveal atrophy secondary to
photic injury and sungazing. Two of the cases were treated by
steroids, and 1 was observed. Irreversible damage occurred in all
3 cases regardless of steroid therapy.
In summary, SD-OCT has dramatically enhanced the ability
to visualize the retina and fovea in vivo and to detect and diagnose disorders while they are still in the early stages. The ultrahigh resolution improves the quality of imaging and quantification of changes to multiple layers of the retina. Further studies of
foveal disorders with SD-OCT may help better understand these
vision-threatening retinal diseases.
References
1. Moussa NB, Georges A, Capuano V, et al. Multicolor imaging in
the evaluation of geographic atrophy due to age-related macular
degeneration. Br J Ophthalmol. 2015; 99:842-847.
2. Kao TY, Chen MS, Jou JR, et al. Focal foveal atrophy of unknown
etiology: clinical pictures and possible underlying causes. J Formos
Med Assoc. 2015; 114:239-245.
3. Chen KC, Jung JJ, Aizman A. High definition spectral domain
optical coherence tomography findings in three patients with solar
retinopathy and review of the literature. Open Ophthalmol J. 2012;
6:29-35.
4. Sheth J, Vidhya N, Sharma A. Spectral-domain optical coherence
tomography findings in chronic solar retinopathy. Oman J Ophthalmol. 2013; 6:208-209.
5. Hossein M, Bonyadi J, Soheilian R, et al. Spectral-domain optical
coherence tomography features of mild and severe acute solar retinopathy. Ophthalmic Surg Lasers Imaging. 2011; 42:e84-e86.
6. Cho HJ, Yoo ES, Kim CG, Kim JW. Comparison of spectraldomain and time-domain optical coherence tomography in solar
retinopathy. Korean J Ophthalmol. 2011; 25:278-281.
7. Kahn JB, Haberman ID, Reddy S. Spectral-domain optical coherence tomography as a screening technique for chloroquine and
hydroxychloroquine retinal toxicity. Ophthalmic Surg Lasers Imaging. 2011; 42:493-497.
Section XI: Imaging
2015 Subspecialty Day | Retina
99
OCT Angiography
Jay S Duker MD and Talisa E de Carlo BA
Introduction
Optical coherence tomography angiography (OCT-A) is a noninvasive imaging modality that uses motion contrast between
OCT images in order to generate volumetric angiograms. By
comparing the decorrelation signal (differences in OCT signal
amplitude / intensity) between repeated OCT B-scans obtained
sequentially at the same retinal cross-section, areas of motion
due to erythrocyte flow can be detected. This creates a contrast
between moving and static tissue from which an angiographic
map of the retina can be generated.1-3
An OCT-A image set currently takes as little as 3 seconds to
obtain and includes 1 volumetric en-face OCT angiogram and
300-500 corresponding OCT B-scans, depending on the device.
The OCT-A volume set can be scrolled through from inner retina
down to the choroid, or it can be segmented into individual
vascular plexuses as the information is depth encoded. The corresponding OCT B-scans are coregistered with the OCT angiograms, so the cross-section of each B-scan can be shown on the
angiogram, allowing for both structural and blood flow information to be viewed in tandem.2
The retinal field of view with the current technology ranges
from 2x2 mm to 12x12 mm. However, because the same number of A-scans are used to produce each acquisition area, the
sampling density (and therefore image resolution) is greatly
reduced with larger scanning sizes.2
of the choroidal vessels. OCT-A, as mentioned previously, is a
3-dimensional depth-resolved data set of both the inner retinal
and choroidal vasculature. In addition, it contains structural
information due to the corresponding OCT B-scans. However,
OCT-A is limited by a smaller field of view. Moving the scanning
area away from the fovea to encompass an area of suspicion and
using a wide-field montage technique are two ways of resolving
this problem.
The blood flow information from FA is dynamic, allowing for
visualization of patterns of dye leakage, pooling, and staining.
OCT-A, meanwhile, provides cross-sectional blood flow information. Therefore leakage is not appreciable. However, more
exact localization and delineation of pathology is possible since
there is no leakage obscuring the lesion.
OCT-A is able to visualize the small perifoveolar retinal capillaries that even high-resolution FA is unable to detect. While
this improves delineation of subtle microvascular changes such
as vessel tortuosity or small areas of capillary nonperfusion, the
dense net of capillaries may make visualization of microaneurysms more difficult. Because microaneurysms are seen as pinpoint areas of leakage on FA and are not obscured by the ability
to see the surrounding capillaries, they are easier to detect using
FA than OCT-A.
Figure 2.
Figure 1.
Motion correction technology can be applied to the OCT
angiograms by merging 2 OCT-A image sets (1 taken in the
XFast direction and 1 taken in the YFast direction). This technique reduces the horizontal line artifacts secondary to blinking
and/or eye movement while improving the signal-to-noise ratio.
Fluorescein Angiography vs. OCT-A
Fluorescein angiography (FA) is a minimally invasive imaging
technique that requires intravenous administration of dye and
subsequent imaging for up to 15 minutes.4,5 OCT-A, in comparison, is noninvasive and non-dye based, and requires about 3
seconds of imaging time.
FA produces 2-dimensional en-face images with a wide
field of view of the inner retinal vasculature, but a poor view
Overall, FA is minimally invasive, time consuming, and
expensive, but it provides a wide field of view. In comparison,
OCT-A is noninvasive, fast, and high resolution, but at present it
provides a limited peripheral field of view.
Utility of OCT-A
Age-related macular degeneration
OCT-A has been studied in both non-neovascular (dry) and neovascular (wet) AMD. In dry AMD eyes, a decrease in the density
of the choroidal vasculature has been shown. Furthermore, in
cases with geographic atrophy (GA), the choriocapillaris below
the GA demonstrates a flow void that follows approximately
the same contour as the GA (Choi et al, unpublished data under
review, presented in part at the Annual Meeting of the Association for Research in Vision and Ophthalmology; May 2014;
Orlando, Florida).
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In wet AMD, CNV can be detected using segmentation of just
the outer retina.6-8 Since normally the outer retina is devoid of
vasculature, blood flow seen in this region can be assumed to be
CNV. Additionally, the corresponding OCT B-scans can be used
to monitor changes in intraretinal and subretinal fluid over time.
Type 1 and 2 CNV can be differentiated by altering the segmentation boundary to look either above or below the retinal pigment epithelium. OCT-A may be superior to FA for the detection
of minimally leaking, type 1 CNV.
Figure 4.
Preretinal neovascularization can also be visualized using
OCT-A by adjusting the segmentation to include only vasculature above the internal limiting membrane (de Carlo et al,
unpublished data in review). Neovascularization of the disc
can be detected using the same method by scanning at the optic
nerve.
Figure 3.
Diabetic retinopathy
Because OCT-A provides such a detailed view of the retinal
capillaries, it is an ideal imaging modality for the evaluation of
diabetic retinopathy (DR). The foveal avascular zone is more easily delineated and has been shown to pathologically increase in a
linear fashion with each stage of DR, from mild nonproliferative
DR through proliferative DR (Salz et al, unpublished data).
OCT-A also provides a detailed view of microvascular abnormalities in DR such as capillary tortuosity and dilation, vascular
remodeling adjacent to the foveal avascular zone, microaneurysms, and capillary nonperfusion.9 More subtle changes are easier to detect using a 3x3-mm OCT angiogram, while more stark
changes such as capillary nonperfusion or intraretinal vascular
abnormalities can be seen using a 6x6-mm OCT angiogram.
Summary
OCT-A is a new, rapid, noninvasive imaging modality for visualizing the retinal and choroidal vasculature. It appears to have
utility in imaging a number of retinal diseases, including AMD
and DR. Studies are in progress to determine the clinical utility of
OCT-A.
2015 Subspecialty Day | Retina
References
1. Spaide RF, Klancnik JM, Cooney MJ. Retinal vascular layers
imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol. 2015; 133(1):45-50.
2. de Carlo TE, Romano A, Waheed NK, Duker JS. A review of optical coherence tomography angiography (OCTA). Int J Retina Vitreous. 2015; 1:5.
3. Matsunaga D, Puliafito CA, Kashani AH. OCT angiography in
healthy human subjects. Ophthalmic Surg Lasers Imaging Retina.
2014; 45(6):510-515.
4. Novotny HR, Alvis DL. A method of photographing fluorescence
in circulating blood in the human retina. Circulation 1961; 24:8286.
5. Novotny HR, Alvis D. A method of photographing fluorescence in
circulating blood of the human eye. Tech Doc Rep SAMTDR USAF
Sch Aerosp Med. 1960; 60-82:1-4.
6. de Carlo TE, Bonini Filho MA, Chin AT, et al. Spectral domain
optical coherence tomography angiography (OCTA) of choroidal
neovascularization. Ophthalmology 2015; 122(6):1228-1238.
7. Moult E, Choi W, Waheed NK, et al. Ultrahigh-speed swept-source
OCT angiography in exudative AMD. Ophthalmic Surg Lasers
Imaging Retina. 2014; 45(6):496-505.
8. Jia Y, Bailey ST, Wilson DJ, et al. Quantitative optical coherence
tomography angiography of choroidal neovascularization in agerelated macular degeneration. Ophthalmology 2014; 121:14351444.
9. Ishibazawa A, Nagaoka T, Takahashi A, et al. Optical coherence
tomography angiography in diabetic retinopathy: a prospective
pilot study. Am J Ophthalmol. 2015; 160(1):35-44.e.1.
Section XI: Imaging
101
102
Section XI: Imaging
2015 Subspecialty Day | Retina
Volume-Rendering 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 numeric representation of
each small volume of tissue is called a voxel. The amount of
decorrelation of these values 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. The amount
of change at any given location leads to a numerical value representing the decorrelation at each voxel in the analyzed images.
The flow information in the volume is also depth resolved, so the
decorrelation related to blood flow exists within a 3-dimensional
matrix of numerical values.
By selecting specific layers of tissue as seen in the structural
OCT, the flow in the vessels ordinarily found in those layers
may be imaged. Viewing of the vascular information in a layerby-layer method has been called “en face imaging.” Each layer
of retina selected encompasses a relatively large surface area of
the retina, with a shallow thickness. For example, we may view
a 3000x3000-micron expanse of the retinal vasculature that
exists in a thickness of 150 microns. The flow data through the
150-micron depth may be displayed using a variety of methods.
One popular method is en face imaging, in which a 2-dimensional image of a specific slab of tissue is made. The slab is
selected by segmentation of the corresponding retinal structural
OCT. The vascular data from that slab is then used to make a
2-D representation by selecting either the average or maximal
value of the voxels along each vertically aligned pixel in the slab.
The data through the limited depth, 150 microns, is flattened to
make a 2-dimensional image, 1 pixel thick. Flattening images
in this manner prevents proper visualization of vascular interrelationships in that specific layer. Other layers selected for viewing are flattened and to help in visualization, these layers may be
color coded.
There are two important weaknesses in en face imaging.
One, which is already apparent, is the flattening of the vascular
information in any specific segmented layer. The brightest pixels
in any one slab are selected and shown as a flattened image; this
creates the impression of many interconnections among vessels that may not necessarily be present.1 Each layer above or
below is also flattened and shown like flat, ordered sheets, when
in fact they may not be flat at all. In the process many of the
inter-relationships among layers are lost.2 By way of analogy,
imagine we segment an aerial photograph of the earth so that
the lower atmosphere appears in one layer while the superficial
earth crust is shown in another. Everything in the atmosphere,
such as clouds at all heights, are shown in one layer, while the
earth’s crust, mountains, valleys, and so forth would be shown
in a lower layer. By this process we lose the height information
of the mountains and valleys, but also interrelationships with the
atmosphere, such as when mountains may be sticking above the
clouds. The second weakness is that segmentation works fine on
healthy retina, but we are primarily interested in scanning diseased retinas. In diabetic macular edema the segmentation algorithms, designed using normal retinas, do not accurately determine the boundaries of massively thickened retinas. Conversely
in MacTel type 2 the retinal layers are thinner or nonexistent. In
that situation the segmentation algorithms still try to find layers
expected to be seen in healthy retinas.
Volume rendering is a technique that uses information from
every voxel while retaining depth interrelationships.1,3,4 The
3-dimensional volume of data can be viewed and also rotated
about 3 axes. Both the angiographic OCT data and the structural OCT data used to derive the flow data exist in matching
3-dimensional data structures. These may be used to perform
volume rendering to visualize either the flow or the structural
data. However, the two datasets are matched in all dimensions,
and so it is possible to segment the structural data for some characteristic of interest, such as fluid in cystoid spaces or intraretinal
lipid accumulation, and match that to the same level in the dataset representing the flow data. As proof of principle, volume rendering of several conditions will be shown. This set of techniques
and extensions thereof may prove useful in understanding the
relationships between flow-derived angiographic structure and
abnormalities within the retina.
Volume rendering is a set of techniques that have been implemented in visualizing computed tomography and MRI for more
than 2 decades. The datasets obtained from OCT angiography
lend themselves to analysis, using volume-rendering techniques
as adapted or developed for the eye.5
References
1. Fishman EK, Ney DR, Heath DG, Corl FM, Horton KM, Johnson
PT. Volume rendering versus maximum intensity projection in CT
angiography: what works best, when, and why. Radiographics
2006; 26(3):905-922.
2. Anderson CM, Saloner D, Tsuruda JS, Shapeero LG, Lee RE. Artifacts in maximum-intensity-projection display of MR angiograms.
Am J Roentgenol. 1990; 154(3):623-629.
3. Calhoun PS, Kuszyk BS, Heath DG, Carley JC, Fishman EK.
Three-dimensional volume rendering of spiral CT data: theory and
method. Radiographics 1999; 19(3):745-764.
4. Lell MM, Anders K, Uder M, et al. New techniques in CT angiography. Radiographics 2006; 26(suppl 1):S45-62.
5. Spaide RF. Volume rendered angiographic and structural optical
coherence tomography. Retina (submitted).
Section XI: Imaging
2015 Subspecialty Day | Retina
103
What Tumor, What Imaging Modality?
Carol L Shields MD
I. Types of Tests for Ocular Oncology
A. Cross-sectional imaging modalities
4. Computed tomography
a. Very little role in management of intraocular
tumors except to confirm calcification with
retinoblastoma
b. More important role in ocular trauma, to rule
out foreign body
1.Ultrasonography
a. This is the “ace of spades” for tumor detection, assessment of shape, calcification, and
extraocular extension.
b. Best for large tumors
c. Most intraocular tumors appear echodense,
but melanoma has a tendency toward echolucency.
d. Mushroom configuration is strongly suggestive of melanoma.
e. Check for vascular pulsation within solid
tumors to rule out hemorrhage.
B. Vascular imaging modalities
1. Intravenous fluorescein angiography (IVFA)
a. Used to differentiate solid vascular mass from
simulating hemorrhage
b. Used to judge radiation retinopathy
2. Indocyanine green angiography (ICG)
a. Little role in ocular oncology except for
identification of choroidal hemangioma that
shows rapid hypercyanescence within 1 minute then rapid washout
b. Most other tumors are relatively hypocyanescent compared to normal choroid.
2.OCT
a. This is the “blackjack” for small intraocular
tumors ≤ 3-mm thick.
b. Choroidal nevus shows a smooth, domeshaped surface, often with drusen, subretinal
cleft with photoreceptor retraction, outer retinal loss, and occasional retinal edema.
c. Small choroidal melanoma shows a smooth,
dome-shaped surface, often with subretinal
fluid and shaggy photoreceptors.
a. Angiography without injection
b. Evolving role in ocular oncology
c. Helpful with radiation retinopathy
d. Choroidal metastasis tends to show a lumpy,
bumpy surface, subretinal fluid, and shaggy
photoreceptors.
e. Choroidal hemangioma is always smooth and
dome-shaped and displays expansion of the
intrinsic choroidal vessels, often with subretinal fluid or edema.
4. Multispectral imaging
a. Angiography without injection
b. Can detect subclinical nevi and freckles
c. Can be used to judge radiation retinopathy
C. Other imaging modalities
3.MRI
3. Optical coherence tomography angiography
(OCT-A)
a. Plays small role in intraocular tumor diagnosis and can evaluate for extrascleral extension. Most tumors are dark on T1-weighted
images and bright on T2 images. The only
exceptions are choroidal hemangioma, which
is bright on T1 and T2 imaging, as well as
scleritis, which is dark on T1 and T2 imaging.
b. Important tool for eyes with dense vitreous
hemorrhage to evaluate for enhancing intraocular mass
c. Important tool to differentiate nonenhancing
choroidal effusion or blood vs. enhancing
choroidal melanoma
1.Autofluorescence
a. Most active choroidal tumors cause hyperautofluorescence from lipofuscin accumulation.
b. Most inactive choroidal tumors cause hypoautofluorescence from retinal pigment epithelial atrophy.
2. Transillumination: Best for ciliary body tumor
evaluation
3. Fundus photography
a. Wide angle imaging with montage, Heidelberg ultrawide angle, RetCam, Panoret, and
Optos
b. Technology improving
II. Tumor Features (General) on Testing (see Table 1)
104
Section XI: Imaging
2015 Subspecialty Day | Retina
Table 1. Tumor Features (General) on Testing
Sclera
Retina
Choroid
Tissue
Tumor
US
OCT
IVFA
ICG
Autofluorescence Transillumination
Nevus
Dense
Dome
Hypo 2+
Hypo 2+
Hypo 2+
Dark shadow
MM large
Hollow
na
Hyper 1+
Hyper 1+
Dark shadow
MM small
Hollow
Dome
Hypo 1+
Hyper 3+
Dark shadow
Metastasis
Dense
Lumpy bumpy
Hypo 1+
Hypo 1+
Hyper 2+
Light shadow
Hemangioma
Dense
Dome
Hyper 2+
Hyper 3+
Hyper 1+
Light shadow
Osteoma
Dense with
shadow
Lamellar lines
Hyper 1+
na
Hyper 1+
na
Leiomyoma
Dense
na
Iso
na
na
Captures light
Lymphoma
Dense
Rippled, seasick
Hyper 1+
na
Retinoblastoma
Dense with
shadow
Jutted
na
Hyper 1+
Light shadow
Astrocytic
hamartoma
Dense with
shadow
Moth-eaten
na
Hyper 1+
na
Hemangioblastoma
Dense
Dome
na
Iso
na
Sclerochoroidal
calcification
Dense with
shadow
Mountain jutting
Hypo 3+
na
Hypo 2+
na
Solitary idiopathic
choroiditis
Dense
Volcanic
Hypo 3+
na
Hypo 3+
na
• Hyper 2+
• Double circulation
• Hyper 1+
• Pinpoint leaks
• Hypo 1+
• Pinpoint leaks
• Hyper 2+
• Feeder vessels
• Hypo 1+
• Corkscrew vessels
• Hyper 3+
• Feeder vessels
Abbreviations: MM indicates malignant melanoma; Mod, moderate; na, not assessed; hypo, hypofluorescent / hypocyanescent / hypoautofluorescent; hyper, hyperfluorescent / hypercyanescent / hyperautofluorescent.
Selected Readings
1. Shields CL, Pellegrini M, Ferenczy SR, Shields JA. Enhanced depth
imaging optical coherence tomography (EDI-OCT) of intraocular
tumors: from placid to seasick to rock and rolling topography. The
2013 Francesco Orzalesi Lecture. Retina 2014; 34(8):1495-1512.
2. Almeida A, Kaliki S, Shields CL. Autofluorescence of intraocular
tumors. Curr Opin Ophthalmol. 2013; 24(3):222-232.
3. Shields CL, Manalac J, Das C, Saktanasate J, Shields JA. Review of
spectral domain enhanced depth imaging optical coherence tomography (EDI-OCT) of tumors of the choroid. Ind J Ophthalmol.
2015; 63:117-121.
4. Shields CL, Manalac J, Das C, Saktanasate J, Shields JA. Review
of spectral domain enhanced depth imaging optical coherence
tomography (EDI-OCT) of tumors of the retina and retinal pigment
epithelium in children and adults. Ind J Ophthalmol. 2015; 63:128132.
Section XI: Imaging
2015 Subspecialty Day | Retina
105
Prediction of Disease Progression and Therapeutic
Response Using Computational Image Analysis
Ursula Schmidt-Erfurth MD
Background
Methods and Technology
A solid prognostic evaluation of disease activity facilitates
individual and overall patient management. Prediction of therapeutic outcomes is a key requirement for efficient interventions.
Advanced retinal imaging using spectral domain OCT (SD-OCT)
is able to identify the pathomorphological fingerprint of retinal
disease and is therefore most appropriate for predicting individual patient disease and response patterns.
Predicting visual function from retinal morphology offers
prognostic value for patients and physicians—an efficient distribution of resources to provide the right treatment for the right
patient at the right time and support of effective clinical trial
designs using relevant imaging biomarkers and more precise
endpoints.
Preprocessing of images
To provide an optimized image database for analysis, raw images
undergo denoising, motion correction, intra- and interpatient
registration, and finally large-scale segmentation.
OCT is an optical signal acquisition method capturing
micrometer-resolution, cross-sectional, 3-dimensional images.
While OCT allows for the visualization of retinal structures,
image quality and contrast is reduced by speckle noise and
obfuscating small, low-intensity structures and boundaries.
Existing denoising methods for OCT images may remove clinically significant imaging features such as texture and boundaries.
Geodesic denoising is a novel patch-based method that reduces
noise while maintaining relevant small pathological structures
such as fluid-filled cystoid regions in diseased retina. The method
was evaluated qualitatively on real pathological OCT scans and
quantitatively on a proposed set of ground truth, noise-free synthetic OCT scans with artificially added noise and pathology.
Eye movements during acquisition of SD-OCT images create
substantial motion artefacts in the volumetric data sets, which
hinder registration and 3-D analysis and can be mistaken for
pathology. A method for correcting these artefacts using a single
volume scan while still retaining the overall contours of the
retina is suggested. The method is validated quantitatively using
a set of synthetic SD-OCT volumes and qualitatively by trained
OCT-grading experts on 100 SD-OCT scans.
Annotation of multiple and different retinal pathologies in
hundreds of dense raster scans per visit and patient result in
large-volume, big data sets of images and cannot be performed
manually. Automated analysis software enables identification and delineation of various pathological features in a reliable, quantitative way. All pathological features are therefore
extracted from all acquired images and can be used for identifying disease activity as well as response to treatment, showing
resolution of pathology or progression.
Figure 1. Spatiotemporal projection.
Figure 2. Spatiotemporal response patterns.
Figure 3. Geodesic denoising.
106
Section XI: Imaging
2015 Subspecialty Day | Retina
Figure 4. Automated annotation.
Figure 6. Multimodal data integration. Sources: Montuoro et al., 2014,1
Garvin et al., IEEE TMI 2009; Schlegl et al., 2015,2 4 Zhang et al., IOVS
2014; 5 Zhang et al, IOVS 2012; 6 Montuoro et al., ARVO 2015; 7 Wu
et al., SPIE 2015; 8 Wu et al., Spie 2014; 9 Montuoro et al, SPIE 2014
Figure 5. Interpatient registration.
In order to perform population analysis, scans that are
acquired from different patients, time points, and modalities
need to be aligned using spatiotemporal registration to align
all scans into a common reference frame. To create this reference frame, fundus-to-fundus registration is performed to align
images between patients. 3-D OCT registration uses the retinal
vessels as a reliable landmark, located just below the upper-most
surface of the retina, with their shadows generated due to light
attenuation, visible most prominently in the retinal pigment epithelium layer at the bottom. In addition, a disease-specific fovea
detection method to automatically extract the fovea position
from an OCT scan is used as a second landmark position.
Image processing: Multimodal data integration
Ideally, multimodal imaging is used to detect and evaluate all
structural features comprehensively, depending on their pathognomonic features visualized in color fundus photography,
infrared imaging, fundus autofluorescence, angiographic OCT,
and structural SD-OCT. Clinical data such as BCVA and treatment type and frequency are added to the algorithms. Additional
information is derived from systemic biomarkers in genetics, proteomics, and metabolomics.
Retinal layer segmentation is based on a validated algorithm
(LOGISMOS) delineating the boundaries of 11 neurosensory
layers. Machine learning enables qualitative and quantitative
evaluation of intra- and subretinal fluid as major hallmarks
of exudative macular disease. The capacity of the computer
algorithm to identify pathognomonic features of disease and
therapeutic response is based on convolutional neural networks
(CNN) that capture characteristic visual appearance patterns
and classify normal retinal tissue as well as distinct pathologies.
The CNN is trained in a supervised manner using approximately
300,000 2-D image patches extracted from 157 OCT image volumes sampled at random positions. Based on the image patches
of the training set, the CNN learns representative and discriminative features (“machine learning”). Pixel-wise classification
results in segmentation of the entire OCT volume into normal
retinal tissue, intraretinal cystoid fluid, subretinal fluid, etc. In
addition to the retinal features, additional patterns at the level
of the retinal pigment epithelium, including pigment-epithelial
detachments (PED) harboring the neovascular lesions, choroidal
features, and alterations of the vitreomacular interface, can be
included into the final analysis.
Section XI: Imaging
2015 Subspecialty Day | Retina
Structure/Function Correlation
The presence of intraretinal cystoid (IRC) fluid has been demonstrated to cause a substantial loss in visual function in neovascular AMD (nAMD). On the other hand, recent evidence suggests
that subretinal fluid (SRF) may be associated with a favorable
visual acuity prognosis. However, studies up to date rely on a
categorical, qualitative grading of the presence or absence of
fluid and therefore preclude precise functional predictions. Structural biomarkers of relevance for macular disease are suggested
by the OCT-imaging literature.
Computational image analyses can reliably correlate quantitative measures of IRC and SRF with BCVA outcomes in antiangiogenic therapy of nAMD. In patients with treatment-naïve subfoveal choroidal neovascularization secondary to AMD receiving
monthly ranibizumab or aflibercept injections for 12 months,
IRC and SRF were segmented on each B-scan of SD-OCT volume scans. A systematic automated search was conducted to
detect fluid-derived variables with the best possible predictive
value for BCVA. An exponential model for BCVA change was
constructed.
Correlations were computed between IRC, SRF, and baseline
BCVA, final BCVA, and BCVA change (exponential and linear)
based on a complete quantification of IRC and SRF in a total
of 19,456 scans. At the treatment-naïve stage, an area-based,
centrally accentuated IRC indicator shows the highest predictive
value and was significantly correlated with baseline BCVA (R² =
0.59, P < .0001).
Figure 7. Pathognomonic lesions in spectral domain OCT.
Correlation of retinal morphology and function in a large
prospective clinical trial revealed that IRC fluid is the major
biomarker for functional loss in neovascular AMD, while SRF
has a positive influence on the prognosis of the disease. During
antiangiogenic therapy, the presence of exudative and persistent,
that is, degenerative, cysts and PED present as significant factors
for prediction of visual outcomes. While PED appears as relevant primary feature, it is the secondary occurrence of cystoid
fluid that is responsible for functional loss during discontinuous
treatment.
Figure 8. Quantification of subretinal fluid.
Table 1. What Influences Function in AMD?
Effect
Estimate
Standard
Error
P-Value
Intercept
56.10
0.84
< .0001
Cysts at baseline
-5.98
0.85
< .0001
Cysts at Week 12
-3.92
1.04
.0002
Subretinal fluid
+4.28
1.02
.0001
Table 2. Function in p.r.n. Regimen
Effect
Estimate
Standard
Error
P-Value
Intercept
65.54
1.07
< .0001
Cysts at baseline &
Week 12
-3.85
0.85
< .0001
PED at baseline &
novel cysts
-2.12
0.97
.0284
Baseline VA
0.65
0.05
< .0001
107
Figure 9. Neovascular AMD.
108
Section XI: Imaging
The same indicator also predicted BCVA outcomes at 12
months (R² = 0.21, P = .0034). BCVA gain from baseline to
Month 12 significantly correlated with a decrease in the IRC
predictor in the exponential model (R² = 0.40, P < .0001) and
the linear model (R² = 0.25, P = .0015). In contrast, SRF was not
statistically significantly associated with baseline BCVA or final
BCVA outcomes.
2015 Subspecialty Day | Retina
Prediction of Recurrence
The ability to predict the future development of a disease is an
extremely important goal, both in clinical and scientific practice and in the general health-care setting. Reliable methods are
needed that are capable of predicting the longitudinal disease
course as well as treatment response patterns based on interpatient aligned longitudinal SD-OCT images within a disease
population.
Patients received initial antiangiogenic injections for 3
months, followed by a p.r.n. regimen. All scans are transformed
into a joint reference space by registering the follow-up scans
within a patient using vessel structure, and in-between patients
by aligning the optical disk center and the foveal center. The
joint reference space thus eliminates the spatial variation coming from different scanning positions and the inter-individually
varying anatomy of the retina. Total retinal thickness maps are
computed using the Iowa reference algorithm. In a 5-fold crossvalidation setting, several sparse and nonlinear regression models
are learned from the pixel-wise thickness values using the common loading phase (ie, baseline to Month 2) in the training set.
On the test set, retinal thickness was predicted for Month 4.
Figure 10. Individualization of p.r.n. treatment.
Figure 12. Ground truth, segmentation, prediction.
Figure 11. Predictive value of baseline BCVA.
IRC-derived morphometric variables can be used to precisely
predict BCVA in the treatment-naïve condition as well as BCVA
outcomes in antiangiogenic therapy of nAMD. While a reduction
in IRC is statistically significantly associated with BCVA gains, a
proportion of IRC-mediated neurosensory damage may remain
permanent. This suggests the future path for personalized determination of visual prognosis based on retinal pathomorphology
and may serve as an important endpoint in clinical trials.
Figure 13. Prediction of recurrence.
2015 Subspecialty Day | Retina
A sparse classifier is trained on the thickness maps and predicts the recurrence / nonrecurrence of macular edema within
the 12-month follow-up period. From the predicted thickness
maps, the mean absolute error (MAE) in micrometers is computed as error measure. From available regression methods
elastic net, LASSO, ridge regression, and random forest regression, elastic net shows the lowest median [mean/std] MAE of
14.32 [19.21/16.54] and a R² of 0.48, followed by LASSO with
15.87 [20.50/16.67], R² of 0.45. Logistic regression with elastic
net regularization produces the best results for the classification
of recurrence / nonrecurrence with a nonrecurrence sensitivity /
specificity (ROC AuC) of 1.00/0.88 (0.99).
Section XI: Imaging
109
Perspectives of Computational Image Analysis
Computational disease-modeling of longitudinal OCT data
enables precise prediction of intensity, timing, and location of
recurrence in the treatment of macular disease, allowing precise
and objective disease management.
Computational imaging using a CNN classifier automatically and highly accurately segments and discriminates between
normal retinal tissue, IRC, and SRF in retinal SD-OCT, with an
overall accuracy of 96%. This may enable precise structure-function correlations based on SD-OCT on a large scale. IRC-derived
morphometric variables can be used to precisely predict BCVA
in disease, as well as BCVA outcomes in therapy. Computational
analyses offer a solid path for personalized determination of
visual prognosis based on retinal pathomorphology and baseline
BCVA.
References and Selected Readings
1. Montuoro A, Wu J, Waldstein S, Gerendas B, Langs G, Simader
C, Schmidt-Erfurth U. Motion artefact correction in retinal optical
coherence tomography using local symmetry. Med Image Comput
Comput Assist Interv. 2014; 17(pt 2):130-137.
2. Schlegl T, Waldstein SM, Schmidt-Erfurth U, Langs G. Predicting
semantic descriptions from medical images with convolutional neural networks. Inf Process Med Imaging. 2015; 9123:437-448.
3. Schmidt-Erfurth U, Waldstein SM, Deak GG, Kundi M, Simader
C. 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.
Figure 14. Prediction of recurrence. Source: Vogl W-D, Waldstein SM,
Gerendas BS, Wu J, Montuoro A, Schmidt-Erfurth U, Langs G. Spatiotemporal signatures to predict retinal disease recurrence. Inf Process Med
Imaging. 2015; 9123:152-163.
This provides proof-of-principle that a precise prediction of
disease development is possible using longitudinal OCT data
transformed to a joint reference space and sparse machine learning methods.
4. Vogl W-D, Waldstein SM, Gerendas BS, Wu J, Montuoro A,
Schmidt-Erfurth U, Langs G. Spatio-temporal signatures to predict retinal disease recurrence. Inf Process Med Imaging. 2015;
9123:152-163.
5. Waldstein SM, Glodan AM, Leitner R, Gerendas BS, Langs G,
Schmidt-Erfurth U. 3D-analysis of intra- and subretinal fluid provides precise prediction of visual acuity in neovascular AMD. Submitted.
6. Wu J, Gerendas BS, Waldstein SM, Langs G, Schmidt-Erfurth U.
Stable registration of pathological 3D SD-OCT scans using retinal
vessels. In: Chen X, Garvin MK, Liu JJ, eds. Proceedings of the
Ophthalmic Medical Image Analysis First International Workshop,
OMIA 2014. Available at: http://ir.uiowa.edu/omia/2014_Proceedings/2014/1/.
110
Section XII: Late Breaking Developments, Part II
Late Breaking Developments, Part II
NOTES
2015 Subspecialty Day | Retina
Section XIII: Oncology Panel
2015 Subspecialty Day | Retina
Oncology Panel
Panel Moderators: Jerry A Schields MD, J William Harbour MD
Panelists: Thomas Aberg Jr MD, Janet Louise Davis MD, Evangelos S Gragoudas MD,
Brian P Marr MD, Miguel A Materin MD, David J Wilson MD
NOTES
111
112
Section XIV: Diabetes
2015 Subspecialty Day | Retina
Laser for Diabetic Macular Edema Is Dead: Pro
Andrew A Moshfeghi MD MBA
This lecture discusses off-label indications of FDA-approved
drugs.
I. Diabetic Macular Edema (DME): Evolving Definitions
A. Clinically significant DME (clinical examination)
B. Center-involved DME (OCT)
II. Natural History of DME
C. May be especially helpful in pseudophakic or
planned pseudophakic patient populations
D. Available in pulse (triamcinolone acetonide) or
depot (dexamethasone intravitreal implant and
fluocinolone acetonide intravitreal implant) formulations with medium- and long-term duration of
action
E. Risk of IOP elevation and less profound visual acuity benefit keep corticosteroid monotherapy from
being first-line option.
F. DRCRnet Protocol I data
G. FAME study data with fluocinolone acetonide intravitreal implant
H. MEAD study data with dexamethasone intravitreal
implant
III. Destructive Therapy With Focal/Grid Macular Laser
Photocoagulation
A. Early Treatment of Diabetic Retinopathy Study
(ETDRS) data
B. Previous gold standard
C. Variability in subjective application of laser among
physicians
D. Variability in retreatment indications and algorithms
E. Variability in response from patient to patient
F. Side effect: Laser lesions may enlarge over years
with microscotomata.
G. Does not improve diabetic retinopathy severity
IV. Nondestructive Therapy With Anti-Vascular Endothelial Growth Factor (anti-VEGF) Monotherapy
A. New gold-standard first-line treatment
B. Rapid reduction in excess retinal thickening
C. Sustained reduction in excess retinal thickening
D. Anatomic improvements lead to rapid and sustained
visual gains.
E. Good chance that injections can be stopped within 3
to 5 years
F. Injections also improve overall diabetic retinopathy
severity
G. RISE and RIDE study data with ranibizumab
H. VIVID and VISTA study data with aflibercept
I. Diabetic Retinopathy Clinical Research Network
(DRCRnet) Protocols I and T data
V. Adjunctive Therapy With Intravitreal Corticosteroids
A. Helps reduce macular edema in patients with persistent or incomplete response to anti-VEGF monotherapy
B. Helps reduce the treatment burden in patients
requiring monthly anti-VEGF injections for sustained periods
VI.Conclusions
A. Destructive thermal laser photocoagulation of the
macula for DME is dead.
B. Nondestructive anti-VEGF monotherapy is the new
gold-standard treatment for DME due to its profound visual benefits and added bonus of mitigating
diabetic retinopathy severity status.
C. What anti-VEGF monotherapy does not adequately
treat is addressed by adjunctive corticosteroids in a
pulse or depot fashion, obviating the need for macular photocoagulation of diabetic macular edema.
Selected Readings
1. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;
103(12):1796-1806.
2. Scott IU, Danis RP, Bressler SB, Bressler NM, Browning DJ, Qin
H; Diabetic Retinopathy Clinical Research Network. Effect of
focal/grid photocoagulation on visual acuity and retinal thickening
in eyes with non-center-involved diabetic macular edema. Retina
2009; 29(5):613-617. 3. Diabetic Retinopathy Clinical Research Network; Writing Committee: Aiello LP, Beck RW, Bressler NM, et al. Rationale for the Diabetic Retinopathy Clinical Research Network treatment protocol
for center-involved diabetic macular edema. Ophthalmology 2011;
118(12):e5-14.
4. Lundberg K, Kawasaki R, Sjølie AK, Wong TY, Grauslund J.
Localized changes in retinal vessel caliber after focal/grid laser treatment in patients with diabetic macular edema: a measure of treatment response? Retina 2013; 33(10):2089-2095.
5. Greenstein VC, Chen H, Hood DC, Holopigian K, Seiple W, Carr
RE. Retinal function in diabetic macular edema after focal laser
photocoagulation. Invest Ophthalmol Vis Sci. 2000; 41(11):36553664.
2015 Subspecialty Day | Retina
6. Elman MJ, Ayala A, Bressler NM, et al.; Diabetic Retinopathy
Clinical Research Network. Intravitreal ranibizumab for diabetic
macular edema with prompt versus deferred laser treatment: 5-year
randomized trial results. Ophthalmology 2015; 122(2):375-381.
7. Diabetic Retinopathy Clinical Research Network; Elman MJ, Qin
H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular
edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology 2012; 119(11):2312-2318.
8. Diabetic Retinopathy Clinical Research Network; Elman MJ, Aiello
LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus
prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010; 117(6):1064-1077.
9. Nguyen QD, Brown DM, Marcus DM, et al.; RISE and RIDE
Research Group. Ranibizumab for diabetic macular edema: results
from 2 Phase III randomized trials: RISE and RIDE. Ophthalmology 2012; 119(4):789-801.
10. Brown DM, Nguyen QD, Marcus DM, et al.; RIDE and RISE
Research Group. Long-term outcomes of ranibizumab therapy for
diabetic macular edema: the 36-month results from two Phase III
trials: RISE and RIDE. Ophthalmology 2013; 120(10):2013-2022. Section XIV: Diabetes
113
11. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal
aflibercept for diabetic macular edema. Ophthalmology 2014;
121(11):2247-2254.
12. Diabetic Retinopathy Clinical Research Network; Wells JA,
Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or
ranibizumab for diabetic macular edema. N Engl J Med. 2015;
372(13):1193-1203.
13. Campochiaro PA, Brown DM, Pearson A, et al.; FAME Study
Group. Sustained delivery fluocinolone acetonide vitreous inserts
provide benefit for at least 3 years in patients with diabetic macular
edema. Ophthalmology 2012; 119(10):2125-2132. 14. Boyer DS, Yoon YH, Belfort R Jr, et al.; Ozurdex MEAD Study
Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular
edema. Ophthalmology 2014; 121(10):1904-1914.
114
Section XIV: Diabetes
2015 Subspecialty Day | Retina
Laser for Diabetic Macular Edema Is Dead: Con
Harry W Flynn Jr MD and Nidhi Relhan MD
Macular edema is a significant cause of central vision impairment among people with diabetic retinopathy. Focal/grid laser
photocoagulation,1,2 intensive glycemic control,3 and blood pressure control4 have been demonstrated to reduce the risk of vision
loss from diabetic macular edema (DME). Although intravitreal
injections of anti-VEGFs and steroids are increasingly used and
recommended for the management of DME, laser photocoagulation treatment for DME continues to have an important role in
current management. Recent clinical trials have divided diabetic
macular edema into center-involving (CI-DME) and non-centerinvolving (nCI-DME). Table 1 highlights a few advantages and
disadvantages of focal/grid laser photocoagulation when used for
treating macular edema.
The Early Treatment of Diabetic Retinopathy Study
(ETDRS)1-2 described “clinically significant macular edema”
(CSME) and demonstrated a 50% reduction (from 24% to
12%) in the rates of moderate vision loss (defined as a loss of
15 or more letters on ETDRS visual acuity charts) in eyes with
CSME treated with focal/grid photocoagulation, compared with
untreated control eyes. The ETDRS demonstrated a definite
benefit in favor of laser photocoagulation in both CI-DME and
nCI-DME. Many retina specialists prefer to now use a modified
ETDRS treatment approach5 for treating nCI-DME. This modified focal/grid treatment includes a less intense laser, greater spacing, direct targeting of microaneurysms, and avoidance of foveal
vasculature within at least 500 µm of the center of the macula.
Technical advances, including subthreshold techniques,6,7 different wavelengths,8 and pattern laser generation,9 offer potentially beneficial options for treating DME. More recently, the
development of navigated laser photocoagulation that combines
fluorescein angiography with image stabilization and tracking
may provide more efficient, accurate, preplanned, automatic,
and precise focal photocoagulation, allowing delineation of the
spots/areas most appropriate for treatment.10-12
As per evidence-based guidelines in treating nCI-DME,
the focal/grid laser treatment is supported by level 1 evidence
(ETDRS).13 For patients with CI-DME,13-16 level 1 evidence
supports the use of focal/grid laser treatment for management as
well as other treatment strategies, including intravitreal ranibizumab with prompt or deferred laser. A prospective, multicenter,
observational, focal/grid photocoagulation Diabetic Retinopathy
Clinical Research Network (DRCRnet) study17 of 122 eyes with
CI-DME (central subfield thickness [CST] ≥ 250 µm) showed
continued improvements in OCT thickness (10% further reduction in CST from 16 to 32 weeks in 42%) and visual acuity (by
at least 5 letters in 36%) at 4 or more months after laser treatment. In 23% to 63% of patients, continued improvement was
observed without additional treatment. This study highlights
the beneficial effects of laser photocoagulation over the long
term. An upcoming DRCRnet study (Protocol V) compares the
effectiveness of modified ETDRS focal/grid laser, observation,
and intravitreal ranibizumab for management of CI-DME in eyes
with very good visual acuity (20/25 or better). This clinical trial
is ongoing now.
Conclusions
Laser photocoagulation remains an important option in the management of DME. For non-central DME, laser photocoagulation
is a safe and effective treatment approach that is time-tested and
reliable.
References
1. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;
103:1796-1806.
Table 1. Advantages and Disadvantages of Focal/Grid Laser Photocoagulation Used for Treating Diabetic Macular Edema
Focal/Grid Laser Photocoagulation for Diabetic Macular Edema
Advantages
Disadvantages
Proven favorable results in nCI-DME
Less effective in diffuse CI-DME macular edema
May be completed in 1 session
Possible initial transient decrease in central vision
Reduced number of clinic visits
Accidental/inadvertent foveal burn
Saves time (convenient for the patient)
Paracentral scotomas
Decreased risk of cataract
Rupture of Bruch membrane
Decreased risk of endophthalmitis
Laser-induced CNVM
Lower one-time treatment cost than intravitreal injections
Expansion of laser scar area (over many years)
No impact on retinopathy severity scale
Cost in maintenance of laser equipment
Abbreviations: nCI-DME indicates non-center-involving diabetic macular edema; CI-DME, center-involving diabetic macular edema; CNVM, choroidal neovascular membrane.
2015 Subspecialty Day | Retina
Section XIV: Diabetes
115
2. Early Treatment Diabetic Retinopathy Study Research Group.
Early photocoagulation for diabetic retinopathy: ETDRS report
number 9. Ophthalmology 1991; 98:766-785.
10. Kernt M, Cheuteu R, Vounotrypidis E, et al. Focal and panretinal
photocoagulation with a navigated laser (NAVILAS®). Acta Ophthalmol. 2011; 89(8):e662-664.
3. The Diabetes Control and Complication Trial Research Group. The
effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986.
11. Kozak I, Kim JS, Oster SF, Chhablani J, Freeman WR. Focal navigated laser photocoagulation in retinovascular disease: clinical
results in initial case series. Retina 2012; 32:930-935.
4. Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner
EM; UK Prospective Diabetes Study Group. Risks of progression of
retinopathy and vision loss related to tight blood pressure control
in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol. 2004;
122:1631-1640.
5. Writing Committee for the Diabetic Retinopathy Clinical Research
Network; Fong DS, Strauber SF, Aiello LP, et al. Comparison of
the modified Early Treatment Diabetic Retinopathy Study and mild
macular grid laser photocoagulation strategies for diabetic macular
edema. Arch Ophthalmol. 2007; 125(4):469-480.
6. Nakamura Y, Mitamura Y, Ogata K, Arai M, Takatsuna Y, Yamamoto S. Functional and morphological changes of macula after
subthreshold micropulse diode laser photocoagulation for diabetic
macular oedema. Eye (Lond). 2010; 24:784-748.
7. Luttrull JK, Musch DC, Mainster MA. Subthreshold diode micropulse photocoagulation for the treatment of clinically significant
diabetic macular oedema. Br J Ophthalmol. 2005; 89(1):74-80.
8. Castillejos-Rios D, Devenyi R, Moffat K, Yu E. Dye yellow vs.
argon green laser in panretinal photocoagulation for proliferative
diabetic retinopathy: a comparison of minimum power requirements. Can J Ophthalmol. 1992; 27(5):243-244.
9. Bolz M, Kriechbaum K, Simader C, et al; Diabetic Retinopathy
Research Group Vienna. In vivo retinal morphology after grid
laser treatment in diabetic macular edema. Ophthalmology 2010;
117(3):538-544.
12. Neubauer AS, Langer J, Liegl R, et al. Navigated macular laser
decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laser. Clin Ophthalmol. 2013;
7:121-128.
13. Preferred Practice Pattern on Diabetic Retinopathy: American
Academy of Ophthalmology Guidelines 2014. Available online
at www.aao.org/preferred-practice-pattern/diabetic-retinopathyppp--2014.
14. Scott IU, Danis RP, Bressler SB, Bressler NM, Browning DJ, Qin
H; Diabetic Retinopathy Clinical Research Network. Effect of
focal/grid photocoagulation on visual acuity and retinal thickening
in eyes with non-center-involved diabetic macular edema. Retina
2009; 29(5):613-617.
15. Diabetic Retinopathy Clinical Research Network; Elman MJ, Aiello
LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus
prompt or deferred laser or triamcinolone plus prompt laser for
diabetic macular edema. Ophthalmology 2010; 117(6):1064-1077.
e35.
16. Elman MJ, Bressler NM, Qin H, et al; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab
plus prompt or deferred laser or triamcinolone plus prompt laser
for diabetic macular edema. Ophthalmology 2011; 118(4):609614.
17. Diabetic Retinopathy Clinical Research Network. The course
of response to focal/grid photocoagulation for diabetic macular
edema. Retina. 2009; 29(10):1436-1443.
116
Section XIV: Diabetes
2015 Subspecialty Day | Retina
There Is a Role for Steroids in Diabetic Macular
Edema: Pro
Baruch D Kuppermann MD PhD
There is a growing body of evidence supporting a key role for
inflammation and associated cytokines in the development of
diabetic macular edema (DME). A series of experimental and
clinical studies have shown that a variety of inflammatory cytokines exhibit progressive elevation in the process of development
of advancing retinopathy and macular edema, including MCP-1,
IL-6, IL-1β, and others, in addition to VEGF. Numerous clinical
studies have shown that steroids are effective in treating DME,
and in the pseudophakic population the efficacy outcomes can be
equivalent to those of anti-VEGF therapy. The effect of steroids
on the treatment of DME appears to be beneficial both early
and late in the development of macular edema, and may be even
more pronounced in chronic macular edema. Conversely, there is
clinical trial evidence that anti-VEGF therapy seems most effective for the treatment of treatment-naïve or nonchronic DME,
and less so with chronic DME. Interestingly, there are clinical
data showing that intravitreal steroid treatment of DME lowers
intraocular levels of a wide variety of inflammatory cytokines
in addition to VEGF, whereas anti-VEGF injections lower only
VEGF levels without any apparent collateral effect on the inflammatory cytokine cascade. Detailed preclinical and clinical data
will be presented supporting the role of inflammation in the
development of macular edema, as well as the relative roles of
intraocular steroids and anti-VEGF compounds for the treatment
of DME.
Selected Readings
1. Ellman MJ, Bressler NM, Qin H, et al; the Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of
ranibizumab plus prompt or deferred laser or triamcinolone plus
prompt laser for diabetic macular edema. Ophthalmology 2011;
118(4):609-614.
2. Cunha-Vaz J, Ashton P, Lezzi R, Campochiaro P, Dugel PU, Holz
FG, Weber M, Danis RP, Kuppermann BD, Bailey C, Billman K,
Kapik B, Kane F, Green K; FAME Study Group. Sustained delivery fluocinolone acetonide vitreous implants: long-term benefit
in patients with chronic diabetic macular edema. Ophthalmology
2014; 121(10): 1892-1903.
3. Boyer DS, Yoon YH, Belfort R Jr, et al; Ozurdex MEAD Study
Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular
edema. Ophthalmology 2014; 121(10):1904-1914.
4. Sohn HJ, Han DH, Kim IT, et al. Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus
bevacizumab for diabetic macular edema. Am J Ophthalmol. 2011;
152:686-694.
2015 Subspecialty Day | Retina
Section XIV: Diabetes
117
There Is a Role for Steroids in Diabetic Macular
Edema: Con
Allen C Ho MD
Currently, the role for steroids in diabetic macular edema (DME)
is unclear—in fact, there is an ongoing Diabetic Retinopathy
Clinical Research Network (DRCR) network pilot study, Protocol U, seeking to address what role, if any, intravitreal steroids
may play for persistent DME; results are pending at this time.
There is no evidence to support the use of intravitreal steroids for
first-line DME therapy, and while steroids can effect OCT reduction of DME (I am certain my opponent will show you images),
there is still no randomized clinical trial supporting intravitreal
steroids as second-line therapy for DME not responsive to firstline therapy. Just because your macula is less thick does not
mean that the patients will see better over the short and long
term in DME. For center-involved DME, anti-VEGF therapy
remains first-line therapy (better efficacy and safety), and many
retina specialists will consider macular laser photocoagulation
for non-center involved DME. Intravitreal steroids are less safe
in the eye than anti-VEGF agents (cataract, ocular hypertension,
glaucoma), and there is no evidence that they are more safe systemically than intravitreal anti-VEGF agents. Considering these
points, the role for steroids in DME is unclear at this time; forthcoming data from DRCR Network Protocol U will provide pilot
study information on this issue.
Selected Readings
1. DRCR Network Protocol U, assessed Sept. 13, 2015: Short-term
evaluation of combination corticosteroid+anti-VEGF treatment
for persistent central-involved diabetic macular edema following
anti-VEGF therapy. Available at: https://clinicaltrials.gov/ct2/show/
NCT01945866.
2. DRCR Network Protocol T: Diabetic Retinopathy Clinical
Research Network; Wells JA, Glassman AR, Ayala AR, et al.
Aflibercept, bevacizumab, or ranibizumab for diabetic macular
edema. N Engl J Med. 2015; 372:1193-1203.
3. MEAD Study: Boyer DS, Yoon YH, Belfort R Jr, et al. Three-year,
randomized, sham-controlled trial of dexamethasone intravitreal
implant in patients with diabetic macular edema. Ophthalmology
2014; 121(10):1904-1914.
4. FAME Study: Campochiaro PA, Brown DM, Pearson A, et al;
FAME Study Group. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema.
Ophthalmology 2011; 118(4):626-635.e2.
5. DRCR Protocol I: Elman MJ, Ayala A, Bressler NM, et al; Diabetic
Retinopathy Clinical Research Network. Intravitreal ranibizumab
for diabetic macular edema with prompt versus deferred laser
treatment: 5-year randomized trial results. Ophthalmology 2015;
122(2):375-381.
6. RISE/RIDE: Brown DM, Nguyen QD, Marcus DM, et al. Longterm outcomes of ranibizumab therapy for diabetic macular edema:
the 36-month results from two phase III trials: RISE and RIDE.
Ophthalmology 2013; 120(10):2013-2022.
7. VIVID/VISTA: Korobelnik JF, Do DV, Schmidt-Erfurth U, et al.
Intravitreal aflibercept for diabetic macular edema. Ophthalmology
2014; 121(11):2247-2254.
118
Section XIV: Diabetes
2015 Subspecialty Day | Retina
Chronic Anti-VEGF Injection Is a Systemic Risk in
Diabetic Macular Edema / Diabetic Retinopathy
Patients: Pro
Robert L Avery MD
The use of anti-VEGF injections has revolutionized the treatment
of many retinal diseases. Registration trials have shown good
systemic safety but are not powered to assess safety in uncommon events. Meta-analyses have also shown safety in the overall
populations studied; however, there may be some concern in
certain subgroups of patients.
There are several lines of evidence that imply a biologic plausibility for intravitreal injections to have potential systemic side
effects. There are numerous reports of fellow eye effects, where a
retinal change is observed in the uninjected fellow eye. Also, antiVEGF agents have been shown to escape into the systemic circulation after intravitreal injection and reduce circulating VEGF
levels, sometimes for prolonged periods.
Systemic administration of anti-VEGF agents for cancer has
been shown to increase the risk of arteriovascular events (ATE).
People with diabetes are at much higher risk of these events, and
hence it is reasonable to focus on this population when evaluating systemic risk. A recent Cochrane meta-analysis of treatment
of diabetic macular edema (DME) with anti-VEGF agents did
not show an increased risk of ATE or death. However, the relative risk, which trended toward being protective in the 1-year
follow-up group, trended toward an increased (but not statistically significant) risk with injection in the group with 2 years of
follow-up.
Because in epidemiology it is common to look for factors
associated with an outcome in high-risk groups and to look at
the highest exposed group, a focused meta-analysis was performed of the subgroup of patients with diabetes undergoing the
most intensive anti-VEGF treatment, which was predefined as
monthly injections for 2 years. Only 4 trials met inclusion criteria
for this study: RISE, RIDE, VIVID, and VISTA. Meta-analysis
showed an increased risk of death (P = .003) associated with
anti-VEGF treatment over sham/laser arms.
Although there is no safety signal in the recent meta-analyses
of all patients undergoing anti-VEGF treatment for DME, the
current results suggest that that there could be a significant
increased risk of death associated with the subgroup of DME
patients treated with prolonged and high exposure to anti-VEGF
agents. It may be important to consider total exposure to antiVEGF agents when treating those at high risk for cardiovascular
disease.
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. Avery RL. What is the evidence for systemic effects of intravitreal
anti-VEGF agents, and should we be concerned? Br J Ophthalmol.
2014; 98(suppl 1):7-10.
3. Avery RL, Gordon GM. Systemic safety of intensive anti-VEGF
therapy for diabetic macular edema: systematic review and metaanalysis of randomized trials. Under review.
4. Bakbak B, Ozturk BT, Gonul S, et al. Comparison of the effect of
unilateral intravitreal bevacizumab and ranibizumab injection on
diabetic macular edema of the fellow eye. J Ocul Pharmacol Ther.
2013; 29:728-732.
5. The IVAN Study Investigators; 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(7):1399-1411.
6. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal
aflibercept for diabetic macular edema. Ophthalmology 2014;
121(11):2247-2254.
7. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for
diabetic macular edema: results from 2 Phase III randomized trials:
RISE and RIDE. Ophthalmology 2012; 119(4):789-801.
8. Virgili G, Parravano M, Menchini F, Evans JR. Anti-vascular
endothelial growth factor for diabetic macular oedema (Cochrane
Review). In: Cochrane Database of Systematic Reviews, 2014, Issue
10, Art. No.:CD007419.
9. Wang X, Sawada T, Sawada O, et al. 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(4):738-744 e1.
10. Yanagida Y, Ueta T. Systemic safety of ranibizumab for diabetic
macular edema: meta-analysis of randomized trials. Retina 2014;
34(4):629-635.
Section XIV: Diabetes
2015 Subspecialty Day | Retina
119
Chronic Anti-VEGF Injection Is a Systemic Risk in
Diabetic Macular Edema / Diabetic Retinopathy
Patients: Con
There are no concerns.
Usha Chakravarthy MBBS PhD
Vascular endothelial growth factor (VEGF) is a key mediator of
angiogenesis,1 which has been studied extensively and is recognized for its trophic roles in health and the normal functioning of
many mammalian tissues and cells. Meta-analyses of the original
pivotal clinical trials in the patient population with exudative
AMD2 who were exposed to anti-VEGF drugs or the standard
of care arms (which were observation only or photodynamic
therapy) did not find differences in the rates of serious adverse
events. Anti-VEGF agents are now the standard of care for diabetic macular edema (DME), and the systemic involvement of the
vasculature as a consequence of diabetes may render this population more susceptible to arteriothrombotic events (ATEs).
Serum concentrations of VEGF inhibitors measured in a limited number of DME patients indicate that a slightly higher systemic exposure cannot be excluded compared to those observed
in neovascular AMD patients. We know that anti-VEGF agents
given intraocularly do egress into the systemic circulation3
and have the potential to influence vascular health, and small
increases in the absolute risk of ATEs, notably stroke and MI,
cannot be ruled out. However, the body of evidence to date suggests no difference in risk of serious systemic adverse events due
to anti-VEGF agents or between anti-VEGF agents.
References
1. Ferrara N. VEGF and the quest for tumour angiogenesis factors.
Nat Rev Cancer. 2002; 2:795-803.
2. Ueta T, Yanagi Y, Tamaki Y, Yamaguchi T. Cerebrovascular accidents in ranibizumab. Ophthalmology 2009; 116:362.
3. Chakravarthy U, Harding SP, Rogers CA, et al.; IVAN study investigators. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised
controlled trial. Lancet 2013; 382(9900):1258-1267.
120
Section XIV: Diabetes
2015 Subspecialty Day | Retina
Anti-VEGF Injection Is the New Standard of Care for
Proliferative Diabetic Retinopathy: Pro
Michael S Ip MD
For the several decades since publication of the Diabetic Retinopathy Study (DRS) results, we have relied on panretinal laser
photocoagulation (PRP) as a standard of care therapy for eyes
that have or are approaching high-risk proliferative diabetic retinopathy. PRP is an effective therapy that can reduce the chance
of severe vision loss, but it is an inherently destructive procedure.
New evidence is emerging that repeated injections of anti-VEGF
drugs are effective at causing regression of proliferative diabetic
retinopathy. Clinical research to investigate whether or not antiVEGF injections can substitute for PRP and whether or not antiVEGF injections can prevent the development of proliferative
diabetic retinopathy is needed and will be forthcoming.
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 of retinopathy. Ophthalmology 2014;
18(14):822-827.
2. Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term
effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol. 2012; 130(9):1145-1152.
3. Bressler SB, Qin H, Melia M, et al. Exploratory analysis of the
effect of intravitreal ranibizumab or triamcinolone on worsening of
diabetic retinopathy in a randomized clinical trial. JAMA Ophthalmol. 2013; 131(8):1033-1040.
Section XIV: Diabetes
2015 Subspecialty Day | Retina
121
Anti-VEGF Injection Is the New Standard of Care for
Proliferative Diabetic Retinopathy: Con
Rishi P Singh MD
Scatter, or panretinal, photocoagulation is the mainstay of treatment for proliferative diabetic retinopathy. After panretinal
photocoagulation, there is improved oxygen supply to areas of
inner retina that had become oxygen deprived because of poor
perfusion of inner retinal vessels. Several randomized clinical trials have evaluated the efficacy of panretinal photocoagulation
in patients with proliferative diabetic retinopathy; these studies
were summarized in a systematic review in 2007.1 Treatment
with panretinal photocoagulation is completed in one or more
sittings, depending on the patient’s tolerance for the discomfort
of the laser. While multiple studies have concluded that VEGF
is a major cause of neovascularization in diabetic eye disease,
only clinical case reports and small case series have shown that
anti-VEGF therapy can result in transient regression of neovascularization in proliferative diabetic retinopathy.2-7 Although
anti-VEGF treatment has been shown to reduce neovascularization, it remains unclear how many injections would be necessary
to sustain this benefit and whether the risks and costs of periodic
intravitreal injections would outweigh the benefits of avoiding the side effects of panretinal photocoagulation. The cost of
panretinal photocoagulation was estimated to be approximately
$1080 on the basis of the average Medicare charges for this
procedure, far lower than any FDA-approved anti-VEGF for this
condition. Therefore panretinal laser photocoagulation provides
a long-term, cost-effective, and vision-sustaining treatment for
proliferative diabetic retinopathy.
References
1. Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: a systematic review. JAMA 2007; 298:902-916.
2. Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment
of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 2006; 26: 275-278.
3. Oshima Y, Sakaguchi H, Gomi F, Tano Y. Regression of iris
neovascularization after intravitreal injection of bevacizumab in
patients with proliferative diabetic retinopathy. Am J Ophthalmol.
2006; 142:155-158.
4. Mason JO 3rd, Nixon PA, White MF. Intravitreal injection of bevacizumab (Avastin) as adjunctive treatment of proliferative diabetic
retinopathy. Am J Ophthalmol. 2006; 142:685-688.
5. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab
(Avastin) in the treatment of proliferative diabetic retinopathy.
Ophthalmology 2006; 113(10):1695.e1-1695.e15.
6. Isaacs TW, Barry C. Rapid resolution of severe disc new vessels
in proliferative diabetic retinopathy following a single intravitreal
injection of bevacizumab (Avastin). Clin Experiment Ophthalmol.
2006; 34:802-803.
7. Adamis AP, Altaweel M, Bressler NM, et al. Changes in retinal
neovascularization after pegaptanib (Macugen) therapy in diabetic
individuals. Ophthalmology 2006; 113:23-28.
8. Javitt JC, Aiello LP. Cost-effectiveness of detecting and treating diabetic retinopathy. Ann Intern Med. 1996; 124:164-169.
122
Section XIV: Diabetes
2015 Subspecialty Day | Retina
Ocriplasmin Is Safe and Its Indications Should Be
Expanded: Pro
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),2 suggest the safety profile
of ocriplasmin has been consistent with the Phase 3 clinical
trials. Recent publications have also contributed to a better
understanding of the safety profile of ocriplasmin and suggest
the pharmacologic action of ocriplasmin on the vitreous and
vitreoretinal interface can cause symptoms associated with
changes in tractional forces caused by ocriplasmin.3,4 Several
Phase 4 studies, currently ongoing, will also help further characterize the long-term efficacy and safety profile of ocriplasmin in real-world settings.5 In particular, the Ocriplasmin for
Treatment for Symptomatic Vitreomacular Adhesion including
Macular Hole (OASIS) study is designed to follow patients over
a 2-year period and includes a substudy evaluation of full-field
electroretinogram.5-7 Currently, ocriplasmin is being evaluated
for additional indications, including diabetic retinopathy and
retinal vein occlusion.8
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 Review. 2015;
8(1):55-59.
6. Press release – ThromboGenics announces positive topline results
from OASIS study. March 24, 2015. ThromboGenics.com.
7. Sergott RC, et al. American Academy of Ophthalmology. Abstract.
2015.
8. Press release – ThromboGenics starts evaluating JETREA® for
the Treatment of retinal vein occlusion (RVO). April 23, 2015.
­ThromboGenics.com.
2015 Subspecialty Day | Retina
Section XIV: Diabetes
123
Ocriplasmin Is Safe and Its Indications Should Be
Expanded: Con
Mark W Johnson MD
Review of safety data from Phase 2 and 3 clinical trials combined
with numerous postmarketing reports reveal that ocriplasmin
injection may cause substantial acute panretinal structural and
functional abnormalities in a subset of eyes. The symptoms and
signs of acute ocriplasmin retinopathy include varying degrees
of the following: acute reduction in visual acuity (sometimes
to very low levels), bizarre photopsias (eg, continuous bright
curved or kaleidoscopic lines, sparkles, white floaters on a dark
background), dyschromatopsia (eg, chromatic tinting, black and
white or “negative” vision), nyctalopia, visual field constriction,
afferent pupillary defect, anisocoria, retinal vascular attenuation
or constriction, disruption / loss of outer retinal signals on spectral domain OCT imaging, macular hole enlargement, macular
detachment, reduced (sometimes flat) ERG responses, autofluorescence abnormalities, and lens subluxation or phacodonesis.
Enzymatic degradation of laminin and/or other intraretinal
proteins by this nonspecific protease is the mechanism that most
plausibly explains the various manifestations of the retinopathy. Although the incidence of acute retinal dysfunction after
ocriplasmin injection is unknown, the best available evidence
suggests that some degree of retinopathy occurs in 30%-50%
of eyes. Most of the retinal adverse effects have been shown to
be transient or mostly reversible over time, typically within 2
months after injection. However, some reports have shown that
visual acuity loss, nyctalopia, ERG changes, ellipsoid zone alterations, and/or subretinal fluid may persist in some patients beyond
6 months of follow-up. Ocriplasmin should be used with caution
pending further study results about the mechanism, incidence,
and reversibility of its harmful effects on the eye.
Selected Readings
1. Johnson MW, Fahim AT, Rao RC. Acute ocriplasmin retinopathy.
Retina 2015; 35:1055-1058.
2. Kaiser PK, Kampik A, Kuppermann BD, et al. Safety profile of
ocriplasmin for the pharmacologic treatment of symptomatic vitreomacular adhesion/traction. Retina 2015; 35:1111-1127.
3. Hahn P, Chung MM, Flynn HW, et al. Safety profile of ocriplasmin
for vitreomacular adhesion: a comprehensive analysis of pre- and
post-marketing experiences. Retina 2015; 35:1128-1134.
4. Quezada C, Pieramici DJ, Nasir M, et al. Outer retina reflectivity
changes on SD-OCT following intravitreal ocriplasmin for vitreomacular traction and macular hole. Retina 2015; 35:1144-1150.
5. Reiss B, Smithen L, Mansour S. Transient vision loss following ocriplasmin injection. Retina 2015; 35:1107-1110.
6. Freund KB, Shah SA, Shah VP. Correlation of transient vision loss
with outer retinal disruption following intravitreal ocriplasmin. Eye
2013; 27:773-774.
7. Fahim AT, Khan NW, Johnson MW. Acute panretinal structural
and functional abnormalities after intravitreous ocriplasmin injection. JAMA Ophthalmol. 2014; 132:484-486.
8. Tibbetts MD, Reichel E, Witkin AJ. Vision loss after intravitreal
ocriplasmin: correlation of spectral-domain optical coherence
tomography and electroretinography. JAMA Ophthalmol. 2014;
132:487-490.
9. Miller JB, Kim LA, Wu DM, et al. Ocriplasmin for treatment of
stage 2 macular holes: early clinical results. Ophthalmic Surg Lasers
Imaging Retina. 2014; 45:293-297.
10. Thanos A, Hernandez-Siman J, Marra KV, Arroyo JG. Reversible
vision loss and outer retinal abnormalities after intravitreal ocriplasmin injection. Retin Cases Brief Rep. 2014; 8:330-332.
11. Singh RP, Li A, Bedi R, et al. Anatomical and visual outcomes following ocriplasmin treatment for symptomatic vitreomacular traction syndrome. Br J Ophthalmol. 2014; 98:356-360.
12. Itoh Y, Kaiser PK, Singh RP, et al. Assessment of retinal alterations
after intravitreal ocriplasmin with spectral domain-optical coherence tomography. Ophthalmology 2014; 121:2506-2607.
13. Quezada Ruiz C, Pieramici DJ, Nasir M, et al. Severe acute vision
loss, dyschromatopsia, and changes in the ellipsoid zone on SDOCT associated with intravitreal ocriplasmin injection. Retin Cases
Brief Rep. 2015; 9:145-148.
14. Warrow DJ, Lai MM, Patel A, et al. Treatment outcomes and
spectral-domain optical coherence tomography findings of eyes
with symptomatic vitreomacular adhesion treated with intravitreal
ocriplasmin. Am J Ophthalmol. 2015; 159:20-30.
15. Hager A, Seibel I, Riechardt A, et al. Does ocriplasmin affect the
RPE-photoreceptor adhesion in macular holes? Br J Ophthalmol.
2015; 99:635-638.
16. European Medicines Agency. Ocriplasmin assessment report. January 17, 2013. Available at: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002381/
WC500142228.pdf. Accessed June 30, 2015.
17. Sakuma T, Tanaka M, Mizota A, et al. Safety of in vivo pharmacologic vitreolysis with recombinant microplasmin in rabbit eyes.
Invest Ophthalmol Vis Sci. 2005; 46:3295-3299.
18. Beebe DC. Understanding the adverse effects of ocriplasmin. JAMA
Ophthalmol. 2015; 133:229.
19. Johnson MW, Fahim AT. Understanding the adverse effects of ocriplasmin—reply. JAMA Ophthalmol. 2015; 133:230.
20. Chen W, Mo W, Sun K, et al. Microplasmin degrades fibronectin
and laminin at vitreoretinal interface and outer retina during enzymatic vitrectomy. Curr Eye Res. 2009; 34:1057-1064.
21. Libby RT, Champliaud MF, Claudepierre T, et al. Laminin expression in adult and developing retinae: evidence of two novel CNS
laminins. J Neurosci. 2000; 20:6517-6528.
22. Libby RT, Lavallee CR, Balkema GW, et al. Disruption of laminin
beta2 chain production causes alterations in morphology and function in the CNS. J Neurosci. 1999; 19:9399-9411.
23. Biehlmaier O, Makhankov Y, Neuhauss SC. Impaired retinal differentiation and maintenance in zebrafish laminin mutants. Invest
Ophthalmol Vis Sci. 2007; 48:2887-2894.
24. 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;
44:334-343.
124
Section XIV: Diabetes
2015 Subspecialty Day | Retina
Statistical Significance vs. Clinical Significance:
What Really Matters in Practice?
Challenges in Applying the Results of Clinical Trials to Clinical Practice
Marco Zarbin MD PhD FACS
I.Background
Application of clinical trial results to clinical practice
often is not straightforward for a number of reasons.
Two important factors are restrictive enrollment criteria and publication bias.
c. Prinz et al6 reported that only 25% of 67
published seminal basic research studies were
reproducible.
d.Ioannidis7 reported that 16% of 45 highly
cited original clinical research studies claiming that an intervention was effective were
contradicted by subsequent studies; 16%
reported effects that were stronger than those
of subsequent studies
A. Restrictive enrollment criteria:1 Results in poor
external validity because patients are not representative.
1. In a Medline-based study, 238 of 283 studies
(84%) had at least 1 poorly justified exclusion
criterion.
5. Suggested approach
a. Policy makers: To reduce the risks associated
with generalizing the results of a single study,
replicate the results. For registration of a
drug, the U.S. FDA requires 2 pivotal studies.
b. Individual clinicians: The likelihood that a
single research finding is true depends on:
2. Conflict of interest: Enrollment-based payment to
study centers, aggressive recruitment techniques
B. Publication bias:2 An evaluation of 340 articles in
prognostic markers and 1575 articles on cancer
prognostic markers showed that almost all (~98%)
articles on cancer prognostic marker studies highlighted some statistically significant results.
II. Problems of Interpretation of Clinical Trial Results and
Proposed Approaches
i. Prior evidence: Is the result consistent with
findings from relevant previously published studies?
ii. Study design: Are enough patients enrolled
to reliably estimate the treatment effect of
interest? Is the study population representative of your patients?
iii. Level of statistical significance: Is the
tested hypothesis pre-specified or post
hoc? [level of significance] (Post hoc
endpoints are subject to bias and less reliable. Is the P value << pre-specified type 1
error (α)? P<<α affords greater confidence
than P≈α that null hypothesis should be
rejected.)
A. Not all “statistically significant” results are reproducible.
1. Example: VIEW 1 showed that 2-mg intravitreal
aflibercept every 4 weeks gave a mean 10.9 letter gain in BCVA, whereas 0.5-mg intravitreal
ranibizumab every 4 weeks gave a mean 8.1
letter gain, and the difference was statistically
significant.3 VIEW 2 showed the direction of
benefit was reversed (7.6 letter gain for 2-mg
aflibercept vs. 9.7 letter gain for ranibizumab),
although the difference was not clinically significant. Thus, VIEW 2 did not replicate the results
of VIEW 1.
2. Even if all conditions are equal for two studies,
there is a chance that by random variation, the
results will differ. This outcome does not necessarily mean that anything is wrong with the conduct or underlying truth of the study.
3. Despite similar demographics and disease para­
meters, variation in “twin” studies is not uncommon.
4.Furthermore:
a. Aarts et al4 reported that only 39% of 100
studies published in psychological science
were reproducible.
b. Begley and Ellis5 reported that only 11% of
53 published landmark studies in basic cancer
research were reproducible.
B. Not all “statistically significant” results are “clinically significant.”
1. Example: Comparison of monthly vs. p.r.n.
treatment of choroidal neovascularization in the
Comparison of AMD Treatment Trial (CATT)
showed that at Year 2 there was a mean 2.4 letter better visual outcome in the monthly injection
cohort, a difference that was significant with P =
.046 and a 95% confidence interval of +0.1 to
+4.8 ETDRS letters. The result was statistically
significant. Was it clinically significant?
2. Suggested approach:
a. Step 1: Decide, a priori, what a clinically
meaningful difference between 2 treatments
would be.
i. Requires knowledge of the disease and
knowledge of the patients we wish to treat
2015 Subspecialty Day | Retina
ii. This choice is based on good clinical judgment and is not always clear or obvious.
iii. The choice of the smallest clinically beneficial outcomes (eg, 4 ETDRS letter visual
improvement in BCVA) and harmful
effects defines regions of beneficial, harmful, and trivial outcomes. The smallest
clinically beneficial and harmful outcomes
are usually equal in magnitude and opposite in sign. This choice is not referring to
systemic side risks of treatment.
Section XIV: Diabetes
125
b. Step 2: Instead of focusing on P-values, focus
on confidence intervals.
i. If the 95% confidence interval lies entirely
within the beneficial range of outcomes
or even extends into the trivial range, the
result is both clinically and statistically significant.
ii. If the 95% confidence interval lies mostly
within the beneficial range but extends
into the trivial range, even crossing the
value of 0 (no difference between the 2
treatments), then the result is clinically significant but not statistically significant.
iii. If the 95% confidence interval lies mostly
in the trivial range, including crossing the
value 0, but extends into the beneficial
range slightly, the treatment is not likely
to be clinically significant and definitely is
not statistically significant.
iv. If the 95% confidence interval lies entirely
within the trivial range but does not
include the value 0, then the result is statistically significant, but it is not clinically
significant.
C. Clinically significant results can fail to reach statistical significance, and statistically significant results
may not be clinically significant.
Applying this analysis to CATT data (above) and
assuming that a 4 ETDRS letter change is the minimum improvement needed to judge the outcome as
clinically significant, then the 95% confidence interval lies mostly within the trivial range of outcomes,
although it does not cross the value of 0. If one
judges a 2 ETDRS letter change in BCVA to be clinically significant, however, then most of the 95%
confidence interval lies within the beneficial range!
Thus, good clinical judgment can be critical in determining whether the statistically significant results of
a clinical trial are clinically significant.
References
1. Smith GA. Review of patient inclusion exclusion criteria. 2013.
Available at: www.fda.gov/downloads/Drugs/NewsEvents/
UCM341154.pdf.
2. Kyzas PA, Denaxa-Kyza D, Ioannidis JP. Almost all articles on cancer prognostic markers report statistically significant results. Eur J
Cancer. 2007; 43:2559-2579.
Figure 1. Adapted from Batterham AM, Hopkins, W. G. Making meaningful inferences about magnitudes. Sportscience 2005;9:6-13.
Figure 2. Adapted from Batterham AM, Hopkins, W. G. Making meaningful inferences about magnitudes. Sportscience 2005;9:6-13.
3. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF
trap-eye) in wet age-related macular degeneration. Ophthalmology
2012; 119:2537-2548.
4. Open Science C. PSYCHOLOGY. Estimating the reproducibility of
psychological science. Science 2015;349:aac4716.
5. Begley CG, Ellis LM. Drug development: Raise standards for preclinical cancer research. Nature 2012;483:531-3.
6. Prinz F, Schlange T, Asadullah K. Believe it or not: how much can
we rely on published data on potential drug targets? Nature reviews
2011;10:712.
7. Ioannidis JP. Contradicted and initially stronger effects in highly
cited clinical research. JAMA 2005;294:218-28.
8. Goodman SN. Toward evidence-based medical statistics. 1: The P
value fallacy. Ann Intern Med. 1999;130:995-1004.
9. Goodman SN. Toward evidence-based medical statistics. 2. The
Bayes factor. Ann Intern Med. 1999;130:1005-13.
10. Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012;119:1388-98.
11. Batterham AM, Hopkins, W. G. Making meaningful inferences
about magnitudes. Sportscience 2005;9:6-13.
126
Section XV: First-time Results of Clinical Trials, Part II
2015 Subspecialty Day | Retina
Stem Cell-Derived Retinal Pigment Epithelium
Transplantation for Atrophic Macular Degeneration
and Stargardt Macular Dystrophy: Phase 1 Results and
Ongoing Trials
Steven D Schwartz MD
Overview
• Promise of regenerative medicine
• Unmet medical need
– AMD and Stargardt macular degeneration (SMD)
• Why the eye for first in man?
• Why the RPE for first in eye?
• Why human embryonic stem cells (hESC)?
– Source of cell line: embryonic, IPS, other
• Preclinical basic science
– Confirm: RPE product, purity, viability post-transit of
surgical device, engraftment, polarity, function
– Bruch membrane considerations and other approaches
• Hypothesis: hESC-derived RPE can be safely transplanted
into the subretinal space of eyes with atrophic AMD and
SMD in suspension.
• Safety issues
– Teratomas and other tumors
– Immune rejection
– Differentiation into unwanted cell types
– Surgical issues
• Clinical trial design
• Surgical considerations
– Transition zone recapitulates central macula early in
the course of disease
– Address viable neurosensory tissue hypothetically amenable to neuroprotection, rescue and regeneration
• Results
Pluripotent stem cells have the capacity for unlimited selfrenewal and have been proposed as a potential source of
therapeutic cells for regenerative medicine. This report
provides the first description of the short- and long-term
safety of hESC progeny transplanted into human patients.
2015 Subspecialty Day | Retina
Section XV: First-time Results of Clinical Trials, Part II
127
Induced Pluripotent Stem Cell-Derived Retinal
Pigment Epithelium Transplantation
Yasuo Kurimoto MD PhD
Introduction
Age-related macular degeneration (AMD) is one of the leading causes of social blindness in elderly people in industrialized
countries.1,2 Although the senescent deterioration of retinal pigment epithelium (RPE) is believed to be a key cause of AMD,
the current standard treatments for patients with exudative
AMD, such as anti-VEGF injections and photodynamic therapy,
cannot cure the RPE deterioration. Further, there is no effective
treatment for dry AMD.
Background for the Current Trial
As RPE replacement was suggested as a fundamental therapy
in patients with AMD, allogeneic or autologous RPE cell transplantations have been already attempted for cases of exudative
AMD3-5 and dry AMD.6,7 However, most of these clinical trials
have failed to show favorable results because of immune rejection and graft failure. Although autologous RPE sheet transplantation has been shown to be effective in restoring the visual
function in patients with exudative AMD,8 the surgical procedures were too invasive to become a standard treatment.
Recently, it has become possible to generate mature RPE cells
from embryonic stem (ES) cells,9 and attempts of transplantation of ES cell-derived RPE cells to patients with AMD have
been carried out.10,11 Since the generation of ES cells involves
destruction of the preimplantation stage embryo, however, there
is controversy surrounding ES cell use. In addition to the ethical concerns, a problem of immune rejection is associated with
the transplantation using ES cell lineages because of allogeneic
donor.
Newly developed induced pluripotent stem (iPS) cells are
pluripotent stem cells that can be generated directly from adult
cells.12,13 Since iPS cells can be derived from almost any adult
tissues, each individual can have their own pluripotent stem cell
line. By using patient-derived autologous iPS cells, ethical concerns and immunological issues associated with ES cells can be
escaped.
A Pilot Clinical Study: Protocol
We have started an open-label study of the transplantation
of autologous iPS cell-derived RPE cell sheets in patients with
advanced exudative AMD in whom the current standard treatments had not been effective. In the first stage of this clinical
study, a 4-mm biopsy of tissue will be collected from the skin
of the patient’s upper arm and cultured in a cell processing
center. The skin cells will then be used to generate iPS cells.
The autologous iPS cells will next be differentiated in culture
into monolayer “sheets” of RPE suitable for transplantation.
The entire process, including regular assessments of safety and
quality, will require approximately 10 months for each patient.
Once complete, the RPE cell sheet will be subretinally transplanted in a single eye from which the neovascular tissue has
first been removed. Subjects will be monitored and followed
up for 4 years following transplantation. The primary outcome
to be assessed in this pilot study is the safety of this therapeutic
protocol.
A Pilot Clinical Study: Ongoing Results
In September 2014, we carried out the first-ever iPS cell-based
transplantation successfully. The submacularly transplanted
autologous iPS cell-derived RPE sheet survives well without
any findings of immune rejection or adverse proliferation. Any
significant adverse events with the therapeutic protocol have not
been observed so far. Postoperative observation is still ongoing
now.
References
1. Augood CA, Vingerling JR, de Jong PT, et al. Prevalence of agerelated maculopathy in older Europeans: the European Eye Study
(EUREYE). Arch Ophthalmol. 2006; 124:529-535.
2. Bourne RR, Jonas JB, Flaxman SR, et al. Prevalence and causes of
vision loss in high-income countries and in Eastern and Central
Europe: 1990-2010. Br J Ophthalmol. 2014; 98:629-638.
3. Binder S, Stolba U, Krebs I, et al. Transplantation of autologous
retinal pigment epithelium in eyes with foveal neovascularization
resulting from age related macular degeneration: a pilot study. Am
J Ophthalmol. 2002; 133:215-225.
4. van Meurs JC, ter Averst E, Hofland LJ, et al. Autologous peripheral retinal pigment epithelium translocation in patients with subfoveal neovascular membranes. Br J Ophthalmol. 2004; 88:110113.
5. Algvere PV, Berglin L, Gouras P, et al. Transplantation of fetal retinal pigment epithelium in age-related macular degeneration with
subfoveal neovascularization. Graefes Arch Clin Exp Ophthalmol.
1994; 232:707-716.
6. Algvere PV, Berglin L, Gouras P, et al. Transplantation of RPE in
age-related macular degeneration: observations in disciform lesions
and dry RPE atrophy. Graefes Arch Clin Exp Ophthalmol. 1997;
235:149-158.
7. Algvere PV, Gouras P, Dafgard Kopp E. Long-term outcome of
RPE allografts in non-immunosuppressed patients with AMD. Eur
J Ophthalmol. 1999; 9:217-230.
8. van Zeeburg EJ, Maaijwee KJ, Missotten TO, et al. A free retinal
pigment epithelium-choroid graft in patients with exudative agerelated macular degeneration: results up to 7 years. Am J Ophthalmol. 2012; 153:120-127.
9. Kawasaki H, Suemori H, Mizuseki K, et al. Generation of dopaminergic neurons and pigmented epithelia from primate ES cells
by stromal cell-derived inducing activity. Proc Natl Acad Sci USA.
2002; 99:1580-1585.
10. Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem
cell-derived retinal pigment epithelium in patients with age-related
macular degeneration and Stargardt’s macular dystrophy: followup of two open-label phase 1/2 studies. Lancet 2015; 385:509-516.
128
Section XV: First-time Results of Clinical Trials, Part II
11. Song WK, Park KM, Kim HJ, et al. Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients. Stem Cell Reports.
2015; 4:860-872.
12. Takahashi K, Yamanaka S. Induction of pluripotent stem cells
from mouse embryonic and adult fibroblast cultures by defined
factors. Cell 2006; 126:663-676.
13. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent
stem cells from adult human fibroblasts by defined factors. Cell
2007; 131:861-872.
2015 Subspecialty Day | Retina
2015 Subspecialty Day | Retina
Section XV: First-time Results of Clinical Trials, Part II
DAVE Trial (Diabetic Anti-VEGF): Widefield Guided
Panretinal Photocoagulation for Diabetic Macular
Edema: Eighteen-Month Results
Prospective Trial of 0.3 mg Ranibizumab for Diabetic Macular Edema:
Monotherapy vs. Combination Therapy With Ultrawide Field 200°
Angiography Guided Targeted-Retinal Photocoagulation (IND: 113691/
ML27954)
David M Brown MD, Charles C Wykoff, Rui Wang, and Daniel Croft for the DAVE-Study Group
I.Methods
A. Inclusion criteria: Consenting adults with type 1
or type 2 diabetes mellitus with center-involving
diabetic macular edema (DME) causing visual acuity loss to 26-78 ETDRS letters (Snellen equivalent
20/320-20/32) with extensive peripheral retinal capillary nonperfusion identified with ultrawide-field
200° fluorescein angiograph.
B. Phase 1/2, multicenter, randomized, trial (n = 40
patients)
C. Randomized arms
1. Anti-VEGF only (n = 20)
Four monthly intravitreal injections of 0.3-mg
ranibizumab followed by monthly visits with
p.r.n. retreatment with intravitreal 0.3-mg
ranibizumab based on the predefined criteria
(presence of DME on examination or spectral
domain OCT).
Figure 1. Study entry demonstrating capillary dropout.
2. Anti-VEGF + Targeted-Retinal Photocoagulation
(TRP) (n = 20)
Four mandatory intravitreal injections of 0.3mg ranibizumab followed by monthly visits
with p.r.n. retreatment with intravitreal 0.3-mg
ranibizumab based on the predefined criteria
(presence of DME on examination or spectral
domain OCT).
a. At V3 (Day 7), TRP is applied to areas of
peripheral retinal capillary nonperfusion
based on ultrawide-field 200° angiography.
b. Ultrawide-field 200° angiography is repeated
at Month 6 and additional TRP is applied to
peripheral areas of retinal capillary nonperfusion if needed.
Figure 2. Example of Laser in Patient randomized to PRP
129
130
Section XV: First-time Results of Clinical Trials, Part II
II. Outcome Measures
A. Primary outcome measures
1. Mean change over time in ETDRS BCVA
through Month 18
2. Comparative difference of total number of intravitreal injections between Cohort 1 and Cohort 2
2015 Subspecialty Day | Retina
B. Secondary outcome measures
1. Percentage of subjects who experience a loss of
15 or more letters from baseline to Month 18 in
ETDRS BCVA
2. Percentage of subjects who experience a gain of
15 or more letters from baseline to Month 18 in
ETDRS BCVA
3. Mean change in central retinal thickness over
time through Month 18 as assessed by highresolution OCT
4. Mean change in peripheral visual field as measured by Goldmann visual field assessed through
Month 18
III.Results
Table 1. Baseline Demographics
Cohort 1
Cohort 2
Total
% OD (OD/OS)
35% (7/13)
55% (11/9)
45% (18/22)
Mean age (range)
56 (44-73)
56 (31-73)
56 (31-73)
% Male (Male/Female)
20% (16/4)
75% (15/5)
78% (31/9)
Mean HbA1C (range)
8.8 (5.9-12.9)
8.0 (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)
Abbreviations: DM indicates diabetes mellitus; DME, diabetic macular edema.
Table 2. Treatment Course
# Patients
Completed M18
# Patients
Dropped
# Possible
Visits*
# Missed Visits
% Visits Missed
Anti-VEGF only
17
2
359
41
11%
Anti-VEGF + TRP
18
1
380
32
8%
*Of patients who have completed M18
Table 3. Treatment Course.
Gain of 10 Letters
Gain of 15 Letters
Loss of 10 Letters
Loss of 15 Letters
Anti-VEGF only
50% (10)
25% (5)
0% (0)
0% (0)
Anti-VEGF + TRP
40% (8)
25% (5)
0% (0)
0% (0)
Section XV: First-time Results of Clinical Trials, Part II
2015 Subspecialty Day | Retina
Figure 3.
Table 4. ETDRS Best Corrected Visual Acuity
Baseline
Months 6
Months 12
Month 18
Anti-VEGF only
59.2
68.1
73.3
70.9
Anti-VEGF + TRP
60.1
69.2
69.8
70.2
Baseline
Months 6
Months 12
Month 18
Anti-VEGF only
579
378
290
277
Anti-VEGF + TRP
496
370
335
327
Figure 4.
Table 5. Central Macular Thickness
131
132
Section XV: First-time Results of Clinical Trials, Part II
2015 Subspecialty Day | Retina
Figure 5.
Figure 6.
Table 6. Injections Administered
% p.r.n. Year 1
% p.r.n. Year 2
% p.r.n. Year 3
Anti-VEGF only
85% (116/140)
74% (106/147)
67% (54/81)
Anti-VEGF + TRP
92% (140/153)
79% (124/169)
67% (55/82)
IV.Conclusion
In this prospective randomized trial of 40 eyes with
center-involving 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 18 months of follow-up. In this study population (DME with extensive
peripheral nonperfusion) there is no evidence (to date)
that TRP reduced treatment burden in the management
of DME with ranibizumab. Up-to-date follow-up data
will be presented on the entire cohort.
2015 Subspecialty Day | Retina
Section XV: First-time Results of Clinical Trials, Part II
133
Results of the Nexus Study: An Investigation
of iSONEP, A Monoclonal Antibody Targeting
Sphingosine-1-Phosphate in Patients With Wet AMD
Thomas A Ciulla MD on behalf of the NEXUS Study Investigators
I.Introduction
A. Retinal pigment epithelial (RPE) cells are a major
source of sphingosine-1-phosphate (S1P) in the posterior segment of the eye.1
B. S1P could be responsible for the pathological angiogenesis, vascular permeability, fibrosis, and inflammation in wet AMD.
D. Released S1P also serves a paracrine function to
promote choroidal endothelial cells and pericytes to
form new blood vessels, leading to CNV.
E. S1P also promotes the inflammatory component of
wet AMD by either directly activating macrophages
or indirectly promoting their survival.
F. Sonepcizumab is a recombinant, humanized, IgG1κ
monoclonal antibody that binds to S1P.
G. Anti-S1P mAbs block pathologic laser-induced
CNV lesions in a mouse model.2,3
H. Anti-S1P mAbs block retinal neovascularization and
vascular permeability using an OIR (ROP) model of
ischemic retinopathy and a STZ model of diabetic
retinopathy.4,5
I. Anti-S1P mAbs block macrophage infiltration and
subretinal fibrosis in the setting of pathological
angiogenesis.4
J. In a Phase 1 study, intravitreal (IVT) sonepcizumab
(iSONEP) was safe and well tolerated in 15 patients
with wet AMD at doses up to 1.8 mg/eye.6
A. NEXUS is a Phase 2a, multicenter, masked, randomized, comparator-controlled study conducted in
the United States.
B. Study objectives: To evaluate efficacy, safety, and
tolerability of sonepcizumab (iSONEP) as either
monotherapy or adjunctive therapy to Lucentis,
Avastin, or Eylea vs. Lucentis, Avastin, or Eylea
alone for the treatment of subjects with CNV secondary to AMD.
2. Key secondary endpoints
a. Proportion of subjects gaining or losing
greater than or equal to 0, 5, 10, and 15 letters
b. Proportion of subjects with ETDRS BCVA of
20/40 or better
c. Mean change in central subfield retinal thickness from baseline to Day 120 as determined
by OCT
d. Mean change in CNV lesion area from baseline to Day 120 as determined by fluorescein
angiogram
C. Safety endpoints
1. Incidence of adverse events and changes in vital
sign measurements, visual acuity, IOP, and laboratory tests
2. Patients had previously received a minimum of
3 IVT injections of Lucentis and/or Avastin and/
or Eylea within the 12-month period prior to
screening.
3. To also qualify, patients were “subresponders”
to previous Lucentis, Avastin, or Eylea treatment—ie, meeting the following entry criteria:
II.Methods
Mean change in the Early Treatment of Diabetic
Retinopathy Study (ETDRS) BCVA from Day
0 (baseline) to Day 120 of each of the sonepcizumab-containing treatment groups compared to
the VEGF-alone group
C. In nonclinical models of ocular neovascularization,
S1P acts in an autocrine fashion to further activate
RPE cells and promote their differentiation to a
myofibroblast, profibrotic phenotype capable of
expressing collagen.
1. Primary endpoint
a. Residual subretinal or intraretinal fluid
observed on Cirrus or Spectralis spectral
domain OCT
b. Leakage on fluorescein angiogram, and
c. An average central subfield thickness of ≥
250 μm
4. Intravitreal injections were administered approximately every 4 weeks at Days 0, 30, 60, and 90
in a total of 160 patients, 40 per group, in the
treatment groups shown in Table 1.
134
Section XV: First-time Results of Clinical Trials, Part II
2015 Subspecialty Day | Retina
Table 1. NEXUS Study Treatment Groups
Treatment Group
Sonepcizumab (mg)
Lucentis, Avastin,
or Eylea (mg)
Total
Subject Number
Group 1
4.0
Sham
40
Group 2
0.5
0.5 / 1.25 / 2
40
Group 3
4.0
0.5 / 1.25 / 2
40
Group 4
Sham
0.5 / 1.25 / 2
40
Table 2. NEXUS Study Demographics
Sonepcizumab Alone
(n = 38)
Sonepcizumab 0.5 mg +
anti-VEGF (n = 40)
Age
Sonepcizumab 4.0 mg +
anti-VEGF (n = 39)
Anti-VEGF Alone
(n = 41)
Mean (SD)
76.1 (7.53)
77.2 (7.43)
77.6 (7.86)
76.5 (7.95)
Min, Max
58, 92
57, 89
61, 91
59, 94
Male
16 (42.1%)
20 (50.0%)
18 (46.2%)
21 (51.2%)
Female
22 (57.9%)
20 (50.0%)
21 (53.8%)
20 (48.8%)
Hispanic or Latino
2 (5.3%)
3 (7.5%)
2 (5.1%)
3 (7.3%)
Not Hispanic or Latino
36 (94.7%)
37 (92.5%)
37 (94.9%)
38 (92.7%)
Sex
Ethnicity
Race
American Indian or Alaska
Native
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Asian
0 (0.0%)
0 (0.0%)
0 (0.0%)
1 (2.4%)
Black or African American
2 (5.3%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
Native Hawaiian or Other
Pacific Islander
0 (0.0%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
White
36 (94.7%)
39 (97.5%)
39 (100.0%)
40 (97.6%)
Other
0 (0.0%)
1 (2.5%)
0 (0.0%)
0 (0.0%)
D. Subjects were to be followed for long-term safety for
up to 9 months following the first administration of
study treatment on Day 0 (6 months following their
fourth monthly IVT study treatment on Day 90).
E. During the follow-up period, after completion of the
study treatments, the clinical investigators provided
“standard of care” therapy for wet AMD to patients
through Month 9 as needed and based on their clinical judgement.
III.Results
A. A total of 158 patients were enrolled in the study
and were included in both the efficacy intent-totreat (ITT) and safety analyses.
B. Demographics and baseline characteristics are summarized in Tables 2 and 3, respectively.
Section XV: First-time Results of Clinical Trials, Part II
2015 Subspecialty Day | Retina
Table 3. NEXUS Study Baseline Characteristics
Sonepcizumab Alone
(n = 38)
Sonepcizumab 0.5 mg +
Anti-VEGF (n = 40)
Sonepcizumab 4.0 mg +
Anti-VEGF (n = 39)
Anti-VEGF Alone
(n = 41)
Predominantly classic
4 (10.5%)
6 (15.0%)
5 (12.8%)
9 (22.0%)
Minimally classic
2 (5.3%)
2 (5.0%)
2 (5.1%)
3 (7.3%)
Occult
29 (76.3%)
31 (77.5%)
31 (79.5%)
25 (61.0%)
Unreadable
2 (5.3%)
0 (0.0%)
0 (0.0%)
1 (2.4%)
Missing
1 (2.6%)
1 (2.5%)
1 (2.6%)
3 (7.3%)
CNV lesion type
BCVA (ETDRS)
Mean (SD)
56.2 (15.84)
58.7 (10.75)
61.3 (9.20)
63.2 (7.88)
Min, Max
18, 79
32, 73
36, 74
38, 76
Figure 1. Mean change in BCVA through Day 120.
C. In the ITT population the anti-VEGF alone group
on average gained 4.2 letters from baseline to Day
120. During the same period, the iSONEP-alone
group on average lost 3.0 letters (P = .0005) while
the sonepcizumab 0.5-mg dose plus anti-VEGF and
the sonepcizumab 4.0-mg dose plus anti-VEGF on
average gained 4.28 letters (P = .9529) and 3.56 letters (P = .7286), respectively (see Figure 1).
135
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Section XV: First-time Results of Clinical Trials, Part II
2015 Subspecialty Day | Retina
Figure 2. Mean change in BCVA through Month 9.
D. None of the key visual acuity or anatomical secondary endpoints showed a significant difference in
favor of any of the 3 iSONEP study groups vs. the
anti-VEGF arm. In the safety population a similar
proportion of patients reported at least 1 treatmentemergent adverse event in the sonepcizumab-­
containing groups, compared to the VEGF-alone
group (range: 75.6% to 82.1%).
Treatment-emergent serious adverse events were
more frequent in the VEGF-alone and sonepcizumab-alone groups (14.6% and 10.5%, respectively) compared to the sonepcizumab 0.5 mg plus
anti-VEGF and sonepcizumab 4.0 mg plus antiVEGF treatment groups (5.0% and 5.1%, respectively).
During the follow-up period, from Day 120
to Month 9, mean BCVA in the safety population remained stable in the iSONEP-alone group
(2.88 letter loss at Month 9 vs. Day 0) and in the
­sonepcizumab 4.0 mg plus anti-VEGF group (3.65
letter gain at Month 9 vs. Day 0). During the same
follow-up period mean BCVA decreased in both
the sonepcizumab 0.5 mg plus anti-VEGF and the
anti-VEGF-alone groups (a 1.59-letter gain and a
0.65-letter loss vs. Day 0, respectively).
IV.Conclusions
Four monthly injections of sonepcizumab, alone or in
combination with anti-VEGF, on average did not provide additional visual acuity benefit in a patient population subresponding to previous anti-VEGF therapy.
In all 3 sonepcizumab-containing groups, the study
treatments were safe and well tolerated through the
9-month time point.
References
1. Sabbadini R. Sphingosine-1-phosphate antibodies as potential
agents in the treatment of cancer and age-related macular degeneration: a review. Br J Pharmacol. 2011; 162:1225-1238.
2. Caballero S, Swaney J, et al. Anti-sphingosine-1-phosphate monoclonal antibodies inhibit angiogenesis and sub-retinal fibrosis in a
murine model of laser-induced choroidal neovascularization. Exp
Eye Res. 2009; 88(3):367-377.
3. O’Brien N, Jones ST, Williams DG, et al. Production and characterization of monoclonal anti-sphingosine-1-phosphate antibodies. J
Lipid Res. 2009; 50(11):2245-2257.
4. Xie B, Shen J, Dong A, Rashid A, Stoller G, Campochiaro PA.
Blockade of sphingosine-1-phosphate reduces macrophage influx
and retinal and choroidal neovascularization. J Cell Physiol. 2009;
218(1):192-198.
5. Aiello LP. Unpublished.
6. Ciulla T, Stoller G, et al. A phase 1 investigation of iSONEP, a
sphingosine-1-phosphate monoclonal antibody for wet AMD in a
subset of Subjects with PED. Poster #111. Annual Meeting of the
American Society of Retina Specialists; 2010.
Section XVI: Uveitis
2015 Subspecialty Day | Retina
Uveitis
Panel Moderator: Sunil K Srivastava MD
Panelists: Thomas A Albini MD, Annabelle A Okada MD, Quan Dong Nguyen MD,
P Kumar Rao MD, Wendy M Smith MD
NOTES
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Section XVII: Non-neovascular AMD
2015 Subspecialty Day | Retina
What Is the Evidence of Complement Involvement in
Retinal Pigment Epithelial Cell Loss?
Jayakrishna Ambati MD
Age-related macular degeneration (AMD) refers to the progressive degeneration of the macula that commonly occurs in people
over 60 years of age. The retinal pigment epithelium (RPE) is a
monolayer of cells situated at the posterior border of the retina,
whose primary function is to provide trophic support for photoreceptors. The first clinical feature of early “dry” AMD is
the presence of drusen, which are extracellular deposits below
the RPE that comprise lipid- and protein-rich debris. Advanced
AMD manifests predominantly in one of two forms, termed
“wet” and “dry.” Wet AMD most commonly refers to the invasion of choroidal blood vessels through the RPE layer and into
the normally avascular outer retina, causing blindness. The dry
form of AMD involves progressive degeneration of the RPE,
which progresses to geographic atrophy (GA) in which large,
confluent patches of RPE degenerate, leading to photoreceptor
death and irreversible blindness. The molecular mechanisms that
drive RPE degeneration are of great interest, as their delineation
holds promise for the identification of a target for the first-ever
approved treatment for this condition.
One potential target is the complement system, an ancient
immune defense system that is hypothesized to become overactive in AMD. The complement cascade is a central component
of the innate immune response in humans; although the complement cascade can be initiated by multiple different pathogenic
insults, the end result is the creation of the membrane attack
complex (MAC), which is used to lyse invading pathogens.1
The MAC complex can be assembled via activation of either the
classical, alternative, or lectin pathways; all pathways converge
upon C3 activation for assembly of the C5b-9 protein complex
(ie, MAC).2 The classical pathway requires antibody binding to
antigen for activation by the C1 protein complex,2 and this same
set of complement proteins (C2, C4, etc.) is activated through
recognition of mannose residues on pathogen surfaces by mannose-binding lectin-associated serine proteases (MASP) 1 and
MASP2.3 Unlike the classical and lectin pathways, the alternative
pathway makes use of a different set of complement activating
proteins (eg, CFB, CFD) for C3 activation.2
This interest in complement signaling in AMD was sparked
by the joint discoveries in 2005 of the association of the Y402H
polymorphism of complement factor H (CFH) with increased
statistical risk of developing either wet or dry AMD. This finding has been independently reproduced in subsequent studies in
diverse populations and extended by follow-up discoveries of
polymorphisms in other complement-related genes as associating with modified risk for AMD development. Other evidence
supports a role for complement in AMD, including a 1992 finding that subretinal membranes surgically removed from AMD
patients contained complement proteins C1q, C3c, and C3d.4 It
was found later that C5 and C9 complement components could
be detected in both hard and soft drusen in AMD patients5 and
that immunohistological sections of AMD patient samples were
positively labeled for C3, C5, and C5b-9.6 Conversely, with the
exception of CD59,7 there is no evidence of deficiency of complement negative regulators in AMD.
However, clear evidence supports the concept that complement dysregulation alone is not sufficient to induce AMD.
Millions of individuals carrying complement risk alleles never
develop disease, and thousands with so-called protective alleles
develop disease. Further, it is important to recognize that
although retinal complement activation correlates to AMD, it
has also been detected in healthy eyes of aged and young persons
alike.8 Despite a strong statistical association between CFH polymorphisms and AMD development in human patients, Cfh null
mice exhibit an extremely weak phenotype, with minimal photoreceptor degeneration and thickening of the Bruch membrane
at 2 years of age.9 AMD patients have regions of RPE and retinal
atrophy; there seems to be very little effect on the RPE of Cfh
mutant mice despite the fact that they accumulate more C3 in the
eye.9 This suggests that although CFH may inhibit C3 deposition, C3 itself may not be sufficient to induce AMD phenotypes.
This finding has been reproduced in humans; despite the fact that
C3 deposition occurs in the eye, many humans with C3 or C5b-9
deposition never develop AMD.8,10 Confusingly, ablation of C3
enhances retinal pathologies due to Cfh ablation, questioning the
therapeutic strategy of indiscriminant complement inhibition.11
Indeed, attempts at targeting complement in clinical settings
have been largely unsuccessful. Targeting of C3 or C5 using
various modalities including monoclonal antibody, aptamer or
peptide inhibitor have been unsuccessful thus far.12 One trial of
a compound by Genentech targeting Factor D reported efficacy
in reducing growth of GA size in a Phase 1b/2 trial. However,
the results of this study have not yet been published, the effect
required subgroup analysis, and the finding has not yet been
reproduced, although Phase 3 trials are under way.
Overall, the early returns on clinical translation of complement inhibition are underwhelming and suggest a refinement of
our understanding of the extent to which and the mechanisms by
which complement signaling induces RPE loss in AMD.
References
1. Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: therapeutic interventions. J Immunol. 2013;
190(8):3839-3847.
2. Bora NS, Matta B. Lyzogubov VV, Bora PS. Relationship between
the complement system, risk factors and prediction models in agerelated macular degeneration. Mol Immunol. 2015; 63(2):176-183.
3. Hajela K, et al. The biological functions of MBL-associated serine
proteases (MASPs). Immunobiology 2002; 205(4-5):467-475.
4. Baudouin C, et al. Immunohistological study of subretinal membranes in age-related macular degeneration. Jpn J Ophthalmol.
1992; 36(4):443-451.
5. Hageman GS, et al. An integrated hypothesis that considers drusen
as biomarkers of immune-mediated processes at the RPE-Bruch’s
membrane interface in aging and age related macular degeneration.
Prog Retin Eye Res. 2001; 20(6):705-732.
6. Anderson DH, et al. A role for local inflammation in the formation
of drusen in the aging eye. Am J Ophthalmol. 2002; 134(3):411431.
2015 Subspecialty Day | Retina
7. Ebrahimi KB, et al. Decreased membrane complement regulators in
the retinal pigmented epithelium contributes to age-related macular
degeneration. J Pathol. 2013; 229(5):729-742.
8. Mullins RF, et al. The membrane attack complex in aging human
choriocapillaris: relationship to macular degeneration and choroidal thinning. Am J Pathol. 2014; 184(11):3142-3153.
9. Coffey PJ, et al. Complement factor H deficiency in aged mice
causes retinal abnormalities and visual dysfunction. Proc Natl Acad
Sci USA. 2007; 104(42):16651-16656.
10. Anderson DH, et al. The pivotal role of the complement system in
aging and age related macular degeneration: hypothesis re-visited.
Prog Retin Eye Res. 2010; 29(2):95-112.
11. Hoh Kam J, et al. Complement component C3 plays a critical role
in protecting the aging retina in a murine model of age-related
macular degeneration. Am J Pathol. 2013; 183(2):480-492.
12. Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related
macular degeneration. Nat Rev Immunol. 2013; 13(6):438-451.
Section XVII: Non-neovascular AMD
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Section XVII: Non-neovascular AMD
2015 Subspecialty Day | Retina
Do Visual Cycle Metabolites Really Cause AMD?
Janet R Sparrow PhD
Interest in a role for retinal pigment epithelium (RPE) lipofuscin
in AMD stems from its age-related increase,1 an accumulation
that is more pronounced in central retina outside perifovea,1 a
propensity for adverse effects on RPE2-4 and links to drusen formation.5 The bisretinoid fluorophores of RPE lipofuscin are not
of interest only because they are the source of short-wavelengthfundus autofluorescence (SW-AF); they also may contribute to
the pathogenesis of retinal disease.
The fluorescent pigments of RPE lipofuscin are a complex
mixture of bisretinoids that are produced in photoreceptor outer
segments from nonenzymatic reactions of vitamin A aldehyde.6
The bisretinoids are transferred to RPE cells within phagocytosed outer segment membrane7 and accumulate in the cells. In
ABCA4-associated disease, RPE bisretinoids form in abundance,
causing elevated SW-AF.8 The accumulation of these compounds
in RPE is considered to ultimately cause RPE atrophy.
The photoreactive properties of RPE lipofuscin are likely critical to their damaging properties. Studies of RPE lipofuscin9,10
and individual bisretinoid lipofuscin fluorophores such as A2E
have shown that these compounds initiate photoreactive processes and undergo photodegradation,11-15 leading to the release
of aldehyde-bearing cleavage products that include methylglyoxal and glyoxal.16 These reactive dicarbonyls form adducts with
proteins.
The dicarbonyls released by photodegradation of bisretinoids
provoke the formation of advanced glycation end products
(AGE) that deposit extracellularly.5,17 Since AGEs are detected in
drusen,18,19 they reflect a link between RPE bisretinoid lipofuscin
and the formation of sub-RPE deposits. Photo-oxidation of A2E
and all-trans-retinal dimer has also been shown to incite complement activation.20
The photodegradation of bisretinoids likely contributes to
Bruch membrane thickening21 and photoreceptor cell degeneration22 in Abca4 mutant mice and are a cause of the increased vulnerability of albino Abca4-/- mice to retinal light damage.23
SW-AF emitted from RPE bisretinoids is commonly regarded
as a way to monitor the health of RPE. Given that these lightsensitive compounds undergo photodegradation, the lipofuscin
in RPE that is recorded by SW-AF may consist of only some
portion of these compounds that accumulate over a lifetime.
Since the products of bisretinoid photodegradation can be damaging,5,16 consideration should be given to the possibility that
lipofuscin lost by photo-oxidation / photodegradation is more
significant than the lipofuscin remaining in the cells.
References
1. Delori FC, Goger DG, Dorey CK. Age-related accumulation and
spatial distribution of lipofuscin in RPE of normal subjects. Invest
Ophthalmol Vis Sci. 2001; 42:1855-1866.
2. Sparrow JR, Nakanishi K, Parish CA. The lipofuscin fluorophore
A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci. 2000; 41:1981-1989.
3. Sparrow JR, Parish CA, Hashimoto M, Nakanishi K. A2E, a lipofuscin fluorophore, in human retinal pigmented epithelial cells in
culture. Invest Ophthalmol Vis Sci. 1999; 40:2988-2995.
4. Finnemann SC, Leung LW, Rodriguez-Boulan E. The lipofuscin
component A2E selectively inhibits phagolysosomal degradation of
photoreceptor phospholipid by the retinal pigment epithelium. Proc
Natl Acad Sci USA. 2002; 99:3842-3847.
5. Yoon KD, Yamamoto K, Ueda K, Zhou J, Sparrow JR. A novel
source of methylglyoxal and glyoxal in retina: implications for agerelated macular degeneration. PLoS One. 2012; 7:e41309.
6. Liu J, Itagaki Y, Ben-Shabat S, Nakanishi K, Sparrow JR. The biosynthesis of A2E, a fluorophore of aging retina, involves the formation of the precursos, A2-PE, in the photoreceptor outer segment
membrane. J Biol Chem. 2000; 275:29354-29360.
7. Katz ML, Drea CM, Eldred GE, Hess HH, Robison WG Jr. Influence of early photoreceptor degeneration on lipofuscin in the retinal
pigment epithelium. Exp Eye Res. 1986; 43:561-573.
8. Burke TR, Duncker T, Woods RL, et al. Quantitative fundus autofluorescence in recessive Stargardt disease. Invest Ophthalmol Vis
Sci. 2014; 55:2841-2852.
9. Rozanowska M, Jarvis-Evans J, Korytowski W, Boulton ME, Burke
JM, Sarna T. Blue light-induced reactivity of retinal age pigment:
in vitro generation of oxygen-reactive species. J Biol Chem. 1995;
270:18825-18830.
10. Gaillard ER, Atherton SJ, Eldred G, Dillon J. Photophysical studies
on human retinal lipofuscin. Photochem Photobiol. 1995; 61:448453.
11. Ben-Shabat S, Itagaki Y, Jockusch S, Sparrow JR, Turro NJ,
Nakanishi K. Formation of a nonaoxirane from A2E, a lipofuscin
fluorophore related to macular degeneration, and evidence of singlet oxygen involvement. Angew Chem Int Ed Engl. 2002; 41:814817.
12. Jang YP, Matsuda H, Itagaki Y, Nakanishi K, Sparrow JR. Characterization of peroxy-A2E and furan-A2E photooxidation products
and detection in human and mouse retinal pigment epithelial cell
lipofuscin. J Biol Chem. 2005; 280:39732-39739.
13. Kim SR, Jang YP, Jockusch S, Fishkin NE, Turro NJ, Sparrow JR.
The all-trans-retinal dimer series of lipofuscin pigments in retinal
pigment epithelial cells in a recessive Stargardt disease model. Proc
Natl Acad Sci USA. 2007; 104:19273-19278.
14. Sparrow JR, Zhou J, Ben-Shabat S, Vollmer H, Itagaki Y, Nakanishi K. Involvement of oxidative mechanisms in blue-light-induced
damage to A2E-laden RPE. Invest Ophthalmol Vis Sci. 2002;
43:1222-1227.
15. Gaillard ER, Avalle LB, Keller LMM, Wang Z, Reszka KJ, Dillon
JP. A mechanistic study of the photooxidation of A2E, a component of human retinal lipofuscin. Exp Eye Res. 2004; 79:313-319.
16. Wu Y, Yanase E, Feng X, Siegel MM, Sparrow JR. Structural
characterization of bisretinoid A2E photocleavage products and
implications for age-related macular degeneration. Proc Natl Acad
Sci USA. 2010; 107:7275-7280.
2015 Subspecialty Day | Retina
17. Zhou J, Cai B, Jang YP, Pachydaki S, Schmidt AM, Sparrow JR.
Mechanisms for the induction of HNE-, MDA-, and AGE-adducts,
RAGE and VEGF in retinal pigment epithelial cells. Exp Eye Res.
2005; 80:567-580.
18. Cano M, Fijalkowski N, Kondo N, Dike S, Handa J. Advanced glycation endproduct changes to Bruch’s membrane promotes lipoprotein retention by lipoprotein lipase. Am J Pathol. 2011; 179:850859.
19. Crabb JW, Miyagi M, Gu X, et al. Drusen proteome analysis: an
approach to the etiology of age-related macular degeneration. Proc
Natl Acad Sci USA. 2002; 99:14682-14687.
20. Zhou J, Jang YP, Kim SR, Sparrow JR. Complement activation
by photooxidation products of A2E, a lipofuscin constituent of
the retinal pigment epithelium. Proc Natl Acad Sci USA. 2006;
103:16182-16187.
21. Radu RA, Hu J, Yuan Q, et al. Complement system dysregulation
and inflammation in the retinal pigment epithelium of a mouse
model for Stargardt macular degeneration. J Biol Chem. 2011;
286:18593-18601.
22. Wu L, Nagasaki T, Sparrow JR. Photoreceptor cell degeneration in
Abcr (-/-) mice. Adv Exp Med Biol. 2010; 664:533-539.
23. Wu L, Ueda K, Nagasaki T, Sparrow JR. Light damage in Abca4
and Rpe65rd12 mice. Invest Ophthalmol Vis Sci. 2014; 55:19101918.
Section XVII: Non-neovascular AMD
141
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2015 Subspecialty Day | Retina
What Causes Autofluorescence Changes at the Border
of Geographic Atrophy? New Findings About GA
Christine A Curcio PhD
Fundus autofluorescence (AF) is a projection image through
tissue layers. AF signal is multifactorial in origin, incorporating concentration of bisretinoid fluorophore in retinal pigment
epithelium (RPE), efficiency of the fluorophores for exciting
wavelengths, emission wavelengths relative to detector sensitivity, extracellular blocking (by subretinal cells, photoreceptor pigment, edema, blood, vitreous floaters), intracellular blocking by
RPE melanosomes, number and 3-dimensional disposition of fluorophore-containing granules, and variable path length through
these granules due to RPE shape. Granules that emit at 488-nm
excitation wavelengths are lipofuscin and melanolipofuscin (LF/
ML), of lysosomal origin.
The subcellular bases of AF in aging and AMD are now
clearer due to recently published histology.1-3 The first digital
maps of RPE cell number and LF/ML-attributable AF demonstrate that AF increases with age while RPE cell number is stable.
In AMD eyes LF/ML granules are lost either singly or by aggregation and basolateral shedding, in concert with cytoskeleton
derangement indicating cellular stress. The histological basis
of variable AF at the GA border is double-layers of RPE or tall
individual cells that effectively increase path length of exciting
light through fluorophores (see Figure 1). There is little evidence
of high intracellular concentration of AF granules in individual
cells beyond granule aggregates (5-20 µm in diameter), which are
below current clinical detection.
The border of GA has been historically defined by the absence
of a pigmented layer on color fundus photography. The biological border of GA has been newly investigated in studies of
outer retinal tubulation (ORT). This gliotic formation of cone
photoreceptors and Müller cells is common in advanced AMD as
revealed by OCT.4-7 The external limiting membrane (ELM) is a
defining feature of ORT. The ELM of ORT is continuous with
the border of GA, where fingers of subretinal space protrude
into the atrophic area with the ELM wrapped around them. In
cross-sectional view, the ELM is seen to curve externally to meet
the RPE layer and Bruch membrane, thus delimiting the atrophic area (containing only degenerating cone photoreceptors)
from the non-atrophic area (containing rods and cones that are
potentially salvageable). The RPE does not necessarily respect
this ELM border. Many fully pigmented cells are now known to
Figure 1. Retinal pigment epithelium (RPE) morphologies and associated histologic autofluorescence (AF) in eyes with geographic atrophy. Bars,
20 µm. Top row: summed AF across the retinal layers is a surrogate to the projection image seen in fundus AF. Middle row: histologic AF captured at
488-nm excitation, laser confocal microscopy. Bottom row: differential interference contrast microscopy shows refractive index gradients in the same
tissue sections, which are unstained. Left column: Uniform morphology and AF is found outside the atrophic area. Middle column: Sloughed cells in
the subretinal space leave an epithelial layer behind (arrowhead). High AF is due primarily to vertical superimposition of multiple cells (double arrow).
Right column: Shedding cells drop granule aggregations (left-pointing arrow) into underlying basal laminar deposit. Intraretinal cells are fully pigmented (right-pointing arrow). Figure is adapted from Rudolf M, Vogt SD, Curcio CA, Huisingh C, et al. Histologic basis of variations in retinal pigment epithelium autofluorescence in eyes with geographic atrophy. Ophthalmology 2013; 120(4):821-828. Nomenclature for RPE morphology from
Zanzottera EC, Messinger JD, Ach T, Smith RT, Freund KB, Curcio CA. The Project MACULA retinal pigment epithelium grading system for histology
and optical coherence tomography in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2015; 56(5):3253-3268.
2015 Subspecialty Day | Retina
localize to the atrophic area.8-10 These cells are considered RPE
that remain after the layer disintegrates, as neighboring cells die
or transdifferentiate to migratory phenotypes and leave.
At a GA border defined by the ELM, the precise geometry
of healthy RPE becomes highly variable.11 The overall effect is
thickening of the layer, as cells round up to migrate out of the
layer and into the retina (see Figures 2 and 3). Sloughed and
intraretinal RPE are packed with characteristic granules. Visible
as hyper-reflective spots on OCT, they could also be sought by
fundus AF. Interestingly, melanosome-containing cells out of the
RPE layer express macrophage markers.12,13 High-resolution histology has shown transitional forms between epithelial RPE and
out-of-layer RPE-derived cells, supporting transdifferentiation.
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143
Collectively, new quantitative data from human eye pathology suggest that lipofuscin content of RPE is a marker of cellular
health, its loss is a sign of declining health, and that hyperAF at
the GA border signifies hypertrophy and transdifferentiation of
individual cells that can be followed in living patients with information from OCT. Attribution of hyperAF at the GA border to
high intracellular content of LF/ML granules has been considered
in vivo evidence for their toxicity.14 Histologic data support
alternate explanations, newly elucidate human retinoid metabolism and the complexity of AMD’s neurodegeneration, and synergize with longitudinal clinical imaging showing that hyperAF is
nonpredictive for atrophy.15
Figure 2. Histology of geographic atrophy secondary to AMD. Submicrometer epoxy section and toluidine blue stain (adapted from Zanzottera EC,
Ach T, Huisingh C, Messinger JD, Spaide RF, Curcio CA. Retinal pigment epithelium phenotypes at the biological border of geographic atrophy in agerelated macular degeneration. In preparation). Arrowheads, external limiting membrane; ONL, outer nuclear layer; INL, inner nuclear layer. RPE thickness measurements shown in Figure 3 were made at the indicated locations. The RPE varies in thickness near the border of GA, which impacts fundus
AF.
Figure 3. Thickness of RPE in 13 eyes with geographic atrophy secondary to AMD. (Adapted from Zanzottera EC, Ach T, Huisingh C, Messinger JD,
Spaide RF, Curcio CA. Retinal pigment epithelium phenotypes at the biological border of geographic atrophy in age-related macular degeneration. In
preparation.) Distances are expressed relative to the descent of the external limiting membrane (ELM). Sample includes 171 assessments bracketing 72
ELM transitions and demonstrates thickening of RPE that impacts AF near the geographic atrophy border.
144
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2015 Subspecialty Day | Retina
References
1. Rudolf M, Vogt SD, Curcio CA, et al. Histologic basis of variations
in retinal pigment epithelium autofluorescence in eyes with geographic atrophy. Ophthalmology 2013; 120(4):821-828.
2. Ach T, Huisingh C, McGwin G Jr, Messinger JD, Zhang T, Bentley
MJ, Gutierrez DB, Ablonczy Z, Smith RT, Sloan KR, Curcio CA.
Quantitative autofluorescence and cell density maps of the human
retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2014;
55(8):4832-4841.
3. Ach T, Tolstik E, Messinger JD, Zarubina AV, Heintzmann R,
Curcio CA. Lipofuscin re-distribution and loss accompanied by
cytoskeletal stress in retinal pigment epithelium of eyes with agerelated macular degeneration. Invest Ophthalmol Vis Sci. 2015;
56(5):3242-3252.
4. Curcio CA, Medeiros NE, Millican CL. Photoreceptor loss in agerelated macular degeneration. Invest Ophthalmol Vis Sci. 1996;
37(7):1236-1249.
5. Zweifel SA, Engelbert M, Laud K, Margolis R, Spaide RF, Freund
KB. Outer retinal tubulation: a novel optical coherence tomography
finding. Arch Ophthalmol. 2009; 127(12):1596-1602.
6. Litts KM, Messinger JD, Dellatorre K, Yannuzzi LA, Freund KB,
Curcio CA. Clinicopathological correlation of outer retinal tubulation in age-related macular degeneration. JAMA Ophthalmology.
2015; 133(5):609-612.
7. Schaal KB, Freund KB, Litts KM, Zhang Y, Messinger JD, Curcio
CA. Outer retinal tubulation in age-related macular degeneration:
optical coherence tomographic findings correspond with histology.
Retina 2015; 35.
8. Gocho K, Sarda V, Falah S, et al. Adaptive optics imaging of geographic atrophy. Invest Ophthalmol Vis Sci. 2013; 54(5):36733680.
9. Zanzottera EC, Messinger JD, Ach T, Smith RT, Freund KB, Curcio CA. The Project MACULA retinal pigment epithelium grading
system for histology and optical coherence tomography in agerelated macular degeneration. Invest Ophthalmol Vis Sci. 2015;
56(5):3253-3268.
10. Zanzottera EC, Messinger JD, Ach T, Smith RT, Curcio CA.
Subducted and melanotic cells in advanced age-related macular
degeneration are derived from retinal pigment epithelium. Invest
Ophthalmol Vis Sci. 2015; 56(5):3269-3278.
11. Zanzottera EC, Ach T, Huisingh C, Messinger JD, Spaide RF, Curcio CA. Retinal pigment epithelium phenotypes at the biological
border of geographic atrophy in age-related macular degeneration.
In preparation.
12. Sennlaub F, Auvynet C, Calippe B, et al. CCR2(+) monocytes infiltrate atrophic lesions in age-related macular disease and mediate
photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice. EMBO Mol Med. 2013; 5(11):17751793.
13. Lad EM, Cousins SW, Van Arnam JS, Proia AD. Abundance of
infiltrating CD163+ cells in the retina of postmortem eyes with dry
and neovascular age-related macular degeneration. Graefes Arch
Clin Exp Ophthalmol. Epub ahead of print 2015 July 7.
14. Holz FG, Bellman C, Staudt S, Schutt F, Volcker HE. Fundus
autofluorescence and development of geographic atrophy in agerelated macular degeneration. Invest Ophthalmol Vis Sci. 2001;
42(5):1051-1056.
15. Hwang JC, Chan JW, Chang S, Smith RT. Predictive value of fundus autofluorescence for development of geographic atrophy in
age-related macular degeneration. Invest Ophthalmol Vis Sci. 2006;
47(6):2655-2661.
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145
Membrane Attack Complex—Is the Choroid the Real
Site to Worry About?
Robert F Mullins PhD MS
I. The Complement System
A. Component of innate immune system
B. Multiple modes of activation
C. Multiple inhibitors, including CFH
D. Activation can ultimately result in formation of the
membrane attack complex (MAC).
II. The MAC in Aging and AMD
A. Biochemical quantification
B. Immunohistochemical localization
1. Sub-retinal pigment epithelial deposits
2.Choriocapillaris
III. High-risk Complement Factor H Genotype
A. Association with increased choroidal MAC
B. Association with decreased choroidal thickness
IV. Is the MAC Harmful to Choroidal Endothelial Cells?
A. In vitro studies
B. Morphometric studies of human donor eyes
V. Proposed Mechanism of Early AMD
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2015 Subspecialty Day | Retina
What Does Macular Pigment Do?
Paul S Bernstein MD PhD
I. Historical Context
A. Discovery of the macula lutea (yellow spot) by early
anatomists
B. Initial identification as a xanthophyll carotenoid by
Wald in the 1940s
C. Preliminary identification of lutein and zeaxanthin
as the macular pigment by Bone and Landrum in the
1980s
D. Identification of meso-zeaxanthin as the third macular carotenoid in the 1990s by Bone and Landrum
E. Identification of specific binding proteins, GSTP1
(zeaxanthins) and StARD3 (lutein), by the Bernstein
laboratory in the 2000s
II. Chemical and Biological Properties
B. Hydroxyl groups make them members of the xanthophyll subgroup.
C. Lutein, zeaxanthin, and meso-zeaxanthin differ only
in double-bond location and stereochemistry at the
3’ position.
D. Synthesized exclusively by plants and microorganisms
E. All carotenoids in vertebrates must be obtained
from the diet or from supplements.
F. Common dietary sources include dark green leafy
vegetables and orange and yellow fruits and vegetables.
1. Enhanced contrast sensitivity
2. Better glare tolerance
3. Decreased chromatic aberration
4. Improved visual acuity
A.C40H56O2 conjugated polyenes in the carotenoid
family
B. Improved visual performance
C. Possible developmental effects
1. Macular pigment is present at birth.
2. Deposition occurs in the third trimester, at the
time when the fovea is taking form.
3. Macular pigment is very low in disorders with
poor foveal development such as albinism.
IV. Measurement of Macular Pigment
A. High-performance liquid chromatography (HPLC)
B.Psychophysical
1. Heterochromatic flicker photometry (HFP)
2. Minimum motion photometry
C. Image based
1. Autofluorescence attenuation
2.Reflectometry
3. Resonance Raman spectroscopy
V. Macular Pigment’s Roles in Retinal Health and Disease
A.AMD
1. Low macular pigment is associated with many
AMD risk factors.
G. Poor water solubility—must be protein-bound or
embedded in membranes
2. High-dose supplementation raises macular pigment levels.
H. Intense yellow color due to peak absorption in the
blue range (~450 nm)
3. AREDS2 supports the safety and efficacy of
lutein and zeaxanthin, especially as a substitute
for β-carotene.
I. High-efficiency antioxidants
J. Minimal toxicity
K. Excellent stability in biological matrices
L. Highly concentrated in the Henle fiber layer and in
the inner plexiform layer of the fovea
III. Physiological Functions
B. Macular telangiectasia type II (MacTel)
1. Abnormal macular pigment distribution is one of
the first signs of MacTel.
2. Underlying mechanism is unknown.
3. Supplementation with lutein or zeaxanthin
enhances the ring-shaped pattern but does not
normalize the distribution.
A. AMD protection
1. Screening pigment that can counteract blue light
damage.
2. Localized depot of antioxidants in a region at
high risk for oxidative stress
3. Possible prevention of A2E formation
C. Retinitis pigmentosa and various macular dystrophies
1. Low macular pigment occurs in some conditions
such as Stargardt disease.
2. Minimal response to supplementation in most
clinical studies to date
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147
Selected Readings
1. Age-Related Eye Disease Study 2 (AREDS2) Research Group; Chew
EY, Clemons TE, Sangiovanni JP, et al. Secondary analyses of the
effects of lutein/zeaxanthin on age-related macular degeneration
progression: AREDS2 report No. 3. JAMA Ophthalmol. 2014;
132:142-149.
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; 309:2005-2015.
3. Age-Related Eye Disease Study Research Group; SanGiovanni JP,
Chew EY, Clemons TE, et al. The relationship of dietary carotenoid
and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. Arch Ophthalmol. 2007; 125:1225-1232.
4. Bernstein PS, Delori FC, Richer S, van Kuijk FJ, Wenzel AJ. The
value of measurement of macular carotenoid pigment optical densities and distributions in age-related macular degeneration and other
retinal disorders. Vision Res. 2010; 50:716-728.
5. Li B, Vachali PP, Gorusupudi A, et al. Inactivity of human beta,
beta-carotene-9’,10’-dioxygenase (BCO2) underlies retinal accumulation of the human macular carotenoid pigment. Proc Natl Acad
Sci USA. 2014; 111:10173-10178.
6. Nolan JM, Meagher K, Kashani S, Beatty S. What is meso-zeaxanthin, and where does it come from? Eye (Lond). 2013; 27:899-905.
7. Sabour-Pickett S, Nolan JM, Loughman J, Beatty S. A review of
the evidence germane to the putative protective role of the macular
carotenoids for age-related macular degeneration. Mol Nutr Food
Res. 2012; 56:270-286.
8. SanGiovanni JP, Neuringer M. The putative role of lutein and
zeaxanthin as protective agents against age-related macular degeneration: promise of molecular genetics for guiding mechanistic
and translational research in the field. Am J Clin Nutr. 2012;
96:1223S-1233S.
9. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids,
vitamins A, C, and E, and advanced age-related macular degeneration. JAMA. 1994; 272:1413-1420.
148
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2015 Subspecialty Day | Retina
Is the Problem the Bruch Membrane? Is the Future
Home of Transplanted Retinal Pigment Epithelial
Cells a Hostile Environment?
Lucian V Del Priore MD PhD
I. Stem Cell Transplantation
A. Single donor human embryonic stem cell (hESC)
line
B. Differentiated into retinal pigment epithelium (RPE)
C. Transplanted into subretinal space in
1. AMD (geographic atrophy)
2. Stargardt disease
II. Nine Patients With AMD, 9 Patients With Stargardt
Figure 1
hESC-derived RPE in patients with AMD and Stargardt’s macular dystrophy: follow-up of 2 open-label
Phase 1/2 studies (see Figure 1)
2015 Subspecialty Day | Retina
III. Results (see Figures 2-4)
A. 13 of 18 patients (72%) had an increase in subretinal pigmentation.
B. Pigmented tissue was present at border of the atrophic lesion.
C. Increased in density and size with time after surgery
Figure 2.
Figure 3.
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150
Section XVII: Non-neovascular AMD
Figure 4.
IV. Fate of Human RPE Cells Seeded Onto Layers of
Human Bruch Membrane
Figure 5.
Figure 6.
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Section XVII: Non-neovascular AMD
2015 Subspecialty Day | Retina
V. Reattachment Rate
151
VIII. Aging Effect
Comparison of fetal RPE and hESC-derived-RPE
behavior on aged human Bruch’s membrane. (Sugino et
al. Invest Opthalmol Vis Sci.)
Figure 7.
VI. Apoptosis Rate in 24 Hours
Figure 10.
A. Compared hESC-derived RPE and fetal RPE behavior seeded onto unmodified human Bruch’s membrane
B. hESC-derived RPE were divided into 3 categories
based on degrees of pigmentation.
C. All cells were cultured on human Bruch membrane
explants.
D. Most fetal RPE retained RPE markers. hESCderived RPE showed impaired initial attachment
compared to fetal RPE.
Figure 8.
IX. Reengineering of Aged Bruch Membrane to Enhance
RPE Repopulation
VII. Proliferation Rate in 24 Hours
Figure 9.
A. Yes: 2 steps
1. Cleaning with detergent
2. Coating with new proteins
X.Summary
A. ESC-derived RPE was safe in Phase 1/2 trials.
B. Visual acuity results suggest efficacy.
C. Pigmented cells cluster at margin of GA.
D. Pigment then migrates centrally.
E. Pigmentation pattern is consistent with donor cell
attachment to residual basement membrane and/or
RPE edge.
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2015 Subspecialty Day | Retina
Rod Function in AMD
Catherine A Cukras MD PhD
Introduction
The assessment of visual function in AMD has primarily centered on visual acuity, which demonstrates the greatest loss in
late AMD but can show some decrease with intermediate AMD.1
Other methods of assessing visual function may provide valuable
insights into the mechanism of retinal dysfunction in AMD and
may identify risk factors for progression to late AMD. This could
lead to further ability to stratify eyes with AMD into subgroups
that may be at more or less risk for progression based on findings
beyond the anatomic ones currently used.
Dark adaptation is one measure of visual function that has
been identified to reveal abnormalities in AMD.2-5 The aging
process itself is associated with some impairment in dark adaptation as psychophysical studies demonstrate decreases in static
scotopic thresholds, rightward shifts of the dark adaptation
curve, and a slower recovery rate in older adults compared with
younger adults.5,6 Histological examination of donor retinas
demonstrates that aging is associated with a steady decline in
number and density of rods, while cones are mostly spared.7
AMD patients exhibit even more impairment in dark adaptation than the impairment observed in normal aging.4 Examination of pathology in AMD eyes demonstrates preferential loss of
rod cells in the macula of eyes with early disease compared with
age-matched controls, with the greatest loss in the region 0.5-3.0
mm from the fovea.8 Previous work has demonstrated that the
rod-mediated scotopic sensitivity and recovery time constants
are impaired at the parafovea and within the macula of eyes with
early and intermediate AMD while sparing cone-mediated function.3,4
Study Objectives
This current study investigates the association between AMD
severity and dark adaptation impairment. It also investigated
other eye-based and person-based factors that affect dark adaptation.
Study Design
Cross-sectional, single-center, observational study
Participants
Participants included 116 adults older than 50 years of age both
with and without AMD who were recruited from the eye clinic at
the National Eye Institute, National Institutes of Health (NIH).
Eligible participants were separated into groups based on their
fundus features. Eligible eyes were screened for the presence
of reticular pseudodrusen, and these eyes were placed into a
separate group (Group RPD). The remaining eyes were grouped
according to increasing order of AMD severity, based on the
presence of large drusen (≥ 125 µm) and/or advanced AMD. The
control group, Group 0, consisted of participants without any
large drusen or advanced AMD (CNV or central GA) in either
eye. Group 1 consisted of participants with large drusen in 1
eye only and no late AMD in either eye. Group 2 included participants with large drusen in both eyes without any late AMD.
Group 3 included participants with large drusen in 1 eye and late
AMD in the other eye (either GA or CNV).
Methods
Participants underwent BCVA testing, ophthalmoscopic examination, and multimodal imaging. Presence of reticular pseudodrusen (RPD) was assessed by masked grading of fundus images
and confirmed with OCT. Eyes were also graded for AMD
features (drusen, pigmentary changes, late AMD) to generate a
person-based AMD severity groups. One eye was designated the
study eye for dark adaptation testing using a prototype of the
AdaptDx device (Maculogix; Hummelstown, PA). Nonparametric statistical testing was performed on all comparisons.
Main Outcome Measure
The primary outcome of this study was the rod-intercept time
(RIT), which is defined as the time for a participant’s visual
sensitivity to recover to a stimulus intensity of 5x10-3 cd/m2 (a
decrease of 3 log units), or until a maximum test duration of 40
minutes was reached.
Results
A total of 116 study eyes in 116 participants (mean age: 75.4 ±
9.4 years; 58% female) were analyzed. Increased RIT was significantly associated with increasing age (r = 0.34, P = .0002),
decreasing BCVA (r = -0.54, P < .0001), pseudophakia (P = .03),
and decreasing subfoveal choroidal thickness (r = -0.27, P =
.003). Study eyes with RPD (15/116, 13%) had a significantly
greater mean RIT than eyes without RPD in any AMD severity
group (P < .02 for all comparisons), with 80% reaching the dark
adaptation test ceiling.
Conclusion
Impairments in dark adaptation increase with age, worse visual
acuity, presence of RPD, AMD severity, and decreased subfoveal
choroidal thickness. Analysis of covariance found the multivariable model that best fit our data included age, AMD group, and
presence of RPD (R2 = 0.56), with the presence of RPD conferring the largest parameter estimate.
References
1. Chew EY, Clemons TE, Agron E, et al. Ten-year follow-up of agerelated macular degeneration in the age-related eye disease study:
AREDS report no. 36. JAMA Ophthalmol. 2014; 132(3):272-277.
2. Jackson GR, Edwards JG. A short-duration dark adaptation protocol for assessment of age-related maculopathy. J Ocul Biol Dis
Infor. 2008; 1(1):7-11.
2015 Subspecialty Day | Retina
3. Owsley C, Jackson GR, Cideciyan AV, et al. Psychophysical evidence for rod vulnerability in age-related macular degeneration.
Invest Ophthalmol Vis Sci. 2000; 41(1):267-273.
4. Owsley C, Jackson GR, White M, et al. Delays in rod-mediated
dark adaptation in early age-related maculopathy. Ophthalmology
2001; 108(7):1196-1202.
5. Jackson GR, Owsley C, McGwin G Jr. Aging and dark adaptation.
Vision Res. 1999; 39(23):3975-3982.
6. Jackson GR, Owsley C, Cordle EP, Finley CD. Aging and scotopic
sensitivity. Vision Res. 1998; 38(22):3655-3662.
7. Curcio CA, Millican CL, Allen KA, Kalina RE. Aging of the human
photoreceptor mosaic: evidence for selective vulnerability of rods in
central retina. Invest Ophthalmol Vis Sci. 1993; 34(12):3278-3296.
8. Curcio CA, Medeiros NE, Millican CL. Photoreceptor loss in
age-related macular degeneration. Invest Ophthalmol Vis Sci.
1996;37(7):1236-49.
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Section XVII: Non-neovascular AMD
2015 Subspecialty Day | Retina
What Should We Be Measuring as a Geographic
Atrophy Endpoint?
Karl G Csaky MD
Background
It has been well established that visual acuity changes in patients
with geographic atrophy (GA) associated with dry AMD occur
slowly and do not correlate with the degree of enlargement of
the GA.1 At the NEI/FDA Ophthalmic Clinical Trial Design and
Endpoints Symposium in 2007, the FDA identified the expansion
of GA as an endpoint for trials in dry AMD.2 Loss of the retinal
pigment epithelium (RPE) detected by reduced fundus autofluorescence (FAF) appears to be the most reliable method to detect
areas of GA.3
More rapid rates of GA expansion, as determined by expanding FAF, appear to correlate with a prior rapid rate of enlargement, the presence of rim hyperautofluorescence,3 and multifocal
areas of GA. An important question surrounding the use of FAF
as an indicator of the boundary of the GA is the state of the
retina just beyond the edge of reduced FAF. Recently, several
investigators have noted that the area immediately surrounding
the reduced FAF demonstrates signs of retinal degeneration.4
Therefore treatments to limit the expansion of GA must successfully treat already degenerated retina in addition to slowing the
rate of RPE loss. These are some of the reasons that to date no
drug has been approved for the treatment of GA.
An additional endpoint for dry AMD that was also outlined
at the symposium was the development of GA in eyes without
pre-existing GA but evidence of dry AMD.2 This is an intriguing
endpoint for dry AMD clinical trials because recently changes
in OCT that precede the development of GA have been identified.5,6 These changes include the presence of hyper-reflective foci
in the retina overlying drusen, a subsidence of the inner nuclear
layer (INL) and outer plexiform layer (OPL) with the development of hyporeflective, wedge-shaped bands, and increased signal transmission below the level of the RPE (see Figures 1 and 2).
These anatomic changes might be used to identify patients early
in the course of GA development who might still be at a reversible stage and therefore amenable to intervention.
Figure 1. Hyper-reflective foci (HRF) as demonstrated by spectral domain OCT present above a
drusenoid lesion preceding the development of GA at various time points: A1, Baseline infrared
image. A2, Baseline OCT without HRF. A3, 7 months with definite HRF. B1, baseline infrared
image. B2, definite HRF above a drusenoid lesion at baseline. B3, disappearance of HRF.6
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Section XVII: Non-neovascular AMD
155
Figure 2. Subsidence of the inner nuclear layer (INL) and outer plexiform layer (OPL) (top) and early increased
signal transmission below the RPE as a first feature of a pre-GA lesion. The subsequent development of a hyporeflective wedge-shaped band (bottom) within the OPL is accompanied by a regression of drusen material and
maintenance of the increased signal transmission below the RPE.5
Additional Considerations for an Anatomic Endpoint
in Dry AMD Trials
To determine the effects on functional vision loss in the absence
of visual acuity loss, the use of reading speed, low luminance
visual acuity, and mesopic microperimetry are being investigated
as alternative endpoints in ongoing clinical trials for GA. All of
these measures are reduced in dry AMD and may provide important functional implications of the loss of retinal tissue.
Dark adaptometry
Dark adaptation is altered in patients with varying forms of dry
AMD, based on the observation that thickening and changes
in the composition of the Bruch membrane is an early and consistent finding in patients with dry AMD and thus alters the
function of the RPE.7,8 Two units that are able to quantify dark
adaptation include the Goldman-Weekers Dark Adaptometer
and the AdapDx (Maculogix; Hummelstown PA). The AdapDx
has been most extensively studied in dry AMD patients. This
machine measures the ability of the retina to respond to a low
luminance spot placed on the retina at various times following
light exposure. The curve that is generated (see Figure 3a) indicates the time to light sensitivity of the rods at a time termed the
“cone-rod break.” This time is progressively delayed in advancing forms of dry AMD (see Figure 3b).8 The exact correlates of
quality of life for progressive loss of dark adaptation remain to
be detailed, but this function now appears to be quantifiable.
Figure 3. Demonstration of results of dark adaptometry (A) showing the
typical break in the slope of initial cone sensitivity to rod sensitivity that
is markedly delayed in advancing forms of dry AMD (B).8
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Section XVII: Non-neovascular AMD
Scotopic microperimetry
It has been demonstrated that rod photoreceptors are preferentially affected before cone cells,9 leading to the finding of low
luminance deficits in patients with dry AMD. Therefore selectively measuring rod sensitivities could be a useful measure of
these low luminance functional deficits.10 Using the fact that rod
cells are more sensitive to blue light simulation, 2-color micro­
metry has begun to be used to directly quantify rod function.
The unit that is being most extensively studied is the Nidek
Microperimeter -1S (Nidek; Padova, Italy). The unit has automated eye tracking and fixation analysis, allowing for reanalysis
of exacts points on the retina between study visits as well as
the ability to measure rod sensitivities over a 50-dB range. Patterns entailing 56 points centered over rod-intensive areas of the
retina11 (see Figure 4) can be obtained over a period of 10-15
minutes following a period of dark adaptation. The unit is being
incorporated in various trials, including those studying GA and
Stargardt disease. Recently scotopic microperimeters that utilize
light emitting diodes with semiautomation have been developed
(Medmont International; Nunawading, Australia, and CenterVue SpA; Padova, Italy) that will produce more rapid and reproducible methods to measure rod function. As with dark adapto­
metry, though, correlates to low luminance quality of life have
not been determined.
2015 Subspecialty Day | Retina
References
1. Sunness JS, Gonzalez-Baron J, Applegate CA, et al. Enlargement
of atrophy and visual acuity loss in the geographic atrophy form
of age-related macular degeneration. Ophthalmology 1999;
106:1768-1779.
2. Csaky KG, Richman EA, Ferris FL 3rd. Report from the NEI/
FDA Ophthalmic Clinical Trial Design and Endpoints Symposium.
Invest Ophthalmol Vis Sci. 2008; 49:479-489.
3. Schmitz-Valckenberg S, Fleckenstein M, Scholl HP, Holz FG. Fundus autofluorescence and progression of age-related macular degeneration. Surv Ophthalmol. 2009; 54:96-117.
4. Bird AC, Phillips RL, Hageman GS. Geographic atrophy: a histopathological assessment. JAMA Ophthalmol. 2014; 132:338-345.
5. Wu Z, Luu CD, Ayton LN, et al. Optical coherence tomographydefined changes preceding the development of drusen-associated
atrophy in age-related macular degeneration. Ophthalmology
2014; 121:2415-2422.
6. Ouyang Y, Heussen FM, Hariri A, Keane PA, Sadda SR. Optical
coherence tomography-based observation of the natural history of
drusenoid lesion in eyes with dry age-related macular degeneration.
Ophthalmology 2013; 120:2656-2665.
7. Steinmetz RL, Haimovici R, Jubb C, Fitzke FW, Bird AC. Symptomatic abnormalities of dark adaptation in patients with agerelated Bruch’s membrane change. Br J Ophthalmol. 1993; 77:549554.
8. Jackson GR, Scott IU, Kim IK, Quillen DA, Iannaccone A, Edwards
JG. Diagnostic sensitivity and specificity of dark adaptometry for
detection of age-related macular degeneration. Invest Ophthalmol
Vis Sci. 2014; 55:1427-1431.
9. Curcio CA, Medeiros NE, Millican CL. Photoreceptor loss in agerelated macular degeneration. Invest Ophthalmol Vis Sci. 1996;
37:1236-1249.
10. Scholl HP, Bellmann C, Dandekar SS, Bird AC, Fitzke FW. Photopic and scotopic fine matrix mapping of retinal areas of increased
fundus autofluorescence in patients with age-related maculopathy.
Invest Ophthalmol Vis Sci. 2004; 45:574-583.
11. Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. Human photoreceptor topography. J Comp Neurol. 1990, 292:497-523.
Figure 4. Pattern of rod sensitivity points placed on the rod-rich areas in
quantifying scotopic sensitivities.
2015 Subspecialty Day | Retina
Section XVII: Non-neovascular AMD
157
A Newly Recognized Risk and Disease Modifier in
AMD: Pachychoroid
K Bailey Freund MD
The term “pachychoroid” describes a set of choroidal characteristics shared by a group of related diseases that includes pachychoroid pigment epitheliopathy (PPE), central serous chorioretinopathy (CSC), and pachychoroid neovasculopathy (PNV).
The specific features of a focal or diffuse increase in choroidal
thickness, choroidal hyperpermeability, and dilated choroidal
vessels were first described using indocyanine green angiography
(ICGA) and spectral domain OCT (SD-OCT) in patients with
CSC. More recently, en face imaging with swept source OCT
(SS-OCT) and OCT angiography (OCT-A) have revealed new
findings that have helped refine our understanding of this pachychoroid spectrum of macular disorders.
Patients with unilateral frank CSC can manifest in the fellow
eye nonspecific retinal pigment epithelial changes that correlate
with choroidal features of CSC, even in the absence of neurosensory detachment. PPE refers to such changes that are believed to
represent a forme fruste or precursor of CSC. When PPE occurs
in older patients without a history of CSC, the clinical and imaging findings may be mistaken for those of AMD or pattern dystrophy. Some patients may manifest findings that have features
of both PPE and AMD.
Acute CSC is usually self-limited, but chronic CSC, which
persists for 6 months or more, may lead to secondary visionthreatening complications including atrophy, cystic retinal
degeneration, and CNV. Pachychoroid neovasculopathy refers
to the occurrence of type 1 (sub-retinal pigment epithelium, or
sub-RPE) neovascularization in eyes with PPE or CSC. Choroidal
thickening and absent drusen distinguish PNV from AMD and
other degenerative conditions that predispose to type 1 neovascularization. As the neovascular tissue of PNV evolves, some eyes
may develop polypoidal choroidal vasculopathy (PCV).
Imaging of the choroid by traditional photographic and
angiographic modalities is impeded by the relative opacity of the
RPE to visible light. The absorption spectrum of melanin overlaps with both the excitation and emission spectra of fluorescein.
While this enables pre-RPE and sub-RPE components of vascular
lesions to be distinguished, it prevents visualization of the choroid by fluorescein angiography (FA). The greater transparency
of the RPE to longer wavelengths enables choroidal vessels to
be delineated better by ICGA, but due to vertical summation,
angiographic features cannot be localized to their respective tissue layers.
OCT is able to achieve depth resolution by rendering crosssectional B-scans of the posterior pole. OCT technology has
undergone an evolutionary process, and successive developments, such as eye-tracking, averaging, and enhanced depth
imaging, have improved image quality, especially of deeper
structures, though often at the expense of acquisition time. Long
wavelength SS-OCT enables the choroid and choroid-scleral
interface to be imaged at greater depth and using shorter acquisition times than those required for enhanced depth imaging with
SD-OCT. The increased scanning speed also allows for raster
scans to be taken with sufficient density to produce volume
maps of the choroid from which coronal, or en face, sections can
be constructed in software. SS-OCT has the ability not only to
quantify choroidal thickness profiles throughout the volume scan
but also to expose the morphology of intermediate and large
choroidal vessels. En face imaging with SS-OCT has revealed
new findings that refine the definition of the pachychoroid phenotype to emphasize the morphological characteristics of pathologically dilated choroidal vessels (“pachy-vessels”) over absolute
choroidal thickness.
OCT-A is a novel modality for examining microvascular circulation in vivo without the need for intravenous dye or contrast
injection. It relies on detection of temporal changes in reflectivity that are related to the dynamic nature of components of
intravascular blood. OCT-A therefore differs from conventional
angio­graphy in that it identifies blood flow but not permeability
and the scan data is depth-resolved, allowing for en face segmentation. We have noted that OCT-A is particularly well suited for
detecting blood flow in relatively shallow flat PEDs given the
more reliable and consistent segmentation of retinal and choroidal layers in these eyes than in other neovascular lesion subtypes.
A recent study comparing dye-based angiography with crosssectional SD-OCT has suggested that only about 19% of eyes
with flat, irregular PEDs in in the context of CSC harbor type 1
neovascularization. However, our findings suggest that approximately 92% of flat, irregular PEDs in pachychoroid eyes actually
harbor a form of type 1 neovascularization that is characterized
by large caliber tangled vessels and recognized with considerable
specificity by OCT-A.
The multimodal imaging features seen in this “pachychoroid
spectrum” of disorders are reviewed in Figure 1.
158
Section XVII: Non-neovascular AMD
2015 Subspecialty Day | Retina
Figure 1. Pachychoroid spectrum.
Selected Readings
1. Sato T, Kishi S, Watanabe G, Matsumoto H, Mukai R. Tomographic features of branching vascular networks in polypoidal choroidal vasculopathy. Retina 2007; 27(5):589-594.
2. Warrow DJ, Hoang QV, Freund KB. Pachychoroid pigment epitheliopathy. Retina 2013; 33(8):1659-1672.
3. Ferrara D, Mohler KJ, Waheed N, et al. En face enhanced-depth
swept-source optical coherence tomography features of chronic central serous chorioretinopathy. Ophthalmology 2014; 121(3):719726.
4. Pang CE, Freund KB. Pachychoroid neovasculopathy. Retina 2015;
35(1):1-9.
5. Fung AT, Yannuzzi LA, Freund KB. Type 1 (sub-retinal pigment
epithelial) neovascularization in central serous chorioretinopathy
masquerading as neovascular age-related macular degeneration.
Retina 2012; 32(9):1829-1837.
6. Hage R, Mrejen S, Krivosic V, Quentel G, Tadayoni R, Gaudric A.
Flat irregular retinal pigment epithelium detachments in chronic
central serous chorioretinopathy and choroidal neovascularization.
Am J Ophthalmol. 2015; 159(5):890-903.
7. Bonini Filho MA, de Carlo TE, Ferrara D, et al. Association of choroidal neovascularization and central serous chorioretinopathy with
optical coherence tomography angiography. JAMA Ophthalmol.
Epub ahead of print 2015 May 21. doi: 10.1001/jamaophthalmol.2015.1320.
Section XVIII: Vitreoretinal Surgery, Part II
2015 Subspecialty Day | Retina
159
Optic Pit Maculopathy Management
Akito Hirakata MD
I.Introduction
Congenital pit of the optic nerve head is a rare anomaly
first described by Wiethe in 1882. Approximately
two-thirds of patients have a concurrent or previous
associated serous macular detachment. The age at
onset of the macular detachment is variable, with the
mean being 30 years. In 1988, based on a study of
stereoscopic transparencies and visual fields, Lincoff
et al proposed that fluid from the optic disc pit creates
a schisis-like inner layer separation of the retina. The
outer layer detachment centered over the macula was
suggested to be a secondary phenomenon. OCT has
confirmed the observation of Lincoff et al that there
was frequently a retinoschisis-like separation of the retina present during the development of serous macular
detachment. However, the pathogenesis of optic disc
pit maculopathy remains unclear, and the treatment of
macular detachment is still controversial.
A. An optic pit consists of herniation of dysplastic
retina into a collagen-lined pocket extending posteriorly through a defect in the lamina cribrosa into
the subarachnoid space, suggesting that the vitreous
cavity, subarachnoid space, and subretinal space
may all be interconnected in these conditions.
1. Swept source OCT findings
2. Intracranial migration of silicone oil
3. Pulsating droplets of fluid of possible cerebrospinal fluid origin within silicone oil
II.Histopathology
B. Communication between vitreous cavity and subarachnoid space
C. Trigger of the start of retinoschisis
1. Liquefaction of vitreous gel (syneresis) + traction
of vitreous fibers attached to the herniated neural
tissue in the pit
2. Traction of glial tissue or condensed vitreous gel
at the optic disc pit
3. Ocular blunt trauma
D. Defect of lamina cribrosa (histopathology or OCT
findings)
E. Shape of pit cavity or running vessels besides the
optic disc pit (fluorescein angiography or OCT findings)
V.Management
A. Observation expecting spontaneous resolution
(especially for children)
B. Posterior vitreous collagen connected to the herniated dysplastic retina
B. Juxtapapillary laser photocoagulation alone: barrier
to both intraretinal and subretinal fluid migration
C. Defect of lamina cribrosa
C. Macular buckling
III. Course of Macular Detachment
D. Intravitreous gas injection
E.Vitrectomy
A. Visual acuity: < 20/70 at the later in the course of
optic pit maculopathy
B. Some detachments resolved spontaneously with
or without posterior vitreous detachment (PVD),
whereas others persisted for years.
C. Long-term studies showed that untreated macular
detachments have an overall poor prognosis (Sobol
et al, 1990).
1. Vitrectomy + juxtapapillary laser + gas tamponade
2. Vitrectomy with induction of PVD (see Figure 1)
3. Vitrectomy with induction of PVD + gas tamponade
4. Vitrectomy with induction of PVD + gas tamponade + juxtapapillary laser
5. Vitrectomy with induction of PVD + internal
limiting membrane peeling
6. Vitrectomy + inner retinal fenestration
7. Vitrectomy + glial tissue removal at the optic disc
pit
8. Vitrectomy + small plug of autologous sclera
(complicated cases)
9. Vitrectomy + autologous fibrin
IV. Possible Pathogenic Mechanisms
A. Dynamic pressure gradients
1. Vitreous substitutes such as gas, silicone oil,
and perfluorocarbon liquid can migrate into the
subretinal space after vitrectomy (surface tension
physics dictate that passage of intravitreal gas
through a small opening is not possible without a
substantial pressure gradient across the opening)
(Johnson et al, 2004).
2. Vitreous strands or debris being sucked into
optic pits
10.Others
160
Section XVIII: Vitreoretinal Surgery, Part II
2015 Subspecialty Day | Retina
VI.Conclusion
Through our experience, vitrectomy with induction
of a PVD at the optic disc without gas tamponade or
laser photocoagulation seems to be an effective method
of managing macular detachment resulting from optic
disc pits. Complete retinal reattachment was achieved
in most eyes, although these eyes required nearly 1 year
to reach this state. In addition, juxtapapillary laser or
adjunctive techniques such as small plug autologous
fibrin may be useful for the complicated cases.
References and Selected Readings
1. Wiethe T. Ein fall von angeborener Difformitat der Sehnervenpapille. Arch Augenheilk. 1882; 11:14-19.
2. Kranenburg EW. Crater-like holes in the optic disc and central
serous retinopathy. Arch Ophthalmol. 1960; 64:912-924.
3. Brown GC, Shields JA, Goldberg RE. Congenital pits of the nerve
head: II. Clinical studies in humans. Ophthalmology 1980; 87:5165.
4. Sobol WM, Blodi CF, Folk JC, et al. Long-term visual outcome in
patients with optic nerve pit and serous retinal detachment of the
macula. Ophthalmology 1990; 97:1539-1542.
5. Lincoff H, Lopez R, Kreissig I, et al. Retinoschisis associated with
optic nerve pits. Arch Ophthalmol. 1988; 106:61-67.
6. Rutledge BK, Puliafito CA, Duker JS, et al. Optical coherence
tomography of macular lesions associated with optic nerve head
pits. Ophthalmology 1996; 103:1047-1053.
7. Krivoy D, Gentile R, Liebmann JM, et al. Imaging congenital
optic disc pits and associated maculopathy using optical coherence
tomography. Arch Ophthalmol. 1996; 114:165-170.
8. Gass JDM. Serous detachment of the macula: secondary to congenital pit of the optic nervehead. Am J Ophthalmol. 1969; 67:821841.
9. Gass JDM. Optic nerve diseases that may masquerade as macula
diseases. In: Gass JDM, ed. Stereoscopic Atlas of Macular Diseases:
Diagnosis and Treatment, 3d ed. Vol 2. St Louis: CV Mosby;
1987:728-733.
10. Irvine AR, Crawford JB, Sullivan JH. The pathogenesis of retinal
detachment with morning glory disc and optic pit. Retina 1986;
6:146-150.
11. Bonnet M. Serous macular detachment associated with optic nerve
pits. Graefes Arch Clin Exp Ophthalmol. 1991; 229:526-532.
12. Rii T, Hirakata A, Inoue M. Comparative findings in childhoodonset versus adult-onset optic disc pit maculopathy. Acta Ophthalmol. 2013; 91:429-433.
13. Polunina AA, Todorova MG, Palmowski-Wolfe AM. Function and
morphology in macular retinoschisis associated with optic disc pit
in a child before and after its spontaneous resolution. Doc Ophthalmol. 2012; 124:149-155.
Figure 1. Thirty-seven-year-old male. OCT findings showing before and
after surgery for optic disc pit maculopathy. We performed vitrectomy
with induction of PVD without laser or gas tamponade.
14. Parikakis EA, Chatziralli IP, Peponis VG, et al. Spontaneous resolution of long-standing macular detachment due to optic disc pit
with significant visual improvement. Case Rep Ophthalmol. 2014;
5:104-110.
15. Johnson TM, Johnson MW. Pathogenic implications of subretinal
gas migration through pits and atypical colobomas of the optic
nerve. Arch Ophthalmol. 2004; 122:1793-1800.
2015 Subspecialty Day | Retina
Section XVIII: Vitreoretinal Surgery, Part II
161
16. Jain N, Johnson MW. Pathogenesis and treatment of maculopathy
associated with cavitary optic disc anomalies. Am J Ophthalmol.
2014; 158:423-435.
26. Tobe T, Nishimura T, Uyama M. Laser photocoagulation for pitmacular syndrome [in Japanese]. Ganka-Rinshoiho 1991; 85:124130.
17. Berdahl JP, Allingham RR. Intracranial pressure and glaucoma.
Curr Opin Ophthalmol. 2010; 21:106-111.
27. Lincoff H, Kreissig I. Optical coherence tomography of pneumatic
displacement of optic disc pit maculopathy. Br J Ophthalmol.1998;
82:367-372.
18. Hirakata A, Hida T, Wakabayashi T, et al. Unusual posterior hyaloid strand in a young child with optic disc pit maculopathy: intraoperative and histopathological findings. Jpn J Ophthalmol. 2005;
49:264-266.
19. Ohno-Matsui K, Hirakata A, Inoue M, et al. Evaluation of congenital optic disc pits and optic disc colobomas by swept-source optical
coherence tomography. Invest Ophthalmol Vis Sci. 2013; 54:77697778.
20. Kuhn F, Kover F, Szabo I, et al. Intracranial migration of silicone
oil from an eye with optic pit. Graefes Arch Clin Exp Ophthalmol.
2006; 244:1360-1362.
21. Czajka MP, Stopa M, Sosnowski P, et al. New insight into the
pathology of macular detachment associated with an optic disc pit.
Acta Ophthalmol. 2010; 88:e241-242.
22. Akiba J, Kakehashi A, Hikichi T, et al. Vitreous findings in cases of
optic nerve pits and serous macular detachment. Am J Ophthalmol.
1993; 116:38-41.
23. Imamura Y, Zweifel SA, Fujiwara T, et al. High-resolution optical
coherence tomography findings in optic pit maculopathy. Retina
2010; 30:1104-1112.
24. Doubal FN, Mac Lullich AMJ, Ferguson KF, et al. Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke 2010; 41:450-454.
25. Cox MS, Witherspoon CD, Morris RE, et al. Evolving techniques
in the treatment of macular detachment caused by optic nerve pits.
Ophthalmology 1988; 95:889-896.
28. Theodossiadis GP. Treatment of maculopathy associated with optic
disk pit by sponge explant. Am J Ophthalmol. 1996; 121:630-637.
29. Hirakata A, Okada AA, Hida T. Long-term results of vitrectomy
without laser treatment for macular detachment associated with an
optic disc pit. Ophthalmology 2005; 112:1430-1435.
30. Theodossiadis PG, Grigoropoulos VG, Emfietzoglou J, et al.
Vitreous findings in optic disc pit maculopathy based on optical
coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2007;
245:1311-1318.
31. Spaide RF, Fisher Y, Ober M, et al. Surgical hypothesis: inner
retinal fenestration as a treatment for optic disc pit maculopathy.
Retina 2006; 26:89-91.
32. Ooto S, Mittra RA, Ridley ME, et al. Vitrectomy with inner retinal
fenestration for optic disc pit maculopathy. Ophthalmology 2014;
121:1727-1733.
33. Travassos AS, Regadas I, Alfaiate M, et al. Optic pit: novel surgical
management of complicated cases. Retina 2013; 33:1708-1714.
34. Ozdek SC. Persistent optic pit maculopathy: surgical management
with autologous fibrin. Paper presented at Retina Subspecialty Day,
Annual Meeting of the American Academy of Ophthalmology;
2014.
162
Section XVIII: Vitreoretinal Surgery, Part II
2015 Subspecialty Day | Retina
Emerging Therapies for Proliferative Vitreoretinopathy
Richard S Kaiser MD
Proliferative vitreoretinopathy (PVR) remains the most significant obstacle to successful retinal reattachment surgery, accounting for 75% of all primary surgical failures, with a cumulative
risk of 5% to 10% of all retinal detachment repairs.1 PVR is
characterized by proliferation of cells either on the retinal surface or in the vitreous cavity, multiplication of which can lead to
contraction and foreshortening of the retina, resulting in traction
and recurrent detachment of the retina. Specific risk factors for
PVR that have been identified include uveitis; large, giant, or
multiple tears; vitreous hemorrhage; preoperative or postoperative choroidal detachments; aphakia; multiple previous surgeries;
and large detachments involving greater than two quadrants of
the eye.1,2
The PVR process is not completely understood. The most
important cell types in PVR pathogenesis are the retinal pigment
epithelial cells, which are believed to dedifferentiate and migrate
through a retinal break and proliferate on the retinal surface.
Retinal glial cells and macrophages may also play an important
role, perhaps by providing the scaffold for membrane formation or by releasing trophic factors.3,4 This process is driven by
and modulated by numerous growth factors (eg, platelet derived
growth factor,5 vascular endothelial growth factor,6 transforming growth factor beta [TGF-b], epidermal growth factor, tumor
necrosis factor alpha [TNF-a], TNF-b, and fibroblast growth
factor7) and cytokines (eg, interleukin-1 [IL-1], IL-6, IL-8, IL-10,
and interferon gamma [INF-g]8), which have been and continue
to be explored as potential targets for pharmacologic prevention
and treatment.9 Even with these advances, however, the primary
prevention of PVR remains elusive.
Despite our increasing knowledge about the pathogenesis of
PVR and possible targets for prevention, the mainstay of PVR
management remains surgical. Erakgun and Egrilmez10 retrospectively reviewed outcomes of 40 eyes undergoing repair of
tractional and PVR-related retinal detachments with 23-gauge
vitrectomy and silicone oil tamponade. Single-surgery anatomical
success was achieved in 97.5% of patients at a mean follow-up
of 6.5 months. Riemann et al11 similarly reported outcomes with
25-gauge vitrectomy. In a retrospective review of 35 patients
undergoing 25-gauge vitrectomy and silicone oil tamponade for
complex retinal detachment, 6 patients reviewed had PVR. At a
mean follow-up of 7 months, no patient with PVR had recurrent
detachment, and final visual acuity ranged from 20/80 to counting fingers.
Storey et al12 compared single-surgery anatomical success
rates in patients with retinal detachments deemed to be at high
risk for PVR development and undergoing combined PPV and
scleral buckle vs. PPV alone. Of note, lens status and choice of
tamponade agent (gas vs. silicone oil) were not independently
associated with single-surgery anatomical success rate. Age
younger than 65 years, however, was associated with a significantly higher single-surgery success rate (84.6 vs. 46.2%
for PPV-scleral buckle vs. PPV alone, respectively; P = .017),
whereas age older than 65 years was associated with no difference in single-surgery success rate between groups (50.0% for
PPV-scleral buckle vs. 50.0% for PPV alone; P = 1.0). Mean
visual acuity and rate of development of PVR did not differ sig-
nificantly between groups at final follow-up, regardless of age or
lens status.
Multiple studies report favorable outcomes with the use of
inferior retinectomy. Quiram et al13 retrospectively reviewed outcomes of 56 patients treated with PPV and inferior retinectomy
for recurrent PVR-related retinal detachment. Complete retinal
reattachment was observed in 93% of eyes at a mean 25 months
of follow-up. Similarly, Tsui and Schubert14 reported a 90%
anatomical success rate at final follow-up in 41 patients who
underwent PPV, 180° retinotomy, and anterior retinectomy for
treatment of severe PVR. The use of retinectomy was evaluated
in patients with anterior PVR in particular. Tan et al15 retrospectively reviewed 123 patients undergoing retinectomy without
scleral buckling for anterior PVR. Ninety-six patients (77.2%)
required no additional surgeries, 21 patients (17.1%) required
1 additional operation, and 4 patients (3.8%) required 2 additional operations.
The Silicone Study Group established the superiority of longer
acting tamponade agents, namely silicone oil and perfluoropropane (C3F8), over sulfur hexafluoride (SF6) in patients with
Grade C or worse PVR.16 Since these pivotal studies, efforts to
improve tamponade to the inferior retina, given concerns regarding inferior displacement of proinflammatory mediators and subsequent recurrent PVR, led to the development of heavy silicone
oils. At the present time, heavy silicone oil tamponade agents are
not approved by the U.S. FDA but have been evaluated overseas.
Multiple studies report excellent anatomical outcomes with the
use of heavy silicone oils. Rizzo et al17 evaluated outcomes in
32 consecutive patients with inferior PVR treated with PPV,
membrane peel, and tamponade with the heavy silicone oil HWS
46-3000. Single-surgery success rate was 84.6%, and overall
anatomical success rate of 100% at 6 months and improvement
in logMAR visual acuity was observed. In comparative trials,
however, no direct benefit of heavy silicone oils vs. standard silicone oil has been observed.
Anti-inflammatory Agents
Interventions aimed at curbing inflammation have long been the
focus of PVR treatment strategies. Attempts to evaluate the role
of IVTA in randomized controlled trials have not demonstrated
a clear beneficial effect. Ahmadieh et al18 randomized 75 patients
with at least Grade C PVR to PPV and silicone oil tamponade
with or without a single injection of 4-mg IVTA at the conclusion of surgery. At 6 months, no statistically significant difference in anatomical success rate, visual acuity, or prevention of
PVR was observed Similar results have been found with oral
prednisone. Dehghan et al 19 evaluated the outcomes of primary
scleral buckling surgery in phakic patients who received a 10-day
course of oral prednisone (1 mg/kg dose) vs. placebo postoperatively. With a sample size of 52 eyes, no statistically significant
difference in PVR formation between groups was observed.
Recent case reports have suggested that Ozurdex (0.7-mg
intravitreal dexamethasone implant) may be helpful in the prevention of PVR after retinal detachment surgery.20 Clinical trials
are planned to better characterize the use of the dexamethasone
2015 Subspecialty Day | Retina
implant on the outcomes of patients with pre-existing PVR
undergoing retinal detachment surgery.21
Low molecular weight heparin (LMWH) and 5-fluorouracil
(5-FU) have been used in combination to mitigate the risk of
postoperative PVR. A few retrospective studies have suggested
a benefit to preventing PVR, but in general most studies show
no statistically significant difference in reattachment rate, reoperation rates because of PVR, or visual acuity. Small numbers
and follow-up intervals limit true conclusions. There could be
benefits for patients at high risk for PVR, but larger studies are
needed to clarify efficacy.
Numerous preclinical studies have demonstrated benefit of
isotretinoin (13-cis-retinoic acid) in preventing or mitigating
experimental PVR,22-25 leading to evaluation in human studies.
In a retrospective study published in 1995, Fekrat et al26 first
reported that isotretinoin may be of benefit in increasing the rate
of retinal reattachment. Given the suggestion of benefit, a prospective randomized placebo-controlled trial is currently ongoing
at Wills Eye Hospital to better evaluate the benefit of isotretinoin
in treating and preventing PVR.
References
1. Pastor JC. Proliferative vitreoretinopathy: an overview. Surv Ophthalmol. 1998; 43:3-18.
2. Pastor JC, de la Rúa ER, Martín F. Proliferative vitreoretinopathy:
risk factors and pathobiology. Prog Retin Eye Res. 2002; 21:127144.
3. Garweg JG, Tappeiner C, Halberstadt M. Pathophysiology of
proliferative vitreoretinopathy in retinal detachment. Surv Ophthalmol. 2013; 58:321-329.
4. Moysidis SN, Thanos A, Vavvas DG. Mechanisms of inflammation
in proliferative vitreoretinopathy: from bench to bedside. Mediators
Inflamm. 2012; 2012 (11).
5. Lei H, Rheaume M-A, Kazlauskas A. Recent developments in our
understanding of how platelet-derived growth factor (PDGF) and
its receptors contribute to proliferative vitreoretinopathy. Exp Eye
Res. 2010; 90:376-381.
6. Pennock S, Kim D, Mukai S, et al. Ranibizumab is a potential prophylaxis for proliferative vitreoretinopathy, a nonangiogenic blinding disease. Am J Pathol. 2013; 182:1659-1670.
7. Lei H, Velez G, Hovland P, et al. Growth factors outside the PDGF
family drive experimental PVR. Invest Ophthalmol Vis Sci. 2009;
50:3394-3403.
8. Sadaka A, Giuliari GP. Proliferative vitreoretinopathy: current and
emerging treatments. Clin Ophthalmol. 2012; 6:1325-1333.
9. Wladis EJ, Falk NS, Iglesias BV, et al. Analysis of the molecular biologic milieu of the vitreous in proliferative vitreoretinopathy. Retina
2013; 33:807-811.
10. Erakgun T, Egrilmez S. Surgical outcomes of transconjunctival
sutureless 23-gauge vitrectomy with silicone oil injection. Indian J
Ophthalmol. 2009;57:105-109.
11. Riemann CD, Miller DM, Foster RE, Petersen MR. Outcomes of
transconjunctival sutureless 25-gauge vitrectomy with silicone oil
infusion. Retina 2007; 27:296-303.
Section XVIII: Vitreoretinal Surgery, Part II
163
12. Storey P, Alshareef R, Khuthaila M, et al. Pars plana vitrectomy
and scleral buckle versus pars plana vitrectomy alone for patients
with rhegmatogenous retinal detachment at high risk for proliferative vitreoretinopathy. Retina 2014; 34:1945-1951.
13. Quiram PA, Gonzales CR, Hu W, et al. Outcomes of vitrectomy
with inferior retinectomy in patients with recurrent rhegmatogenous retinal detachments and proliferative vitreoretinopathy. Ophthalmology 2006; 113:2041-2047.
14. Tsui I, Schubert HD. Retinotomy and silicone oil for detachments
complicated by anterior inferior proliferative vitreoretinopathy. Br
J Ophthalmol. 2009; 93:1228-1233.
15. Tan HS, Mura M, Oberstein SYL, de Smet MD. Primary retinectomy in proliferative vitreoretinopathy. Am J Ophthalmol. 2010;
149:447-452.
16. Vitrectomy with silicone oil or sulfur hexafluoride gas in eyes with
severe proliferative vitreoretinopathy: results of a randomized
clinical trial. Silicone Study Report 1. Arch Ophthalmol. 1992;
110:770-779.
17. Rizzo S, Genovesi-Ebert F, Vento A, et al. A new heavy silicone
oil (HWS 46-3000) used as a prolonged internal tamponade agent
in complicated vitreoretinal surgery: a pilot study. Retina 2007;
27:613-620.
18. Ahmadieh H, Feghhi M, Tabatabaei H, et al. Triamcinolone acetonide in silicone-filled eyes as adjunctive treatment for proliferative vitreoretinopathy: a randomized clinical trial. Ophthalmology
2008; 115:1938-1943.
19. Dehghan MH, Ahmadieh H, Soheilian M, et al. Effect of oral prednisolone on visual outcomes and complications after scleral buckling. Eur J Ophthalmol. 2010; 20:419-423.
20. Reibaldi M, Russo A, Longo A, et al. Rhegmatogenous retinal
detachment with a high risk of proliferative vitreoretinopathy
treated with episcleral surgery and an intravitreal dexamethasone
0.7-mg implant. Case Rep Ophthalmol. 2013; 4:79-83.
21. Banerjee PJ, Bunce C, Charteris DG. Ozurdex (a slow-release dexamethasone implant) in proliferative vitreoretinopathy: study protocol for a randomised controlled trial. Trials 2013; 14:358.
22. Takahashi M, Refojo MF, Nakagawa M, et al. Anti proliferative
effect of retinoic acid in 1% sodium hyaluronate in an animal
model of PVR. Curr Eye Res. 1997; 16:703-709.
23. Araiz JJ, Refojo MF, Arroyo MH, et al. Antiproliferative effect
of retinoic acid in intravitreous silicone oil in an animal model of
proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 1993;
34:522-530.
24. Veloso AA Jr, Kadrmas EF, Larrosa JM, et al. 13-cis-retinoic acid in
silicone-fluorosilicone copolymer oil in a rabbit model of proliferative vitreoretinopathy. Exp Eye Res. 1997; 65:425-434.
25. Nakagawa M, Refojo MF, Marin JF, et al. Retinoic acid in silicone
and silicone-fluorosilicone copolymer oils in a rabbit model of
proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 1995;
36:2388-2395.
26. Fekrat S, de Juan E Jr, Campochiaro PA. The effect of oral 13-cisretinoic acid on retinal redetachment after surgical repair in
eyes with proliferative vitreoretinopathy. Ophthalmology 1995;
102:412-418.
164
Section XVIII: Vitreoretinal Surgery, Part II
2015 Subspecialty Day | Retina
Avoiding and Managing Retinal Folds
Types of Folds
Dean Eliott MD
I. Choroidal folds involve the choroid, Bruch membrane,
and retinal pigment epithelium (RPE).
A.Symptoms
1.Asymptomatic,
2. Metamorphopsia, or
3.Hyperopia
a. May have pain, tenderness and/or proptosis
b. Causes include posterior scleritis, thyroid eye
disease, uveal effusion syndrome, collagen
vascular disease
c. Ultrasound useful
3.Papilledema
a. Increased optic nerve sheath pressure and/or
disc edema can cause adjacent folds.
b. Folds may persist after resolution of papilledema.
4. Retrobulbar mass: Intraconal and extraconal
masses can indent the globe.
5. Choroidal tumor / hemorrhage: Folds may occur
at the posterior edge of the lesion.
6. Extraocular implants: Scleral buckle can cause
folds along posterior slope; also radioactive
plaques and orbital implants.
7. Choroidal neovascular membrane / disciform
scar: Contracted lesion causes focal choroidal
shrinkage; radial pattern.
8. Idiopathic: Usually have acquired hyperopia;
folds often bilateral and symmetric; may rarely
develop crowded disc syndrome.
1.Ophthalmoscopy
a. Often subtle, alternating yellow and dark
bands
b. Crests of the folds appear yellow or less pigmented corresponding to areas of thinned
RPE, and troughs appear dark corresponding
to areas of compressed RPE.
2.Angiography
a. Usually striking, alternating bands of hyperand hypofluorescence
b. Relatively thin RPE transmits background
choroidal fluorescence better than compressed RPE
c. Crests appear hyperfluorescent corresponding
to areas of thinned RPE and thickened choroid beneath the crests, and troughs appear
hypofluorescent corresponding to areas of
compressed RPE.
II. Outer retinal folds involve only the outer neurosensory
retina (photoreceptor ellipsoid zone and outer nuclear
layer).
3. OCT: Folding of the choroid, RPE, and sometimes also the overlying neurosensory retina
B. Appearance: Due to folding of the choroid and
RPE—the RPE stretches and becomes thin over the
crest or elevated portion of the fold and becomes
compressed or compacted at the trough; location is
usually posterior pole; pattern is usually curvilinear
and parallel but may be circular and concentric with
the disc, radial, or randomly distributed.
2.Inflammation
A. Associated with rhegmatogenous retinal detachment, usually bullous
1. Symptoms: Peripheral with or without central
visual loss due to retinal detachment
2.Appearance
4. Ultrasonography may be useful in determining
etiology.
C. Etiology/pathophysiology: Any condition that alters
the inner surface of the choroid and/or sclera, such
as compression, contraction (shrinkage), or thickening (edema, congestion)
1.Hypotony
a. Characteristic maculopathy
b. Horizontal folds or folds radiating temporally
from disc
c. May also have overlying central macular horizontal inner retinal fold
a. Ophthalmoscopy: Prominent pale lines within
outer retina, termed “hydration lines” or
“corrugations”
b. OCT: Outer retinal cysts and undulations in
area of detached retina, normal smooth inner
retinal surface
3. Etiology / pathophysiology: Outer retinal edema
associated with extensive subretinal fluid causes
large outer retinal folds, likely due to outer retinal ischemia and other causes
B. Associated with repaired rhegmatogenous retinal
detachment
1. Symptoms: Asymptomatic or metamorphopsia
Section XVIII: Vitreoretinal Surgery, Part II
2015 Subspecialty Day | Retina
2.Appearance
a. Ophthalmoscopy: Fine pale outer retinal lines
b. OCT: Outer retinal hyper-reflectivity with
characteristic “jumping fish” or “flying
seagull” appearance
c. Autofluorescence: Hypoautofluorescent lines
correspond to outer retinal folds.
4. Prevention: None
5.Management
a.None
b. Important to distinguish postoperative outer
retinal folds from full thickness retinal folds,
as outer folds will resolve spontaneously.
B.Appearance
1. Very fine wrinkles of retinal surface
2. No color
3. Not seen on angiography
1. Epiretinal membrane: Most common cause
2. Optic disc edema:
a. Termed “Paton’s lines”
b. Pattern is concentric around swollen disc.
3. Hypotony: May have 1 prominent horizontal
fold through fovea or multiple small folds that
radiate from fovea
a. Scleritis and uveal effusion syndrome
b. May radiate from fovea
a. Dome-shaped detachment of ILM with or
without underlying blood
b. Outer retinal hyper-reflective lesion below
edge of ILM detachment
1. Nonaccidental trauma
a. Shaken-baby syndrome
b. Perimacular fold was previously thought to be
pathognomonic for nonaccidental trauma.
3. Valsalva retinopathy: Less likely than other
causes to result in perimacular fold
V. Full-thickness retinal folds involve entire neurosensory
retina.
A. Falciform fold: May be congenital or acquired
1. Appearance: Usually 1 large linear full-thickness
fold from optic disc to inferotemporal periphery
2. Etiology / pathophysiology: peripheral retinal
pathology in pediatric patient, such as familial
exudative vitreoretinopathy, ROP, toxocariasis,
retinoblastoma
B. Postoperative full-thickness retinal fold: After repair
of rhegmatogenous retinal detachment
1. After vitrectomy for retinal detachment due to
giant retinal tear
a. Symptoms: Usually asymptomatic
b. Appearance: Peripheral circumferential fold
in area of giant retinal tear
c. Etiology / pathophysiology: Posterior retinal
slippage in region of giant retinal tear associated with intravitreal gas and incomplete
drainage of subretinal fluid
d. Prevention: Complete drainage of subretinal
fluid; perfluorocarbon-silicone oil exchange
5. Chorioretinal scar: uncommon, due to contracted scar
Along edge of dome-shaped detachment of ILM, usually associated with premacular sub-ILM hemorrhage
2.OCT
2. Terson syndrome: perimacular fold is a common
finding.
IV. Perimacular Retinal Folds
c. Usually in association with sub-ILM hemorrhage but fold usually remains after resolution of blood
4.Inflammation
C. Etiology / pathophysiology: Traction or distortion
of the retinal surface
III. Inner retinal folds involve only the inner neurosensory
retina (nerve fiber layer and internal limiting membrane
[ILM]); retinal striae.
A. Symptoms: Asymptomatic or metamorphopsia
b. At insertion of detached ILM to nerve fiber
layer
B. Etiology / pathophysiology: Abrupt rise in intracranial pressure transmitted through perineural sheath
results in shearing forces, hemorrhage dissects and
separates the retinal layers; when blood resolves,
ILM remains detached and perimacular fold usually
persists.
C. Associated with X-linked juvenile retinoschisis
3. Etiology / pathophysiology: Outer retinal edema
(hydration lines) associated with rhegmatogenous retinal detachment may slowly resolve
during postoperative period and appear as fine
outer retinal folds.
2. After vitrectomy for subtotal retinal detachment
(without giant retinal tear)
A.Appearance
1.Ophthalmoscopy
a. White oval or round border of dome-shaped
detachment of ILM
165
a.Symptoms
i. Decreased vision, distortion, or diplopia
ii. Asymptomatic if outside macula
166
Section XVIII: Vitreoretinal Surgery, Part II
2015 Subspecialty Day | Retina
b.Appearance
i. Ophthalmoscopy: Linear or curvilinear
fold at inferior edge of prior subtotal retinal detachment
ii. OCT: Full-thickness retinal fold without
intervening subretinal fluid constitutes a
dry fold.
c. Etiology / pathophysiology: Inferior retinal
displacement associated with intravitreal gas
and incomplete drainage of subretinal fluid
and possibly also lack of immediate postoperative face-down positioning
e. Management: Vitrectomy with subretinal
saline injection to redetach area involving the
fold, then use of perfluorocarbon liquid to
displace subretinal fluid peripherally, complete drainage of subretinal fluid, and immediate postoperative face-down positioning
3. After scleral buckle for retinal detachment
a. Symptoms: Usually asymptomatic
b. Appearance: Depends on etiology
c. Etiology / pathophysiology
i. Encircling buckle that was placed too high
(radial fold on posterior slope)
ii. Radial buckle that was placed too far
posteriorly (radial or curvilinear folds at
posterior edge)
iii. External drainage site associated with retinal incarceration (radial folds extending
outward from drainage site)
d.Prevention
i. Complete drainage of subretinal fluid
ii. In cases with some remaining subretinal
fluid, use steamroll technique at conclusion of surgery and/or immediate postoperative face-down positioning.
2015 Subspecialty Day | Retina
Section XVIII: Vitreoretinal Surgery, Part II
167
Techniques for Managing Suprachoroidal Hemorrhages
John W Kitchens MD
Introduction
Suprachoroidal hemorrhage (SCH), the accumulation of blood
in the suprachoroidal space, is a potentially devastating complication of both anterior and posterior segment surgery. Although
the occurrence of SCH is rare, it can occur following glaucoma
surgery, corneal transplant surgery, cataract surgery, trauma,
or vitreoretinal surgery. Management intraoperatively at the
time of occurrence by securing the operative wound, controlling
blood pressure, etc. is critical to minimize the size of the SCH
as well as to reduce the risk of the expulsion of ocular contents
(expulsive choroidal hemorrhage).
In the postoperative setting, SCH can be managed both medically and surgically. Medical management includes cycloplegia
and topical and oral steroids, along with pain management
utilizing either traditional analgesics or gabapentin (Neurontin).
Many cases of SCH will resolve with conservative management and will not require additional surgical management. In
the case of appositional, nonresolving SCH or SCH associated
with retinal detachment, surgical intervention can result in an
improvement in the ocular anatomy and visual acuity. Drainage
of the choroidal hemorrhage can be performed in a more traditional fashion with a conjunctival “take-down” followed by a
posterior sclerotomy or utilizing a transconjunctival approach
with either vitreoretinal cannulas or a guarded needle approach.
The timing of drainage is critical as the blood must have time to
“liquify.” Traditionally, the appropriate timing of drainage is
2-3 weeks after the initial event. However, a more direct determination of the “liquefaction” of the hemorrhage is best determined by preoperative echography.
Medical Management
•
•
•
•
Topical cycloplegia (eg, atropine 1% b.i.d.)
Topical corticosteroid drops (eg, difluprednate q.i.d.)
Topical IOP medications, if IOP elevated
Oral gabapentin 300 mg t.i.d. starting dose, for pain
Surgical Management: Transconjunctival Approach
The transconjunctival approach to choroidal drainage (hemorrhagic or serous) may be preferred particularly in cases of
choroidal hemorrhage after glaucoma filtering surgery, as it
preserves the conjunctiva to a greater degree than the traditional
approach. The key to this approach is ensuring that the hemorrhage has liquefied to the point that it can be drained properly.
This is best determined using preoperative echography.
Step 1. Placement of infusion
In order to drain fluid or hemorrhage from the choroidal space,
one must have a replacement volume of fluid for the vitreous
cavity. This is best achieved by placing an infusion line in the
vitreous cavity. Because SCHs can occupy almost the entire
vitreous cavity, one must take care to avoid placing the infusion line too far posterior or in an area of the greatest choroidal
height. Typically the 6 o’clock or 12 o’clock positions will have
the greatest room for placement of the cannula. Utilizing an illuminated infusion line will give direct visualization of the drainage via the wide-angle view systems commonplace in vitreoretinal surgery (eg, Biom system). It is essential that the cannula be
visualized in the vitreous cavity because misplacement into the
SC space can result in worsening of the SCH. The chandelier
light assists with this visualization. If there is insufficient room
to place the infusion line into the vitreous cavity, then placement
into the anterior chamber is necessary. Fluid will flow around
the lens and into the posterior segment in this scenario.
Step 2. Transconjunctival drainage with the guarded needle
approach
One must prepare the guarded needle for drainage of the liquefied hemorrhage. A 26-gauge 3/8-inch needle (BD Medical) is
ideal for draining subretinal fluid, suprachoroidal fluid, and
liquefied SC blood. I prefer to attach the needle to the extrusion line of the vitrectomy machine to provide a closed system,
with the footpetal-actuated aspiration allowing for a more
controlled drainage. The needle can be guarded using a cut 270
scleral buckle sleeve allowing for 3-4 mm of exposed needle tip.
This guarded technique prevents overpenetration of the needle,
which can lead to iatrogenic injury to the retina or choroid. The
guard can be secured to the needle with viscoelastic placed in the
270 sleeve prior to sliding it over the needle or by perforating
the 270 sleeve with the needle tip prior to sliding the sleeve over
the needle. In most cases, the most ideal place for drainage is the
temporal sclera at 3 or 9 o’clock. The reason is two-fold: this is
often the location of the highest choroidal detachment and this
is the location of most posterior access to the sclera.
The needle should be advanced through the conjunctiva and
sclera 8-11 mm posterior to the limbus. The needle guard will
stop the needle from overpenetrating. At this point, the wideangle viewing system can be maneuvered into position. Engaging aspiration, there will be a gentle egress of the choroidals.
Using the closed system, one can easily stop aspiration to better
survey the drainage. Drainage can be performed until at least
80% of the SCH has been evacuated. Care must be taken not
to drain the SCH completely to avoid iatrogenic injury to the
choroid or retina by the needle. Once drainage is successful, the
needle can be withdrawn.
Step 2 (alternate technique). Transconjunctival drainage with
cannulas
In some situations, this approach may be more appropriate than
the guarded needle technique—particularly in cases where one is
unsure of the status of the hemorrhage liquefaction. In the past,
polyamide cannulas were particularly useful for two reasons:
(1) they could be trimmed from 4 mm to 2 mm, reducing the
chance for iatrogenic injury to the retina, and (2) they did not
contain valves, which can impede drainage. Unfortunately, polyamide cannulas are no longer available and have been replaced
by metal cannulas, most of which are valved. This does not preclude using the newer cannulas for drainage and in some ways
the valve will reduce the chances of iatrogenic damage by allowing for a more controlled drain.
168
Section XVIII: Vitreoretinal Surgery, Part II
With this approach, use the 25- or 27-gauge cannula / trocar system in a fashion similar to the guarded needle (temporal
approach, 8-11 mm posterior to the limbus). If the choroidals
are appositional, there is little risk of iatrogenic damage upon
initial placement. Regardless, beveling the incision allows for
a more angulated placement of the cannula, allowing for more
complete drainage. Engaging infusion prior to placement is critical to assist with initial entry. Once the cannula is placed, the
wide-angle viewing system can be moved into position. Forceps
(0.12) are then used to open the valve of the cannula, allowing
egress of the SCH. Occasionally, clotted blood can occlude the
cannula. In this case BSS can be gently infused through the cannula to dislodge the clot. If the clot persists, the vitrectomy hand
piece can be used to remove the clot. Care must be taken not to
cause iatrogenic injury with the cutter.
Step 3. Vitrectomy
In most cases, upon successful drainage a two- or three-port
vitrectomy should be carried out. It is not uncommon to find
peripheral pathology (retinal tears) created either by the SCH
or during the drainage process. These defects are difficult to
visualize without the aid of vitrectomy surgery and wide-angle
viewing systems. I prefer to perform a gas-fluid exchange with
a slightly expansile gas concentration placed at the end of the
case. This may reduce the risk of recurrent SCH due to postop
hypotony and allows for tamponade in the presence of retinal
defects. Subtenon triamcinolone is helpful in reducing intraocular inflammation after drainage.
2015 Subspecialty Day | Retina
Postoperative Management
After suffering from an SCH, it is not uncommon for patients
to have persistent and chronic pain in the absence of intraocular
abnormalities (eg, dislocated lens, intraocular inflammation).
These patients are best managed with oral gabapentin at a starting dose of 300 mg t.i.d. These patients may require consultation with a neurologist as this discomfort is most similar to that
of trigeminal neuralgia and can be difficult to manage.
Summary
SCH can be a devastating complication of ophthalmic surgery
or trauma. Although medical management is the mainstay of
treatment early on, the advent of newer instrumentation has
allowed for less invasive techniques that can yield improved surgical results.
Section XVIII: Vitreoretinal Surgery, Part II
2015 Subspecialty Day | Retina
169
Complications of Perfluorocarbon Liquid and How to
Avoid Them
Masahito Ohji MD
I.History
A. 1966: Animal experiments supporting respiration
B. 1982: Animal experiments as vitreous substitute
C. 1987: Patients with retinal detachment
3. Atrophy of retinal pigment epithelium
4. Corneal endothelial cell damage
V. Incidence of and Risk Factors for Complications
A. Incidence of retained PFCL, corneal abnormality,
elevated IOP
II. PFCL Types and Properties (see Table 1)
A. Optical clear, colorless
B. Different refractive index from saline
C. High specific gravity
D. Low surface tension and high interfacial tension
E. Low viscosity
F. Immiscibility with water, blood, and silicone oil
G. Higher boiling point than water
H.Odorless
1. Retained PFCL: Perfluoron < Vitreon
2. Corneal abnormality: Perfluoron < Vitreon
3. Elevated IOP: Perfluoron < Vitreon
III.Indications
B. Incidence of and risk factors for retained subretinal
PFCL
1.0%-11.9%
2. Perfluorodecalin vs. perfluoro-n-octane: No difference
3. 20-gauge < 23-gauge (without valve)
4. Retinotomy of 120 degrees or larger
5. Lack of saline rinse during fluid-air exchange
A. Giant tears
B. Proliferative vitreoretinopathy (PVR)
C. Retinal detachment without PVR
D. Dislocated crystalline lens or IOL
E. Subretinal hemorrhage and/or suprachoroidal hemorrhage
1. Inject slowly and submerge the tip of the cannula
in the formed PFCL bubble.
2. Minimize or prevent turbulence at the interface
resulting from a jet-stream of infusion.
F. Internal limiting membrane flap
G. Ocular trauma
IV.Toxicity
A.Chemical
1. High oxygen carrying capacity
2.Impurity
VI. Prevention of Subretinal PFCL
B. Relieve traction.
C. Rinse with saline during fluid-air exchange.
D. Large retinal tears
B. Mechanical (higher specific gravity)
1. Loss of outer plexiform layer
2. Displacement of photoreceptor nuclei into the
outer segments
A. Prevent formation of small bubbles of PFCL.
VII. Retained Subretinal PFCL
A. Migrate toward inferiorly or posteriorly
B. Retinal thinning, hole
C. Vision loss
D. Vision and scotoma may be partially recovered following removal of PFCL.
Table 1. Properties of Types of PFCL
PFCL
Chemical
Formula
Molecular
Weight (g/mol)
Specific
Gravity
Surface Tension Refractive
(dyn/cm)
Index
Vapor Pressure
(mmHg)
Viscosity
(cSt)
Perfluoro-n-octane
(Perfluoron)
C8F18
438
1.76
14
1.27
50
0.8
Perfluoro-phenanthrene
(Vitreon)
C14F24
624
2.03
16
1.33
< 1
8.03
Perfluoro-decaline
C10F18
462
1.94
16
1.31
13.5
2.7
170
Section XVIII: Vitreoretinal Surgery, Part II
VIII. Removal of Retained Subretinal PFCL
A. Surgical approach
1. Direct removal with 39/41/50-gauge needle
2. Inject BSS into subretinal space, followed by
aspiration through retinotomy with flute needle.
2015 Subspecialty Day | Retina
B. Nonsurgical approach
1. Head tilting in eyes with enough subretinal fluid
2. Head tilting following injection of BSS into subretinal space
C. Duration of retained subretinal PFCL and postoperative visual acuity (see Figure 1)
IX.Summary
A. PFCL is a useful and indispensable adjunct in vitreous surgery.
B. Use perfluoro-n-octane.
C. Avoid small bubbles.
D. Remove PFCL from subretinal space and/or anterior
chamber.
Selected Readings
1. Clark LC Jr, Gollan F. Survival of mammals breathing organic
liquids equilibrated with oxygen at atmospheric pressure. Science
1966; 152(3730):1755-1756.
2. Haidt SJ, Clark LC Jr, Ginsberg J. Liquid perfluorocarbon
replacement of the eye. Invest Ophthalmol Vis Sci. 1982;
22(suppl):233(abstract).
3. Chang S. Low viscosity liquid fluorochemicals in vitreous surgery.
Am J Ophthalmol. 1987; 103(1):38-43.
4. Blinder KJ, et al. Vitreon, a new perfluorocarbon. Br J Ophthalmol.
1991; 75:7240-244.
5. Shin MK, et al. Perfluoro-n-octane-assisted single-layered inverted
internal limiting membrane flap technique for macular hole surgery.
Retina 2014; 34(9);1905-1910.
Figure 1.
11. Le Tien V, Pierre-Kahn V, Azan F, Renard G, Chauvaud D. Displacement of retained subfoveal perfluorocarbon liquid after vitreoretinal surgery. Arch Ophthalmol. 2008; 126(1):98-101.
12. Escalada Gutiérrez F , Mateo García C. Extraction of subfoveal liquid perfluorocarbon. Arch Soc Esp Oftalmol. 2002; 77(9):519-521.
13. Shulman M, Sepah YJ, Chang S, Abrams GW, Do DV, Nguyen
QD. Management of retained subretinal perfluorocarbon liquid.
Ophthalmic Surg Lasers Imaging Retina. 2013; 44(6):577-583.
14. Lee GA , Finnegan SJ, Bourke RD. Subretinal perfluorodecalin toxicity. Aust NZ J Ophthalmol. 1998; 26(1):57-60.
15. de Queiroz JM Jr, Blanks JC, Ozler SA, Alfaro DV, Liggett PE.
Subretinal perfluorocarbon liquids: an experimental study. Retina
1992; 12(3 suppl):S33-39.
16. Sakurai E, Ogura Y. Removal of residual subfoveal perfluoron-octane liquid. Graefes Arch Clin Exp Ophthalmol. 2007;
245(7):1063-1064.
17. Lesnoni G, Rossi T, Gelso A. Subfoveal liquid perfluorocarbon.
Retina 2004; 24(1):172-176.
18. Lai JC, Postel EA, McCuen BW 2nd. Recovery of visual function
after removal of chronic subfoveal perfluorocarbon liquid. Retina
2003; 23(6):868-870.
19. Lemley CA, Kim JE. Subretinal perfluorocarbon removal: perfluorocarbon volume estimation and cannula choice. Retina 2008;
28(1):167-170.
6. Chang S, Kwun RC. Perfluorocarbon liquids in vitreoretinal surgery. In: Ryan RJ, ed. Retina, 4th ed. 2006:2179-2190.
20. Garcia-Arumi J, Castillo P, Lopez M, Boixadera A, Martinez-Castillo V, Pimentel L. Removal of retained subretinal perfluorocarbon
liquid. Br J Ophthalmol. 2008; 92(12):1693-1694.
7. Wong IY, Wong D. Special adjuncts to treatment. In: Ryan RJ, ed.
Retina, 5th ed. 2013:1735-1783.
21. Roth DB, Sears JE, Lewis H. Removal of retained subfoveal perfluoro-n-octane liquid. Am J Ophthalmol. 2004; 138(2):287-289.
8. Scott IU, Murray TG, Flynn HW Jr, Smiddy WE, Feuer WJ, Schiffman JC. Outcomes and complications associated with perfluoron-octane and perfluoroperhydrophenanthrene in complex retinal
detachment repair. Ophthalmology 2000; 107(7):860-865.
22. Oshima Y, Ohji M, Tano Y. Pars plana vitrectomy with peripheral
retinotomy following preoperative intravitreal tissue plasminogen
activator: a modified procedure to drain massive subretinal hemorrhage. Br J Ophthalmol. 2007; 91(2):193-198.
9. Garg SJ, Theventhiran AB. Perfluorocarbon liquid in microincision
23-gauge versus traditional 20-gauge vitrectomy for retinal detachment. Retina 2012; 32(10):2127-2132.
23. Cohen SY, Dubois L, Elmaleh C. Retinal hole as a complication
of long-standing subretinal perfluorocarbon liquid. Retina 2006;
26(7):843-844.
10. Garcia-Valenzuela E, Ito Y, Abrams GW. Risk factors for retention
of subretinal perfluorocarbon liquid in vitreoretinal surgery. Retina
2004; 24(5):746-752.
24. Wilbanks GA, Apel AJG, Jolly SS, Devenyi RG, Rootman DS.
Perfluorodecalin corneal toxicity: five case reports. Cornea 1996;
15(3)329-334.
Section XVIII: Vitreoretinal Surgery, Part II
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171
Complications of Silicone Oil and How to Avoid Them
Derek Y Kunimoto MD JD
NOTES
172
Section XVIII: Vitreoretinal Surgery, Part II
2015 Subspecialty Day | Retina
Pearls for Maximizing Outcomes of Retinal
Detachment Repair by Pneumatic Retinopexy
How to Improve the Outcome Even If the Pneumatic Fails
Paul E Tornambe MD
I. Purpose of Presentation
A. To improve pneumatic retinopexy (PR) outcomes
B. To improve outcomes in eyes that failed PR
II. What Happens to Eyes That Fail PR?
III. CMS Quality Measure for RD Repair
A. Single operation success (SOS) will be used as the
primary parameter to measure quality of care, and
physician reimbursement will be adjusted by both
SOS and cost.
1. 7 centers
2. Variability between centers
3. Standardized procedure to minimize variability
A. Avoid excessive cryotherapy
B. Reoperate promptly (< 3-5 days)
VI. I Prefer PR Because:
A. It gives the best chance of returning predetachment
vision.
B. Even if it fails, if PR is properly performed, no harm
is done.
A.Study
V. How I Minimize the Chances That a Failed PR Will
Cause Harm
B. CMS assumes single operation success results in the
best visual outcome and is least costly.
IV. PR Trial: One Can’t Separate the Surgeon From the
Surgery
VII. My Pneumatic Secrets: The 10 Pearls of PR, Part 1
• How to maximize the chances for PR success
• How to minimize chances for harm
B.Methods
1. Retrospectively reviewed 43 consecutive primary
retinal detachments (RDs) repaired with PR since
9/2011
2. One surgeon (PET)
3. Followed minimum of 4 months
C. Cohort: phakic status
D. Cohort: macula status
E. Cohort: PR anatomic success
F. Cohort: failed eyes
G. VA results: VA > 20/40
H. Reoperations: failed cases
I. Results: total procedures/location
J. Cost analysis
1. 43 RDs first treated with PR with SOS = 81%
2. 43 RDs first treated with pars plana vitrectomy
(PPV) assumes 90% SOS rate.
K. Cost comparison: PR vs. PPV including reoperations
L. Conclusion #1: A failed pneumatic does not disadvantage the eye to ultimate RD.
N. Conclusion #3: The cost of PR, including reoperations, is half the cost of PPV.
M. Conclusion #2: A failed pneumatic does not disadvantage the ultimate visual recovery.
#1. Pick the right patient.
a. Mental and physical ability to comprehend
the procedure and positioning
b. The patient is your co-surgeon.
c. Positioning aids help.
#2. Pick the right eye.
a. Large eyes require large bubbles.
b. Lens opacities, blood, which limit the view
#3. Pseudophakia Is OK!!!
#4. Use the Right Technique.
a. If shallow break(s), light cryo is OK.
b. Breaks below 3-9 may stay open.
c. Cryo liberates pigment.
d. Cryo immediately decreases sensory retina
adherence to retinal pigment epithelium
(RPE).
e. Staged surgery: Wait for the hole to close,
then apply cryo or laser.
VIII. Technique: Anesthesia and Prep
A. Always subconjunctival anesthesia, never retrobulbar
B. Always lid speculum
C. Always 5% betadine
D. ± subconjunctival antibiotics
E. + postop antibiotic drops x 5 days
2015 Subspecialty Day | Retina
Section XVIII: Vitreoretinal Surgery, Part II
IX. The Ten Pearls of PR, Part 2
• How to maximize the chances for PR success
• How to minimize chances for harm
#5. Always perform a paracentesis: #30 plungerless
syringe
a. Always prior to gas insertion
b. Avoids a hard eye
c. Avoids displacement of the bubble into the
anterior chamber
d. Avoids iris incarceration
#8. Make sure the patient has a clear understanding
of positioning.
a.Requirements
b. Use the pneumo level.
c. Get family involved.
d. Men don’t listen.
#9. Close follow-up
a. Always postoperative Day #1
b. Can usually add laser if staged
c. If break not flat, there is a problem.
#6. Proper gas bubble insertion
a. Always at 3 or 9 o’clock
b. Almost always 100% SF6
c. Always away from large breaks
d. Always #32 needle
e. Inject with needle in 3-4 mm, perpendicular
to the wall of the eye and the floor
f. Brisk injection
g. Have planned injected volume in barrel of
syringe
i. A deep penetrating thrust to puncture the
anterior hyaloid face
ii. Gas injected into space of petit
iii. To avoid subretinal gas, never inject inferiorly.
#7. Use the bubble as a steamroller.
a. Rolls bubble from optic nerve toward the
break (medium size or large)
b. Usually done to debulk subretinal fluid (SRF)
i. Minimizes chances of displacing the SRF
beneath the macula
ii. Minimizes chances of displacing SRF into
inferior breaks or lattice
iii. Minimizes chances of smaller bubbles
entering the subretinal space
173
i. Not positioning correctly
ii. Bubble is too small.
iii. Missed a break
d. Staged PR-laser PC
#10. Reoperate promptly (< 3-5 days)
a. Reop is usually PPV.
b. Occasionally just add more gas
c. Concerned about RPE cells in vitreous cavity
d. 360 laser advised if there is extensive peripheral pathology, lattice, inferior holes in
attached retina.
X. PR Trial Results
174
Section XIX: Video Surgical Complications—What Would You Do?
2015 Subspecialty Day | Retina
Video Surgical Complications—What Would You Do?
Subretinal Air Displacement of Submacular
Hemorrhage
Entry Site Hemorrhage: An Unexpected
Complication
Tamer H Mahmoud MD
David Fonseca Martins MD
Postoperative Roll Cake-Like Macular Fold After
Retinal Detachment Surgery: A Case Report
Incidental Subfoveal Perfluorocarbon Heavy Liquids
After Vitrectomy for Giant Retinal Tear
Yumiko Machida MD
Gerardo Ledesma-Gil MD
Acute Intraocular Bleeding Due to Explosive
Separation of Silicone Oil Injector
Jay M Stewart MD
2015 Subspecialty Day | Retina
175
Financial Disclosure
Transparency through disclosure of relationships with companies is one step in the Academy’s process of ensuring that all its
educational activities are fair, balanced, and not commercially
biased. The Academy’s Board of Trustees supports the position
that having a financial relationship should not restrict expert
scientific, clinical or non-clinical presentation or publication or
participation in Academy leadership or governance, provided
that appropriate disclosure of such relationship is made. Similarly, it should not restrict participation in AAO leadership or
governance, so long as appropriate disclosure is made. As an
ACCME accredited provider of CME, the Academy seeks to
ensure balance, independence, objectivity, and scientific rigor in
all individual or jointly sponsored CME activities.
All contributors to Academy educational and leadership
activities must disclose all financial relationships (defined below)
to the Academy annually. The ACCME requires the Academy to
disclose the following to participants prior to the activity:
• All financial relationships with Commercial Companies
that contributors and their immediate family have had
within the previous 12 months. A commercial company is
any entity producing, marketing, re-selling or distributing
health care goods or services consumed by, or used on,
patients.
• Meeting presenters, authors, contributors or reviewers
who report they have no known financial relationships to
disclose.
The Academy will request disclosure information from meeting presenters, authors, contributors or reviewers, committee
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change. At the time of submission of a Journal article or materials for an educational activity or nomination to a leadership
position, each Contributor should specifically review his/her
statement on file and notify the Academy of any changes to his/
her financial disclosures. These requirements apply to relationships that are in place at the time of or were in place 12 months
preceding the presentation, publication submission, or nomination to a leadership position. Any financial relationship that may
constitute a conflict of interest will be resolved prior to the delivery of the activity.
Financial Relationship Disclosure
For purposes of this disclosure, a known financial relationship
is defined as any financial gain or expectancy of financial gain
brought to the Contributor or the Contributor’s immediate family (defined as spouse, domestic partner, parent, child or spouse
of child, or sibling or spouse of sibling of the Contributor) by:
• Direct or indirect compensation;
• Ownership of stock in the producing company;
• Stock options and/or warrants in the producing company,
even if they have not been exercised or they are not currently exercisable;
• Financial support or funding to the investigator, including
research support from government agencies (e.g., NIH),
device manufacturers, and/or pharmaceutical companies;
or
• Involvement with any for-profit corporation that is likely
to become involved in activities directly impacting the
Academy where the Contributor or the Contributor’s family is a director or recipient
Description of Financial Interests
Category Code Description
Consultant / Advisor
C
Consultant fee, paid advisory
boards or fees for attending a
meeting
Employee E
Employed by a commercial company
Lecture Fees L
Lecture and speakers bureau
fees (honoraria), travel fees or
reimbursements when speaking
at the invitation of a commercial
company
Equity Owner
O
Equity ownership/stock options
(publicly or privately traded
firms, excluding mutual funds).
Patents / Royalty
P
Patents and/or royalties that
might be viewed as creating a
potential conflict of interest
Grant Support
S
Grant support from all sources
176
2015 Subspecialty Day | Retina
Financial Disclosures
Thomas M Aaberg Jr MD
Carl C Awh MD
Mark S Blumenkranz MD
Allergan: L
Synergetics, Inc.: C
ArcticDx, Inc.: C,O
Bausch + Lomb: C
Genentech: C,S
GlaxoSmithKline: S
Janssen: C
Katalyst: C,O
Regeneron Pharmaceuticals, Inc.: S
Synergetics, Inc.: C,O,P
Tyrogenenics: S
Volk Optical: C
Avalanche Biotechnology: O,P
Digisight: O
Oculeve: O
Oculogics: O
Optimedica: O,P
Presby Corp.: O
Vantage Surgical: C,O
Anita Agarwal MD
None
Thomas A Albini MD
Alcon Laboratories, Inc.: C
Allergan: C
Bausch + Lomb: C
DORC International, bv/Dutch
Ophthalmic, USA: C
Eleven Biotherapeutics: C
Santen, Inc.: C
Jayakrishna Ambati MD
Allergan: C,L
iVeena Delivery: O
iVeena Holdings: O
iVeena Pharma: O
J Fernando Arevalo MD FACS
Alcon Laboratories, Inc.: C,L
Bayer Healthcare Pharmaceuticals: C
DORC International, bv/Dutch
Ophthalmic, USA: C,L
EyEngineering, Inc.: C
King Khaled Eye Specialist Hospital: S
Second Sight Medical Products, Inc.:
C,L
Springer SBM, LLC: P
Sophie J Bakri MD
Allergan: C
Francesco M Bandello MD FEBO
Alcon Laboratories, Inc.: C
Alimera Sciences, Inc.: C
Allergan, Inc.: C
Bausch + Lomb Surgical: C
Bayer Schering Pharma: C
Farmila-Thea Pharmaceuticals: C
Genentech: C
Hoffman La Roche, Ltd.: C
Novagali Pharma: C
Novartis Pharmaceuticals Corp.: C
Sanofi Aventis: C
ThromboGenics: C
Caroline R Baumal MD
Allergan: C
Optovue: S
Robert L Avery MD
Paul S Bernstein MD PhD
Alcon Laboratories, 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
OHR Pharma: O
QLT Phototherapeutics, Inc.: C,S
Regeneron Pharmaceuticals, Inc.: C,O
Replenish: C,O,P
Lowy Medical Research Insititute: S
Makindus: C
National Eye Institute: S
NuSkin/Pharmanex: P
ScienceBased Health: C
ZeaVision: S
Marcos P Avila MD
None
Audina M Berrocal MD
Visunex: C
Maria H Berrocal MD
Alcon Laboratories, Inc.: L,C
Susanne Binder MD
Zeiss Meditec: C
Disclosures current as of 10/9/2015
Check the online program/mobile meeting guide for the most current financial disclosures
Francesco Boscia MD
Alcon Laboratories, Inc.: C
Allergan: C
Bayer Healthcare Pharmaceuticals: L
Novartis Pharmaceuticals Corp.: C,L
Pfenex: C
David S Boyer MD
Aeripo: C
Alcon Laboratories, Inc.: C,L
Alimera Sciences, Inc.: C
Allegro: C,O
Allergan: C,L
Bausch + Lomb: C
Bayer Healthcare Pharmaceuticals: C
Genentech: C,L
GSK: C
Merck & Co., Inc.: C
Neurotech: C,O
NotalVision, Ltd.: C
Ohr: C,O
Pfizer, Inc.: C
Quantel Medical: C
Regeneron: C
Santen, Inc.: C
Neil M Bressler MD
American Medical Association: S
Bayer Healthcare Pharmaceuticals: S
Genentech, Inc.: S
Lumenis, Inc.: S
National Eye Institute: S
Novartis Pharma AG: S
Regeneron Pharmaceuticals, Inc.: S
The EMMES Corp.: S
Susan B Bressler MD
Bayer Healthcare Pharmaceuticals: S
Boehringer Ingelheim Pharma: S
GlaxoSmithKline: C
Notal Vision, Inc.: S
Novartis Pharmaceuticals Corp.: S
Financial Disclosures
2015 Subspecialty Day | Retina
David M Brown MD
R V Paul Chan MD
Christine Curcio PhD
Alcon Laboratories, Inc.: C,S
Alimera Sciences, Inc.: C,S
Allergan: C,S
Avalanche: C
Bayer Healthcare Pharmaceuticals: C
Genentech: C,S
Heidelberg Engineering: C
Notal Vision, Inc.: C
Optos, Inc.: C
Quantel Medical: C
Regeneron Pharmaceuticals, Inc.: C,S
Santen, Inc.: C,S
Alcon Laboratories, Inc.: C
Allergan: C
Genentech: C
Stanley Chang MD
Alcon Laboratories, Inc.: C,P
Alcon Laboratories, Inc.: C
DigiSight, Inc.: O
Neurotech, Inc.: O
Ophthotech, Inc.: O
PanOptica, Inc.: C
Nauman A Chaudhry MBBS
Janet Louise Davis MD
Eye Formatics: O
ABBVIE: C
Sanofi Fovea: S
Gary C Brown MD
None
Lucian V Del Priore MD PhD
David R Chow MD
Alimera Sciences, Inc.: C
Mesoblast: C
Ocata: C
Center for Value-Based Medicine: O
David J Browning MD PhD
Aerpio: S
Alimera Sciences, Inc.: C
Diabetic Retinopathy Clinical
Research: S
Genentech: S
Novartis Pharmaceuticals Corp.: S
Pfizer, Inc.: S
Regeneron Pharmaceuticals: S
Peter A Campochiaro MD
Advanced Cell Technology: C
Aerpio: C,S
Alimera Sciences, Inc.: C
Allergan: C
Applied Genetic Technologies: C
Asclipix: C
Eleven Biotherapeutics: C
Gene Signal: C
Genentech: C,S
Genzyme: S
GlaxoSmithKline: S
Kala Pharmaceuticals: C
Norvox: C
Oxford BioMedica: S
Regeneron: C
Rixi: C
Roche: S,C
Antonio Capone Jr MD
Allergan: S,C,L
FocusROP: P,O
Genentech: S
Pfizer, Inc.: S
Retinal Solutions: P,O
Usha Chakravarthy MBBS PhD
Alimera Sciences, Inc.: C
Novartis Pharmaceuticals Corp.: C,L
Ophthotech: L
Roche: C
Alcon Laboratories, Inc.: C
Steven T Charles MD
Emily Y Chew MD
Alcon Laboratories, Inc.: C
Allergan: L
Bayer Healthcare Pharmaceuticals: C
DORC International, bv/Dutch
Ophthalmic, USA: C,L
Synergetics, Inc.: O
Thomas A Ciulla MD
Acucela: S
Alcon Laboratories, Inc.: S
Lpath, Inc.: S
Ohr: C,S
Ophthotec: S
Pfizer, Inc.: S
Stealth: C
ThromboGenics: C,S
Xoma: S
Carl C Claes MD
Alcon: C
Borja F Corcóstegui MD
Allergan: L
Bayer Healthcare Pharmaceuticals: L
Scott W Cousins MD
None
Karl G Csaky MD
Allergan: C
Genentech: S,C
GlaxoSmithKline: C
Heidelberg Engineering: C
Notal Vision, Inc.: C
Novartis Pharmaceuticals Corp.: L,C
Ophthotech: O,C
Regeneron Pharmaceuticals, Inc.: C
Catherine A Cukras MD PhD
None
Wiley Andrew Chambers MD
Emmett T Cunningham Jr MD
PhD MPH
None
None
Donald J D’Amico MD
Diana V Do MD
Allergan: S, C
Avalanche Biotechnologies: C
Genentech: C,S
Regeneron Pharmaceuticals, Inc.: C,S
Santen, Inc.: C, S
Kimberly A Drenser MD PhD
Allergan: C
FocusROP: O
Retinal Solutions: O
Synergetics, Inc.: C
ThromboGenics: L
Didier H Ducournau MD
None
Pravin U Dugel MD
Abbott Medical Optics: C
Acucela: C
Alcon Laboratories, Inc.: C
Alimera Sciences, Inc.: C,O
Allergan: C
Digisight: O
Genentech: C
Novartis Pharmaceuticals Corp.: C
Ophthotech: C,O
Ora: C
Regeneron: C
ThromboGenics: C
Jay S Duker MD
Alcon Laboratories, Inc.: C
Carl Zeiss Meditec: C
Eyenetra: C,O
Hemera Biosciences: O
Nicox: C
Ophthotech: C
Optovue: C
ThromboGenics, Inc.: C
Jacque L Duncan MD
None
Disclosures current as of 10/9/2015
Check the online program/mobile meeting guide for the most current financial disclosures
177
178
Financial Disclosures
2015 Subspecialty Day | Retina
Claus Eckardt MD
K Bailey Freund MD
J William Harbour MD
DORC International, bv/Dutch
Ophthalmic, USA: P
Bayer Healthcare Pharmaceuticals: C
Genentech: C
Heidelberg Engineering: C
Ohr Pharmaceutical: C
Optos, Inc.: C
Optovue: C
ThromboGenics: C
Castle Biosciences: P,C
Justis P Ehlers MD
Alcon Laboratories, Inc.: C
Bioptigen: C,P
Carl Zeiss Meditec: C
Genentech: S
Leica: C
National Eye Institute: S
Ohio Department of Development: S
Synergetics, Inc.: P
ThromboGenics: C,S
Ehab N El Rayes MD PhD
Alcon Laboratories, Inc.: C
Bayer Healthcare Pharmaceuticals: C
DORC International, bv/Dutch
Ophthalmic, USA: P
Medone Surgical: P
Novartis Pharmaceuticals Corp.: C
Dean Eliott MD
Acucela: C
Alimera: C
Allergan: C
Arctic: O
Avalanche: C
Ocata: S
ThromboGenics: C
Martin Friedlander MD
None
Sunir J Garg MD FACS
Allergan, Inc.: C,S
Centocor, Inc.: S
Deciphera: C
ThromboGenics, Inc.: C
Xoma: S
Alain Gaudric MD
Bayer Healthcare Pharmaceuticals: S
Novartis: S,C
Senju: S
ThromboGenics, Inc.: C
Zeiss Meditec: L
Ronald C Gentile MD
Alcon Laboratories, Inc.: C,S
Genentech: S
National Eye Institute: S
Regeneron Pharmaceuticals, Inc.: S
Michel Eid Farah MD
Mark C Gillies MD PhD
None
Allergan: C,L,S
Bayer Healthcare Pharmaceuticals: C,L,S
Novartis Pharmaceuticals Corporation:
C,L,S
Philip J Ferrone MD
Alcon Laboratories, Inc.: C
Allergan: C,L
ArcticDx, Inc.: O
Carl Zeiss, Inc.: L
Genentech: L,C
Regeneron Pharmaceuticals, Inc.: C
Marta Figueroa MD
Evangelos S Gragoudas MD
Advanced Cell Technology: C
Aura Biosciences: C
MPM Capital, LLC: C
QLT Phototherapeutics, Inc.: P
Alcon Laboratories, Inc.: C
Allergan: C
Bayer Healthcare Pharmaceuticals: C
Novartis Pharmaceuticals Corp.: C
Jeffrey G Gross MD
Gerald A Fishman MD
Advanced Cell Technology: C
Alcon Laboratories, Inc.: C
Allergan, Inc.: C
Lpath, Inc.: C
Merck & Co., Inc.: C
Regeneron: C
Second Sight Medical Products, Inc.: C
ThromboGenics: C
None
Harry W Flynn Jr MD
None
David Fonseca Martins MD
None
Acucela: S
Jaeb Center for Health Research: S
Julia A Haller MD
Dennis P Han MD
Alcon Laboratories, Inc.: C
Allergan, Inc.: S
Disclosures current as of 10/9/2015
Check the online program/mobile meeting guide for the most current financial disclosures
Tarek S Hassan MD
Alcon Laboratories, Inc.: C
Allergan: C
ArcticDx, Inc.: O
Bayer Healthcare Pharmaceuticals: C
Genentech: C
Insight Instruments: C,P
Janssen: C
Novartis Pharmaceuticals Corp.: C
Regeneron Pharmaceuticals, Inc.: C
Roche: C
Jeffrey S Heier MD
Acucela: C,S
Aerpio: C
Alcon Laboratories, Inc.: S
Allergan: C,S
Avalanche: C
Bausch + Lomb: C
Bayer Healthcare Pharmaceuticals: C
DORC International, bv/Dutch
Ophthalmic, USA: C
Endo Optiks, Inc.: C
Forsight Vision: C
Genentech: C,S
Heidelberg Engineering: C
Icon Therapeutics: C
Janssen R&D: C
Kala Rx: C,S
Kanghong: C
Kato Pharmaceuticals: S
Neurotech: C,S
Notal Vision, Inc.: C
Novartis Pharmaceuticals Corp.: C,S
Ohr Pharmaceuticals: C,S
Ophthotech: S
Optovue: C
QLT Phototherapeutics, Inc.: S
Quantel: C
Regeneron Pharmaceuticals, Inc.: C,S
RetroSense: C
Sanofi Fovea: S
Shire: C
Stealth BioTherapeutics: C,S
ThromboGenics, Inc.: C,S
Xcovery: C
Akito Hirakata MD
Not submitted by press date
Financial Disclosures
2015 Subspecialty Day | Retina
179
Allen C Ho MD
Michael S Ip MD
Szilard Kiss MD
Alcon Laboratories, Inc.: C,L,S
Allergan: S
Digisight: C,O
Genentech: C,L,S
Janssen: C,L,S
NEI/NIH: S
NeuroTech: C,O
Ophthotech: C,S
Optovue: C
PanOptica: C,S
PRN: C,O,S
Regeneron: C,L,S
Second Sight: C,S
ThromboGenics: C,L,S
Alimera Sciences, Inc.: C
ThromboGenics, Inc.: C
Alimera Sciences, Inc.: L,C
Allergan: L,C
Avalanche Biotechnologies: O,C
Bausch + Lomb: C
Genentech: S,C,L
Optos, Inc.: C,L
Regeneron Pharmaceuticals, Inc.: L,C
Nancy M Holekamp MD
Alimera Sciences, Inc.: C
Allergan: S,C,L
Genentech: S,C,L
Katalyst: P,C
Regeneron Pharmaceuticals, Inc.: S,C,L
Frank G Holz MD
Alcon Laboratories, Inc.: C
Allergan: S,C
Bayer Healthcare Pharmaceuticals: S,C
Genentech: S,C
Heidelberg Engineering: S,C
Hoffman La Roche, Ltd.: C,S
Novartis Pharmaceuticals Corp.: L,C,S
Suber S Huang MD MBA
AECOM: C
Biofirst: C
i2i Innovative Ideas Inc: O
Lumoptik: O
Regenerative Patch Technologies: C
Second Sight: C
Spark: C
Mark S Humayun MD PhD
1Co., Inc.: C,O
Alcon Laboratories, Inc.: C,L
Bausch + Lomb Surgical: C,L,P
Clearside: C
Envisia: C
Iridex: C,P
Reflow: C,O,P
Regenerative Patch Technologies (RPT):
C,O
Replenish: C,L,O,P
Second Sight: C,O,P
Viomedix: C,O
Raymond Iezzi MD
Alimera Sciences: C,O
Tatsuro Ishibashi MD
None
Timothy L Jackson MBChB
NeoVista, Inc.: S
Novartis Pharmaceuticals Corp.: S
Oraya: S
Glenn J Jaffe MD
Alcon Laboratories, Inc.: C
Heidelberg Engineering: C
Neurotech: C
Novartis Pharmaceuticals Corp.: C
Roche: C
Lee M Jampol MD
John W Kitchens MD
Allergan: C
Bayer Healthcare Pharmaceuticals: C,L
Carl Zeiss Meditec: C
Genentech: S
Optos, Inc.: C
Regeneron Pharmaceuticals, Inc.: C
Synergetics, Inc.: C
Derek Y Kunimoto MD JD
GlaxoSmithKline: C
Hoffman La Roche, Ltd.: S
Allergan: C
Bausch + Lomb: C
DORC International, bv/Dutch
Ophthalmic, USA: C
Genentech: C
Synergetics, Inc.: C
Kazuaki Kadonosono MD
Baruch D Kuppermann MD PhD
None
Richard S Kaiser MD
AcuFocus, Inc.: C
Alcon Laboratories, Inc.: C
Allegro: C
Allergan: C,S
Ampio: C
Aqua Therapeutics: C
Bausch Lomb: C
Genentech: C,S
Glaukos Corporation: C
GlaxoSmithKline: S
Neurotech: C
Novagali: C
Novartis Pharmaceuticals
Corporation: C
Ophthotech: C,S
Regeneron Pharmaceuticals, Inc.: C,S
SecondSight: C
Staar Surgical: C
Teva Pharmaceutical Industries, Ltd.: C
ThromboGenics, Inc.: S
Ophthotech: C,O
Pan Optica: C
Yasuo Kurimoto MD PhD
National Eye Institute: S
Mark W Johnson MD
Peter K Kaiser MD
Aerpio: C
Alcon Laboratories, Inc.: C,L
Alimera Sciences, Inc.: C,L
Allegro: C
Bayer Healthcare Pharmaceuticals: C,L
Biogen, Inc.: C
Digisight: C
Genentech: C
Kanghong: C
Novartis Pharmaceuticals Corp.: C,L
Ohr: C,O
Ophthotech: C,L,O
Regeneron Pharmaceuticals, Inc.: C,L
Santen: C
ThromboGenics: C
Judy E Kim MD
Alimera Sciences, Inc.: C
Allergan: C
Bayer Healthcare Pharmaceuticals: L
Notal Vision, Inc.: S
Novartis Pharmaceuticals Corp.: L
OMIC-Ophthalmic Mutual Insurance
Company: S
Optos, Inc.: S
Disclosures current as of 10/9/2015
Check the online program/mobile meeting guide for the most current financial disclosures
Alcon Laboratories, Inc.: L,S
Allergan: S
Bayer Healthcare Pharmaceuticals: L
Hoya: S
Novartis Pharmaceuticals Corp.: L
Pfizer, Inc.: L
Santen, Inc.: L,S
Senju: L,S
180
Financial Disclosures
2015 Subspecialty Day | Retina
Michael Larsen MD
Brian P Marr MD
Yuichiro Ogura MD PhD
Allergan: C,L
Bayer Healthcare Pharmaceuticals: C,L
Novartis Pharmaceuticals Corp.: C,L
Ophthotech: C,L
None
Gerardo Ledesma-Gil MD
Carlos Mateo MD
Alcon Laboratories, Inc.: C,L
Bayer Healthcare Pharmaceuticals: C,L
Novartis Pharmaceuticals Corp.: C,L
Santen, Inc.: C,L
Senju, Inc: L
Wakamoto, Inc: C,L
None
None
Thomas C Lee MD
Miguel A Materin MD
Endooptiks: C
None
Xiaoxin Li MD
H Richard McDonald MD
None
None
Jennifer Irene Lim MD
William F Mieler MD
Alcon Laboratories, Inc.: C
Alexion: C
Genentech: C,L,S
Icon Bioscience: C,S
Lumenis, Inc.: C
Pfizer, Inc.: S
Regeneron Pharmaceuticals, Inc.: C,L,S
Santen, Inc.: C
Genentech: C
Anat Loewenstein MD
Alcon Laboratories, Inc.: C
Allergan, Inc.: C,L
Bayer: C,L
Notal Vision, Ltd.: C
Novartis Pharmaceuticals Corp.: C,L
Teva Pharmaceutical Industries, Ltd.: C
Zhizhong Ma MD
None
Mathew W MacCumber MD PhD
Allergan: C,S
Carl Zeiss, Inc.: C
Genentech: C
National Eye Institute: S
Neurotech, USA: S
Optos, Inc.: S
Regeneron: C,S
StemCells, Inc.: S
ThromboGenics: C,S
Yumiko Maschida MD
None
Robert E MacLaren MBChB
NightStarX, Ltd: C,E,O,P
University of Oxford: E,P
Albert M Maguire MD
Novartis Pharmaceuticals Corp.: C
Daniel F Martin MD
None
Joan W Miller MD
Alcon Laboratories, Inc.: C
Amgen: C
Elsevier: P
Kalvista Pharmaceuticals: C
Maculogix, Inc.: C
Mass Eye & Ear/Valeant
Pharmaceuticals: P
ONL Therapeutics, LLC: P
Andrew A Moshfeghi MD MBA
Alimera Sciences, Inc.: C
Allergan: C
Genentech: C
OptiStent: O
Optos, Inc.: C
Darius M Moshfeghi MD
Genentech, Inc.: C
Grand Legend Technology, Ltd.: C,O
InSitu Therapeutics, Inc.: C,O,P
Oraya Therapeutics, Inc.: C,O
Synergetics, Inc.: C
Visunex Medical Systems Co., Ltd.: C,O
Robert F Mullins PhD MS
None
Timothy G Murray MD MBA
Masahito Ohji MD
Alcon Laboratories, Inc.: C,S,L
Bausch + Lomb: C
Bayer Healthcare Pharmaceuticals: L,C
Hoya: S,C
MSD: L
Novartis Pharmaceuticals Corp.: L,C,S
Otuska: L,S
Pfizer, Inc.: S,L,C
Santen, Inc.: C,L,S
Senju: S,L
Kyoko Ohno-Matsui MD
None
Annabelle A Okada MD
Bayer Healthcare Pharmaceuticals: C
Bayer Japan: L,S
Mitsubishi Tanabe Pharma: L,S
Novartis Pharma Japan: C,L
Novartis Pharmaceuticals Corp.: C
Pfizer Japan: L
Santen, Inc.: L
Xoma: C
Timothy W Olsen MD
A Tissue Support Structure: P
Abraham J and Phyllis Katz
Foundation: S
Genentech: S
National Eye Institute: S
Research to Prevent Blindness: S
Scleral Depressor: P
The Fraser Parker Foundation: S
The R Howard Dobbs Jr.
Foundation: S
Yusuke Oshima MD
Alcon Laboratories, Inc.: C
Alcon Laboratories, Inc.: L
Synergetics, Inc.: C
Quan Dong Nguyen MD
Kirk H Packo MD
Bausch + Lomb: C
Genentech: C,S
Novartis Pharmaceuticals Corp.: C
Regeneron Pharmaceuticals, Inc.: C,S
Santen, Inc.: C,S
XOMA: C
Abbott Medical Optics, Inc.: S
Alcon Laboratories, Inc.: C,L,S
Alimera Sciences, Inc.: S,L,C
Allergan: S,L
Covalent Medical: O
Genentech: S
Mobius: S
Optoview: S
Regeneron Pharmaceuticals, Inc.: S
Stem Cells, Inc.: S
US Retina: O
Tamer H Mahmoud MD
Alcon Laboratories, Inc.: C
Alimera Sciences, Inc.: C
Allergan: C
Disclosures current as of 10/9/2015
Check the online program/mobile meeting guide for the most current financial disclosures
Financial Disclosures
2015 Subspecialty Day | Retina
181
David W Parke II MD
Carl D Regillo MD FACS
Philip J Rosenfeld MD PhD
OMIC-Ophthalmic Mutual Insurance
Company: C
Alimera Sciences, Inc.: C
Allergan: S
Bayer Healthcare Pharmaceuticals: C
Genentech: C,S
Johnson & Johnson: C
Regeneron Pharmaceuticals, Inc.: S
Santen, Inc.: S,C
ThromboGenics, Inc.: C,S
Acucela: C,S
Advanced Cell Technology: S
Alcon Laboratories, Inc.: C,S
Alimera Sciences, Inc.: C,S
Allergan: C,S
Bausch Lomb: C
Genentech: C,S
NotalVision, Ltd.: C,S
Novartis Pharmaceuticals
Corporation: C
Pfizer, Inc.: C
Regeneron Pharmaceuticals, Inc.: C,S
Santen, Inc.: S
Second Sight Medical Products, Inc.: S
ThromboGenics, Inc.: C,S
Eric A Pierce MD PhD
Elias Reichel MD
Agilent: L
AGTC: C
Allergan: C
Biogen Inc: C
Editas: C
Illumina: L
Isis Pharmaceuticals: C
Novartis Pharmaceuticals Corporation:
S,C
ReNeuron: C
Vision Medicines: C
Akorn, Inc.: P
Hemera Biosciences: O
Ophthotech: O
Regeneron Pharmaceuticals, Inc.: L
Achillion Pharmaceuticals: C
Acucela: C,S
Alcon Laboratories, Inc.: C
Alexion: C
Allergan: C
Apellis: O,S
Bayer Healthcare Pharmaceuticals: C
Carl Zeiss Meditec: S
Chengdu Kanghong Biotech: C
CoDa Therapeutics: C
Digisight: O
Genentech: C,S
GlaxoSmithKline: S
Healios K.K.: C
Hoffman La Roche, Ltd.: C
Neurotech: S
Ocata Therapeutics: C,S
Ocudyne: C
Regeneron Pharmaceuticals, Inc.: C
Stealth BioTherapeutics: C
Tyrogenex: C
Vision Medicines: C
Grazia Pertile MD
None
Dante Pieramici MD
John S Pollack MD
Covalent Medical: O
DORC International, bv/Dutch
Ophthalmic, USA: C
Genentech: C
Regeneron Pharmaceuticals, Inc.: S
Vestrum Health: O
Kourous Rezaei MD
Alcon Laboratories, Inc.: C,L,S
Bayer Healthcare Pharmaceuticals: S
BMC: C,L
Genentech: L,S
Ophthotec: C,O,E
Regeneron: L,S
ThromboGenics: C,L,S
William L Rich III MD FACS
None
Christopher D Riemann MD
P Kumar Rao MD
Aerepio: S
Alcon Laboratories, Inc.: C,L,S
Alimera Sciences, Inc.: L
Allergan: L
Genentech: S
Haag Streit Surgical: C,L
Haag Streit USA: C
Johnson & Johnson: C,P
Kaleidoscope: C
Macor Industries: O,C
MedOne Surgical: C,P
Northmark Pharmacy: O
Regeneron Pharmaceuticals, Inc.: S
National Eye Institute: S
Regeneron Pharmaceuticals, Inc.: S
Stanislao Rizzo MD
Jonathan L Prenner MD
Alcon Laboratories, Inc.: C
Neurotech: C
Ophthotech: O
Panoptica: O
Regeneron Pharmaceuticals, Inc.: C
Carmen A Puliafito MD MBA
Humphrey Zeiss: P
None
Edwin Hurlbut Ryan Jr MD
Alcon Laboratories, Inc.: P,C
Srinivas R Sadda MD
Alcon Laboratories, Inc.: C
Allergan, Inc.: C,S
Carl Zeiss Meditec: C,S
Genentech: C,S
Iconic, Inc.: C
Novartis Pharmaceuticals Corp.: C
Optos, Inc.: C,S
Roche Diagnostics: C
Taiji Sakamoto MD PhD
Alcon Laboratories, Inc.: L
Bausch + Lomb: C
Bayer Healthcare Pharmaceuticals: L
Novartis Pharmaceuticals Corp.: C
Santen, Inc.: L
Senju: L
David Sarraf MD
Alcon: S
Allergan: S
Genentech: C,S
Heidelberg: S
Notal Vision, Inc.: S
Optovue: S
Regeneron: S
Andrew P Schachat MD
AnGes: C
Easton Capital: O
Elsevier: P
Disclosures current as of 10/9/2015
Check the online program/mobile meeting guide for the most current financial disclosures
182
Financial Disclosures
2015 Subspecialty Day | Retina
Ursula M Schmidt-Erfurth MD
Janet R Sparrow PhD
Jennifer K Sun MD
Alcon Laboratories, Inc.: C
Bayer Healthcare Pharmaceuticals: C
Novartis Pharmaceuticals Corp.: C
Alcon Research Institute: S
Arnold and Mabel Beckman
Foundation: S
Foundation Fight Blindness Macula
Vision: S
Macula Vision Research Foundation: S
National Eye Institute: S
Research to Prevent Blindness: S
Steinbach Fund: S
Allergan: C
Bayer Healthcare Pharmaceuticals: L
Boston Micromachines: S
Genentech: S
Kalvista: S
Novartis Pharmaceuticals
Corporation: C
Optovue: S
Regeneron Pharmaceuticals, Inc.: C
Sunil K Srivastava MD
Ramin Tadayoni MD PhD
Alcon Laboratories, Inc.: C
Allergan: S
Bausch + Lomb Surgical: C,S
Bioptigen: P
Carl Zeiss, Inc.: C
Novartis Pharmaceuticals Corp.: S
Sanofi Fovea: C
Santen, Inc.: C,L
Synergetics, Inc.: P
Alcon Laboratories, Inc.: C,L,S
Alimera Sciences, Inc.: C,L
Allergan: C,L,S
Bausch + Lomb: C,L
Bayer Healthcare Pharmaceuticals: C,L
Genentech: C
Novartis Pharmaceuticals Corp.: C,L,S
ThromboGenics, Inc.: C
Zeiss: C,L
Peter W Stalmans MD PhD
Hiroko Terasaki MD
None
Alcon Laboratories, Inc.: C,L
Bausch + Lomb: S
DORC International, bv/Dutch
Ophthalmic, USA: L
ThromboGenics, Inc.: S
Jerry A Shields MD
Giovanni Staurenghi MD
None
Alcon Laboratories, Inc.: C
Allergan: C
Bayer Healthcare Pharmaceuticals: C
Centervue: L,S
Genentech: C
Heidelberg Engineering: C,L,S
Novartis Pharmaceuticals Corp.: C,S
Optovue: L,S
Roche: C
Zeiss: C
Alcon Laboratories, Inc.: L,S
Astellas Pharma, Inc.: L
Bayer Healthcare Pharmaceuticals: L,S,C
Kowa: L,S
Nidek, Inc.: L,P
Novartis Pharmaceuticals Corp.: L
Ono Pharmaceutical Co., Ltd.: C
Otsuka Pharmaceutical Co., Ltd.: L
Pfizer, Inc.: L,S
Santen, Inc.: L,S
Senju: L,S
Wakamoto: L,S
Hendrik P Scholl MD
Hoffman La Roche, Ltd.: C
Quadralogic Phototherapeutics: S,C
Sanofi Fovea: C
Shire: C
StemCells, Inc.: C
Vision Medicines, Inc.: C
Steven D Schwartz MD
None
Ingrid U Scott MD MPH
Genentech: C,L
ThromboGenics: C
Gaurav K Shah MD
Alcon Laboratories, Inc.: C,L
Allergan: C,S
QLT Phototherapeutics, Inc.: L
Regeneron Pharmaceuticals, Inc.: L
Carol L Shields MD
Fumio Shiraga MD
Alcon Laboratories, Inc.: S
Novartis Pharmaceuticals Corp.: S,C
Santen, Inc.: S,C
Paul A Sieving MD PhD
None
Rishi P Singh MD
Alcon Laboratories, Inc.: C,S
Genentech: C,S
Regeneron Pharmaceuticals, Inc.: C,S
Shire: C
Jay M Stewart MD
Wendy M Smith MD
Allergan: C,S
Boehringer-Ingelheim: C
Regeneron Pharmaceuticals, Inc.: C,S
None
Eric H Souied MD PhD
Eye Science: O
Forsight Vision4: C
Michael W Stewart MD
Allergan: C
Bayer Healthcare Pharmaceuticals: L,C
Novartis Pharmaceuticals Corp.: L,C
Edwin M Stone MD PhD
Richard F Spaide MD
AGTC: C
Clayton Foundation for Research: S
National Eye Institute: S
Oxford BioMedica/Sanofi: C
RetroSense: C
SPARK Therapeutics: C
StemCells, Inc: C
United States Patent Office: P
Genentech: C
Topcon Medical Systems, Inc.: P,C
None
J Timothy Stout MD PhD MBA
Disclosures current as of 10/9/2015
Check the online program/mobile meeting guide for the most current financial disclosures
John T Thompson MD
Kaleidoscope: C
Paul E Tornambe MD
Inspire Pharmaceuticals, Inc.: C
Cynthia A Toth MD
Alcon Laboratories, Inc.: P
Bioptigen: S
Genentech: S
Michael T Trese MD
Focus ROP: C,O
Genentech: C
Nu-Vue Technologies, Inc.: C,O
Retinal Solutions, LLC: C,O
Synergetics, Inc.: C
ThromboGenics Inc.: C,O
Laurent Velasque MD
None
Nadia Khalida Waheed MD
Carl Zeiss Meditec: S
Iconic Therapeutics: C
ThromboGenics, Inc.: L
Financial Disclosures
2015 Subspecialty Day | Retina
Yu Wakaatsuki MD
Tien Yin Wong MBBS
Francis S Mah MD
None
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
Abbott Medical Optics Inc.: L
Alcon Laboratories, Inc.: C,S
Allergan: C,L
Bausch + Lomb: C,L
CoDa: C
ForeSight: C
Imprimis: C
Nicox: C
Ocular Therapeutix: C,S
Omeros: C
PolyActiva: C
Shire: C
TearLab: C
John A Wells III MD
Allergan: S
Ampio Pharmaceuticals: 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
Santen, Inc.: S
David F Williams MD
Allergan: C
Genentech: C
Regeneron Pharmaceuticals, Inc.: C
George A Williams MD
Alcon Laboratories, Inc.: C
Allergan, Inc.: C,S
ForSight: C,O
Johnson & Johnson: C
Neurotech: C,O,S
OMIC-Ophthalmic Mutual Insurance
Company: E
OptiMedica: C,O
ThromboGenics: C,O
David J Wilson MD
AGTC: S
Foundation Fighting Blindness: S
National Eye Institute: S
Research to Prevent Blindness: S
Sanofi Fovea: S
Sebastian Wolf MD PhD
Alcon Laboratories, Inc.: C
Allergan: C
Bayer Healthcare Pharmaceuticals: C,L,S
Heidelberg Engineering: C,S
Novartis Pharmaceuticals Corp.: C,S
Optos, Inc.: S
Roche: C
Thomas J Wolfensberger MD
Lihteh Wu MD
Bayer Health: C,L
Charles C Wykoff MD PhD
Alcon Laboratories, Inc.: C,L
Allergan: C,L
Genentech: C,L
Regeneron: C,L
Lawrence A Yannuzzi MD
Genentech: C
Marco A Zarbin MD PhD FACS
Calhoun Vision, Inc.: C
EyEngineering: C
Genentech: C
Helios, KK: C
Hoffman La Roche, Ltd.: C
Makindus: C
Novartis Pharmaceuticals Corp.: C
Ophthotech, Inc.: C
Rutgers University: P
Subspecialty Day
Advisory Committee
William F Mieler MD
Genentech: C
Jonathan B Rubenstein MD
Alcon Laboratories, Inc.: C
Bausch + Lomb: C,L
R Michael Siatkowski MD
National Eye Institute: S
Nicholas J Volpe MD
None
AAO Staff
Christa Fernandez
None
Ann L’Estrange
None
Melanie Rafaty
None
Debra Rosencrance
Donald L Budenz MD MPH
None
Alcon Laboratories, Inc.: C
Ivantis: C
Beth Wilson
Daniel S Durrie MD
Abbott Medical Optics: S
AcuFocus, Inc.: C,L,O,S
Alcon Laboratories, Inc.: L,O,S
Allergan: S
Alphaeon: C,O
Avedro: L,O,S
Strathspey Crown LLC: C,L,O
Wavetec: C,O,P
None
Disclosures current as of 10/9/2015
Check the online program/mobile meeting guide for the most current financial disclosures
None
183
Emergency exits
Escalators
Stairs
Utilities: On columns
Ceiling height: 13’-4”
Low ceiling height: 8’-2”
Columns
2’-6” round,
set on 30’ centers
ENTRANCE
The Academy, Sands Expo and their contractors can
make no warranties as to the accuracy of the floorplans.
The floorplan is not final and is subject to change.
To/From Level 2
Exhibition
To Halls A and B
108 137 140 169 172 201 204 233 236 265 268 297
13 19 42 49 74 81 104 110 135 142 167 174 199 206 231 238 263 270 295
14 18 43 48 75 80 105 109 136 141 168 173 200 205 232 237 264 269 296
15
44 47 76 79
16 17 45 46 77 78 106 107 138 139 170 171 202 203 234 235 266 267 298
Scientific Posters
HALL G
A
1 2 3 4 5 6 7 8 9 10
21 22 23 24 25 26 27 28 29 30
20 19 18 17 16 15 14 13 12 11
41 42 43 44 45 46 47 48 49 50
40 39 38 37 36 35 34 33 32 31
61 62
63 64 65 66 67
68
60 59 58 57 56 55 54 53 52 51
79 80 81 82 83 84 85 86 87 88
78 77 76 75 74 73 72 71 70 69
EXHIBIT FLOOR PLAN
2
1
20'
3
20'
20'
Business Suites
20'
20'
20'
To/From Level 2
Exhibition
To Halls C and D
8
4
20'
7
20'
20'
20'
20'
10'
5
6
9
20'
20'
20'
10'
10'
10'
405
406
407
RETINA SUBSPECIALTY DAY
Sands Expo
Palazzo Ballroom
Nov 13 & 14
402
403
404
EXHIBITS
Sands Expo
Level 1, Hall G
Friday, Nov 13
2015 Subspecialty Day | Retina
Retina Exhibits
AK Vertriebs GmbH 87
Alcon 8, 9, 10
Alimera Sciences 30
Allergan 3
American Society of Retina Specialists A
Avella Specialty Pharmacy 21
Bausch + Lomb 1, 2
Beaver-Visitec International 11
Besse Medical 79
Bryn Mawr Communications 17
Castle Biosciences, Inc. 69
DGH Technology, Inc. 27
Diopsys, Inc. 65
Doctorsoft 18
DORC International, bv/Dutch Ophthalmic, USA 49, 50
Ellex 15
Elsevier 67
FCI Ophthalmics 40
Focus ROP, PLC 55
Genentech 5
Haag-Streit USA 26
Heidelberg Engineering 12, 13, 28, 29
IFA United I-Tech, Inc. 57
Innova Systems, Inc. 16
Insight Instruments, Inc. 51, 52
Intelligent Retina Imaging Systems 86
Iridex 22, 23
Keeler Instruments, Inc. 31
Kowa American Corp. 47
Leiter’s Compounding 64
Lightmed Corp. 82
LKC Technologies, Inc. 41
Lumenis Vision 6
Macular Health 59
MacuLogix, Inc. 81
Mallinckrodt Pharmaceuticals 76
Marasco & Associates, Healthcare Architects &
Consultants 7
McKesson Specialty Health 80
MedOne Surgical, Inc. 48
Nextech 4
Notal Vision 36
Ocular Instruments, Inc. 33
Oculus Surgical, Inc. 61, 62
OCuSOFT, Inc. 68
OD-OS, Inc. 54
OMIC – Ophthalmic Mutual Insurance Company 25
Optos, Inc. 66
Optovue, Inc. 42
Phoenix Clinical, Inc. 56
Pine Pharmaceuticals 53
PODIS 83
Quantel Medical 24
Regeneron Pharmaceuticals 46
Retina Specialist 70
Retinal Physician 34
Second Sight Medical Products, Inc. 78
Sensor Medical Technology 63
SLACK Incorporated 39
Sonomed Escalon 37
Synergetics, Inc. 35
ThromboGenics, Inc., Medical Affairs 58
Topcon Medical Systems 43, 44, 45
USRetina 77
Vindico Medical Education 14
VisionCare Ophthalmic Technologies 38
Visunex Medical Systems 88
Volk Optical, Inc. 32
Wolters Kluwer 60
Zeiss 19, 20
185
186
2015 Subspecialty Day | Retina
Presenter Index
Agarwal, Anita 90
Ambati*, Jayakrishna 138
Avery*, Robert L 118
Baumal*, Caroline R 32
Bernstein*, Paul S 146
Berrocal*, Maria H 7
Blumenkranz*, Mark S 37
Boyer*, David S 58
Bressler, Neil M 110
Brown*, David M 129
Campochiaro*, Peter A 44, 49
Chakravarthy*, Usha 119
Chambers, Wiley Andrew 39
Chang*, Stanley 9
Charles*, Steven 30
Chaudhry, Nauman A 77
Chew, Emily Y 62, 110
Chow*, David R 1
Ciulla*, Thomas A 133
Claes*, Carl C 10
Cousins, Scott W 67
Csaky*, Karl G 154
Cukras, Catherine A 152
Curcio*, Christine 142
Del Priore*, Lucian V 148
Drenser*, Kimberly A 48
Ducournau, Didier H 2
Dugel*, Pravin U 44, 61
Duker*, Jay S 99
Duncan, Jacque L 84
Eckardt*, Claus 29
Ehlers*, Justis P 14
El Rayes*, Ehab N 23
Eliott*, Dean 164
Farah, Michel Eid 71
Ferrone*, Philip J 20
Fishman, Gerald A 46
Flynn, Harry W 114
Fonseca Martins, David 174
Freund*, K Bailey 157
Friedlander, Martin 75
Garg*, Sunir J 28
Gaudric*, Alain 86
Gentile*, Ronald C 45
Gillies, Mark C 110
Gross*, Jeffrey G 56
Haller*, Julia A 22
Han*, Dennis P 15
Heier*, Jeffrey S 60, 110
Hirakata, Akito 159
Ho*, Allen C 117
Ip*, Michael S 120
Jackson*, Timothy L 72
Johnson*, Mark W 123
Kaiser*, Peter K 79, 110
Kaiser*, Richard S 162
Kim*, Judy E 81
Kitchens*, John W 167
Kunimoto*, Derek Y 171
Kuppermann*, Baruch D 116
Kurimoto*, Yasuo 127
Larsen*, Michael 64
Ledesma-Gil, Gerardo 174
Li, Xiaoxin 68
Loewenstein*, Anat 98
Ma, Zhizhong 45
MacCumber*, Mathew W 21
Machida, Yumiko 174
Maguire, Albert M 110
Mahmoud*, Tamer H 174
Moshfeghi*, Andrew A 112
Moshfeghi*, Darius M 34
Mullins, Robert F 145
Murray*, Timothy G 26
*Indicates that the presenter has financial interest.
No asterisk indicates that the presenter has no financial interest.
Ohji*, Masahito 169
Ohno-Matsui, Kyoko 89
Oshima*, Yusuke 3
Packo*, Kirk H 11
Parke II*, David W 41
Pieramici*, Dante 13
Pollack*, John S 25
Prenner*, Jonathan L 5
Regillo*, Carl D 110
Rich III, William L 38
Riemann*, Christopher D 16
Rosenfeld, Philip J 82
Ryan Jr*, Edwin Hurlbut 17
Sadda*, Srinivas R 97
Sarraf*, David 95
Schmidt-Erfurth*, Ursula M 105
Schwartz, Steven D 126
Shah*, Gaurav K 18
Shields, Carol L 103
Singh*, Rishi P 121
Spaide*, Richard F 102
Sparrow, Janet R 140
Stalmans*, Peter W 122
Stewart*, Jay M 174
Stewart*, Michael W 31
Stone, Edwin M 65
Thompson*, John T 12
Tornambe*, Paul E 172
Toth*, Cynthia A 45
Velasque, Laurent 45
Wakatsuki, Yu 45
Wells III*, John A 35, 54
Williams*, David F 33
Williams*, George A 43
Wong*, Tien Yin 66
Wykoff, Charles C 110
Zarbin*, Marco A 124