Diagnosis & Treatment of Uveitis C Stephen Foster, Albert T Vitale
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1DIAGNOSIS AND TREATMENT OF UVEITIS
2DIAGNOSIS AND TREATMENT OF UVEITIS
SECOND EDITION
C Stephen FosterMD FACS FACR Founder and President Massachusetts Eye Research and Surgery Institution Ocular Immunology and Uveitis Foundation Cambridge, Massachusetts, USA Clinical Professor of Ophthalmology Harvard Medical School Boston, Massachusetts, USA Albert T VitaleMD Clinical Professor of Ophthalmology and Visual Sciences Chief, Uveitis Division Member, Vitreoretinal Division John A Moran Eye Center University of Utah Salt Lake City, Utah, USA Foreword Frederick A Jakobiec
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Diagnosis and Treatment of Uveitis
First Edition: 2002
Second Edition: 2013
9789350255728
Printed at
4Dedicated to
My wife, Frances Barrett Foster, without whom nothing would get done; she is my everything.
C Stephen Foster
My wife, Patricia, with profound gratitude for her unconditional love and support, wisdom and humor, the keeper of the big picture throughout, always the best part of my everyday.
My children, Jazz, Alexandra, Sophia and Ryan; may the approach to your chosen professions be imbued with passion, a sense of wonder and a commitment to service such that your paths are punctuated by quanta of joy daily.
My patients, from whom I receive so much more than I can possibly give in allowing me the privilege to be their physician and in whose presence I truly understand humility.
Albert T Vitale
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7Contributors
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16Foreword
The uvea is the highly pigmented, vascularized middle tissue or tunic of the eye, sandwiched on the inside by the neuroretina and on the outside by the collagenous sclera. If the sclera is topographically an extension of the dura of the optic nerve, then the uvea is an extension of the pia-arachnoid, whereas the axons of the optic nerve are extensions from the innermost ganglion cells of the retina. The uvea comprises, posteriorly, the choroid; more anteriorly, the smooth muscle of the ciliary body; and up front, the stroma of the iris. The choroid can leak on inflammatory or immunologic provocation to create an effusion; inflammations situated primarily in the sclera and less often the retina may also cause secondary choroidal inflammations and effusions. It is interesting to note that large cell lymphoma of the retina and brain elicits an intense non-neoplastic chronic nongranulomatous inflammation of the choroid and other parts of the uvea. On the other hand, in systemic nodal lymphoma, the neoplastic lymphocytes settle in the choroid and hardly ever in the retina, and do not typically incite a secondary reactive inflammatory response.
In addition to its abundant blood vessels, the choroid possesses scattered melanocytes and fibroblasts, the latter basically unable to proliferate as scar tissue in the wake of inflammation or infection (the sclera also has limited powers of healing). Most true scar production featuring collagen within the eye is the result of fibrous metaplasia of the retinal pigment epithelium (itself, curiously, a neuroectodermal derivative), which is on the retinal side of Bruch's membrane. The lobular arrangement of the fenestrated choriocapillaris, which nourishes the outer retina and is situated right next to Bruch's membrane on the choroidal side, can be the focus of inflammations and infections, sometimes leading to proliferations of the pigment epithelium such as Dalen-Fuchs nodules in sympathetic ophthalmia. There are no lymphatics in the choroid, and none in either the retina or the sclera; thus, immunologic events in the eye may deviate from those elsewhere in the body (immune privilege). The uveal tissues of the choroid, ciliary body and iris are all derivatives of the neural crest, owing to the fact that there are no paired paraxial mesodermal somites in the head and neck region.
It is against the foregoing unusual anatomic and reparative features of the choroid and other parts of the uvea that one must analyze the idiopathic inflammations and infectious diseases that cause uveitis. This textbook edited by C Stephen Foster and Albert T Vitale, is the most comprehensive, scholarly and up-to-date effort at encompassing the diagnosis, etiopathogenesis and therapy for this often arcane spectrum of diseases. There is no doubt that the textbook, containing 83 chapters encompassing approximately 1300 pages, will become the dominant reference and touchstone for those with a sophisticated and deeply committed interest in uveitis [C Stephen Foster's earlier textbook on the Sclera (Springer-Verlag, 2nd edn, 2012) has already become a classic]. Having read through many chapters of this textbook in galleys, I can testify to the richness, accuracy and pure pleasure attendant on reading a treatise that brings the greatest degree of scientific precision to dissipate the miasma that too often envelops the subspecialty of uveitis.
This textbook would have been unthinkable and undoable without its impresario C Stephen Foster harnessing the energy and knowledge of many of his past and present trainees, including his co-editor Albert T Vitale. I have long been an admirer of Dr Foster's intellect and accomplishments, and my other colleagues locally, regionally, nationally and internationally often regard his as the court of last appeal for totally enigmatic and “hopeless” cases. I can think of no one else who combines his intellectual capacity, knowledge, experience, surgical skills and powers of communication in dealing with all facets of uveitis; he is probably in the company of no more than six individuals internationally who can manage these difficult problems. Through his training in Ophthalmology, Internal Medicine and Immunology, and his highly systematic approach to the patient, he has mastered the cabalistic field of uveitis. Consequently, he has been able to restore vision to innumerable patients who otherwise would have lost their sight. Dr Foster's inquisitive mind propels him to produce continually new laboratory and clinical research at the highest levels, with enormous patient relevancy and applicability. This textbook is a treasure, and will further enlighten the ophthalmic community about many recondite infectious and autoimmune diseases. Moreover, it also demonstrates the unsurpassed skills of one of the world's foremost ophthalmologists, C Stephen Foster.
Frederick A Jakobiec MD DSc (Med)
Henry Willard Williams Professor of Ophthalmology
Professor of Pathology, and Chairman of Ophthalmology
Harvard Medical School
Chief of Ophthalmology
Massachusetts Eye and Ear Infirmary
17Preface to the Second Edition
The first edition of this work, published by W B Saunders Company (no longer in existence) in 2002, was an unexpected sell out success, and thus when approached by M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India to reprise the work as an updated edition, we were very pleased to accept the offer and to take up the challenge of inviting all prior authors to update their chapters and to create new chapters to address the many advances, which have occurred in the diagnosis and treatment of uveitis over the past decade. The overall organization of the work has been retained and divided into six sections encompassing the basic principles of uveitis, our diagnostic and therapeutic approach, a comprehensive treatment of infectious and noninfectious uveitic diseases, masquerade syndromes and other uveitic entities. New chapters include Clinical Trials and Evidence-Based Medicine in the Medical Management of Uveitis, Emergent Viral Infections, Other Vector-Borne Parasitic Infections, Pediatric Uveitis and Pregnancy and Uveitis. New authors have been added as some prior authors declined the burden imposed by such work. Where more than 50% of prior authors' writing has been preserved, those authors have been retained in the authorship; otherwise, the authorship is devoted to the revising author(s). New authors were recruited for new chapters. The effort has been enormous. We have read and edited every line of every chapter, and it is with great satisfaction that we can now offer to you this one of a kind encyclopedic treatise on the subject of Diagnosis and Treatment of Uveitis.
The guiding principles, which formed the philosophical underpinnings of the writings in the first edition, remain unchanged: (1) Diagnosis matters; we advocate a comprehensive approach to diagnosing the underlying cause of a patient's uveitis. (2) Intolerance to chronic, even low-grade inflammation; history abundantly teaches that, eventually, such chronic inflammation produces permanent damage to structures critical to good vision. (3) Intolerance to the chronic use of corticosteroids in an effort to control inflammation; history shows and all uveitis specialists agree that such chronic use of corticosteroids inevitably produces damage itself. (4) A stepladder algorithmic approach to achieve the goal: no inflammation on no corticosteroids. (5) Collaboration with a chemotherapist or with an ocular immunologist who is, by virtue of training and experience, truly expert in the use of immunomodulatory medications, so that no significant drug-induced side effects occur in the exploitation of the stepladder algorithmic approach to achieving the goal of no inflammation on no corticosteroids.
After nearly 30 years on the geographic full-time Harvard faculty based at the Massachusetts Eye and Ear Infirmary, Dr Foster chose to create a private institution in Cambridge, The Massachusetts Eye Research and Surgery Institution (MERSI), along with a tax exempt foundation for research and education devoted to ocular inflammatory disease, The Ocular Immunology and Uveitis Foundation (OIUF). Many fellows have already completed their Ocular Immunology and Uveitis fellowship training at MERSI and OIUF, and many are now authors or coauthors on chapters within this second edition of our textbook. Dr Albert T Vitale has also changed venues since the publication of the first edition, now on faculty at the John A Moran Eye Center at the University of Utah, Salt Lake City, Utah, USA. He too has worked with Residents and Fellows in crafting chapters for this edition. We extend to them and to all participating chapters, authors our most heartfelt thanks for the work that they have done in producing this work, and for their tolerance for our requests for revisions, new references, new pictures, etc.
Our collective hope in bringing forth this new edition is that more ophthalmologists will learn not only new lessons in diagnosis and treatment of uveitis, but also the wisdom of moving past corticosteroid therapy in instances in which evidence-based analyses show quite clearly that corticosteroid monotherapy no longer represents the standard of care. Additionally, we hope that all who read this work will embrace the paradigm of steroid-sparing immunomodulatory therapy in the quest for remission. We believe that the evidence is very clear on the matter of cure: complete freedom of any recurrence of inflammation, off all medication, after a finite period of durable remission achieved through that paradigm.
C Stephen Foster MD FACS FACR
Albert T Vitale MD
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Dr C Stephen Foster was born and raised in West Virginia, received his Bachelor of Science degree in Chemistry at Duke University, with distinction and Phi Beta Kappa in 1965, and received his Doctor of Medicine degree at Duke University Medical Center, in 1969, being elected to Alpha Omega Alpha. He trained in Internal Medicine at Duke University Hospital from 1969 to 1970, and at the National Heart and Lung Institute, at the National Institutes of Health in Bethesda, Maryland, from 1970 to 1972, during which time he also taught Internal Medicine with an appointment as Instructor in Medicine at the George Washington University Hospital in Washington, DC. In 1972, he entered his Ophthalmology Residency Training Program at Washington University (Barnes Hospital), in St. Louis, Missouri, and having completed that in 1975, traveled to Boston to do two additional Fellowship trainings in Cornea and External Diseases and in Ocular Immunology. He completed this training in 1977 and was invited to join the full-time faculty of the Department of Ophthalmology of Harvard Medical School, where he was a member of the Cornea Service and Director of the Residency Training Program at the Massachusetts Eye and Ear Infirmary. He began his independent research in 1977 and has since been continuously funded by grants from the National Institutes of Health.
After 30 years on the full-time faculty of Massachusetts Eye and Ear Infirmary, Dr Foster decided to establish his own private practice—The Massachusetts Eye Research and Surgery Institution, a state-of-the-art 12,000 square foot practice with its own chemotherapy infusion suite and phlebotomy laboratory. He continues to direct a research laboratory at the Massachusetts Eye Research and Surgery Institution (MERSI) through the support of his newly created research foundation, The Ocular Immunology and Uveitis Foundation (OIUF), and continues his teaching activities and training fellows as a Clinical Professor of Ophthalmology at Harvard Medical School. He has also authored over 900 published papers and eight textbooks.
Dr Albert T Vitale is the Clinical Professor of Ophthalmology and Visual Sciences, Member of the Vitreoretinal Division and Director of the Uveitis Division at the John A Moran Eye Center at the University of Utah in Salt Lake City, Utah, USA. He attended Stanford University as an undergraduate and New York Medical College. Following internship in Internal Medicine at the University Health Centers of Pittsburgh, and residency in ophthalmology at St. Vincent's Hospital and Medical Center, he completed fellowship training in ocular immunology and uveitis at the Massachusetts Eye and Ear Infirmary followed by vitreoretinal fellowship at the Retina Specialists of Boston.
Prior to coming to the University of Utah and the John A Moran Eye Center, Dr Vitale served as Chief of the Uveitis Division and Senior Consultant Ophthalmologist in the Vitreoretinal Division at the King Khaled Eye Specialist Hospital in Saudi Arabia where he established the first uveitis service at this institution.
At the Moran Eye Center, Dr Vitale's clinical practice encompasses the medical and surgical treatment of patients with complex ocular inflammatory disease and vitreoretinal pathology and is the only provider with such dual training and expertise in the intermountain West. He has incorporated his research interests into clinical practice and is focused on novel drugs and delivery systems for the treatment of ocular inflammatory disease and age-related macular degeneration, diagnostic and therapeutic vitreoretinal surgery in the management of uveitis, pediatric uveitis, and the interface between ocular inflammatory disease and age-related macular degeneration. In addition, he is involved in the delivery of comprehensive and sustainable retinal care in the developing world through the Division of International Ophthalmology at the Moran Eye Center and ORBIS and for the indigent and underserved in Salt Lake City, serving as Medical Director for the Moran Eye Clinic at the Fourth Street Homeless Clinic.
Dr Vitale is committed to education, not only among Residents and Fellows at the Moran Eye Center, but nationally and internationally, serving as contributing editor for several American Academy of Ophthalmology (AAO) publications, including Focal Points and the Basic and Clinical Science Series as well as an invited speaker at numerous continuing medical educational symposia around the world. In recognition for his service to the AAO, he has received an honor award. He has published numerous articles in peer-reviewed literature, reviews, and book chapters and has been a reviewer for major ophthalmology journals including Ophthalmology, the American Journal of Ophthalmology, Archives of Ophthalmology, the British Journal of Ophthalmology, and Ocular Immunology and Inflammation.
19Preface to the First Edition
When the invitation came from W B Saunders Company, nearly a decade ago, to write this textbook, it contained three primary charges: (1) that the textbook should be comprehensive, even “encyclopedic”; (2) that it should emphasize more modern, aggressive approaches to treating uveitis that have evolved over the past 20 years; (3) that it should be a single-authored text. And although this invitation was incredibly tempting, I was unprepared and unwilling to take on the task single-handedly. Eventually, agreement was reached that one of my former fellows, Dr Albert T Vitale, would co-edit a multiauthored textbook with me, and that the opportunity would be exploited to reconnect with former fellows and colleagues who share our therapeutic philosophy: an attempt at total control of all inflammation and freedom from all relapses, while at the same time eliminating the need for chronic use of corticosteroids.
The challenge posed by the charge from the publisher has been enormous. Other books on the subject of uveitis have met this challenge by increasing their focus on particular matters, avoiding the problems posed by being encyclopedic. In particular, textbooks by Opermcak, by Smith and Nozik, by Kraus-MacKiw and O'Connor, by Nussenblatt, Palestine, and Whitcup, and by BenEzra are all excellent textbooks addressing the issue of diagnosis and therapy of uveitis. We have met the challenge posed by the publisher through the participation of 74 contributors, all of whom have had a relationship with the Massachusetts Eye and Ear Infirmary Ocular Immunology and Uveitis Service, and all of whom share in our basic philosophy of a complete intolerance to chronic, even low-grade intraocular inflammation, and at the same time a philosophy of steroid-sparing anti-inflammatory therapy.
The overriding philosophical principles that underpin the writings within this textbook are as follows: (1) Diagnosis matters; we advocate a comprehensive approach to diagnosing the underlying cause of a patient's uveitis. (2) Intolerance to chronic, even great low-grade inflammation; history abundantly teaches that, eventually, such chronic inflammation produces permanent damage to structures within the eye that are critical to good vision. (3) Intolerance to the chronic use of corticosteroids in an effort to control inflammation; history shows and all physicians agree that such chronic use of corticosteroids inevitably produces damage itself. (4) A stepladder algorithmic approach to achieve the goal: no inflammation on no steroids. (5) Collaboration with a rheumatologist or other individual who is, by virtue of training and experience, truly expert in the use of immunomodulatory medications, so that no significant drug-induced side effects occur in the exploitation of the stepladder algorithmic approach to achieving the goal of no inflammation on no steroids.
The experience of writing this textbook has been indescribable. The knowledge gained has been worth the effort itself. The reconnection with former fellows and colleagues has doubled the pleasure. Working with Dr Albert T Vitale has made it all infinitely easier, and indeed has made it possible. The effort has also refocused and sharpened my attention to many aspects in the care of our patients.
The Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary was established in 1977. The first Research Fellow was accepted into the laboratory in 1980. The first Clinical Fellow arrived in 1984. During this same year, a generous donation from Ms Susan Hilles, a patient of the Service, provided for the construction of a new, state-of-the-art immunology laboratory: the Hilles Immunology Laboratory. A second gift from Mr Richard Rhodes, another of the Service's patients, enabled us to equip an additional laboratory, the Rhodes Molecular Immunology Laboratory, in 1990. These laboratories are described as applied research laboratories—that is, we have attempted to bring to the clinic as soon as practicable the discoveries and lessons learned from the laboratory.
Our hope in producing this textbook is that a new generation of ophthalmologists will not only learn the lessons of the past with respect to diagnosis and treatment of uveitis in the usual way, with corticosteroids, but will also learn that the prevalence of blindness from uveitis, unchanged since the improvements occurring after the introduction of corticosteroids, can be further reduced by the adoption of the therapeutic principles espoused herein.
C Stephen Foster MD
References
  1. Opermcak EM. Uveitis: A Clinical Manual for Ocular Inflammation. Springer-Verlag;  New York:  1995.
  1. Smith RE, Nozik RM. Uveitis: A Clinical Approach to Diagnosis and Management. Williams and Wilkins;  Baltimore:  1989.
  1. 20 Kraus-MacKiw E, O'Connor GR. Uveitis: Pathophysiology and Therapy. Thieme Verlag;  New York:  1986.
  1. Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis: Fundamentals and Clinical Practice. Mosby Year Book;  St. Louis:  1996.
  1. BenEzra D. Ocular Inflammation: Basic and Clinical Concepts. Blackwell Science;  London:  1999.
It has been an honor and a privilege to participate in the creation of this text. This work represents much more than the concerted efforts and efficient team-work of a group of individuals dedicated to a multiauthored book; it is the product of an extended family bound by similar philosophical values in their care for patients with ocular inflammatory disease. Indeed, the essence of this philosophy, the pleasure of reconnecting and collaborating with the current and former fellows of the Ocular Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary, and the refocusing and crystallization of the state of the art with respect to many aspects of patient care as a result of this effort have all been articulated in Dr Foster's preface. What is not mentioned is the personal and professional respect and gratitude that I myself and the members of this extended family share for our association with Dr Foster. The ultimate and most important beneficiaries, of course, are our patients who suffer from uveitis.
Albert T Vitale MD
21Acknowledgments
We wish here to thank thousands of patients with uveitis who have entrusted their care to us. It is through them that the inspiration for this work arose over a decade ago, and it is primarily for them that this textbook is dedicated. They form the basis for our continuing education and for the training of fellows who have decided to subspecialize in the field of ocular immunology and uveitis. Dr Foster extends his sincere thanks to the staff at the Massachusetts Eye Research and Surgery Institution (MERSI) for their support, for their loyalty and for their extraordinary patient-centered, customer-friendly attitudes at MERSI everyday. Special thanks go to Mr Scott Evans, Chief Operating Officer at MERSI, to Mr Brian Schurko and Ms Jamie Lynne Metzinger, managers of the great volume of manuscripts and wrangling of all the contributors, and to Dr Tongzhen Zhao, Manager of the Pathology Laboratory of the Ocular Immunology and Uveitis Foundation. Dr Vitale would like to extend his most sincere gratitude to the uveitis team at the John A Moran Eye Center, University of Utah, Salt Lake City, Utah, USA, past and present, for their tireless dedication to the total care of our patients with ocular inflammatory disease, especially Diana Ramirez, Julie Connors, Kimberley Wegener, Deborah Harrison, Julia Kleinschmidt, Paul Yang, Mike Anderson, Justin Knight, Stephen Goodin, Karla Mackay, Jade Springmeyer, Jennifer Harmon Tham, Elizabeth Stocks, Earleen Smith, Stephanie Helene Stephens and Michelle Burgin (Mitchell). He would also like to acknowledge the members of the imaging department at the John A Moran Eye Center, past and present: James Gilman, Paula Morris, Glen Jenkins, Cyrie Fry and Beth Snodgrass. We would especially like to credit Jazz Vitale for his extremely innovative, original work of art incorporated into the cover design. Finally, we extend our thanks and acknowledgment to all the referring physicians all across America, Europe, Asia and the Middle East, who have consistently referred patients to us for consultation.