The Sclera

c. Stephen Foster Maite Sainz de la Maza

The Sclera

Foreword by Frederick A. lakobiec

With 134 Illustrations and 33 Color Plates

Springer Science+Business Media, LLC

C. Stephen Foster, MD Associate Professor of Ophthalmology Harvard Medical School Director, Immunology and Uveitis Service Massachusetts Eye and Ear Infirmary Boston, MA 02114 USA

Maite Sainz de la Maza, MD, PhD Assistant Professor of Ophthalmology Central University of Barcelona 08036 Barcelona Spain

Cover illustration: The eye of a patient with rheumatoid arthritis who has developed pro­gressively destructive necrotizing scleritis.

Library of Congress Cataloging-in-Publication Data Foster, C. Stephen (Charles Stephen), 1942-

The sclera/C. Stephen Foster and Maite Sainz de la Maza. p. cm.

Includes bibliographical references and index. ISBN 978-1-4757-2345-8 ISBN 978-1-4757-2343-4 (eBook) DOI 10.1007/978-1-4757-2343-4 1. Sclera-Diseases. I. Maza, Maite Sainz de lao II. Title. [DNLM: 1. Scleritis. 2. Sclera. WW 230 F754s 1993]

RE328.F67 1993 617.7' 19-dc20 DNLMIDLC for Library of Congress

Printed on acid-free paper. © 1994 Springer Science+ Business Media New York Originally published by Springer-Verlag New York, Inc. in 1994 Softcover reprint of the hardcover 1st edition 1994

93-10235

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987654321

ISBN 978-1-4757-2345-8

To our parents: Carson and Martha Foster Julio and Teresa Sainz de la Maza

Foreword

Over the past five years, in sharing patients with him, following his research, and benefitting from his teaching, I have come to marvel at Dr. Stephen Foster's mind, dedication, and productivity. No one has a richer or more challenging clinical practice, has approached his clinical care with more critical questioning, or has produced as much useful clinical and basic research in his field.

Steve has kept meticulous clinical records with elegant photographic documentation, which serve as the basis for the creation of this treatise. He has been fortunate in his co-author, Dr. Sainz de la Maza, who initially inveigled Steve to participate in this project and then set herself the enormous task of repairing the lacuna occasioned by the nonavail­ability of the classic text by Watson and Hazeiman, The Sclera and Systemic Disorders. Steve has taken great pride in the trainees who have passed through his fellowship program, and has methodically tried to select them from around the world in order to extend the influence of his clinical and research traditions. Dr. Sainz de la Maza, who practices academic ophthalmology in Barcelona, Spain, is a superb exemplar of the fruits of this strategy; the ophthalmic communities, both American and international, are in their debt for producing this textbook.

I have read many of the chapters in this textbook, and they augment one's impressions of Steve's high standards of scholarship and originality. Steve has also generously noted that the Massachusetts Eye and Ear Infirmary's unique resources are very much embedded in the content of this book. I have had several in-depth discussions with Steve and Dr. Sainz de la Maza regarding pathogenetic concepts of scleritis, auto­immune diseases, and vasculitis, and have personally profited from those dialogues. Now trainees, general ophthalmologists, specialists, and parti­cularly patients far and wide will benefit from the dissemination of this unique database and codification of the principles of clinical management. My admiration for Steve's work, which was great from a distance when I was in New York, has simply mushroomed in proximity to him in Boston.

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I am pleased to contemplate that this textbook will bring him and his accomplishments closer to the entire ophthalmic community.

Frederick A. Jakobiec, M.D. Henry Willard Williams Professor of Ophthalmology Professor of Pathology, and Chairman of Ophthalmology Harvard Medical School

Chief of Ophthalmology Massachusetts Eye and Ear Infirmary

Foreword

Preface

The sclera composes 80% of the geographic extent of the exterior confines or wall of the eyeball, yet it receives relatively little attention in the ophthalmic literature. This is understandable, given the fact that disorders of the sclera are not common and the fact that, when relatively minor problems of the sclera do develop, healing without consequence is the usual outcome. After all, a scar in the sclera is of little importance, because the sclera is an opaque structure. Such a scar in the cornea, or an opacity in the lens or vitreous, or a scar in the macula, of course, carries infinitely more visual significance. But it is exactly this rarity of significant scleral problems, coupled with the profound systemic implications that some inflammatory disorders of the sclera carry, that makes studies of the sclera and its disorders important. Indeed, a substantial proportion of individuals who develop serious scleral inflammation are discovered to have an occult systemic disease; in The Sclera and Systemic Disorders Watson and Hazleman* emphasized that 27% of patients who develop necrotizing scleritis are dead within 5 yr from a systemic, vasculitic lesion. Watson and Hazleman also emphasized that because of the comparative rarity of scleral disease, the diagnosis is often missed, and 40% of eyes reported in one series of enucleated eyes had had a primary diagnosis of scleritis.

We have written this book because the finest book ever written on this subject, The Sclera and Systemic Disorders, by Watson and Hazleman (published in 1976 by W.B. Saunders, Philadelphia, as Volume 2 in their series, Major Problems in Ophthalmology), has been out of print, un­available through any source whatsoever, since 1985. Dr. Sainz de la Maza was frustrated by this; she could find no copies of this magnificent book in the medical library in Barcelona. Watson gave me his last copy of the book, which he obtained from the attic of his home, and inscribed to me "with all best wishes." It is this rare treasure that our efforts try to emulate. The two books are different in style, organization, patient populations that form the basis of the material, and, to a small degree, point of view. But in many respects the books are quite similar: our

* Watson PG, Hazleman BL: The Sclera and Systemic Disorders, WB Saunders, Philadelphia, 1976.

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experiences corroborate theirs, and the philosophies born of those separate experiences are identical.

We began with all that we had learned from Watson and Hazleman and built on that excellent foundation. The basis of our experience springs from the Immunology Service at the Massachusetts Eye and Ear Infirmary, which was begun in 1977, and which has been devoted to the study and care 'of patients with any inflammatory problem related to the eye, from the lids to the optic nerve. The first Research Fellow joined the service in 1980, and the first Clinical Fellow arrived in 1984. Between 1977 and 1992 approximately 45,000 patient visits have occurred, ap­proximately 6000 new patients have been evaluated, and 40 Ocular Immunology Fellows have been trained in the Service. Dr. Sainz de la Maza was one of those Fellows, and in the course of training she developed a special interest in and affinity for patients with scleritis. It was her initiative that was at the heart of the genesis of this project, and it is entirely through her efforts that this project has been successfully completed.

Our hope is that this book will serve as a resource for residents in ophthalmology, for cornea and immunology fellows in training, and for those ophthalmologists in practice and on faculties who have an interest in patients with diseases of the sclera. The majority of the book is devoted to scleral inflammation, because scleritis represents, by far, the most common scleral disorder encountered in ophthalmic practice, and because of the profound systemic implications of scleritis. The references at the end of each chapter, although not exhaustive, are generous in number and should provide the reader with more than enough original source material for further reading. Finally, for those who have access to a copy of the book by Watson and Hazleman, we would enthusiastically encourage you to read their book as well as this one.

Preface

Acknowledgments

We acknowledge the help, patience, and understanding provided by our patients in the course of treatment. This book, which is based on their personal experiences, would not exist without them. So, too, we grate­fully acknowledge the generosity of referring physicians throughout New England: not only have they referred patients, with all their varieties of ocular inflammatory disorders, to the Immunology Service, but they have allowed us to care for them longitudinally as well.

The physicians who have chosen to spend additional years training in ocular immunology deserve special thanks. In the course of their training, they assumed increasing amounts of responsibility in the care of our patients, and without their help much of the work that has been done would not have been finished. These individuals are listed separately on the following page. The research associates and laboratory technicians of the Hilles Immunology Laboratory and of the Rhoads Molecular Immunology Laboratory are also gratefully acknowledged. These in­dividuals include Drs. Robin Campbell, Peter Wells, and Soon Jin Lee, and Carolyn DiSiena, Lou Ann Caron, Beverly Rice, Tom Ihley, James Dutt, Tong Zhen Zhao, Victor Correa, and Jane Lui.

Anterior segment and posterior segment photographers Kit Johnson and Phil Ruderman, and retinal photographers Jeff Napoli, Martha Cunningham, Ann Elias-Dreiker (CRA), and Alice George are respon­sible for most of the clinical illustrations that are included in this book, and we are grateful to them for the fine quality of their work. Similarly, we acknowledge Lauri Cook for her superb medical illustrations and Richard Fleischer for his help in making publication prints. The per­sonnel of the Immunology Service, technicians, nurses, and secretaries, are also acknowledged for their help in running an efficient operation, which allows us to accomplish the day's work.

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Fellows of the Ocular Immunology Service, Massachusetts Eye and Ear Infirmary

Former Fellows

LESLIE FUJIKAWA, M.D., Associate, University of the Pacific RICHARD WETZIG, M.D., Private Practice, Colorado Springs, CO JAMES KALPAXIS, M.D., Private Practice, San Antonio, TX ROBIN CAMPBELL, Ph.D., Industry (Burroughs-Wellcome) INGER SANDSTROM, M.D., Assoc. Professor, Karolinska Institute, Sweden PAUL THOMPSON, M.D., Assoc. Professor, University of Montreal, Canada RICHARD BAZIN, M.D., Assoc. Professor, Lasoli University, Quebec, Canada PETER WELLS, Ph.D., Industry (Upjohn Pharmaceuticals) LYE PHENG FONG, M.D., Assoc. Professor, University of Melbourne, Australia MICHAEL RAIZMAN, M.D., Assoc. Professor, Tufts University, Boston, MA E. MITCHEL OPREMCAK, M.D., Assoc. Professor, Ohio State University GURINDER SINGH, M.D., Private Practice, Anaheim, CA BARRY GOLUB, M.D., Assoc. Professor, SUNY Stonybrook JOSEPH TAUBER, M.D., Assist. Professor, University of Missouri, Kansas City HUM CHUNG, M.D., Assoc. Professor, Seoul University, Seoul, Korea MAITE SAINZ DE LA MAZA, M.D., Assist. Professor, University of Barcelona,

Spain THANH HOANG-XUAN, M.D., Assoc. Professor, University of Paris, France MANDl ZALTAS, M.D., Fellow in Glaucoma, Boston, MA NEIL TOLCHIN, M.D., Resident in Ophthalmology EUGENE Lru, M.D., Resident in Ophthalmology MARGARITA CALONGE, M.D., Assist. Professor, University of Valladolid, Spain JOHN BAER, M.D., Assoc. Professor, University of Maryland ALEJANDRO GARCIA RODRIGUEZ, M.D., University of Monterey, Mexico TUYET MAl PHAN, M.D., Private Practice, Los Angeles, CA RAMZI HEMADY, M.D., Assist. Professor, University of Maryland RICHARD TAMESIS, M.D., University of Nebraska SARKIS SOUKASIAN, M.D., Private Practice, Lahey Clinic, Burlington, MA MANFRED ZIERHUT, M.D., Assist. Professor, Tubingen University, Germany NADA JABBUR, M.D., Resident in Ophthalmology, George Washington University XIN XIN CAl, M.D., Ph.D. Program, Tufts University, Boston, MA MARTIN FILIPEC, M.D., Assoc. Professor, University of Prague, Czechoslovakia SOON JIN LEE, Ph.D., Assist. Professor, University of Missouri RON NEUMANN, M.D., Director of Immunology Research, Pharmos Corp.,

Israel NEAL BARNEY, M.D., Assist. Professor, University of Wisconsin

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xiv Fellows of the Ocular Immunology Service

HELEN WU, M.D., Assist. Professor, Tufts University, Boston, MA ARND HEILIGENHAUS, M.D., Assist. Professor, University of Essen, Germany ADAM KAUFMAN, M.D., Assist. Professor, University of Cinncinnatti AMYNA MERCHANT, M.D., Resident in Ophthalmology VICTOR CORREA, Ph.D., Fellow, Harvard Medical School ALEJANDRO BERRA, Ph.D., Chairman, Dept. of Immunology, University of

Moron, Buenos Aires, Argentina ELISABETH MESSMER, M.D., Resident in Ophthalmology, University of Munich,

Germany ZHENGZm LI, M.D., Research Assoc., St. Louis University YONCA AKOVA, M.D., Assist. Professor, University of Ankara, Turkey

Current Fellows

ALEJANDRO GARCIA RODRIGUEZ, M.D., Mexico MIGUEL PEDROZA-SERES, M.D., Mexico ALBERT VITALE, M.D., USA LEON LANE, M.D., USA JESUS MERAYO-LLOVES, M.D., Spain WILLIAM POWER, M.D., Ireland RENATa NEVES, M.D., Brazil WILLIAM AYLIFFE, M.D., England

Contents

Foreword by Frederick A. Jakobiec . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Preface.. . ........... . . ...... . . . ......... . . ..... . .... . ...... lX

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Fellows of the Ocular Immunology Service, Massachusetts Eye

and Ear Infirmary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Xlll

Color Plates follow front matter

1 Structural Considerations of the Sclera 1

2 Immunological Considerations of the Sclera . . . . . . . . . . . . . . . . . . 33

3 Diagnostic Approach to Episcleritis and Scleritis . . . . . . . . . . . . . . 59

4 Clinical Considerations of the Episc1eritis and Scleritis: The Massachusetts Eye and Ear Infirmary Experience .......... 95

5 Pathology in Scleritis: The Massachusetts Eye and Ear Infirmary Experience. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 137

6 Noninfectious Scleritis: The Massachusetts Eye and Ear Infirmary Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 171

7 Infectious Scleritis: The Massachusetts Eye and Ear Infirmary Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 242

8 Noninflammatory Diseases of the Sclera ................... " 278

9 Treatment: The Massachusetts Eye and Ear Infirmary Experience. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 299

Index...................................................... 309

xv

FIGURE 3.1. Episcleritis. Note the vascular dilatation of conjunctival vessels, and superficial episcleral and deep episcleral vascular plexuses. There is no underlying scleral edema or loss of sclera, and the eye appears bright red.

FIGURE 3.2. Scleritis. Note the bluish-red appearance of the inflamed eye, owing to the loss of some of the scle­ral fibers under the conjunctiva and episcleral tissue.

FIGURE 3.18. Slit-lamp photomicrograph, patient with episcleritis. Note that there is no displacement of the slit beam from underlying scleral edema.

FIGURE 3.19. Slit-lamp photomicrograph, patient with scleritis. Note the displacement, anteriorly, of the slit beam as it sweeps across an area of scleral edema un­derlying the dilated vessels of the conjunctiva and the superficial and deep episcleral vascular plexuses.

FiGURE 3.22. Peripheral corneal ulcer in a patient with diffuse anterior scleritis (slit-lamp photomicrograph). Note the presence of a peripheral corneal ulcer extend­ing from approximately 3:30 clockwise to 8:30.

FIGURE 3.32. Immunofluorescence photomicrograph: conjunctival biopsy, patient with scleritis. Anti-IgG antibody has been used. Note the presence ofIgG in the vessel wall, indicating the presence of inflammatory microangiitis. (Magnification, X28.)

FIGURE 4.l. Episcleritis prior to instillation of 10% phenylephrine drops.

FIGURE 4.2. Same eye as in Fig. 4.1 after the instillation of 10% phenylephrine drops. Note the dramatic reduc­tion in the inflamed appearance of the globe, because of the vasoconstrictor effect on the episcleral vascular plexuses, indicating that this patient probably has epis­cleritis rather than true scleritis.

FIGURE 4.3. Nodular episcleritis. The nodule is mobile, that is, not incorporated into sclera or part of sclera.

FIGURE 4.4. Scleritis. Note the slightly violaceous char­acter of the inflammation. The patient complains of pain, and the globe is tender to palpation through the upper lid.

FIGURE 4.5. Same eye as in Fig. 4.4, 2 years after the photograph in Fig. 4.4 was taken. The scleritis has been successfully treated and has been held in remission for 1 year. Note, however, the areas of scleral loss with uveal "show" through the remaining scleral fibers.

FIGURE 4.6. Patient with necrotizing scleritis prior to instillation of 10% phenylephrine.

FIGURE 4.7. Same eye as in Fig. 4.6, 10 min after instilla­tion of 10% phenylephrine drops. Note that the degree of clinical inflammatory signs is virtually unchanged, indicating that this patient's inflammation, even in areas outside the focus of frank necrotizing scleritis, repre­sents true scleritis.

FIGURE 4.12. Nodular scleritis. This nodule is incorporat­ed into sclera, indeed, is part of the sclera and, therefore, is immobile as one tries to palpate and move it.

FIGURE 4.14. Necrotizing scleritis. Note not only the loss of sclera, but also the pronounced vascularity in the area.

FIGURE 4.22. Fundus photomicrograph of patient with posterior scleritis. Note the choroidal folds, as shown by the alternating light and dark lines.

FIGURE 4.34. Slit-lamp photomicrograph. Note the area in the inferior cornea of peripheral corneal thinning in this patient, who has had multiple bouts of diffuse ante­rior scleritis.

FIGURE 4.36. Slit-lamp photomicrograph: peripheral sclerosing keratitis. Note the peripheral keratitis with associated neovascularization and opacification of the peripheral cornea in this patient, who has had chronic anterior scleritis.

FIGURE 5.5. Scleral biopsy of a specimen from a patient with scleritis. Note the large number of purple-stained cells in the specimen, the mast cells. (Magnification, x40; alkaline Giemsa stain.)

FIGURE 5.6. Scleral biopsy, Note the striking presence of eosinophils in this specimen. (Magnification, x60; hematoxylin-eosin stain.)

FIGURE 5.8. Immunofluorescence microscopy: specimen is from a patient with scleritis. The antibody is anti-der­matan sulfate antibody. Note (in comparison to Fig. 5.9) the dramatic reduction in the presence of dermatan sul­fate in the scleritis specimen.

FIGURE 5.9. Immunofluorescence microscopy: biopsy of normal sclera. Antibody is anti-dermatan sulfate anti­body. Note the large amount of bright apple-green fluo­rescence, indicating rather large amounts of dermatan sulfate in normal sclera. (Magnification, X 100.)

FIGURE 5.15, Scleral biopsy of patient with scleritis. Note the inflammatory microangiopathy, with clustering of inflammatory cells around the vessel. Because the vessel lacks a true vascular wall, however, the criteria typically used by general pathologists to declare the presence of a true vasculitis cannot be used in analyzing these specimens. (Magnification, x60; hemaloxylin­eosin stain.)

FIGURE 5.10. Immunofluorescence microscopy: scleral biopsy from a patient with scleritis. Note (particularly in relationship to Fig. 5.11) the relative lack of bright staining, except around the vessels, indicating a relative paucity of chondroitin sulfate in this scleral specimen. (Magnification, X40.)

FIGURE 5.11. Immunofluroescence microscopy: normal sclera. Antibody is anti-chondroitin sulfate antibody. Note the relative abundance of bright apple-green fib­rils, indicating a relatively large amount of chondroitin sulfate in normal sclera. (Magnification, x40.)

FIGURE 5.28. Forty-nine-year-old man with scleritis and associated keratitis. Note the feathery central advancing edge of the keratitis (arrow).

FIGURE 5.29. Same patient as in Fig. 5.28: different area and view. Note the intense scleritis.

FIGURE 5.30. Immunofluorescence microscopy: conjunc­tival biopsy from the same patient illustrated in Figs. 5.28 and 5.29. Antibody is anti-herpes simplex virus antibody . Note the striking positivity of the nuclei in the epithelial cells and in some of the keratocytes, indicat­ing the presence of herpes simplex virus in the tissue.

FIGURE 5.31. Negative control for the anti-herpes anti­body immunohistochemical staining, eliminating the first (anti-herpes) antibody in a two-step, indirect immu­nofluorescence technique. This negative control is im­portant: it makes it clear that the findings shown in Fig. 5.30 are indeed true positives.

FIGURE 5.33. Scleral biopsy from a 67-year-old patient with necrotizing scleritis, which developed following trauma to the right eye, inflicted by a cow's tail. Scleral biopsy has been stained with Gomori methenamine sil­ver stain. Note the large number of filamentous fungi (black) in this scleral biopsy specimen.

FIGURE 6.5. Keratoconjunctivitis sicca. Rose bengal dye (l %) has been instilled into the cul-de-sac. Note the punctate staining of the conjunctival epithelium in the interpalpebral fissure.

FIGURE 6.8. Hands of a patient with systemic lupus ery­thematosus and Raynaud's phenomenon. The patient's hands had been exposed to the cold just prior to her arriving in the clinic, and they were markedly blanched during the exposure to the cold. They were painful then and were still painful at the time that this photograph was taken, with venous dilatation producing the dramat­ic, bluish color of the fingers, particularly those of the right hand.