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Uveitis 2012 The Challenges Continue...

But the Future Is Bright


Program Directors
C Stephen Foster MD and Quan Dong Nguyen MD

In conjunction with the American Uveitis Society


McCormick Place Chicago, Illinois Saturday, November 10, 2012 Presented by: The American Academy of Ophthalmology

Uveitis 2012 Planning Group C Stephen Foster MD Program Director Quan Dong Nguyen MD Program Director Debra A Goldstein MD Russell W Read MD PhD Eric Suhler MD

Subspecialty Day Advisory Committee William F Mieler MD Associate Secretary Donald L Budenz MD MPH Daniel S Durrie MD Robert S Feder MD Leah Levi MBBS R Michael Siatkowski MD Jonathan B Rubenstein MD Secretary for Annual Meeting

Staff Melanie R Rafaty CMP, Director, Scientific Meetings Ann LEstrange, Scientific Meetings Specialist Brandi Garrigus, Presenter Coordinator Debra Rosencrance CMP CAE, Vice President, Meetings & Exhibits Patricia Heinicke Jr, Editor Mark Ong, Designer Gina Comaduran, Cover Design

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

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2012 Subspecialty Day|Uveitis

Dear Colleague: On behalf of the American Academy of Ophthalmology and the American Uveitis Society, it is our great pleasure to welcome you to Chicago and to Uveitis 2012: The Challenges Continue... But the Future Is Bright. We hope that you will find this years Uveitis Subspecialty Day program exciting and beneficial to your practice and your patients. We are especially honored to have planned this event, which we hope will provide clinicians with practical information that can be used to treat ocular inflammation. The international faculty for this meeting have been carefully selected to provide you with the most up-to-date and pertinent information on the current state of the art for diagnosis and treatment of ocular inflammatory diseases and uveitis, and most particularly, information gleaned from evidence-based medicine exercises as a consequence of an extensive review of the worlds peer-reviewed medical literature. This years program presentations will emphasize the gaps in the diagnosis and management of uveitis and ocular inflammatory diseases. What challenges do we face in managing scleritis, peripheral ulcerative keratitis, retinal vasculitis, and anterior, intermediate, and posterior uveitis, among others? What should we know, as clinician scientists caring for patients with uveitis, that we either do not know or are misinformed about? We will also emphasize again the principles of diagnosis of ocular inflammatory disorders in order to initiate appropriate, disease-directed evaluations. What happens if appropriate and timely evaluation and referral are not conducted? Based on currently recommended preferred practice patterns from recognized inflammatory disease subspecialty bodies, some of the faculty will discuss the principles of steroidal and nonsteroidal therapies in the management of ocular inflammatory diseases, as well as the important and appropriate role of immunomodulatory therapy for patients with selected, specific ocular inflammatory diseases and also for patients with steroid-dependent inflammation. Others will describe the potentially new therapeutic options and pharmacologic agents that are coming into use in our clinics, and the role of surgical management of ocular inflammatory disorders. Based on comments from past attendees, we have provided more time for Case Discussion sessions, where you will see, live and in person, how uveitis experts approach challenging cases! We are very grateful for the expertise that the faculty members bring to the program. In an effort to put together innovative and interesting Subspecialty Day Meetings in the future, we sincerely request that you assist us by completing the evaluation. We will carefully review all comments to better understand your needs, so please indicate the strengths and shortcomings of todays program. Again, we welcome you to Uveitis 2012: The Challenges Continue... But the Future Is Bright. Please share with us any of your comments, either in the evaluation, in an e-mail at a later time, or directly to one of us during conversation. We hope to make future programs even better and more beneficial so that our patients with uveitis and ocular inflammatory diseases around the world will get the best possible care. With warmest regards,

C Stephen Foster MD Program Director Quan Dong Nguyen MD MSc Program Director

2012 Subspecialty Day|Uveitis 

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Uveitis 2012 Contents

Section I: Section II: Section III: Section IV: Section V: Section VI: Section VII: Section VIII: Section IX:

Program Directors Welcome Letter ii CMEiv Faculty Listingvi Program Schedulexiii The Uveitis Puzzle for the Non-uveitis Specialist 1 Uveitis Potpourris 10 External Ocular Inflammatory Diseases 15 Infectious UveitisHow Can One Tell if the Problem Is Microbial? 23 On the Special Matter of Pediatric Uveitis 28 Puzzling White DotsWhats a Doctor to Do? 31 The Puzzling Matter of Treatment-Resistant Uveitis 42 Potential New Therapies for UveitisPharmacologic Agents in Development 46 Late Breaking News 50 Faculty Financial Disclosure 51 Presenter Index 55

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

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2012 Subspecialty Day|Uveitis

CME Credit

Academys CME Mission Statement


The purpose of the American Academy of Ophthalmologys Continuing Medical Education (CME) program is to present ophthalmologists with the highest quality lifelong learning opportunities that promote improvement and change in physician practices, performance or competence, thus enabling such physicians to maintain or improve the competence and professional performance needed to provide the best possible eye care for their patients. The American Medical Association has determined that non U.S. licensed physicians who participate in this CME activity are eligible for AMA PRA Category 1 Credits TM. Attendees registered as exhibitors, spouses or guests are not eligible to receive CME credit.

2012 Uveitis Subspecialty Day CME Credit


The American Academy of Ophthalmology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Academy of Ophthalmology designates this live activity for a maximum of 7 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Scientific Integrity and Disclosure of Financial Interest


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

2012 Uveitis Subspecialty Day Meeting Learning Objectives


Upon completion of this activity, participants should be able to: Identify the challenges in recognizing the various forms of ocular inflammatory diseases, including cicatricial pemphigoid, retinal vasculitis, and anterior, intermediate, and posterior uveitis Construct a differential diagnosis for various forms of uveitis Classify the principles of diagnosis of ocular inflammatory disorders in order to initiate appropriate, disease-directed evaluations Identify the important and appropriate role of immunomodulatory therapy for patients with selected, specific ocular inflammatory diseases, and also for patients with steroid-dependent inflammation Describe the various gaps that currently exist in the management of uveitis and ocular inflammatory diseases such as failure to recognize the sight-saving benefits of pursuing durable remission, failure to understand the paradigm shift away from corticosteroid monotherapy to a stepladder algorithm, and failure to recognize the elements essential to successful control of uveitic glaucoma, among others Describe the potential new treatments for uveitis and ocular inflammatory diseases, including selected therapeutic agents in development, based on recent and current work and studies

Attendance Verification for CME Reporting


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

CME Credit Reporting


Grand Concourse Level 2.5; Academy Resource Center, Hall A - Booth 508 Attendees whose attendance has been verified (see above) at the 2012 Joint Meeting can claim their CME credit online during the meeting. Registrants will receive an e-mail during the meeting with the link and instructions on how to claim credit. Onsite, you may report credits earned during Subspecialty Day and/or the Joint Meeting at the CME Credit Reporting booth. Academy Members: The CME credit reporting receipt is not a CME transcript. CME transcripts that include 2012 Joint Meeting credits entered onsite will be available to Academy members on the Academys website beginning Dec. 3, 2012. NOTE: CME credits must be reported by Jan. 16, 2013. After the 2012 Joint Meeting, credits can be claimed at www.aao.org/cme.

2012 Uveitis Subspecialty Day Meeting Target Audience


The intended audience for this program includes general ophthalmologists, comprehensive ophthalmologists, uveitis specialists, and other ophthalmologic subspecialists (cornea, retina, etc.) and allied health personnel who are involved in the management of patients with uveitis and ocular inflammatory diseases.

2012 Subspecialty Day|Uveitis

CME Credit

The Academy transcript cannot list individual course attendance. It will list only the overall credits spent in educational activities at Subspecialty Day and/or the Joint Meeting. Nonmembers: The Academy will provide nonmembers with verification of credits earned and reported for a single Academysponsored CME activity, but it does not provide CME credit transcripts. To obtain a printed record of your credits, you must report your CME credits onsite at the CME Credit Reporting booths.

Proof of Attendance
The following types of attendance verification will be available during the Joint Meeting and Subspecialty Day for those who need it for reimbursement or hospital privileges, or for nonmembers who need it to report CME credit: CME credit reporting/proof-of-attendance letters Onsite Registration Form Instruction Course Verification Visit the Academys website for detailed CME reporting information.

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Faculty

No photo available

Massimo Accorinti MD PhD


Rome, Italy MD, PhD Sapienza Universit di Roma

Esen K Akpek MD
Baltimore, MD Associate Professor of Ophthalmology Johns Hopkins University School of Medicine Director, Ocular Surface Diseases and Dry Eye Clinic Division of Cornea and External Diseases The Wilmer Eye Institute

Hassan A Al-Dhibi MD
Riyadh, Saudi Arabia Vitreoretinal & Uveitis Senior Academic Consultant King Khald Eye Specialist Hospital (KKESH) Clinical Assistant Professor King Saud University Medical Center

Nisha Acharya MD
San Francisco, CA Associate Professor F I Proctor Foundation University of California, San Francisco

Sofia N Androudi MD PhD Thomas A Albini MD


Coral Gables, FL Associate Professor of Clinical Ophthalmology Bascom Palmer Eye Institute Thessaloniki, Greece Lecturer Larissa University Hospital, Greece

Yonca A Akova MD
Ankara, Turkey Professor of Ophthalmology Bayindir Kavaklidere Hospital Chief of Ophthalmology Bayindir Kavaklidere Hospital

Lourdes Arellanes MD
Mexico City, DF, Mexico Chief, Inflammatory Eye Disease Clinic Asociacin Para Evitar la Ceguera en Mxico Professor of Ophthalmology Universidad Nacional Autnoma de Mxico

2012 Subspecialty Day|Uveitis

Faculty Listing

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No photo available

William Ayliffe MBBS


London, England Professor of Medicine Gresham College London

Neal P Barney MD
Madison, WI Professor of Ophthalmology and Visual Sciences University of Wisconsin School of Medicine and Public Health

Laure E Caspers MD
Brussels, Belgium

Chi-Chao Chan MD Alay S Banker MD


Ahmedabad, India Director, Vitreoretinal Surgeon, and Uveitis Specialist Bankers Retina Clinic and Laser Centre Bethesda, MD Chief, Immunopathology Section National Eye Institute Head, Histology Core National Eye Institute

Rubens Belfort Jr MD PhD


So Paulo, SP, Brazil Head Professor of Ophthalmology Vision Institute, Hospital So Paulo, Federal University of So Paulo Member, Academia Ophthalmologica Internationalis

Talin Barisani-Asenbauer MD
Vienna, Austria Associate Professor Medical University of Vienna Scientific Director Laura Bassi Centre of Expertise for Ocular Inflammation and Infection

Soon-Phaik Chee MD
Singapore, Singapore Senior Consultant and Head of Ocular Inflammation and Immunology Singapore National Eye Centre Associate Professor Department of Ophthalmology National University of Singapore

Bahram Bodaghi MD PhD


Paris, France Professor of Ophthalmology University of Paris VI (Pierre and Marie Curie)

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Faculty Listing

2012 Subspecialty Day|Uveitis

No photo available

David S Chu MD
Newark, NJ Associate Professor of Ophthalmology New Jersey Medical School University of Medicine and Dentistry, New Jersey

Janet Louise Davis MD


Miami, FL Professor of Ophthalmology University of Miami Miller School of Medicine Director, Uveitis Service Bascom Palmer Eye Institute

C Stephen Foster MD
Cambridge, MA Clinical Professor of Ophthalmology Harvard Medical School Founder and President Massachusetts Eye Research and Surgery Institution

Cristobal A Couto MD
Buenos Aires, Argentina Professor of Ophthalmology University of Buenos Aires Assistant Professor of Ophthalmology Catholic University of Salta

James Philip Dunn Jr MD


Baltimore, MD Associate Professor of Ophthalmology The Wilmer Eye Institute The Johns Hopkins School of Medicine

Debra A Goldstein MD
Chicago, IL Professor of Ophthalmology University of Illinois at Chicago

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

Yosuf El Shabrawi MD
Klagenfurt, Austria MD, General Hospital Klagenfurt

Amod K Gupta MBBS


Panchkula, Haryana, India Professor of Ophthalmology Post Graduate Institute of Medical Education and Research Professor of Ophthalmology Advanced Eye Centre, PGI, Chandigarh

2012 Subspecialty Day|Uveitis

Faculty Listing

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Vishali Gupta MBBS


Chandigarh, UT, India Professor of Ophthalmology Post Graduate Institute of Medical Education and Research

Henry J Kaplan MD
Louisville, KY Evans Professor of Ophthalmology University of Louisville Chairman, Department of Ophthalmology and Visual Sciences University of Louisville

Erik Letko MD
Littleton, CO Physician and Surgeon Corneal Consultants of Colorado

John J Huang MD
Bethany, CT Associate Professor of Ophthalmology Yale University

Careen Yen Lowder MD PhD John H Kempen MD


Philadelphia, PA Associate Professor of Ophthalmology and Epidemiology Perelman School of Medicine University of Pennsylvania Director, Ocular Inflammation Service & Ophthalmic Epidemiology Scheie Eye Institute Cleveland, OH Full Professional Staff Cleveland Clinic Cole Eye Institute

Douglas A Jabs MD MBA


New York, NY Professor and Chair, Department of Ophthalmology Mount Sinai School of Medicine CEO, Faculty Practice Associates Mount Sinai School of Medicine

Elisabetta Miserocchi MD
Milano, Italy Ophthalmologist University Vita-Salute Scientific Institute San Raffaele

Phuc Lehoang MD PhD


Paris, France Professor and Chair Department of Ophthalmology Universite Pierre et Marie Pitie-Salpetriere Hospital

Faculty Listing

2012 Subspecialty Day|Uveitis

Quan Dong Nguyen MD


Baltimore, MD Associate Professor of Ophthalmology Wilmer Eye Institute Diseases of the Retina and Vitreous, and Uveitis Johns Hopkins University School of Medicine

Sumru Onal MD
Istanbul, Turkey Associate Professor of Ophthalmology Department of Ophthalmology V K Foundation American Hospital

Narsing A Rao MD
Los Angeles, CA Professor of Ophthalmology Doheny Eye Institute University of Southern California

Emil Mitchel Opremcak MD Robert B Nussenblatt MD


Bethesda, MD Chief Laboratory of Immunology National Eye Institute Associate Director NIH Center for Human Immunology National Institutes of Health Columbus, OH Clinical Associate Professor of Ophthalmology The Ohio State University

S R Rathinam MD PhD
Tamil Nadu, India Professor and Head of the Uveitis Department Aravind Eye Hospital & PG Institute of Ophthalmology Professor of Ophthalmology The Tamil Nadu Dr MGR Medical University, Chennai

Victor L Perez MD
Miami, FL Associate Professor of Ophthalmology, Microbiology & Immunology Bascom Palmer Eye Institute University of Miami Miller School of Medicine

Annabelle A Okada MD
Tokyo, Japan Professor of Ophthalmology Kyorin University School of Medicine

Russell W Read MD PhD


Birmingham, AL Associate Professor of Ophthalmology and Pathology University of Alabama at Birmingham Executive Secretary American Uveitis Society

2012 Subspecialty Day|Uveitis

Faculty Listing

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Maite Sainz de la Maza MD


Barcelona, Spain Associate Professor of Ophthalmology Hospital Clinico of Barcelona Professor of Ophthalmology Central University of Barcelona

Ariel Schlaen MD
Buenos Aires, Argentina Staff Member Hospital Universitario Austral Staff Member Hospital de Clnicas, Universidad de Buenos Aires

Ronald E Smith MD
Los Angeles, CA Professor and Chairman Department of Ophthalmology University of Southern California Keck School of Medicine Doheny Eye Institute

No photo available

C Michael A Samson MD
New York, NY Codirector, Uveitis Service Department of Ophthalmology The New York Eye & Ear Infirmary Assistant Professor of Ophthalmology New York Medical College

Hatice N Sen MD
Bethesda, MD Director, Uveitis and Ocular Immunology Fellowship Program National Eye Institute National Institutes of Health Associate Clinical Professor of Ophthalmology The George Washington University

Lucia Sobrin MD
Boston, MA Assistant Professor of Ophthalmology Harvard Medical School Attending Physician Retina and Uveitis Services Massachusetts Eye and Ear Infirmary

Virender S Sangwan MBBS


Hyderabad, Andhra Pradesh, India Dr. L.V. Prasad Eye Institute

Sunil K Srivastava MD Justine R Smith MD


Portland, OR Associate Professor of Ophthalmology Oregon Health & Science University Cleveland, OH Staff Physician Cole Eye Institute Cleveland Clinic Foundation

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Faculty Listing

2012 Subspecialty Day|Uveitis

Eric Suhler MD
Portland, OR Associate Professor of Ophthalmology Oregon Health & Science University Chief of Ophthalmology Portland VA Medical Center

Jennifer E Thorne MD PhD


Baltimore, MD Associate Professor of Ophthalmology Johns Hopkins University School of Medicine Associate Professor of Epidemiology Johns Hopkins University Bloomberg School of Public Health

Albert T Vitale MD
Salt Lake City, UT Professor of Ophthalmology Moran Eye Center University of Utah

Johnny Tang MD
Cleveland, OH Director Retina and Uveitis Service Louis Stokes Cleveland VA Medical Center Assistant Professor University Hospitals Case Medical Center

Steven Yeh MD Harvey S Uy MD


Quezon City, Philippines Clinical Associate Professor of Ophthalmology University of the Philippines Manila Consultant Uy Eye Clinics Atlanta, GA Assistant Professor of Ophthalmology Emory Eye Center Emory University School of Medicine

Manfred Zierhut MD
Tbingen, Germany Professor of Ophthalmology University of Tbingen

Joseph Tauber MD
Kansas City, MO Medical Director Tauber Eye Center

Russell N Van Gelder MD PhD


Seattle, WA Boyd K Bucey Memorial Chair, Professor, and Chairman of Ophthalmology University of Washington School of Medicine Director UW Medicine Eye Institute

2012 Subspecialty Day|Uveitis 

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Uveitis 2012: The Challenges Continue... But the Future Is Bright


In conjunction with the American Uveitis Society
SATURDAY, NOVEMBER 10, 2012
7:00 AM 7:50 AM 7:55 AM REGISTRATION/ MATERIAL PICKUP/ CONTINENTAL BREAKFAST Welcome and Opening Remarks Pre-test C Stephen Foster MD* Quan Dong Nguyen MD* C Stephen Foster MD*

Section I:
8:00 AM 8:10 AM 8:20 AM 8:30 AM 8:40 AM

The Uveitis Puzzle for the Non-uveitis Specialist


Moderator: Alay S Banker MD How to Consider a Uveitic Entity and When to Refer a Patient With Uveitis How to Treat: A Stepladder Algorithm How to Orchestrate Comanagement for Immunomodulatory Therapy Managing Glaucoma in Patients With Uveitis Therapeutic Vitrectomy Douglas A Jabs MD MBA* Sofia N Androudi MD PhD Justine R Smith MD* Sumru Onal MD Emil Mitchel Opremcak MD 1 2 4 5 8

Section II: Uveitis Potpourris


8:50 AM 9:00 AM 9:10 AM 9:20 AM Moderator: Harvey S Uy MD* Recurrent Nongranulomatous Anterior Uveitis: E&M Pars Planitis: What to Do When the Intermediate Uveitis Is Idiopathic Retinal Vasculitis Case Presentations and Panel Discussion #1 (With Audience Response) Managing All the Uveitis Coming to Your Office Moderator: James Philip Dunn Jr MD Panelists: Massimo Accorinti MD PhD, Victor L Perez MD*, Harvey S Uy MD*, Albert T Vitale MD*, Manfred Zierhut MD* REFRESHMENT BREAK and JOINT MEETING EXHIBITS Jennifer E Thorne MD PhD* Janet Louise Davis MD* William Ayliffe MBBS* 10 11 14

9:50 AM

Section III: External Ocular Inflammatory Diseases


10:20 AM 10:30 AM 10:40 AM 10:50 AM Moderator: Maite Sainz de la Maza MD* Chronic Conjunctivitis: Is It Ocular Cicatricial Pemphigoid? Peripheral Ulcerative Keratitis: Moorens, Terriens, or Something More Ominous? Is Keratoconjunctivitis Sicca an Inflammatory Disease? Case Presentations and Panel Discussion #2 (With Audience Response) Inflammation of External Ocular Structures Moderator: Neal P Barney MD* Panelists: Talin Barisani-Asenbauer MD, Erik Letko MD, Maite Sainz de la Maza MD*, C Michael A Samson MD*, Joseph Tauber MD* C Stephen Foster MD* Virender S Sangwan MBBS Esen K Akpek MD* 15 17 19

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

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Program Schedule Advocating for Patients LUNCH and JOINT MEETING EXHIBITS

2012 Subspecialty Day|Uveitis

11:20 AM 11:25 PM

Russell N Van Gelder MD PhD*21

Section IV:
12:20 PM 12:30 PM 12:40 PM

Infectious UveitisHow Can One Tell if the Problem Is Microbial?


Moderator: Russell N Van Gelder MD PhD* Herpes, Syphilis, and Tuberculosis Infectious Uveitis, the Most Common Problem Worldwide: What Else to Consider? Case Presentations and Panel Discussion #3 (With Audience Response) Infectious Uveitis: How Not to Miss It Moderator: Emmett T Cunningham Jr MD PhD MPH Panelists: Soon-Phaik Chee MD*, John J Huang MD*, Annabelle A Okada MD*, Ariel Schlaen, Johnny Tang MD, Steven Yeh MD Amod K Gupta MBBS Rubens Belfort Jr MD PhD* 23 26

Section V:
1:10 PM 1:20 PM 1:30 PM

On the Special Matter of Pediatric Uveitis


Moderator: Lucia Sobrin MD Differential Diagnosis of Uveitis in the Pediatric Population: Sarcoid, Tubulointerstitial Nephritis and Uveitis Syndrome, and Beyond Juvenile Idiopathic Arthritis-Associated Uveitis: When to Move Off Corticosteroid Therapy? Case Presentations and Panel Discussion #4 (With Audience Response) How to Evaluate a Pediatric Patient With Uveitis Moderator: Bahram Bodaghi MD PhD* Panelists: Thomas A Albini MD*, Lourdes Arellanes MD, Careen Yen Lowder MD PhD*, Elisabetta Miserocchi MD*, Lucia Sobrin MD Debra A Goldstein MD* Laure E Caspers MD 28 29

Section VI:
2:00 PM 2:10 PM 2:20 PM

Puzzling White DotsWhats a Doctor to Do?


Moderator: Hassan A Al-Dhibi MD Is It Birdshot Retinochoroidopathy, and If So, How Should I Treat It? What About Serpiginous Choroiditis? Is It Autoimmune? Or Herpes? Or Tuberculosis? Punctate Inner Choroidopathy, Presumed Ocular Histoplasmosis Syndrome, Multifocal Choroiditis, and Panuveitis: Does Each of These Require Immunomodulatory Therapy? Albert T Vitale MD* Narsing A Rao MD Phuc Lehoang MD PhD* 31 37 38

2:30 PM 2:40 PM

Acute Posterior Multifocal Placoid Pigment Epitheliopathy and Henry J Kaplan MD* Ampiginous Choroiditis: Should These Be Treated, and If So, With What? Case Presentations and Panel Discussion #5 (With Audience Response) I Hate Those White Dots! Moderator: Russell W Read MD PhD* Panelists: Nisha Acharya MD*, Hassan A Al-Dhibi MD, Henry J Kaplan MD*, S R Rathinam MD PhD, Sunil K Srivastava MD REFRESHMENT BREAK and JOINT MEETING EXHIBITS

40

3:10 PM

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

2012 Subspecialty Day|Uveitis

Program Schedule

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Section VII:
3:40 PM 3:50 PM 4:00 PM 4:10 PM

The Puzzling Matter of Treatment-Resistant Uveitis


Moderator: Yosuf El Shabrawi MD* Is It Infectious, Autoimmune, or Malignant? The Importance of Diagnostic Surgery Current Concepts in Managing Ocular Malignancy: What Are Our Colleagues in Neuro-Oncology Doing? On the Matter of Autoimmune Retinopathy: A Diagnostic and Therapeutic Puzzle Case Presentations and Panel Discussion #6 (With Audience Response) What to Do When There Is No Response Moderator: Quan Dong Nguyen MD* Panelists: Yonca A Akova MD, Cristobal A Couto MD*, Yosuf El Shabrawi MD*, Vishali Gupta MBBS*, John H Kempen MD* Russell N Van Gelder MD PhD*42 Chi-Chao Chan MD Hatice N Sen MD 43 44

Section VIII: Potential New Therapies for UveitisPharmacologic Agents in Development


4:40 PM 4:50 PM 5:00 PM Moderator: Ronald E Smith MD* Systemic Pharmacologic Agents in Development for Uveitis: Voclosporin, Adalimumab, and AIN457 Local Pharmacologic Agents in Development for Uveitis: Sirolimus and Others Novel Drug Delivery Approaches for Uveitis: Iontophoresis and Others Eric Suhler MD* Quan Dong Nguyen MD* David S Chu MD* 46 47 48

Section IX:
5:10 PM 5:20 PM 5:21 PM

Late Breaking News


Top 10 Mishaps in Managing Uveitis Closing Remarks and Post-test ADJOURN Robert B Nussenblatt MD C Stephen Foster MD* Quan Dong Nguyen MD* 50

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

2012 Subspecialty Day|Uveitis

Section I: The Uveitis Puzzle for the Non-uveitis Specialist

How to Consider a Uveitic Entity and When to Refer a Patient With Uveitis
Douglas A Jabs MD MBA
Selected Readings
1. Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behets syndrome. N Engl J Med. 1990; 322:281-285. 2. Rosenbaum JT, Wernick R. The utility of routine screening of patients with uveitis for system lupus erythematosus or tuberculosis. Arch Ophthalmol. 1990; 108:1291-1293. 3. Dana MR, Merayo-Lloves J, Schaumberg DA, Foster CS. Prognosticators for visual outcome in sarcoid uveitis. Ophthalmology 1996; 103:1846-1853. 4. McCannel CA, Holland GN, Helm CJ, et al. Causes of uveitis in the general practice of ophthalmology: UCLA community based uveitis study group. Am J Ophthalmol. 1996; 121:35-46. 5. Rothova A, Suttorp-Van Schulten MS, Frits Treffers W, Kijlstra A. Causes and frequency of blindness in patients with intraocular inflammatory disease. Br J Ophthalmol. 1996; 80:332-336. 6. Thorne JE, Jabs DA, Peters GB, Hair D, Dunn JP, Kempen JH. Birdshot retinochoroidopathy: ocular complications and visual impairment. Am J Ophthalmol. 2005; 140:45-51. 7. Bykhovskaya I, Thorne JE, Kempen JH, Dunn JP, Jabs DA. VogtKoyanagi-Harada disease: clinical outcomes. Am J Ophthalmol. 2005; 140:674-678. 8. The Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data: results of the first international workshop. Am J Ophthalmol. 2005; 140:509-516. 9. Da Silva JA, Jacobs JW, Kirwan JR, et al. Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis. 2006; 65:285-293. 10. Thorne JE, Wittenberg SE, Jabs DA, Peters GB, Kedhar SR, Dunn JP. Multifocal choroiditis with panuveitis: incidence of ocular complications and loss of visual acuity. Ophthalmology 2006; 113:2310-2316. 11. Thorne JE, Jabs DA, Kedhar SR, Peters GB, Dunn JP. Loss of visual field among patients with birdshot chorioretinopathy. Am J Ophthalmol. 2008; 145:23-28. 12. Kempen JH, Daniel E, Dunn JP, et al. Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive therapy: retrospective cohort study. Brit Med J. 2009; 339:b2480. 13. Zamecki KJ, Jabs DA. HLA typing in uveitis: use and misuse. Am J Ophthalmol. 2010; 149:189-193. 14. Kempen JH, Altaweel MM, Holbrook JT, et al. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Ophthalmology 2011; 118:1916-1926.

Section I: The Uveitis Puzzle for the Non-uveitis Specialist

2012 Subspecialty Day|Uveitis

How to Treat: A Stepladder Algorithm


Sofia Androudi MD PhD

I. Goals of Therapy in Patients With Uveitis A. Eliminate ocular inflammation B. Reduce ocular and systemic morbidity We suggest a stepladder, algorithmic approach to the treatment of noninfectious uveitis. The process of deciding which medication to choose for treating uveitis is based upon a multitude of factors. Some of these factors include age, sex, social and past medical history, compliance factors, and most importantly, the specific ocular inflammatory disease. The administration of these medications and the monitoring of these patients becomes a joint effort between the ophthalmologist and multiple subspecialists (rheumatology, oncology, and hematology). II. The First Step A. The first step for many patients with ocular inflammation begins with the initiation of corticosteroid treatment; this may be dispensed topically, through local injection, or systemically. Corticosteroids are often started because they are usually able to control inflammation quickly. Although excellent at quelling inflammation initially, oftentimes these agents are not curative, as many times patients are unable to completely wean off corticosteroid therapy without having a recurrence of their uveitis. B. Why not use steroids as monotherapy to control the ocular inflammation? 1. Steroid complications a. Nonocular i. Endocrine (adrenal insufficiency, Cushing syndrome, growth failure, menstrual disorders) ii. Neuropsychiatric (pseudotumor cerebri, insomnia, mood swings, psychosis) iii. Gastrointestinal (peptic ulcer, intestinal perforation) iv. Musculoskeletal (osteoporosis, aseptic hip necrosis) v. Cardiovascular (hypertension, sodium and fluid retention) vi. Metabolic (secondary diabetes mellitus, obesity, hyperlipidemia) vii. Dermatologic (acne, striae, hirsutism) viii. Immunologic (impaired inflammatory response, delayed tissue healing)

b. Ocular i. Cataract ii. Glaucoma iii. Central serous retinopathy iv. Susceptibility to infection

2. Steroid limitations: Poor outcomes as monotherapy in ophthalmology for: a. Adamantiades-Behet disease b. Juvenile idiopathic arthritis (JIA) c. Wegener granulomatosis d. Serpiginous e. Birdshot

III. The Second Step The next step in the stepladder algorithm is the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Treatment with these drugs requires periodic monitoring of kidney and liver function, and in some patients gastrointestinal prophylaxis. If the patient continues to have chronic or recurrent active inflammation, a more aggressive approach in terms of therapy is required, with induction of immunomodulatory agents. The emotional transition to the induction of chemotherapy for most patients, as well as for many physicians, can be the most formidable challenge to the achievement of corticosteroid-free durable remission. The choice of chemotherapeutic agents is case specific and escalates in a stepwise approach. The chosen drug should offer the most favorable side-effect profile and efficacy for the patients specific ocular disease. Once treatment is initiated, the patient must be consistently monitored to safeguard against toxicity and intolerable side effects. As needed, it may be necessary to titrate the dosage, add a second or a third agent, or discontinue the drug altogether in case of low tolerance or efficacy. IV. Current Status The vast majority of the worlds ophthalmologists do not recommend or use immunomodulatory therapy for their patients with progressive, blinding, inflammatory eye disease. V. Reasons for Slow Acceptance A. Wrong association with risks and side effects of cancer therapy B. Unfamiliarity of the therapeutic index of immunosuppressive therapy for the treatment of autoimmune and ocular inflammatory disease

2012 Subspecialty Day|Uveitis

Section I: The Uveitis Puzzle for the Non-uveitis Specialist XI. Key Principles

C. Inexperience with immunosuppressive drugs D. Reserving immunomodulatory treatment for severe, endstage disease or when complications of steroids have developed E. Not FDA approved/off-label use VI. Absolute Indications for Immunomodulatory Therapy A. Adamantiades-Behets disease with retinal involvement B. JIA C. Vogt-Koyanagi-Harada D. Necrotizing scleritis E. Wegener granulomatosis F. Polyarteritis nodosa G. Relapsing polychondritis H. Ocular cicatricial pemphigoid I. Sympathetic ophthalmia VII. Relative Indications

A. Close monitoring of patient: Before therapy and at 1 to 6-8 weeks intervals B. Periodic complete hemograms (differential and platelet counts) C. Avoid suppressing leucocytes <3500 c/l XII. The Future A. Other therapeutic approaches B. Blockade of chemokine receptors, adhesion molecules, complement components, and transcription factors regulating the inflammatory response A. Immunosuppressive and immunomodulatory agents play an important role in the management of ocular inflammatory disease. B. They should be administered by those appropriately trained in the use of such agents. C. They may potentially be safer than long-term corticosteroid therapy. D. The newer biological agents hold promise. E. Uncertainties of long-term safety F. Cost issues G. More studies will elucidate some of these unknowns.

XIII. Summary

A. Intermediate uveitis B. Severe vasculitis C. Severe chronic iridocyclitis A. Intermediate uveitis in children B. Sarcoid-associated uveitis inadequately responsive to steroid C. Keratoplasty with multiple rejections IX. Key Principles of Immunomodulatory Treatment

VIII. Possible Indications

Selected Readings
1. Foster CS, Raizman MB. Therapeutic response to systemic immunosuppressive chemotherapy agents in patients with Behcets syndrome effecting the eyes. In ODuffy J, ed. Behets Disease: Basic and Clinical Aspects. New York: Marcel Dekker; 1991:581-588. 2. Foster CS, Vitale AT. Immunosuppressive chemotherapy. In Foster CS, Vitale AT, eds. Diagnosis and Treatment of Uveitis. Philadelphia: WB Saunders; 2002:177-214. 3. Durrani K, Zakka FR, Ahmed M, Memon M, Siddique SS, Foster CS. Systemic therapy with conventional and novel immunomodulatory agents for ocular inflammatory disease. Surv Ophthalmol. 2011; 56:474-510. 4. Galor A, Jabs DA, Leder HA, et al. Comparison of antimetabolite drugs as corticosteroid-sparing therapy for noninfectious ocular inflammation. Ophthalmology 2008; 115:1826-1832. 5. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000; 130:492-513.

A. Do No Harm!!!!! B. Use immunosuppressive agents only with appropriate training and expertise. C. Carefully discuss risks and benefits with the patient and family members. D. Exclude infectious or other treatable causes. E. Use a stepladder algorithm. F. Begin early enough. G. Start with low dose and titrate up. H. Collaborate. X. How to Decide? The choice of immunosuppressive is individualized. A. Clinical condition and systemic associations B. Safety and efficacy C. Medical status D. Experience with drug E. Access and cost

Section I: The Uveitis Puzzle for the Non-uveitis Specialist

2012 Subspecialty Day|Uveitis

How to Orchestrate Comanagement for Immunomodulatory Therapy


Justine R Smith MD
I. Refer to a uveitis specialist for advice early and often. A. Academy ophthalmologist directory: www.aao .org/find_eyemd.cfm?&CFID=23517065 &CFTOKEN=48810696 B. American Uveitis Society uveitis specialist directory: www.uveitissociety.org/pages/specialists.html C. Massachusetts Eye Research and Surgery Institution uveitis specialist directory: www.uveitis.org/ patients/list-of-specialists II. Identify an appropriately qualified local physician who will work with you. A. Uveitis without systemic association 1. Treatment with antimetabolite: rheumatologist 2. Treatment with calcineurin inhibitor: transplant specialist 3. Treatment with alkylating agent: rheumatologist + reproductive medicine specialist 4. Treatment with tumor necrosis factor blocker: rheumatologist B. Uveitis with systemic disease association 1. Seronegative spondyloarthropathy: rheumatologist 2. Sarcoidosis: pulmonologist or rheumatologist 3. Inflammatory bowel disease: gastroenterologist 4. Behet disease: rheumatologist 5. Multiple sclerosis: neurologist 6. Juvenile idiopathic arthritis-associated uveitis: pediatric rheumatologist or pediatrician 7. Tubulointerstitial uveitis and nephritis syndrome: pediatric nephrologist or pediatrician A. Coexistent infectious disease (eg, tuberculosis, herpes virus infection, human immunodeficiency virus infection): Consult infectious disease specialist. B. Pregnancy: Consult perinatologist. IV. Clearly define management responsibilities of each provider.

III. Obtain advice on other relevant issues.

2012 Subspecialty Day|Uveitis

Section I: The Uveitis Puzzle for the Non-uveitis Specialist

Managing Glaucoma in Patients With Uveitis


Sumru Onal MD

I. Introduction A. In a patient with uveitis, glaucoma should not be considered synonymous with elevated IOP, but the diagnosis should be reserved for those situations where there is either glaucomatous disc damage or visual field loss. B. A patient with elevated IOP due to synechial angle closure secondary to uveitis is mostly classified as having uveitic glaucoma without evidence of optic disc changes or visual field loss, because these changes are inevitable without appropriate intervention. C. The overall prevalence of uveitic glaucoma ranges between 10% and 20%, but is much more common in chronic uveitis and can be as high as 46%. II. Uveitic Conditions Most Commonly Associated With Glaucoma A. Juvenile idiopathic arthritis B. Fuchs heterochromic iridocyclitis C. Sarcoid uveitis D. Intermediate uveitis/ pars planitis E. Viral iridocyclitis F. Glaucomatocyclitic crisis (Posner-Schlossman syndrome) G. Recent studies suggest uveitis with iris transillumination, pigment dispersion, and severe early IOP rise as a possible adverse drug reaction of systemic fluoroquinolone treatment, particularly moxifloxacin. III. Treatment of Primary Disease A. Corticosteroid therapy 1. Corticosteroids are still the mainstay of treatment of acute intraocular inflammation. 2. Elevation of IOP can occur with all routes of corticosteroid treatment. 3. Raised IOP induced by corticosteroid response represents a significant proportion of IOP elevation in uveitic eyes, and occurs more commonly in uveitis patients than in the normal population. 4. Topical difluprednate 0.05% has superior intraocular penetration compared with other topical corticosteroids; however, it should be used cautiously in pediatric patients with uveitis because of a high rate of corticosteroid-induced IOP elevation in this population. 5. Intravitreal triamcinolone injection is associated with substantial risk of corticosteroid-induced IOP elevation.

6. Elevated IOP is a common and significant complication in patients with uveitis treated with fluocinolone acetonide intravitreal implants; 25% of implant-treated eyes require glaucoma surgery over 24 months. 7. Fluocinolone acetonide intravitreal implantation can be combined with glaucoma drainage device placement in eyes with uveitis and elevated IOP receiving maximum tolerated IOP-lowering therapy. B. Cycloplegics 1. Used to prevent or break posterior synechiae 2. Relieve the discomfort of ciliary muscle spasm C. Conventional immunomodulatory therapy (IMT) 1. Their off-label use is the standard of care in the uveitis practice. 2. Apart from controlling the intraocular inflammation, they exert corticosteroid-sparing effect and have the potential to induce durable remission. D. Biologic therapies 1. Are indicated in uveitic entities refractory to conventional IMT 2. There is ongoing debate about their use as firstline therapy in certain uveitic conditions. E. Specific treatment of infectious etiologies of uveitis

IV. Medical Treatment of Glaucoma A. Medical therapy 1. Beta-blockers 2. Topical and oral carbonic anhydrase inhibitors 3. Alpha-2 agonists 4. Prostaglandin (PG) agonists a. Initially thought to have a propensity to increase the activity of uveitis b. PG agonists were shown to be effective in lowering IOP in patients with uveitic glaucoma, in whom the uveitis is controlled on IMT, without increasing the rate of flare-ups of uveitis. 5. Hyperosmotic drugs B. Uveitic glaucoma patients often require more than one drug to control their IOP. C. Most of the patients respond to medical treatment; only 4% to 30% of patients require surgical treatment.

Section I: The Uveitis Puzzle for the Non-uveitis Specialist D. A higher percentage of pediatric uveitis patients need surgery. V. Laser Therapy A. Argon and/or Nd:YAG laser iridotomy 1. Indicated for pupillary block glaucoma due to a secluded pupil from extensive posterior synechiae or fibrin membrane 2. In some cases, a surgical iridectomy may be required if the laser iridotomy closes secondary to intense inflammation. B. Argon laser trabeculoplasty 1. Usually not useful in uveitic eyes 2. Has been shown to have low success rates in uveitic glaucoma patients because of angle alterations C. Transscleral laser cyclophotocoagulation 1. Reserved for cases where all other efforts to lower IOP have failed. 2. Should be used cautiously because the risk of permanent hypotony is increased with a cyclodestructive procedure in uveitic eyes with compromised ciliary epithelium function A. Glaucoma filtration surgery 1. Filtration surgery is indicated when IOP is uncontrolled on maximum tolerated IOP-lowering therapy. 2. Long-term success of trabeculectomy has increased with antimetabolic agents such as intraoperative mitomycin C (MMC) and intra-/ postoperative 5-fluorouracil. 3. Success rate of MMC trabeculectomy for uveitic glaucoma ranges from 50% to 90% with various criteria of success. B. Glaucoma drainage devices 1. Used with increasing frequency in uveitic glaucoma, either as the initial glaucoma surgery or when trabeculectomy fails 2. Success rate is up to 94% at 1 year and 50% at 4 years with various criteria of success. 3. IOP control is especially favorable in JIA-associated glaucoma. C. Newer glaucoma implants 1. Ex-PRESS mini glaucoma shunt a. A miniature stainless steel shunt developed for use as an alternative procedure to trabeculectomy b. A nonvalved, flow-restricting implant with a 400-m (27-gauge) external diameter, a 50or 200-m inner diameter, and a rounded and beveled tip

2012 Subspecialty Day|Uveitis

c. The procedure is similar to a standard trabeculectomy. d. Main advantages are ease of insertion, formation of a standard size filtration opening, and elimination of the iridectomy, which may reduce inflammation. e. Disadvantages are necessity of a filtration bleb and antifibrotic use, fibrosis over the opening, and possible device-related complications. f. Not studied in uveitic glaucoma 2. Others

VII. Other Surgical Procedures A. Goniotomy 1. A low-risk and effective first-line surgery for young patients with refractory glaucoma associated with chronic uveitis 2. Outcome is adversely affected by increased age, peripheral anterior synechiae, prior surgeries, and aphakia. B. Deep sclerectomy 1. Not proven to be superior to trabeculectomy 2. Nonpenetrating surgery is associated with less inflammation during the early postoperative period. A. Glaucoma is a frequent complication of uveitis arising from the inflammatory disease process itself or from corticosteroid use or both. B. Treatment should be first directed at aggressive and comprehensive control of intraocular inflammation and the underlying systemic disease. C. Uncontrolled IOP is often managed with glaucoma medical therapy, and recalcitrant cases require surgical intervention. D. Improved long-term success rates are reported with glaucoma drainage implants.

VI. Surgical Therapy

VIII. Summary

References
1. Hinkle DM, Dacey MS, Mandelcorn E, et al. Bilateral uveitis associated with fluoroquinolone therapy. Cutan Ocul Toxicol. 2012; 31:111-116. 2. Tugal-Tutkun I, Onal S, Garip A, et al. Bilateral acute iris transillumination. Arch Ophthalmol. 2011; 129:1312-1319. 3. Slabaugh MA, Herlihy E, Ongchin S, van Gelder RN. Efficacy and potential complications of difluprednate use for pediatric uveitis. Am J Ophthalmol. 2012; 153:932-938. 4. Sallam A, Sheth HG, Habot-Wilner Z, Lightman S. Outcome of raised intraocular pressure in uveitic eyes with and without a corticosteroid-induced hypertensive response. Am J Ophthalmol. 2009; 148:207-213.e1. 5. Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, Kempen JH, Altaweel MM, Holbrook JT, et al. Random-

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Section I: The Uveitis Puzzle for the Non-uveitis Specialist


15. Vuori ML. Molteno aqueous shunt as a primary surgical intervention for uveitic glaucoma: long-term results. Acta Ophthalmol. 2010; 88:33-36. 16. Rachmiel R, Trope GE, Buys YM, Flanagan JG, Chipman ML. Ahmed glaucoma valve implantation in uveitic glaucoma versus open-angle glaucoma patients. Can J Ophthalmol. 2008; 43:462467. 17. Papadaki TG, Zacharopoulos IP, Pasquale LR, Christen WB, Netland PA, Foster CS. Long-term results of Ahmed glaucoma valve implantation for uveitic glaucoma. Am J Ophthalmol. 2007; 144:62-69. 18. Ozdal PC, Vianna RN, Deschenes J. Ahmed valve implantation in glaucoma secondary to chronic uveitis. Eye 2006; 20:178-183.

ized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Ophthalmology 2011; 118:1916-1926. 6. Malone PE, Herndon LW, Muir KW, Jaffe GJ. Combined fluocinolone acetonide intravitreal insertion and glaucoma drainage device placement for chronic uveitis and glaucoma. Am J Ophthalmol. 2010; 149:800-806.e1. 7. Fortuna E, Cervantes-Castaeda RA, Bhat P, Doctor P, Foster CS. Flare-up rates with bimatoprost therapy in uveitic glaucoma. Am J Ophthalmol. 2008; 146:876-882. 8. Markomichelakis NN, Kostakou A, Halkiadakis I, Chalkidou S, Papakonstantinou D, Georgopoulos G. Efficacy and safety of latanoprost in eyes with uveitic glaucoma. Graefes Arch Clin Exp Ophthalmol. 2009; 247:775-780. 9. Carreo E, Villarn S, Portero A, Herreras JM, Maquet JA, Calonge M. Surgical outcomes of uveitic glaucoma. J Ophthalmic Inflamm Infect. 2011; 1:43-53. 10. Kaburaki T, Koshino T, Kawashima H, et al. Initial trabeculectomy with mitomycin C in eyes with uveitic glaucoma with inactive uveitis. Eye (Lond). 2009; 23:1509-1517. 11. Noble J, Derzko-Dzulynsky L, Rabinovitch T, Birt C. Outcome of trabeculectomy with intraoperative mitomycin C for uveitic glaucoma. Can J Ophthalmol. 2007; 42:89-94. 12. Wright MM, McGehee RF, Pederson JE. Intraoperative mitomycinC for glaucoma associated with ocular inflammation. Ophthalmic Surg Lasers. 1997; 28:370-376. 13. Ceballos EM, Beck AD, Lynn MJ. Trabeculectomy with antiproliferative agents in uveitic glaucoma. J Glaucoma. 2002; 11:189-196. 14. Towler HM, McCluskey P, Shaer B, Lightman S. Long term followup of trabeculectomy with intraoperative 5-fluorouracil for uveitisrelated glaucoma. Ophthalmology 2000; 107:1822-1828.

19. Kafkala C, Hynes A, Choi J. Ahmed valve implantation for uncontrolled pediatric uveitic glaucoma. J AAPOS. 2005; 9:336-340. 20. Ceballos EM, Parrish RK, Schiffman JC. Outcome of Baerveldt glaucoma drainage implants for the treatment of uveitic glaucoma. Ophthalmology 2002; 109:2256-2260. 21. Molteno AC, Sayawat N, Herbison P. Otago glaucoma surgery outcome study: long-term results of uveitis with secondary glaucoma drained by Molteno implants. Ophthalmology 2001; 108:605-613. 22. Da Mata A, Burk SE, Netland PA, Baltatzis S, Christen W, Foster CS. Management of uveitic glaucoma with Ahmed glaucoma valve implantation. Ophthalmology 1999; 106:2168-2172. 23. Francis BA, Singh K, Lin SC, et al. Novel glaucoma procedures: a report by the American Academy of Ophthalmology. Ophthalmology 2011; 118:1466-1480. 24. Ho CL, Wong EY, Walton DS. Goniosurgery for glaucoma complicating chronic childhood uveitis. Arch Ophthalmol. 2004; 122(6):838-444. 25. Dupas B, Fardeau C, Cassoux N, Bodaghi B, LeHoang P. Deep sclerectomy and trabeculectomy in uveitic glaucoma. Eye (Lond) 2010; 24:310-314.

Section I: The Uveitis Puzzle for the Non-uveitis Specialist

2012 Subspecialty Day|Uveitis

Therapeutic Vitrectomy
E Mitchel Opremcak MD

I. Vitrectomy for Repair of Structural Complications of Uveitis A. Vitreous opacification, debris, and hemorrhage B. Lens-induced uveitis C. Epiretinal membranes and cystoid macular edema (CME) D. Traction or rhegmatogenous retinal detachment E. Hypotony and cyclitic membranes F. Uveitic glaucoma and posterior tube placement II. Vitrectomy for the Control of Uveitis Activity A. Theoretic mechanism of action 1. Removal of ocular autoantigens: Type II collagen and lens antigens 2. Removal of autoreactive immune cells and cytokines (IL-1, IL-2, TNF-a, etc.) 3. Alter the immunologic milieu with aqueous humor: ACAID a. Anti-inflammatory cytokines: TGF-B and VIP b. Inhibition of complement fixation c. Apoptosis 1. Diamond and Kaplan (1978) a. Pars plana vitrectomy (PPV) and lensectomy (PPL) in 15 uveitis patients b. Increased vision, decreased CME, and reduced uveitis activity c. Kaplan suggested PPV for intermediate uveitis over immunosuppression (1992). 2. Algvere, Alanko, Dickoff, Lahde, and Saari (1981) a. PPV alone in 14 patients with chronic uveitis b. Improved vision in 10 and cells disappeared from the aqueous 3. Becker and Davis (1981-2005), Summary a. Literature review of PPV in 1575 uveitis patients and 1762 eyes from 44 articles b. Intermediate uveitis in 841 eyes (48%) c. Biased, noncontrolled, heterogenous diagnoses and nonstandard visual acuities (VA) d. Improved vision in 68%, reduced systemic medications in 57%, and CME reduced from 36% to 18%

e. PPV for uveitis was recommended in 41 of 44 papers (93%). f. Complications included retinal detachment (4%), cataract (6%), and vitreous hemorrhage (1%). g. Based on the evidence in the literature, PPV is possibly relevant to the outcomes of improving vision and reducing inflammation and CME. h. Randomized and controlled trials are needed for PPV as an adjunct to the medical treatment of uveitis. 4. Scott, Haynes, Orr, Cooling, Pavesio, and Charteris (2003)

a. Retrospective review of PPV in 41 eyes in 38 patients with endogenous posterior uveitis b. Intermediate uveitis (46%), panuveitis (32%), and posterior uveitis (22%) c. VA improved by 2 Snellen lines in 61% (P < .05), and CME was reduced from 44% to 20% (P < .05). d. Significant increase in the percentage of eyes per month that did not suffer any episodes of uveitis from 70% to 84% (P < .0012). e. Complications included retinal detachment (n = 1) and cataract (n = 1). 5. Tranos, Scott, Zambarajki, Ayliffe, Pavesio, and Charteris (2006), randomized and controlled

B. Clinical evidence (selected reports)

a. Prospective, randomized, and controlled pilot study of PPV in 23 medically unresponsive patients with intermediate or posterior uveitis b. Randomized into PPV (n = 12) and corticosteroid/IMT (n = 11) arms c. The PPV group had statistically significant improved VA from logMAR 1.0 to 0.55 (P < .011) and 42% at 20/40 or better, while the medical arm had no significant improvement in VA. d. CME improved in 4 eyes (33%) following PPV and 1 eye (14%) with medical therapy. e. No significant intraoperative or postoperative complications 6. Trittibach, Koerner, Sarra, and Garweg (2006) a. Retrospective review of 29 eyes in 23 pediatric patients with chronic uveitis following therapeutic PPV

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Section I: The Uveitis Puzzle for the Non-uveitis Specialist

b. Intermediate uveitis (n = 22) and retinal vasculitis (n = 7) c. Statistically significant with improved logMAR VA from 0.91 to 0.33 (P < .001), CME resolution in 8 of 10 eyes (P < .021), and active disease from 15 eyes (62%) to 7 eyes (30%) (P < .042) d. Three eyes developed cataract and 1 eye developed hypotony. 7. Giuliari, Chang, Thakuria, Hinkle, and Foster (2010)

b. Preoperative IOP on maximal medical therapy (avg. 2.5 meds) was 32 mmHg and postoperative IOP was 13 mmHg (avg 0.69 meds) c. VA was was unchanged or improved in 21/32 eyes (65%). d. 19/32 eyes (60%) had no recurrence of uveitis following PVV. e. Complication included choroidals (n = 1), tube occlusion by vitreous resolved with YAG laser (n = 2), and elevated IOP requiring cylcophotocoagulation (n = 1). f. PPV, gas tamponade, and posterior tube placement controlled both IOP and uveitis complications. 1. Based on the evidence in the literature, PPV appears to be safe and helpful in controlling inflammation, reducing CME, improving VA, and reducing the number of medications required to control uveitis in selected patients. 2. A well-designed, multicentered, randomized, and controlled clinical trial is needed to confirm these observations and conclusions.

a. Retrospective review of 28 eyes (20 patients) following vitrectomy for pediatric uveitis b. Pars planitis (n = 15), idiopathic panuveitis (n = 8), and JIA-associated iridocyclitis (n = 5) c. All 28 eyes had active uveitis on medications at PVV. d. 27 eyes (96%) were controlled at last followup (13.5 months average) with reduced systemic medications following PPV. e. Five of 6 eyes with associated retinal vasculitis were now controlled. f. Two eyes had intraoperative retinal tear, and 4 developed a cataract. 8. Quinones, Choi, Yilmaz, Kafkala, Letko, and Foster (2010)

C. Conclusions

References
1. Gupta P, Gupta A, Gupta V, Singh R. Successful outcome of pars plana vitreous surgery in chronic hypotony due to uveitis. Retina 2009; 29:638-643. 2. Becker M, Davis J. Perspectives: vitrectomy in the treatment of uveitis. Am J Ophthalmol. 2005; 140:1096-1105. 3. Scott RA, Haynes RJ, Orr GM, Cooling RJ, Pavesio CE, Charteris DG. Vitreous surgery in the management of chronic endogenous uveitis. Eye 2003; 17:221-227. 4. Tranos P, Scott R, Zambarajki H, Ayliffe W, Pavesio C, Charteris DG. The effect of pars plana vitrectomy on cystoids macular oedema associated with chronic uveitis: a randomized controlled pilot study. Br J Ophthalmol. 2006; 90:1107-1110. 5. Trittibach P, Koerner F, Sarra G-M, Garweg JG. Vitrectomy for juvenile uveitis: prognostic factor for the long-term functional outcome. Eye 2006; 20:184-190. 6. Giuliari GP, Chang PY, Thakuria P, Hinkle DM, Foster CS. Pars plana vitrectomy in the management of paediatric uveitis: the Massachusetts eye research and surgery Institution experience. Eye 2010; 24:7-13. 7. Quinones K, Choi YJ, Yilmaz T, Kafkala C, Letko E, Foster CS. Pars plana vitrectomy versus immunomodulatory therapy for intermediate uveitis: a prospective, randomized pilot study. Ocul Immunol Inflamm. 2010; 18;411-417.

a. Prospective, randomized pilot study on 18 eyes (16 patients) with recalcitrant intermediate uveitis b. In the PPV group 9 of 11 eyes (82%) had disease resolution off systemic medications at 5.93 years, with better VA, IOP, and vitreous cell reduction. c. In the IMT group, 4 of 7 eyes (57%) failed and required PVV. d. CME resolved in 3 of 3 eyes with PVV and in 2 of 3 eyes with IMT. e. There were no surgical complications with PVV, and 2 patients on IMT had a reversible anemia and leukopenia. 9. Patronas, Baker, and Opremcak (2012) a. Retrospective review of 32 eyes (26 patients) with uveitic glaucoma treated with PPV, gas tamponade, and posterior glaucoma tube placement between 1994 and 2011, with average follow-up of 33 months (1-204 months)

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Section II: Uveitis Potpourris

2012 Subspecialty Day|Uveitis

Recurrent Nongranulomatous Anterior Uveitis: E&M


Jennifer E Thorne MD PhD

I. Anterior Uveitis A. SUN/IUSG definition: Primary location of inflammation is the anterior chamber. B. Epidemiology 1. Most common form of uveitis 2. Incidence: 8 per 100,000 population per year 3. Incidence increases with age (100-300 cases/100,000 person-years for those > 65 years old) C. Granulomatous vs. nongranulomatous D. Course of uveitis 1. Acute 2. Recurrent (only one eye affected, alternating, bilateral asynchronous, bilateral simultaneous) 3. Chronic A. HLA-B27 disease B. Tubulointerstitial nephritis and uveitis (TINU) C. Posner-Schlossman syndrome (glaucomatocyclitic crisis) D. Lens-related: postoperative uveitis E. Drug-related uveitis F. Infectious 1. Syphilis 2. Lyme 3. Strep 4. Herpetic/CMV

G. Other considerations 1. Chronic uveitis entities may present uncommonly as recurrent disease (eg, JIA). 2. Granulomatous disease may present with nongranulomatous features (eg, sarcoidosis). 3. Anterior uveitis may be beginning of posterior disease (eg, Behet disease). H. Idiopathic III. Workup A. Dilated examination: gonioscopy with elevated IOP B. The usual suspects: HLA-B27, FTA-Abs, chest x-ray C. History-driven tests D. Region-specific test IV. Treatment A. Topical corticosteroids B. Other local corticosteroids C. Topical cycloplegics D. Systemic medications V. Complications A. Evolution into chronic uveitis B. Macular edema C. Ocular hypertension/glaucoma D. Cataract

II. Differential Diagnosis

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Section II: Uveitis Potpourris

11

Pars Planitis: What to Do When the Intermediate Uveitis Is Idiopathic


Janet Louise Davis MD
I. Explain to your patient what intermediate uveitis means. A. Inflammation primarily involves the vitreous cavity. B. Variable anterior segment inflammation 1. Sudden, acute granulomatous anterior uveitis suggests MS-related uveitis. 2. Severe iritis with intermediate uveitis suggests either spillover or an occult panuveitis. C. Retinal vascular leakage common, often extensive 1. Pattern of leakage distinctive 2. Occlusion uncommon 3. Neovascularization possible 4. Cystoid macular edema (CME) common, often visually disabling A. Back up your explanation by reviewing the test results. 1. Pediatric and adolescent a. CBC, creatinine, ANA, FTA b. Other common uveitides in this age group are juvenile rheumatoid arthritis and tubulointerstitial nephritis and uveitis syndrome. c. Leukemic infiltration is a concern. Syphilis is a concern at any age. d. No chest X-ray or chest CT scan e. Sarcoid is an unusual cause of intermediate uveitis in children, and only 30% of sarcoid in children involves the lungs. f. Radiation exposure undesirable g. No MRI of brain i. If MS is present, this is not idiopathic but MS-related uveitis. ii. If MS is not present, lesions on MRI will not lead to a diagnosis. iii. Cases with pediatric idiopathic intermediate uveitis and MS as adults are reported. a. Differential clearly includes syphilis and sarcoidosis. b. No ANA, but chest x-ray and angiotensin converting enzyme indicated. c. CT scan of chest with contrast originally described as having higher sensitivity than chest x-ray in elderly patients. Applicability to other groups is uncertain. 1. Fluorescein angiography 2. OCT C. Explain the possibility of other systemic disease developing later. III. Stage the Degree of Inflammation A. Vision 1. 20/40 vision as an indication to start treatment is no longer an acceptable standard. 2. Consider treatment for CME, which is damaging. 3. Consider treatment for symptomatic vision loss to 20/25 or worse. B. Vitreous opacity 1. Consider the option to treat symptomatic vitreous opacities. a. Impairment in vision caused by vitreous opacities is difficult to measure in the clinic. b. Assess whether mainly collagenous or inflammatory. 2. Medical or surgical option, depending on other associated signs of disease (ie, requirement for treatment of anterior or retinal vascular inflammation) C. Retinal vascular leakage 1. Stage according to intensity, small vessel or occlusions worse 2. Stage according to location, posterior to equator worse D. Pars plana exudate 1. Complications that may require treatment a. Neovascularization b. Vitreous hemorrhage c. Coats-like response d. Peripheral retinal angioma 2. Association with active focal vitreous opacities vs. quiescent, collagenous extracellular disease

B. Review ocular imaging

II. Explain to your patient what idiopathic means.

2. Adults

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Section II: Uveitis Potpourris IV. Match the Treatment to the Disease A. Avoid structural damage 1. Posterior synechiae 2. Cataract from corticosteroids, especially in children 3. Glaucoma from corticosteroids, especially in children 4. Vision loss from CME B. Assess progression 1. Most idiopathic intermediate uveitis does not change pattern or intensity much over time. 2. Waxing and waning is possible. 3. Most pediatric intermediate uveitis diminishes in adulthood. 4. If patients are stable without progression and minimal signs of disease, observation may produce fewer complications than treatment. C. Assess severity 1. Qualitative assessment of the angiographic findings 2. Qualitative assessment of the OCT findings D. Consider standard therapies. 1. Local therapy a. Cryotherapy to areas of exudative detachment b. Laser photocoagulation to peripheral retina anterior to equator adjacent to snowbanks c. Regional steroid injection d. Pars plana vitrectomy combined with the above 2. Systemic therapy a. Immunomodulatory agents i. Methotrexate ii. Cyclosporine iii. Mycophenolate mofetil or mycophenolic acid iv. Azathioprine b. Biologics i. Interferons ii. TNF-inhibitors: TB testing and MRI prior to use

2012 Subspecialty Day|Uveitis

VI. Arrange for Monitoring A. Follow-up every 3 months 1. More often if in early stages 2. Less often if stable and in late stages or has very mild disease B. Laboratory monitoring as appropriate for the agents used C. Periodic angiography and OCT to check retinal inflammation

Selected Readings, 2010 to 2012


1. Simmons-Rear A, Yeh S, Chan-Kai BT, et al. Characterization of serous retinal detachments in uveitis patients with optical coherence tomography. J Ophthalmic Inflamm Infect. Epub ahead of print 2 June 2012. PMID: 22661129. 2. Ossewaarde-Van Norel J, Camfferman LP, Rothova A. Discrepancies between fluorescein angiography and optical coherence tomography in macular edema in uveitis. Am J Ophthalmol. Epub ahead of print 26 Apr 2012. PMID:22541651. 3. Taylor SR, Lightman SL, Sugar EA, et al. The impact of macular edema on visual function in intermediate, posterior, and panuveitis. Ocul Immunol Inflamm. 2012; 20(3):171-181. 4. Shields JA, Reichstein D, Mashayekhi A, Shields CL. Retinal vasoproliferative tumors in ocular conditions of childhood. J AAPOS. 2012; 16(1):6-9. 5. Cantarini L, Simonini G, Frediani B, Pagnini I, Galeazzi M, Cimaz R. Treatment strategies for childhood noninfectious chronic uveitis: an update [review]. Expert Opin Investig Drugs. 2012; 21(1):1-6. 6. Esterberg E, Acharya NR. Corticosteroid-sparing therapy: practice patterns among uveitis specialists. J Ophthalmic Inflamm Infect. 2012; 2(1):21-8. 7. Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group; Kempen JH, Altaweel MM, Holbrook JT, et al. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Ophthalmology. 2011; 118(10):1916-1926. Erratum in: Ophthalmology. 2012; 119(2):212. 8. Gregoire MA, Kodjikian L, Varron L, Grange JD, Broussolle C, Seve P. Characteristics of uveitis presenting for the first time in the elderly: analysis of 91 patients in a tertiary center. Ocul Immunol Inflamm. 2011; 19(4):219-226. 9. Leder HA, Jabs DA, Galor A, Dunn JP, Thorne JE. Periocular triamcinolone acetonide injections for cystoid macular edema complicating noninfectious uveitis. Am J Ophthalmol. 2011; 152(3):441448. 10. Kalinina Ayuso V, ten Cate HA, van den Does P, Rothova A, de Boer JH. Young age as a risk factor for complicated course and visual outcome in intermediate uveitis in children. Br J Ophthalmol. 2011; 95(5):646-651. 11. Taylor SR, Isa H, Joshi L, Lightman S. New developments in corticosteroid therapy for uveitis [review]. Ophthalmologica 2010; 224 suppl 1:46-53. 12. Quinones K, Choi JY, Yilmaz T, Kafkala C, Letko E, Foster CS. Pars plana vitrectomy versus immunomodulatory therapy for intermediate uveitis: a prospective, randomized pilot study. Ocul Immunol Inflamm. 2010; 18(5):411-417.

V. Consider Subspecialty Consultation A. Neurology for those with symptoms B. Pulmonary for those with abnormal testing C. Rheumatology for help with administering or monitoring drug therapy

2012 Subspecialty Day|Uveitis 13. Nguyen QD, Hatef E, Kayen B, et al. A cross-sectional study of the current treatment patterns in noninfectious uveitis among specialists in the United States. Ophthalmology 2011; 118(1):184-190. 14. Miserocchi E, Modorati G, Mosconi P, Colucci A, Bandello F. Quality of life in patients with uveitis on chronic systemic immunosuppressive treatment. Ocul Immunol Inflamm. 2010; 18(4):297304. 15. Jalil A, Dhawahir-Scala FE, Jones NP. Nonprogressive tractional inferior retinal elevation in intermediate uveitis. Ocul Immunol Inflamm. 2010; 18(1):60-63. 16. Lin P, Loh AR, Margolis TP, Acharya NR. Cigarette smoking as a risk factor for uveitis. Ophthalmology 2010; 117(3):585-590. 17. Daniel E, Thorne JE, Newcomb CW, et al. Mycophenolate mofetil for ocular inflammation. Am J Ophthalmol. 2010; 149(3):423-432. e1-2. 18. Deuter CM, Doycheva D, Stuebiger N, Zierhut M. Mycophenolate sodium for immunosuppressive treatment in uveitis. Ocul Immunol Inflamm. 2009; 17(6):415-419.

Section II: Uveitis Potpourris

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Section II: Uveitis Potpourris

2012 Subspecialty Day|Uveitis

Retinal Vasculitis
William Ayliffe MBBS

Introduction
Retinal vasculitis is a sight-threatening inammatory eye disease involving the retinal blood vessels. Recent recognition of an increasing number of causes, particularly emerging infections, and the therapeutic role of newer anti-inflammatory agents and cytokines is changing the way this condition is managed. Retinal vasculitis is diagnosed clinically by the observation of focal, perivascular sheathing of the retinal blood vessels. Leakage of fluid through the normally impermeable vessel wall leads to retinal edema. If the vessels become occluded, retinal ischemia and its sequelae can develop. Primary retinal vasculitis affecting the eye vasculature without evidence of any systemic or other eye disease is called idiopathic retinal vasculitis. It is uncommon. Infections of the eye, particularly with toxoplasmosis and herpes virus, represent the most frequent cause. However, retinal vasculitis is also seen as a manifestation of systemic diseases such as Adamantiades-Behet disease, sarcoidosis, and more rarely autoimmunity or even malignancy. A recent chart review of 1390 patients attending a North American uveitis clinic found that systemic vasculitis was the cause of retinal vasculitis in only 1.4% of cases.

comes in some patients with posterior uveitis, including retinal vasculitis.

Surgical Intervention
Retinal photocoagulation is used for obliterative vasculitides, Eales disease, cases of focal ischemia, and as an alternative to cryotherapy in some cases of pars planitis. Vitrectomy may be needed to clear persistent inflammatory debris or hemorrhage and to remove epiretinal membranes. Retinal tears and detachment, particularly cases of acute retinal necrosis, require vitreoretinal intervention.

Summary
Retinal vasculitis is not a single disease but a response to various insults. Some are restricted to the eyes, but others represent a manifestation of systemic disease or infection. The eye may be their herald organ. Some systemic diseases such as sarcoid or multiple sclerosis may not manifest for years after their initial presentation as retinal vasculitis. Treatment has to be timely and sufficient to control inflammation. Low doses of anti-inflammatory drugs, allowing smouldering disease, lead to progressive ocular damage. Chronic use of steroids, particularly doses above 7.5 mg/d prednisone equivalent, should be avoided. With modern treatments a substantial cohort of patients maintain their vision in the long term.

Investigations
The major diagnostic yield comes from careful history and examination of the eyes and any other involved site. Fluorescein angiography identifies areas not visible by ophthalmoscopy alone and is therefore helpful to assess the extent of the disease and to identify areas of ischemia that may need photocoagulation. Occult causes are rare, and therefore laboratory investigations can be limited in most patients. A suggested basic screen would include a full blood count, sedimentation rate, serology for syphilis, and perhaps a chest x-ray or Mantoux skin test in certain endemic areas to exclude exposure to tuberculosis. Other tests are directed by history and geographic origin of the patient.

Selected Readings
1. Rosenbaum JT, Ku J, Ali A, Choi D, Suhler EB. Patients with retinal vasculitis rarely suffer from systemic vasculitis. Semin Arthritis Rheum. 2012; 41(6):859-865. 2. Cunningham ET Jr, Wender JD. Practical approach to the use of corticosteroids in patients with uveitis. Can J Ophthalmol. 2010; 45(4):352-358. 3. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000; 130:492-513. 4. Tabbara KF, Al-Hemidan AI. Infliximab effects compared to conventional therapy in the management of retinal vasculitis in Behcet disease. Am J Ophthalmol. 2008; 146:845-850. 5. Cunningham ET, Zierhut M. TNF inhibitors for uveitis: balancing efficacy and safety. Ocul Immunol Inflamm. 2010; 18(6):421-423. 6. Suhler EB, Smith JR, Giles TR, et al. Infliximab therapy for refractory uveitis: 2-year results of a prospective trial. Arch Ophthalmol. 2009; 127:819-822. 7. Pulido JS, Pulido JE, Michet CJ, Vile RG. More questions than answers: a call for a moratorium on the use of intravitreal infliximab outside of a well-designed trial. Retina 2010; 30(1):1-5. 8. Ku JH, Ali A, Suhler EB, Choi D, Rosenbaum JT. Characteristics and visual outcome of patients with retinal vasculitis. Arch Ophthalmol. 2012; 11:1-6.

Treatment
Once infection has been excluded or treated and sight-threatening changes are present, then high-dose prednisone is commenced at 1 mg/kg/day, reducing by 10 mg/day each week (if no relapse) to 10 mg/day maintenance. If disease is not controlled, immunomodulatory therapy (IMT) is introduced. Antimetabolitesmethotrexate, mycophenolate mofetil, and azathioprinehave a slow onset but a low rate of serious side effects. If rapid control of disease is required, cyclosporine or tacrolimus is used. These expensive drugs require careful monitoring. In general they are not used for very longterm control. Third-line therapy includes anti-TNF antibodies; infliximab infusions, or adalimumab (Humira) injections. For Behets, interferon therapy has a role. Alkylating drugs, typically cyclophosphamide, are reserved for systemic vasculitis and resistant cases. Intravitreal administration of steroids, immunosuppressives, and even biologics have been reported to improve out-

2012 Subspecialty Day|Uveitis

Section III: External Ocular Inflammatory Diseases

15

Chronic Conjunctivitis: Is It Ocular Cicatricial Pemphigoid?


C Stephen Foster MD
I. Mucous Membrane Pemphigoid A. Immunopathology 1. Linear deposits at the epithelial basement membrane zone (BMZ) a. IgG b. IgA c. C3 2. Circulating antibodies: By IDIF, RIA, or ELIZA B. Autoimmune 8 different epithelial BMZ targets 1. BPA 1 2. BPA 2 3. Laminin-5 4. Laminin-6 6. Keratin 7. Uncein 8. 168-kDa epi protein We have identified the -4 subunit of -6/ -4 integrin as the target antigen in patients with ocular cicatricial pemphigoid (OCP). Tyagi, Bhol, Natarajan, Livir-Rallatos, Hemler, Foster, and Ahmed. Ocular cicatricial pemphigoid antigen: partial sequence and characterization. Proc Nat Acad Sci. 1996; 93:14714-14719. IV. OCP Autoantibodies A. Autoantibodies to conjunctival BMZ can be detected in all OCP patients when the disease is active. B. The autoantibodies are pathogenic. C. The binding of the autoantibody to the autoantigen of the epithelial BMZ sets in motion a complex drama in which an impressive cast of characters participates. V. Lesion Production A. Two hit hypothesis 1. Genetic susceptibility 2. Environmental trigger a. Systemic medication b. Topical medication c. Microbe 1. Against 4 peptide of 6/4 integrin others 2. Autoantibody binding to an intracellular epitope of basal epithelial cells C. Effect on signal transduction 1. Effect on attachment molecule relationships 2. Effect on cytokines and inflammatory cell recruitment D. Inflammatory cell infiltration 1. Amplification 2. Cytokine effects on fibroblasts a. TGF- b. IFN- 1. Conjunctival shrinkage 2. MG and other ductule scar 3. Lash follicle misdirection 4. Mucosal epithelial squamous metaplasia and GC dysfunction F. Keratopathy 1. Scarring 2. Neovascularization 3. Epi defects and ulceration A. We have reported that the following genes are associated with OCP: 1. HLA-DRB1*04 2. HLA-DRB4*0101 3. HLA-DQB1*0301 A. Genetic predisposition: HLA-DQw7; DQB1*0301 B. Environmental trigger: drugs; virus? C. Autoantibody production against a 205 kD protein in the upper lamina lucida of the BMZ A. Stage 1: Chronic conjunctivitis and subepithelial fibrosis

B. Autoantibody production

5. -4 integrin

E. Fibrosis

II. OCP Target Antigen Identification

III. 4 Subunit of 6 / 4 Integrin: OCP Antigen

VI. OCP Susceptibility Gene Identification

VII. Cicatricial Pemphigoid: Pathogenesis

VIII. OCP: Ocular Manifestations

16

Section III: External Ocular Inflammatory Diseases B. Stage 2: Fornix foreshortening C. Stage 3: Symblepharon formation D. Stage 4: End stage keratinization IX. OCP Clinical Course A. Conjunctival shrinkage at first observation 1. <25% 2. 25%-50% 3. >50% B. Patients with disease progression in 2 years 1. 50% 2. 75% 3. 78% A. All treatments except those that suppress abnormal (dysregulated) immune responses (autoimmune responses) have failed to stop the progressive conjunctival scarring characteristic of OCP. B. Our ventures into this field began in 1978. 1. 1982: Foster, Wilson and Ekins. Ophthalmology 89:340-353. 2. 1986: Foster. Trans Am Ophthalmol Soc. 84:527-663. A. Dapsone B. Methotrexate (MTX) C. Imuran D. CellCept E. Cytoxan F. Cytosine arabinoside G. IV immunoglobulin (IV-Ig) H. Rituximab A. Example 1 1. Presentation: Progressive disease and mild to moderate inflammation 2. Treatment: Dapsone or MTX or CellCept or Imuran first; next add IV-Ig if necessary; proceed to rituximab + IV-Ig as needed. B. Example 2 1. Presentation: Progressive disease and marked inflammation 2. Treatment: Cytoxan with prednisone; transition to IV-Ig at 6 months

2012 Subspecialty Day|Uveitis

XIII. Mucous Membrane Pemphigoid A heterogenous group of chronic inflammatory blistering diseases that manifest a varying constellation of lesions. A. Oral B. Ocular C. Skin D. Genital E. Esophageal F. Nasopharangeal A. Mucous membrane pemphigoid affecting the eye (ocular cicatricial pemphigoid, OCP) is a systemic autoimmune disorder that produces progressive conjunctival cicatrization with secondary blinding keratopathy. B. Effective treatment of OCP requires systemic immunomodulation.

XIV. Summary

X. OCP

References
1. Bhol KC, Dans MJ, Simmons RK, Foster CS, Giancotti FG, Ahmed AR. The autoantibodies to alpha 6 beta 4 integrin of patients affected by ocular cicatricial pemphigoid recognize predominantly epitopes within the large cytoplasmic domain of human beta 4. J Immunol. 2000; 165(5):2824-2829. 2. Rice BA, Foster CS. Immunopathology of cicatricial pemphigoid affecting the conjunctiva. Ophthalmology 1990; 97(11):14761483. 3. Bernauer W, Wright P, Dart JK, Leonard JN, Lightman S. The conjunctiva in acute and chronic mucous membrane pemphigoid: an immunohistochemical analysis. Ophthalmology 1993; 100(3):339346. 4. Ahmed M, Zein G, Khawaja F, Foster CS. Ocular cicatricial pemphigoid: pathogenesis, diagnosis and treatment. Prog Retin Eye Res. 2004; 23:579-592. 5. Eschle-Meniconi ME, Ahmad SR, Foster CS. Mucous membrane pemphigoid: an update. Curr Opin Ophthalmol. 2005; 16:303307. 6. Bruch-Gerharz D, Hertl M, Ruzicka T. Mucous membrane pemphigoid: clinical aspects, immunopathological features and therapy. Eur J Dermatol. 2007; 17(3):191-200. 7. Foster CS. Cicatricial pemphigoid. Trans Am Ophthalmol. 1986; 84:527-663.

XI. OCP Therapy

XII. Examples

2012 Subspecialty Day|Uveitis

Section III: External Ocular Inflammatory Diseases

17

Peripheral Ulcerative Keratitis: Moorens, Terriens, or Something More Ominous?


Virender S Sangwan MBBS
Introduction
When encountered with a central corneal ulcer, the first differential to cross the corneal physicians mind is usually an infectious etiology. However, a peripheral corneal ulcerative pathology opens up a Pandoras box. It is often a nightmare for physicians, as the diagnosis may vary from simple corneal infectious pathology to any of a gamut of systemic collagen vascular diseases that present with a peripheral ulcerative keratitis (PUK) or a number of mimics of the condition. It is imperative for the physician to identify various signs that would help in differentiating one from the other. Additionally systemic evaluation using hematological and radiological investigation may provide important clues to the diagnosis. The immunological basis of disease in most instances and role of immunosuppression demands a team approach with an internist for adequate immunosuppression and systemic evaluation and monitoring of these cases. The purpose of this outline is to provide a comprehensive overview of the differential diagnosis of peripheral ulcerative keratitis and to briefly discuss our stepladder approach for management of PUK and Mooren ulcer. PUK is classically described as peripheral crescent-shaped inflammation of corneal stroma adjacent to the limbus, with or without associated scleral inflammation, with or without underlying systemic or ocular diseases, characterized by thinning of the affected area. What makes PUK an important issue is that it is often the first sign or the presenting sign of a number of systemic collagen vascular disorders. The progressive nature of the disease demands aggressive therapy to curtail the devastating corneal destruction. Additionally, it is often important to identify the underlying ocular or systemic disease and also sometimes to differentiate this condition from a number of masquerades that may mimic as PUK. A systematic approach that includes identification of classical clinical signs, ordering appropriate investigations based on the clinical features, and an algorithm-based stepwise management provides good results in these cases. Table 1. Differential Diagnosis of PUK Ocular Infectious Causes
Bacterial: Staphylococcus, Streptococcus, Moraxella, Haemophilus Viral: herpes simplex, herpes zoster Acanthamoeba Fungal

Ocular Noninfectious Causes


Mooren ulcer Terrien marginal degeneration Keratoconjunctivitis sicca Blepharitis Neurotrophic keratitis Chemical injury Contact lens Trauma

Systemic Infectious Causes


Tuberculosis Syphilis Varicella zoster HIV

Systemic Noninfectious Causes


Rhematoid arthritis Giant cell arteritis Wegener granulomatosis Systemic lupus erythematosus Malignancies Rosacea Polyarteritis nodosa Sarcoidosis Behet disease Progressive systemic sclerosis

Approach to PUK
We follow a systematic, stepwise approach to PUK as summarized in following algorithm: Step 1: Assessment of corneal lesion a. Look for signs of disease activity: Ulcer location, size (in terms of clock hours of involvement), depth of stromal loss, infiltration, ulcer edges. b. Presence of infiltration mark disease to be active. It is important to rule out an infectious process in these cases. Appropriate microbiological investigations including smears, cultures, and immunological tests (PCR) help to identify causative infectious organisms in case of infectious etiology. c. Look for vascularization of bed (suggests chronic disease), presence of lipid deposits with vascularization (Terriens disease- painless, non ulcerative process)

d. Epithelial status: Absence of epithelial defect rules out an active PUK. Pellucid marginal corneal degeneration and Senile furrow degeneration are common etiologies that may seldom be confused with PUK and are differentiated by presence of an intact epithelium. e. Lucid interval between the epithelial defect and the limbus points toward etiologies such as phlycten and catarrhal ulcers.

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Section III: External Ocular Inflammatory Diseases

2012 Subspecialty Day|Uveitis

Step 2: Examination of conjunctiva, sclera, and lids Associated scleritis rules out etiology such as Mooren ulcer. Presence of scleritis points toward underlying systemic collagen vascular disorders. Presence of meibomian gland dysfunction and blepharitis may be associated with marginal keratitis that may sometimes be confused with PUK. Step 3: Systemic evaluation a. Thorough history of systemic manifestations may point toward possible underlying diagnosis: Skin rash, easy sunburns, depigmentation: SLE Respiratory symptoms: Wegener granulomatosis, Churg-Strauss syndrome Joint pains: RA, SLE Swollen ear lobes: Relapsing polychondritis b. Investigations: ESR, rheumatoid factor, ANA, ANCA, CRP, x-ray chest, VDRL Of the various etiologies associated with PUK, Mooren ulcer is an important entity. It is an idiopathic disease seen in young healthy adults with no systemic disease. The disease is characterized by a relentless and aggressive course with multiple relapses. The disease involves limbus, spreads circumferentially and then centrally to eventually leave only a central island of cornea or quiescence only after complete destruction of corneal stroma. The disease has a male preponderance. Younger patients have severe disease with bilateral involvement. There is essentially no scleral involvement in Mooren ulcer. The disease needs an aggressive immunosuppressive regimen (described later) for control and prevention of recurrence. Collagen vascular disorders as a cause of PUK are characterized by associated scleral involvement in the form of scleritis and scleromalaciaperforans in severe cases. A prompt identification of the underlying disease and its appropriate management is important for both visual and life salvage, especially in cases such as Wegener granulomatosis.

Table 2. Immunosuppression Regimen Features


Unilateral cases, less than 2 quadrants of peripheral corneal involvement, less than 50% stromal loss Bilateral cases, more than 2 quadrants of peripheral corneal involvement, more than 50% stromal loss Steroid intolerance, young patients (<50 years), bilateral disease, single eyed Bilateral, single eyed, more than 3 quadrants of peripheral corneal involvement, >50% stromal loss, impending perforation Bilateral, single eyed, more than 3 quadrants of peripheral corneal involvement, perforation, early postoperative period after keratoplasty

Immunosuppression
Topical steroids

Oral steroids

Oral methotrexate IV methylprednisolone

IV methylprednisolone + IV cyclophosphamide

References
1. Srinivasan M, Zegans ME, Zelefsky JR, et al. Clinical characteristics of Moorens ulcer in South India. Br J Ophthalmol. 2007; 91:570-575. 2. Mathur A, Ashar J, Sangwan VS. Moorens ulcer in children. Br J Ophthalmol. 2012; 96:796-800. 3. Foster CS, Forstot SL, Wilson LA. Mortality rate in rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis. Ophthalmology 1984; 91:1253-1255. 4. Messmer EM, Foster CS. Vasculitic peripheral ulcerative keratitis. Surv Ophthalmol. 1999; 43:379-389. 5. Chen J, Xie H, Wang Z, et al. Moorens ulcer in China: a study of clinical characteristics and treatment. Br J Ophthalmol. 2000; 84:1244-1249.

Management
A stepladder approach to management of PUK provides good outcomes. 1. Antimicrobial therapy for infectious etiology 2. After ruling out infectious etiology, the following approach may be followed for autoimmune-mediated or vasculitic PUK: Medical therapy: We prefer to use the severity-based immunosuppression regimen that is presented in Table 2. Surgical therapy: Conjunctival resection with tissue adhesive and bandage contact lens Crescentric patch graft/ lamellar graft/ penetrating keratoplasty Boston keratoprosthesis

2012 Subspecialty Day|Uveitis

Section III: External Ocular Inflammatory Diseases

19

Is Keratoconjunctivitis Sicca an Inflammatory Disease?


Esen Karamursel Akpek MD

Although often underrecognized and underappreciated, keratoconjunctivitis sicca, commonly referred to as dry eye, is a growing public health concern that affects as many as 17% of women and 11.1% of men in the United States. This is likely an underestimate if the self-treating patients and milder/periodic cases are considered. A recent International Dry Eye Workshop (DEWS) defined dry eye as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. The DEWS also recognized two subgroups of dry eye syndrome based on etiopathogenesis: aqueous deficient and evaporative. Among the aqueous deficient group, there are two major subclasses: Sjgren syndrome (SS) dry eye and non-SS dry eye. According to the classification criteria from the European American collaboration, two forms of SS were identified. Primary Sjgren syndrome (pSS) consists of aqueous-deficient dry eye syndrome in combination with symptoms of dry mouth in the presence of autoantibodies, with evidence of reduced salivary secretion and a positive focus score on minor salivary gland biopsy. Secondary SS (sSS) consists of the features of pSS together with the features of an overt autoimmune connective tissue disease, the most common of which is rheumatoid arthritis. A previous retrospective study from a single tertiary eye care center determined that pSS is underdiagnosed in patients with dry eye syndrome and should be the focus of diagnostic evaluations. A more recent multicenter, prospective study confirmed these findings in a group of more than 300 patients with clinically significant aqueous deficient dry eye. The study concluded that ophthalmologists caring for patients with clinically significant dry eye should have a high index of suspicion for underlying SS and a low threshold for diagnostic workup. Older age and female sex seem to be the two most common risk factors for dry eye, based on multiple epidemiological studies. (Peri- and postmenopausal females seem to be particularly at risk.) This suggests perhaps that dry eye is an involutional disorder. In addition, hormonal studies demonstrate that sex hormones influence ocular surface conditions through their effects on aqueous tear secretion, meibomian gland function, and conjunctival goblet cell density. Thus, a lack of hormones (eg, following menopause) might cause dry eye. Many other factors are known to precipitate and/or exacerbate dry eye, such as longterm contact lens wear, refractive laser surgery, smoking, and extended visual tasks such as computer use, television watching, and prolonged reading. Dry eye can also be worsened by low relative humidity conditions that are common in office environments, air-conditioned cars, airplane cabins, and extreme hot or cold weather. Certain systemic medications such as diuretics or antihistamines can cause dry eye. Frequent use (>4-6 times daily) of preserved eye drops may also contribute to dry eye because of the well-established toxicity of preservatives such as benzalkonium chloride. Regardless of the presence of any identifiable underlying local or systemic inflammatory disorder, dry eye seems to be

invariably associated with ongoing ocular surface inflammation, although it is not known whether the inflammation is the cause or the consequence of dryness. Recognition of the role of inflammation in dry eye has been one of the most important factors to have aided dry eye treatment. There is growing evidence from the past decade that shows dry eye-related ocular surface inflammation is mediated by T-cell lymphocytes. Based on histopathological evaluations, patients with both SS-related dry eye as well as non-SS dry eye have identical conjunctival inflammation manifested by inflammatory cell infiltrates and upregulation of expression in markers of immune activation. These results suggested that clinical symptoms of dry eye may be more dependent on T-cell activation and resultant inflammation than previously believed. Multiple other studies followed and demonstrated the role of inflammatory cytokines and matrix metalloproteinases (MMPs) in the pathogenesis of dry eye. Interleukin (IL)-1 is one of the most studied cytokines accompanying dry eye. An increase in the proinflammatory forms of IL-1 (IL-1 and mature IL-1) and a decrease in the biologically inactive precursor IL-1 have been found in the tear film of dry eye patients. The source of the increased levels of IL-1 was thought to be the conjunctival epithelium. Recently, reactive nitrogen species have been investigated in dry eye, and it has been suggested by one study that they might be involved in the pathogenesis or self-propagation of SS-related dry eye. In the same study, IL-1, IL-6, IL-8, and tumor necrosis factor (TNF) were also investigated. More staining appeared in the cytokines of dry eyes compared with normal eyes. The response of cells to extracellular stimuli such as ocular surface stress, including increased tear film and ultraviolet light exposure, is mediated in part by a number of intracellular kinase and phosphatase enzymes. Stress-activated protein kinases have been identified for this purpose. It has been documented that activation of these stress pathways results in transcription of stress-related genes, including inflammatory cytokines such as IL-1 and TNF- and MMPs, mainly MMP-9. In another study, mitogen-activated protein kinases (MAPKs) were found to stimulate the production of inflammatory cytokines and MMPs, including IL-, TNF-, and MMP-9. As mentioned above, hyperosmolarity is one of the factors that contribute to ocular surface inflammation. In one study investigating whether exposure of human limbal epithelial cells to hyperosmotic stress activates the MAPK pathways and induces production of proinflammatory cytokines, researchers concluded that hyperosmolarity induces inflammation in human limbal epithelial cells by increasing expression and production of proinflammatory cytokines and chemokines such as IL-1, TNF, and the C-X-C chemokine IL-8. This process appears to be mediated through activation of the c-Jun N-terminal kinases and extracellular-regulated kinase MAPK signaling pathways. These factors should not be considered important only as they relate to the pathogenesis of dry eye; they should also be kept in mind when discussing treatment strategies. For instance, the efficacy of corticosteroids and doxycycline, which are mostly used for treating ocular surface diseases, may be explained by their ability

20

Section III: External Ocular Inflammatory Diseases

2012 Subspecialty Day|Uveitis 12. Schlote T, Kadner G, Frudenthaler N. Marked reduction and distinct pattern of eye blinking in patients with moderately dry eyes during video display terminal use. Graefes Arch Clin Exp Ophthalmol. 2004; 242:306-312. 13. Wolkoff P, Njaard JK, Franck C, Skov P. The modern office environments desiccate the eye? Indoor Air. 2006; 16:258-265. 14. Management and therapy of dry eye disease: Report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007; 5:163-178. 15. Kunert KS, Tisdale AS, Stern ME, et al. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol. 2000; 118:1489-1496. 16. Stern ME, Gao J, Schwalb TA, et al. Conjunctival T-cell subpopulations in Sjgrens and non-Sjgrens patients with dry eye. Invest Ophthalmol Vis Sci. 2002; 43:2609-2614. 17. Solomon A, Dursun D, Liu Z, et al. Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci. 2001; 42:22832292. 18. Cejkov J, Ardan T, Simonov Z, et al. Nitric oxide synthase induction and cytotoxic nitrogen-related oxidant formation in conjunctival epithelium of dry eye (Sjgrens syndrome). Nitric Oxide. 2007; 17:10-17. 19. Paul A, Wilson S, Belham CM, et al. Stress-activated protein kinases: activation, regulation and function. Cell Signal. 1997; 9:403-410. 20. Pflugfelder SC, de Paiva CS, Tong L, et al. Stress-activated protein kinase signaling pathways in dry eye and ocular surface disease. Ocul Surf. 2005; 3(suppl 4):154-157. 21. Luo L, Li DQ, Doshi A, et al. Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface. Invest Ophthalmol Vis Sci. 2004; 45:4293-4301. 22. Li DQ, Luo L, Chen Z, et al. JNK and ERK MAP kinases mediate induction of IL-1beta, TNF-alpha and IL-8 following hyperosmolar stress in human limbal epithelial cells. Exp Eye Res. 2006; 82:588596. 23. De Paiva CS, Corrales RM, Villarreal AL, et al. Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye. Exp Eye Res. 2006; 83:526-535.

to suppress JNK and ERK signaling activation and inflammatory mediator production in the limbal epithelium. In conclusion, regardless of the underlying etiology, dry eye seems to be associated with chronic and perhaps subclinical inflammation that might eventually cause ocular surface damage. Novel treatments should aim toward targeting specific mediators involved in the inflammatory cascade that mediate dry eye.

Selected Readings
1. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol. 2000; 118:1264-1268. 2. Lemp MA, Baudouin C, Baum J, et al. The definition and classification of dry eye disease: report of the definition and classification subcommittee of the international dry eye workshop (2007). Ocul Surf. 2007; 5:75-92. 3. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjgren syndrome: a revised version of the European criteria proposed by the American-European consensus group. Ann Rheum Dis. 2002; 61:554-558. 4. Akpek EK, Klimava A, Thorne JE, et al. Evaluation of patients with dry eye for the presence of underlying Sjgren syndrome. Cornea 2009; 28:493-497. 5. Liew M, Zhang M, Kim E, Akpek EK. Prevalence and predictors of Sjogrens syndrome in a prospective cohort of patients with aqueous deficient dry eye. Br J Ophthalmol. Epub ahead of print 21 Sept 2012. 6. The epidemiology of dry eye disease: Report of the Epidemiology Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf. 2007; 5:93-107. 7. Connor CG, Flockencier LL, Hall CW. The influence of gender on the ocular surface. J Am Optom Assoc. 1999; 70:182-186. 8. Krenzer KL, Dana MR, Ullman MD, Cermak JM, Tolls DB, Evans JE, et al. Effect of androgen deficiency on the human meibomian gland and ocular surface. J Clin Endocrinol Metab. 2000; 85:48744882. 9. Schaumberg DA, Buring JE, Sullivan DA. Hormone replacement therapy and dry eye syndrome. JAMA. 2001; 286:2114-2119. 10. Ang RT, Dartt DA, Tsubota K. Dry eye after refractive surgery. Curr Opin Ophthalmol. 2001; 12:318-322. 11. Lee AJ, Lee J, Saw SM, Gazzard G, Koh D, Widjaja D, et al. Prevalence and risk factors associated with dry eye symptoms: a population based study in Indonesia. Br J Ophthalmol. 2002; 86:13471351.

2012 Subspecialty Day|Uveitis

Advocating for Patients

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2012 Advocating for Patients


Russell N Van Gelder MD PhD

Ophthalmologys goal in protecting quality patient eye care remains a key priority for the Academy. As health care delivery evolves, with narrowing practice margins making efficiency of increasing importance, all Eye M.D.s should consider their contributions to the following three funds as (a) part of their costs of doing business and (b) their individual responsibility in advocating for patients: 1. OPHTHPAC Fund 2. Surgical Scope Fund (SSF) 3. State Eye PAC While the Academy fully supports the concept of an integrated eye care delivery team, it also remains firm on defining appropriate roles for the various eye care providers as demonstrated via its Surgery by Surgeons campaign.

thalmologys priorities as over 350 Eye M.D.s had scheduled CAD visits to members of Congress in conjunction with the Academys 2012 Mid-Year Forum in Washington. The AUS remains a crucial partner to the Academy in its ongoing federal and state advocacy initiatives.

Surgical Scope Fund (SSF)


At the state level, the Academys Surgery by Surgeons campaign has demonstrated a proven track record. While Kentucky was an outlier, the Academys SSF has helped 33 state/ territorial ophthalmology societies reject optometric surgery language. The Academys Secretariat for State Affairs, in partnership with state ophthalmology societies, battled optometry across the country in 2011 to protect patient access to quality medical surgical care. Several ophthalmic subspecialty societies also provided critical support when called upon. Although there was a setback in Kentucky, ophthalmology derailed O.D. surgery initiatives in 7 states and achieved its first proactive victory in Oklahoma. The SSF is a critical tool of the Surgery by Surgeons campaign to protect patient quality of care and our collective fund to ensure that optometry does not legislate the right to perform surgery. The Academy relies not only on the financial contributions via the SSF by individual Eye M.D.s but also the contributions made by ophthalmic state, subspecialty and specialized interest societies. The AUS contributed to the SSF in 2011 and the Academy counts on its contribution in 2012. With last years passage of legislation in Kentucky that allowed optometrists to perform laser surgery, the American Academy of Ophthalmologys partnership with ophthalmic subspecialty and state societies in the Surgery by Surgeons campaign became even more important in protecting quality patient eye care across the country. The Academys Secretariat for State Affairs redoubled its efforts with target states, including Tennessee and others, while adding professional media training to the resources provided to prepare Eye M.D.s in advance of any anticipated legislative or regulatory move.

OPHTHPAC Fund
OPHTHPAC is acrucial part of the Academys strategy to protect and advance ophthalmologys interests in key areas, including physician payments in Medicare as well as protecting ophthalmology from federal scope of practice threats. Established in 1985, today OPHTHPAC is one of the largest and most successful political action committees in the physician community. In 2010, Politico highlighted OPHTHPAC as one of the most successful health PACs in strategic giving in the 2010 election. By making strategic election campaign contributions and independent expenditures, OPHTHPAC helps us elect friends of ophthalmology to federal leadership positions, ultimately resulting in beneficial outcomes for all Eye M.D.s. For example, 20 physicians, including 2 ophthalmologists, were elected to Congress in 2010. Thanks to the OPHTHPAC contributions made in the 2007-2010 timeframe, ophthalmology realized an 8% increase in Medicare payments (other specialties experienced significant decreases). Among the significant impacts of OPHTHPAC: Averted significant cuts to Medicare payments due to the Sustainable Growth Rate (SGR) formula Protected Practice Expense increases for ophthalmology when attacked by other specialties Exempted ultrasound from imaging cuts Protected the in-office ancillary services exception Secured physician exemption from Red Flag (creditor) rules Secured reversal of a CMS decision to cut reimbursement for Avastin Delayed Medicare penalties dates in health reform law Secured appointment of full-time ophthalmology national program director in the Department of Veterans Affairs Leaders of the American Uveitis Society (AUS) are part of the American Academy of Ophthalmologys Ophthalmic Advocacy Leadership Group (OALG), which has met for the past five years in the Washington, DC, area to provide critical input and to discuss and collaborate on the Academys advocacy agenda. As 2012 Congressional Advocacy Day (CAD) partners, the AUS ensured a strong presence of uveitis specialists to support oph-

State Eye PAC


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

Action Requested: Advocate for Your Patients!!


PAC contributions are necessary at the state and federal level to help elect officials who will support the interests of our patients. Academy SSF contributions are used to support the infrastructure necessary in state legislative/ regulatory battles and for public education. Contributions across the board are needed. SSF contributions are completely confidential and may be made with

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Advocating for Patients OPHTHPAC Fund


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

2012 Subspecialty Day|Uveitis

Surgical Scope Fund


Scope of practice at the state level Lobbyists, media, public education, administrative needs Contributions: Unlimited Contributions are 100% confidential

State EyePAC
Support for candidates for State House and Senate Campaign contributions, legislative education

Contributions: Limited to $5,000 Contributions above $200 are on the public record

Contribution limits vary based on state regulations Contributions are on the public record

corporate checks or credit cardsunlike PAC contributions, which must be made by individuals and which are subject to reporting requirements. Please respond to your Academy colleagues who are volunteering their time on your behalf to serve on the OPHTHPAC* and SSF** Committees, as well as your state ophthalmology society leaders, when they call on you and your subspecialty society to contribute. Advocate for your patients now!

**Surgical Scope Fund Committee


Thomas A Graul MD (NE) Chair Arezio Amirikia MD (MI) Ronald A Braswell MD (MS) Kenneth P Cheng MD (PA) John P Holds MD (MO) Bryan S Lee MD PhD (MD) Consultant Stephanie J Marioneaux MD (VA) Andrew Tharp MD (IN) Ex-Officio Members: Cynthia A Bradford MD Daniel J Briceland MD

*OPHTHPAC Committee
Donald J Cinotti MD (NJ) Chair Charles C Barr MD (KY) William Z Bridges Jr MD (NC) Dawn C Buckingham MD (TX) Robert A Copeland Jr MD (Washington DC) James E Croley III MD (FL) Anna Luisa Di Lorenzo MD (MI) Andrew P Doan MD PhD (CA) Warren R Fagadau MD (TX) Michael L Gilbert MD (WA) Alan E Kimura MD (CO) Lisa Nijm MD JD (IL) Andrew J Packer MD (CT) Andrew M Prince MD (NY) Kristin E Reidy DO (NM) Ruth E Williams MD (IL) Ex-Officio Members: Cynthia A Bradford MD (OK) Gregory P Kwasny MD (WI) Michael X Repka MD (MD)

2012 Subspecialty Day|Uveitis

Section IV: Infectious UveitisHow Can One Tell if the Problem Is Microbial?

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Herpes, Syphilis, and Tuberculosis

The Challenges Continue, but the Future Is Bright


Amod Gupta MBBS, Reema Bansal MBBS, Vishali Gupta MBBS, and Aman Sharma MD
It is critical to differentiate autoimmune uveitis from masquerades and the infective uveitides. Unlike the autoimmune uveitides, which require long-term corticosteroid/ immunosuppressive therapy and tend to recur and often run a chronic course, the infective uveitides, if managed in a timely manner, have good visual outcomes. However, the infective uveitides require a high index of suspicion and pattern recognition. rescent in the late frames. Retinal vessels may show occlusive changes. The retinal vessels show staining of the vessel walls. Serological tests are diagnostic. Both nontreponemal such as VDRL and RPR and specific treponemal (TPHA, FTA-Abs) may be ordered. In patients with HIV infection, the former tests may be negative. Since uveitis is often seen in patients with neurosyphilis, serological tests, WBC counts, and protein estimation from CSF is ordered. All patients with syphilitic uveitis should be treated as neurosyphilis with intravenous crystalline penicillin 4 M units given every 4 hours for 2-3 weeks. Concomitant use of oral/topical corticosteroids is recommended. If treated promptly, uveitis carries a good prognosis for visual recovery. If treatment is delayed, patients may permanently lose vision, complaining of night blindness and optic atrophy.

Syphilis
This sexually transmitted bacterial disease, caused by Treponema pallidum and once considered on the wane, has reemerged in the last decade, especially in the United States, Canada, and several European countries. Up to 5% of patients with tertiary syphilis may develop ocular syphilis, and increasing numbers are being reported. Human immunodeficiency virus infection may coexist in 60%-70% of patients with syphilis, especially in men having sex with men. Uveitis is one of the most common manifestations of ocular syphilis but requires a very high index of suspicion because of a wide spectrum of clinical manifestations. Ocular syphilis may be the presenting symptom of HIV infection. Men are predominantly affected. There are no pathognomonic signs of syphilitic uveitis. Since these patients frequently have neurosyphilis, they may complain of headache, deafness, nausea, and unsteady gait. Patients may present with bilateral anterior, intermediate, posterior, or panuveitis. Patients with HIV infection may develop uveitis in early or late stages of syphilis and present more often with posterior uveitis. Patients with HIV infection and higher reagin titers also present with more severe inflammation. Uveitis may have either acute or insidious onset and if untreated may run a chronic course. In posterior uveitis, patients may present with single or multifocal yellow, creamy, placoid lesions with overlying significant vitritis. Necrotizing retinitis may be seen uncommonly. There may be variable exudative retinal detachment. Uncommonly, punctate retinitis and preretinal infiltrates may be seen. Optic disc hyperemia and peripapillary retinal swelling may be significant (see Figure 1), and late stages show optic atrophy. Posterior segment may show leopard skin lesions. On fundus fluorescein angiography, the placoid lesions show hypofluorescence during the dye transit that becomes hyperfluo-

Herpes
Herpetic anterior uveitis is commonly caused by herpes simplex virus (HSV) and varicella zoster virus (VZV), followed by cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpes virus (HHV). It is characterized by a recurrent, granulomatous iridocyclitis, frequently associated with corneal involvement in the form of corneal scar or active keratitis. Iris atrophy and transiently raised IOP due to trabeculitis are common (see Figure 2). Scleritis has been recently reported to be associated with herpetic infection. Posterior segment involvement may occur in the form of acute retinal necrosis (ARN) or progressive outer retinal necrosis (PORN). ARN usually occurs in immunocompetent individuals and PORN in severely immunocompromised persons.

Figure 2. (a) Anterior segment photograph of a 18-year-old male with herpetic anterior uveitis in the right eye with pigmented keratic precipitates. PCR from aqueous fluid was positive for HSV. (b) Three weeks after initiating oral antiviral therapy, the anterior segment was quiescent.

Figure 1. Fundus photograph (a) and fluorescein angiograph (b) of a 43-year-old male with decreased vision in right eye for 20 days (6/12) who presented with syphilitic neuroretinitis. He received intravenous penicillin for 2 weeks and recovered 20/20 visual acuity with mild optic disc pallor.

ARN is characterized by peripheral necrotizing retinitis involving all retinal layers, occlusive vasculitis predominantly arteritis, and significant vitritis. It is usually unilateral but may be bilateral in a few cases. The diagnosis is primarily clinical, with yellow-white retinitis lesions that are tongue-shaped, begin in periphery, and advance circumferentially. PCR may yield a positive result from the aqueous or vitreous fluid, but a negative PCR does not rule out the diagnosis. HSV and VZV have been known to be the common viruses causing ARN. The disease is sight-threatening because of rapid necrosis of retina causing atro-

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Section IV: Infectious UveitisHow Can One Tell if the Problem Is Microbial?

2012 Subspecialty Day|Uveitis

phic retinal holes, which increase the risk of developing retinal detachment. Fellow eye may get involved within 6 weeks. Intravenous acyclovir is recommended, with an initial dosage of 15 mg/kg 3 times daily for 10 days, followed by oral acyclovir 800 mg 5 times/day for at least 6 weeks, tapered gradually over the next few months. The patients should be monitored for renal function tests. In patients not responding to acyclovir, oral famciclovir or ganciclovir have been recommended. Other drugs that can be used include valaciclovir and foscarnet. Oral corticosteroids are used to control active inflammation, and should be started at a high dose (1 mg/kg/day), and tapered gradually. A low-dose aspirin (100 mg/day) is beneficial in view of occlusive retinal arteritis. Vitreous surgery is indicated for retinal detachment or prophylactic for debulking the inflammatory cells and releasing vitreous traction. The role of prophylactic laser photocoagulation is controversial. Besides fulminant necrotizing retinitis, slow-progressing necrotizing and non-necrotizing variants have also been recognized, due to HSV and VZV. PORN is characterized by large areas of necrosis with deep retinal opacification and minimal involvement of retinal vessels (see Figure 3). Vitritis is minimal. The posterior pole is affected early because of confluence of progressing lesions. It is usually bilateral. The diagnosis is often clinical. Treatment is with intravenous acyclovir, intravitreal ganciclovir, and HAART if patients are HIV infected.

Figure 4. Right eye of a 45-year-old female with a positive tuberculin skin test, showing a choroidal tuberculoma with surrounding exudative retinal detachment. PCR was positive for M TB.

Figure 3. Fundus photograph of right (a) and left (b) eyes of a 45-yearold male showing progressive outer retinal necrosis with visual acuity 6/9 in both eyes. He had undergone renal transplant 5 years ago and had developed chicken pox a month before becoming visually symptomatic.

CMV retinitis is commonly associated with AIDS. Hemorrhagic retinitis lesions and perivascular infiltration near the posterior pole may be seen affecting one or more quadrants.

Tuberculosis
Tuberculosis (TB) has long been recognized as a cause of uveitiswith increasing reports, particularly from endemic regions of the world. It usually occurs in the absence of any systemic evidence of TB. The clinical spectrum is extremely wide, and any part of the eye can get affected, with chronic recurrent granulomatous anterior uveitis, retinal vasculitis, serpiginouslike choroiditis, choroidal tubercules (see Figure 4), or neuroretinitis as common clinical signs. Fundus autofluorescence in serpiginouslike choroiditis can reliably monitor lesions as they evolve from the acute to the healed stage.

The diagnosis is usually presumptive, based on clinical findings, corroborative indirect evidence of a latent TB infection, and exclusion of other specific uveitic entities. The tuberculin skin test (TST) is the most common laboratory test performed. Recently, interferon-gamma release assays (IGRAs), such as the QuantiFERON-TB Gold In-Tube (QFT) (Cellestis, Inc.; Australia) and ELISpotPLUS (T-SPOT.TB, Oxford Immunotec; Abingdon, UK) have found significant use in detection of TB uveitis. These measure interferon-gamma response produced by the T cells after antigenic stimulation. The diagnostic accuracy is known to improve with their use. Chest radiography has a very limited role, and direct microscopic or histopathologic evidence of intraocular TB by demonstration of acid-fast bacilli (AFB) on direct smear or culture of mycobacteria from ocular fluids or tissue specimens is extremely rare. Direct evidence by PCR is gaining worldwide use. Real-time PCR and multitargeted PCR (MPCR) are newer diagnostic aids for TB uveitis. MPCR uses 3 target genes simultaneously for diagnosis of TB, namely, IS6110, MPB64, and protein b. Using 3 primers in intraocular fluids has shown a high sensitivity and specificity for diagnosing TB uveitis (unpublished data). Treatment is started with 4-drug antitubercular therapy for the first 2-3 months, followed by 2-drugs for at least 7 more months. Corticosteroids are tapered depending upon the clinical response. Recurrences are known to be significantly reduced with administration of antitubercular therapy. Patients on therapy should be monitored for hepatotoxicity.

References
Syphilis 1. Chao JR, Khurana RN, Fawzi AA, Reddy HS, Rao NA. Syphilis: reemergence of an old adversary. Ophthalmology 2006; 113:20742079. 2. Tucker JD, Li JZ, Robbins GK, et al. Ocular syphilis among HIVinfected patients: a systemic analysis of the literature. Sex Transm Infec. 2011; 87:4-8.

2012 Subspecialty Day|Uveitis

Section IV: Infectious UveitisHow Can One Tell if the Problem Is Microbial?
Tuberculosis

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3. Ormerod LD, Puklin JE, Sobel JD. Syphilitic posterior uveitis: correlative findings and significance. Clin Infect Dis. 2001; 32:16611673. 4. Anshu A, Cheng CL, Chee S-P. Syphilitic uveitis: an Asian perspective. Br J Ophthalmol. 2008; 92:594-597. 5. Wickremasinghe S, Ling C, Stawell R, et al. Syphilitic punctate inner retinitis in immunocompetent gay men. Ophthalmology 2009; 116:1195-1200. 6. Marra CM. Update on neurosyphilis. Curr Infect Dis. 2009; 11:127-134. Herpes 7. Tugal-Tutkun I, Otuk-Yasar B, Altinkurt E. Clinical features and prognosis of herpetic anterior uveitis: a retrospective study of 111 cases. Int Ophthalmol. 2010; 30: 559-565. 8. Holland GN; the Executive Committee of the American Uveitis Society. Standard diagnostic criteria for the acute retinal necrosis syndrome. Am J Ophthalmol. 1994; 117:663-667. 9. Kawaguchi T, Spencer DB, Mochizuki M. Therapy for acute retinal necrosis. Semin Ophthalmol. 2008; 23:285-290. 10. Kim SJ, Equi R, Belair ML, Fine HF, Dunn JP. Long-term preservation of vision in progressive outer retinal necrosis treated with combination antiviral drugs and highly active antiretroviral therapy. Ocul Immunol Inflamm. 2007; 15(6):425-427.

11. Gupta A, Bansal R, Gupta V, Sharma A, Bambery P. Ocular signs predictive of tubercular uveitis. Am J Ophthalmol. 2010; 149:562570. 12. Gupta V, Gupta A, Arora S, et al. Presumed tubercular serpiginouslike choroiditis: clinical presentations and management. Ophthalmology 2003; 110:1744-1749. 13. Gupta A, Bansal R, Gupta V, Sharma A. Fundus autofluorescence in serpiginouslike choroiditis. Retina 2012; 32(4):814-825. 14. Ang M, Htoon HM, Chee SP. Diagnosis of tubercular uveitis: clinical application of an interferon-gamma release assay. Ophthalmology 2009; 116:1391-1396. 15. Gupta A, Gupta V, Arora S, et al. PCR-positive tubercular retinal vasculitis: clinical characteristics and management. Retina 2001; 21:435-444.

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Section IV: Infectious UveitisHow Can One Tell if the Problem Is Microbial?

2012 Subspecialty Day|Uveitis

Infectious Uveitis, the Most Common Problem Worldwide: What Else to Consider?
Rubens Belfort Jr MD, Cristina Muccioli MD
Infectious Uveitis
Classic and emerging infectious agents Infectious uveitis comprises 10 to 60% of cases. Bacteria, virus, parasites and fungi More than 100 etiologies (see Table 1) Direct invasion to the eye or uveitis secondary to infection and immunologic changes elsewhere. Marked differences globally Risk factors Socio economic conditions Water, food and soil contamination Health conditions of population (such as HIV infection, etc.) Geographic distribution patterns Table 1. Examples of Important Infectious Uveitis
Toxoplasmosis Cytomegalovirus Tuberculosis Syphilis Herpes DUSN Toxocariais Bartonella Borrelia Dengue Fever Leprosy Leptospirosis Onchocerciasis Rickettsiosis West Nile virus infection Rift valley fever Chikungunya Candidiasis

Table 2. Wrong Concepts in Ocular Toxoplasmosis


All cases are congenital. Must present as a retinochoroiditis. Vertical transmission (pregnancy) occurs only once in life. Cats and meat are the only source. There is no treatment to avoid recurrences. All patients need antitoxoplasmic drugs for 4-6 weeks. Recurrences are related only to persistent retinal cysts.

Background Necrotizing retinochoroiditis satellite lesion adjacent to old hyperpigmented scars accompanied by vitreous inflammation, retinal vasculitis, and anterior uveitis. Immunosuppressed patients have a tendency to present bilateral lesions with diffuse retinitis and less vitreous involvement. Diagnosis Based on the clinical picture. Laboratory Serology (circulating antibodies to T. gondii), PCR (aqueous humor and vitreous), genotyping. Complications Macular edema, retinal neovascularization, vascular occlusion, vitreous hemorrhage, epiretinal and subretinal neovascular membranes, retinal detachment, glaucoma and cataract. Treatment Antitoxoplasmic drugs associated with steroids (decrease the inflammation and improve vision). Table 3. Therapy for Ocular Toxoplasmosis
Weeks to months, depending on clinical picture and response Systemic steroids always associated to antitoxoplasmic drugs Pyrimethamine + sulfadiazine (or trimethoprim + sulfamethoxazole) Systemic or intraocular clindamycin and combination of trimethoprim/sulfamethoxazole have also been used. Folinic acid: during pyrimethamine therapy

Diagnosis Pattern of uveitis, plus specific epidemiological data confirmed by the presence of immune response to the specific pathogen or the identification of it preferably in the eye. In any patient with uveitis, an infectious cause should be ruled out first. New diagnostic techniques (such as panmicrobial microarrays) confirm higher number of pathogens as cause of uveitis until recently diagnosed as noninfectious (eg, Fuchs heterochromic cyclitis caused by rubella or toxoplasma and anterior uveitis caused by cytomegalovirus).

Ocular Toxoplasmosis (OT)


Caused by an obligate, intracellular protozoan parasite (Toxoplasma gondii) and the most important and frequent cause of infectious retinal disease and posterior uveitis. Many concepts related to OT have changed in the last years (see Table 2).

Prevention of recurrences Combination of trimethoprim/ sulfamethoxazole given for many months may decrease the number of recurrences and may be considered in higher-risk patients.

2012 Subspecialty Day|Uveitis

Section IV: Infectious UveitisHow Can One Tell if the Problem Is Microbial?

27

Dengue Fever
Background Arthropod-borne viral disease (transmitted by Aedes mosquitoes) in over 120 countries, including the Southern United States Ocular disease Asymmetric-bilateral, posterior uveitis. Decreased vision, floaters, retinal hemorrhages, bilateral choroidal effusion, capillary occlusion, retinal hemorrhages, cotton wool spots, vascular sheathing, choroidal vasculopathy and neuropathy. Laboratory diagnosis Circulating IgM specific antibodies Treatment Systemic steroids, prompt hospital-based treatment of systemic complications and avoid aspirin

Diffuse Unilateral Subacute Neuroretinitis (DUSN)


Background Caused by nematodes, usually unilateral, and before the third decade of life Ocular disease Mild vitritis, progressive optic atrophy, narrowed retinal vessels, pigment epithelial stippling and visual field loss Diagnosis Slitlamp retinal exam that discloses a worm moving under the retina Treatment Photocoagulation of the worm or systemic antihelmintic agents (albendazole or thiabendazole)

Cytomegalovirus (CMV) Retinitis and Anterior Uveitis


Ocular disease Progressive retinitis with vasculitis and hemorrhages in immunocompromised hosts (AIDS, transplanted patients receiving immunosuppressive medications). Three clinical forms: Necrotizing, granular, and frosted-branch angiitis. Treatment Systemic or intraocular therapy with anti-CMV drugs. HAART leads to recovery of immune function, allows individuals to discontinue their CMV therapy but some develop uveitis secondary to the immune recovery. CMV has also been recognized as the etiology of anterior uveitis and endotheliitis in nonimmunosuppressed individuals.

Leprosy
Background Important and neglected cause of blindness Ocular disease Chronic anterior uveitis with iris pearls (represent miliary lepromas), vitreous opacities, retinal detachment, extensive iris atrophy, and intractable glaucoma. Posterior uveal involvement is rare. Treatment Treatment of iridocyclitis is mandatory, as well as protection of anesthetic corneas from exposure, erosion, and ulceration in the face of lagophthalmos.

Selected Readings
1. Arevalo JF, Chee SP, Cunningham ET Jr, Kestelyn P, Rathinam SR. Uveitis in the Developing World. Preface. Int Ophthalmol Clin. 2010; 50(2). 2. Belfort Jr R, Silveira C, Muccioli C. Retina. In: Ryan SJ, et al, eds. Ocular Toxoplasmosis. Oxford, UK: Saunders; 2013. 3. Commodaro AG, Belfort RN, Rizzo LV, et al. Ocular toxoplasmosis: an update and review of the literature [review]. Mem Inst Oswaldo Cruz. 2009; 104(2):345-350. 4. Grigg ME, Ganatra J, Boothroyd JC, et al. Unusual abundance of atypical strains associated with human ocular toxoplasmosis. J Infect Dis. 2001; 184(5):633-639. 5. De Groot-Mijnes JD, de Visser L, Zuurveen S, et al. Identification of new pathogens in the intraocular fluid of patients with uveitis. Am J Ophthalmol. 2010; 150(5):628-636. 6. Nussenblatt RB, Whitcup S. Uveitis, 3rd ed. Mosby; 2004. 7. Perry LJP, Chodosh J, Durand M. Advances in detection and treatment of ocular infections. Int Ophthalmol Clin. 2011; 53(4).

Toxocariasis
Background Caused by the ingestion of larvae of Toxocara canisor cati. Three basic forms of ocular involvement: diffuse (endophthalmitis), posterior pole and pars plana granulomas. It may follow or not clinical visceral larva migrans syndrome. Tends to occur in older children and young adults as unilateral disease. Diagnosis Clinical picture and serum antibodies to Toxocara Treatment/prognosis Visual outcome is usually poor due to late diagnosis. Mebendazole or diethylcarbamazine kill the nematode larvae. Prednisone should be used as an adjunct to anti-helminthic therapy in patients with ocular active inflammation.

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Section V: On the Special Matter of Pediatric Uveitis

2012 Subspecialty Day|Uveitis

Differential Diagnosis of Uveitis in the Pediatric Population: Sarcoid,Tubulointerstitial Nephritis and Uveitis Syndrome, and Beyond
Debra A Goldstein MD
N otes

2012 Subspecialty Day|Uveitis

Section V: On the Special Matter of Pediatric Uveitis

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Juvenile Idiopathic Arthritis Associated Uveitis: When to Move Off Corticosteroid Therapy?
Laure Caspers MD, Emmanuelle Leys, Irina Balikova, Xavier Janssens, Florence Duchateau, Franois Willermain, Alice Ferster, and Le Phu Quoc
Introduction
Approximately 6% of all cases ofuveitisarise in children.1 The most frequent cause of chronic intraocular inflammation among children is juvenile idiopathic arthritis (JIA)-associated uveitis.2 JIA, as defined by the American Rheumatism Association (ARA), is the presence of arthritis (chronic, seronegative, and peripheral) before age 16 years, of at least 3 months duration, when other causes have been excluded. It is classified by 1 of 3 types of onset:3 oligoarticular (pauciarticular), polyarticular, and systemic. Oligoarticular onset of JIA (40%-60%) is more common in girls (5:1). Onset peaks at age 2 years. About 75% of these patients test positive for antinuclear antibody (ANA). This mode of onset has a high risk for uveitis.3 The polyarticular onset JIA (20%-40%) has an intermediate risk for uveitis. It is also more common in girls (3:1), and the onset peaks around the age of 3 years. Approximately 40% of these patients test positive for ANA. Systemic-onset JIA has a very low risk for uveitis. Uveitis is the most common manifestation of JIA after arthritis and is seen in up to 30% of antinuclear antibody (ANA)-positive patients with JIA. Chronic iridocyclitis occurs in 10%-20% of all patients with JIA.3 It is typically asymptomatic. There is a progressive morbidity with 30%-40% of patients with severe loss of vision as leading to possible blindness. Treatment has not been standardized. Topical corticosteroid therapy (TCST) remains the first choice, followed by immunomodulatory therapy (IMT). Little is known about when systemic corticosteroid treatment (SCST) should be introduced and arrested in uveitis-related JIA, and the goal of the study is to assess this question. ranged from 1.5 to 11.8 years, with a mean of 3.13 years. The age of patients at diagnosis of JIA uveitis ranged from 0.75 to 11.8 years, with a mean of years 3.9 years. The age of patients at end of follow-up ranged from 4 to 40 years, with a mean age of 19 years. The duration of follow-up ranged from 4 to 36 years, with a mean of 10.6 years. TCST was used in all the patients. Corticosteroid was injected intravitreously or periocularly in 6 patients. Ten patients had a SCST. Fifteen patients had an IMT constituted of at least methotrexate. Eleven patients had an anti-TNF alpha treatment. Eight patients had a final VA <20/40 at least in one eye, and these patients had SCST for mean duration of 4.2 years, while those with a final VA 20/40 had SCST for a mean duration of 3.6 years. SCST were stopped because of temporary remissions in most patients but also because of toxicity in 3 cases. Flare-up was frequently observed after SCST withdrawal, which was then replaced by IMT. Two drugs were associated in 4 cases and 3 drugs were associated in 4 cases in order to better control inflammation and prevent toxicity. We had no severe Cushingoid syndrome like those sent to our clinic after years of SCS treatment as unique therapy. All but 1 patient with a final VA <20/40 at least in one eye had methotrexate treatment. Five of these patients had no anti-TNF alpha treatment; two had etanercept (Enbrel) and one had infliximab (Remicade), while in patients with a final VA 20/40, adalimumab (Humira) or infliximab (Remicade) or etanercept (Enbrel) followed by adalimumab (Humira) and infliximab (Remicade) and 1 patient who had no anti-TNF alpha treatment. Cataract was observed in all but 2 patients. An elevated IOP was observed in 14 patients. Among the 4 patients with normal IOP, no SCST was used in 2 of them and no TCST or TCST was used in 1 of them. Four patients had retinal detachment and had all 4 TCST and SCST. Seven patients had hypotony, all but 1 had SCST and 2 of them had 2 or 3 successive anti-TNF alpha treatment. All but 1 of them had also additional methotrexate. Inactivity was observed at the end of follow-up with ongoing IMT in 10 patients and was observed without IMT in 3 patients still under TCST. One of these patients was at the end of very long followup and the 2 others had only SCST but no IMT and were probably less severe patients. Most side effects of corticosteroids were reversible except in 1 patient who had a osteonecrosis at the age of 35 years.

Methods
Chart review of 18 patients with JIA-associated chronic or recurrent uveitis with an ongoing follow up in the Brussels University Hospitals was done. Inclusion criteria were disease onset between the age of 1-16 years, diagnosis of JIA by a rheumatologist, presence of uveitis consistent with JIA-associated uveitis. The data collected for each patient were gender, age at diagnosis of uveitis and arthritis, duration of follow-up, subtype of arthritis, ANA positivity, family history of JIA, age at which TCST, SCST, IMT were started and ended, the various IM drugs used, total duration of TCST, SCST IMT, reasons for withdrawal of TCST, SCST, IMT, initial and final visual acuity (VA) with a significant VA change above 2 Snellen lines, side effects, and time to relapse after withdrawal. Remission was defined as <1+ cells in the anterior chamber or vitreous. None of the authors have a financial interest, and this retrospective study was approved by the IRB of the hospital.

Discussion
The medical treatment of JIA-associated uveitis has changed with time. The mainstay of initial treatment for uveitis remains corticosteroids.7 For patients requiring chronic therapy, the initial agents of choice are typically antimetabolites including methotrexate, (mycophenolate mofetil and azathioprine). The use of immunosuppressive therapy has been shown in a retrospective study to be associated with an important reduction of severe side effects of JIA-associated uveitis.6 Cyclosporine has limited value in the treatment of JIA-associated uveitis.4 The use of biologics in JIA is now well known and include adalimumab

Results
Eighteen patients (14 F) with JIA diagnosed by a rheumatologist were included; 11 patients had an oligoarticular subtype; 12 patients tested positive for ANA. Four patients had a family history of JIA. The age of patients at diagnosis of JIA arthritis

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Section V: On the Special Matter of Pediatric Uveitis

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(Humira), infliximab (Remicade), and etanercept (Enbrel, TNFalpha blockers, and abatacept (Orentia) a T cell activation.7 Prospective randomized clinical trials are currently under way to investigate the effectiveness of TNF-alpha inhibitors for JIAassociated uveitis. As more patients receive immunosuppressive therapy for ocular inflammatory disease, the long-term safety profile of these treatments becomes important, particularly in children with JIA, who may require systemic treatment for decades. Corticosteroids long-term use in children has many well-known severe side effects including growth decrease, Cushingoid changes, and osteoporosis. Long-term toxicity of antimetamolites has been evaluated in adults. A recent largescale retrospective cohort study by Kempen et al5 included 7957 U.S. residents with noninfectious ocular inflammatory disease, of whom 2340 received immunosuppressive therapy. Patients who took antimetabolites, T cell inhibitors, and corticosteroids had overall and cancer-related mortality similar to patients who never took immunosuppressive medications and similar to the general U.S. population. Patients who took TNF-alpha inhibitors had increased overall and cancer-related mortality.5 The MERSI study presented at ARVO in 2012 suggested that treatment of chronic recurrent JIA-associated uveitis at a younger age and soon after the diagnosis with IMT for a 2-year period of quiescence on IMT and off all corticosteroid therapy increases the odds of the patient to maintain remission after IMT is discontinued. Our preliminary results did suggested that most patients are still treated with ongoing IMT and TCS at the end of follow-up and that the 3 patients without IMT at the end of follow-up still needed topical treatment. SCST. Bi-therapy and tri-therapy were both used in 4 cases to avoid side effect of SCST and IMT. Cataract and glaucoma were observed in most patients and did not appear to be related to corticosteroids. Retinal detachments and hypotony might be related to corticosteroid treatment. Most side effect of corticosteroids were reversible except one patient who had a osteonecrosis at age of 35 years. The early addition of anti-TNFalpha to ledertrexate with or without SCST might have been the most effective treatment is those patients. This needs to be further evaluated.

Conclusion
Cataract and glaucoma were observed in most patients with JIA uveitis independently from therapeutic regimen. Severe hypotony and retinal detachement were more often observed in patients with SCST and methotrexate than in those treated with antiTNF. The combination of several IMT with or without low dosage of SCST as a bi- or tri-therapy was found to be effective and helpful to prevent toxicity. JIA-associated uveitis remains a challenging disease to treat, with ocular morbidity lasting well into adulthood. Randomized controlled trials are needed to assess the efficacy and safety of antimetabolites, as these remain the first-line treatment for chronic JIA-associated uveitis. Long-term safety of biologic treatment is a concern, especially since children with JIA require years of treatment. Long standing high dosage of corticosteroids were never used in our referral center, but some patients with JIA-related uveitis were occasionally referred to our clinic after years of SCST as a unique therapy with high level of toxicity and absolutely needed to move off their SCST.

References
1. Nguyen QD, Foster CS. Saving the vision of children with juvenile rheumatoid arthritis-associated uveitis. JAMA. 1998; 280(13):1133-1134. 2. Pivnsalo-Hietanen T, Tuominen J, Saari KM. Uveitis in children: population-based study in Finland. Acta Ophthalmol Scand. 2000; 78(1):84-88. 3. Kesen MR, Setlur V, Goldstein DA. Juvenile idiopathic arthritisrelated uveitis. Int Ophthalmol Clin. 2008; 48(3):21-38. 4. Tappeiner C, Roesel M, Heinz C, et al. Limited value of cyclosporine A for the treatment of patients with uveitis associated with juvenile idiopathic arthritis.Eye (Lond). 2009; 23(5):1192-1198. 5. Kempen JH, Daniel E, Dunn JP, et al. Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive drugs: retrospective cohort study.BMJ. 2009; 339:b2480. 6. Thorne JE, Woreta F, Kedhar SR, et al. Juvenile idiopathic arthritisassociated uveitis: incidence of ocular complications and visual acuity loss.Am J Ophthalmol.2007; 143(5):840-846. 7. Qian Y, Acharya NR. Juvenile idiopathic arthritis associated uveitis. Curr Opin Ophthalmol.2010;21(6):468-472.

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Section VI: Puzzling White DotsWhats a Doctor to Do?

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Is It Birdshot Retinochoroidopathy, and If So, How Should I Treat It?


Albert T Vitale MD
I. History and Epidemiology A. Ryan and Maumenee (1980), Gass (1981) B. Epidemiology 1. Uncommon: 1.2%-7.9% PU tertiary setting 2. Later onset: mean age 50 years (35-70) 3. Caucasian, Northern European 4. Female predominance (50%-70%) 5. No consistent systemic disease association a. Hypertension b. Atopy 5. Abnormal color 6. Frequently excellent VA B. VA poor surrogate for disease severity 1. Symptoms 2. Clinical findings C. Lesion characteristics 1. Ovoid, cream-colored 50-1500 mm 2. Indistinct borders 3. Level of the choroid or retinal pigment epithelium (RPE) 4. Post-equatorial fundus 5. Radial distribution, nasal 6. Indirect ophthalmoscopy 7. Not correlated with BCVA 8. Pigmentation associated with symptoms a. Blurred, vibrating VA b. Nyctalopia 1. Retinal vasculitis 2. CME (60%) 3. Optic-nerve edema 4. Mild nongranulomatous iritis 5. Diffuse vitritis with precipitates on the vitreous face E. Late findings 1. Attenuated retinal vessels 2. Optic atrophy 3. Epiretinal membranes (19%) 4. CNVM (6%) 5. RPE atrophy A. Inconsistent findings: Depends on age lesion, phase of study B. Early lesions: Early hypofluorescence with subtle late staining C. Old lesions: No significant window defects D. Highly sensitive for detection disease activity: Optic nerve (ON) leakage, segmental phlebitis, CME, CNV

II. Pathogenesis A. Immunogenetics 1. HLA-A-29 + (80%-98%) 2. 7% general white population a. HLA - A29*02 (Caucasian) b. HLA - A29*01 (Asian) 3. 50-fold to 224-fold risk 4. 96% sensitive, 93% specific B. Retinal autoimmunity 1. Lymphocyte proliferation to retinal S antigen 2. Similarity between birdshot retinochoroidopathy and experimental autoimmune uveitis 3. Mixed T and B cells in choroidal lesions, no organisms C. Mechanism 1. expression self peptides to T cells A29 molecule? 2. Polymorphisms in linkage disequilibrium with HLA-A29? 3. Molecular mimicry with microbial antigen? a. Antigen specific vs. nonspecific bystander activation

D. Active disease

IV. Fluorescein Angiography (FA)

b. Borrelia burgdorferi III. Ophthalmic Findings A. Presentation 1. Blurred visual acuity (VA) 2. Floaters, photopsias 3. Paracentral scotomas 4. Nyctalopia

32

Section VI: Puzzling White DotsWhats a Doctor to Do? V. Indocyanine Green Angiography A. Hypofluorescent round lesions, intermediate phase 1. Remain hypofluorescent/ become isoflourescent, late B. Fuzzy, indistinct choroidal vessels and late-diffuse choroidal hyperfluorescence during active disease C. More numerous than IVFA, exam 1. Larger than multiple evanescent white dot syndrome, multifocal choroiditis/panuveitis (MCP) 2. Smaller than acute multifocal placoid pigment epitheliopathy (AMPPE), Vogt-KoyanagiHarada syndrome (VKH) D. Distributed along choroidal vessels 1. Not clustered around ON A. Complimentary to FA B. BCVA (N = 80) 1. Vascular leakage 2. Macular thickness: Increased or decreased 3. Loss third highly reflective band OCT a. Photoreceptors inner/outer segment junction b. Blurred VA, color, vibration c. Reversible? VI. OCT

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E. Variety abnormalities despite normal BCVA 1. Multiple foci, arcuate defects 2. Associated with retinal damage a. Loss of third highly reflective band on OCT 1. BCVA, color contrast sensitivity 2. Symptoms: Blurry VA, nyctalopia, loss of contrast sensitivity G. Objective measure to follow disease activity IX. Electrophysiology A. Inner retinal dysfunction rod and cone systems 1. 30 HZ flicker implicit time delay 2. Scotopic bright flash amplitudes reduced a. Electronegative maximal ERG, b/a ratio 3. May reflect degree retinal vasculopathy B. Serial ERG 1. Improvement retinal function with systemic treatment 2. Objective tool to assess disease activity 3. Guide to initiate therapy 4. Predictor of disease recurrence during taper of IMT A. Required 1. Bilateral 2. Birdshot lesions 3 inferior or nasal to ON 3. Low grade anterior chamber inflammation 4. Low grade vitreous inflammation B. Supportive 1. HLA-A29 positivity 2. Retinal vasculitis 3. CME C. Exclusion 1. Keratic precipitates 2. Posterior synechiae 3. Other infectious, neoplastic, inflammatory entity causing multifocal choroidal lesions A. Inflammatory 1. Sarcoidosis 2. White dot syndromes (APMPPE, punctate inner choroidopathy, MCP, subretinal fibrosis with uveitis, SFU) 3. VKH F. Mean deviation related to disease characteristics

VII. Fundus Autofluorescence (FAF) A. Hypoautofluorescence due to RPE atrophy B. Nonuniform correspondence hypoautofluorescence/ birdshot lesions C. Linear hypoautofluorescent streaks along retinal blood vessels 1. Corresponding visible changes at RPE D. Placoid hypoautofluorescence macula, no visible RPE change 1. Correlated with BCVA 20/50 (P < .05) E. Choroid and maybe RPE damaged independently. F. Macular RPE atrophy as measured by FAF predictor central VA A. Visual field (VF) loss common over time. B. May better reflect loss of function than VA C. Abnormal Goldmann VF score 1. 75% (48 eyes) at presentation of at least 1 (I-4) isopter 2. Rate 0.11 to 0.18/EY 3. Immunomodulatory therapy (IMT) may reverse VF loss. D. Standardized Humphrey VF (Fastpac 30-2)

X. Research Diagnostic Criteria

VIII. Perimetry

XI. Differential Diagnosis

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Section VI: Puzzling White DotsWhats a Doctor to Do? 2. Preservation, reversal of VF loss, ERG parameters

33

4. Sympathetic ophthalmia 5. Idiopathic retinal vasculitis, systemic vasculitides 6. Posterior scleritis B. Infectious: Syphilis, TB, toxoplasmosis, brucellosis C. Masquerade syndromes: Lymphoma, metastatic carcinoma, myelodysplasia

3. Reduction of risk of CME: Prevalence reduced 80% 4. Disappearance of classic birdshot spots B. Induction of long-term remission A. Antimetabolites 1. Methotrexate 2. Mycophenolate mofetil 3. Azathioprine B. T-cell transduction inhibitors 1. Cyclosporine 2. Tacrolimus 3. Combination with MTX, mycophenolate mofetil C. Biologics 1. Infliximab 2. Adalimumab 3. Daclizumab D. IVIG E. Fluocinolone acetonide implant F. Emerging therapies 1. Voclosproin 2. Anti-interleukin-17 monoclonal 3. Interferon alpha-2a A. Symptomatic patient: Photopsias, floaters, nyctalopia, altered color perception B. Vitritis C. Retinal vasculitis: IVFA, ICG D. CME: OCT E. Peripheral retinal dysfunction: VF, ERG A. Randomized, double masked study of CSA compared to prednisolone in the treatment of endogenous uveitis (Nussenblatt RG, et al. Am J Ophthalmol. 1991; 112:138-146.)

XII. Natural History A. Multiple exacerbations and remissions B. Progressive visual loss 1. Structural complications: CME (10% EY), ERM, cataract, glaucoma, optic neuropathy 2. Global retinal dysfunction: VF loss, ERG dysfunction 3. Longer duration of disease 4. Independent of previous oral corticosteroid therapy A. Few maintain good VA without treatment B. VA 20/200 affected eye 1. 8% onset 2. 30% at 5 years 3. 39% at 10 years (Rothova A, et al. Ophthalmology 2004; 111:954-959.) C. 20% 20/200 (Thorne JE, et al. Am J Ophthalmol. 2005; 140:45-51.) 1. 20% 5 year cumulative incidence 2. VA 20/50: 13% per eye-year (EY) incidence rate 3. VA 20/200: 4% per EY incidence rate A. Periocular/intravitreal/systemic corticosteroids 1. Short-term management vitritis, CME 2. Inconsistent efficacy long- term a. Maintainence > 15 mg/day to prevent CME recurrence b. Steroid resistance, intolerance, severe adverse effects 1. Inherent anti-inflammatory effect 2. Steroid sparing (< 10 mg/day) 3. Extended treatment anticipated A. Preservation of visual function 1. Reduction of inflammation, recurrences

XVI. Therapeutic Options

XIII. Visual Prognosis

XVII. Treatment Indications

XIV. Treatment

XVIII. Cyclosporine 10 mg/kg Day

B. Early introduction of IMT

1. 5 patients with BSRC 2. 2 treated with CSA with good response B. 21 patients (42 eyes) BSCR (Le Hoang P, et al. Transplant Proc. 1998; 20:128-130.) 1. 10 mg/kg CSA (16 patients), 5mg/kg (5 patients) 2. Marked intraocular inflammation (vitritis) in all eyes

XV. Treatment Outcomes

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Section VI: Puzzling White DotsWhats a Doctor to Do? 3. Dramatic retinal vasculitis, retinal vascular leakage

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2. Median total patient follow-up: 52.6 months (19.7-153.5) B. 12-month time point

4. VA 23 (54.8%) eyes, stabilization in 11 (26.2%) 5. Nephrotoxicity, hypertension A. 19 patients (35 eyes) 1. 8 patients CSA (2.5-5.0 mg/kg) 2. 5 patients CSA plus azathioprine (1.5-2.0 mg/kg day) 3. 6 patients systemic/periocular steroids B. Vitreous inflammation controlled in 23 (88.5%) eyes C. VA improved or stabilized in 20 (83.8%) D. Reduction inflammatory recurrences E. No nephrotoxic side effects (Vitale AT, et al. Ophthalmology 1994; 101:822-831.) F. 28 patients BSRC (mean follow-up: 81.2 months) G. All treated with systemic IMT 1. CSA (93%) alone or in combination with: a. Mycophenolate mofetil (68%) b. Azathioprine (18%) c. Methotrexate (11%) d. Daclizumab (7%) XIX. Cyclosporine 2.5-5.0 mg/kg day

1. Vitreous inflammatory scores O.D./O.S. (P < .0001; P < .0001) 2. CME, angiographic leakage O.D./O.S. (P < .025; P < .001) 3. No 30 HZ amplitude/implicit times O.D./O.S. (P = .14, P = .17) 4. 37 (92.5%) inflammatory control off systemic corticosteroids 5. 24 (64.9%) long-term remission, no relapses 6. 13 (35.1%) at least 1 relapse, require change in IMT 7. Mean logMAR VA not statistically different O.U. (Cervantes-Castaneda RA, et al. Eur J Ophthalmol. 2009; 19(1):118-123.) A. 8 patients BSRC refractory to conventional IMT 1. 1mg/kg IV every 2 weeks 2. Follow-up mean: 25.6 months B. Outcomes 1. 7 stabilization/improvement of VA O.U.; complete resolution of vitritis 2. 6 resolution vasculitis on IVFA 3. 4 discontinued other IMT while on daclizumab

XXII. Daclizumab

H. VA stable or improved in 78.6% (O.D.), 89.3% (O.S.) I. ERG 1. Stable bright flash scotopic amplitudes 2. 30 Hz flicker implicit times in majority of patients during follow-up (Kiss S, et al. Ophthalmology 2005; 112:1066-1071.) A. 76 patients HLA-A29 BSRC; 46 followed for 5 years, 18 for >10 years B. Treatment regimes / yearly change logMAR VA 1. None / - 0.020 P = .034 2. Corticosteroids / 0.034 P = .71 3. Low dose MTX / 0.028 P = .006 C. Initial MTX treatment 1. Gradual increased VA contrast to other groups (P = .003) (Rothova A, et al. Retina, 2011.) A. 40 patients (80 eyes) 1. Median time CSA/MM treatment: 25.6 months (12-96.6)

4. 30 HZ implicit times and bright scotopic amplitudes in some despite effective inflammatory control (Sorbin L, et al. Arch Ophthalmol. 2008; 126:186-189.) C. High doses (8 mg/kg followed by 4 mg/kg) 1. 2 patients to achieve more rapid control inflammation (Yeh S, et al. J Autoimmun. 2008; 31:9197.) A. 22 patients with BSRC refractory to conventional IMT 1. Mean duration disease pre infliximab 58.62 months 2. Mean duration infliximab therapy 13.55 months 3. Previous BMR 10 pts B. Outcomes (baseline / 6 months /12 months) 1. Inflammatory: control / 81.82% / 75% 2. CME: 22.73% / 13.89% / 5.56% 3. VA 20/40: 84.09% / 91.67% / 94.44% 4. Three patients had active inflammation during therapy.

XX. Methotrexate

XXIII. Infliximab

XXI. CSA/Mycophenolate Mofetil

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Section VI: Puzzling White DotsWhats a Doctor to Do?

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5. Six patients developed adverse events requiring drug discontinuation: Neuropathy, drug-induced lupus, allergic reaction, fungal infection (Artornsombudh P, et al. Ophthalmology 2012; in press,) A. IVIg used treatment of human autoimmune disease

C. Treatment threshold, markers of progressive disease 1. Clinical indices of intraocular inflammation 2. Imaging modalities (IVFA, ICG, OCT, FAF) 3. Visual fields (GVF, HVF) 4. Electroretinograph indices of retinal dysfunction A. Initial treatment with prednisone 1 mg/kg day 1. Up to 60 mg daily for 3-4 weeks 2. Taper off if possible, and if not, < 10 mg/day B. Initial treatment with antimetabolite 1. CellCept 1 gm b.i.d.; maximum 1.5 gm b.i.d. failing prednisone taper 2. Methotrexate 15 mg/weekly with 1 mg folic acid daily; maximum 25 mg/weekly failing prednisone taper 3. Consider initial combined CSA/ mycophenolate mofetil C. Adjunctive periocular/intravitreal steroid for CME D. Add CSA (2.5-5.0 mg/kg/day) or tacrolimus (0.10 0.15 mg/kg/day) to antimetabolite with significant inflammatory recurrence/failure prednisone taper. E. Advance to TNF inhibitor (infliximab, adalimumab) failing combined IMT with significant inflammatory recurrence/failure prednisone taper. Discontinue CSA/tacrolimus. F. Consider fluocinolone acetonide implant. Systemic steroid/IMT failure or intolerance

XXIV. Intravenous Immune Globulin (IVIg) 1. Guillain-Barr, Kawasaki, juvenile dermatomyositis 2. Uveitis 3. Cancer-associated retinopathy B. Mechanism action not known 1. Blunt B-cell responses, alter cytokine production, inhibit phagocytosis, neutralize C3a, C5b 2. Prevent expression EAU, induce peripheral T-cell anergy C. 18 patients (36 eyes), follow-up mean 39 months D. IVIg monotherapy 1. 1.6 g/kg every 4 weeks for 6 months 2. Subsequent IVIg 1.2 to 1.6 g/kg every 6-8 weeks E. 14/26 (53.8%) VA 2 lines; 2/26 VA F. Decreased CME in 17/23, improved VF in 20/26 G. Benign side effects in 12 patients: Transient HTN, HA, eczematous lesions, hyperthermia (LeHoang et al. Occul Immunol Inflamm. 2000; 8:49-57.) A. 22 patients (36 eyes) HLA-A29 + BSRC 1. Follow-up: 3 years 2. 19 (32 eyes) completed 1 year B. Outcomes baseline: 1 year 1. Vitreous haze of 0 26% (7/27) / 100% (30/30) 2. CME 36% (13/36) / 6% (2/32) 3. VA (median) 20/50 20/40 (P = .15) 4. IMT 82% (18/22) / 5% (1/19) (P < .001) C. Complications 1. Cataract Sx: All except for 5/24 phakic eyes exit baseline 2. Ocular HTN: 100% 3. Glaucoma Sx: 33% (12/36) (Rush RB, et al. Am J Ophthalmol. 2011; 151:630-636.) A. BSRC chronic progressive, sight-threatening disease B. Early and aggressive IMT 1. Limit ocular structural damage 2. Preserve global visual function 3. Induction of long-term remission

XXVII. Treatment Protocol

XXV. Fluocinolone Acetonide Implant

Selected Readings
1. Ryan SJ, Maumenee AE. Birdshot retinochoroidopathy. Am J Ophthalmol. 1980; 89(1):31-45. 2. Gass JD. Vitiliginous chorioretinitis. Arch Ophthalmol. 1981; 99(10):1778-1787. 3. Shah KH, et al., Birdshot chorioretinopathy. Surv Ophthalmol. 2005; 50(6):519-541. 4. Priem HA, Oosterhuis JA. Birdshot chorioretinopathy: clinical characteristics and evolution. Br J Ophthalmol. 1988; 72(9):646659. 5. Kiss S, et al. Long-term follow-up of patients with birdshot retinochoroidopathy treated with corticosteroid-sparing systemic immunomodulatory therapy. Ophthalmology 2005; 112(6):1066-10671. 6. Monnet D, et al. Longitudinal cohort study of patients with birdshot chorioretinopathy: I. Baseline clinical characteristics. Am J Ophthalmol. 2006; 141(1):135-142. 7. Thorne JE, et al. Birdshot retinochoroidopathy: ocular complications and visual impairment. Am J Ophthalmol. 2005; 140(1):4551. 8. Becker MD, et al. Long-term follow-up of patients with birdshot retinochoroidopathy treated with systemic immunosuppression. Ocul Immunol Inflamm. 2005; 13(4):289-293. 9. Rothova A, et al. Birdshot chorioretinopathy: long-term manifestations and visual prognosis. Ophthalmology 2004; 111(5):954-959.

XXVI. Summary

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10. Oh KT, Christmas NJ, Folk JC. Birdshot retinochoroiditis: long term follow-up of a chronically progressive disease. Am J Ophthalmol. 2002; 133(5):622-629. 11. LeHoang P, et al. HLA-A29.2 subtype associated with birdshot retinochoroidopathy. Am J Ophthalmol. 1992; 113(1):33-35. 12. Vitale AT, Rodriguez A, Foster CS. Low-dose cyclosporine therapy in the treatment of birdshot retinochoroidopathy. Ophthalmology 1994; 101(5):822-831. 13. Levinson RD, et al. Research criteria for the diagnosis of birdshot chorioretinopathy: results of an international consensus conference. Am J Ophthalmol. 2006; 141(1):185-187. 14. Le Hoang P, et al. Cyclosporine in the treatment of birdshot retinochoroidopathy. Transplant Proc. 1988; 20(3 suppl 4):128-130. 15. Nussenblatt RB, et al. Birdshot retinochoroidopathy associated with HLA-A29 antigen and immune responsiveness to retinal S-antigen. Am J Ophthalmol. 1982; 94(2):147-158. 16. Zamecki KJ, Jabs DA. HLA typing in uveitis: use and misuse. Am J Ophthalmol. 2010; 149(2):189-193 e2. 17. Levinson RD, et al. Human leukocyte antigen A29 subtypes associated with birdshot retinochoroidopathy. Am J Ophthalmol. 2004; 138(4):631-634. 18. Boisgerault F, et al. Definition of the HLA-A29 peptide ligand motif allows prediction of potential T-cell epitopes from the retinal soluble antigen, a candidate autoantigen in birdshot retinopathy. Proc Natl Acad Sci U S A. 1996; 93(8):3466-3470. 19. Suttorp-Schulten MS, et al. Birdshot chorioretinopathy and Lyme borreliosis. Am J Ophthalmol. 1993; 115(2):149-153. 20. Gaudio PA, Kaye DB, Crawford JB. Histopathology of birdshot retinochoroidopathy. Br J Ophthalmol. 2002; 86(12):1439-1441. 21. Fardeau C, et al. Indocyanine green angiography in birdshot chorioretinopathy. Ophthalmology 1999; 106(10):1928-1934. 22. Herbort CP, et al. Differential inflammatory involvement in retina and choroid in birdshot chorioretinopathy. Klin Monbl Augenheilkd. 2004; 221(5):351-356. 23. Monnet D, et al. Longitudinal cohort study of patients with birdshot chorioretinopathy: III. Macular imaging at baseline. Am J Ophthalmol. 2007; 144(6):818-828. 24. Forooghian F, Gulati N, Jabs DA. Restoration of retinal architecture following systemic immunosuppression in birdshot chorioretinopathy. Ocul Immunol Inflamm. 2010; 18(6):470-471. 25. Koizumi H, Pozzoni MC, Spaide RF. Fundus autofluorescence in birdshot chorioretinopathy. Ophthalmology 2008; 115(5):e15-20. 26. Yeh S, et al. Fundus autofluorescence imaging of the white dot syndromes. Arch Ophthalmol. 2010; 128(1):46-56.

27. Zacks DN, et al. Electroretinograms as an indicator of disease activity in birdshot retinochoroidopathy. Graefes Arch Clin Exp Ophthalmol. 2002; 240(8):601-607. 28. Sobrin L, et al. Electroretinographic monitoring in birdshot chorioretinopathy. Am J Ophthalmol. 2005; 140(1):52-64. 29. Ladas JG, Arnold AC, Holland GN. Control of visual symptoms in two men with birdshot retinochoroidopathy using low-dose oral corticosteroid therapy. Am J Ophthalmol. 1999; 128(1):116-118. 30. Thorne JE, et al. Loss of visual field among patients with birdshot chorioretinopathy. Am J Ophthalmol. 2008; 145(1):23-28. 31. Gordon LK, et al. Standardized visual field assessment for patients with birdshot chorioretinopathy. Ocul Immunol Inflamm. 2006; 14(6):325-332. 32. Gordon LK, et al. Longitudinal cohort study of patients with birdshot chorioretinopathy. IV. Visual field results at baseline. Am J Ophthalmol. 2007; 144(6):829-837. 33. Jabs DA, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000; 130(4):492-513. 34. Nussenblatt RB, Palestine AG, Chan CC. Cyclosporine therapy for uveitis: long-term followup. J Ocul Pharmacol. 1985; 1(4):369382. 35. Nussenblatt RB, et al. Randomized, double-masked study of cyclosporine compared to prednisolone in the treatment of endogenous uveitis. Am J Ophthalmol. 1991; 112(2):138-146. 36. Vitale AT, Rodriguez A, Foster CS. Low-dose cyclosporin A therapy in treating chronic, noninfectious uveitis. Ophthalmology 1996; 103(3):365-373; discussion 373-374. 37. Callanan DG, Cheung MK, Martin DF, et al. Outcome of uveitis patients treated with long-term cyclosporine. Invest Ophthalmol Vis Sci. 1994; 35:2094. 38. Rothova A, et al. Efficacy of low-dose methotrexate treatment in birdshot chorioretinopathy. Retina 2011; 31(6):1150-1155. 39. LeHoang P, et al. Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy. Ocul Immunol Inflamm. 2000; 8(1):49-57. 40. Sobrin L, et al. Daclizumab for treatment of birdshot chorioretinopathy. Arch Ophthalmol. 2008; 126(2):186-191. 41. Yeh S, et al. High-dose humanized anti-IL-2 receptor alpha antibody (daclizumab) for the treatment of active, non-infectious uveitis. J Autoimmun. 2008; 31(2):91-97. 42. Rush RB, et al. Outcomes of birdshot chorioretinopathy treated with an intravitreal sustained-release fluocinolone acetonide-containing device. Am J Ophthalmol. 2011; 151(4):630-636.

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What About Serpiginous Choroiditis? Is It Autoimmune? Or Herpes? Or Tuberculosis?


Narsing A Rao MD
Serpiginous choroiditis (SC) is a posterior uveitis displaying a geographic pattern of choroidal changes typically extending from juxtapapillary choroid in a centrifugal pattern and a recurrent progressive choroiditis from margins of healed choroidal lesions. Limited histopathologic studies of eyes with SC revealed a chronic inflammatory process, and current ocular imaging studies support the inflammatory nature of the SC with predominant involvement of inner choroid, choriocapillaris, retinal pigment epithelium (RPE), and outer retina. Although the etiology of SC is not clear, there are 3 likely inflammatory mechanisms that could induce this recalcitrant choroiditis; the suggestive mechanisms include (a) organ-specific autoimmune process, (b) infectious etiology, among which Mycobacterium tuberculosis and varicella zoster virus are likely causes, and (c) idiopathic. Although variations in clinical features of SC have been amply described, including macular variant and simulating SC, such as multifocal serpiginoid choroiditis (multifocal serpiginous-like choroiditis) and serpiginous-like choroiditis, there are distinct differences in the clinical features of typical SC compared to the simulating SC. The typical SC reveals choroidal inflammation extending from juxtapapillary choroid with recurrences progressing in centrifugal pattern with minimal or no inflammatory vitreous reaction. In contrast the simulating SC are associated with infectious etiology, and they display multifocal lesions, usually sparing the juxtapapillary choroid during initial presentations and moderate vitreous inflammatory response. I. Autoimmune Etiology A. Favorable response to immunosuppressive agents B. HLA association: HLA-B7, HLA-A2, HLA-B8, and HLA-DW3. C. T-cell immune response to retinal S-antigen II. Infectious Etiology Primarily presents as multifocal serpiginoid choroiditis. A. Tuberculosis 1. Hutchinson reported infectious etiology over a century ago. 2. Case reports based on tuberculin skin test (TST) and interferon gamma release assays 3. Association with pulmonary tuberculosis 4. Molecular studies (PCR) 5. Response to anti-TB agents 6. Geographic distribution B. Herpes infection (VZV and HSV) 1. Association with herpes zoster ophthalmicus 2. Molecular studies (PCR) 3. Response to antiviral agents A. Histopathology B. Molecular studies (PCR) IV. Differential Diagnosis A. Ampiginous B. Relentless placoid chorioretinitis C. Others

III. Idiopathic

Studies seeking a unifying etiology are inconclusive; however, therapeutic intervention studies suggest SC could be autoimmune or idiopathic inflammatory process. There appears to be a subset of patients with atypical features mimicking SC, which are likely related to infectious etiology; primarily tuberculosis in endemic regions of this infection or herpetic viral infection without restrictions to a particular geographic part of the world. Although superficially these infectious serpiginous-like choroiditis may be mistaken for the typical SC, there are several distinct differences; the latter is seen in relatively older individuals from non-tuberculosis endemic regions with or without mild vitreous inflammatory reaction and negative history of exposure to tuberculosis and negative TST and -interferon release assay test results (QuantiFERON Gold TB or similar tests) and negative chest x-ray. It is essential to differentiate classic SC from mimicking conditions of infectious etiology for proper treatment.

Selected Readings
1. Hutchinson J. Serpiginous choroiditis in scrofulous subjects: choroidal lupus. Arch Surg (Lond). 1900; 11:126-135. 2. Gupta V, Gupta A, Rao NA. Intraocular tuberculosis: an update. Surv Ophthalmol. 2007; 52(6):561-587. 3. Priya K, Madhavan HN, Reiser BJ, Biswas J, Saptagirish R, Narayana KM, Rao NA. Association of herpes viruses in the aqueous humor of patients with serpiginous choroiditis: a polymerase chain reaction-based study. Ocul Immunol Inflamm. 2002; 10(4):247261. 4. Vasconcelos-Santos DV, Rao PK, Davies JB, Sohn EH, Rao NA. Clinical features of tuberculous serpiginous-like choroiditis in contrast to classic serpiginous choroiditis. Arch Ophthalmol. 2010; 128(7):847-848.

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Section VI: Puzzling White DotsWhats a Doctor to Do?

2012 Subspecialty Day|Uveitis

Punctate Inner Choroidopathy, Presumed Ocular Histoplasmosis Syndrome, Multifocal Choroiditis, and Panuveitis: Does Each of These Require Immunomodulatory Therapy?
Phuc Lehoang MD PhD
Introduction
The visual prognosis of punctate inner choroidopathy (PIC), presumed ocular histoplasmosis syndrome (POHS), and multifocal choroiditis with panuveitis (MFCPU) is linked to the involvement of the macula. There is no standardized treatment for these three entities. lesion from CNV in the definition of the POHS, but only in 5% of patients with histo spots at the earliest stage of the disease. Although unpredictable, early detection of a macular threat warrant a close follow-up with repeated patients self-evaluations (blurred vision, metamorphopsia, scotomas, photopsia), OCTs, fundus pictures (including FAF) and angiograms (FA, ICG-A) when indicated.

Background
Punctate inner choroidopathy, presumed ocular histoplasmosis syndrome, multifocal choroiditis and panuveitis are three rare type of choroiditis of unknown origin. They share common features: Patients are frequently myopic, predominantly of Caucasian extraction, with bilateral involvement in more than 60% of the cases, with the absence of systemic findings although POHS was initially thought to be related to Histoplasma capsulatum infection. They suffer from unpredictable recurrent choroiditis with possible development of secondary choroidal neovascularization, both of which can threaten the macula. Some characteristics can help to differentiate one entity from another: POHS frequently occurs in histoplasma endemic areas in the United States, although it can be observed worldwide in nonendemic regions. In fact the causative role of the fungus Histoplasma capsulatum is unclear, explaining why the term presumed has appeared in its name. It is characterized by the presence of disseminated atrophic histo spots, a maculopathy, peripapillary pigment alterations, and a clear vitreous. MFCPU is characterized by multiple creamy chorioretinal lesions in their active phase before becoming atrophic scars, similar to those observed in the POHS. They are scattered throughout the fundus and, in most cases, accompanied by vitritis and anterior uveitis requiring a complete uveitis workup. PIC generally shows multiple, small, punched-out, deep yellow-white lesions evolving toward atrophic and pigmented spots. Their distribution is mostly limited to the posterior pole. Peripapillary alterations of the retinal pigment epithelium and vitritis are absent.

Rationale for an Anti-inflammatory and Immunosuppressive Treatment


Any treatment should aim at decreasing the rate of inflammatory recurrences and the risk of CNV. Several studies clearly demonstrate the important role of inflammatory mechanisms in the development of CNV in AMD and moreover in uveitic conditions. These mechanisms involve inflammatory cells (macrophages, microglia, lymphocytes) and inflammatory factors (complement factors, cytokines, chemokines, oxidative stress inflammatory products). CNV develops in direct response to low-grade chronic intraocular inflammation and, therefore, may respond to anti-inflammatory agents and to immunomodulatory therapy. Because proangiogenic growth factors and cytokines released during chronic inflammation are both thought to contribute significantly to CNV formation, the treatment can combine three approaches in selected patients (lesions at the posterior pole threatening the macula, presence of CNV): 1. Anti-inflammatory agents either by local or systemic routes (corticosteroids, immunosuppressive drugs). They can be effective in treating the inflammatory lesions during the acute stages. Corticosteroids has been proven effective in limiting and decreasing the CNV either locally or by systemic route. However, their action is transient and their administration cannot be prolonged because of severe side effects. Therefore, immunomodulatory therapy should be considered in order to limit the number of recurrences of CNV and reduce the risk for developing any posterior pole complication during follow-up. Several papers have reported beneficial effects of various immunomodulating agents (methotrexate, mycophenolate mofetil, cyclosporine, azathioprine, cyclophosphamide, rapamycin, thalidomide, IFN beta 1A) in a limited number of patients with PIC, MFCPU, or POHS with regression of CNV and improvement or maintenance of vision (provided to exclude any infectious component, particularly fungal infection in POHS). Although warranted, a randomized controlled trial is difficult to set up because of the rarity of those entities. 2. Anti-angiogenesis therapy (intravitreal injections of antiVEGF agents) 3. Destruction of the new vessels (direct laser photocoagulation, photodynamic therapy)

Prognosis
The visual prognosis of these three entities depends upon the rate of inflammatory recurrences, the involvement of the foveola, and particularly upon the possible development of submacular choroidal neovascularization (CNV). CNV occurs in 28% of multifocal choroiditis, in 70% of punctate inner choroidopathy, and in 100% of presumed ocular histoplasmosis syndrome if one includes a macular disciform

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Conclusion
Immunosuppression appears to: Prevent the recurrence of progressive choroiditis and reduce the risk for developing posterior pole complications during follow-up Facilitate the regression of CNV, limit the number of recurrences of CNV and prevent the occurrence of CNV in the contralateral eye Therefore, early and aggressive therapy with immunosuppressive drugs may help to preserve good visual acuity in selected patients with PIC, MFCPU, or POHS suffering from frequent inflammatory recurrences, choroidal lesions threatening the macula, and CNV.

4. Durrani K, Zakka FR, Ahmed M, Memon M, Siddique SS, Foster CS. Systemic therapy with conventional and novel immunomodulatory agents for ocular inflammatory disease. Surv Ophthalmol. 2011; 56(6):474-510. 5. Essex RW, Wong J, Fraser-Bell S, et al. Punctate inner choroidopathy: clinical features and outcomes. Arch Ophthalmol. 2010; 128(8):982-987. 6. Gerstenblith AT, Thorne JE, Sobrin L, et al. Punctate inner choroidopathy: a survey analysis of 77 persons. Ophthalmology 2007; 114(6):1201-1204. 7. Nussenblatt RB, Coleman H, Jirawuthiworavong G, et al. The treatment of multifocal choroiditis associated choroidal neovascularization with sirolimus (rapamycin). Acta Ophthalmol Scand. 2007; 85(2):230-231. 8. OToole L, Tufail A, Pavesio C. Management of choroidal neovascularization in uveitis. Int Ophthalmol Clin. 2005; 45(2):157-177. 9. Suttorp-Schulten MS, Bollemeijer JG, Bos PJ, Rothova A. Presumed ocular histoplasmosis in The Netherlands: an area without histoplasmosis. Br J Ophthalmol. 1997; 81(1):7-11. 10. Thorne JE, Wittenberg S, Jabs DA, et al. Multifocal choroiditis with panuveitis incidence of ocular complications and of loss of visual acuity. Ophthalmology 2006; 113(12):2310-2316. 11. Turkcuoglu P, Chang PY, Rentiya ZS, et al. Mycophenolate mofetil and fundus autofluorescence in the management of recurrent punctate inner choroidopathy. Ocul Immunol Inflamm. 2011; 19(4):286-292.

Selected Readings
1. Amer R, Lois N. Punctate inner choroidopathy. Surv Ophthalmol. 2011; 56(1):36-53. 2. Dees C, Arnold JJ, Forrester JV, Dick AD. Immunosuppressive treatment of choroidal neovascularization associated with endogenous posterior uveitis. Arch Ophthalmol. 1998; 116(11):14561461. 3. Dhingra N, Kelly S, Majid MA, Bailey CB, Dick AD. Inflammatory choroidal neovascular membrane in posterior uveitis-pathogenesis and treatment. Indian J Ophthalmol. 2010; 58(1):3-10.

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Section VI: Puzzling White DotsWhats a Doctor to Do?

2012 Subspecialty Day|Uveitis

Acute Posterior Multifocal Placoid Pigment Epitheliopathy and Ampiginous Choroiditis: Should These Be Treated, and If So, With What?
Henry J Kaplan MD
I. What is acute posterior multifocal placoid pigment epitheliopathy (APMPPE)? A. Clinical presentation1,2 1. Uncommon condition 2. Healthy young adults affected, frequently with influenza-like illness (30%) 3. Bilateral, but may be asymmetric 4. Rapid onset of blurred vision, photopsias, paracentral and central scotomas 5. Visual in 58% eyes prognosis3: Relatively benign, but 20/40 2. Stage 1b acute phase (2-4 days later): Flattening of dome, thickening of IS/OS junction, increased reflectivity of ONL 3. Stage 2 subacute phase (2 weeks later): + SRF with separation of IS/OS junction and RPE, fading of hyper-reflectivity of ONL 4. Stage 3 late phase (from 1.5-6 months later): Disruption of IS/OS junction, increased hyperreflectivity of RPE 5. Stage 4 resolution phase (~ 3 months after onset): Two bands of IS/OS junction and RPE regain normal appearance, except for minimal persistent irregularity in RPE

B. Etiology: Unknown4-12 1. Associated with multiple conditions: Lyme disease, pulmonary TB, group A streptococcal infection, hepatitis B vaccine, mumps, sarcoid, Wegner granulomatosis, ulcerative colitis, systemic necrotizing vasculitis; viral prodrome 2. HLA-B7, DR213 C. Diagnosis 1. Characteristic clinical presentation (as above) 2. Characteristic fundus findings a. Funduscopy: Multiple, flat, yellowish-white, placoid lesions, varying in size, at level of retinal pigment epithelium (RPE); lesions fade over course of time, gradually, with atrophy and hypertrophy of RPE; new lesions may be observed over several weeks from onset b. Fluorescein angiography: Hypofluorescent early (blocked), hyperfluorescent late (staining) c. ICG angiography: Hyperreflective lesions in outer photoreceptor layer d. Fundus autofluorescence: Foveal hypofluorescence visual acuity (VA) impairment e. Associated ocular conditions: central retinal vein occlusion,14 papillitis, periphlebitis, exudative NSD 1. Stage 1a hyperacute phase: Demarcated domeshaped elevation of the inner segment/outer segment (IS/OS) junction, SRF (yellowish-gray fundus lesion)

II. What is ampiginous choroiditis? Clinical Presentation23-25 A. Variant of APMPPE and serpiginous choroiditis = relentless placoid chorioretinitis B. Distinguishing features on presentation 1. Distribution of lesions periphery (mid and far) and macula 2. Morphology of lesions 3. Mild vitritis (25%) 4. Prolonged relapsing course: 35%-65% within 6 months to 5 years 5. Complications differed a. Present: subretinal fibrosis and epiretinal membrane b. Absent: episcleritis, optic disc swelling, CNV, subretinal fluid, retinal detachment 6. Possible association with systemic autoimmune disease A. Rationale for treatment of disease Kaplans modification of Occams razor: Treat the cause and If you dont know the cause, invoke autoimmunity and inflammation as the cause. B. Treatment choices 1. Acute suppression of immunity (ie, corticosteroids) 2. Chronic suppression of immunity: Immunomodulatory therapy (IMT)alkylating agents, antimetabolites, T cell inhibitors, biologics

III. Should either of these diseases be treated?

D. Stages of disease by spectral domain OCT15-22

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3. Ampiginous choroidopathy: forme fruste of serpiginous choroidopathy C. Treatment recommendations 1. If central macular involved or VA 20/25: Systemic corticosteroids with IMT monotherapy (methotrexate, mycophenolate mofetil or azathioprine) 2. If VA > 20/25 and central macular not threatened: Watchful waiting 3. If patient older than 50 years of age (has a lesion resembling serpiginous choroidopathy): Very watchful waiting 4. In either case, follow the patient closely, with judicious use of serial OCT examinations (remembering that Medicare and insurance companies will probably not pay for the studies)

12. Wilson CA, Choromokos EA, Sheppard R. Acute posterior multifocal placoid pigment epitheliopathy and cerebral vasculitis. Arch Ophthalmol. 1998; 106:796-800. 13. Wolf MD, Folk JC, Panknen CA, Goeken NE. HLA-B7 and HLADR2 antigens and acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol. 1990; 108:698-700. 14. Alle SD, Marks SJ. Acute posterior multifocal placoid pigment epitheliopathy with bilateral central retinal vein occlusion. Am J Ophthalmol. 1998; 126:309-312. 15. Goldenberg D, Habot-Wilner Z, Loewenstein A, Goldstein M. Spectral domain optical coherence tomography classification of acute posterior multifocal placoid pigment epitheliopathy. Retina 2012; 32(7):1403-1410. 16. Lofoco G, Ciucci F, Bardocci A, Quercioli P, Steigerwalt RD, Gaetano D. Optical coherence tomography findings in a case of acute multifocal posterior placoid pigment epitheliopathy (AMPPPE). Eur J Ophthalmol. 2005; 15(1):143-147. 17. Souka AA, Hillenkamp J, Gora F, et al. Correlation between optical coherence tomography and autofluorescence in acute posterior multifocal placoid pigment epitheliopathy. Graefes Arch Clin Exp Ophthalmol. 2006; 244:1219-1223. 18. Lim LL, Watzke RC, Lauer AK, Smith JR. Ocular coherence tomography in acute posterior multifocal placoid pigment epitheliopathy [letter]. Clin Experiment Ophthalmol. 2006; 34:810-812. 19. Birnbaum AD, Blair MP, Tessler HH, Goldstein DA. Subretinal fluid in acute posterior multifocal placoid pigment epitheliopathy. Retina 2010; 30:810-814. 20. Scheufele Ta, Witkin AJ, Schocket LS, et al. Photoreceptor atrophy in acute posterior multifocal placoid pigment epitheliopathy demonstrated by optical coherence tomography. Retina 2005; 25:11091112. 21. Cheung CM, Yeo IY, Koh A. Photoreceptor changes in acute and resolved acute posterior multifocal placoid pigment epitheliopathy documented by spectral-domain optical coherence tomography. Arch Ophthalmol. 2012; 128:644-646. 22. 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; 19:42-47. 23. Jones BE, Jampol LM, Yannuzzi LA. Relentless placoid chorioretinitis: a new entity or an unusual variant of serpiginous chorioretinitis? Arch Ophthalmol. 2000; 118:931-938. 24. Biswas J, Kazi S. Relentless placoid chorioretinitis. AIOC 2006 proceedings. 25. Jyotirmay B, Jafferji SS, Sudharshan S. Kalpana B. Clinical profile, treatment, and visual outcome of ampiginous choroiditis. Ocul Immunol Inflamm. 2012; 18(1):46-51.

References
1. Gass JD. Acute posterior multifocal placoid pigment epitheliopathy. Arch Ophthalmol. 1968; 80(2):177-185. 2. Quillen DA, Davis JB, Gottlieb JL, et al. Perspective: the white dot syndromes. Am J Ophthalmol. 2004; 137(3): 538-550. 3. Fiore T, Iaccheri B, Androudi S, et al. Acute posterior multifocal placoid pigment epitheliopathy: outcome and visual prognosis. Retina 2009; 29:994-1001. 4. Anderson K, Patel KR, Webb L, Dutton GN. Acute posterior multifocal placoid pigment epitheliopathy associated with pulmonary tuberculosis. Br J Ophthalmol. 1996; 80:186. 5. Lowder CY, Foster RE, Gordon SM, Gutman FA. Acute posterior multifocal placoid pigment epitheliopathy after acute group A streptococcal infection. Am J Ophthalmol. 1996; 122:115-117. 6. Bourges JL, Pisella PJ, Laurens C, Limon S. Multifocal placoid epitheliopathy and anti-hepatitis B vaccination. J Fr Ophthalmol. 1998; 21:696-700. 7. Borruat FX, Piguet B, Herbort CP. Acute posterior multifocal placoid pigment epitheliopathy following mumps. Ocul Immunol Inflamm. 1998; 6:189-193. 8. Darugar A, Mathian A, LeHoang P, Bodaghi B. Acute posterior multifocal placoid pigment epitheliopathy as the initial manifestations of sarcoidosis. J Ophthal Vis Res. 2011; 6(4):338-343. 9. Chiquet C, Lumbroso L, Denis P, et al. Acute posterior multifocal placoid pigment epitheliopathy associated with Wegeners granulomatosis. Retina 1999; 19:309-313. 10. Wolf MD, Folk JC, Nelson JA, Peeples ME. Acute, posterior, multifocal, placoid, pigment epitheliopathy and Lyme disease. Arch Ophthalmol. 1992; 110:750. 11. Hsu CT, Harlan JB, Goldberg MF, Dunn JP. Acute posterior multifocal placoid pigment epitheliopathy associated with a systemic necrotizing vasculitis. Retina 2003; 23:64-68.

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Section VII: The Puzzling Matter of Treatment-Resistant Uveitis

2012 Subspecialty Day|Uveitis

Is It Infectious, Autoimmune, or Malignant? The Importance of Diagnostic Surgery


Russell N Van Gelder MD PhD
I. Background II. Indications for Diagnostic Surgery III. Techniques for Diagnostic Surgery A. Aqueous tap B. Vitreous tap/diagnostic vitrectomy C. Endoretinal biopsy IV. Laboratory Testing for Diagnostic Tap A. Histology B. Gram stain, culture, and sensitivity C. Polymerase chain reaction (PCR) 1. Viral PCR/quantitative PCR 2. 16S universal bacterial PCR 3. 18S universal fungal PCR 4. Emerging deep sequencing techniques
3. Fekkar A, Bodaghi B, Touafek F, Le Hoang P, Mazier D, Paris L. Comparison of immunoblotting, calculation of the Goldmann-Witmer coefficient, and real-time PCR using aqueous humor samples for diagnosis of ocular toxoplasmosis. J Clin Microbiol. 2008; 46(6):1965-1967. 4. Kanoff J, Sobrin L. New diagnosis and treatment paradigms in acute retinal necrosis. Int Ophthalmol Clin. 2011; 51(4):25-31. 5. Kimura K, Usui Y, Goto H; The Japanese Intraocular Lymphoma Study Group. Clinical features and diagnostic significance of the intraocular fluid of 217 patients with intraocular lymphoma. Jpn J Ophthalmol. 2012; 56(4):383-389. 6. Margolis R. Diagnostic vitrectomy for the diagnosis and management of posterior uveitis of unknown etiology. Curr Opin Ophthalmol. 2008; 19(3):218-224. 7. Recchia FM, Scott IU, Brown GC, Brown MM, Ho AC, Ip MS. Small-gauge pars plana vitrectomy: a report by the American Academy of Ophthalmology. Ophthalmology 2010; 117(9):1851-1857. 8. Scott AW, Mruthyunjaya P, McCallum RM, Jaffe GJ. Diagnostic yield of vitreous biopsy in presumed sarcoidosis-related posterior segment inflammation. Graefes Arch Clin Exp Ophthalmol. Epub ahead of print. 21 Mar 2012. 9. Talabani H, Asseraf M, Yera H, et al. Contributions of immunoblotting, real-time PCR, and the Goldmann-Witmer coefficient to diagnosis of atypical toxoplasmic retinochoroiditis. J Clin Microbiol. 2009; 47(7):2131-2135. 10. Van Gelder RN. Applications of the polymerase chain reaction to diagnosis of ophthalmic disease. Surv Ophthalmol. 2001; 46(3):248-258. 11. Westeneng AC, Rothova A, de Boer JH, de Groot-Mijnes JD. Infectious uveitis in immunocompromised patients and the diagnostic value of polymerase chain reaction and Goldmann-Witmer coefficient in aqueous analysis. Am J Ophthalmol. 2007; 144(5):781785.

V. Intraocular Antibody Testing VI. Cytokine Analysis VII. Case Examples

Selected Readings
1. de Visser L, Rothova A, de Boer JH, et al. Diagnosis of ocular toxocariasis by establishing intraocular antibody production. Am J Ophthalmol. 2008; 145(2):369-374. 2. Eide N, Walaas L. Fine-needle aspiration biopsy and other biopsies in suspected intraocular malignant disease: a review. Acta Ophthalmol. 2009; 87(6):588-601.

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Current Concepts in Managing Ocular Malignancy: What Are Our Colleagues in Neuro-Oncology Doing?
Chi-Chao Chan MD
I. Ocular Malignancies in Neuro-Oncology A. Primary vitreoretinal lymphoma (PVRL) B. Optic nerve glioma: surgery, radiation, chemotherapy C. Optic sheath meningioma: radiation II. The optimal therapy for PVRL is not defined. A. Reserve systemic therapy for those with CNS disease. B. Local therapy for disease confined to the eye C. Careful and close follow-up for CNS disease D. Consult ophthalmologist III. Recommendations A. Without CNS or systemic involvement 1. Only 1 eye involved: Use local therapywhether it is local intravitreal methotrexate and rituximab alone or carefully given between 30-35 Gy external beam is still in contention. 2. Both eyes involved: There is still a preference toward local therapy, although systemic treatment may not be excluded. Addition of intravitreal chemotherapeutic agents in addition to the systemic therapy would be considered. B. With CNS involvement 1. High-dose methotrexate-based therapy (possibly with systemic rituximab) in conjunction with local therapy given the limited penetration of systemic agents into the vitreous cavity 2. Consideration of whole-brain radiotherapy in conjunction with ocular radiotherapy in those who have failed systemic therapy and are too debilitated or do not meet criteria for more aggressive therapy such as ASCT

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Section VII: The Puzzling Matter of Treatment-Resistant Uveitis

2012 Subspecialty Day|Uveitis

On the Matter of Autoimmune Retinopathy: A Diagnostic and Therapeutic Puzzle


Hatice Nida Sen MD
Introduction and Definition
Autoimmune retinopathy (AIR) is an inflammatory retinopathy characterized by vision loss, scotomas, visual field deficits, photoreceptor dysfunction, and the presence of circulating autoantibodies against retinal antigens. AIR presumably results from an immunologically mediated attack on the retina by antiretinal autoantibodies, but the mechanisms by which these antibodies cause retinal dysfunction are not entirely understood. AIR can be studied in two groups: paraneoplastic and non-paraneoplastic. Paraneoplastic AIR was described by Sawyer et al in 1976, and the term paraneoplastic retinopathy was first used by Klingele et al in 1984.1,2 This presentation will focus on nonparaneoplastic form of AIR. Evidence from paraneoplastic retinopathies suggests that AIR may be triggered by molecular mimicry between retinal proteins and presumed viral or bacterial proteins. Multiple retinal proteins have been found to be antigenic, some of these are retinaspecific (recoverin) and others are not (enolase). Among these, recoverin and enolase are the most extensively studied antigens in AIR. These antiretinal antibodies can target any retinal cell type, including photoreceptor cells, ganglion cells, or bipolar cells. However, the presence of antiretinal antibodies alone is not sufficient for the diagnosis of this ill-defined ocular disorder.3-5 Although it is believed to be rare, the prevalence of AIR is currently unknown. The overlap of clinical features with other degenerative retinal disorders and the lack of standardized diagnostic criteria, clinical and laboratory, may be contributing to underestimation of its prevalence. outlined above are critical to diagnosing nonparaneoplastic AIR. A family or a personal history of systemic autoimmune disease can be common among patients with AIR. There is a female preponderance (63%-66%), and average age at diagnosis appears to range from 51 years to 56 years.8-11 Seemingly most important factor in diagnosis, antiretinal antibody detection, has its own limitations. Firstly, the techniques used to detect these antibodies are not highly sensitive or specific, and secondly, their presence does not always indicate pathogenicity. Some of these antiretinal antibodies can be found in multiple autoimmune diseases, other ocular diseases, and even in healthy subjects.12-15 Regardless of its caveats, western blot (WB) and immunohistochemistry (IHC) are the more commonly performed techniques. Differential diagnoses of AIR include paraneoplastic AIR (eg, cancer-associated retinopathy, melanoma-associated retinopathy), white-dot syndrome spectrum disorders, particularly acute zonal occult outer retinopathy, retinal degenerative disorders such as RP, cone-rod dystrophy and noninfectious and infectious uveitis syndromes. Because of significant implications, it is important to differentiate paraneoplastic AIR from non-paraneoplastic AIR. RP patients can have very similar clinical features to AIR and some demonstrate antiretinal antibodies, which makes differentiating these two entities with overlapping features very difficult. Some uveitis syndromes can also demonstrate antiretinal antibodies, but most of these syndromes have typical fundus findings that help differentiate them from AIR.

Treatment
Because of the presumed autoimmune nature of AIR, various forms of immunomodulatory approaches have been tried. However, the ambiguity in diagnosis creates an enormous challenge in the management of AIR. Because of limitations in diagnostic testing and lack of our understanding of the underlying mechanisms, immunomodulatory therapy can be considered empiric at this time. Most of the knowledge regarding therapy comes from paraneoplastic retinopathy. Common approaches include systemic or local corticosteroids, intravenous immunoglobulin (IVIG), or plasmapheresis, antimetabolites such as mycophenolate mofetil, azathioprine, and T-cell inhibitors such as cyclosporine.8,9 Less frequently, targeted B-cell therapy, such as antiCD20 monoclonal antibody (rituximab), has also been used in the treatment of AIR.16,17 The benefit of immunosuppressive therapy in AIR is unclear at this time, and adding to the challenges in the management is the lack of parameters to guide treatment. There are no prognostic indicators, and whether timing of therapy is important or whether autoantibodies can be used to guide therapy is still unclear. A long-term treatment is usually needed in most cases, and therapy is unlikely to be helpful once widespread retinal degeneration occurs. Early treatment attempts would require establishing a clear diagnosis using sensitive and specific assays and more definitive clinical criteria that can only be achieved with a better understanding of the disease.

Clinical Findings
Patients with AIR typically present with subacute vision loss, scotomas, photopsias, nyctalopia, or photoaversion, and dyschromatopsia. On examination the fundus may appear unremarkable. Despite the heterogeneity in their circulating antiretinal antibodies, common clinical features in AIR patients include retinal vascular attenuation, diffuse retinal atrophy, retinal pigment epithelial (RPE) changes, and waxy disc pallor. AIR is usually bilateral but it can be asymmetric. There is usually minimal or no clinically detectable intraocular inflammation.6,7 Visual field testing shows constricted visual fields and central or paracentral scotomas, and electroretinogram (ERG) can show abnormalities in rods, cones, or bipolar cell responses or a combination of these. Visual acuity, particularly in the earlier stages, may be deceivingly good. Ancillary testing with fluorescein angiography (FA) or OCT may show mild retinal vascular staining or leakage, or cystoid macular edema (CME) in some cases.8,9

Diagnosis and Differential Diagnosis


Diagnosis of AIR is a challenge because there are no standardized diagnostic criteria. Most AIR patients may have been diagnosed with retinitis pigmentosa (RP) prior to presentation. Absence of malignancy and family history of RP and the presence of antiretinal antibodies in the setting of appropriate clinical findings as

2012 Subspecialty Day|Uveitis

Section VII: The Puzzling Matter of Treatment-Resistant Uveitis

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References
1. Sawyer RA, Selhorst JB, Zimmerman LE, et al. Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol. 1976; 81:606-613. 2. Klingele TG, Burde RM, Rappazzo JA, et al. Paraneoplastic retinopathy. J Clin Neuroophthalmol. 1984; 4(4):239-245. 3. Polans A, Witkowska D, Haley T, et al. Recoverin, a photoreceptor-specific calcium-binding protein, is expressed by the tumor of a patient with cancer-associated retinopathy. Proc Natl Acad Sci USA. 1995; 92:9176-9180. 4. Weleber RG, Watzke RC, Shults WT, et al. Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies. Am J Ophthalmol. 2005; 139(5):780-794. 5. Ren G, Adamus G. Cellular targets of anti-alpha-enolase autoantibodies of patients with autoimmune retinopathy. J Autoimmun. 2004; 23:161-167. 6. Weinstein JM, Kelman SE, Bresnick GH, et al. Paraneoplastic retinopathy associated with antiretinal bipolar cell antibodies in cutaneous malignant melanoma. Ophthalmology 1994; 101:12361243. 7. Jacobson DM, Thirkill CE, Tipping SJ. A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol. 1990; 28:162-167. 8. Ferreyra HA, Jayasundera T, Khan NW, et al. Management of autoimmune retinopathies with immunosuppression. Arch Ophthalmol. 2009; 127(4):390-397. 9. Larson TA, Gottlieb CC, Zein WM, Nussenblatt RB, Sen HN. Autoimmune retinopathy: prognosis and treatment. Invest Ophthalmol Vis Sci. 2010; 51: E-Abstract 6375. 10. Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol. 2004; Jun 4:4:5. 11. Mantel I, Ramchand KV, Holder GE, et al. Macular and retinal dysfunction of unknown origin in adults with normal fundi: evidence for an autoimmune pathophysiology. Exp Mol Pathol. 2008; 84(2):90-101. 12. Shin SJ, Kim BC, Kim TI, et al. Anti-alpha-enolase antibody as a serologic marker and its correlation with disease severity in intestinal Behets disease. Dig Dis Sci. 2011; 56(3):812-818. 13. Lee JH, Cho SB, Bang D, et al. Human anti-alpha-enolase antibody in sera from patients with Behets disease and rheumatologic disorders. Clin Exp Rheumatol. 2009; 27(2 suppl 53):S63-66. 14. Forooghian F, Adamus G, Sproule M, et al. Enolase autoantibodies and retinal function in multiple sclerosis patients. Graefes Arch Clin Exp Ophthalmol. 2007; 245(8):1077-1084. 15. Vermeulen N, Arijs I, Joossens S, et al. Anti-alpha-enolase antibodies in patients with inflammatory bowel disease. Clin Chem. 2008; 54(3):534-541. 16. Sen HN, Chan CC, Caruso RC, et al. Waldenstrms macroglobulinemia-associated retinopathy. Ophthalmology 2004; 111(3):535539. 17. Mahdi N, Faia LJ, Goodwin J, et al. A case of autoimmune retinopathy associated with thyroid carcinoma. Ocul Immunol Inflamm. 2010; 18(4):322-323.

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Section VIII: Potential New Therapies for Uveitis

2012 Subspecialty Day|Uveitis

Systemic Pharmacologic Agents in Development for Uveitis: Voclosporin, Adalimumab, and AIN457
Eric Suhler MD
N otes

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Section VIII: Potential New Therapies for Uveitis

47

Local Pharmacologic Agents in Development for Uveitis: Sirolimus and Others


Quan Dong Nguyen MD
Sirolimus
Sirolimus, also known as rapamycin, was isolated in the 1970s from Streptomyces hygroscopicus in soil samples from Easter Island. Sirolimus is an immunosuppressant that works through inhibition of the mammalian target of rapamycin (mTOR) by binding to the immunophilin FK protein 12 (FKBP-12), thus interrupting the inflammatory cascade that leads to T-cell activation and proliferation. It also suppresses T-cell proliferation through the inhibition of IL-2, IL-4, and IL-15, employing Ca2+dependent or Ca2+-independent pathways. Owing to its unique mechanism of action and favorable side effects profile, sirolimus has been increasingly proposed as an alternative immunosuppressant in organ transplantation, although its side effects with systemic administration are also recognized. Sirolimus is the active ingredient in two FDA-approved products, specifically Rapamune, an immunosuppressive agent used in renal transplant patients, and the CYPHER Sirolimuseluting Coronary Stent, approved for improving coronary luminal diameter in patients with symptomatic ischemic disease. In order to allow higher target tissue levels and reduce systemic exposure, a proprietary local formulation of sirolimus was developed that, based on preclinical animal toxicity and pharmacokinetic studies, is amenable to both intraocular (intravitreal [IVT]) and extraocular (subconjunctival [SCJ]) injection. When administered by SCJ injection, a drug depot is formed that subsequently dissolves slowly and diffuses across sclera based on the physicochemical properties of sirolimus. Blood levels of sirolimus after SCJ administration peaks on Day 0 to dose-dependent levels: 3.62 ng/ml for a dose of 440 g and 9.32 ng/ml for a dose of 1320 g. By Day 7, sirolimus blood levels decrease to less than 3 ng/ml and subsequently, become minimally quantifiable, if at all, by Day 14 and beyond. Following intravitreal administration, the formulation forms a nondispersive depot in the vitreous and localizes in the inferior portion of the vitreous humor. The depot subsequently dissolves slowly and sirolimus diffuses through the vitreous humor to other ocular layers, with the highest concentration in vitreous followed by retina and choroid and lowest concentration in sclera and blood with detectable ocular tissue levels extending for 60 days after a single intravitreal administration. After intravitreal administration of 352 g, sirolimus blood levels peaks to <2ng/mL by the second day and decreases subsequently over the following days, with a half-life of 8-9 days. It is also important to recognize that the lowest therapeutic levels of sirolimus in organ transplant and cardiac patients is 5-15 ng/ml. Based on the current knowledge of sirolimus and its potential anti-inflammatory effect, we have set forth to evaluate the potential role of locally administered sirolimus in noninfectious uveitis. The interim results of the SAVE (Sirolimus as a Therapeutic Approach for Non-Infectious UVEitis) studies will be discussed. Other Agents Several other immunomodulatory therapeutic agents, including cyclosporin and methotrexate, are being developed as locally delivered, sustained-release, pharmacologic agents. Details will be discussed if public information is available.

Selected Readings
1. Gupta R, Murray PI. Chronic non-infectious uveitis in the elderly: epidemiology, pathophysiology and management. Drugs and Aging 2006; 23:535-558. 2. Napoli KL, Taylor PJ. From beach to bedside: history of the development of sirolimus. Ther Drug Monit. 2001; 23:559-586. 3. Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem. 1998; 4-31. 4. Mudumba S, Takanaga H, Bezwada P, et al. Intravitreal administration of ocular formulation of sirolimus in rabbits and humans. Invest Ophthalmol Vis Sci. 2012; 53:3198. 5. Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology 1985; 92:467-471.

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Section VIII: Potential New Therapies for Uveitis

2012 Subspecialty Day|Uveitis

Novel Drug Delivery Approaches for Uveitis: Iontophoresis and Others


David S Chu MD
I. Introduction The eye presents anatomical and physiologic challenges in ocular drug delivery: the cornea and conjunctival epithelium and tear drainage. In addition, the bloodretinal barrier and the lens-iris diaphragm further complicate drug delivery to the posterior segment. Treatment of uveitis can potentially be more effective and safer with more efficient drug delivery methods. II. Standard Drug Delivering Options for Eyes With Uveitis A. Topically: eye drops and ointment 1. Least invasive 2. Need to overcome epithelium and the rest of cornea and conjunctiva 3. Tear physiology: Aqueous production and blood flow can affect efficacy. 4. May require frequent instillation to achieve therapeutic level B. Systemic 1. Need to overcome blood-retinal barrier 2. Unwanted systemic side effects C. Periocular injections 1. Risk of globe injury 2. Need to overcome blood-retinal barrier 3. Requires repeated injections 4. Cataract formation and glaucoma D. Intravitreal implants and intraocular injections 1. Risk of retinal detachment, cataract formation, glaucoma and others A. Use of electrical current to facilitate delivery of medication or ions into the tissue for therapeutic purposes B. Based on the physical principle that like charges repel each other C. Potential advantages 1. Safety 2. Avoids systemic toxicity 3. Physician-controlled dosing D. Leduc demonstrated transcutaneous iontophoretic administration of strychnine in rabbits in early 1900s. E. Studied and used in many fields early on F. Many reports until about 1960, but usefulness in ophthalmology seemed to be overestimated. G. Many of the published studies lacked carefully controlled trials and details on toxicity. H. The techniques were limited by the technological development of the devices and ocular electrodes. I. It was never adopted as a standard procedure in ophthalmology. IV. Clinical Applications A. Dermatologic 1. Delivery of anesthetic through skin 2. Primary focal hyperhidrosis B. Sweat test by pilocarpine iontophoresis for the diagnosis of cystic fibrosis C. Administration of acetylcholine and sodium nitroprusside for assessing risk of development and progression of cardiovascular disease D. Administration of nonsteroidal anti-inflammatory drugs or corticosteroids for musculoskeletal disorders E. Administration of verapamil for treating Peyronie disease F. Administration of vitamin C for treating melasma G. Renewed interest in ophthalmic use H. Advancement of technology I. Studied for treatment of: 1. Dry eye 2. Bacterial keratitis 3. Herpes simplex keratitis 4. Corneal graft rejection 5. Glaucoma 6. Macular degeneration 7. Uveitis A. In the literature 1. 1989: Lam et al showed transscleral dexamethasone delivery more effective than drops and subconjunctival injections. 2. 1997: Behar-Cohen et al developed rat uveitis model treated with iontophoresis of dexamethasone.

III. Iontophoresis Technology

V. Uveitis Therapy

2012 Subspecialty Day|Uveitis

Section VIII: Potential New Therapies for Uveitis 3. Phase 3 a. EGP-437 vs. prednisolone acetate i. Double-masked placebo controlled

49

B. EyeGate FDA Trials 1. Iontophoresis system: First commercial ocular iontophoresis system developed by EyeGate Pharma 2. Phase 1/2 a. Evaluation of dexamethasone phosphate delivered by ocular iontophoresis for treating noninfectious anterior uveitis. Cohen et al. Ophthalmology Jan. 2012. i. To determine safe, effective, iontophoretic doses of EGP-437 (dexamethasone phosphate formulated for iontophoresis) in patients with noninfectious anterior uveitis and to evaluate systemic drug exposures ii. Multicenter, double-masked, parallel group, randomized clinical trial iii. Study design (a) 40 subjects with diagnosis of noninfectious anterior segment uveitis studied for 28 days (b) Four treatment groups with a single treatment of ocular iontophoresis (~4 min) with EGP-437 (c) No concurrent uveitis treatments during study (d) Rescue therapy with prednisolone acetate, if needed iv. Results (a) 19 of 40 patients (48%) achieved anterior chamber cell score of 0 at Day 14. By Day 28, 24 of 40 patients (60%) achieved score of 0. (b) 1.6 mA-min dose was the most effective and revealed an inverse dose response; median days to an ACC score of 0 were 11.5 days in the 1.6 mA-min group vs. 31 days in the 14.0 mA-min group. (c) All ocular adverse events deemed possibly or probably related to device or procedure; no adverse events were deemed related to study medication. (d) Mean IOP remained within normal range and mean best-corrected visual acuity at 4 meters remained relatively stable.

ii. Dexamethasone phosphate solution (EGP437) delivered by iontophoresis treatment (4.0 mA-min at 1.5 mA) on Day 0 and Day 7 with accompanying placebo eye drops vs. placebo iontophoresis treatment with accompanying prednisolone acetate ophthalmic suspension (1%) (positive control) eye drops iii. Currently enrolling b. Contact lens i. Ability to absorb drugs and release over a period of time ii. Silicon-hydrogel loaded with vitamin E has been shown to increase dexamethasone release period to from 1 day to 7 to 9 days. c. Nanoparticles i. Potential advantages: Ability to penetrate tissue better, more controlled release of drug over longer duration ii. Tamoxifen-loaded nanoparticles injected intravitreally have been shown to be effective in treating experimental autoimmune uveitis models whereas nonencapsulated tamoxifen had no effect. iii. Betamethasone-encapsulated particles have successfully treated EAU models.

Selected Readings
1. Behar-Cohen FF, Parel JM, Pouliquen Y, et al. Iontophoresis of dexamethasone in the treatment of endotoxin-induceduveitis in rats. Exp Eye Res. 1997; 65:533. 2. de Kozak Y, Andrieux K, Villarroya H, et al. Intraocular injection of tamoxifen-loaded nanoparticles: a new treatment of experimental autoimmune uveoretinitis. Eur J Immunol. 2004; 34:3702-3712. 3. Kim, J, Peng CC, Chauhan A. Extended release of dexamethasone from silicone-hydrogel contact lenses containing vitamin E. J Control Rel. 2010; 148:110-116. 4. Lam TT, Edward DP, Zhu XA, Tso MO. Transscleral iontophoresis of dexamethasone. Arch Ophthalmol. 1989; 107(9):1368-1371. 5. Sakai T, Kohno H, Ishihara T, et al. Treatment of experimental autoimmune uveoretinitis with poly(lactic acid) nanoparticles encapsulating betamethasone phosphate. Exp Eye Res. 2006; 82:657-663.

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Section IX: Late Breaking News

2012 Subspecialty Day|Uveitis

Top 10 Mishaps in Managing Uveitis


Robert Nussenblatt MD

1. The use of short-term intraocular or periocular steroids to treat chronic disease. The problem of reacting to reactivations rather than prevention. 2. Topical therapy to treat posterior pole disease. The phakic patients eye will not usually permit enough steroid to get to the posterior pole. 3. Triamcinolone therapy in severe uveitis; risk of infection. Intraocular injections can certainly be helpful but beware of infections. A good history and evaluation is critical. 4. Behet vs. acute retinal necrosis. Under the right circumstances these can be similar, with serious consequences if a mistake is made. 5. Undertreating anterior segment disease in children. We always wish to minimize, particularly when it comes to children, whether to add systemic medication or surgery. This can have a very negative effect on outcome. 6. Following intraocular inflammation with no therapy if vision remains good because of good vision. We know that it is a matter of time before the vision will decrease. 7. No therapy for relatively mild, chronic disease such as birdshot. 8. PPD positivity and ocular disease masquerading a masquerade. Its not always easy, but dont fall back on systemic tests if your clinical impression tells you otherwise. 9. MRI: Repeat and repeat. 10. Avastin to treat active uveitis.

2012 Subspecialty Day|Uveitis 

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Financial Disclosure

The Academys Board of Trustees has determined that a financial relationship should not restrict expert scientific, clinical, or nonclinical presentation or publication, provided that appropriate disclosure of such relationship is made. As an Accreditation Council for Continuing Medical Education (ACCME) accredited provider of CME, the Academy seeks to ensure balance, independence, objectivity, and scientific rigor in all individual or jointly sponsored CME activities. All contributors to Academy educational activities must disclose any and all financial relationships (defined below) to the Academy annually. The ACCME requires the Academy to disclose the following to participants prior to the activity: any known financial relationships a meeting presenter, author, contributor, or reviewer has reported with any manufacturers of commercial products or providers of commercial services within the past 12 months any meeting presenter, author, contributor, or reviewer (hereafter referred to as the Contributor) who report they have no known financial relationships to disclose For purposes of this disclosure, a known financial relationship is defined as any financial gain or expectancy of financial gain brought to the Contributor or the Contributors family, business partners, or employer by: direct or indirect commission; ownership of stock in the producing company; stock options and/or warrants in the producing company, even if they have not been exercised or they are not currently exercisable; financial support or funding from third parties, including research support from government agencies (e.g., NIH), device manufacturers, and/or pharmaceutical companies; or involvement in any for-profit corporation where the Contributor or the Contributors family is a director or recipient of a grant from said entity, including consultant fees, honoraria, and funded travel. The term family as used above shall mean a spouse, domestic partner, parent, child or spouse of a child, or a brother, sister, or spouse of a brother or sister, of the Contributor.

Category Consultant / Advisor

Code Description C Consultant fee, paid advisory boards or fees for attending a meeting (for the past one year) Employed by a commercial entity Lecture fees (honoraria), travel fees or reimbursements when speaking at the invitation of a commercial entity (for the past one year) Equity ownership/stock options of publicly or privately traded firms (excluding mutual funds) with manufacturers of commercial ophthalmic products or commercial ophthalmic services Patents and/or royalties that might be viewed as creating a potential conflict of interest Grant support for the past one year (all sources) and all sources used for this project if this form is an update for a specific talk or manuscript with no time limitation

Employee Lecture fees

E L

Equity owner

Patents / Royalty

Grant support

52

2012 Subspecialty Day|Uveitis

2012 Uveitis Planning Group Financial Disclosures

C Stephen Foster MD
Abbott Medical Optics: C,S Alcon Laboratories, Inc.: C,S Allergan, Inc.: C,S Eyegate Pharmaceuticals, Inc.: O,S Lux Biosciences, Inc.: C,S Novartis Pharmaceuticals Corp.: C,S

AAO Staff Brandi Garrigus


None

Ann LEstrange
None

Debra A Goldstein MD
Abbott Pharmaceuticals: C Allergan, Inc.: L Bausch + Lomb Surgical: C,L

Melanie Rafaty
None

Debra Rosencrance
None

Quan Dong Nguyen MD


Abbott Pharmaceuticals, Inc.: S Bausch + Lomb Surgical: C Genentech: S Heidelberg Engineering: S Lux Biosciences, Inc.: S Optos, Inc.: S Pfizer, Inc.: S Regeneron Pharmaceuticals, Inc.: S Santen, Inc.: C,S

Beth Wilson
None

Russell W Read MD PhD


EyeSight Foundation of Alabama: S International Retinal Research Foundation: S Research to Prevent Blindness: S

Eric Suhler MD
Abbott Pharmaceuticals: C,S Bristol-Myers Squibb: S EyeGate: S Genentech: S Lux Bio: C,S Novartis Pharmaceuticals Corp.: S

2012 Subspecialty Day|Uveitis 

53

Faculty Financial Disclosures

Massimo Accorinti MD PhD


None

Laure E Caspers MD
None

Douglas A Jabs MD MBA


Abbott Laboratories: C Alcon Laboratories, Inc.: C Allergan Pharmaceutical Corp.: C Applied Genetic Technologies Corp.: C Corcept Therapeutics: C Genentech: C Genzyme Corp.: C GlaxoSmithKline: C Novartis Pharmaceuticals Corp.: C Regeneron Pharmaceuticals, Inc.: C Roche Pharmaceuticals: C

Nisha Acharya MD
Bausch + Lomb: S GlaxoSmithKline: C National Eye Institute: S Research to Prevent Blindness: S Xoma: C

Chi-Chao Chan MD
None

Soon-Phaik Chee MD
Bausch + Lomb Surgical: C,L HOYA Medical Singapore Pte. Ltd.: C,L Technolas Singapore Pte Ltd: C,L

Yonca A Akova MD
None

David S Chu MD
Alcon Laboratories, Inc.: C,L Analysis Group, Inc.: C Eyegate: S Lux Bioscience: S Novartis Pharmaceuticals Corp.: S

Esen K Akpek MD
Alcon Laboratories, Inc.: S Allergan, Inc.: S

Henry J Kaplan MD
Advanced Ocular Technology: O,P Alcon Laboratories, Inc.: C Assenti: O Caremark: C Pfizer, Inc.: C RegenaSight: O,P Santen, Inc.: C

Thomas A Albini MD
Alcon Laboratories, Inc.: C,L Allergan, Inc.: C Bausch + Lomb Surgical: L

Cristobal A Couto MD
Allergan: L

Hassan A Al-Dhibi MD
None

Emmett T Cunningham Jr MD PhD MPH


None

John H Kempen MD
Alcon Laboratories, Inc.: C Allergan, Inc.: C Celtic: C Eyegate: S Food and Drug Administration: S Harbor: C Lux Biosciences: C Mackall Foundation: S National Eye Institute: S Research to Prevent Blindness: S University of Pennsylvania: E Xoma: C

Sofia N Androudi MD PhD


None

Janet Louise Davis MD


Santen, Inc.: S

Lourdes Arellanes MD
None

James Philip Dunn Jr MD


None

William Ayliffe MBBS


Santen, Inc.: C

Yosuf El Shabrawi MD
Allergan: C Merck & Co., Inc.: L

Alay S Banker MD
None

C Stephen Foster MD
Abbott Medical Optics: C,S Alcon Laboratories, Inc.: C,S Allergan, Inc.: C,S Eyegate Pharmaceuticals, Inc.: O,S Lux Biosciences, Inc.: C,S Novartis Pharmaceuticals Corp.: C,S

Talin Barisani-Asenbauer MD
None

Phuc Lehoang MD PhD


Allergan, Inc.: C Novartis Pharmaceuticals Corp.: C Santen, Inc.: C,S

Neal P Barney MD
Alcon Laboratories, Inc.: S

Erik Letko MD
None

Rubens Belfort Jr MD PhD


Alcon Laboratories, Inc.: C,L,S Allergan, Inc.: C,L,S Bayer: C

Debra A Goldstein MD
Abbott Pharmaceuticals: C Allergan, Inc.: L Bausch + Lomb Surgical: C,L

Careen Yen Lowder MD PhD


Allergan: C

Bahram Bodaghi MD PhD


Allergan, Inc.: C Bausch + Lomb Surgical: C Lux Biosciences: S Novartis Pharmaceuticals Corp.: S Xoma: C

Amod K Gupta MBBS


None

Elisabetta Miserocchi MD
Abbott Immunology: C Allergan: C Bausch + Lomb: C Lux Biosciences: L Teva: C

Vishali Gupta MBBS


None

John J Huang MD
Allergan: C

54

Faculty Financial Disclosures

2012 Subspecialty Day|Uveitis

Quan Dong Nguyen MD


Abbott Pharmaceuticals, Inc.: S Bausch + Lomb Surgical: C Genentech: S Heidelberg Engineering: S Lux Biosciences, Inc.: S Optos, Inc.: S Pfizer, Inc.: S Regeneron Pharmaceuticals, Inc.: S Santen, Inc.: C,S

Maite Sainz de la Maza MD


Alcon Laboratories, Inc.: L Allergan: L Merck & Co., Inc.: L

Johnny Tang MD
None

Joseph Tauber MD
Allergan, Inc.: C,L Bausch + Lomb: C Biolase: C Eleven Bio: C Merck & Co., Inc.: C

C Michael A Samson MD
CLS Pharmaceuticals: C,E,O Lux Biosciences: C PCAsso: O

Robert B Nussenblatt MD
None

Virender S Sangwan MBBS


None

Jennifer E Thorne MD PhD


Allergan: C National Eye Institute: S Research to Prevent Blindness: S Xoma: C

Annabelle A Okada MD
Mitsubishi Tanabe Pharma: L,S Novartis Pharma Japan: L Novartis Pharmaceuticals Corp.: C Pfizer Japan: L XOMA: C

Ariel Schlaen MD
None

Hatice N Sen MD
None

Harvey S Uy MD
Alcon Laboratories, Inc.: C,L LensAR: L

Justine R Smith MD
Collins Medical Trust: S National Eye Institute: S

Sumru Onal MD
None

Russell N Van Gelder MD PhD


Alcon Laboratories, Inc.: S Chromologic, LLC: S PanOptica: C Photoswitch Therapeutics: S

Emil Mitchel Opremcak MD


None

Ronald E Smith MD
Calhoun Vision, Inc.: O Clarity Vision: O Lacrimal Gland Device: P

Victor L Perez MD
Alcon Laboratories, Inc.: C,L,S Bausch + Lomb: C

Albert T Vitale MD
Aciont, Inc.: C Bausch + Lomb Surgical: C

Lucia Sobrin MD
None

Narsing A Rao MD
None

Sunil K Srivastava MD
Allergan: S Bausch + Lomb Surgical: C,S Novartis Pharmaceuticals Corporation: S

Steven Yeh MD
None

S R Rathinam MD PhD
None

Manfred Zierhut MD
Abbott Pharmaceutical Co.: L Allergan: L Bausch + Lomb: L

Russell W Read MD PhD


EyeSight Foundation of Alabama: S, International Retinal Research Foundation: S Research to Prevent Blindness: S

Eric Suhler MD
Abbott Pharmaceuticals: C,S Bristol-Myers Squibb: S EyeGate: S Genentech: S Lux Bio: C,S Novartis Pharmaceuticals Corp.: S

2012 Subspecialty Day|Uveitis 

55

Presenter Index

Akpek*, Esen K 19 Androudi, Sofia N 2 Ayliffe*, William 14 Belfort*, Rubens 26 Caspers, Laure E 29 Chan, Chi-Chao 43 Chu*, David S 48 Davis*, Janet Louise 11 Foster*, C Stephen 15 Goldstein*, Debra A 28 Gupta, Amod K 23 Jabs*, Douglas A 1 Kaplan*, Henry J 40 Lehoang*, Phuc 38 Nguyen*, Quan Dong 47 Nussenblatt, Robert B 50 Onal, Sumru 5 Opremcak, Emil Mitchel 8 Rao, Narsing A 37 Sangwan, Virender S 17 Sen, Hatice N 44 Smith*, Justine R 4 Suhler*, Eric 46 Thorne*, Jennifer E 10 Van Gelder*, Russell N 21, 42 Vitale*, Albert T 31

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