Atlas of Uveitis: Diagnosis and Treatment [1 ed.] 9789811537257, 9789811537264

Citation preview

Peizeng Yang

Atlas of Uveitis Diagnosis and Treatment

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Atlas of Uveitis

Peizeng Yang

Atlas of Uveitis Diagnosis and Treatment

Peizeng Yang The First Affiliated Hospital of Chongqing Medical University Chong Qing People’s Republic of China

ISBN 978-981-15-3725-7    ISBN 978-981-15-3726-4 (eBook) https://doi.org/10.1007/978-981-15-3726-4 © Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 This work is subject to copyright. All rights are reserved by the Publishers, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publishers, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publishers nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publishers remain neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Foreword by Quan Dong Nguyen

The world of uveitis and ocular inflammatory diseases has been challenged by many difficulties in diagnosis and management throughout the decades. There remain much that are not known about the pathophysiology of many uveitic entities and how clinician scientists can manage them. However, for students of uveitis—any individual who wishes to learn about uveitis and patients with uveitis and how he or she can care for them; I am humbled to be such a student— fortunately, there are great teachers who are dedicated and devoted to share their years of experiences and expertise to enable and ensure transmission of enhanced knowledge from one generation to the next. Among the living greats in Uveitis is Prof. Peizeng Yang of China. Known and respected throughout the world as a brilliant thought leader in the field of uveitis and ocular immunology, Prof. Yang is currently the Director of the Uveitis Service at the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute in Chongqing, China. However, despite his many successes and international fame, among his most distinguished achievements are his mentorship and teaching of many students, residents, fellows, and young faculty members throughout China and around the world over the years to help them with their careers. And now, as a master of teaching, a teacher of teachers, Prof. Yang has composed one of the most comprehensive textbooks in English for Uveitis, Atlas of Uveitis: Diagnosis and Treatment. Having the honor of serving as editor of several books, I appreciate very much that it is not a simple task or always possible to share one’s many years of protean experiences and extensive knowledge in one textbook. But Prof. Yang has so beautifully composed a masterpiece employing his 30 years of expertise. With 52 chapters and pages of educational photos and images, as one opens the book and turns the pages—and I recommend doing so with attention and care as not to miss important facts and relevant clinical pearls within each chapter—one will learn about the epidemiology of uveitis, from Asia to America, Europe to Africa, across the continents; the unique nature and characteristics of different uveitic entities, infectious and noninfectious; and the clinical pearls, based on decades of managing thousands of patients, in diagnosing and managing the different types of uveitis and different kinds of patients with uveitis, as well as other specialists who often partner with ophthalmologists in managing uveitic patients. Along the way, as one marvels through each page of the Atlas, one will be rewarded with beautiful, pathognomonic, and atypical images of different modalities that Prof. Yang has collected throughout the decades. The field of uveitis and the students of uveitis are now gifted with another outstanding resource for learning. Please treasure this most valuable reference as it represents the dedication and legacy of a teacher and an educator who has devoted all his life to further the understanding of the pathophysiology, diagnosis, and management of uveitis. The Atlas deserves to be in a prominent place in one’s library and the master who gave birth to the Atlas deserves,

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Foreword by Quan Dong Nguyen

although he certainly does not want it, a sincere thanks from the profession, the field and its clinicians and scientists, and the patients. With deep admiration and respect for Prof. Yang, Quan Dong Nguyen Byers Eye Institute, Wu Tsai Neurosciences Institute Stanford University School of Medicine Palo Alto, CA, USA International Ocular Inflammation Society (IOIS) Brussels, Belgium December 2019

Foreword by Aize Kijlstra

I have known Prof. Peizeng Yang since 1994, and it is an honor to write a foreword for this atlas on uveitis. He came to my laboratory to study the mechanisms of uveitis and did this by working on an experimental animal model. In between experiments, he was always studying the textbooks and literature that were available in our department and in the library of the Academic Medical Centre of the University of Amsterdam in The Netherlands. It was at that time he started working on the first textbook on uveitis in Chinese. This was followed by several updated editions, and I am now glad to see that his vast experience in diagnosing and treating uveitis patients has culminated in this extensive atlas on uveitis. I have visited Prof. Peizeng Yang many times in China and have seen his dimly lit laboratory with only a small table centrifuge and two microscopes at the Zhongshan Ophthalmic Centre in Guangzhou change into the most advanced laboratory at the Chongqing Medical University, where now more than 20 students and postdocs perform research according to the latest state of the art in the world. Professor Yang’s team has made great contributions to the understanding of mechanisms involved in uveitis; especially in Behcet’s disease, Vogt– Koyanagi–Harada disease, and acute anterior uveitis, through a series of outstanding studies on immunology and genetics. Recently, their studies on gut microbiota in uveitis have opened a new avenue for the study of prevention and treatment of uveitis. Collectively, the studies that Prof. Yang’s team has performed have enriched our knowledge of uveitis clinically and basically and improved approaches to therapy. It can be said that Prof. Yang single-handedly put the uveitis research in China on the international map through his own notable scientific achievements. During my visits to China, I also witnessed Prof. Yang at his outpatient uveitis center where he often sees more than 100 patients during a long day. Patients come from all regions of China and even patients from abroad often seek his help. Due to his tremendous strong working attitude, he has now seen thousands of uveitis patients of whom many have been meticulously documented. Thanks to this huge library of the ocular manifestations of the various uveitis entities he has been able to build this phenomenal atlas of uveitis with examples of the many manifestations that may occur. The book is confined to patients seen in China but may be an important teaching tool for many ophthalmologists across the globe and is a must for those willing to specialize in the field of clinical uveitis. Aize Kijlstra University Eye Clinic Maastricht Maastricht University Medical Center Maastricht, The Netherlands

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Foreword by Shigeaki Ohno

Uveitis is described as an inflammation of the uveal tract such as iris, ciliary body, and choroid. However, other structures, including retina and vitreous, are frequently involved. It is well known that uveitis has apparent racial and geographic differences. It is, therefore, important for ophthalmologists to focus on the geographic area of uveitis patients. There have been several famous textbooks on uveitis in the world. However, most of them have been published from the Western countries, and clinical features of uveitis in Caucasian patients have mainly been described. This textbook, Atlas of Uveitis: Diagnosis and Treatment, was written by the world-famous uveitis specialist, Professor Peizeng Yang in China. Professor Yang is an avid uveitis researcher and excellent clinician. He has been engaged in the prevention of blindness resulting from intractable inflammatory eye diseases not only in China but also in various Asian countries. He has collected so many typical figures of Asian-specific uveitis entities such as Vogt–Koyanagi– Harada disease and Behcet’s disease. This is why this uveitis textbook is so unique and valuable, since his collection of clinical pictures on Asian-specific uveitis is excellent and never been found in other textbooks. In addition, Professor Yang is a superb basic immunologist and scientist. He and his team have performed a number of cutting-edge studies in uveitis and profoundly renewed the knowledge about the pathogenesis of uveitis, and they are leading the study on uveitis and intraocular inflammation in the world. They showed that Th17 cells (IL-23/IL-17 pathway) play an important role in the development of uveitis, including Vogt–Koyanagi–Harada disease and Behcet’s disease. They also identified a network of molecules in the modulation of Th17 cell. A number of genetic variances have been identified by them to be associated with Behcet’s disease, Vogt– Koyanagi–Harada disease, acute anterior uveitis with or without ankylosing spondylitis, pediatric uveitis, sympathetic ophthalmia, Fuchs’ syndrome, and presumed virus-associated uveitis. These studies have greatly contributed to our understanding of genetic background of various uveitis entities. Interestingly, the recent study by them revealed that abnormalities in gut microbiota are involved in the development of Behcet’s disease, Vogt–Koyanagi–Harada disease, and acute anterior uveitis. Importantly, they showed, for the first time, that gut microbiota could mediate autoimmunity by antigenic mimicry and adjuvant effects. These studies have opened a new avenue for the studies on prevention and treatment of uveitis using strategy of manipulating gut microbiota. Additionally, Professor Yang’s team have established the largest database including the clinical data of more than 20,000 uveitis patients and sample biobank of uveitis (more than 30,000 samples including blood, aqueous humor, iris, feces, and cerebrospinal fluid collected from patients with various uveitis) in the world. These database and sample biobank provide fundamental support for the future studies on the clinical diagnosis, treatment, as well as the mechanisms underlying the development of uveitis. He has published more than 230 original papers in the world-famous peer-reviewed top journals as first author and/or corresponding author. Fortunately, he also integrates these updated basic research results into this uveitis textbook. His recent works on the molecular immunological therapy in uveitis have greatly changed the visual prognosis of the patients frequently seen in Asian population. Therefore, uveitis may not be an intractable difficult disease any more in the near future and this is in part from great academic contributions of Professor Yang. ix

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This textbook contains most recent information on uveitis, and I sincerely hope that this truly exceptional textbook will be distributed to all over the world. Shigeaki Ohno Medicine and Granduate School of Medicine, Hokkaido University Sapporo, Hokkaido, Japan

Foreword by Manfred Zierhut

Uveitis still remains a mysterious disorder for most ophthalmologists. Why is uveitis still so nebulous? It may be that small textbooks, describing the whole of ophthalmology in just 200– 300 pages, will only have enough space to mention the briefest details about uveitis. Also, it is easier to write about more straightforward conditions, such as cataract and glaucoma. Inflammatory ocular disorders, especially associated with intraocular inflammation, are much more challenging diseases. The reasons for this may be in part due to the variety of disease entities, pattern differences in different cultures, and different clinical findings depending on the age of the patient. All new good textbooks explaining uveitis are large volume books as “Uveitis” is no longer thought of as just one condition. The diagnosis of uveitis requires much more elucidation. The diagnostic pathway starts with taking a clear, directed history, then clinical findings have to be detected that lead to ordering appropriate and targeted investigations. The uveitis expert follows the steps of a detective, like Sherlock Holmes. Small clinical findings may be the key to making the correct diagnosis. Caring for uveitis patients is now an intellectual challenge, with the goal to find the optimal (personalized) treatment. You will not find patients who are more appreciative than long-term suffering uveitis patients when they finally end up with a quiet eye under acceptable treatment. So, it is worthwhile becoming an expert in this field. But how do you become an expert? My suggestion is to learn from experienced people, use the best books, stay critical to your own diagnostic and therapeutic decisions, and show interest in new scientific work in this field. This will lead to success, and it will be enjoyable with great job satisfaction. The field of uveitis has developed tremendously over the last 30 years. One of the major reasons for this is the grade of diversification inside the uveitis family that is growing from day to day. Disorders that for years were lumped, e.g., as “anterior uveitis,” can now be split into various subtypes. Conversely, some previously differentiated forms of uveitis are now recognized as phenotypes associated with, e.g., TB or even syphilis. The development of imaging in this field is also at a giddy height, allowing further differentiation of highly similar uveitis entities. Our knowledge about pathogenesis has also increased, particularly with recent developments in modular imaging. It is with great pleasure that we now have a superb book on uveitis, written by Prof. Peizeng Yang. This book shows that apart from an enormous clinical experience, Prof. Yang has a tremendous scientific background. The unique collection of high-quality photos, allowing to call it an “Atlas,” reflects this. He knows how to explain the pathophysiology of immune-mediated entities very clearly and carefully because often these explanations mirror his own high-quality published work. This Atlas fills a major gap by presenting a large amount of photos from conditions that on first glance appear to look all the same. Yet the quality of the images allows being able to identify and differentiate the important differences, a very educational experience. The book has a clear structure, allowing one to find important details in seconds. Besides general chapters about history-taking, examination, further diagnostics and treatment the most important part is the very detailed description of 38 different uveitis entities. It is enjoyable to xi

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“walk” through the gallery of photos and to discover pathological findings very clearly described that I had never seen before. The spectrum of uveitic signs and entities in this book is remarkable. Often the photos show the evolution of the clinical entity, allowing us to recognize the “typical” features of some of these conditions. This results in an optimal treatment strategy and better prognosis. Looking back at the quality of images from older textbooks, it is easy to see why uveitis achieved “mystical” status. Yet working with this book allows you to learn about uveitis at the highest level. Less “mystic” but more happy, healed patients! Manfred Zierhut University of Tuebingen Tuebingen, Germany

Foreword by Amod Gupta

Professor Peizeng Yang is to be congratulated for bringing out a single author textbook that sums up his three-decade experience of research and clinical practice in uveitis and intraocular inflammations in the Peoples’ Republic of China. I have known Prof. Yang to be an avid researcher, basic scientist of repute, and an astute clinician who has published more than 200 research papers in high impact journals that have been extensively cited in the contemporary literature. His researches have led to a better understanding of several inflammatory eye diseases, especially the Bechet’s disease and the VKH disease. The field of immunology and uveitis is rapidly evolving both in the lab and the clinic. It is extremely challenging for a physician to keep track of new developments in the laboratory sciences and so is true of a basic scientist to track rapid evolution of the documentation of uveitis entities using a variety of imaging technologies. Professor Yang is uniquely placed to bring the two together for an easy understanding by the clinicians and researchers interested in studying and treating patients with ocular inflammations. In recent years, there has also been an increasing realization that there are remarkable racial and geographic differences in the phenotypic expression and spectrum of inflammatory diseases of the eye. In the long run, understanding these regional differences would lead to new insights into the pathogenesis of these poorly understood diseases and prevent needless blindness thereof. The Peoples’ Republic of China is host to nearly one-fifth of the world’s population. Professor Yang presents a unique perspective of uveitis as it is seen in this population. In the past, Prof. Yang has published many textbooks on the subject in Chinese. Presently, he translates his vast experience into an encyclopedic tome on uveitis in English, immensely beneficial to the international community of researchers and clinicians. Profusely illustrated with more than 3000 images of exceptionally high quality, he brings out the nuanced presentations of the inflammatory diseases of the eye in this Atlas of Uveitis: Diagnosis and Treatment. Divided into four distinct sections and 52 chapters the highly organized book comprehensively covers all aspects of uveitis, namely the anatomical and physiological aspects of uveitis, ocular examination techniques, ocular and systemic imaging techniques, and various treatment modalities of uveitis. Each inflammatory entity is described under the definition, epidemiology, etiology, pathogenesis, pathology, systemic and ocular manifestations, diagnosis, differential diagnosis, treatment, and prognosis. I believe Atlas of Uveitis: Diagnosis and Treatment would be an extremely valuable and useful resource for comprehensive ophthalmologists, residents, fellows, and the experts alike. The encyclopedic collection of images presented in this book carefully chosen by Prof. Yang from millions of images in his repertoire would go a long way in training and patient care all over the world. Amod Gupta Post Graduate Institute of Medical Education and Research Chandigarh, India

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Preface

Uveitis is one of the common causes of blindness. More than 100 uveitis entities have been documented. The causes and entities of this disease vary greatly with countries, races, geographical areas, and even economic conditions. Toxoplasmosis is more commonly seen in Europe and America. Behcet’s disease mainly occurs in the countries along the “old silk road.” Vogt–Koyanagi–Harada disease is commonly seen in Chinese, Japanese, and other pigmented races. The manifestations of uveitis may be different in different races. For instance, Fuchs’ syndrome in Caucasian populations typically manifests as heterochromia and mild inflammation in the anterior segment. However, heterochromia is rarely observed in Chinese patients with Fuchs’ syndrome. Misdiagnosis in pigmented patients with Fuchs’ syndrome is, therefore, very common. The treatment of uveitis may also vary with races. An example is that a higher dose of systemic corticosteroids is frequently used for the treatment of uveitis in white people, while a lower dose of this drug is found by us to be sufficient to control the intraocular inflammation in most Chinese uveitis patients. The clinical features, diagnosis, and treatment of uveitis entities have been well described in uveitis books from Western countries. However, no books in English are available to depict the clinical features and treatment of uveitis in Chinese patients, although we have published a series of papers to address these issues in international peer-reviewed journals. It is definitely necessary to publish a uveitis textbook to enrich the understanding and management of uveitis, based on clinical data of Chinese patients which are, by and large, similar to those from Japan and Korea. It is also important to provide a complete spectrum of uveitis for ophthalmologists in the world. The strong sense of mission for providing data based on Chinese uveitis patients for international resource and contributing Chinese wisdom and achievement in the study of uveitis has stimulated me since 1987 when I started to pursue my PhD in the Zhongshan Ophthalmic Center. I and my team have made continuous efforts during the past 30 years. We have now established the biggest database of uveitis medical records (about 30,000 patients) and specimen biobank for patients with various uveitis entities (more than 30,000 samples including blood, aqueous humor, iris, vitreous body, feces, urine, saliva, and cerebrospinal fluid). Both the database and the specimen biobank have greatly facilitated our study and yielded a series of important findings. More than 240 papers have been published in international peer-reviewed journals, including Nature Genetics, JACI, ARD, Prog Retin Eye Res, Ophthalmology, JAMA Ophthalmology, IOVS, and so forth. The clinical features of Behcet’s disease, Vogt–Koyanagi–Harada (VKH) disease, HLAB27+ acute anterior uveitis (AAU) with or without ankylosing spondylitis, relapsing polychondritis, psoriasis-associated uveitis, sympathetic ophthalmia, and scleritis have been well described in Chinese patients. We have developed the phasing criteria and diagnostic criteria for VKH disease according to the data from a large number of Chinese patients. Various therapeutic regimens have been designed and used for different uveitis entities with promising results. In basic research studies, we found that the IL-23/IL-17 pathway plays an important role in the development of Behcet’s disease and VKH disease. A number of molecules have been found to regulate this pathway. Various genetic variants have been identified to be susceptible factors for Behcet’s disease, VKH disease, acute anterior uveitis, pediatric uveitis, and Fuchs’ syndrome. More recently, our study using metagenomic sequencing of fecal samples revealed that abnormal gut microbiota compositions are present in Behcet’s disease and acute anterior uveitis patients. All of xv

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these results have contributed to or renewed our understanding of the pathogenesis and treatment of uveitis and provided new avenues for studies in the future. Taking advantage of the database of uveitis established during the past 30 years, I have written four uveitis books in Chinese, including a 400-page Uveitis, a 790-page Clinical Uveitis, a 1300-page Diagnosis and Treatment, and a 640-page Essentials of the Diagnosis and Treatment of Uveitis. Three years ago, I started to write this book on uveitis in English, Atlas of Uveitis: Diagnosis and Treatment. It is hard for me to spare time for writing due to my busy schedule filled with clinical duties and attending domestic and international academic meetings. What’s more challenging is choosing the best ones from millions of photographs obtained from more than 20,000 uveitis patients. This book is finally completed with the assistance of my students and colleagues. It provides ophthalmologists with a practical guideline through concise and clear descriptions. More than 3000 photos are included to show the typical changes or dynamic changes of the anterior and posterior segment as well as images of auxiliary examinations in various uveitis entities. More importantly, these photographs provide the whole spectrum of the ocular changes not only in severity but also in disease course of various uveitis entities. Therefore, the book depicts the whole picture of various uveitis entities, especially those encountered commonly in Chinese patients, in the context of photographs and images, and assists doctors to make a rapid and correct diagnosis based on clinical examinations as well as patient’s medical history. A chapter named as Ideology, Fundamental Principles, and Strategies in the Management of Uveitis is presented to show the experiences and correct mode of thinking refined by the author in clinical practice during the past 30 years. The book also contains the most up-to-date information and achievements in the diagnosis and treatment of uveitis worldwide. Key references are listed in each chapter for further study. I hope that this book will benefit ophthalmologists at all levels not only in their clinical practice but also in their scientific career. It may also be useful in the clinical practice for internists, rheumatologists, and other doctors in relevant fields. I would like to thank my tutors Prof. Xiaofang Zhang, Prof. Winifred Mao, and Prof. Shaozhen Li for their guidance during my study for a master’s degree and PhD. I would like to extend thanks to my patients coming from all over China as well as from other countries. Their trust and compliance give me tremendous encouragement and make my life valuable although there are hardships in the study of uveitis. I want to extend my sincere thanks to the colleagues working with me without complaining, especially Hongyan Zhou, Chunjiang Zhou, and Yao Wang, for their great assistance. I also want to extend my thanks and acknowledgment to all the ophthalmologists who provide help to me in the study of uveitis or have referred uveitis patients to us for treatment. Special thanks go to Guannan Su, Jia Shu, Xiaojie Feng, Weiting Liao, and Wanyun Zhang for their extraordinarily hard and perfect work in typing and editing the book and photographs. Special thanks are also given to Prof. James T Rosenbaum, Prof. Feng Wen, Prof. Junjie Ye, and Prof. Yuansheng Yuan for kindly offering photographs and auxillary examination results or assistance in editing this book. I am grateful to Prof. Chi-Chao Chan, Prof. Chengren Luo, Prof. Jiaqi Chen, Prof. Jinsong Zhang, Prof. Jingcun Yang, Prof. Shigeaki Ohno, Prof. Manfred Zierhut, Prof. Quan Dong Nguyen, Prof. Amod Gupta , Prof. Rachel Caspi, Prof. Narsing Rao, and Prof. Justine Smith for their assistance, support, and cooperation in our uveitis study. I am immensely grateful to my good friend, Prof. Aize Kijlstra, for his great assistance and help for the last 25 years. I have visited and worked in his lab four times in the past and have collaborated with him since 1994. His kindness, talents, and scientist’s discriminating eye impress me deeply. Finally, a million thanks go to my family for their great support in my life. I would like to dedicate this book to them. This book was supported by Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003), the Natural Science Foundation Project of Chongqing (cstc2017shmsA130073), and Chongqing Outstanding Scientist Project (2019), Chongqing Chief Medical Scientist project. Peizeng Yang The First Affiliated Hospital of Chongqing Medical University Chongqing Key Laboratory of Ophthalmology Chongqing Eye Institute Chongqing, China

Contents

Part I Overview 1 Anatomy and Physiology of Uveitis���������������������������������������������������������������������������   3 1.1 Anatomy of the Eyeball���������������������������������������������������������������������������������������   3 1.2 Eye Content���������������������������������������������������������������������������������������������������������   3 1.3 The Cornea�����������������������������������������������������������������������������������������������������������   3 1.4 The Sclera �����������������������������������������������������������������������������������������������������������   4 1.5 The Uveal Tract���������������������������������������������������������������������������������������������������   4 1.6 The Retina�����������������������������������������������������������������������������������������������������������   4 1.7 The Aqueous Humor �������������������������������������������������������������������������������������������   5 1.8 The Lens���������������������������������������������������������������������������������������������������������������   5 1.9 The Vitreous���������������������������������������������������������������������������������������������������������   5 References���������������������������������������������������������������������������������������������������������������������   5 2 Classification of Uveitis ���������������������������������������������������������������������������������������������   7 2.1 Classification of Uveitis���������������������������������������������������������������������������������������   7 2.2 Anatomic Classification���������������������������������������������������������������������������������������   7 2.3 Classification Based on Course���������������������������������������������������������������������������   8 2.4 Classification Based on Clinical and Pathological Features �������������������������������   8 2.5 Classification Based on Causative Agents�����������������������������������������������������������   8 References���������������������������������������������������������������������������������������������������������������������   9 Part II Diagnosis of Uveitis 3 History-Taking in Uveitis Patients�����������������������������������������������������������������������������  13 3.1 Overview�������������������������������������������������������������������������������������������������������������  13 3.2 Geographical and Racial Distribution of Uveitis�������������������������������������������������  13 3.3 Age at Onset of Uveitis���������������������������������������������������������������������������������������  13 3.4 Sex Distribution in Uveitis�����������������������������������������������������������������������������������  14 3.5 Unilateral or Bilateral Involvement���������������������������������������������������������������������  14 3.6 Family History�����������������������������������������������������������������������������������������������������  14 3.7 Personal History���������������������������������������������������������������������������������������������������  15 3.8 Systemic Manifestations (Systemic Disorders)���������������������������������������������������  15 References���������������������������������������������������������������������������������������������������������������������  16 4 Ocular Examinations �������������������������������������������������������������������������������������������������  19 4.1 The Purposes of Ocular Examinations in Uveitis Patients ���������������������������������  19 4.2 Visual Acuity�������������������������������������������������������������������������������������������������������  19 4.3 Lid Changes May Be Associated with the Following Entities of Uveitis�����������  20 4.4 Conjunctival Changes May Be Seen in the Following Uveitis Entities���������������  21 4.5 Episcleritis�����������������������������������������������������������������������������������������������������������  21 4.6 Scleritis ���������������������������������������������������������������������������������������������������������������  21 4.7 Red Reflex Through the Sclera ���������������������������������������������������������������������������  22 xvii

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4.8 Corneal Changes �������������������������������������������������������������������������������������������������  23 4.9 Ciliary Injection���������������������������������������������������������������������������������������������������  26 4.10 Keratic Precipitates (KPs)�����������������������������������������������������������������������������������  27 4.11 Anterior Chamber Alterations�����������������������������������������������������������������������������  32 4.12 Changes in the Iris and Pupil�������������������������������������������������������������������������������  40 4.13 Changes of the Anterior Chamber Angle�������������������������������������������������������������  52 4.14 Changes of the Lens���������������������������������������������������������������������������������������������  53 4.15 Changes of the Vitreous���������������������������������������������������������������������������������������  55 4.16 The Fundus Changes in Uveitis���������������������������������������������������������������������������  60 References���������������������������������������������������������������������������������������������������������������������  79 5 Auxiliary Ocular Examinations���������������������������������������������������������������������������������  81 5.1 Ultrasound Biomicroscopy (UBM)���������������������������������������������������������������������  81 5.1.1 Overview�������������������������������������������������������������������������������������������������  81 5.1.2 The Changes Disclosed by UBM in Uveitis Patients �����������������������������  81 5.2 Ultrasonography��������������������������������������������������������������������������������������������������� 108 5.2.1 Overview������������������������������������������������������������������������������������������������� 108 5.2.2 The Changes Detected by Ultrasonography in Uveitis Patients ������������� 108 5.3 Fundus Fluorescein Angiography (FFA)������������������������������������������������������������� 114 5.3.1 Overview������������������������������������������������������������������������������������������������� 114 5.3.2 The Changes Detected by FFA in Uveitis Patients ��������������������������������� 114 5.4 Indocyanine Green Angiography (ICGA)����������������������������������������������������������� 127 5.4.1 Overview������������������������������������������������������������������������������������������������� 127 5.4.2 The Changes Detected by ICGA in Uveitis Patients������������������������������� 127 5.5 Optical Coherence Tomography (OCT) Imaging ����������������������������������������������� 132 5.5.1 Overview������������������������������������������������������������������������������������������������� 132 5.5.2 The Changes Disclosed by OCT in Uveitis Patients������������������������������� 132 References��������������������������������������������������������������������������������������������������������������������� 138 6 Systemic Imaging and Laboratory Investigations��������������������������������������������������� 139 6.1 X-ray ������������������������������������������������������������������������������������������������������������������� 139 6.2 Computed Tomography (CT)������������������������������������������������������������������������������� 139 6.3 Magnetic Resonance Imaging (MRI)������������������������������������������������������������������� 139 6.4 Laboratory Investigations������������������������������������������������������������������������������������� 139 References��������������������������������������������������������������������������������������������������������������������� 140 Part III Treatment of Uveitis 7 Ideology, Fundamental Principles, and Strategies in Management of Uveitis����� 145 7.1 Ideology in Uveitis Management������������������������������������������������������������������������� 145 7.2 Fundamental Principles��������������������������������������������������������������������������������������� 147 7.3 Strategies������������������������������������������������������������������������������������������������������������� 147 References��������������������������������������������������������������������������������������������������������������������� 148 8 Corticosteroids ����������������������������������������������������������������������������������������������������������� 149 8.1 Overview������������������������������������������������������������������������������������������������������������� 149 8.2 Topical Corticosteroids ��������������������������������������������������������������������������������������� 149 8.3 Periocular Corticosteroids����������������������������������������������������������������������������������� 149 8.4 Intravitreal Corticosteroids ��������������������������������������������������������������������������������� 150 8.5 Systemic Corticosteroids������������������������������������������������������������������������������������� 150 References��������������������������������������������������������������������������������������������������������������������� 154 9 Steroid-sparing Immunosuppressive Agents ����������������������������������������������������������� 155 9.1 Overview������������������������������������������������������������������������������������������������������������� 155 9.2 Cyclophosphamide����������������������������������������������������������������������������������������������� 155

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9.3 Chlorambucil������������������������������������������������������������������������������������������������������� 156 9.4 Cyclosporine A (CsA)����������������������������������������������������������������������������������������� 156 9.5 FK506 ����������������������������������������������������������������������������������������������������������������� 158 9.6 Methotrexate ������������������������������������������������������������������������������������������������������� 158 9.7 Azathioprine��������������������������������������������������������������������������������������������������������� 159 9.8 Mycophenolate Mofetil��������������������������������������������������������������������������������������� 159 9.9 Biological Agents������������������������������������������������������������������������������������������������� 160 References��������������������������������������������������������������������������������������������������������������������� 160 10 Non-steroidal Anti-inflammatory Drugs������������������������������������������������������������������� 163 10.1 Overview����������������������������������������������������������������������������������������������������������� 163 10.2 Topical NSAIDs������������������������������������������������������������������������������������������������� 163 10.3 Systemic NSAIDs ��������������������������������������������������������������������������������������������� 163 References��������������������������������������������������������������������������������������������������������������������� 164 11 Complications and Their Management��������������������������������������������������������������������� 165 11.1 Overview����������������������������������������������������������������������������������������������������������� 165 11.2 Cataract ������������������������������������������������������������������������������������������������������������� 165 11.3 Ocular Hypertension and Glaucoma����������������������������������������������������������������� 166 11.4 Macular Edema ������������������������������������������������������������������������������������������������� 167 References��������������������������������������������������������������������������������������������������������������������� 168 Part IV Specific Uveitis Entities, Scleritis and Episcleritis 12 Acute Anterior Uveitis ����������������������������������������������������������������������������������������������� 171 12.1 Definition����������������������������������������������������������������������������������������������������������� 171 12.2 Epidemiology����������������������������������������������������������������������������������������������������� 171 12.3 Common Entities����������������������������������������������������������������������������������������������� 171 12.4 Less Common Entities��������������������������������������������������������������������������������������� 172 12.5 Symptoms ��������������������������������������������������������������������������������������������������������� 172 12.6 Signs������������������������������������������������������������������������������������������������������������������� 172 12.7 Complications ��������������������������������������������������������������������������������������������������� 181 12.8 Diagnosis����������������������������������������������������������������������������������������������������������� 182 12.9 Differential Diagnosis ��������������������������������������������������������������������������������������� 182 12.10 Treatment����������������������������������������������������������������������������������������������������������� 184 12.11 Prognosis����������������������������������������������������������������������������������������������������������� 184 References��������������������������������������������������������������������������������������������������������������������� 184 13 Intermediate Uveitis��������������������������������������������������������������������������������������������������� 187 13.1 Definition����������������������������������������������������������������������������������������������������������� 187 13.2 Epidemiology����������������������������������������������������������������������������������������������������� 187 13.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 187 13.4 Clinical Manifestations ������������������������������������������������������������������������������������� 188 13.4.1 Symptoms ��������������������������������������������������������������������������������������������� 188 13.4.2 Signs������������������������������������������������������������������������������������������������������� 188 13.5 Complications ��������������������������������������������������������������������������������������������������� 189 13.6 Diagnosis����������������������������������������������������������������������������������������������������������� 189 13.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 190 13.8 Treatment����������������������������������������������������������������������������������������������������������� 192 13.9 Prognosis����������������������������������������������������������������������������������������������������������� 192 References��������������������������������������������������������������������������������������������������������������������� 193 14 Posterior Uveitis ��������������������������������������������������������������������������������������������������������� 195 14.1 Definition����������������������������������������������������������������������������������������������������������� 195 14.2 Epidemiology����������������������������������������������������������������������������������������������������� 195

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14.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 196 14.4 Entities of Posterior Uveitis������������������������������������������������������������������������������� 196 14.5 Diagnosis and Differential Diagnosis ��������������������������������������������������������������� 197 14.6 Treatment����������������������������������������������������������������������������������������������������������� 200 14.7 Prognosis����������������������������������������������������������������������������������������������������������� 200 References��������������������������������������������������������������������������������������������������������������������� 200 15 Uveitis Associated with Ankylosing Spondylitis������������������������������������������������������� 203 15.1 Definition����������������������������������������������������������������������������������������������������������� 203 15.2 Epidemiology����������������������������������������������������������������������������������������������������� 203 15.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 203 15.4 Systemic Manifestations ����������������������������������������������������������������������������������� 204 15.5 Ocular Manifestations��������������������������������������������������������������������������������������� 205 15.6 Complications ��������������������������������������������������������������������������������������������������� 209 15.7 Diagnosis����������������������������������������������������������������������������������������������������������� 212 15.8 Differential Diagnosis ��������������������������������������������������������������������������������������� 212 15.9 Treatment����������������������������������������������������������������������������������������������������������� 214 15.10 Prognosis����������������������������������������������������������������������������������������������������������� 220 References��������������������������������������������������������������������������������������������������������������������� 220 16 Uveitis Associated with Reactive Arthritis��������������������������������������������������������������� 221 16.1 Definition����������������������������������������������������������������������������������������������������������� 221 16.2 Epidemiology����������������������������������������������������������������������������������������������������� 221 16.3 Systemic Manifestations ����������������������������������������������������������������������������������� 221 16.4 Ocular Manifestations��������������������������������������������������������������������������������������� 222 16.5 Diagnosis����������������������������������������������������������������������������������������������������������� 224 16.6 Differential Diagnosis ��������������������������������������������������������������������������������������� 225 16.7 Treatment����������������������������������������������������������������������������������������������������������� 225 16.8 Prognosis����������������������������������������������������������������������������������������������������������� 226 References��������������������������������������������������������������������������������������������������������������������� 226 17 Uveitis Associated with Psoriasis������������������������������������������������������������������������������� 227 17.1 Definition����������������������������������������������������������������������������������������������������������� 227 17.2 Epidemiology����������������������������������������������������������������������������������������������������� 227 17.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 227 17.4 Systemic Manifestations ����������������������������������������������������������������������������������� 228 17.5 Ocular Manifestations��������������������������������������������������������������������������������������� 231 17.6 Complications ��������������������������������������������������������������������������������������������������� 236 17.7 Diagnosis����������������������������������������������������������������������������������������������������������� 236 17.8 Differential Diagnosis ��������������������������������������������������������������������������������������� 238 17.9 Treatment����������������������������������������������������������������������������������������������������������� 238 17.10 Prognosis����������������������������������������������������������������������������������������������������������� 242 References��������������������������������������������������������������������������������������������������������������������� 242 18 Uveitis Associated with Inflammatory Bowel Diseases������������������������������������������� 243 18.1 Definition����������������������������������������������������������������������������������������������������������� 243 18.2 Epidemiology����������������������������������������������������������������������������������������������������� 243 18.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 243 18.4 Systemic Manifestations ����������������������������������������������������������������������������������� 244 18.5 Ocular Manifestations��������������������������������������������������������������������������������������� 244 18.6 Complications ��������������������������������������������������������������������������������������������������� 245 18.7 Diagnosis����������������������������������������������������������������������������������������������������������� 245 18.8 Differential Diagnosis ��������������������������������������������������������������������������������������� 246 18.9 Treatment����������������������������������������������������������������������������������������������������������� 246 18.10 Prognosis����������������������������������������������������������������������������������������������������������� 247 References��������������������������������������������������������������������������������������������������������������������� 247

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19 Anterior Uveitis Associated with Herpesviruses ����������������������������������������������������� 249 19.1 Definition����������������������������������������������������������������������������������������������������������� 249 19.2 Epidemiology����������������������������������������������������������������������������������������������������� 249 19.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 249 19.4 Clinical Manifestations ������������������������������������������������������������������������������������� 250 19.5 Complications ��������������������������������������������������������������������������������������������������� 261 19.6 Diagnosis����������������������������������������������������������������������������������������������������������� 261 19.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 264 19.8 Treatment����������������������������������������������������������������������������������������������������������� 267 19.9 Prognosis����������������������������������������������������������������������������������������������������������� 267 References��������������������������������������������������������������������������������������������������������������������� 267 20 Fuchs Syndrome��������������������������������������������������������������������������������������������������������� 269 20.1 Definition����������������������������������������������������������������������������������������������������������� 269 20.2 Epidemiology����������������������������������������������������������������������������������������������������� 269 20.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 269 20.4 Clinical Manifestations ������������������������������������������������������������������������������������� 270 20.5 Complications ��������������������������������������������������������������������������������������������������� 284 20.6 Diagnosis����������������������������������������������������������������������������������������������������������� 284 20.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 285 20.8 Treatment����������������������������������������������������������������������������������������������������������� 285 20.9 Prognosis����������������������������������������������������������������������������������������������������������� 287 References��������������������������������������������������������������������������������������������������������������������� 287 21 Posner–Schlossman Syndrome ��������������������������������������������������������������������������������� 289 21.1 Definition����������������������������������������������������������������������������������������������������������� 289 21.2 Epidemiology����������������������������������������������������������������������������������������������������� 289 21.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 289 21.4 Clinical Manifestations ������������������������������������������������������������������������������������� 289 21.5 Complications ��������������������������������������������������������������������������������������������������� 292 21.6 Diagnosis����������������������������������������������������������������������������������������������������������� 292 21.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 292 21.8 Treatment����������������������������������������������������������������������������������������������������������� 294 21.9 Prognosis����������������������������������������������������������������������������������������������������������� 294 References��������������������������������������������������������������������������������������������������������������������� 294 22 Uveitis in Children ����������������������������������������������������������������������������������������������������� 295 22.1 Definition����������������������������������������������������������������������������������������������������������� 295 22.2 Epidemiology����������������������������������������������������������������������������������������������������� 295 22.3 Specific Concerns About Uveitis in Children ��������������������������������������������������� 295 22.4 Complications ��������������������������������������������������������������������������������������������������� 296 22.5 Diagnosis����������������������������������������������������������������������������������������������������������� 296 22.6 Treatment����������������������������������������������������������������������������������������������������������� 297 22.7 Prognosis����������������������������������������������������������������������������������������������������������� 299 References��������������������������������������������������������������������������������������������������������������������� 306 23 Uveitis-associated with Juvenile Idiopathic Arthritis ��������������������������������������������� 307 23.1 Definition����������������������������������������������������������������������������������������������������������� 307 23.2 Epidemiology����������������������������������������������������������������������������������������������������� 307 23.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 308 23.4 Systemic Manifestations ����������������������������������������������������������������������������������� 308 23.5 Ocular Manifestations��������������������������������������������������������������������������������������� 308 23.6 Complications ��������������������������������������������������������������������������������������������������� 311 23.7 Diagnosis����������������������������������������������������������������������������������������������������������� 312 23.8 Differential Diagnosis ��������������������������������������������������������������������������������������� 318

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23.9 Treatment����������������������������������������������������������������������������������������������������������� 318 23.10 Prognosis����������������������������������������������������������������������������������������������������������� 322 References��������������������������������������������������������������������������������������������������������������������� 325 24 Blau Syndrome ����������������������������������������������������������������������������������������������������������� 327 24.1 Definition����������������������������������������������������������������������������������������������������������� 327 24.2 Etiology and Pathogenesis��������������������������������������������������������������������������������� 327 24.3 Systemic Manifestations ����������������������������������������������������������������������������������� 327 24.4 Ocular Manifestations��������������������������������������������������������������������������������������� 327 24.5 Complications ��������������������������������������������������������������������������������������������������� 328 24.6 Diagnosis����������������������������������������������������������������������������������������������������������� 329 24.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 329 24.8 Treatment����������������������������������������������������������������������������������������������������������� 331 24.9 Prognosis����������������������������������������������������������������������������������������������������������� 331 References��������������������������������������������������������������������������������������������������������������������� 331 25 Tubulointerstitial Nephritis and Uveitis Syndrome������������������������������������������������� 333 25.1 Definition����������������������������������������������������������������������������������������������������������� 333 25.2 Epidemiology����������������������������������������������������������������������������������������������������� 333 25.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 333 25.4 Clinical Manifestations ������������������������������������������������������������������������������������� 333 25.5 Diagnosis����������������������������������������������������������������������������������������������������������� 334 25.6 Differential Diagnosis ��������������������������������������������������������������������������������������� 337 25.7 Treatment����������������������������������������������������������������������������������������������������������� 338 25.8 Prognosis����������������������������������������������������������������������������������������������������������� 338 References��������������������������������������������������������������������������������������������������������������������� 338 26 Behcet’s Disease����������������������������������������������������������������������������������������������������������� 339 26.1 Definition����������������������������������������������������������������������������������������������������������� 339 26.2 Epidemiology����������������������������������������������������������������������������������������������������� 339 26.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 340 26.4 Ocular Lesions��������������������������������������������������������������������������������������������������� 340 26.5 Extraocular Manifestations ������������������������������������������������������������������������������� 349 26.6 Ocular Complications ��������������������������������������������������������������������������������������� 368 26.7 Diagnosis����������������������������������������������������������������������������������������������������������� 380 26.8 Diagnostic Criteria��������������������������������������������������������������������������������������������� 404 26.9 Differential Diagnosis ��������������������������������������������������������������������������������������� 404 26.10 Treatment����������������������������������������������������������������������������������������������������������� 404 26.11 Prognosis����������������������������������������������������������������������������������������������������������� 409 References��������������������������������������������������������������������������������������������������������������������� 410 27 Vogt–Koyanagi–Harada Disease������������������������������������������������������������������������������� 411 27.1 Definition����������������������������������������������������������������������������������������������������������� 411 27.2 Epidemiology����������������������������������������������������������������������������������������������������� 411 27.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 411 27.4 Clinical Manifestations ������������������������������������������������������������������������������������� 412 27.4.1 Ocular Manifestations [1, 11] ��������������������������������������������������������������� 412 27.4.2 Extraocular Manifestations [1–4] ��������������������������������������������������������� 412 27.4.3 Manifestations in Different Stages [1, 4, 12]����������������������������������������� 413 27.5 Complications ��������������������������������������������������������������������������������������������������� 473 27.6 Auxiliary Examinations������������������������������������������������������������������������������������� 477 27.7 Diagnosis����������������������������������������������������������������������������������������������������������� 530 27.8 Differential Diagnosis ��������������������������������������������������������������������������������������� 531 27.9 Treatment����������������������������������������������������������������������������������������������������������� 533 27.10 Prognosis����������������������������������������������������������������������������������������������������������� 536 References��������������������������������������������������������������������������������������������������������������������� 537

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28 Sympathetic Ophthalmia������������������������������������������������������������������������������������������� 539 28.1 Definition����������������������������������������������������������������������������������������������������������� 539 28.2 Epidemiology����������������������������������������������������������������������������������������������������� 539 28.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 540 28.4 Ocular Manifestations��������������������������������������������������������������������������������������� 540 28.5 Extraocular Manifestations ������������������������������������������������������������������������������� 547 28.6 Complications ��������������������������������������������������������������������������������������������������� 547 28.7 Diagnosis����������������������������������������������������������������������������������������������������������� 548 28.8 Differential Diagnosis ��������������������������������������������������������������������������������������� 553 28.9 Management������������������������������������������������������������������������������������������������������� 561 28.10 Prognosis����������������������������������������������������������������������������������������������������������� 561 References��������������������������������������������������������������������������������������������������������������������� 561 29 Retinal Vasculitis��������������������������������������������������������������������������������������������������������� 563 29.1 Definition����������������������������������������������������������������������������������������������������������� 563 29.2 Retinal Vasculitis Associated with Systemic Vasculitis������������������������������������� 563 29.3 Retinal Vasculitis Secondary to Infectious Diseases����������������������������������������� 566 29.4 Primary Retinal Vasculitis��������������������������������������������������������������������������������� 567 29.5 Clinical Manifestation��������������������������������������������������������������������������������������� 567 29.5.1 Symptoms ��������������������������������������������������������������������������������������������� 567 29.5.2 Signs������������������������������������������������������������������������������������������������������� 568 29.6 Complications ��������������������������������������������������������������������������������������������������� 571 29.7 Diagnosis����������������������������������������������������������������������������������������������������������� 572 29.8 Differential Diagnosis ��������������������������������������������������������������������������������������� 579 29.9 Management������������������������������������������������������������������������������������������������������� 579 29.10 Prognosis����������������������������������������������������������������������������������������������������������� 584 References��������������������������������������������������������������������������������������������������������������������� 586 30 Eales Disease��������������������������������������������������������������������������������������������������������������� 589 30.1 Definition����������������������������������������������������������������������������������������������������������� 589 30.2 Epidemiology����������������������������������������������������������������������������������������������������� 589 30.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 589 30.4 Clinical Manifestations ������������������������������������������������������������������������������������� 589 30.4.1 Symptoms ��������������������������������������������������������������������������������������������� 589 30.4.2 Signs������������������������������������������������������������������������������������������������������� 590 30.5 Complications ��������������������������������������������������������������������������������������������������� 590 30.6 Diagnosis����������������������������������������������������������������������������������������������������������� 590 30.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 590 30.8 Treatment����������������������������������������������������������������������������������������������������������� 592 30.9 Prognosis����������������������������������������������������������������������������������������������������������� 596 References��������������������������������������������������������������������������������������������������������������������� 596 31 Frosted Branch Angiitis��������������������������������������������������������������������������������������������� 597 31.1 Definition����������������������������������������������������������������������������������������������������������� 597 31.2 Epidemiology����������������������������������������������������������������������������������������������������� 597 31.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 597 31.4 Clinical Manifestations ������������������������������������������������������������������������������������� 598 31.5 Complications ��������������������������������������������������������������������������������������������������� 599 31.6 Diagnosis����������������������������������������������������������������������������������������������������������� 599 31.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 609 31.8 Treatment����������������������������������������������������������������������������������������������������������� 609 31.9 Prognosis����������������������������������������������������������������������������������������������������������� 609 References��������������������������������������������������������������������������������������������������������������������� 609 32 Ocular Sarcoidosis ����������������������������������������������������������������������������������������������������� 611 32.1 Definition����������������������������������������������������������������������������������������������������������� 611 32.2 Epidemiology����������������������������������������������������������������������������������������������������� 611

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32.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 611 32.4 Systemic Manifestations ����������������������������������������������������������������������������������� 612 32.5 Ocular Manifestations��������������������������������������������������������������������������������������� 612 32.6 Diagnosis and Diagnostic Criteria��������������������������������������������������������������������� 613 32.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 620 32.8 Treatment����������������������������������������������������������������������������������������������������������� 624 32.9 Prognosis����������������������������������������������������������������������������������������������������������� 625 References��������������������������������������������������������������������������������������������������������������������� 625 33 Systemic Lupus Erythematosus��������������������������������������������������������������������������������� 627 33.1 Definition����������������������������������������������������������������������������������������������������������� 627 33.2 Epidemiology����������������������������������������������������������������������������������������������������� 627 33.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 627 33.4 Systemic Manifestations ����������������������������������������������������������������������������������� 628 33.5 Ocular Manifestations��������������������������������������������������������������������������������������� 628 33.6 Diagnosis����������������������������������������������������������������������������������������������������������� 630 33.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 631 33.8 Treatment����������������������������������������������������������������������������������������������������������� 633 33.9 Prognosis����������������������������������������������������������������������������������������������������������� 633 References��������������������������������������������������������������������������������������������������������������������� 641 34 Uveitis Associated with Relapsing Polychondritis��������������������������������������������������� 643 34.1 Definition����������������������������������������������������������������������������������������������������������� 643 34.2 Epidemiology����������������������������������������������������������������������������������������������������� 643 34.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 643 34.4 Ocular Manifestations��������������������������������������������������������������������������������������� 643 34.5 Systemic Manifestations ����������������������������������������������������������������������������������� 646 34.6 Diagnosis����������������������������������������������������������������������������������������������������������� 648 34.7 Treatment����������������������������������������������������������������������������������������������������������� 650 34.8 Prognosis����������������������������������������������������������������������������������������������������������� 650 References��������������������������������������������������������������������������������������������������������������������� 650 35 Subretinal Fibrosis and Uveitis Syndrome��������������������������������������������������������������� 651 35.1 Definition����������������������������������������������������������������������������������������������������������� 651 35.2 Epidemiology����������������������������������������������������������������������������������������������������� 651 35.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 651 35.4 Clinical Manifestations ������������������������������������������������������������������������������������� 651 35.5 Diagnosis����������������������������������������������������������������������������������������������������������� 653 35.6 Differential Diagnosis ��������������������������������������������������������������������������������������� 657 35.7 Treatment����������������������������������������������������������������������������������������������������������� 658 35.8 Prognosis����������������������������������������������������������������������������������������������������������� 658 References��������������������������������������������������������������������������������������������������������������������� 658 36 Multifocal Choroiditis and Panuveitis ��������������������������������������������������������������������� 659 36.1 Definition����������������������������������������������������������������������������������������������������������� 659 36.2 Epidemiology����������������������������������������������������������������������������������������������������� 659 36.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 659 36.4 Clinical Manifestations ������������������������������������������������������������������������������������� 659 36.5 Complications ��������������������������������������������������������������������������������������������������� 660 36.6 Diagnosis����������������������������������������������������������������������������������������������������������� 663 36.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 663 36.8 Treatment����������������������������������������������������������������������������������������������������������� 665 36.9 Prognosis����������������������������������������������������������������������������������������������������������� 666 References��������������������������������������������������������������������������������������������������������������������� 671

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37 Serpiginous Choroiditis ��������������������������������������������������������������������������������������������� 673 37.1 Definition����������������������������������������������������������������������������������������������������������� 673 37.2 Epidemiology����������������������������������������������������������������������������������������������������� 673 37.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 673 37.4 Clinical Manifestations ������������������������������������������������������������������������������������� 674 37.5 Complications ��������������������������������������������������������������������������������������������������� 674 37.6 Diagnosis����������������������������������������������������������������������������������������������������������� 674 37.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 676 37.8 Treatment����������������������������������������������������������������������������������������������������������� 676 37.9 Prognosis����������������������������������������������������������������������������������������������������������� 677 References��������������������������������������������������������������������������������������������������������������������� 693 38 Acute Retinal Pigment Epitheliitis ��������������������������������������������������������������������������� 695 38.1 Definition����������������������������������������������������������������������������������������������������������� 695 38.2 Epidemiology����������������������������������������������������������������������������������������������������� 695 38.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 695 38.4 Clinical Manifestations ������������������������������������������������������������������������������������� 695 38.5 Diagnosis����������������������������������������������������������������������������������������������������������� 695 38.6 Differential Diagnosis ��������������������������������������������������������������������������������������� 696 38.7 Treatment����������������������������������������������������������������������������������������������������������� 696 38.8 Prognosis����������������������������������������������������������������������������������������������������������� 696 References��������������������������������������������������������������������������������������������������������������������� 696 39 Punctate Inner Choroidopathy ��������������������������������������������������������������������������������� 697 39.1 Definition����������������������������������������������������������������������������������������������������������� 697 39.2 Epidemiology����������������������������������������������������������������������������������������������������� 697 39.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 697 39.4 Clinical Manifestations ������������������������������������������������������������������������������������� 697 39.5 Diagnosis����������������������������������������������������������������������������������������������������������� 698 39.6 Differential Diagnosis ��������������������������������������������������������������������������������������� 698 39.7 Treatment����������������������������������������������������������������������������������������������������������� 698 39.8 Prognosis����������������������������������������������������������������������������������������������������������� 698 References��������������������������������������������������������������������������������������������������������������������� 698 40 Birdshot Chorioretinopathy��������������������������������������������������������������������������������������� 699 40.1 Definition����������������������������������������������������������������������������������������������������������� 699 40.2 Epidemiology����������������������������������������������������������������������������������������������������� 699 40.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 699 40.4 Clinical Manifestations ������������������������������������������������������������������������������������� 699 40.5 Complications ��������������������������������������������������������������������������������������������������� 701 40.6 Diagnosis����������������������������������������������������������������������������������������������������������� 701 40.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 702 40.8 Treatment����������������������������������������������������������������������������������������������������������� 702 40.9 Prognosis����������������������������������������������������������������������������������������������������������� 702 References��������������������������������������������������������������������������������������������������������������������� 702 41 Acute Posterior Multifocal Placoid Pigment Epitheliopathy ��������������������������������� 703 41.1 Definition����������������������������������������������������������������������������������������������������������� 703 41.2 Epidemiology����������������������������������������������������������������������������������������������������� 703 41.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 703 41.4 Clinical Manifestations ������������������������������������������������������������������������������������� 703 41.5 Diagnosis����������������������������������������������������������������������������������������������������������� 704 41.6 Differential Diagnosis ��������������������������������������������������������������������������������������� 705 41.7 Treatment����������������������������������������������������������������������������������������������������������� 705 41.8 Prognosis����������������������������������������������������������������������������������������������������������� 705 References��������������������������������������������������������������������������������������������������������������������� 705

xxvi

42 Multiple Evanescent White Dot Syndrome��������������������������������������������������������������� 707 42.1 Definition����������������������������������������������������������������������������������������������������������� 707 42.2 Epidemiology����������������������������������������������������������������������������������������������������� 707 42.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 707 42.4 Clinical Manifestations ������������������������������������������������������������������������������������� 707 42.5 Diagnosis����������������������������������������������������������������������������������������������������������� 708 42.6 Differential Diagnosis ��������������������������������������������������������������������������������������� 708 42.7 Treatment and Prognosis����������������������������������������������������������������������������������� 708 References��������������������������������������������������������������������������������������������������������������������� 708 43 Ocular Tuberculosis ��������������������������������������������������������������������������������������������������� 709 43.1 Definition����������������������������������������������������������������������������������������������������������� 709 43.2 Epidemiology����������������������������������������������������������������������������������������������������� 709 43.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 709 43.4 Clinical Manifestations ������������������������������������������������������������������������������������� 710 43.5 Complications ��������������������������������������������������������������������������������������������������� 712 43.6 Diagnosis����������������������������������������������������������������������������������������������������������� 712 43.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 714 43.8 Treatment����������������������������������������������������������������������������������������������������������� 715 43.9 Prognosis����������������������������������������������������������������������������������������������������������� 715 References��������������������������������������������������������������������������������������������������������������������� 718 44 Syphilitic Uveitis��������������������������������������������������������������������������������������������������������� 721 44.1 Definition����������������������������������������������������������������������������������������������������������� 721 44.2 Epidemiology����������������������������������������������������������������������������������������������������� 721 44.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 722 44.4 Phasing of Syphilis ������������������������������������������������������������������������������������������� 722 44.5 Ocular Manifestations��������������������������������������������������������������������������������������� 724 44.6 Complications ��������������������������������������������������������������������������������������������������� 725 44.7 Diagnosis����������������������������������������������������������������������������������������������������������� 727 44.8 Differential Diagnosis ��������������������������������������������������������������������������������������� 728 44.9 Treatment����������������������������������������������������������������������������������������������������������� 728 44.10 Prognosis����������������������������������������������������������������������������������������������������������� 733 References��������������������������������������������������������������������������������������������������������������������� 748 45 Ocular Toxoplasmosis������������������������������������������������������������������������������������������������� 749 45.1 Definition����������������������������������������������������������������������������������������������������������� 749 45.2 Epidemiology����������������������������������������������������������������������������������������������������� 749 45.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 749 45.4 Systemic Manifestations ����������������������������������������������������������������������������������� 750 45.5 Ocular Manifestations��������������������������������������������������������������������������������������� 750 45.6 Manifestations in Immunocompromised Individuals ��������������������������������������� 751 45.7 Complications ��������������������������������������������������������������������������������������������������� 751 45.8 Diagnosis����������������������������������������������������������������������������������������������������������� 751 45.9 Auxiliary Examinations������������������������������������������������������������������������������������� 751 45.10 Differential Diagnosis ��������������������������������������������������������������������������������������� 754 45.11 Treatment����������������������������������������������������������������������������������������������������������� 755 45.12 Prognosis����������������������������������������������������������������������������������������������������������� 756 References��������������������������������������������������������������������������������������������������������������������� 756 46 Ocular Toxocariasis ��������������������������������������������������������������������������������������������������� 757 46.1 Definition����������������������������������������������������������������������������������������������������������� 757 46.2 Epidemiology����������������������������������������������������������������������������������������������������� 757 46.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 757 46.4 Clinical Manifestations ������������������������������������������������������������������������������������� 757

Contents

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46.5 Diagnosis����������������������������������������������������������������������������������������������������������� 759 46.6 Treatment����������������������������������������������������������������������������������������������������������� 759 46.7 Prognosis����������������������������������������������������������������������������������������������������������� 759 References��������������������������������������������������������������������������������������������������������������������� 759 47 Uveitis Associated with Human Immunodeficiency Virus ������������������������������������� 761 47.1 Definition����������������������������������������������������������������������������������������������������������� 761 47.2 Epidemiology����������������������������������������������������������������������������������������������������� 761 47.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 761 47.4 Systemic Manifestations ����������������������������������������������������������������������������������� 762 47.5 Ocular Disease��������������������������������������������������������������������������������������������������� 762 47.6 Diagnosis����������������������������������������������������������������������������������������������������������� 764 47.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 765 47.8 Treatment����������������������������������������������������������������������������������������������������������� 765 References��������������������������������������������������������������������������������������������������������������������� 765 48 Cytomegalovirus Retinitis ����������������������������������������������������������������������������������������� 767 48.1 Definition����������������������������������������������������������������������������������������������������������� 767 48.2 Epidemiology����������������������������������������������������������������������������������������������������� 767 48.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 767 48.4 Systemic Diseases��������������������������������������������������������������������������������������������� 767 48.5 Ocular Manifestations��������������������������������������������������������������������������������������� 768 48.6 Diagnosis����������������������������������������������������������������������������������������������������������� 769 48.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 772 48.8 Treatment����������������������������������������������������������������������������������������������������������� 773 48.9 Prognosis����������������������������������������������������������������������������������������������������������� 777 References��������������������������������������������������������������������������������������������������������������������� 781 49 Acute Retinal Necrosis Syndrome����������������������������������������������������������������������������� 783 49.1 Definition����������������������������������������������������������������������������������������������������������� 783 49.2 Epidemiology����������������������������������������������������������������������������������������������������� 783 49.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 783 49.4 Clinical Manifestation��������������������������������������������������������������������������������������� 784 49.5 Complications ��������������������������������������������������������������������������������������������������� 785 49.6 Diagnosis����������������������������������������������������������������������������������������������������������� 785 49.7 Differential Diagnosis ��������������������������������������������������������������������������������������� 789 49.8 Treatment����������������������������������������������������������������������������������������������������������� 793 49.9 Prognosis����������������������������������������������������������������������������������������������������������� 794 References��������������������������������������������������������������������������������������������������������������������� 797 50 Masquerade Syndrome����������������������������������������������������������������������������������������������� 799 50.1 Overview����������������������������������������������������������������������������������������������������������� 799 50.2 Intraocular Lymphoma��������������������������������������������������������������������������������������� 800 50.2.1 Definition����������������������������������������������������������������������������������������������� 800 50.2.2 Epidemiology����������������������������������������������������������������������������������������� 800 50.2.3 Clinical Manifestations ������������������������������������������������������������������������� 800 50.2.4 Diagnosis����������������������������������������������������������������������������������������������� 800 50.2.5 Differential Diagnosis ��������������������������������������������������������������������������� 803 50.2.6 Treatment����������������������������������������������������������������������������������������������� 803 50.2.7 Prognosis ����������������������������������������������������������������������������������������������� 804 50.3 Retinoblastoma (Rb) ����������������������������������������������������������������������������������������� 804 50.3.1 Definition����������������������������������������������������������������������������������������������� 804 50.3.2 Epidemiology����������������������������������������������������������������������������������������� 805 50.3.3 Clinical Manifestations ������������������������������������������������������������������������� 805 50.3.4 Diagnosis����������������������������������������������������������������������������������������������� 806

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50.3.5 Differential Diagnosis ��������������������������������������������������������������������������� 806 50.3.6 Treatment����������������������������������������������������������������������������������������������� 806 50.3.7 Prognosis ����������������������������������������������������������������������������������������������� 806 50.4 Leukemia����������������������������������������������������������������������������������������������������������� 815 50.4.1 Definition����������������������������������������������������������������������������������������������� 815 50.4.2 Clinical Manifestations ������������������������������������������������������������������������� 815 50.4.3 Diagnosis����������������������������������������������������������������������������������������������� 819 50.4.4 Treatment����������������������������������������������������������������������������������������������� 819 50.5 Uveal Melanoma����������������������������������������������������������������������������������������������� 819 50.6 Metastasis to the Eye����������������������������������������������������������������������������������������� 819 50.6.1 Definition����������������������������������������������������������������������������������������������� 819 50.6.2 Epidemiology����������������������������������������������������������������������������������������� 822 50.6.3 Clinical Manifestations ������������������������������������������������������������������������� 822 50.6.4 Diagnosis and Differential Diagnosis ��������������������������������������������������� 823 50.6.5 Treatment����������������������������������������������������������������������������������������������� 823 References��������������������������������������������������������������������������������������������������������������������� 823 51 Scleritis������������������������������������������������������������������������������������������������������������������������� 825 51.1 Definition����������������������������������������������������������������������������������������������������������� 825 51.2 Epidemiology����������������������������������������������������������������������������������������������������� 825 51.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 825 51.4 Anterior Scleritis����������������������������������������������������������������������������������������������� 826 51.5 Posterior Scleritis����������������������������������������������������������������������������������������������� 835 51.6 Panscleritis��������������������������������������������������������������������������������������������������������� 841 51.7 Complications ��������������������������������������������������������������������������������������������������� 841 51.8 Diagnosis and Differential Diagnosis ��������������������������������������������������������������� 842 51.9 Treatment����������������������������������������������������������������������������������������������������������� 852 51.10 Prognosis����������������������������������������������������������������������������������������������������������� 856 References��������������������������������������������������������������������������������������������������������������������� 857 52 Episcleritis������������������������������������������������������������������������������������������������������������������� 859 52.1 Definition����������������������������������������������������������������������������������������������������������� 859 52.2 Epidemiology����������������������������������������������������������������������������������������������������� 859 52.3 Etiology and Pathogenesis��������������������������������������������������������������������������������� 859 52.4 Clinical Manifestations ������������������������������������������������������������������������������������� 859 52.5 Treatment����������������������������������������������������������������������������������������������������������� 860 52.6 Prognosis����������������������������������������������������������������������������������������������������������� 860 References��������������������������������������������������������������������������������������������������������������������� 860

Part I Overview

1

Anatomy and Physiology of Uveitis

Contents

1.1

1.1  Anatomy of the Eyeball

 3

1.2  Eye Content

 3

1.3  The Cornea

 3

1.4  The Sclera

 4

1.5  The Uveal Tract

 4

1.6  The Retina

 4

1.7  The Aqueous Humor

 5

1.8  The Lens

 5

1.9  The Vitreous

 5

References

 5

Anatomy of the Eyeball

• Out layer: the cornea and sclera. • Middle layer: the uveal tract including the iris, ciliary body, and choroid [1]. • Inner layer: the retina.

1.2

Eye Content

• The aqueous humor • The lens • The vitreous body

1.3

The Cornea

• The cornea is a transparent tissue and composed of five layers: the epithelium, Bowman’s layer, the stroma, Descemet’s membrane, and endothelium. • Cornea involvement could be observed as a composition of uveitis.

–– Corneal epithelial or subepithelial lesion and peripheral corneal ulceration are observed in a number of connective tissue diseases. –– Corneal lesions including infiltrates, ulceration, and neovascularization may be associated with an obvious anterior chamber reaction or anterior uveitis. –– Corneal lesions may be secondary to uveitis. Keratic precipitates (KPs) are the most common signs of anterior uveitis and panuveitis. Descemet folds are observed in patients with severe anterior uveitis. Band keratopathy is a common complication of pediatric chronic uveitis and other chronic anterior uveitis. Corneal decompensation may occur in patients with viral anterior uveitis or those with persistently increased intraocular inflammation. Corneal haze may develop as a result of rapidly increasing intraocular pressure frequently secondary to complete posterior synechiae.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_1

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4

1.4

1  Anatomy and Physiology of Uveitis

The Sclera

• The sclera is composed almost entirely of collagen. It forms a strong outer coating of the eye. • The episclera is a thin layer of fine elastic tissue covering the anterior sclera. It provides nourishment to the sclera. • The inflammation in the sclera may occur alone or as a part of systemic diseases. • Severe scleritis may cause anterior uveitis or posterior uveitis. • Scleritis may be associated with systemic diseases. • Episcleritis is less commonly associated with systemic diseases.

1.5

The Uveal Tract

• The uveal tract is a highly vascular and pigmented tissue [2]. • It consists of the iris, ciliary body, and choroid. • The uveal tract nourishes the out portion of the retina, maintains intraocular pressure, and regulates the temperature within the retina. • The uveal tract contains melanin-associated antigen, which can induce uveitis in some individuals [3]. • The iris is the anterior part of the uveal tract. It is a flat disc with a round aperture inferonasal to its center, the pupil. –– It forms a diaphragm and separates the anterior chamber from the posterior chamber. –– It controls the light entering the eye through regulating the size of the pupil. –– As the iris lies closely to the surface of the lens, posterior synechiae readily occurs as a result of development of fibrous exudates. –– A variety of pupil deformations could be observed as a consequence of posterior synechiae. –– A network of macrophages has been disclosed in the iris and ciliary body of the rat, suggesting a role of these cells in the maintenance of microenvironment within the eye [4, 5]. • The ciliary body is the middle part of the uveal tract. –– It is roughly triangular in cross section. –– The anterior part, one third of ciliary body, is called pars plicata whereas the posterior part, two thirds of this tissue, is called pars plana. –– The inflammation in the pars plicata manifests as cells in the anterior vitreous body and therefore is classified into anterior uveitis. –– The inflammation of the pars plana typically shows vitreous opacity and snowbank lesion, and is classified into intermediate uveitis.

• The choroid is the posterior part of the uveal tract. –– It is a highly vascular tissue with the highest flow rate in relation to tissue mass. –– The choroid is divided into four layers histologically: suprachoroid, stroma, choriocapillaris, and Bruch’s membrane. –– The choriocapillaris is thin-walled and has many fenestrae which allow the entering of relatively large molecules. –– The entering of microorganisms or the deposit of immune complex through the fenestrated choriocapillaris may cause inflammation in this tissue. –– The pigment in this tissue may stimulate immune response and in turn cause uveitis in response to the alterations of intraocular microenvironment. –– The close relationship between the choroid and the retina anatomically and physiologically makes it possible that the inflammation of the choroid readily affects the retina and vice versa. –– There is also a network of macrophages and MHC Class II positive dendritic cells in the choroid of rat. These cells may play a role in the development of uveitis through presentation of antigen to T cells [6].

1.6

The Retina

• The retina is a semitransparent neural tissue, lining the inner aspect of the posterior part of the eye ball. • It is divided into 10 layers, which are as follows from its inner aspect: –– Internal limiting membrane. –– Nerve fiber layer. –– Ganglion cell layer. –– Inner plexiform layer. –– Inner nuclear layer of bipolar, amacrine, and horizontal cell bodies. –– Outer plexiform layer. –– Outer nuclear layer of photoreceptor cell nuclei. –– External limiting membrane. –– Photoreceptor layer of rod and cone inner and outer segment. –– Retinal pigment epithelium. • The retina contains a number of autoantigens including retina S-antigen and interphotoreceptor retinoid-binding protein. These antigens may cause autoimmune reactions and, in turn, uveoretinitis. • There is a network of HLA-DR+ cells and CD68+ macrophages in the retina. These cells may be potentially involved in the local antigen presentation and initiation of the inflammation in this tissue if normal immune microenvironment is disrupted [7, 8].

References

1.7

The Aqueous Humor

• Aqueous humor produced by the ciliary body fills the posterior and anterior chambers of the eye. • The aqueous composition is, by and large, similar to that of plasma. • Increased protein concentration is observed in the individuals with breakdown of the blood-aqueous barrier arising from trauma, elevated intraocular pressure, and anterior segment inflammation. • Aqueous inflammatory cells, aggregations of cells, and fibrous exudates are common signs of anterior uveitis.

1.8

The Lens

• The lens is a biconvex transparent structure, providing about one third of dioptric power for the eye. • Complicated cataract is a common complication of chronic anterior uveitis, intermediate uveitis or panuveitis. • Complicated cataract usually displays subcapsular opacity. • With the development of new surgical modalities, the visual prognosis after cataract surgery is greatly improved in patients with complicated cataract.

1.9

The Vitreous

• The vitreous is an avascular gelatinous body filling the space between the lens and retina. • The vitreous is usually involved in intermediate uveitis, posterior uveitis, and panuveitis.

5

• Vitreous cells and opacification are common manifestations in posterior uveitis, especially retinal vasculitis and retinitis. • Snowballs and aggregations of inflammatory cells are typical findings in intermediate uveitis. • Vitreous hemorrhage and proliferative membrane are also observed in posterior uveitis.

References 1. Rathinam SR, Messaoud R. Anatomic basis of imaging in uveitis. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 3–13. 2. Foster CS, Gion N. The uvea: anatomy, histology and embryology. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2013. p. 5–19. 3. Fierz FC, Meier F, Chaloupka K, et  al. Intraocular inflammation associated with new therapies for cutaneous melanoma—case series and review. Klin Monatsbl Augenheilkd. 2016;233(4):540–4. 4. Chen L, Zwart R, Yang P, et  al. Macrophages and MHC class II positive dendritiform cells in the iris and choroid of the pig. Curr Eye Res. 2003;26(5):291–6. 5. Yang P, de Vos AF, Kijlstra A. Immunohistochemical studies on the endotoxin-induced uveitis. Chin Med J. 1998;111(3):252–6. 6. Yang P, de Vos AF, Kijlstra A.  Macrophages and MHC class II positive cells in the choroid during endotoxin induced uveitis. Br J Ophthalmol. 1997;81(5):396–401. 7. Chen L, Yang P, Kijlstra A. Distribution, markers, and functions of retinal microglia. Ocul Immunol Inflamm. 2002;10(1):27–39. 8. Yang P, Das PK, Kijlstra A.  Localization and characterization of immunocompetent cells in the human retina. Ocul Immunol Inflamm. 2000;8(3):149–57.

2

Classification of Uveitis

Contents

2.1

2.1  Classification of Uveitis

 7

2.2  Anatomic Classification

 7

2.3  Classification Based on Course

 8

2.4  Classification Based on Clinical and Pathological Features

 8

2.5  Classification Based on Causative Agents

 8

References

 9

Classification of Uveitis

Table 2.1  The SUNa Working Group Anatomic Classification of Uveitisb

• Uveitis is a group of inflammatory diseases affecting the uveal tract, retina, and retinal blood vessels. • It can be classified using different approaches, including classifications based on anatomic locations, causes, clinical and pathologic manifestations, and disease courses [1, 2].

Type Anterior uveitis Intermediate uveitis Posterior uveitis

2.2

Panuveitis

Anatomic Classification

• In 1999, International Uveitis Study Group proposed a classification system for uveitis based on anatomic locations of the inflammation, which was published in Am J Ophthalmol in 2001. The Standardization of Uveitis Nomenclature (SUN) Working Group endorsed these criteria in 2004 (Table 2.1) [2]. • According to anatomic position of inflammation, this disease is divided into anterior uveitis, intermediate uveitis, posterior uveitis, and generalized uveitis (panuveitis) [3]. –– Anterior uveitis refers to the primary inflammation of the iris and anterior ciliary body and mainly shows inflammatory cells in the anterior chamber and/or anterior vitreous body. It includes iritis, iridocyclitis, and anterior cyclitis. Iritis refers to the presence of inflammatory cells in the anterior chamber without cells in the anterior vitreous body.

Primary site of inflammation Anterior chamber Vitreous Retina or choroid

Includes Iritis, iridocyclitis, anterior cyclitis Pars planitis, posterior cyclitis, hyalitis Focal, multifocal, or diffuse choroiditis; chorioretinitis, retinochoroiditis, retinitis, neuroretinitis

Anterior chamber, vitreous, and retina or choroid

SUN = Standardization of uveitis nomenclature Reprinted with permission from Jabs DA, Nussenblatt RB, Rosenbaum JT.  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 a

b

Iridocyclitis refers to the presence of inflammatory cells in both anterior chamber and anterior vitreous body. Cyclitis refers to the primary inflammation in the anterior ciliary body, mainly showing inflammatory cells in the anterior vitreous body. Intensive anterior uveitis may cause cystoid macular edema, optic disc swelling and subclinical retinal vasculitis as identified by fundus

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_2

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2  Classification of Uveitis

fluorescence angiography. Therefore, obvious anterior chamber inflammation accompanying these fundus alterations should be classified into anterior uveitis rather than generalized uveitis or posterior uveitis. Intensive inflammation of the cornea and the anterior sclera or certain inflammatory corneal diseases such as disciform keratitis caused by herpes simplex virus or varicella zoster virus may be associated with anterior uveitis. Anterior uveitis secondary to keratitis is named as keratoiritis or keratoiridocyclitis. Whereas anterior uveitis secondary to anterior scleritis is named as scleroiritis or scleroiridocyclitis. –– Intermediate uveitis Intermediate uveitis refers to the primary inflammation in pars plana of the ciliary body and the base of the vitreous body. It is characterized by snowbank formation in the pars plana and peripheral retina (pars planitis) or by snowballs in the vitreous body (hyalitis). Intermediate uveitis frequently causes anterior chamber reaction including keratic precipitates, aqueous flare and cells, posterior synechiae, peripheral anterior synechiae, or goniosynechiae. It is also associated with cystoid macular edema and retinal vasculitis identified by fundus fluorescein angiography (FFA). Therefore, the accompanying signs should not be misdiagnosed as posterior uveitis or panuveitis. –– Posterior uveitis Posterior uveitis refers to the primary inflammation in the choroid, retina, and retinal vasculature. As a close relationship between the retina and the choroid, the primary inflammation in the choroid may involve the retina and vice versa. Therefore, there are a number of subtypes of posterior uveitis including retinitis, retinochoroiditis, choroiditis, chorioretinitis, retinal pigment epitheliitis, and retinal vasculitis. Posterior uveitis, especially retinitis or retinal vasculitis, is usually associated with vitreous opacity and cells, proliferative alterations and, sometimes, hemorrhage. It may also be accompanied by anterior chamber reaction, such as aqueous cells and flare. The vitreous changes or the anterior chamber reaction observed in posterior uveitis should be considered as accompanying signs rather than those seen in panuveitis or intermediate uveitis.

–– Panuveitis (Generalized uveitis) Panuveitis refers to the inflammation involving both anterior and posterior segment simultaneously or one after the other. Panuveitis may manifest as anterior uveitis, retinitis, or retinal vasculitis frequently in association with vitreous opacity and cells. This type of inflammation is frequently seen in Behcet’s disease (BD), ocular sarcoidosis, ocular tuberculosis, and syphilitic uveitis. Panuveitis may also manifest as anterior uveitis plus choroiditis. Sympathetic ophthalmia and Vogt–Koyanagi–Harada disease are two typical disorders of this type of panuveitis.

2.3

Classification Based on Course

• Uveitis is divided into acute and chronic uveitis according to SUN Working Group proposal. • Acute uveitis shows an intraocular inflammation with sudden onset and limited duration (less than 3 months). • Chronic uveitis usually occurs insidiously and lasts for more than 3 months. • Acute or chronic uveitis is categorized depending on the natural duration of inflammation without treatment. Undoubtedly, it is not real case in the natural clinical practice. In fact, the author categorizes it mostly according to its onset, the clinical manifestations, the previous attacks as well as the associated systemic diseases.

2.4

 lassification Based on Clinical C and Pathological Features

• Uveitis has long been divided into granulomatous and nongranulomatous inflammation based on pathologic findings and clinical manifestations (Table 2.2). • Granulomatous uveitis is always diagnosed based on typical clinical manifestations rather than pathological evidence.

2.5

 lassification Based on Causative C Agents

• Uveitis can be caused by infectious agents, immune response or non-infectious diseases (masquerade syndrome). • Differentiation between infectious uveitis or endophthalmitis and non-infectious uveitis entities is very important

References

9

Table 2.2  Differentiation of granulomatous and nongranulomatous uveitis Features Onset Time course Recurrence Ciliary injection Anterior segment

Vitreous opacity Ocular fundus

•

•

•

•

Granulomatous uveitis Mostly insidious Longer than 3 months Common +~++

Nongranulomatous uveitis Mostly acute Shorter than 3 months Relatively common ++~+++ Fine and dusty keratic precipitates Fibrous exudates Hypopyon

Mutton fat keratic precipitates, iris nodules (Busacca nodules, Koeppe nodules) or granulomas, trabecular meshwork nodules Snowballs or string of pearls

Diffuse

Dalen–Fuchs nodules Choroidal granulomas Candle wax drippings around the retinal vasculature

Diffused retinal edema Necrotizing retinitis

because their treatment strategies are completely different. The common infectious factors which are able to cause uveitis or endophthalmitis include tuberculosis, treponema pallidum, various viruses, toxoplasm, toxocara, fungi, and bacteria. Uveitis may be caused by immune response or autoimmune response. Most entities such as Vogt–Koyanagi– Harada (VKH) disease, Behcet’s disease (BD), Fuchs syndrome, and sympathetic ophthalmia belong to this group of uveitis. It may be present alone (Table 2.3) or as one component of systemic diseases (Table 2.4). Idiopathic uveitis refers to the intraocular inflammation in which causative factors or specific entities are not identified. It accounts for about 50% of the total patients with uveitis. Masquerade syndrome is a group of diseases that are not inflammatory disorders in nature but may simulate uveitis clinically. –– The masquerade syndrome includes a number of malignant disorders including intraocular-central nervous system lymphoma, leukemias, malignant melanoma, retinoblastoma, and metastatic diseases. –– Non-malignant disorders such as retained intraocular foreign body, ocular ischemia, retinal detachment, and retinitis pigmentosa may also cause manifestations similar to those seen in uveitis and are therefore named as masquerade syndrome.

Table 2.3  Immune-related uveitis usually without systemic diseases Fuchs syndrome Posner–Schlossman syndrome Lens-induced uveitis Idiopathic anterior uveitis Idiopathic intermediate uveitis Idiopathic retinal vasculitis Idiopathic posterior uveitis Birdshot chorioretinopathy Multifocal choroiditis and panuveitis Multiple evanescent white dot syndrome Acute posterior multifocal placoid pigment epitheliopathy Acute retinal pigment epitheliitis Serpiginous choroiditis Subretinal fibrosis and uveitis syndrome Punctate inner choroid Acute zonal occult outer retinopathy

Table 2.4  Immune-related uveitis associated with systemic diseases or systemic involvement Behcet’s disease (BD) Vogt–Koyanagi–Harada (VKH) disease Sympathetic ophthalmia Uveitis associated with ankylosing spondylitis Uveitis associated with reactive arthritis (Reiter’s syndrome) Uveitis associated with psoriasis Ocular sarcoidosis Uveitis associated with inflammatory bowel disease Uveitis associated with juvenile idiopathic arthritis Polyarteritis nodosa Giant cell arteritis Scleroderma Granulomatosis with polyangiitis (Wegener’s granulomatosis) Uveitis associated with Kawasaki disease Uveitis associated with relapsing polychondritis Tubulointerstitial nephritis and uveitis syndrome Multiple sclerosis Systemic lupus erythematosus

References 1. Davis JL, Zierhut M. Classification and terminology. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 31–8. 2. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop. Am J Ophthalmol. 2005;140(3):509–16. 3. Michel SS, Foster CS. Definition, classification, etiology and epidemiology. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 20–32.

Part II Diagnosis of Uveitis

3

History-Taking in Uveitis Patients

Contents

3.1

3.1  Overview

 13

3.2  Geographical and Racial Distribution of Uveitis

 13

3.3  Age at Onset of Uveitis

 13

3.4  Sex Distribution in Uveitis

 14

3.5  Unilateral or Bilateral Involvement

 14

3.6  Family History

 14

3.7  Personal History

 15

3.8  Systemic Manifestations (Systemic Disorders)

 15

References

 16

Overview

• History-taking is very important to the diagnosis of disease, especially for a disease with such numerous causes and entities like uveitis [1]. • History-taking is time-consuming. However, a comprehensive history may allow the ophthalmologists easily to narrow the possibility in searching for the underlying causes or entities of uveitis, and even to make an accurate diagnosis. • More than 90% of the diagnosis can be achieved through medical history and ocular examination [2]. • The details of history include the place where the patients were born and live, family history, ages at disease onset, sex, nationality, personal history, and systemic diseases [2–4].

• Vogt–Koyanagi–Harada (VKH) disease frequently occurs in certain pigmented races such as Chinese, Japanese, and Native Americans [6]. • Ocular toxoplasmosis mainly occurs in South America, North America, and Europe [7]. However, it is uncommon in China. • Birdshot chorioretinopathy predominantly affects Caucasian [8]. No patient with birdshot chorioretinopathy is seen in more than 15,000 Chinese uveitis patients referred to our uveitis center during past 10 years. • Tuberculosis is endemic in India [9]. • Presumed ocular histoplasmosis syndrome is mostly observed in Mississippi and Ohio river valleys and parts of Maryland. • Lyme disease mainly occurs in forest district. • Leprosy is commonly seen in the tropical zone.

3.2

3.3

 eographical and Racial Distribution G of Uveitis

• Behcet’s disease (BD) is frequently observed in people living in the countries along the old silk route such as China, Japan, Korea, Turkey, Iran, and Iraq [5].

Age at Onset of Uveitis

• Infants and children tend to develop the following uveitis: –– Congenital toxoplasmosis –– Congenital syphilitic uveitis

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_3

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–– Congenital viral retinitis –– Masquerade syndrome arising from retinoblastoma –– Masquerade syndrome arising from leukemia –– Ocular toxocariasis –– Frosted branch angiitis –– Tubulointerstitial nephritis and uveitis syndrome –– Idiopathic chronic anterior uveitis –– Juvenile idiopathic retinal vasculitis –– Uveitis associated with juvenile idiopathic arthritis –– Blau syndrome –– Uveitis associated with Kawasaki disease • Young and middle-aged adults tend to develop the following diseases: –– Uveitis associated with ankylosing spondylitis –– Idiopathic acute anterior uveitis –– HLA-B27+ acute anterior uveitis –– Vogt–Koyanagi–Harada disease –– Behcet’s disease –– Eales disease –– Fuchs syndrome –– Sympathetic ophthalmia –– Intermediate uveitis –– Uveitis associated with reactive arthritis (Reiter’s syndrome) –– Uveitis associated with psoriasis –– Multiple sclerosis –– Multifocal evanescent white dot syndrome –– Posner–Schlossman syndrome –– Ocular toxoplasmosis –– Idiopathic retinal vasculitis –– Birdshot chorioretinopathy –– Serpiginous choroiditis –– Uveitis associated with psoriasis –– Uveitis associated with inflammatory bowel disease • The elderly tend to develop uveitis entities as listed below: –– Idiopathic vitritis –– Idiopathic anterior uveitis –– Primary central nerve system lymphoma/primary intraocular lymphoma –– Malignant carcinoma metastatic to the eye

3.4

Sex Distribution in Uveitis

• The following uveitis entities are more likely to affect the males: –– Sympathetic ophthalmia [10] –– Behcet’s disease –– Uveitis associated with ankylosing spondylitis –– Uveitis associated with Lyme disease –– Uveitis associated with reactive arthritis (Reiter’s syndrome) –– Uveitis associated with Whipple’s disease

–– Eales disease –– Leprosy –– Nodular arteritis –– Acute retinal pigment epitheliitis • The following uveitis entities are more likely to affect the females: –– Uveitis associated with juvenile idiopathic arthritis –– Idiopathic chronic uveitis in children –– Juvenile idiopathic retinal vasculitis –– Subretinal fibrosis and uveitis syndrome –– Tubulointerstitial nephritis and uveitis syndrome –– Systemic lupus erythematosus –– Multiple evanescent white dot syndrome –– Inner punctate choroidopathy –– Multifocal choroiditis and panuveitis

3.5

Unilateral or Bilateral Involvement

• Unilateral involvement is mainly observed in the inflammatory conditions as listed below: –– Fuchs syndrome [11] –– Posner–Schlossman syndrome –– Herpesvirus-associated anterior uveitis –– Multiple evanescent white dot syndrome –– Acute retinal pigment epitheliitis –– Diffuse unilateral subacute neuroretinitis –– Acute anterior uveitis (Attack is often unilateral although bilateral involvement is common) –– Endogenous ophthalmitis –– Lens-associated uveitis • Bilateral involvement is frequently observed in uveitis entities as listed below: –– Sympathetic ophthalmia –– Vogt–Koyanagi–Harada disease [6, 12] –– Behcet’s disease –– Acute posterior multifocal placoid pigment epitheliopathy –– Multifocal choroiditis and panuveitis –– Punctate inner choroiditis –– Birdshot chorioretinopathy –– Serpiginous choroidopathy –– Uveitis associated with ankylosing spondylitis

3.6 • • • • • •

Family History

Uveitis associated with ankylosing spondylitis Behcet’s disease Vogt–Koyanagi–Harada disease Masquerade syndrome arising from retinoblastoma Ocular tuberculosis (history of family contact) Blau syndrome

3.8  Systemic Manifestations (Systemic Disorders)

3.7

Personal History

• Individuals living with dog or cat are prone to developing ocular toxoplasmosis and ocular toxocariasis. • Individuals eating the undercooked meat or unwashed vegetables or drinking contaminated water tend to develop ocular toxoplasmosis and ocular toxocariasis. • Homosexual and heterosexual contact may predispose the individuals to developing syphilis, acquired immunodeficiency syndrome, herpetic uveitis, and reactive arthritis. • Drug abuse may predispose the individuals to developing endogenous fungal endophthalmitis, acquired immunodeficiency syndrome, and cytomegalovirus retinitis. Persons closely exposed to the patients with active tuberculosis are at high risk to development of tuberculosis. • Sudden onset is noted in the following uveitis entities: –– Acute anterior uveitis with or without ankylosing spondylitis –– Bacterial endophthalmitis –– Behcet’s disease –– Vogt–Koyanagi–Harada disease –– Posner–Schlossman syndrome –– Acute retinal necrosis syndrome • Insidious onset is noted in the following uveitis entities: –– Idiopathic uveitis in childhood, especially in girls –– Uveitis associated with juvenile idiopathic arthritis –– Idiopathic chronic anterior uveitis –– Juvenile idiopathic retinal vasculitis –– Intermediate uveitis –– Fuchs syndrome –– Syphilitic uveitis –– Ocular sarcoidosis –– Masquerade syndrome

3.8

15

 ystemic Manifestations (Systemic S Disorders)

• Systemic manifestations are very important clues to the identification of entities or causes of uveitis. • Oral ulcerations may be seen in the following diseases [5, 13]: –– Behcet’s disease –– Uveitis associated with reactive arthritis (Reiter’s syndrome) –– Uveitis associated with inflammatory bowel disease –– Herpetic uveitis –– Syphilitic uveitis • Skin lesions may be seen in the following diseases: –– Behcet’s disease

•

•

•

•

•

•

–– Uveitis associated with Lyme disease –– Syphilitic uveitis –– Systemic lupus erythematosus –– Uveitis associated with psoriasis –– Uveitis associated with inflammatory bowel disease –– Ocular sarcoidosis –– Leprosy –– Ocular tuberculosis –– Granulomatosis with polyangiitis –– Blau syndrome –– Uveitis associated with Kawasaki disease Vitiligo may be seen in the following diseases: –– Vogt–Koyanagi–Harada disease –– Sympathetic ophthalmia –– Acute posterior multifocal placoid pigment epitheliopathy Alopecia may be seen in the following diseases: –– Vogt–Koyanagi–Harada disease –– Sympathetic ophthalmia –– Syphilitic uveitis –– Systemic lupus erythematosus –– Application of chlorambucil, cyclophosphamide and, occasionally, azathioprine and methotrexate. Neil changes may be seen in the following diseases: –– Uveitis associated with psoriasis –– Behcet’s disease –– Uveitis associated with reactive arthritis (Reiter’s syndrome) Poliosis is mainly seen in the following diseases: –– Vogt–Koyanagi–Harada disease –– Sympathetic ophthalmia Axial arthritis may be seen in the following diseases: –– Uveitis associated with ankylosing spondylitis –– Uveitis associated with reactive arthritis (Reiter’s syndrome) –– Uveitis associated with psoriasis –– Uveitis associated with inflammatory bowel disease –– Behcet’s disease Peripheral arthritis may be seen in the following diseases: –– Uveitis associated with ankylosing spondylitis –– Behcet’s disease –– Uveitis associated with reactive arthritis (Reiter’s syndrome) –– Uveitis associated with psoriasis –– Uveitis associated with juvenile idiopathic arthritis –– Uveitis associated with inflammatory bowel disease –– Uveitis associated with Lyme disease –– Syphilitic uveitis –– Uveitis associated with relapsing polychondritis –– Uveitis associated with Cogan syndrome –– Blau syndrome

16

• Gastrointestinal disorder may be seen in the following diseases: –– Uveitis associated with inflammatory bowel disease –– Behcet’s disease –– Ocular tuberculosis –– Whipple’s disease –– Uveitis associated with Cogan syndrome –– Uveitis associated with reactive arthritis (Reiter’s syndrome) • Auditory impairment may be seen in the following diseases: –– Vogt–Koyanagi–Harada disease –– Sympathetic ophthalmia –– Uveitis associated with Cogan syndrome –– Behcet’s disease • Cardiovascular disorder may be seen in the following diseases: –– Behcet’s disease –– Uveitis associated with Cogan syndrome –– Ocular sarcoidosis –– Whipple’s disease • Lung lesions may be seen in the following diseases: –– Granulomatosis with polyangiitis –– Ocular tuberculosis –– Ocular sarcoidosis –– Behcet’s disease –– Acquired immunodeficiency syndrome –– Whipple’s disease –– Systemic lupus erythematosus –– Giant cell arteritis • Genitourinary changes may be seen in the following diseases: –– Syphilitic uveitis –– Uveitis associated with reactive arthritis (Reiter’s syndrome) –– Behcet’s disease –– Herpetic uveitis • Genital ulcers may be seen in the following diseases: –– Behcet’s disease –– Crohn’s disease –– Syphilitic uveitis • Epididymitis may be seen in the following diseases: –– Behcet’s disease –– Ocular tuberculosis –– Polyarteritis nodosa • Enlargement of lymph nodes may be seen in the following diseases: –– Behcet’s disease –– Ocular sarcoidosis –– Ocular tuberculosis –– Acquired immunodeficiency syndrome –– Leprosy

3  History-Taking in Uveitis Patients

–– Viral uveitis –– Uveitis associated with Kawasaki disease –– Ocular toxoplasmosis –– Uveitis associated with Lyme disease –– Uveitis associated with juvenile idiopathic arthritis –– Systemic lupus erythematosus –– Syphilitic uveitis –– Masquerade syndrome arising from lymphoma –– Carcinoma metastatic to eye • Neurological involvement may be seen in the following diseases: –– Vogt–Koyanagi–Harada disease –– Behcet’s disease –– Uveitis associated with Lyme disease –– Multiple sclerosis –– Ocular tuberculosis –– Herpetic uveitis –– Masquerade syndrome arising from intraocular or central nervous system lymphoma and leukemia –– Whipple disease –– Cytomegalovirus (CMV) retinitis –– Syphilitic uveitis –– Uveitis associated with Kawasaki disease –– Systemic lupus erythematosus –– Ocular toxoplasmosis –– Uveitis associated with relapsing polychondritis –– Acute posterior multifocal placoid pigment epitheliopathy

References 1. Yang P, Du L, Ye Z. How to deal with uveitis patients? Curr Mol Med. 2017;17(7):468–70. 2. Nussenblatt RB, Whitcup SM, Palestine AG. History taking in the patient with uveitis. In: Uveitis fundamentals and clinical practice. 2nd ed. St. Louis: Mosby-Year Book, Inc.; 1996. p. 51–7. 3. Jones N.  History, examination and ophthalmic imaging. Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 15–54. 4. Chorich LJ III, Klisovic DD, Foster CS. Diagnosis of uveitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2013. p. 101–30. 5. Ohno S, Namba K, Takemoto Y. Behcet’s disease. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 785–95. 6. Du L, Kijlstra A, Yang P.  Vogt-Koyanagi-Harada disease: novel insights into pathophysiology, diagnosis and treatment. Prog Retin Eye Res. 2016;52:84–111. 7. Oréfice F, Vasconcelos-Santos DV, Costa RA, et al. Toxoplasmosis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 1379–412. 8. Pavesio CE, Lehoang P. Birdshot chorioretinopathy. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 929–39.

References 9. Gupta A, Gupta V, Bansal R, et  al. Ocular tuberculosis: A. ocular tuberculosis in endemin areas. In: Gupta A, Gupta V, Herbort CP, et  al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 563–89. 10. Yang P, Liu S, Zhong Z, et  al. Comparison of clinical fea tures and visual outcome between sympathetic ophthalmia and ­Vogt-­Koyanagi-­Harada disease in Chinese patients. Ophthalmology. 2019;126(9):1297–305.

17 11. Yang P, Fang W, Jin H, et al. Clinical features of Chinese patients with Fuchs’ syndrome. Ophthalmology. 2006;113(3):473–80. 12. Yang P, Ren Y, Li B, et  al. Clinical characteristics of Vogt-­ Koyanagi-­Harada syndrome in Chinese patients. Ophthalmology. 2007;114(3):606–14. 13. Yang P, Fang W, Meng Q, et al. Clinical features of chinese patients with Behcet’s disease. Ophthalmology. 2008;115(2):312–8.

4

Ocular Examinations

Contents

4.1

4.1   The Purposes of Ocular Examinations in Uveitis Patients

 19

4.2   Visual Acuity

 19

4.3   Lid Changes May Be Associated with the Following Entities of Uveitis

 20

4.4   Conjunctival Changes May Be Seen in the Following Uveitis Entities

 21

4.5   Episcleritis

 21

4.6   Scleritis

 21

4.7   Red Reflex Through the Sclera

 22

4.8   Corneal Changes

 23

4.9   Ciliary Injection

 26

4.10   Keratic Precipitates (KPs)

 27

4.11   Anterior Chamber Alterations

 32

4.12   Changes in the Iris and Pupil

 40

4.13   Changes of the Anterior Chamber Angle

 52

4.14   Changes of the Lens

 53

4.15   Changes of the Vitreous

 55

4.16   The Fundus Changes in Uveitis

 60

References

 79

 he Purposes of Ocular Examinations T in Uveitis Patients

• To determine whether the disease is inflammatory in nature or other conditions. • To determine whether there is an active inflammation. • To further identify the cause or entity of uveitis if it is inflammatory disease. • To follow the changes of the eye during the course of uveitis and effectiveness of therapy.

4.2

Visual Acuity

• The degree of impaired vision varies greatly with the forms and severity of uveitis. • Blurred vision or slightly decreased vision is frequently observed in acute anterior uveitis, Fuchs syndrome, Posner–Schlossman syndrome, chronic anterior uveitis, intermediate uveitis, and various forms of posterior uveitis without macular or optic nerve involvement. • Markedly decreased vision is frequently seen in Vogt– Koyanagi–Harada (VKH) disease, Behcet’s disease

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_4

19

20

4  Ocular Examinations

(BD), acute anterior uveitis associated with marked aqueous exudations and macular edema, acute retinal necrosis syndrome, bacterial or fungal endophthalmitis, and various forms of posterior uveitis with macular and optic nerve involvement, complicated cataract, persistently increased intraocular pressure, retinal and optic nerve atrophy. • Irreversible visual loss is noted in optic nerve atrophy, extensive retinal atrophy and phthisis bulbi.

4.3

a

 id Changes May Be Associated L with the Following Entities of Uveitis

• Kaposi’s sarcoidoma is seen in acquired immunodeficiency syndrome [1]. • Eyelid swelling and blepharophimosis may be seen in severe scleritis (Fig.  4.1), severe acute anterior uveitis, and endophthalmitis. • Vitiligo and white lashes are observed in VKH disease (Fig. 4.2) and sympathetic ophthalmia [2, 3]. • Ulcerations and palpebral abscess may be seen in ocular tuberculosis. • Herpes zoster ophthalmicus may affect the upper lid (Fig. 4.3). • Chancres may be seen in the eyelid of the patients with syphilis. • Loss of eyelashes and eyebrow, eyelid ectropion, and trichiasis may be seen in leprosy. • Skin ulcerative nodules and chilblain lupus may occur in ocular sarcoidosis. • Silver scale change and skin erythema may occur in psoriasis.

Fig. 4.1  Eyelid swelling observed in a male patient with severe anterior scleritis

b

Fig. 4.2  Poliosis of cilia (a, b) and vitiligo around both eyes (b) observed in patients with VKH disease

Fig. 4.3  Herpes zoster ophthalmicus in a patient with herpes zoster virus infection and iridocyclitis

4.6 Scleritis

4.4

 onjunctival Changes May Be Seen C in the Following Uveitis Entities

21

4.5

Episcleritis

• Episcleritis manifests as congestion of superficial epi• Conjunctival chemosis may be seen in severe sclerouvescleral plexus. itis (Fig.  4.4), endophthalmitis, severe anterior uveitis, • It may occur in BD, ocular sarcoidosis, Lyme disease, lepand very occasionally VKH disease. rosy, Epstein-Barr virus (EBV)-associated uveitis, • Conjunctivitis may be seen in herpesvirus-associated uveherpesvirus-­associated uveitis, ocular tuberculosis, syphiitis, ocular tuberculosis, rubella virus associated uveitis, litic uveitis, acute posterior multifocal placoid pigment acquired immunodeficiency syndrome, cytomegalovirus-­ epitheliopathy, psoriasis, giant cell arteritis, reactive arthriassociated uveitis, psoriasis, ankylosing spondylitis, reactis, systemic lupus erythematosus, polyarteritis nodosa, tive arthritis, granulomatosis with polyangiitis, relapsing granulomatosis with polyangiitis, inflammatory bowel polychondritis, systemic lupus erythematosus, Lyme disdisease, tubulointerstitial nephritis and uveitis syndrome. ease, syphilitic uveitis, and inflammatory bowel disease. • Dry keratoconjunctivitis may be seen in ocular sarcoidosis, polyarteritis nodosa, juvenile idiopathic arthritis, 4.6 Scleritis and relapsing polychondritis. • Scleritis manifests as congestion of the deep vascular plexus (Figs. 4.5 and 4.6) and scleral swelling. • It may occur in BD, ocular sarcoidosis, rheumatoid arthritis, leprosy, herpesvirus-associated uveitis, ocular tuberculosis, syphilitic uveitis, psoriasis, ankylosing spondylitis, giant cell arteritis, reactive arthritis, systemic lupus erythematosus, polyarteritis nodosa, relapsing polychondritis, granulomatosis with polyangiitis, and inflammatory bowel disease [4]. • Necrotizing scleritis may occur in BD, fungal scleritis, leprosy, ocular tuberculosis, psoriasis, relapsing polychondritis, granulomatosis with polyangiitis, and inflammatory bowel disease. Fig. 4.4  Chemosis observed in a patient with severe anterior scleritis

Fig. 4.5  Vascular congestion of deep vascular plexus observed in a patient with diffuse anterior scleritis

22

4  Ocular Examinations

a

b

Fig. 4.6  Vascular congestion in episcleral vessels and deep plexus (a) in a patient with scleritis. Instillation of 10% phenylephrine drops could decongest the episcleral vessels but not the deep plexus (b)

Fig. 4.7  Red reflex via the whole sclera is observed under slit-lamp microscopy in a patient with VKH disease, suggesting severe depigmentation in the choroid and ciliary body

Fig. 4.8  Red reflex through the temporal sclera observed in patients with VKH disease

4.7

Red Reflex Through the Sclera

• Red reflex through the sclera is observed when a slope beam is placed in the pupil of a patient with striking depigmentation of the choroid and retinal pigment epithelium during slit-lamp biomicroscopy (Figs. 4.7 and 4.8).

• Red reflex through the sclera is commonly seen in VKH patients with a long course of intraocular inflammation and significant sunset glow fundus. • It is occasionally observed in patients with sympathetic ophthalmia if intraocular inflammation is recurrent or lasts for a long time.

4.8 Corneal Changes

4.8

Corneal Changes

23

• Band keratopathy (Fig. 4.11) is frequently seen in chronic anterior uveitis in childhood, juvenile idiopathic arthritis• Descemet’s folds (Fig.  4.9) may be observed in severe associated uveitis, VKH disease, and idiopathic chronic acute anterior uveitis, endophthalmitis, recurrence of anterior uveitis. VKH disease, and uveitis in the elderly. • Bullous keratopathy (Fig. 4.12) may occur in herpes zos• Interstitial keratitis may occur in ocular tuberculosis, ter virus-associated uveitis, herpes simplex virus-­ syphilitic uveitis, leprosy, Lyme disease, herpes zoster associated uveitis, chronic anterior uveitis and, virus-associated uveitis, and herpes simplex virus-­ occasionally, Fuchs syndrome with persistently increased associated uveitis. intraocular pressure. • Keratitis and other corneal changes (Fig. 4.10) may occur • Diffuse corneal edema (Fig. 4.13) is seen in the patients in psoriasis, ocular tuberculosis, acquired immunodefiwith phthisis bulbi or severe endophthalmitis. ciency syndrome, giant cell arteritis, reactive arthritis, • Corneal neovascularization (Fig.  4.14) may be noted in juvenile idiopathic arthritis, herpes zoster virus-­associated patients with extensive peripheral anterior synechiae, uveitis, herpes simplex virus-associated uveitis, inflam­keratouveitis, or sclero-keratouveitis. matory bowel disease, granulomatosis with polyangiitis, • Corneal neovascularization associated with corneal relapsing polychondritis, polyarteritis nodosa, Whipple’s edema, disappearance of the anterior chamber, and comdisease, syphilitic uveitis, systemic lupus erythematosus, plicated cataract (Fig.  4.15) are prognosticators of very leprosy, Lyme disease, ocular sarcoidosis, and BD. poor visual outcome in patients with uveitis.

Fig. 4.9  Descemet’s folds observed in patients with severe anterior uveitis

Fig. 4.10  Corneal lesions associated with mutton fat keratic precipitates observed in a patient with keratouveitis

24

Fig. 4.11  Band keratopathy with various appearances observed in patients with chronic anterior uveitis

Fig. 4.12  Bullous keratopathy observed in patients with chronic uveitis

4  Ocular Examinations

4.8 Corneal Changes

Fig. 4.13  Corneal edema and opacities observed in patients with uveitis

Fig. 4.14  Corneal edema, opacity, and neovascularization observed in patients with keratouveitis

25

26

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Fig. 4.15  Corneal neovascularization and edema observed in a patient with chronic anterior uveitis

Fig. 4.17  Localized ciliary congestion observed in a patient with sclerouveitis

Fig. 4.16  Ciliary injection observed in a patient with acute anterior uveitis

4.9

Ciliary Injection

• Ciliary injection refers to circumcorneal hyperemia (Fig. 4.16). • It is a common finding in corneal inflammation and anterior segment inflammation. • Ciliary injection varies greatly in severity or extent and is positively associated with the degree of the inflammation in most patients. • Localized ciliary injection is frequently observed in sclerouveitis (Fig.  4.17), keratouveitis, and herpesvirus-­ associated uveitis. • Ciliary injection is usually observed in the following uve- Fig. 4.18  Ciliary injection accompanied by hyperemia of the fornix conjunctiva observed in patients with severe anterior uveitis itis entities: –– Acute anterior uveitis. –– BD. –– VKH disease. –– Herpesvirus-associated anterior uveitis. –– Various anterior segment inflammations associated • Ciliary injection may be accompanied by hyperemia of with or without systemic diseases. the fornix conjunctiva (Fig.  4.18). It is seen in severe –– Abruptly increased intraocular pressure secondary to acute anterior uveitis, endophthalmitis, severe sclerouvepupil block. itis, and herpesvirus-associated uveitis.

4.10 Keratic Precipitates (KPs)

4.10 Keratic Precipitates (KPs) • KPs refer to the accumulation of inflammatory cells and/ or pigment on the corneal endothelium. • KPs vary considerably with size, shape, color, quantity, and distribution. • Shapes and sizes of KPs. –– Fine and dust-like KPs (Fig. 4.19) are observed in nongranulomatous anterior uveitis [5, 6].

27

–– Mutton fat KPs are usually round but may be irregular in appearance (Fig. 4.20) [3]. –– Confluence of these fresh mutton fat KPs is occasionally observed in some patients (Fig. 4.21). –– Mutton fat KPs are always suggestive of granulomatous inflammation and often seen in Vogt–Koyanagi–Harada disease, sympathetic ophthalmia, ocular sarcoidosis, ocular tuberculosis, syphilitic uveitis, herpesvirus-associated uveitis, fungal and bacterial endophthalmitis.

Fig. 4.19  Dust-like KPs observed in patients with nongranulomatous uveitis

Fig. 4.20  Fresh mutton fat KPs observed in patients with granulomatous uveitis

28

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Fig. 4.21  Confluence of mutton KPs in patients with granulomatous anterior uveitis

Fig. 4.22  Medium-sized KPs observed in a patient with Fuchs syndrome

–– Medium-sized KPs (Fig. 4.22) are observed in Fuchs syndrome, Posner–Schlossman syndrome, herpesvirus-­ associated uveitis, granulomatous inflammation in late phase and, occasionally, primary intraocular lymphoma. Stellate medium-sized KPs are frequently observed in Fuchs syndrome (Fig. 4.23) [7]. • Distributions of KPs. –– KPs are mostly distributed inferiorly and in a base-­ down pyramidal manner (Fig. 4.24) which are seen in most uveitis entities. –– KPs may be distributed diffusely on the entire corneal endothelium (Fig.  4.25). This form of distribution is observed in Fuchs syndrome, herpesvirus-associated uveitis, masquerade syndrome, fungal and bacterial Fig. 4.23 Stellate-like KPs observed in a patient with Fuchs endophthalmitis and, occasionally, severe VKH disease. syndrome –– KPs are sometimes observed on the central corneal endothelium (Figs.  4.26 and 4.27). Centrally distrib–– Local distribution of KPs is usually present underneath uted KPs are usually noted in Fuchs syndrome, the affected area of the cornea. Disciform keratitis is Posner–Schlossman syndrome, herpesvirus-associated usually associated with a local distribution of KPs. uveitis and, occasionally, VKH disease (Fig. 4.28) and • Quantity of KPs. pediatric uveitis. –– Myriad KPs are observed in acute anterior uveitis and BD.

4.10 Keratic Precipitates (KPs)

29

Fig. 4.24  Mutton fat KPs distributed in a base-down pyramidal manner observed in patients with granulomatous uveitis

a

b Fig. 4.25  Medium-sized KPs distributed diffusely on the corneal epithelium observed in a patient with Fuchs syndrome

–– Numerous KPs are present in VKH disease, ocular sarcoidosis, sympathetic ophthalmia and, occasionally, Fuchs syndrome. –– A small number of KPs are usually associated with herpesvirus-associated uveitis, Fuchs syndrome, and Posner–Schlossman syndrome. • Color and appearance of KPs. –– Fresh mutton fat KPs display a roundish, creamy appearance (Fig.  4.29) and indicate the presence of active inflammation. –– Fresh mutton fat KPs toned with pigment (Fig. 4.30) are usually observed in herpesvirus-associated uveitis and occasionally in Vogt–Koyanagi–Harada disease, sympathetic ophthalmia, and chronic anterior uveitis in childhood. –– Old mutton fat KPs usually show a shrunken, less translucent appearance, indicating regression of the intraocular inflammation (Fig. 4.31).

Fig. 4.26  A few of KPs distributed at the pupil area observed in a patient with Fuchs syndrome (a) or Posner–Schlossman syndrome (b)

–– Mutton fat KPs usually disappear completely without leaving any alteration. However, they may end by leaving permanent imprints (Fig. 4.32). –– Pigmentary KPs are usually observed in herpesviruses-­ associated uveitis or recurrent, chronic uveitis (Fig. 4.33)

30

4  Ocular Examinations

Fig. 4.27  KPs distributed at the pupil area observed in a patient with keratouveitis

Fig. 4.28  Mutton fat KPs distributed at pupil area observed in a VKH patient

Fig. 4.29  Densely distributed KPs with creamy appearance observed in a patient with granulomatous anterior uveitis

Fig. 4.30  Mutton fat KPs toned with pigment observed in patients with granulomatous anterior uveitis

4.10 Keratic Precipitates (KPs)

31

Fig. 4.31  Old mutton fat KPs observed in patients with less active or inactive anterior uveitis

Fig. 4.32  Permanent imprints left on corneal endothelium observed in patients with granulomatous uveitis after regression of the inflammation

32

4  Ocular Examinations

Fig. 4.33  Pigmentary KPs observed in patients with herpesvirus-associated uveitis

4.11 Anterior Chamber Alterations • Aqueous flare –– Aqueous flare refers to a visible beam of light in the anterior chamber when examined by slit-lamp biomicroscopy (Fig. 4.34). –– Aqueous flare indicates the presence of a high concentration of proteins, suggesting a breakdown of blood– aqueous barrier. –– Aqueous flare is always associated with cells in various inflammatory conditions (Fig.  4.35). However, it may be present alone in the recovery phase of the inflammation. –– Aqueous flare is divided into five grades according to standardization of uveitis nomenclature (Table 4.1) [8]. –– In general, aqueous flare is positively proportional to the quantity of aqueous cells. However, they may disassociate with each other. For instance, patients with BD may have numerous aqueous cells, but minor aqueous flare (Fig.  4.36). Contrary to BD, VKH disease and, sometimes, acute anterior uveitis at certain phase may have significant aqueous flare but with a few aqueous cells (Fig. 4.37). –– Aqueous flare may be present without aqueous cells in uveitis patients because the recovery of the blood– aqueous barrier always lags behind the regression of the intraocular inflammation. –– Aqueous flare can be quantitatively evaluated with laser flare-cell meter. • Anterior chamber cells –– Anterior chamber cells refer to the visible inflammatory cells migrated into the anterior chamber during

Fig. 4.34  Aqueous flare without cells observed in a patient with uveitis at convalescent stage

––

––

–– ––

anterior uveitis, which manifest as uniform dust-like particles (Fig.  4.38) when examined by slit-lamp biomicroscopy. The number of anterior chamber cells is closely associated with the severity of the inflammation (Fig. 4.39) and graded as from 0 to 4+ by standardization of uveitis Nomenclature Working Group (Table 4.2) [8]. The disappearance of aqueous cells implies the resolution of the inflammation and therefore aqueous flare without cells is not an indication of topical corticosteroids. Laser flare-cell meter has been used to quantitatively evaluate the flare and cells in the anterior chamber. Cells, other than inflammatory cells, such as tumor cells, red blood cells (erythrocytes), and pigmentary cells, may also be observed in the anterior chamber of patients with various conditions.

4.11 Anterior Chamber Alterations

33

Fig. 4.35  Aqueous flare is proportionally associated with aqueous cells in uveitis patients Table 4.1  The SUNa Working Group grading scheme for anterior chamber flareb Grade 0 1+ 2+ 3+ 4+

Description None Faint Moderate (iris and lens details clear) Marked (iris and lens details hazy) Intense (fibrin or plastic aqueous)

SUN = Standardization of uveitis nomenclature Reprinted with permission from Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workgroup. Am J Ophthalmol 2005; 140 (3): 509–516 a

b

Fig. 4.36  A large number of aqueous cells associated with relatively minor aqueous flare observed in patients with BD

Fig. 4.37  Significant aqueous flare with very few cells observed in patients with anterior uveitis

34

Fig. 4.38  Inflammatory cells in the anterior chamber manifest as uniform particles under slit-lamp microscopy

Fig. 4.39  Aqueous cells in different number observed in patients with anterior uveitis

4  Ocular Examinations

4.11 Anterior Chamber Alterations

–– Aggregation of cellular debris or proteins forms big particles, which are usually named as aqueous floaters (Fig. 4.40), is also present in anterior uveitis. • Fibrinous exudation –– Fibrous exudation is formed in the anterior chamber as a result of leakage of fibrinogen.

35

–– Fibrinous exudation may take the form of either membrane or web-like strands (Fig.  4.41) and is usually observed in severe acute anterior uveitis and, rarely, in BD and VKH disease [3, 5, 9].

Table 4.2  The SUNa Working Group grading scheme for anterior chamber cellsb Grade 0 0.5+ 1+ 2+ 3+ 4+

Cells in fieldc 50

SUN = Standardization of uveitis nomenclature Reprinted with permission from Jabs DA, Nussenblatt RB, Rosenbaum JT.  Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workgroup. Am J Ophthalmol 2005; 140(3): 509–516 c Field size is a 1 mm by 1 mm slit beam a

b

Fig. 4.40  Aggregates of proteins, numerous aqueous cells, and striking flare observed in a patient with acute anterior uveitis

Fig. 4.41  Exudates with different appearances observed in the anterior chamber of patients with active uveitis

36

4  Ocular Examinations

Fig. 4.42  Gel-like exudates observed in a patient with granulomatous uveitis

–– Fibrin formation is usually associated with posterior or anterior synechiae. –– Gel-like exudates are occasionally observed in patients with granulomatous uveitis (Fig. 4.42) • Hypopyon –– Hypopyon refers to the white or creamy-colored pool in the inferior anterior chamber (Fig. 4.43) [5]. –– It is usually suggestive of a severe inflammation. –– It mainly occurs in acute anterior uveitis especially that associated with ankylosing spondylitis, BD, bacterial or fungal endophthalmitis and severe bacterial or fungal corneal ulceration and, occasionally, in juvenile idiopathic arthritis (JIA)-associated uveitis, herpesvirus-­ associated anterior uveitis, ­cytomegalovirus (CMV) uveitis, acute retinal necrosis syndrome, relapsing polychondritis (RP), and VKH disease [5]. –– Hypopyon in acute anterior uveitis (AAU) is relatively fixed and immobile, whereas that in BD readily shifts with gravity as the patient change head position (Fig. 4.44) [9]. –– Hypopyon may be associated with ciliary injection (hot hypopyon) (Fig. 4.45) or without ciliary injection (cold hypopyon) (Fig. 4.46). –– It should be differentiated from pseudohypopyon, which is usually darker or snowflake-like in appearance and contains debris of cells (Fig.  4.47). Pseudohypopyon is mainly observed in masquerade syndrome such as intraocular primary lymphoma, retinoblastoma, leukemia, and lens-associated uveitis.

Fig. 4.43  Hypopyon observed in a patient with acute uveitis

–– Hypopyon mixed with blood is occasionally observed in recurrent anterior uveitis and masquerade syndrome (Fig. 4.48). –– Nasty hypopyon or hypopyon with irregular appearances is usually suggestive of infectious inflammation (Figs. 4.49, 4.50, and 4.51) or masquerade syndrome. • Hyphema –– Hyphema refers to a layer of blood or blood clot in the inferior anterior chamber. –– It is rare in uveitis patients. –– It is occasionally observed in virus-associated anterior uveitis, recurrent or chronic anterior uveitis (Fig. 4.52), and masquerade syndrome (Fig. 4.53).

4.11 Anterior Chamber Alterations

37

a

b

c

d

Fig. 4.44  Hypopyon readily shifts with gravity as the patient changes head position (a–d)

Fig. 4.45  Hypopyon associated with ciliary congestion observed in a patient with BD

38

Fig. 4.46  “Cold” hypopyon (without obvious ciliary congestion) observed in patients with BD

Fig. 4.47  Pseudohypopyon observed in patients with masquerade syndrome arising from retinoblastoma

Fig. 4.48  Hemorrhagic hypopyon observed in patients with masquerade syndrome

4  Ocular Examinations

4.11 Anterior Chamber Alterations

Fig. 4.49  Hypopyon observed in a patient with endogenous fungal endophthalmitis

39

Fig. 4.52 Hyphema observed in a patient with chronic anterior uveitis

Fig. 4.50  Hypopyon secondary to fungal keratoscleritis

Fig. 4.51  Nasty hypopyon observed in a patient with endogenous fungal endophthalmitis

40

4  Ocular Examinations

4.12 Changes in the Iris and Pupil

Fig. 4.53  Hyphema in a patient with intraocular-central nervous system lymphoma

• Swelling of the iris stroma. –– It is not common in acute anterior uveitis. –– It may blunt the fibrillary radial structure. –– It is more commonly observed in a granulomatous inflammation and usually displays swollen or plumpy appearance (Fig. 4.54). –– It is more readily detectable by ultrasound biomicroscopy (UBM). Diffuse or localized swelling is observed in VKH disease, sympathetic ophthalmia, and other forms of granulomatous uveitis. • Iris atrophy and heterochromia. –– Iris atrophy may develop in various anterior uveitis with high frequency of recurrence.

Fig. 4.54  Swelling of the iris observed in patients with granulomatous uveitis

4.12 Changes in the Iris and Pupil

41

Fig. 4.55  Focal depigmentation and atrophy lesions in the iris observed in patients with herpesvirus-associated uveitis

–– Iris atrophy may be localized (patchy) (Fig.  4.55) or generalized (diffuse) (Fig. 4.56). –– Iris atrophy usually occurs in virus-associated anterior uveitis, Fuchs syndrome, and chronic anterior uveitis (Fig. 4.57). –– Diffuse depigmentation and atrophy of anterior border layer as seen in Fuchs syndrome may result in heterochromia (Fig. 4.58) [7, 10]. –– Diffuse depigmentation of the iris stroma is common in Fuchs syndrome (Fig. 4.59). –– Depigmentation of pupillary ruff, and moth eaten-like appearance may also be noted in Fuchs syndrome. –– Transillumination defects due to loss of the posterior pigmented epithelium may also be observed in Fuchs syndrome as well as other chronic anterior uveitis. –– We have classified the depigmentation of the iris into four degrees (Fig. 4.60) [7]. • Red reflex via significantly diffuse depigmentation of the iris is occasionally observed in VKH patients (Fig. 4.61).

• Iris nodules [11] –– There are four types of iris nodules: Koeppe nodules, Busacca nodules, granuloma, and nodules on the surface of the iris. –– Koeppe nodules are located at pupillary border and usually small in size. Fluffy Koeppe nodules (Fig. 4.62) are usually suggestive of nongranulomatous inflammation, frequently observed in Fuchs syndrome and occasionally in other forms of anterior uveitis. Sago-like Koeppe nodules with a semi-­ transparent appearance (Fig. 4.63) are usually indicative of granulomatous inflammation and often observed in VKH disease, sympathetic ophthalmia, ocular sarcoidosis, ocular tuberculosis, and syphilitic uveitis. In a few patients, gel-like Koeppe nodules may be observed (Fig. 4.64). Koeppe nodules are usually located at the areas of posterior synechiae (Fig. 4.65).

42

4  Ocular Examinations

Fig. 4.56  Extensive depigmentation and atrophy of the iris in patients with recurrent herpesvirus-associated uveitis

Fig. 4.57  Iris atrophy and depigmentation observed in a patient with recurrent anterior uveitis

a

b

Fig. 4.58  Diffuse depigmentation and slight heterochromia observed in a patient with Fuchs syndrome (a: affected eye; b: normal eye)

4.12 Changes in the Iris and Pupil

43

a

b

c

d

Fig. 4.59  Uniformly diffuse iris depigmentation is observed in the affected eyes as compared to the normal eyes in patients with Fuchs syndrome (a, c: normal eye; b, d: affected eye)

a

b

c

d

Fig. 4.60  Grading of the iris depigmentation: 0: no iris depigmentation (a); I: slight iris depigmentation (b); II: obvious iris depigmentation (c); III: striking iris depigmentation (d)

44

Fig. 4.61  Red reflex through the depigmented iris observed under slit-lamp microscopy in a VKH patient

Fig. 4.62  Fluffy Koeppe nodules observed in a patient with Fuchs syndrome

Fig. 4.63  Sago-like Koeppe nodules observed in patients with granulomatous uveitis

4  Ocular Examinations

4.12 Changes in the Iris and Pupil

Fig. 4.64  Gel-like Koeppe nodules observed in a patient with granulomatous uveitis

Fig. 4.65  Posterior synechiae occurs at the sites of Koeppe nodules observed in patients with granulomatous uveitis

–– Busacca nodules are located in the iris stroma and vary greatly in number and size (Fig. 4.66) Sago-like Busacca nodules are common and usually seen in granulomatous uveitis including VKH disease,

45

sympathetic ophthalmia, ocular sarcoidosis, ocular tuberculosis, syphilitic uveitis, fungal or bacterial endophthalmitis. Fluffy Busacca nodules are less common and only observed in Fuchs syndrome (Fig. 4.67). Sago-like Busacca nodules may be associated with visible iris blood vessels. These blood vessels usually regress with the disappearance of Busacca nodules. –– Granuloma refers to the large pink nodules in the iris stroma. Granuloma manifests as large and opaque nodule (Fig. 4.68). It may be single or multiple. Granuloma is mainly observed in ocular sarcoidosis, less commonly in syphilitic uveitis, ocular tuberculosis and, occasionally, in idiopathic pediatric uveitis and juvenile idiopathic arthritis-associated uveitis. Granuloma may regress entirely without leaving any trace. –– Nodules on the surface of the iris are a rare sign. It is occasionally observed in masquerade syndrome arising from retinoblastoma (Fig. 4.69). • Iris neovascularization. –– It is uncommon in uveitis. –– It is usually associated with severely increased intraocular pressure secondary to complete pupil block (Fig. 4.70). –– Iris vessels may regress following the normalization of intraocular pressure through iridectomy (Fig. 4.71). • Posterior and anterior synechiae. –– Posterior synechiae refers to the adhesions between the iris and anterior lens capsule, usually occurring at pupil margin. –– Anterior synechiae refers to the adhesions between the iris and corneal endothelium, normally being observed at periphery (Fig. 4.72) although it may also occur in the central cornea (Fig. 4.73). –– Posterior synechiae is much more common than anterior synechiae. –– Anterior uveitis, usually chronic and recurrent, may lead to both posterior and anterior synechiae. –– Complete posterior synechiae (seclusion of the pupil) (Fig.  4.74) may lead to iris bombe and abruptly increased intraocular pressure due to pupil block. –– Permanent fibrous membrane may be seen in the pupil area following the disappearance of active inflammation (Fig. 4.75). • Iris bombe. –– It occurs as a result of complete posterior synechiae.

46

Fig. 4.66  Busacca nodules in different numbers and appearances observed in patients with granulomatous uveitis

4  Ocular Examinations

4.12 Changes in the Iris and Pupil

47

Fig. 4.67  Busacca nodules with a fluffy appearance observed in patients with Fuchs syndrome

a

b

c

d

e

f

Fig. 4.68  Granuloma observed in patients with granulomatous uveitis (a, b, c, e: photographs; d, f: UBM results)

48

Fig. 4.69  Nodules on the surface of the iris revealed by UBM in a patient with masquerade syndrome arising from retinoblastoma

a

4  Ocular Examinations

–– Iris bombe may be generalized or localized (Figs. 4.76 and 4.77). • Unusual exudates on the surface of the iris –– They are rare in uveitis patients. –– They usually develop in the patients with chronic or recurrent anterior uveitis (Fig. 4.78). • Changes of the pupil. –– Acute anterior uveitis is often associated with a small pupil and some degree of posterior synechiae. –– Fresh posterior synechiae may be broken following the use of mydriatic and cycloplegic agents. –– Irregular pupil may be seen in patients with various uveitis entities (Fig. 4.79). –– Sectorial paralysis, usually seen in herpesvirus-­ associated uveitis, is frequently associated with the pupil displacement. –– Red reflex in the pupil area is observed in VKH patients with overt sunset glow fundus. –– Yellow or white reflex in the pupil area is noted in endophthalmitis and masquerade syndrome (Fig. 4.80). b

Fig. 4.70  Iris neovascularization observed in patients with chronic anterior uveitis (a) or BD (b)

a

b

Fig. 4.71  Iris neovascularization (a) subsides following laser iridotomy observed in a uveitis patient with both seclusion of the pupil and elevated intraocular pressure (b)

4.12 Changes in the Iris and Pupil

Fig. 4.72  Anterior synechiae at periphery observed in a patient with anterior uveitis

Fig. 4.73  Anterior synechiae occurred in central cornea observed in a patient with anterior uveitis

Fig. 4.74  Complete posterior synechiae observed in both eyes of a patient with uveitis

49

50

4  Ocular Examinations

Fig. 4.75  Old fibrous membrane left after the regression of uveitis observed in a patient with chronic anterior uveitis

Fig. 4.76  Iris bombe observed in a patient with uveitis

a

b

Fig. 4.77  Localized iris bombe observed in a patient with chronic anterior uveitis (a, b: photographs; c, d: UBM results)

4.12 Changes in the Iris and Pupil

c

Fig. 4.77 (continued)

Fig. 4.78  Unusual exudates observed in patients with chronic uveitis

51

d

52

4  Ocular Examinations

Fig. 4.79  Deformation of the pupil with different appearances observed in patients with uveitis

Fig. 4.80  Yellow-white pupil reflex observed in patients with fungal endophthalmitis

4.13 C  hanges of the Anterior Chamber Angle • Various changes of the chamber angle have been observed in uveitis patients.

• The changes include hypopyon, synechiae (Fig.  4.81), granuloma (Fig.  4.82), and trabecular meshwork nodules. • Trabecular meshwork nodules may be seen in granulomatous uveitis, especially in ocular sarcoidosis.

4.14 Changes of the Lens

53

4.14 Changes of the Lens

Fig. 4.81  Goniosynechiae observed in a patient with uveitis

• Uveitis, especially chronic or recurrent anterior segment inflammation, along with the inadequate long-term use of corticosteroids, frequently leads to complicated cataract. • Complicated cataract usually manifests as subcapsular opacification (Fig. 4.83). • Anterior capsular opacity (Fig. 4.84) and total lens opacity (Fig. 4.85) may also be observed in uveitis patients. • Residual pigmentation or fibrin on the anterior capsule of the lens may follow the breaking of posterior synechiae (Fig. 4.86) • Pigmentation on the anterior surface of the lens may develop in recurrent and chronic anterior uveitis (Fig. 4.87). • Precipitates on posterior capsule similar to keratic precipitates are occasionally observed in patients with uveitis (Fig. 4.88).

a

b

Fig. 4.82  Granuloma located at inferior anterior chamber angle (a) completely regresses following treatment with systemic and topical corticosteroids observed in a patient with granulomatous uveitis (b)

Fig. 4.83  Posterior subcapsular opacity observed in patients with uveitis

54

4  Ocular Examinations

Fig. 4.83 (continued)

Fig. 4.86  Annular pigmentation on the surface of the lens after dissociation of fresh posterior synechiae by cycloplegic/mydriatic agent

Fig. 4.84  Anterior capsular opacity observed in a patient with uveitis

Fig. 4.85  Complicated cataract observed in patients with uveitis

4.15 Changes of the Vitreous

55

Fig. 4.87  Pigmentation associated with posterior synechiae observed in both eyes of a patient with chronic anterior uveitis

Fig. 4.88  Precipitates on the posterior capsule observed in a patient with granulomatous uveitis

4.15 Changes of the Vitreous • Vitreous cells are usually observed in patients with intermediate uveitis, retinitis, and retinal vasculitis. • In general, choroiditis is less commonly associated with vitreous cells. • Fresh cells are usually rounded and plumpy in appearance and distributed diffusely in the vitreous (Fig. 4.89). • Old cells are usually shrinking and unevenly distributed in the vitreous (Fig. 4.90).

• Clumps or aggregation of inflammatory cells are usually seen in the patients with chronic inflammation. • Snowballs, formed by clumps of cells and debris, are a typical sign for intermediate uveitis and ocular sarcoidosis. • Various vitreous opacities may be observed in patients with uveitis (Fig. 4.91). • Strings of pearls as formed by collection of snowballs are seen in ocular sarcoidosis and fungal endophthalmitis. • Pigmented debris or particles are observed in herpesvirus-­ associated uveitis and occasionally in VKH disease and other chronic uveitis (Fig. 4.92). • White or yellow-white clumps are usually observed in infectious endophthalmitis (Fig. 4.93). • Vitreous opacity or haze presenting as the exudates, debris and protein has been graded as 0–4 (Table 4.3) by Nussenlatt RB, et al. [12]. Vitreous opacity with different grades is shown in Fig. 4.94. • Vitreous flare, like aqueous flare, is indicative of a high level of proteins arising from breakdown of blood–retinal barrier. –– Vitreous flare is frequently associated with cells, pigmented particles, or cellular debris. –– Vitreous flare alone does not indicate the presence of active inflammation. • Posterior vitreous detachment is commonly seen in intermediate uveitis and various entities of posterior uveitis.

56

Fig. 4.89  Inflammatory cells in the anterior vitreous observed in patients with active uveitis

Fig. 4.90  Old inflammatory cells observed in the anterior vitreous at convalescent stage in a patient with uveitis

4  Ocular Examinations

4.15 Changes of the Vitreous

Fig. 4.91  Vitreous opacities with various appearances observed in patients with different uveitis entities or endophthalmitis

57

58

Fig. 4.92  Pigment particles observed in the anterior vitreous in a patient with uveitis

4  Ocular Examinations

• Multiple mutton fat-like precipitates on the posterior vitreous membrane have been observed in patients with syphilitic posterior uveitis (Fig. 4.95). • Vitreous hemorrhage. –– It is an uncommon sign in uveitis. –– It mainly occurs in Eales disease, BD, idiopathic retinal vasculitis, and posterior uveitis with proliferative vitreoretinopathy (Fig. 4.96). –– Numerous microparticles in the vitreous body may be observed in the course of dissolving of vitreous hemorrhage (Fig. 4.97). • Vitreous proliferation. –– It is not uncommon in posterior or intermediate uveitis. –– Vitreous proliferation is frequently associated with retinal proliferation (Fig. 4.98). –– It may be seen in BD, Eales disease, and idiopathic retinitis or retinal vasculitis.

Fig. 4.93  Yellow-white vitreous opacities observed in patients with endogenous fungal endophthalmitis

4.15 Changes of the Vitreous

59

Table 4.3  Grading scheme for vitreous hazea Score 0 0.5 1 2 3 4

Description Nil Minimal Mild Moderate Marked Severe

Clinical findings None Posterior pole clearly visible Posterior pole details slightly hazy Posterior pole details very hazy Posterior pole details barely visible Fundal details not visible

Adapted from Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology 1985; 92:467–471

a

a

b

c

d

e

f

Fig. 4.94  Grading of the vitreous opacities: 0 scale (a); 0.5 scale (b); 1 scale (c); 2 scale (d); 3 scale (e); 4 scale (f)

60

Fig. 4.95  Numerous mutton fat-like precipitates on the posterior vitreous membrane observed in a patient with syphilitic posterior uveitis

4  Ocular Examinations

Fig. 4.97  Tremendous microparticles are observed in the vitreous in the course of dissolving of vitreous hemorrhage in a patient with posterior uveitis

Fig. 4.96  Vitreous hemorrhage observed in patients with posterior uveitis

4.16 The Fundus Changes in Uveitis • Focal or multifocal lesions in the retina (Figs.  4.99 and 4.100) or choroid. • Retinal necrosis (Fig.  4.101), cotton-wool spots (Fig. 4.102), and retinal edema (Fig. 4.103) are frequently associated with numerous vitreous cells and, sometimes, with vasculitis and hemorrhage.

• Retinal vasculitis usually presents as sheathing (Fig. 4.104) and occlusion of retinal blood vessels (Fig.  4.105) frequently associated with retinal hemorrhages (Fig. 4.106), edema and vitreous cells [13, 14]. • Diffuse choroiditis (Fig. 4.107) usually occurs in patients with VKH disease in posterior uveitis stage and those with sympathetic ophthalmia [3, 15].

4.16 The Fundus Changes in Uveitis

Fig. 4.98  Proliferative vitreoretinopathy with various appearances observed in patients with posterior uveitis

Fig. 4.99  Macular lesions and multiple white retinal dots at the posterior pole observed in patients with syphilitic uveitis

61

62

Fig. 4.100  Active retinal lesion adjacent to an old scar observed in a patient with ocular toxoplasmosis (Courtesy of professor James T. Rosenbaum)

4  Ocular Examinations

Fig. 4.102  Ill-defined retinal cotton-wool spots observed in a patient with posterior uveitis

Fig. 4.101  Large zone of retinal lesions observed in a patient with cytomegalovirus (CMV) retinitis (courtesy of professor James T. Rosenbaum)

Fig. 4.103  Extensive retinal edema in association with hemorrhages observed in a patient with BD

• Active inflammation involving the retinal pigment epithelium and choroid usually presents as multiple white or creamy-white subretinal lesions with poorly defined margins (Fig. 4.108). • Serous retinal detachment is common in the inflammation involving the retinal pigment epithelium and choroid (Figs. 4.109 and 4.110). These lesions may regress

without leaving scars, or leaving scarring or punch-out changes. • Macular changes [16, 17] –– Cystoid macular edema (CME) is frequently seen in patients with posterior uveitis and intermediate uveitis. Persistent or recurrent inflammation usually leads to CME.

4.16 The Fundus Changes in Uveitis Fig. 4.104 Vascular sheathing observed in patients with retinal vasculitis

Fig. 4.105 Vascular sheathing, attenuation, and partial occlusion of retinal vessels observed in patients with retinal vasculitis

63

64

Fig. 4.106  Retinal hemorrhages observed in patients with retinal vasculitis

Fig. 4.107  Diffuse choroiditis observed in a VKH patient on day 7 after disease onset

4  Ocular Examinations

4.16 The Fundus Changes in Uveitis

65

Fig. 4.110  Bulbous retinal detachment observed in a patient with VKH disease at posterior uveitis stage

Fig. 4.108  Multiple white subretinal lesions observed in a patient with active multiple choroiditis

Fig. 4.109  Exudative retinal detachment observed in patients with VKH disease at posterior uveitis stage

66

4  Ocular Examinations

Fundus fluorescein angiography (FFA) and optical coherence tomography (OCT) imaging are usually used to detect cystoid macular edema and evaluate the effectiveness of treatment on this change. Persistent CME usually leads to a significant visual impairment. –– Macular exudates It may develop in posterior uveitis. Cotton-wool spots are observed in HIV retinopathy and systemic lupus erythematosus. Macular stellate exudates are seen in VKH disease (Fig. 4.111), sympathetic ophthalmia, and cat-scratch disease.

Fig. 4.111  Stellate exudates observed in a patient with VKH disease

Fig. 4.112  Macular hole observed in patients with posterior uveitis

Macular exudates may regress completely without leaving any sign. –– Macular folds It is an uncommon sign of uveitis. It may be seen in VKH disease, sympathetic ophthalmia, and posterior scleritis. It is readily detected using multispectral imaging. –– Macular hole (Fig. 4.112) It is rare in uveitis. It is usually associated with BD, VKH disease, retinal vasculitis, and other forms of chronic or recurrent posterior uveitis. –– Macular scar is usually noted in ocular toxoplasmosis.

4.16 The Fundus Changes in Uveitis

–– Proliferative changes may occur in BD, retinal vasculitis, ocular toxoplasmosis and ocular toxocariasis. • Optic nerve changes –– Neuroretinitis, typically presenting as optic disc swelling, peripapillary edema and macular stellate exudation, is noted in cat-scratch disease and VKH disease. –– Optic disc swelling is seen in posterior uveitis, intermediate uveitis, VKH disease, sympathetic ophthalmia, ocular sarcoidosis, BD, and posterior scleritis (Figs. 4.113, 4.114 and 4.115). –– Infiltration of tumor cells around the optic nerve and in the peripapillary retina may be observed in masquerade syndrome. –– Optic nerve atrophy is a common sequela of BD and persistently increased intraocular pressure secondary to uveitis. However, it may occur in other forms of posterior uveitis and intermediate uveitis.

67

–– Peripapillary chorioretinal atrophy is a typical finding of VKH disease (Fig. 4.116) and sympathetic ophthalmia [3]. –– Optic disc or peridisc neovascularization may occur in intermediate uveitis, BD, retinal vasculitis, and other forms of posterior uveitis (Figs. 4.117 and 4.118). • Epiretinal membrane –– It is a relatively uncommon complication of posterior uveitis (Fig. 4.119). –– It may occur as a result of recurrent retinitis or retinal vasculitis. –– It may cause retinal folds and retinal detachment. –– Epiretinal membrane may also occur on optic disc (Figs. 4.120 and 4.121) • Retinal detachment –– Uveitis may result in serous, rhegmatogenous, and tractional retinal detachment.

Fig. 4.113  Optic disc swelling with various degrees and appearances observed in patients with uveitis

68

Fig. 4.113 (continued)

Fig. 4.114  Optic disc swelling with retinal folds observed in a patient with posterior uveitis

4  Ocular Examinations

4.16 The Fundus Changes in Uveitis

69

a

b

c

d

e

f

Fig. 4.115  Optic disc swelling observed in a patient with VKH disease (a, b) is greatly improved at 2 weeks (c, d) and completely subsides at 12 weeks (e, f) following treatment with immunosuppressive agents

70

4  Ocular Examinations

Fig. 4.116  Chorioretinal atrophy around the optic nerve with different appearances observed in patients with VKH disease

4.16 The Fundus Changes in Uveitis

71

Fig. 4.117  Optic disc neovascularization observed in patients with posterior uveitis

Fig. 4.118  Hemorrhage secondary to optic disc neovascularization observed in a patient with posterior uveitis

–– Serous retinal detachment usually occurs in VKH disease, sympathetic ophthalmitis, masquerade syndrome, posterior scleritis, and the inflammation involving the pigment epithelium and choroid. –– Tractional retinal detachment occurs frequently in uveitis with proliferative vitreoretinopathy, especially in BD, Eales disease, idiopathic retinitis, or retinal vasculitis and intermediate uveitis. –– Rhegmatogenous retinal detachment occurs frequently in acute retinal necrosis syndrome, cytomegalovirus (CMV) retinitis and progressive outer retinal necrosis syndrome. • Retinal neovascularization –– It is usually associated with retinitis and retinal vasculitis. –– It often causes retinal hemorrhages and vitreous hemorrhages.

72

Fig. 4.119  Epiretinal membrane observed in patients with posterior uveitis

4  Ocular Examinations

4.16 The Fundus Changes in Uveitis

Fig. 4.120  Proliferative membrane on or around the optic nerve with different appearances observed in patients with uveitis

73

74

4  Ocular Examinations

a

b

Fig. 4.121  Proliferative membrane on the optic nerve observed in a patient with posterior uveitis (a: fundus photograph; b: B-scan ultrasonography result)

Fig. 4.122  Diffuse retinal atrophy in association with occlusion of the retinal blood vessels observed in patients with BD

4.16 The Fundus Changes in Uveitis

• Diffuse retinal atrophy –– It is usually observed in BD patients (Fig. 4.122) [9]. –– Focal retinal atrophy is seen in cytomegalovirus (CMV) retinitis and acute retinal necrosis syndrome. • Choroidal neovascularization –– It is often associated with the inflammation involving the choroid and retinal pigment epithelium. –– It is occasionally observed in the patients with retinitis or retinal vasculitis. –– It occurs mostly at the macula (Fig.  4.123) although other regions are also involved. • Chorioretinal lesions –– Fresh choroidal lesions usually show cream-colored appearance with ill-defined margin. –– Chorioretinal lesions subside without leaving any changes or leaving scars or chorioretinal atrophy (Fig. 4.124). • Sunset glow fundus –– It develops as a result of depigmentation of the choroid and retinal pigment epithelium. –– The appearance of sunset glow fundus varies greatly with patients from uniformly red appearance (Fig. 4.125) to uneven white areas with visible sclera and large choroidal blood vessels (Fig. 4.126) [2, 3, 15]. –– The fundus with relatively white appearance is caused by severe depigmentation of the choroid and retinal pigment epithelium. This fundus change is commonly noted in VKH or sympathetic ophthalmia patients with a long history of recurrent or chronic intraocular inflammation. –– Hyperpigmentation is observed in certain patients (Fig. 4.127). –– The fundus with relatively white appearance mottled with red areas is similar to sunset glow fundus in the mecha-

75

nism underlying its formation and therefore the former is described by the author as sunset glow fundus in sense. • Dalen–Fuchs nodules –– It is frequently seen in the patients with VKH disease or sympathetic ophthalmia [3]. –– Fresh Dalen–Fuchs nodules display a white or creamy appearance with fluffy border (Fig. 4.128). –– Old Dalen–Fuchs nodules show atrophy lesions or punch-out appearance with pigmentation (Fig. 4.129)

Fig. 4.124  Old chorioretinal lesions observed in a posterior uveitis patient

Fig. 4.123  Choroidal neovascularization observed in a patient with posterior uveitis

76

Fig. 4.125  Sun-set glow fundus observed in patients with VKH disease or sympathetic ophthalmia

4  Ocular Examinations

4.16 The Fundus Changes in Uveitis

77

Fig. 4.126  Sun-set glow fundus with various appearances, multifocal chorioretinal atrophies, and visible choroidal vessels and sclera observed in patients with VKH disease or sympathetic ophthalmia

78

Fig. 4.126 (continued) Fig. 4.127  Hyperpigmentation observed in a VKH patient

Fig. 4.128  Active Dalen–Fuchs nodules observed under three mirrors in a patient with VKH disease

4  Ocular Examinations

References

79

Fig. 4.129  Multifocal chorioretinal atrophies in patients with VKH disease

8. Jabs DA, Nussenblatt RB, Rosenbaum JT, et al. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140(3):509–16. 9. Yang P, Fang W, Meng Q, et al. Clinical features of chinese patients 1. Durrani K, Cochereau I, Hoang-Xuan T. Human immunodeficiency with Behcet’s disease. Ophthalmology. 2008;115(2):312–8. virus-associated uveitis. In: Foster CS, Vitale AT, editors. Diagnosis 10. Becker MD, Jakob E, Mackensen F.  Fuchs uveitis syndrome. In: & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammaPublishers (P) Ltd.; 2013. p. 688–701. tion. Berlin: Springer; 2016. p. 955–65. 2. Yang P, Ren Y, Li B, et  al. Clinicl characteristics of Vogt-­ 11. Jones N.  History, examination and ophthalmic imaging, Uveitis. Koyanagi-­Harada syndrome in Chinese patients. Ophthalmology. 2nd ed. London: JP Medical Ltd.; 2013. p. 15–54. 2007;114(3):606–14. 12. Nussenblatt RB, Palestine AG, Chan CC, et al. Standardization of 3. Yang P, Liu S, Zhong Z, et  al. Comparison of clinical features vitreal inflammatory activity in intermediate and posterior uveitis. and visual outcome between sympathetic ophthalmia and Vogt-­ Ophthalmology. 1985;92(4):467–71. Koyanagi-­ Harada disease in Chinese patients. Ophthalmology. 13. Jones N.  Vasculitis, Uveitis. 2nd ed. London: JP Medical Ltd.; 2019;126(9):1297–305. 2013. p. 293–314. 4. Yang P, Ye Z, Tang J, et  al. Clinical features and complica 14. Nussenblatt RB, Whitcup SM, Palestine AG.  Examination of the tions of scleritis in Chinese patients. Ocul Immunol Inflamm. patient with uveitis. In: Uvetis fundamentals and clinical practice. 2018;26(3):387–96. St. Louis: Mosby-Year Book, Inc.; 1996. p. 58–68. 5. Yang P, Wan W, Du L, et al. Clinical features of HLA-B27-positive 15. Du L, Kijlstra A, Yang P.  Vogt-Koyanagi-Harada disease: novel acute anterior uveitis with or without ankylosing spondylitis in a insights into pathophysiology, diagnosis and treatment. Prog Retin Chinese cohort. Br J Ophthalmol. 2018;102(2):215–9. Eye Res. 2016;52:84–111. 6. La Maza MSD.  Seronegative spondyloarthropathies. In: Foster 16. Yang P, Ye Z, Xu J, et al. Macular abnormalities in Vogt-Koyanagi-­ CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. Harada disease. Ocul Immunol Inflamm. 2019;27(8):1195–202. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. 17. Deuter C.  Macular edema. In: Zierhut M, Pavesio C, Ohno S, p. 793–813. et  al., editors. Intraocular inflammation. Berlin: Springer; 2016. 7. Yang P, Fang W, Jin H, et al. Clinical features of Chinese patients p. 443–54. with Fuchs’ syndrome. Ophthalmology. 2006;113(3):473–80.

References

5

Auxiliary Ocular Examinations

Contents 5.1  Ultrasound Biomicroscopy (UBM) 5.1.1  Overview 5.1.2  The Changes Disclosed by UBM in Uveitis Patients

5.1

 81  81  81

5.2  Ultrasonography 5.2.1  Overview 5.2.2  The Changes Detected by Ultrasonography in Uveitis Patients

 108  108  108

5.3  Fundus Fluorescein Angiography (FFA) 5.3.1  Overview 5.3.2  The Changes Detected by FFA in Uveitis Patients

 114  114  114

5.4  Indocyanine Green Angiography (ICGA) 5.4.1  Overview 5.4.2  The Changes Detected by ICGA in Uveitis Patients

 127  127  127

5.5  Optical Coherence Tomography (OCT) Imaging 5.5.1  Overview 5.5.2  The Changes Disclosed by OCT in Uveitis Patients

 132  132  132

References

 138

Ultrasound Biomicroscopy (UBM)

5.1.1 Overview • UBM uses high frequency in the range of 40–60 MHz to view real-time high-resolution images of the anterior segment under magnification in vivo [1]. • UBM has been used to evaluate the changes in vivo in the cornea, anterior chamber, posterior chamber, iris, ciliary body, pars plana, peripheral retina, and the anterior vitreous [1, 2].

5.1.2 T  he Changes Disclosed by UBM in Uveitis Patients • Cornea edema is usually detected in uveitis patients with phthisis bulbi (Fig. 5.1) and those with interstitial keratitis (Fig. 5.2).

• Highly reflective superior layer of the cornea is seen in patients with band-shaped keratopathy secondary to chronic anterior uveitis. • Mutton fat keratic precipitates could be detected by UBM in patients with granulomatous uveitis (Fig. 5.3). • Shallow, irregular, or disappeared anterior chamber (Figs. 5.4 and 5.5) and the angle status are readily detected by UBM in uveitis patients. • Highly reflective dots corresponding to inflammatory cells (Fig. 5.6) and aggregations of proteins in the anterior chamber are common findings disclosed by UBM in patients with active anterior segment inflammation [3]. • Cells in the posterior chamber are also detected by UBM in patients with anterior uveitis (Fig. 5.7) • Posterior synechiae (Fig.  5.8), anterior synechiae (Fig. 5.9), and goniosynechiae. • Hypopyon. • Fibrous exudates in the anterior chamber (Fig. 5.10). • Old fibrous membrane (Fig. 5.11) or exudates (Fig. 5.12).

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_5

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82

Fig. 5.1  Corneal edema disclosed by UBM in a uveitis patient with phthisis bulbi

Fig. 5.2  Corneal edema detected by UBM in patients with keratouveitis

Fig. 5.3  Keratic precipitates detected by UBM in patients with granulomatous uveitis

5  Auxiliary Ocular Examinations

5.1 Ultrasound Biomicroscopy (UBM)

83

Fig. 5.4  Changes of the anterior chamber detected by UBM in uveitis patients

• Localized mass-like lesions corresponding to granulomas are detected by UBM in the iris (Figs. 5.13 and 5.14), trabecular meshwork, and ciliary body. • Nodules on the iris surface may be observed in masquerade syndrome (Fig.  5.15) or granulomatous uveitis (Fig. 5.16). • Atrophy of the iris and ciliary body (Fig. 5.17). • Swelling or uneven thickness of the iris caused by inflammation (Fig. 5.18).

• Cysts in the iris (Fig. 5.19) and ciliary body (Fig. 5.20). • Detachment of the iris posterior pigmented epithelium (Figs. 5.21 and 5.22). • Iris bombe (Figs. 5.23 and 5.24). • Thickening and swelling of the ciliary body (Fig. 5.25) • Exudates and inflammatory cells adjacent to the pars plicata and posterior chamber. • Cyclitic membrane attached to the ciliary body. • Detachment of the ciliary body (Figs. 5.26 and 5.27).

84

5  Auxiliary Ocular Examinations

a

b

c

d

e Fig. 5.5  Irregular anterior chamber detected by UBM in a patient with chronic uveitis (a, b: UBM results; c–e: photographs)

5.1 Ultrasound Biomicroscopy (UBM)

85

Fig. 5.6  Numerous highly reflective dots (inflammatory cells) in the anterior chamber detected by UBM in patients with acute anterior uveitis

Fig. 5.7  Inflammatory cells in the posterior chamber detected by UBM in patients with anterior uveitis

• Atrophy of the ciliary body secondary to chronic inflammation (Fig. 5.28). • Detachment of the anterior choroid (Figs.  5.29 and 5.30).

• Exudates or proliferative alterations adjacent to the pars planar or peripheral retina (Figs. 5.31 and 5.32). • Edema of the peripheral choroid (Fig. 5.33). • Thickening of the anterior sclera (Figs. 5.34 and 5.35) [4].

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Fig. 5.8  Posterior synechiae detected by UBM in a uveitis patient

a

b

c

d

Fig. 5.9  Anterior synechiae detected by UBM in a patient with Vogt–Koyanagi–Harada (VKH) disease in recurrent granulomatous anterior uveitis stage (a–e)

5.1 Ultrasound Biomicroscopy (UBM)

e Fig. 5.9 (continued)

Fig. 5.10  Fibrous exudates with various appearances detected by UBM in patients with acute anterior uveitis

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Fig. 5.11  Old fibrous membrane in the pupil area detected by UBM in patients with uveitis

5  Auxiliary Ocular Examinations

5.1 Ultrasound Biomicroscopy (UBM)

89

Fig. 5.12  Old fibrous membrane and fresh exudates in the pupil area detected by UBM in a patient with uveitis

a

b

c

d

Fig. 5.13  Granuloma in the iris and ciliary body detected by UBM in a patient with granulomatous uveitis (a, b: UBM results; c, d: photographs)

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Fig. 5.14  Mass-like lesions in the iris and ciliary body detected by UBM in patients with granulomatous uveitis

5.1 Ultrasound Biomicroscopy (UBM)

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Fig. 5.15  Nodules on the iris surface detected by UBM in a patient with retinoblastoma

a

b

c Fig. 5.16  Nodules on the surface of the iris observed in a patient with granulomatous uveitis (a: photograph; b, c: UBM results)

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Fig. 5.17  Atrophy of the iris and ciliary body detected by UBM in uveitis patients

Fig. 5.18  Swelling of the iris detected by UBM in patients with granulomatous uveitis

5  Auxiliary Ocular Examinations

5.1 Ultrasound Biomicroscopy (UBM)

Fig. 5.19  Cyst of the iris detected by UBM in a uveitis patient

Fig. 5.20  Cysts in the ciliary body detected by UBM in patients with uveitis

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a

b

Fig. 5.21  Detachment of the iris posterior pigmented epithelium detected by UBM (a) recovers following treatment with systemic and topic corticosteroids in a patient with varicella zoster virus-associated uveitis (b)

Fig. 5.22  Detachment of the iris posterior pigmented epithelium with different appearances detected by UBM in patients with uveitis

5.1 Ultrasound Biomicroscopy (UBM)

Fig. 5.23  Iris bombe with different appearances detected by UBM in patients with uveitis

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a

b

c

d

Fig. 5.24  Iris bombe disappeared following laser iridotomy in a patient with uveitis (a, b: before treatment; c, d: after treatment)

5.1 Ultrasound Biomicroscopy (UBM)

Fig. 5.25  Edema of the ciliary body with different appearances detected by UBM in patients with granulomatous uveitis

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98

Fig. 5.25 (continued)

5  Auxiliary Ocular Examinations

5.1 Ultrasound Biomicroscopy (UBM)

Fig. 5.26  Detachment of the ciliary body with various appearances detected by UBM in patients with uveitis

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Fig. 5.26 (continued)

a

b

c

d

Fig. 5.27  Detachment of the ciliary body and peripheral choroid (a, b) completely recovers following an appropriate treatment in a patient with VKH disease (c, d)

5.1 Ultrasound Biomicroscopy (UBM)

Fig. 5.28  Atrophy of the ciliary body detected by UBM in patients with uveitis

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Fig. 5.28 (continued)

Fig. 5.29  Detachment of the ciliary body and anterior choroid detected by UBM in patients with VKH disease

5.1 Ultrasound Biomicroscopy (UBM)

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a

b

c

d

Fig. 5.30  Detachment of the peripheral anterior choroid (a, b) subsides at 3 weeks following treatment with immunosuppressive agents in a patient with VKH disease (c, d)

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Fig. 5.31  Exudates in the anterior vitreous disclosed by UBM in patients with uveitis

Fig. 5.32  Exudates adjacent to the peripheral retina detected by UBM in patients with uveitis

5  Auxiliary Ocular Examinations

5.1 Ultrasound Biomicroscopy (UBM)

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Fig. 5.32 (continued)

a

b

Fig. 5.33  Edema of the peripheral choroid (a, b) detected by UBM subsides completely following treatment with immunosuppressive agents in a patient with VKH disease (c, d)

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c

d

Fig. 5.33 (continued)

Fig. 5.34  Thickening and edema of the anterior sclera and ciliary body detected by UBM in a patient with anterior scleritis

5.1 Ultrasound Biomicroscopy (UBM)

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Fig. 5.34 (continued)

a

b

Fig. 5.35  Thickening of the sclera and its surrounding tissues (a) subsides at 4 months following treatment with immunosuppressive agents (b) in a patient with anterior sclerouveitis

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5.2

5  Auxiliary Ocular Examinations

Ultrasonography

5.2.1 Overview • A- and B-scan ultrasonography have been widely used in the diagnosis of uveitis. A-scan ultrasonography allows doctors to detect the characteristics and sizes of lesions. Whereas B-scan ultrasonography principally provides information about the topographic natures of tissues and lesions. • Ultrasonography has been used to evaluate the changes of the vitreous, retina, choroid, optic disc, sclera, and periocular tissues. It is extremely useful in the diagnosis of uveitis with opacity of ocular media [5].

5.2.2 T  he Changes Detected by Ultrasonography in Uveitis Patients • Vitreous changes. –– Various vitreous opacities (Fig. 5.36) –– Posterior vitreous detachment –– Vitreous hemorrhage –– Proliferative vitreoretinopathy (Fig. 5.37) • Choroidal melanoma. • Tractional or exudative retinal detachment (Figs. 5.38 and 5.39). • Thickening of the posterior coat (Fig. 5.40). • Optic disc edema.

Fig. 5.36  Vitreous opacities with different appearances detected by B-scan ultrasonography in uveitis patients

5.2 Ultrasonography

Fig. 5.36 (continued)

Fig. 5.37  Proliferative alterations in the vitreous disclosed by B-scan ultrasonography in patients with posterior uveitis

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Fig. 5.37 (continued)

• Mass-like lesions in the posterior segment are observed in masquerade syndrome (Figs. 5.41 and 5.42) or posterior scleritis (Fig. 5.43).

• T-sign (Fig.  5.44) presenting as diffuse retinochoroidal thickening and accentuated episcleral space is characteristic of posterior scleritis [4].

5.2 Ultrasonography

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Fig. 5.38  Retinal detachment detected by B-scan ultrasonography in patients with uveitis

a Fig. 5.39  Exudative retinal detachment and thickening of the posterior coat detected by B-scan ultrasonography in patients with uveitis subsides gradually following treatment with immunosuppressive agents.

b (a, c: right eye; b, d: left eye; a, b: before treatment; c, d: 5 months after treatment)

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c

5  Auxiliary Ocular Examinations

d

Fig. 5.39 (continued)

Fig. 5.40  Significant diffused thickening of the choroid detected by B-scan ultrasonography in patients with VKH disease

5.2 Ultrasonography

Fig. 5.41  Alterations revealed by ultrasonography in a patient with masquerade syndrome arising from retinoblastoma

Fig. 5.42  Alterations revealed by ultrasonography in a patient with masquerade syndrome arising from intraocular lymphoma

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a

b

Fig. 5.43  A mass-like lesion in the posterior segment detected by B-scan ultrasonography in a patient with posterior scleritis (a). This lesion completely regresses following 1-year treatment with immunosuppressive agents (b)

Fig. 5.44  T-sign detected by B-scan ultrasonography in patients with posterior scleritis

5.3

 undus Fluorescein Angiography F (FFA)

5.3.1 Overview • FFA has been widely used in the diagnosis or differential diagnosis of uveitis, evaluating the activity and severity of uveitis and determining the patients’ response to therapy [6, 7]. • It is also used to detect the complications such as cystoid macular edema (CME), serous retinal detachment, the involvement of the optic nerve, choroidal lesions, choroidal and retinal neovascularization [6, 8].

5.3.2 T  he Changes Detected by FFA in Uveitis Patients • Hyperfluorescence occurs as a result of either leakage of dye, increased transmission, or absorption of dye by tissues. • Hyperfluorescence caused by leakage is mainly seen in retinal vasculitis, papillitis, and retinal or choroidal neovascularization (CNV). –– Leakage of dye may accumulate in the intraretinal spaces of macula to form petaloid pattern (cystoid macular edema) (Fig. 5.45) or in the subretinal space (multi-lake fluorescence) which is frequently seen in

5.3 Fundus Fluorescein Angiography (FFA)

Fig. 5.45  CMV detected by FFA in both eye of a patient with uveitis

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––

––

–– –– ––

VKH disease, sympathetic ophthalmitis, and posterior scleritis [7, 9, 10]. Hyperfluorescence due to window-defect is usually seen in patients with atrophic or damaged retinal pigment epithelium as commonly seen in VKH disease (Fig. 5.46), sympathetic ophthalmia and the inflammatory diseases involving the retinal pigment epithelium and choroid [11, 12]. Staining usually occurs in the late phase of the angiogram and is seen in active retinitis, retinochoroiditis, chorioretinal scar, and papillitis. CNV shows late staining (Fig. 5.47). Dalen–Fuchs nodules usually show multiple hyperfluorescent spots (Fig. 5.48). Chorioretinal atrophy usually shows late hyperfluorescence (Figs. 5.49 and 5.50).

• Hypofluorescence forms as a result of blockage or lack of circulation in areas of the retina or choroid. It is seen in the following conditions or diseases. –– Blockage of fluorescence due to retinal hemorrhage (Fig.  5.51), pigment clumping, or hyperpigmentation (Fig. 5.52). –– Striped hypofluorescence is observed in VKH patients (Fig. 5.53). –– Hard retinal exudates. –– Active retinitis, retinochoroiditis, and choroiditis. • Retinal vascular leakage [13] –– It is common in Behcet’s disease (BD) and pediatric uveitis (Figs. 5.54 and 5.55). –– A number of uveitis entities without obvious fundus changes may have retinal vascular leakage on FFA [14, 15].

Fig. 5.46  Window-defect disclosed by FFA in a patient with VKH disease

5.3 Fundus Fluorescein Angiography (FFA)

Fig. 5.47  CNV showing staining in the late phase of FFA in a uveitis patient

Fig. 5.48  Dalen–Fuchs nodules showing staining in the late phase of angiogram in a patient with VKH disease

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a

b

c

d

Fig. 5.49  Hyperfluorescence of chorioretinal atrophy disclosed by FFA in a patient with VKH disease (a: fundus photograph; b–d: FFA results)

–– Vascular leakage is much more common than people think in clinical practice (Fig. 5.56). –– FFA is very useful in following up of subclinical retinal vasculitis. • Retinal neovascularization –– It is usually noted in retinitis and retinal vasculitis (Figs. 5.57 and 5.58) [6, 8].

• • • •

–– Retinal neovascularization identified by FFA is more common than clinically observed. Nonperfusion of retinal capillaries (Fig. 5.59). Staining of the vascular wall (Fig. 5.60). Vascular occlusion (Fig. 5.61). Subretinal pooling of fluorescence (Fig. 5.62) [7, 11].

5.3 Fundus Fluorescein Angiography (FFA)

a

b

Fig. 5.50  Chorioretinal atrophy (a) shows late hyperfluorescence on FFA (b) in a patient with VKH disease (a: photographs; b: FFA results)

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a

b

c

Fig. 5.51  Blockage of fluorescence due to hemorrhage observed in a patient with uveitis (a: fundus photograph; b, c: FFA results)

5.3 Fundus Fluorescein Angiography (FFA)

a

121

b

Fig. 5.52  Blockage of fluorescence due to pigment clumping observed in a patient with VKH disease (a: fundus photograph; b: FFA result)

Fig. 5.53  Striped hypofluorescence detected by FFA in a patient with VKH disease

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Fig. 5.54  Diffuse vascular leakages disclosed by FFA in patients with retinal capillaritis

5  Auxiliary Ocular Examinations

5.3 Fundus Fluorescein Angiography (FFA)

Fig. 5.55  Vascular leakages disclosed by FFA in a patient with uveitis

a

b

Fig. 5.56  Vascular leakages disclosed by FFA (a) resolve completely at 9 months following treatment with immunosuppressive agents (b)

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Fig. 5.57  Retinal neovascularization detected by FFA in a patient with posterior uveitis

Fig. 5.58  Retinal neovascularization detected by FFA in a patient with posterior uveitis

5  Auxiliary Ocular Examinations

5.3 Fundus Fluorescein Angiography (FFA)

Fig. 5.59  Nonperfusion of retinal capillaries revealed by FFA in patients with retinal vasculitis

Fig. 5.60  Staining of the retinal vascular wall and dialated retinal vessels disclosed by FFA in a patient with uveitis

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Fig. 5.61  Vascular occlusion and extensive microvascular nonperfusion detected by FFA in a patient with acute retinal necrosis syndrome

Fig. 5.62  Subretinal pooling of fluorescence in the late phase of angiogram detected by FFA in a patient with VKH disease

5.4 Indocyanine Green Angiography (ICGA)

5.4

I ndocyanine Green Angiography (ICGA)

5.4.1 Overview • ICGA is an auxiliary examination used in evaluating the inflammatory lesions of choriocapillaris and choroidal stroma. • It is widely used in the diagnosis of the disorders involving the choroid such as VKH disease, sympathetic ophthalmia, birdshot chorioretinitis, multifocal choroiditis, and ocular sarcoidosis [7, 8, 16].

5.4.2 T  he Changes Detected by ICGA in Uveitis Patients • The typical change of ICGA in posterior uveitis stage and anterior uveal involvement stage of VKH disease is hypofluo-

127

rescent dots (corresponding to choroidal stromal infiltrates or granulomas) or large hypofluorescent areas (corresponding to serous retinal detachment areas) (Fig. 5.63). • ICG hypofluorescence develops as a result of either absence or paucity of ICG macromolecular complex in the affected areas of the choroid or the impaired filling of this complex in the choroid due to the existing space-­ occupying lesions. –– ICG hypofluorescence due to the absence (Fig. 5.64) or decreased extrusion of the complex is observed in the inflammatory diseases of the choriocapillaris. –– ICG hypofluorescence due to space-occupying lesions is noted in stromal inflammatory lesions such as granuloma. These hypofluorescent dots are common in VKH disease, sympathetic ophthalmia, ocular sarcoidosis, multifocal chorioretinitis (Figs.  5.65 and 5.66), and birdshot chorioretinopathy. –– Hypofluorescence may occur as a result of hyperpigmentation (Figs. 5.67 and 5.68).

Fig. 5.63  Multiple hypofluorescent dots in the early phase and large hypofluorescent areas in the late phase of angiogram detected by ICGA in both eyes of a patient with VKH disease

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a

b

c

d

Fig. 5.64  Multiple hypofluorescent areas detected by ICGA in a patient with inactive multiple chorioretinitis (a: fundus photography; b: FFA result; c, d: ICGA results)

• ICG hyperfluorescence develops as a result of enhanced extrusion of ICG macromolecular complex into the choroid by larger choroidal vessels. –– Vasculitis in the choroid is usually associated with hyperfluorescence.

–– Disc hyperfluorescence may be observed in patients with severe inflammation of disc capillaries. –– ICGA of subretinal neovascularization may show focal hyperfluorescence.

5.4 Indocyanine Green Angiography (ICGA)

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a

b

c

d

e

f

Fig. 5.65  A patient with active multifocal chorioretinitis (a, b) showing several hypofluorescent dots corresponding to active choroidal lesions on ICGA (c–f)

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a

b

c

Fig. 5.66  Active choroidal lesions (a: fundus photograph) showing early hypofluorescence and late staining on FFA (b) and persistent hypofluorescence on ICGA (c)

5.4 Indocyanine Green Angiography (ICGA)

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a

b

c

d

e

f

Fig. 5.67  Hypofluorescent dots due to hyperpigmentation (a, b: fundus photographs; c, d: FFA results) are revealed by ICGA (e, f) in a patient with VKH disease

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a

b

c

d

Fig. 5.68  Striped hypofluorescence, corresponding to the pigmentary proliferation (a, b: fundus photographs) detected by ICGA (c, d) in a patient with VKH disease

5.5

 ptical Coherence Tomography (OCT) O Imaging

5.5.1 Overview • OCT imaging is a noninvasive technique and may provide high-resolution and high-speed imaging of the posterior segment in vivo. • It is widely used in evaluating macular abnormalities, serous retinal detachment, choroidal neovascularization, vitreoretinal interface, and structural alteration of the posterior segment [4, 7, 10, 17].

5.5.2 T  he Changes Disclosed by OCT in Uveitis Patients • OCT imaging is now widely used in detecting and following the structural changes of the retina, macula, and optic

nerve in a variety of posterior uveitis entities (Figs. 5.69 and 5.70). • Macular edema –– It is easily detected by OCT imaging. –– It is diffuse or cystoid based on its appearance. –– It may be associated with serous retinal detachment (Fig. 5.71). –– CME is common in posterior uveitis and intermediate uveitis and often results in substantial visual impairment. • Macular hole –– OCT imaging is superior to fundoscopy in the determination of macular hole –– It may occur in various entities of posterior uveitis (Fig. 5.72). • Serous retinal detachment –– It mainly occurs in VKH disease (Fig. 5.73), sympathetic ophthalmia, and posterior scleritis.

5.5 Optical Coherence Tomography (OCT) Imaging

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Fig. 5.69  CNV and abnormalities of the retina disclosed by OCT imaging in a patient with bilateal posterior uveitis

a

b

c

d

Fig. 5.70  Serous retinal detachment (a, b) resolves at 2 months after treatment (c, d) with systemic corticosteroids and cyclosporine in a patient with VKH disease

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Fig. 5.71  CME associated with retinal pigment epithelium detachment detected by OCT imaging in a patient with posterior uveitis

Fig. 5.72  Macular hole detected by OCT imaging in a patient with posterior uveitis

Fig. 5.73  Serous retinal detachment in association with localized retinal pigment epithelium detachment detected by OCT imaging in a patient with VKH disease

5.5 Optical Coherence Tomography (OCT) Imaging

–– Central serous retinopathy may also display serous retinal detachment and therefore should be differentiated from that caused by inflammatory conditions. –– It may be accompanied by retinal pigment epithelium detachment. –– It can be completely resolved following adequate treatment. • Choroidal neovascularization (CNV) –– It usually presents as subretinal hyper-reflective lesions. –– It may be associated with cystoid macular edema. –– It may develop in a number of inflammatory conditions involving the RPE and/or Bruch’s membrane including VKH disease, sympathetic ophthalmia, birdshot chorioretinopathy, multifocal choroiditis, presumed ocular histoplasmosis, and toxoplasmosis. –– CNV usually occurs in the macular, perimacular, and peripapillary areas (Fig. 5.74) although it may occur in other regions (Fig. 5.75).

Fig. 5.74  Peripapillary CNV detected by OCT imaging in a female patient with posterior uveitis

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• Optic nerve changes –– OCT imaging may provide important information about the optic nerve. –– Swelling of the optic disc or papilledema is readily detectable using OCT imaging (Fig. 5.76). –– Swelling of the optic disc occurs in various posterior uveitis entities, intermediate uveitis, and less commonly acute anterior uveitis. –– Enlarged optic cup (Fig. 5.77). –– OCT imaging may provide useful information about the epiretinal membrane and its relationship with other tissues (Fig. 5.78). –– Thickness of the retina (Fig. 5.79) in the posterior pole in uveitis is readily detectable using OCT imaging. –– Subretinal fibrosis (Fig. 5.80) –– Retinal pigment epithelium detachment (Fig. 5.81).

Fig. 5.76  Swelling of the optic disc detected by OCT imaging in a patient with posterior uveitis

Fig. 5.75  CNV inferior to macular area detected by OCT imaging in a patient with posterior uveitis

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Fig. 5.77  Enlarged optic cup detected by OCT imaging in a uveitis patient with persistently elevated intraocular pressure

a

b

c

d

Fig. 5.78  Epiretinal membrane detected by OCT imaging in patients with posterior uveitis (a, b).Thickening and disorganization of the retinal structures arising from epiretinal membrane are observed (c, d)

5.5 Optical Coherence Tomography (OCT) Imaging

Fig. 5.79  Diffuse retinal atrophy detected by OCT imaging in a patient with BD

Fig. 5.80  Subretinal fibrosis detected by OCT imaging in a patient with posterior uveitis

Fig. 5.81  Retinal pigment epithelium detachment detected by OCT imaging in a patient with posterior uveitis

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References 1. Gupta A, Singh R, Gupta V. Ultrasound biomicroscopy. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 167–79. 2. Jones N.  History, examination and ophthalmic imaging. Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 15–54. 3. Yang P, Meng Q, Huang X, et al. Longitudinal study of anterior segment inflammation by ultrasound biomicroscopy in patients with acute anterior uveitis. Acta Ophthalmol. 2009;87(2):211–5. 4. Yang P, Ye Z, Tang J, et  al. Clinical features and complications of scleritis in Chinese patients. Ocul Immunol Inflamm. 2018;26(3):387–96. 5. Restori M.  Ultrasonography. In: Zierhut M, Pavesio C, Ohno S, et  al., editors. Intraocular inflammation. Berlin: 00; 2016. p. 207–15. 6. Gupta V, Gupta P, Herbort CP, et al. Fluorescein angiography. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 61–87. 7. Du L, Kijlstra A, Yang P.  Vogt-Koyanagi-Harada disease: novel insights into pathophysiology, diagnosis and treatment. Prog Retin Eye Res. 2016;52:84–111. 8. Herbort CP. Fluorescein and indocyanine angiography. In: Zierhut M, Pavesio C, Ohno S, et  al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 159–80.

5  Auxiliary Ocular Examinations 9. Tugal-Tutkun I, Onal S, Foster CS. Imaging studies for uveitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 131–91. 10. Yang P, Ye Z, Xu J, et al. Macular Abnormalities in Vogt-Koyanagi-­ Harada Disease. Ocul Immunol Inflamm. 2019;27(8):1195–202. 11. Yang P, Ren Y, Li B, et  al. Clinical characteristics of Vogt-­ Koyanagi-­Harada syndrome in Chinese patients. Ophthalmology. 2007;114(3):606–14. 12. Yang P, Liu S, Zhong Z, et  al. Comparison of clinical features and visual outcome between sympathetic ophthalmia and Vogt-­ Koyanagi-­ Harada disease in Chinese patients. Ophthalmology. 2019;126(9):1297–305. 13. Yang P, Fang W, Meng Q, et al. Clinical features of Chinese patients with Behcet’s disease. Ophthalmology. 2008;115(2):312–8. 14. Yang P, Fang W, Jin H, et al. Clinical features of Chinese patients with Fuchs’ syndrome. Ophthalmology. 2006;113(3):473–80. 15. Yang P, Wan W, Du L, et al. Clinical features of HLA-B27-positive acute anterior uveitis with or without ankylosing spondylitis in a Chinese cohort. Br J Ophthalmol. 2018;102(2):215–9. 16. Herbort CP. Indocyanine green angiography: fundus ICG angiography. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 88–144. 17. Gupta V, Gupta A, van Velthoven ME. Optical coherence tomography. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 180–222.

6

Systemic Imaging and Laboratory Investigations

Contents 6.1  X-ray

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6.2  Computed Tomography (CT)

 139

6.3  Magnetic Resonance Imaging (MRI)

 139

6.4  Laboratory Investigations

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References

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6.1  X-ray

6.4  Laboratory Investigations

• X-ray has been widely used in detecting the lesions in the lung, mediastinum, and bone, such as tuberculosis (TB), sarcoidosis, juvenile idiopathic arthritis (JIA), and the seronegative spondyloarthropathies [1]. • In general, plain film is inferior to CT (computed tomography) or MRI (magnetic resonance imaging) in evaluating the changes in the bone and soft tissue.

• Purposes of laboratory investigations in uveitis –– Making a definite diagnosis. For instance, cultural or cytological examinations of vitreous biopsy may confirm the diagnosis of bacterial or fungal endophthalmitis and intraocular lymphoma. –– Providing additional evidences to the clinical diagnosis. For instance, an increased level of angiotensin-­ converting enzyme supports the diagnosis of sarcoidosis in a patient with granulomatous uveitis [4]. –– Providing clues to suggest whether uveitis is associated with a systemic disease. For instance, an increased erythrocyte sedimentation rate is suggestive of the possible presence of systemic inflammatory disease in the uveitis patients. A further extensive work-up is needed to identify the underlying disease. –– Evaluating the effectiveness of therapy on uveitis. For instance, nonspecific tests for syphilitic uveitis such as rapid plasma reagin test (PRP) and venereal disease research laboratory (VDRL) test are usually suggestive of the disease activity. Decreased antibody titer is generally associated with a beneficial result of the therapy [4, 5]. –– Monitoring the side effects during therapy. The tests used for monitoring the side effects of therapy usually include white blood cell counting and tests of liver and kidney function. These tests should be performed

6.2  Computed Tomography (CT) • CT is used to detect the changes in soft tissues and bony structures. • It is helpful in the diagnosis of tuberculosis, sarcoidosis, and seronegative spondyloarthropathies [1].

6.3  Magnetic Resonance Imaging (MRI) • MRI is extremely useful in detecting the lesions in the central nervous system and musculoskeletal disorders [2, 3]. • It is used in the diagnosis of primary central nervous system lymphoma, neurological involvement of Behcet’s disease (BD), Vogt–Koyanagi–Harada (VKH) disease, multiple sclerosis, and seronegative spondyloarthropathies.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_6

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r­ egularly in patients on a long-term use of immunosuppressive agents. –– Searching for the mechanisms underlying the development of uveitis. Investigations on the patients’ samples including blood, intraocular fluid, feces, and urine may provide us with new substantial information for understanding the mechanisms involved in uveitis although they are currently not used in the diagnosis of uveitis. • Selection of laboratory investigations –– Not all of uveitis patients need laboratory investigations for their diagnosis [4]. The uveitis entities listed below are those examples. Fuchs syndrome Posner–Schlossman syndrome VKH disease Behcet’s disease White anterior uveitis without systemic manifestations Herpesvirus-associated anterior uveitis –– Nonselective tests or some battery of laboratory investigations performed in all of uveitis patients may result in confusion in the diagnosis. As there is high prevalence of a number of infections, such as viruses and T. gondii in populations, positive serological results can be misinterpreted as a cause factor for uveitis. The following tests are usually unselectively and inadequately used in the screening of the patients with uveitis in China. Serum anti-cytomegalovirus (CMV) antibody Serum anti-herpes simplex virus antibody Serum anti-herpes zoster virus antibody Serum anti-rubella virus antibody Serum antibody to T. gondii Serum antibody to Toxocara Anti-nuclear antibodies Rheumatoid factor Tuberculin skin testing Interferon-γ release assay • Selection of laboratory investigations should be based on the history, clinical examinations, and the suspicion of uveitis entity [4]. Indiscriminative searching for any cause or possible underlying disease is always time- and moneyconsuming and, more importantly, forces the doctor to make a misdiagnosis [6]. Therefore, it should be always kept in mind that suspicion-oriented or targeted laboratory investigations are used in the diagnosis of uveitis (Table 6.1). • Production of intraocular specific antibody –– The intraocular antibody could be produced locally or from the blood due to break down of blood–eye barrier as seen in uveitis. –– Locally produced antibodies against pathogens are definitely helpful for the diagnosis of these infections,

6  Systemic Imaging and Laboratory Investigations Table 6.1  Suspicion-oriented laboratory investigations in uveitis entities as undefined clinically Entity Acute anterior uveitis Chronic anterior uveitis in children Sclerouveitis or keratouveitis Endophthalmitis Intraocular lymphoma Ocular toxoplasmosis Syphilis Tuberculosis Sarcoidosis Viral retinitish Retinoblastoma Lyme disease Systemic lupus erythematosus

General selection of tests Complete blood count ESR,a C-reactive protein HLA-B27 antigen typing anti-nuclear antibodies ESR, C-reactive protein, rheumatoid factor ANCA,b anti-nuclear antibodies Culture of vitreous body or aqueous humor Cytology of vitreous sample and CSF,c IL-10, and IL-6, retinal biopsy Goldmann-Witmer coefficient DNA determined by PCR on aqueous or vitreous sample Specific tests (FTA-ABS,d MHA-TPe) and nonspecific tests (RPR,f VDRLg) Tuberculin skin testing, interferon-γ release assay Angiotensin-converting enzyme Lysozyme Goldmann-Witmer coefficient, DNA detected by PCR on aqueous or vitreous samples Lactate dehydrogenase level in aqueous humor, Cytology of intraocular samplesi Antibody to Lyme borreliosis Anti-nuclear antibodies (anti-native DNA, anti-Sm)

ESR erythrocyte sedimentation rate ANCA anti-neutrophil cytoplasmic antibodies c CSF cerebrospinal fluid d FTA-ABS fluorescent treponemal antibody-absorption e MHA-TP microhemagglutination assay for T pallidum f RPR rapid plasma reagin g VDRL venereal disease research laboratory test h Viral retinitis can be diagnosed according to typical clinical manifestation. Specific antibody is measured only in the patients with suspected viral retinitis i It should be always kept in mind that biopsy may cause dissemination of tumor cells a

b

whereas the only presence of these antibodies does not support a diagnosis of intraocular infection [7–9]. –– Goldmann–Witmer coefficient (GWC) is widely used in demonstrating whether the specific antibody is truly produced within the eye or comes from the leakage. –– GWC is used for the diagnosis of ocular toxoplasmosis, toxocariasis, and various virus-associated uveitis [10].

References 1. Pichi F, Margolos R, Lowder CY. Diagnostic imaging procedures. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 237–50. 2. Chan C, Haen SP, Möhle R, et al. Primary intraocular lymphoma. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 1467–85.

References 3. Wahees NK, Foster CS. Masquerade syndromes: malignancies. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 705–35. 4. Chorich LJ III, Klisovic DD, Foster CS. Diagnosis of uveitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 101–30. 5. Yang P, Zhang N, Li F, et  al. Ocular manifestations of syphilitic uveitis in Chinese patients. Retina. 2012;32(9):1906–14. 6. Nussenblatt RB, Whitcup SM, Palestine AG.  Diagnostic testing. Uveitis fundamentals and clinical practice. 2nd ed. St. Louis: Mosby-Year Book, Inc.; 1996. p. 79–90.

141 7. Denis J, Rossignol A, Langlois M, et  al. Coefficient of antibody activity in the aqueous humor to that in the serum in ocular herpes simple. In: Sundmacher R, editor. Herpetische Augenerkrankungen. München: J.F. Bergmann Verlag. 1981;p. 147–58. 8. Dussaix E, Cerqueti PM, Pontet F, et  al. New approaches to the detection of locally produced antiviral antibodies in the aqueous of patients with endogenous uveitis. Ophthalmologica. 1987;194(2–3):145–9. 9. Goldmann H, Witmer R.  Antikörper im Kammerwasser. Ophthalmologica. 1954;127(4-5):323–30. 10. Kijlstra A, Luyendijk L, Baarsma GS, et al. Aqueous humor analysis as a diagnostic tool in toxoplasma uveitis. Int Ophthalmol. 1989;13(6):383–6.

Part III Treatment of Uveitis

7

Ideology, Fundamental Principles, and Strategies in Management of Uveitis

Contents 7.1  Ideology in Uveitis Management

 145

7.2  Fundamental Principles

 147

7.3  Strategies

 147

References

 148

Managing disease, like conducting the war, should be guided by proper ideology, fundamental principles, and strategies. The author has treated about 30,000 patients with uveitis during the past 30 years and developed a set of ideology, fundamental principles, and strategies. Practically, they are useful in guiding management of uveitis as well as other diseases. They are described below in detail.

7.1  Ideology in Uveitis Management • The ideology refers to that motivating of defense function and repairing capability through adequate use of medicines based on comprehensive understanding of the pathophysiological changes is used to deal with uveitis as well as other diseases [1]. • This ideology can be well explained by the five ways of thinking including systemic thinking, dialectical thinking, local thinking, holistic thinking, and aesthetical thinking. –– Systemic thinking It refers to that the management of disease should be performed according to the principle of spatialtemporal sequence. In other words, the management should follow the spatial-temporal procedure. For instance, cataract surgery in uveitis patients with complicated cataract should be performed after uveitis is completely controlled rather than operation before regression of the inflammation. Cataract surgery on an inflamed eye, except the lens induced cataract, usually results in severe sequelae.

Another example is that the vitrectomy always precedes the laser photocoagulation for vaso-occlusive disease if the vitreous opacity obscures the details of the fundus. Systemic thinking highlights the importance of procedure or program of management and the achievement of final good result. –– Dialectical thinking It refers to that the treatment should be instituted according to the uveitis entities, individual conditions, the effectiveness of previous treatment and mechanisms of action of the medicines which are being used. Dialectical thinking highlights the importance of tailored treatment in dealing with uveitis in different individuals and diverse inflammatory conditions. Dialectical thinking is used to recognize the complex of uveitis, evaluate inflammation in nature and its relationship with underlying systemic diseases, and determine whether it is inflammation in nature or manifests as a masquerade syndrome. From the view of uveitis itself, more than 100 entities have been reported to date. Different entities vary considerably with severity, influence on visual acuity, and the evolutional course. Each form of uveitis has its distinct manifestations, evolution process, response to treatment, and visual prognosis. It is obvious that these different uveitis entities cannot be treated by one or two modalities.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_7

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Therefore, accurate diagnosis is very instrumental to the development of tailored therapeutic regimens. From the view of patients with uveitis, there are tremendous differences concerning patient’s age, sex, genetic background, constitution, underlying diseases, economic conditions, and the tolerance to drugs and their side effects. From the view of drugs available in the treatment of uveitis, there are still big differences. The mechanisms by which the drugs operate, the side effects, cost of therapy, routes of administration, and modality are quite different among these drugs. It is wellknown that long-term, large dose of systemic corticosteroids may result in growth failure in children. It should be kept in mind that children with uveitis should be treated with particular attention with respect to the long-term use of corticosteroids. Male uveitis patients who do not have baby seem not to tolerate azoospermia caused by chlorambucil or cyclophosphamide. Additionally, a poor uveitis patient cannot afford the use of very expensive medicines. –– Local thinking (local processing) It refers to that disease should be treated locally to avoid, as much as possible, the side effects of the drugs used in the treatment. A typical example is the topical corticosteroids, normally without systemic administration in the treatment of acute anterior uveitis. For patients with intermediate uveitis as well as posterior uveitis, periocular or intraocular injection of corticosteroid may serve as an adjunct to the systemic corticosteroids and can significantly reduce the systemic side effects. –– Holistic thinking It refers to that disease should be treated systemically in addition to the local treatment. Uveitis occurs within the eye but the causative immune response is always systemic. Therefore, in most cases with posterior, intermediate, or generalized uveitis local treatment alone is not sufficient to cure the inflammation. From the view of the mechanisms involved in the development of uveitis, it is rational to treat the aforementioned uveitis entities with systemic administration of relevant medicines. Here I give an example to show the importance of holistic thinking in the management of disease. Seventeen years ago, a male Turkish patient with Behcet’s disease (BD) was referred to our uveitis center. Two cutaneous ulcerations with 5–6  cm in diameter lasted for 5 years and had been treated by

surgeons at local hospitals. However, there was no improvement of these two ulcerations. Based on the holistic thinking, we treated this patient with systemic corticosteroids in conjunction with other immunosuppressive agents and traditional Chinese medicine herbs. No local treatment was given for this patient. These two ulcerations completely resolved following a more than two-month treatment. This example is highly suggestive of the importance of systemic treatment in patients with BD mediated by systemic immune response. –– Aesthetical thinking [2] It refers to that much attention should be paid to the reestablishing of balance and harmony within the body during management of disease. Balance and harmony are essential rules within human body. The unbalance and disturbance of harmony always result in the development of diseases. In fact, diseases represent physiopathological disturbance induced by various factors. Therefore, elimination of causative agents and reestablishment of physiopathological balance are crucial in the treatment of diseases including uveitis. Aesthetical thinking in the treatment of uveitis emphasizes the importance of modulating immune response rather than over-inhibition of this response. This could be approached through the following strategies including use of as few drugs as possible, minimal dosage, more convenient route, appropriate duration, and selection of the low-cost drugs. In fact, during past decades we have developed a set of therapeutic regimens, using minimal corticosteroids combined with low dose of other immunosuppressive agents to treat Vogt–Koyanagi–Harada (VKH) disease and other forms of chronic uveitis. In a recent study, we found a very promising result of these regimens in controlling of VKH ­disease, without the development of severe side effects in most patients. The severe side effects such as femoral head necrosis, gastrointestinal perforation, and Cushing’s syndrome occurring in the systemic use of corticosteroids further indicate the importance of using adequate drugs and minimizing dosage in the treatment of uveitis. In the clinical practice, it is a common phenomenon that chemotherapy frequently worsens the cancer and in turn results in a more rapid death in some patients with tumor in late stage. If these patients left untreated, they perhaps survive for some time or even for a longer time. This example provides additional evidences to support the aesthetical thing in the management of diseases including uveitis.

7.3 Strategies

7.2  Fundamental Principles • Three fundamental principles have been designed by author in the management of diseases including uveitis. • Individual principle –– As mentioned above, there are big differences concerning the uveitis entities, patient’s individual conditions, and significant differences of drugs in the treatment of uveitis, each patient should be treated individually according to a comprehensive analysis. –– Also for the aforementioned reasons, it is not pertinent to use one or two therapeutic regimens for all kinds of uveitis, even one form of uveitis in different patients. Therefore, it is reasonable that uniform and formatting therapeutic regimens should be avoided in the management of uveitis as well as other diseases. • Simplicity principle –– Simplicity principle refers to that uveitis should be treated with as few drugs as possible, as lower dosage as possible, adequate and more convenient route. –– A large number of the so-called auxiliary drugs, such as neurotrophic drugs, traditional Chinese medicine herbs possessing the role of activating blood circulation to dissipate stasis, have been inadequately used as adjuncts to immunosuppressive agents. In general, these drugs do not have beneficial effect on uveitis. • Permanent principle –– Permanent principle refers to that the treatment aims to control the inflammation permanently or even for the whole life of the patients. –– Therapy with enough long period of time and lower dosage are crucial to the achievement of permanent controlling of uveitis. In practice, we normally use a maintenance dose of corticosteroids (15–20  mg/kg) and cyclosporin (2 mg/kg/day) after controlling of acute or severe intraocular inflammation for a longer time to “tame” the reluctant inflammation in VKH disease, sympathetic ophthalmia, BD, etc. –– These uveitis entities listed above have been considered as recurrent diseases and they are very difficult to be permanently controlled. In fact, a substantial number of the patients with these forms of uveitis have achieved permanent controlling of the intraocular inflammation, even for more than 28 years, by an adequate and enough long time treatment in our uveitis center. –– Large dosage of the drugs used in the treatment of uveitis can, of course, readily control the intraocular inflammation. However, rapid and inadequate termination of the treatment, as seen frequently in the management of refractory uveitis, usually results in recurrences and chronicity of this inflammation.

147

–– Of course, there are still some uveitis patients with recurrent episodes although extensive treatment is used. Novel medicines are expected to develop to control this inflammation in future. Another example for the recurrent inflammation is acute anterior uveitis. To date there is no modality available to prevent the recurrence of this inflammation. Fortunately, it does not result in a poor visual prognosis in most patients.

7.3  Strategies • Five strategies have been developed in the management of uveitis and its complications. • Quickly controlling inflammation with sufficiently high dosage of drugs or adequate modality. –– For the acute and severe intraocular inflammation, sufficient dosage of relevant drugs or adequate modality is needed to rapidly “capture” the inflammation or “extinguish” the inflammatory flaming. –– Acute anterior uveitis is a self-limiting inflammation but can cause complications which sometimes may lead to severe sequela. High frequencies, even as high as one time every 15 min of topical corticosteroid, are used in the patients with severe anterior uveitis. –– Acute retinal necrosis is a rapidly progressive inflammation caused by herpetic virus. Early and adequate treatment using relevant antiviral agent and corticosteroids at sufficient dosage is extremely important to preserve as much of the retina as possible. –– It should be kept in mind that the dosage of drugs should be sufficient to control the acute inflammation rather than very high dosage. It is well known that the efficiency of the drug is in proportion to its dosage within a certain extent. Beyond this extent, increased dosage of the drug does not yield more profound effects. Overdosed use of drugs should be, therefore, avoided in the treatment of diseases including uveitis. • Prolonged strategy –– Prolonged strategy refers to a long lasting use of drugs to control chronic diseases including chronic uveitis. –– For the chronic intraocular inflammation, as seen in VKH disease, sympathetic ophthalmia and BD, a short period of treatment, although it may achieve transiently inflammation quiescence, is not sufficient to achieve completely recovery of the disease. Therefore, a long-­term of treatment with lower dosage, which is sufficient just enough to control the low grade of inflammation, is needed to gradually “tame” the immune response responsible for the disease. –– Prolonged treatment with as much low dosage of drugs as possible is, of course, associated with few or less severe side effects during the treatment.

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–– In fact, chronic inflammation in a variety of uveitis entities is mostly attributed to an early, inadequate termination of the treatment. A strange circle in uveitis management, i.e., inflammation—a short period of extensive treatment—regression—recurrence, can be broken by a prolonged treatment. • Symptomatic treatment in acute condition –– This strategy refers to the immediate and intensive treatment modality or regimen for very devastating or sight-threatening inflammation or complications abruptly being developed. –– Increased intraocular pressure secondary to pupillary block, which could result in severe visual loss, should be immediately treated by a combination of antiglaucoma agents with subsequent iridectomy. –– Another example is VKH disease. The disease can begin ominously and terribly with severe visual loss, bulb retinal detachment, or severe optic nerve involvement. Treatment should be immediately instituted by using periocular or intraocular corticosteroid in conjunction with a sufficient (not very high) systemic dose of corticosteroids. A gradual tapering of dosage and a long period of maintenance dose are followed as it is a chronic disease in nature. –– The immediate treatment for an emergency condition is usually capable of reversing the dangerous situation and gaining the chance for further recovery of the impaired visual function. • Combining strategy [2, 3] –– Combining strategy refers to the treatment with two or more drugs in dealing with uveitis. –– Combining strategy aims at approaching a synergistic effects of the drugs concurrently used and reducing their side effects. –– It is particularly useful in patients with underlying systemic diseases, which are relatively contraindications of certain drugs, and those with pregnancy, impaired liver or kidney function. As different drugs have

diverse side effect, a combination of two or more drugs are absolutely necessary to treat these patients. –– The principles for the combination include: (1) using drugs with different underlying mechanisms and (2) using drugs with different side effects. –– Each drug used in the combination is usually given at a dose lower than that in monotherapy in an attempt to reduce the side effects of the drugs. –– Traditional Chinese medicinal herbs may be used as an adjunct to corticosteroids and other immunosuppressive agents. These herbs are usually useful in reducing the side effects of western medicines including myelosuppression, weakness, gastrointestinal discomfort, and menstrual disorder. • Strengthening body resistance and eliminating pathogenic factors. –– It is one of the strategies in traditional Chinese medicine. –– It highlights the importance of activation of intrinsic resistance to diseases including uveitis. –– It could be achieved through physical exercise, adjustment of self-mental status and balancing of diet. –– A number of traditional Chinese medicinal herbs have been used in uveitis patients in an attempt to achieve a balance between “Yin and Yang”, harmonizing of “qi and blood”, and recovering of good status in mental and physical health according to traditional Chinese medicine theory.

References 1. Yang P, Du L, Ye Z. How to deal with uveitis patients? Curr Mol Med. 2017;17(7):468–70. 2. Yang P, Ye Z, Du L, et al. Novel treatment regimen of Vogt-Koyanagi-­ Harada disease with a reduced dose of corticosteroids combined with immunosuppressive agents. Curr Eye Res. 2018;43(2):254–61. 3. Du L, Kijlstra A, Yang P.  Vogt-Koyanagi-Harada disease: novel insights into pathophysiology, diagnosis and treatment. Prog Retin Eye Res. 2016;52:84–111.

8

Corticosteroids

Contents

8.1

8.1  Overview

 149

8.2  Topical Corticosteroids

 149

8.3  Periocular Corticosteroids

 149

8.4  Intravitreal Corticosteroids

 150

8.5  Systemic Corticosteroids

 150

References

 154

Overview

• Corticosteroids are still the mainstay of the therapy for numerous noninfectious uveitis. • Various synthetic preparations with different efficacies and toxicities are available for clinical usage. • They possess both anti-inflammatory and immunosuppressive effects. • They have been widely used in the management of uveitis by various routes including topical use, periocular and intravitreal injection, and systemic administration [1–3].

8.2

Topical Corticosteroids

• Various corticosteroid preparations for ocular installation are available commercially. • The most commonly used preparations include dexamethasone (0.1% alcohol suspension and 0.1% sodium phosphate solution), prednisolone (1% acetate suspension, 0.5 or 1% sodium phosphate solution), and fluorometholone (0.1 or 0.25% suspension). • Dexamethasone has the most potent anti-inflammatory effect and may readily predispose the patients to the development of increased intraocular pressure. • Fluorometholone is weak in anti-inflammation. Correspondingly, it is associated with a lower rate of increased intraocular pressure.

• Topical corticosteroids are used in patients with noninfectious anterior segment inflammation at varying frequencies [2, 3]. –– For the patients with very severe anterior uveitis, topical corticosteroids are given initially every 30 min for 1–2 h and then followed by gradual tapering according to the amelioration of the inflammation. –– For the patients with moderate anterior uveitis topical corticosteroids are usually given 3–4 times daily. –– For the patients with minor anterior uveitis fluorometholone is normally recommended. –– They are also used as an adjunct to relevant anti-­infectious agents in patients with infectious anterior uveitis. –– Aqueous flare alone (without aqueous cells) is not the indication for the use of topical corticosteroids. –– Prolonged use of topical corticosteroids may be associated with a number of complications such as punctate keratopathy, blurred vision, increased intraocular pressure, and cataract. Therefore, patients on long-­term topical corticosteroids should be carefully followed up.

8.3

Periocular Corticosteroids

• Periocular corticosteroids preparations include hydrocortisone, dexamethasone, methylprednisolone, and triamcinolone. • Hydrocortisone can be used by subconjunctival or sub-­ tenon injection at a dose of 50–125 mg.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_8

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• Methylpredisolone can be administered by subconjunctival and sub-tenon injection at a dose of 40–80 mg. • Triamcinolone can be administered by subconjunctival and sub-tenon injection at a dose of 20–40 mg. • Dexamethasone can be administered by subconjunctival and sub-tenon injection at a dose of 4–8 mg. • Subconjunctival injection of corticosteroids is mainly used in the patients with very severe anterior chamber inflammation such as aqueous fibrous exudation and hypopyon or those with frank corneal lesions. • Sub-tenon injection is usually used in patients with noninfectious intermediate, posterior and generalized uveitis, especially those with macular edema. • Subconjunctival application may be repeated. However, the side effects caused by this treatment should be always kept in mind. • Multiple sub-tenon applications may be needed in some patients. • The side effects of periocular application of corticosteroids include elevated intraocular pressure, cataract, proptosis, atrophy and fibrosis of extraocular muscles and periorbital tissues, hemorrhage, optic never injury, and globe penetration.

8.4

Intravitreal Corticosteroids

• Intravitreal corticosteroid preparations mainly include triamcinolone acetonide, Ozurdex, Retisert and Yutiq [3]. • Triamcinolone acetonide –– It is intravitreally given at a dose of 2–4  mg for the patients with refractory posterior uveitis, intermediate uveitis, and panuveitis, especially for those with both persistent posterior segment inflammation and cystoid macular edema (CME). –– The effectiveness of triamcinolone acetonide usually lasts for 3 weeks. –– Repeated intravitreal injections may be necessary for certain patients. –– Side effects of intravitreal injection of triamcinolone acetonide include increased intraocular pressure, cataract, and sterile or infectious endophthalmitis. • Ozurdex –– It is a sustained-release biodegradable intravitreal implant containing 0.7 mg dexamethasone. –– It is placed into the vitreous body using a 22-gauge applicator. –– It is mainly used for the patients with both persistent posterior segment inflammation and CME. –– The effectiveness of Ozurdex usually lasts for 3–5 months after intravitreal injection. –– The use of Ozurdex in the treatment of uveitis is expected to be approved by the Chinese Food and Drug Administration.

• Retisert –– It is a sustained-release non-biodegradable intravitreal implant containing 0.59 mg fluocinolone acetonide. –– Fluocinolone acetonide is released for approximately 30 months after intravitreal implantation. –– More studies are needed to address the effectiveness and side effects of intravitreal implantation of Retisert in the treatment of persistent posterior segment inflammation in Chinese patients. • Yutiq –– It is a new intravitreal implant containing 0.18 mg fluocinolone acetonide. –– Fluocinolone is slowly released for 36 months and it is very useful for the patients with refractory posterior uveitis.

8.5

Systemic Corticosteroids

• Systemic corticosteroids are usually used for the patients with noninfectious bilateral posterior uveitis, intermediate uveitis (IU), and panuveitis. Unilateral involvement, very severe anterior uveitis and chronic or reluctant anterior uveitis may also necessitate systemic corticosteroids. • Oral administration is usually planned and the doses used vary considerably with the uveitis entities and the doctors. • The author usually uses 0.5–1.0 mg/kg/day as an initial dose and a gradual tapering strategy in the treatment of the patients with various uveitis entities. • A high initial dose (1–2 mg/kg/day) of corticosteroids is also recommended in the literature. • Pulsed intravenous corticosteroid therapy is suggested for the sight-threatening uveitis entities by a number of doctors. The effectiveness is indeed observed in this treatment. However, it is not clear whether pulsed intravenous corticosteroid therapy is superior to oral administration. Based on the author’s experience, it is not necessary to use pulsed intravenous corticosteroid for the patients with uveitis in the context of the long-term effectiveness and visual prognosis. • It is very important to use a pertinent dose and enough long course of therapy for a complete control of the intraocular inflammation. The author usually uses 15–20 mg/ kg as a maintenance dose in the treatment of chronic or highly recurrent uveitis entities such as Behcet’s disease (BD), Vogt–Koyanagi–Harada (VKH) disease [4], sympathetic ophthalmia, and refractory retinal vasculitis. • Systemic corticosteroids are used often in combination with immunosuppressive agents such as cyclosporine, cyclophosphamide, chlorambucil, azathioprine, metho­ trexate, and mycophenolate mofetil for the patients with chronic or recurrent uveitis [5, 6]. • Systemic corticosteroids may cause side effects in various systems [1–3].

8.5 Systemic Corticosteroids

a

Fig. 8.1  Moon-like face (a) and persistent intraocular inflammation were noted in a female VKH patient treated only with a high dose of systemic corticosteroids for one year in other hospitals. Intraocular

151

b

inflammation is controlled and moon-­like face disappeared following a more than one-year treatment with cyclosporine, chlorambucil, and low dose of corticosteroids (b)

Fig. 8.2  Moon-like face observed in a uveitis patient on a long-term treatment with high dose of systemic corticosteroids in other hospitals

–– Endocrine side effects: Cushing’s syndrome (Figs. 8.1 and 8.2), growth failure or retardation (Fig. 8.3), and menstrual disturbance. –– Neuropsychiatric side effects: psychosis, insomnia, mood swings, depression, and pseudotumor cerebri. –– Gastrointestinal side effects: stomach discomfort, peptic ulcer, gastric hemorrhage, gastric or intestinal perforation. –– Musculoskeletal side effects: osteoporosis and aseptic femoral head necrosis. –– Cardiovascular side effects: hypertension, sodium and fluid retention.

Fig. 8.3  A 14-year-old uveitis patient treated with systemic corticosteroids for 5 years (left) in other hospitals shows a height similar to a 7-year-old child (right)

–– Metabolic side effects: secondary diabetes mellitus, centripetal obesity, hyperlipidemia, kaliopenia, hyperosmotic, hyperglycemic or nonketotic coma. –– Dermatologic side effects: subcutaneous tissue atrophy, acne-like skin lesion (Fig. 8.4), cutaneous striae (Fig. 8.5), and secondary herpes zoster (Fig. 8.6).

152

Fig. 8.4  Acne-like skin lesions caused by prolonged systemic use of corticosteroids in patients with uveitis

8 Corticosteroids

8.5 Systemic Corticosteroids

Fig. 8.5  Cutaneous striae caused by long-term use of systemic corticosteroids observed in patients with uveitis

153

154

8 Corticosteroids

These side effects include cataract, increased intraocular pressure or secondary glaucoma, mydriasis, ptosis and impaired corneal wound healing, and recurrence of viral keratitis.

References

Fig. 8.6  Herpes zoster occurred in a uveitis patient who has used systemic corticosteroids for a long time

–– Other side effects: secondary herpes virus infection, secondary fungal infection, and delayed tissue healing. –– Ocular side effects may also occur in the patients on systemic corticosteroids although they are usually associated with topical and regional corticosteroids.

1. Vitale AT, Shulman JP, Foster CS.  Corticosteroids. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 194–214. 2. Jones N.  Anti-inflammatory and immunosuppressive treatment. Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 81–102. 3. Agarwal M, Zierhut M. Corticosteroids. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 273–84. 4. Yang P, Ye Z, Du L, et al. Novel treatment regimen of Vogt-Koyanagi-­ Harada disease with a reduced dose of corticosteroids combined with immunosuppressive agents. Curr Eye Res. 2018;43(2):254–61. 5. Du L, Kijlstra A, Yang P.  Vogt-Koyanagi-Harada disease: novel insights into pathophysiology, diagnosis and treatment. Prog Retin Eye Res. 2016;52:84–111. 6. Liu X, Yang P, Lin X, et  al. Inhibitory effect of Cyclosporin A and corticosteroids on the production of IFN-gamma and IL-17 by T cells in Vogt-Koyanagi-Harada syndrome. Clin Immunol. 2009;131(2):333–42.

9

Steroid-sparing Immunosuppressive Agents

Contents

9.1

9.1  Overview

 155

9.2  Cyclophosphamide

 155

9.3  Chlorambucil

 156

9.4  Cyclosporine A (CsA)

 156

9.5  FK506

 158

9.6  Methotrexate

 158

9.7  Azathioprine

 159

9.8  Mycophenolate Mofetil

 159

9.9  Biological Agents

 160

References

 160

Overview

• Steroid-sparing immunosuppressive agents are generally classified into alkylating agents, antimetabolites, antibiotics, and biological agents. • These immunosuppressive agents exert their effects through the inhibition of immune response. • As immunosuppressive agents are usually associated with overt or even severe side effects, much attention should be paid to the monitoring of these events during a long-term treatment.

9.2

Cyclophosphamide

• Cyclophosphamide is a member of the nitrogen mustard family of alkylating agents. • It exerts its role through alkylating deoxyribonucleic acid (DNA) base pairs in proliferating cells. • It is an effective immunosuppressive agent in the treatment of immunologically driven diseases including noninfectious uveitis.

• It has been used in the treatment of the following uveitis entities [1–3]. –– Uveitis or scleritis associated with granulomatosis with polyangiitis (Wegener’s granulomatosis) –– Noninfectious necrotizing scleritis –– Refractory posterior, intermediate, and generalized uveitis –– Sympathetic ophthalmia –– Vogt–Koyanagi–Harada (VKH) disease unresponsive to systemic corticosteroids and cyclosporine (CsA) –– Behcet’s disease (BD) –– Uveitis associated with relapsing polychondritis (RP) –– Polyarteritis nodosa –– Peripheral ulcerative keratitis –– Uveitis associated with juvenile idiopathic arthritis (JIA) –– Serpiginous choroiditis –– Other noninfectious uveitis unresponsive to corticosteroids • Cyclophosphamide is usually used by oral administration in the morning at an initial dose of 1–2 mg/kg/day. Large amounts of water should be consumed by the patients to

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decrease the risk to the development of hemorrhagic cyclitis. Intravenous administration of cyclophosphamide has been used in the patients with devastating and sight-­ threatening inflammatory diseases such as necrotizing scleritis, granulomatosis with polyangiitis, polyarteritis nodosa, and scleritis associated with relapsing polychondritis or systemic lupus erythematosus (SLE). From the author’s experience, most of these inflammatory conditions can be controlled by oral administration of corticosteroids in combination with other immunosuppressive agents including cyclophosphamide. Side effects are common during the treatment of cyclophosphamide –– Side effects commonly encountered include myelosuppression, alopecia, sterile hemorrhagic cystitis, irregular menstruation, oligospermia, or even aspermia and, if used at a high dose and for a longer time, secondary malignancies. –– Other uncommon side effects include impaired liver and kidney function, irreversible pulmonary fibrosis and weakness. –– It may also be associated with ocular side effects including blurred vision and elevated intraocular pressure. As cyclophosphamide is a teratogen, contraception is absolutely mandatory during the treatment. Application of cyclophosphamide should be careful in view of the potential influence on the fertility. Regular monitoring of relevant side effects is definitely necessary during the treatment.

9.3

Chlorambucil

• Chlorambucil is another member of nitrogen mustard derivatives. • Chlorambucil and cyclophosphamide are similar in the mechanism of action. • The indications of chlorambucil are also similar to those listed in cyclophosphamide [1, 2, 4]. However, it seems to be superior in the treatment of BD as well as cystoid macular edema (CME) associated with refractory intermediate, posterior, and generalized uveitis. • It exerts its role slowly but seems to have longer effects on uveitis as compared to cyclophosphamide. • A number of therapeutic regimens have been recommended by different investigators. –– Initial dose of 2 mg/day with gradually increased dose and finally reaching a maximal dose of 10–12 mg/day. –– Initial dose of 0.15 mg/kg/day with subsequent adjustment according to the therapeutic effect. –– The author usually commences a treatment with a dose of 0.1 mg/kg/day, and then gradually tapers the dose if a favorable effect is clinically observed.

• Side effects are, by and large, similar to those observed in cyclophosphamide. However, there are some differences in side effects between them. –– Chlorambucil is often associated with minor or moderate myelosuppression. However, severe leukopenia may occasionally develop in the patients with a high dose (6–10 mg/day). Additionally, the myelosuppression may last for months even after the termination of this drug. –– Chlorambucil usually causes more severe gonadal dysfunction than cyclophosphamide. In the author’s experience, treatment with a dose of 0.1 mg/kg/day for 3–5 months usually leads to oligospermia or even azoospermia in males and irregular menstruation or amenorrhea in females. Treatment with chlorambucil should be extremely careful in the patients with the willingness to have a baby in the future. • Careful monitoring of side effects is mandatory during the treatment with this drug.

9.4

Cyclosporine A (CsA)

• CsA is a fungal metabolite and poses suppressive effects preferentially on T cells. • CsA exerts its role through suppressing intracellular calcineurin. • CsA has been shown to inhibit the production of IL-2, IL-17 and interferon-γ, replication, and recruitment of CD4+ cells and the function of dendritic cells. • Indications for ocular diseases [5–7] –– Noninfectious intermediate, posterior, and generalized uveitis. –– Behcet’s disease –– VKH disease –– Sympathetic ophthalmia –– Juvenile idiopathic retinal vasculitis –– Uveitis associated with JIA –– Noninfectious scleritis alone or associated with systemic diseases –– Granulomatosis with polyangiitis (Wegener’s granulomatosis) –– Uveitis associated with relapsing polychondritis –– Ocular sarcoidosis –– Birdshot chorioretinopathy (BCR) –– Uveitis associated with multiple sclerosis –– Blau syndrome • In the following conditions, CsA should not be used, or if can, are used with particular care to avoid further worsening the preexisting diseases or side effects. –– Hypertension unresponsive to conventional treatment –– Hepatic disease and impaired function –– Impaired renal function –– Pregnancy

9.4 Cyclosporine A (CsA)

• Dosage and route of administration –– The initial dosage recommended by a number of authors is 5 mg/kg/day. –– The author usually treats the patients at an initial dose of 3–5  mg/kg/day, normally divided twice daily for 3–6 months and then tapers the dose according to its effects on inflammation. The maintenance dose of CsA is 2  mg/kg/day and used for some period of time depending on the forms of uveitis and its • effectiveness. • CsA is used usually in combination with systemic corti- • costeroids and/or other immunosuppressive agents. The commonly recommended combinations are listed below • –– CsA + corticosteroids –– CsA + methotrexate –– CsA + azathioprine –– CsA + colchicine –– CsA + mycophenolate mofetil –– CsA + corticosteroid+other immunosuppressive agents as listed above • CsA in combination with chlorambucil or cyclophosphamide is also used by the author with general beneficial results although this combination is not recommended by a few investigators. • It should be kept in mind that the drugs used in combination are usually those with different mechanisms of action and side effects. Therefore, a synergistic effect can be achieved without increasing side effects or toxicity through the combination of medicines. • Concomitant use of other medicines –– Concomitant use of other medicines may lead to synergistic toxicity or predispose the patients to high risk to the development of certain side effects. –– Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), amphotericin B, ketoconazole, aminoglycosides, melphalan, vancomycin, ranitidine, cimetidine, ciprofloxacin, and trimethoprim-­ sulfamethoxazole may potentially have synergistic nephrotoxicity. –– Concomitant use of itraconazole, ketoconazole, fluconazole, diltiazem, verapamil, bromocriptine, danazol,

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metoclopramide, and erythromycin may enhance CsA effects through inhibiting liver cytochrome p450 microsomal enzyme system. –– Concomitant use of phenytoin, rifampin, phenobarbital, and carbamazepine may induce cytochrome p450 and therefore reduce CsA effects. –– Methylprednisolone may also inhibit cytochrome p450 and therefore enhance CsA effects. Grapefruit and starfruit may raise blood levels of CsA and therefore should not be used in patients taking CsA. Red wine should not be used in patients on CsA because it can reduce the blood level of this drug. Side effects –– The side effects are always positively associated with the dose of CsA used in the treatment. –– Nephrotoxicity, hypertension, hepatotoxicity, and neurological side effects are common during therapy with CsA. –– Nephrotoxicity is usually associated with high-dose of CsA and includes increased serum creatinine, blood urea nitrogen, and decreased creatinine clearance. These changes are usually reversible through reduction of dose or termination of CsA. However, interstitial fibrosis and renal tubular atrophy are occasionally noted in patients on CsA. –– Hypertension is common and occurs in a dose-­ dependent manner. Combination with systemic corticosteroids usually has a synergistic effect on the development of hypertension. –– Hepatotoxicity manifesting as increased liver enzymes is also common. Preexisting of hepatitis may predispose the patients on CsA to the development of hepatotoxicity. –– Hand tremor is a common side effect of patients on CsA. –– Central neurotoxicity including confusion, dystonia, aphasia, catatonia, coma, and other psychiatric disorders may develop during the treatment. –– Other side effects include hirsutism (Fig. 9.1), gingivitis (Fig.  9.2), pigmentation of the skin (Fig.  9.3), fatigue, paresthesia of extremities, nausea, dyspepsia, acute

Fig. 9.1  Hirsutism caused by a prolonged treatment with CsA observed in uveitis patients

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9  Steroid-sparing Immunosuppressive Agents

Fig. 9.2  Gingival hyperplasia caused by a prolonged treatment with CsA observed in uveitis patients

Fig. 9.3  Pigmentation caused by a prolonged treatment with CsA observed in uveitis patients

arrhythmias, normochromic normocytic anemia, increased bilirubin level, elevated total serum cholesterol level, and increased risk of opportunistic infection. –– As numerous side effects may occur during the treatment with cyclosporin, monitoring is extremely important especially in the patients with the underlying diseases or abnormalities which could predispose the patients at significant risk to the development of some adverse reactions.

9.5

FK506

• Tacrolimus is a macrolide antibiotic. • It is similar to CsA in a wide spectrum of activity and action mechanisms. • It has been used in the prevention of immunological rejection after organ transplantation and corneal transplantation.

• It is also used in the treatment of psoriasis and nephrotic syndrome. • Few studies have reported the application of tacrolimus in noninfectious uveitis. However, the efficiency and side effects in the treatment of uveitis are expected to be fundamentally addressed in the future.

9.6

Methotrexate

• Methotrexate is one of antimetabolite immunosuppressive agents and can inhibit dihydrofolate reductase and, in turn, purine synthesis. • Methotrexate is widely used in the treatment of uveitis with or without systemic immune-driven disease due to its effectiveness, safety, low cost, and the convenience in application. • Indications [8, 9]

9.8 Mycophenolate Mofetil

–– –– –– –– –– –– –– –– ––

Uveitis associated with JIA Behcet’s disease VKH disease Sympathetic ophthalmia Idiopathic intermediate uveitis Idiopathic posterior uveitis Primary intraocular lymphoma Primary central nervous system lymphoma Scleritis associated with reactive arthritis or rheumatoid arthritis –– Uveitis associated with seronegative spondyloarthropathies –– Persistent CME associated with posterior segment inflammation • Usage and dosage –– Methotrexate can be used by oral administration, intravitreal, intravenous, or subcutaneous injection. –– Oral administration is usually used in the treatment of uveitis and scleritis. –– Intravitreal injection in a dose of 400  μg/0.1  mL is employed in the treatment of intraocular lymphoma or macular edema associated with uveitis. –– Oral administration usually starts at 7.5–15  mg as a single dose weekly. The dose is titrated thereafter according to the tolerability and efficiency. –– Folic acid should be concurrently used to decrease the rate of side effect. –– In the author’s experience, application of methotrexate alone is usually not sufficient to inhibit ocular inflammation and therefore a combination with systemic corticosteroids or other immunosuppressive agent is recommended. The suggested drugs for the combination are CsA, mycophenolate mofetil, infliximab, and adalimumab. • Side effects –– Liver toxicity is common and usually manifests as an increased level of enzymes. Cirrhosis of the liver may occur occasionally. –– Gastrointestinal disorders including nausea, vomiting, diarrhea, and gastritis may be noted. –– Fatigue and malaise are common but may resolve with reduction of the dosage. –– Other side effects including hair loss, myelosuppression, and idiosyncratic interstitial pneumonitis may occasionally occur in the patients on methotrexate. –– Paramenia may occur in the patients following long-­ term treatment. • As methotrexate may induce very severe side effects, attention should be paid to the matters as listed below. –– The patients with impaired liver function or those who consume large amounts of alcohol are not suitable for methotrexate therapy. –– Cyclosporin also poses liver toxicity and therefore the combination with methotrexate should be particularly

159

careful especially in the patients on long-term treatment. –– As methotrexate may potentially lead to damage to the fetus, pregnancy should be avoided during the treatment. –– The liver function should be regularly monitored during treatment with methotrexate.

9.7

Azathioprine

• Azathioprine is a synthetic thiopurine and metabolized in the liver. • The active metabolites in the liver including 6-­mercaptopurine, 6-thioiosinic acid, and 6-thioguanine are able to interfere with deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein synthesis, and therefore inhibit the immune response. • Indications [9, 10] –– Noninfectious posterior, intermediate, and generalized uveitis –– Scleritis associated with relapsing polychondritis –– Uveitis associated with JIA –– Uveitis associated with seronegative spondylopathy –– Behcet’s disease –– VKH disease –– Sympathetic ophthalmia –– Multifocal choroiditis with panuveitis –– Ocular sarcoidosis • Dosage and route of administration –– The patients are usually treated with a dose of 1–2 mg/ kg/day at a single daily dose or divided twice daily. –– If allopurinol is concurrently used, the dose of azathioprine should be decreased. –– It usually takes 3–6 weeks to work. • Side effects –– Gastrointestinal disturbance including nausea, vomiting, anorexia, and diarrhea are common side effects. –– Bone marrow suppression may occur and manifests as leukopenia, thrombocytopenia, and anemia. In a rare condition, severe myelosuppression may develop within a short period of time after application of this drug. Therefore, regular hematologic monitoring is necessary. –– Impaired liver function, manifesting as an increased level of enzymes, may be occasionally observed. Vigilant monitoring of side effects is necessary during the treatment with this drug.

9.8

Mycophenolate Mofetil

• Mycophenolate mofetil (CellCept) is an immunosuppressive agent and poses selective inhibition effect on T and B cells through interference with purine synthesis.

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• Indications [4, 9, 10] –– Mycophenolate mofetil has been used for the prevention of organ transplant rejection. –– It has also been employed in the treatment of various noninfectious uveitis in an “off-label” fashion. Noninfectious posterior, intermediate, and generalized uveitis Behcet’s disease Sympathetic ophthalmia and VKH disease unresponsive to conventional therapy Noninfectious scleritis • Dosage and route of administration –– Mycophenolate mofetil is used at an initial dose of 0.5 g, twice daily for adults. –– Dosage of as high as 1 g twice daily may be given according to its effects and tolerance of the patients. • Side effects –– In general, mycophenolate mofetil is a potent immunosuppressive agent with less and mild side effects. –– Gastrointestinal discomforts, such as vomiting, nausea, and diarrhea, are common side effects during treatment with mycophenolate mofetil. –– Nephrotoxicity. –– Hepatotoxicity. –– Leukopenia or leukocytosis. –– Increased incidence of opportunistic infection. –– Anemia. –– Other side effects include headache, insomnia, fatigue, skin rash, hair loss, and rarely lymphoma.

9.9

Biological Agents

• Biologic agents exert their effects through targeting specific molecules involved in the immune response or inflammatory process. • They have been successfully used in the treatment of a number of refractory systemic diseases including ankylosing spondylitis (AS), rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD), JIA, and BD [9, 11]. • An increasing use of these agents in refractory noninfectious uveitis has greatly improved their visual prognosis. • Infliximab is a mouse–human chimeric monoclonal antibody and exerts its effects through interfering with the binding between tumor necrosis factor-alpha (TNF-α) and its receptors and in turn inhibits the production of IL-1, IL-6, IL-2, IFN-γ, and antibodies. –– It has been used in the treatment of BD, refractory sympathetic ophthalmia, and vision-threatening noninfectious uveitis which do not respond to conventional treatment or do not tolerate the side effects during treatment [9, 11].

–– Tuberculosis (TB) should be excluded before treatment as infliximab is able to increase the risk of reactivation of this disease. –– It is administrated as an intravenous infusion usually at a dose of 5 mg/kg with an interval of 1–2 months. –– The side effects include reactivation of TB, upper respiratory infection, cough, fatigue, dizziness, disgust, skin itch, headache, stomachache, backache, and urinary tract infection. • Adalimumab is a humanized monoclonal antibody against TNF-α and exerts its effects through blocking TNF-α receptors [9, 11] –– Indications of Adalimumab are similar to those listed in Infliximab. –– It should be always kept in mind that exclusion of TB is absolutely necessary before initiation of treatment with this agent. –– It is subcutaneously given at a dose of 40  mg once every 2 weeks. –– It has been approved in China to be used for patients with refractory posterior segment inflammation. –– The side effects include reactivation of TB, headache, rash, upper respiratory infection, and elevated creatine phosphokinase. • IFN-α is involved in innate immune response against viruses. –– It has been used for refractory BD with a beneficial result in most patients [12, 13] –– Various therapeutic regimens have been developed. In our practice, subcutaneous injection of 3 million units of IFNα-2a is given daily for the first three months. The frequency of injections is gradually decreased if there is no recurrence of uveitis. –– The side effects observed during treatment includes flulike illness, fatigue, gastrointestinal discomfort, lethargy, hair loss, arthralgia, depression, insomnia elevated serum liver enzymes, skin itch, chest distress, and leukopenia.

References 1. Du L, Kijlstra A, Yang P.  Vogt-Koyanagi-Harada disease: novel insights into pathophysiology, diagnosis and treatment. Prog Retin Eye Res. 2016;52:84–111. 2. Yang P, Ye Z, Du L, et  al. Novel treatment regimen of Vogt-­ Koyanagi-­ Harada disease with a reduced dose of corticosteroids combined with immunosuppressive agents. Curr Eye Res. 2018;43(2):254–61. 3. Akpek EK, Jabs DA, Tessler HH, et  al. Successful treatment of serpiginous choroiditis with alkylating agents. Ophthalmology. 2002;109(8):1506–13.

References 4. Nussenblatt RB, Whitcup SM, Palestine AG.  Philosophy, goals, and approaches to medical therapy. Uveitis fundamentals and clinical practice. 2nd ed. St. Louis: Mosby-Year Book, Inc.; 1996. p. 97–134. 5. Baarsma GS, Caspers L, Cyclosporin A. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 331–8. 6. Chi W, Yang P, Zhu X, et  al. Production of interleukin-17  in Behcet’s disease is inhibited by cyclosporin A.  Mol Vis. 2010;16(96–98):880–6. 7. Liu X, Yang P, Lin X, et  al. Inhibitory effect of Cyclosporin A and corticosteroids on the production of IFN-gamma and IL-17 by T cells in Vogt-Koyanagi-Harada syndrome. Clin Immunol. 2009;131(2):333–42. 8. Suhler EB, Biggee K.  Methotrexate. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 355–61.

161 9. Foster CS, Vitale AT. Immunosuppressive chemotherapy. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 238–94. 10. Jones N.  Anti-inflammatory and immunosuppressive treatment. Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 81–102. 11. Accorinti M, Zierhut M. TNF-alpha blocking agents. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 293–307. 12. Yang P, Huang G, Du L, et  al. Long-term efficacy and safety of interferon alpha-2a in the treatment of Chinese patients with Behcet’s uveitis not responding to conventional therapy. Ocul Immunol Inflamm. 2019;27(1):7–14. 13. Stübiger N, Zierhut M. Interferon alpha. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 345–53.

Non-steroidal Anti-inflammatory Drugs

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Contents 10.1  Overview

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10.2  Topical NSAIDs

 163

10.3  Systemic NSAIDs

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References

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10.1 Overview

Postoperative inflammation is mainly caused by prostaglandin production. • Oral non-steroidal anti-inflammatory drugs (NSAIDs) Topical NSAIDs are effective in controlling this include salicylates, fenamates, indoles, phenyl acetic inflammatory reaction following the surgery [7, 8]. acids, phenyl alkanoic acids, pyrazolone, para-­ –– Cystoid macular edema (CME) secondary to a cataract aminophenols, and cycloxygenase-2 inhibitors. operation. • NSAIDs exert their roles mainly through inhibition of CME has also been considered as a result of prostacyclooxygenase and the prostaglandin synthesis [1, 2]. glandin production. • NSAIDs can be used topically or systemically. Topical and systemic NSAIDs have been used in the prophylaxis and treatment of CME occurring after surgery with a beneficial result. 10.2 Topical NSAIDs • Side effects –– Topical administrations of NSAIDs may cause con• Topical NSAIDs are available as flurbiprofen, diclofenac, junctival hyperemia, itching, stinging, and burning. ketorolac, indomethacin, and bromfenac and nepafenac. –– Keratitis and even corneal melting and perforation • Indications of topical NSAIDs [3–6] occasionally occur following topical NSAIDs. –– Episcleritis. Topical NSAIDs are useful in the treatment of episcleritis. 10.3 Systemic NSAIDs Systemic NSAIDs have also been used for this inflammation. • Indications of systemic NSAIDs [3, 4] –– Scleritis. –– JIA-associated uveitis Topical and systematical NSAIDs have been used for –– Uveitis associated with arthropathy the treatment of scleritis. –– Scleritis Based on the author’s experience, NSAIDs are usually • Side effects insufficient to the controlling of this inflammation. –– Gastrointestinal disturbances include nausea, vomitCombination with systemic corticosteroids, someing, development of gastric and intestinal ulceration. times other immunosuppressive agents, is recom–– Central nervous system side effects may occur as mended in the treatment of scleritis. headache, dizziness, confusion, somnolence, light–– Postoperative anterior chamber inflammation after headedness, fatigue, depression, anxiety, and psychotic cataract and glaucoma surgery. episodes. © Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_10

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–– Side effects in the kidney include impaired kidney function, decreased glomerular filtration, chronic or acute renal failure. –– Hematologic side effects include a prolonged bleeding time, and rarely aplastic anemia and agranulocytosis. –– Hepatic side effects include impaired liver function and hepatitis. –– Other side effects include photosensitivity, exanthema, urticaria, pruritus, fluid retention, edema, and myocardial infarction. • Regular monitoring of these side effects is absolutely necessary during the treatment with these agents.

References 1. Colin J. The role of NSAIDs in the management of postoperative ophthalmic inflammation. Drugs. 2007;67(9):1291–308.

10  Non-steroidal Anti-inflammatory Drugs 2. Flach AJ.  Cyclo-oxygenase inhibitors in ophthalmology. Surv Ophthalmol. 1992;36(4):259–84. 3. Saha S, Graham EM.  Non-steroidal anti-inflammatory drugs. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 285–92. 4. Vitale AT, Al-Dhibi H, Foster CS. Nonsteroidal anti-inflammatory drugs. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 225–37. 5. Kim SJ, Flach AJ, Jampol LM.  Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv Ophthalmol. 2010;55(2):108–33. 6. Solomon KD, Donnenfeld ED, Raizman M, et al. Safety and efficacy of ketorolac tromethamine 0.4% ophthalmic solution in post-­ photorefractive keratectomy patients. J Cataract Refract Surg. 2004;30(8):1653–60. 7. Hu K, Lei B, Kijlstra A, et al. Male sex, erythema nodosum, and electroretinography as predictors of visual prognosis after cataract surgery in patients with Behçet disease. J Cataract Refract Surg. 2012;38(8):1382–8. 8. Ji Y, Hu K, Li C, et al. Outcome and prognostic factors of phacoemulsification cataract surgery in Vogt-Koyanagi-Harada uveitis. Am J Ophthalmol. 2018;196:121–8.

Complications and Their Management

11

Contents 11.1  Overview

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11.2  Cataract

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11.3  Ocular Hypertension and Glaucoma

 166

11.4  Macular Edema

 167

References

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11.1 Overview • Uveitis may cause a number of complications such as complicated cataract, elevated intraocular pressure or secondary glaucoma, macular edema, retinal or choroidal neovascularization (CNV). • Complications vary greatly with the locations, severity, duration, and entities of uveitis. • It is very important to adequately deal with these complications as they often lead to severe and even persistent visual impairment.

• •

•

11.2 Cataract • In general, cataract is the most common complication in uveitis patients [1–3]. • It is more commonly seen in the following uveitis entities: –– Uveitis associated with juvenile idiopathic arthritis –– Chronic anterior uveitis, especially in childhood –– Fuchs syndrome –– Intermediate uveitis –– Vogt–Koyanagi–Harada (VKH) disease with chronic or recurrent anterior segment inflammation –– Behcet’s disease (BD) with recurrent anterior segment inflammation

•

–– Chronic anterior uveitis-associated sarcoidosis –– Anterior uveitis associated with psoriasis It mainly presents as posterior subcapsular lenticular opacities. It is mainly caused by the inflammation itself. However, long-term use of topical corticosteroids may also contribute to the formation of cataract. Indications of cataract surgery –– A cataract significantly affecting the patient’s visual acuity but with a potentially good prospect for visual improvement. –– A cataract already precluding fundus details in a uveitis patient with possible fundus alterations which necessitate adequate treatment. –– Uveitis caused by lens cortical materials. Timing of cataract surgery –– Cataract surgery can be performed at any time when patients want to improve their visual acuity [4]. Cataract surgery performed at any time is only used for patients with Fuchs syndrome. The presence of a few of aqueous cells and the keratic precipitates is not a contraindication of the cataract surgery in these patients. The patients with Fuchs syndrome usually have a good visual prognosis if there are no fundus changes.

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–– Cataract surgery could be performed in the interval immunosuppressive agents should be instituted for the between two attacks in the patients with acute anterior patients with severe anterior chamber reaction. uveitis. –– Cataract surgery and intraocular lens implantation The interval between two attacks of uveitis can be Surgical procedure for cataract has been greatly roughly estimated in acute anterior uveitis patients improved during the past decades. based on their previous episodes. Most uveitis patients tolerate well phacoemulsificaFrom the author’s experience, it is difficult to pretion and intraocular lens implantation and achieve a vent the recurrence of certain forms of uveitis, such good visual improvement if the intraocular inflamas acute anterior uveitis. Therefore, it is rational to mation is completely controlled. do cataract surgery during the interval between the –– Complications of cataract surgery include elevated two attacks. intraocular pressure, iris atrophy, posterior capsule –– Cataract surgery can be performed after complete conopacification, posterior synechiae, cystoid macular trolling of intraocular inflammation, under the conedema (CME), hyphema, and ocular hypotony. comitant use of corticosteroids and/or other immunosuppressive agents. It is suitable for the cataract seen in the following forms of uveitis [5, 6] 11.3 Ocular Hypertension and Glaucoma VKH disease Idiopathic uveitis in the elderly • Ocular hypertension or glaucoma may occur in uveitis Idiopathic granulomatous uveitis patients [7, 8]. Intermediate uveitis • The prevalence of ocular hypertension or glaucoma in Behcet’s disease uveitis patients varies considerably with the reports rangUveitis associated with sarcoidosis ing from 10 to 42%. Herpesvirus-associated anterior uveitis • Ocular hypertension or glaucoma can develop from a –– Cataract surgery should be performed after inflammavariety of mechanisms as listed below: tion quiescence for a long period of time. –– Inflammation of trabecular meshwork as seen in It is especially suitable for the uveitis patients with Posner–Schlossman syndrome and herpetic anterior juvenile idiopathic arthritis. uveitis may lead to trabecular dysfunction and, in turn, It is also suitable for a cataract in children with result in elevated intraocular pressure. chronic and recurrent uveitis especially those with –– Cellular debris and pigment deposited in the trabecular complete posterior synechiae. meshwork in uveitis may decrease the outflow and Cataract in sympathetic ophthalmia should also be therefore elevate the intraocular pressure. performed with particular caution due to the fact –– Pupillary block arising from 360° of posterior synthat the injured eye is often severely damaged. echiae may dramatically cause acute elevated intraoc• Perioperative management ular pressure in association with a forward ballooning –– Topical corticosteroids and non-steroid anti-­ of the iris. inflammatory agents are usually needed several days –– Angle closure secondary to widespread peripheral before and one to two weeks after cataract surgery. anterior synechia may cause permanent elevation of –– Topical corticosteroids and non-steroid anti-­ intraocular pressure. inflammatory agents combined with low dose of sys–– Ocular hypertension may also occur as a result of fortemic corticosteroids (normally 20  mg/day) for 2 warding movement of the iris lens diaphragm and neoweeks during perioperative time may be needed for the vascularization [9]. patients with a history of acute anterior uveitis. –– Long-term use of topical corticosteroids and less com–– Perioperative use of topical corticosteroids, non-­steroid monly other methods of administration of these drugs anti-inflammatory agents, mydriatic and cycloplegic may induce elevated intraocular pressure through agents in combination with systemic corticosteroids, reducing aqueous outflow and altering the expression and/or other immunosuppressive agents is recomof myocilin, a molecule with potency to influence tramended for the patients with other forms of uveitis as becular meshwork function. listed above. • The following forms of uveitis are prone to causing ele–– Much attention should be paid to the reformation of vated intraocular pressure: posterior synechiae and the inflammation in the ante–– Posner–Schlossman syndrome rior chamber in children either with juvenile idiopathic –– Herpes simplex virus-associated anterior uveitis arthritis or with idiopathic chronic or recurrent uveitis. –– Herpes zoster virus-associated anterior uveitis A relatively high dose of corticosteroids and other –– Fuchs syndrome

11.4  Macular Edema

–– Granulomatous anterior uveitis –– Diffuse anterior scleritis –– Uveitis associated with juvenile idiopathic arthritis –– Idiopathic chronic anterior uveitis in children –– Acute retinal necrosis syndrome • Therapy –– Therapy of ocular hypertension or uveitis glaucoma should be based on the underlying mechanisms, the degree of elevated intraocular pressure, and the activity of the inflammation. –– In general, anti-glaucoma medications for instance β-blockers (Timolol) and carbonic anhydrase inhibitors should be immediately instituted if elevated intraocular pressure is observed. Abruptly elevated intraocular pressure is frequently observed in patients with complete pupillary block and associated with an overt anterior chamber reaction and even iris neovascularization. Intensive mydriatic and cycloplegic agents combined with topical corticosteroids should be used in an attempt to release posterior synechia, reestablish aqueous flow and inhibit the inflammation in patients with recently formed posterior synechia. A surgical iridectomy should be performed as soon as possible under concomitant use of carbonic anhydrase inhibitors and 20% mannitol. A severe anterior chamber reaction often resolves following the reestablishment of aqueous flow after iridectomy. Laser iridotomy may also be used but the success rate is much lower as compared to surgical iridectomy. Persistently elevated intraocular pressure unresponsive to medication may necessitate relevant surgical management such as trabeculectomy, cyclophotocoagulation, and aqueous shunts in the context of anti-inflammation therapy. –– Elevated intraocular pressure could be readily controlled by medical therapy in most patients with Fuchs syndrome. Surgical intervention is used only in a few of patients with persistent ocular hypertension. –– Ocular hypertension in Posner–Schlossman syndrome usually develops episodically over a long period of time. Anti-glaucoma medications combined with corticosteroids are needed when there is an elevated intraocular pressure. –– Ocular hypertension usually lasts for a long period of time in patients with herpetic virus-associated anterior uveitis. Prolonged use of anti-glaucoma medications combined with corticosteroids is necessary to control the inflammation and elevated intraocular pressure. Surgical intervention is occasionally needed for these patients with persistently elevated intraocular pressure refractory to medical treatment.

167

–– Elevated intraocular pressure arising from inflammation itself, as seen in anterior scleritis and chronic anterior uveitis, is always normalized following quiescence of the inflammation. Therefore, treatment of the inflammation is very important in the management of this kind of ocular hypertension.

11.4 Macular Edema • Macular edema is a common complication in patients with posterior segment inflammation and a main cause of visual impairment in these patients [10–13]. • Macular edema can be divided into cystoid and diffuse edema. • CME refers to an accumulation of intraretinal fluid in the macular area and is more common than diffuse macular edema in patients with uveitis. • Prevalence of CME in uveitis patients varies considerably with the location and entities of uveitis. Generalized, intermediate and posterior uveitis tend to develop CME, whereas anterior uveitis is less commonly associated with this complication. Sarcoidosis, BD, birdshot chorioretinopathy, and idiopathic retinal vasculitis are frequently associated with CME. • Pathogenesis of CME in uveitis –– Inflammatory mediators including IL-1, IL-2, IL-6, IL-8, tumor necrosis factor alpha, and prostaglandins may lead to an influx of fluid from blood vessels into the retina and cause CME through inducing the breakdown of the blood–retinal barrier. –– VEGF has been reported to be involved in the development of CME-associated uveitis. –– Müller cells may also be implicated in the pathogenesis of CME. –– Vitreous traction is also involved in the development of CME associated with uveitis. • Overt CME could be detectable using fundoscopy. However, in most cases it is diagnosed with imaging techniques. –– Fundus fluorescein angiography (FFA) could determine subtle CME. The characteristic finding of CME in FFA is petaloid-like hyperfluorescence. –– Optical coherence tomography (OCT) imaging provides a noninvasive technique and has been widely used in evaluating the macular abnormalities including CME during recent years. • Treatment –– Non-steroidal anti-inflammatory drugs have been used to treat CME secondary to cataract surgery. –– Corticosteroids are widely used in uveitis patients with CME. Topical corticosteroids are usually not sufficient to treat CME.

168

Periocular injection, for instance, posterior subtenon’s injection, has been widely used for the CME patients with unilateral involvement. Intravitreal injection of triamcinolone (2–4 mg) has been used in the treatment of CME patients with noninfectious uveitis with a beneficial result. It usually results in rapid CME improvement. However, repeated injections are needed in most patients. Multiple injections may be associated with side effects and even with high risk to the development of endophthalmitis. In recent years, an intravitreal implant of dexamethasone is used for the treatment of noninfectious uveitis with a beneficial result. More recently fluocinolone acetonide intravitreal implant (Yutiq) has been shown a long effectiveness in noninfectious posterior uveitis. Systemic corticosteroids may be associated with an improvement and even resolution of CME in patients with uveitis. –– Immunosuppressive agents CME could be resolved in uveitis patients following the treatment of immunosuppressive agents. Immunosuppressive agents commonly used include cyclosporine, chlorambucil, cyclophosphamide, methotrexate, azathioprine, and mycophenolate mofetil. CME in different uveitis patients may respond to different immunosuppressive agents. Intravitreal injection of 400  μg methotrexate has been used by us in the treatment of CME associated with uveitis. Beneficial effects are only observed in certain patients. –– Biologic agents Anti-TNFα agents like adalimumab have been used in the CME patients with refractory uveitis with a beneficial result. Interferon alpha is also used in the treatment of CME associated with chronic uveitis especially with BD.

11  Complications and Their Management

Anti-VEGF agents like Conbercept has been used by us in the treatment of persistent CME associated with uveitis. Primary study shows a beneficial result. Repeated intravitreal injection is usually needed to prevent CME recurrence.

References 1. Androudi S, Dastiridou A.  Cataract. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 419–41. 2. Papaliodis GN. Cataracts. In: Papaliodis GN, editor. Uveitis. Cham: Springer International Publishing AG; 2017. p. 337–41. 3. Yang P, Fang W, Meng Q, et al. Clinical features of chinese patients with Behcet’s disease. Ophthalmology. 2008;115(2):312–8. 4. Yang P, Fang W, Jin H, et al. Clinical features of Chinese patients with Fuchs’ syndrome. Ophthalmology. 2006;113(3):473–80. 5. Ji Y, Hu K, Li C, et al. Outcome and prognostic factors of phacoemulsification cataract surgery in Vogt-Koyanagi-Harada uveitis. Am J Ophthalmol. 2018;196:121–8. 6. Hu K, Hou S, Jiang Z, et al. JAK2 and STAT3 polymorphisms in a han Chinese population with Behcet’s disease. Invest Ophthalmol Vis Sci. 2012;53(1):538–41. 7. Sarodia U, Kulkarni A, Barton K.  Glaucoma. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 455–69. 8. Pasquale LR.  Management of glaucoma. In: Papaliodis GN, editor. Uveitis. Cham: Springer International Publishing AG; 2017. p. 355–60. 9. Yang P, Liu X, Zhou H, et  al. Vogt-Koyanagi-Harada disease presenting as acute angle closure glaucoma at onset. Clin Exp Ophthalmol. 2011;39(7):639–47. 10. Deuter C.  Macular edema. In: Zierhut M, Pavesio C, Ohno S, et  al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 443–54. 11. Qian CX, Sobrin L.  Macular edema. In: Papaliodis GN, edi tor. Uveitis. Cham: Springer International Publishing AG; 2017. p. 343–54. 12. Zierhut M, Deuter C, Vitale AT, et  al. Intermediate uveitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1169–87. 13. Yang P, Ye Z, Xu J, et al. Macular abnormalities in Vogt-Koyanagi-­ Harada disease. Ocul Immunol Inflamm. 2019;27(8):1195–202.

Part IV Specific Uveitis Entities, Scleritis and Episcleritis

Acute Anterior Uveitis

12

Contents 12.1  Definition

 171

12.2  Epidemiology

 171

12.3  Common Entities

 171

12.4  Less Common Entities

 172

12.5  Symptoms

 172

12.6  Signs

 172

12.7  Complications

 181

12.8  Diagnosis

 182

12.9  Differential Diagnosis

 182

12.10  Treatment

 184

12.11  Prognosis

 184

References

 184

12.1 Definition • Acute anterior uveitis (AAU) refers to an inflammation occurring in the iris and ciliary body which lasts for less than three months [1, 2]. • AAU may be present alone or as one component of certain systemic diseases, especially the seronegative spondyloarthropathies [3, 4]. • AAU is usually associated with HLA-B27 antigen, especially in the patients with seronegative spondyloarthropathies [5–7].

12.2 Epidemiology • AAU is more commonly seen in Caucasians, Chinese, Japanese, and Koreans. • AAU frequently occurs in the HLA-B27+ individuals.

• HLA-B27+ AAU patients account for 40–70% of all the AAU cases. • AAU is more common in males than in females. • AAU frequently occurs in adults of 20–50 years old. • More than 50% of the HLA-B27+ AAU patients are found to have systemic diseases, including ankylosing spondylitis, reactive arthritis (Reiter’s syndrome), inflammatory bowel disease, and psoriatic arthritis [5, 6]. • The prevalence of AAU in the patients with ankylosing spondylitis is one-fifth to one-third. • Bilateral involvement is common. However, unilateral attack is usual in clinical practice.

12.3 Common Entities • Idiopathic AAU. • HLA-B27 antigen-associated AAU.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_12

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• Behcet’s disease (BD)-associated AAU (Acute anterior chamber inflammation may be present alone, but is more frequently associated with retinal vasculitis) [8]. • Vogt–Koyanagi–Harada (VKH) patients in anterior uveal involvement stage may show nongranulomatous anterior chamber inflammation [9, 10]. • Ankylosing spondylitis-associated AAU [11, 12].

12.4 Less Common Entities • • • • • • •

Reactive arthritis (Reiter’s syndrome)-associated AAU. Inflammatory bowel disease-associated AAU. Psoriatic arthritis-associated AAU. Acute anterior segment inflammation in sarcoidosis. Acute anterior segment inflammation in tuberculosis. Acute anterior segment inflammation in syphilis. Tubulointerstitial nephritis and uveitis (TINU).

12.5 Symptoms • Sudden onset of redness, eye pain or pain around the eye, and photophobia. • Blurred vision is common.

Fig. 12.1  Mixed congestion observed in AAU patients

12  Acute Anterior Uveitis

• Severely impaired vision may be seen in the patients with intensive fibrous exudates in anterior chamber, reactive optic disc edema or macular edema, and in those with complicated cataract and glaucoma. • Acute anterior segment inflammation may be associated with systemic complaints in the patients with systemic diseases, for instance, low back pain (in ankylosing spondylitis), arthralgia, oral ulcers, and diarrhea.

12.6 Signs • Ciliary injection is common. Ciliary injection accompanied by conjunctival injection (Fig.  12.1) may occur in the patients with severe inflammation. Chemosis is occasionally observed in AAU patients (Fig. 12.2). • Fine or dusty keratic precipitates (Kps) (Fig. 12.3). • Descemet’s folds (Fig.  12.4) may occur in the patients with severe anterior uveitis. • Numerous inflammatory cells (Fig. 12.5) and significant flare (Fig. 12.6) in the anterior chamber are usual in AAU patients. • Floaters (Fig.  12.7) and fibrous exudates may occur in patients with severe anterior segment inflammation.

12.6 Signs

a

173

b

Fig. 12.2  Hypopyon in association with ciliary congestion (a) and chemosis (b) observed in a patient with severe acute anterior uveitis

Fig. 12.3  Dusty KPs observed in AAU patients

Fig. 12.4  Descemet’s folds observed in AAU patients

174

a

12  Acute Anterior Uveitis

b

Fig. 12.5  Aqueous inflammatory cells observed in AAU patients

Fig. 12.6  Significant flare observed in AAU patients

Fig. 12.7  Floaters observed in an AAU patient

• Fibrous exudates frequently occur in the pupil area (Figs.  12.8 and 12.9) and inferior anterior chamber (Fig. 12.10). • Fibrous exudates and hypopyon are very rarely associated with bleeding in the anterior chamber (Figs.  12.11 and 12.12). • Hypopyon occurs as a result of tremendous amount of cells in the anterior chamber (Fig. 12.13). • Hypopyon is usually associated with ciliary congestion. However, in BD patients hypopyon may be present without ciliary injection (cold hypopyon) [8]. • Posterior synechiae may develop and result in irregular pupil as its consequence (Fig. 12.14). • Fresh posterior synechiae can be broken using cycloplegic and mydriatic drugs and deposited pigment or fibrous

12.6 Signs

175

a

c

b

d

e

Fig. 12.8  Fibrous exudates observed in an AAU patient (a, b: photographs; c–e: ultrasound biomicroscopy results)

Fig. 12.9  Fibrous exudates and inflammatory cells detected by UBM in AAU patients

176

Fig. 12.10  Hypopyon in association with fibrous exudates observed in an AAU patient

12  Acute Anterior Uveitis

Fig. 12.11  Fibrous exudates accompanying bleeding in the pupil area observed in an AAU patient

a

b

c

d

Fig. 12.12  Fibrous exudates in association with bleeding and hypopyon observed in an AAU patient (a, b). Topical corticosteroids combined with low dose of systemic corticosteroids for 3 weeks significantly inhibite the inflammatory activity (c, d)

12.6 Signs

Fig. 12.13  Hypopyon in association with ciliary injection observed in AAU patients

177

178

12  Acute Anterior Uveitis

Fig. 12.14  Irregular pupil with various appearances caused by posterior synechiae in AAU patients

exudates may be observed on the surface of the lens (Fig. 12.15). • Permanent fibrous membrane may be left after resolution of AAU (Fig. 12.16). • Complete posterior synechiae (seclusion of pupil) may sometimes occur if cycloplegic and mydriatic drops are not used in time. Iris bombe occurs as a result of

pupil block secondary to seclusion of the pupil (Fig. 12.17). • Complete posterior synechiae is occasionally associated with fibrous membrane in the whole pupil area (occlusion of pupil). • Extensive anterior synechiae, complete posterior synechiae, and shallow or disappeared anterior chamber

12.6 Signs

179

Fig. 12.15  Circular or semicircular deposition of pigment or fibrous exudates on surface of the lens in AAU patients

occasionally occur in AAU patients with recurrent inflammatory episodes (Fig. 12.18). These patients usually have very poor visual prognosis. • The posterior segment involvement –– Inflammatory cells are usually observed in the anterior vitreous body (retrolental space) of the patients with acute iridocyclitis. –– Macular edema and papillitis may occur as a result of acute and severe inflammation in the anterior chamber. These alterations usually resolve following

the disappearance of AAU and are normally underestimated due to the opacity of refracting media in acute inflammatory stage. –– Microvasculitis is disclosed by fundus fluorescein angiography (FFA) in certain AAU patients although there is no visible fundus alteration (Figs. 12.19, 12.20, and 12.21) [6]. –– Serous retinal detachment, retinal pigment epithelium detachment, or both may be occasionally observed in AAU patients (Fig. 12.22).

180

12  Acute Anterior Uveitis

Fig. 12.16  Permanent fibrous membrane observed in AAU patients after inflammation resolves

Fig. 12.17  Posterior synechiae and iris bombe detected by UBM in an AAU patient

Fig. 12.18  Complete posterior synechiae associated with extensive anterior synechiae and cataract observed in an AAU patient

12.7 Complications

181

Fig. 12.19  Microvascular leakages, cystoid macular edema, and staining of the optic disc detected by FFA in AAU patients

12.7 Complications • Cataract is uncommon in AAU patients if appropriate treatment is instituted in time. Recurrent inflammation may result in complicated cataract, which usually displays posterior subcapsular opacity of the lens.

• Alterations of intraocular pressure –– Slightly decreased intraocular pressure is sometimes observed in AAU patients. –– Transient increase of intraocular pressure may be occasionally noted in AAU patients with a large number of exudates in the anterior chamber.

182

12  Acute Anterior Uveitis

a

b

Fig. 12.20  Microvascular leakages are disclosed by FFA in an AAU patient (a). These changes disappear following four-week treatment with a low dose of systemic and topical corticosteroids (b)

–– Very extremely persistent increase of intraocular pressure may occur as a consequence of complete posterior synechiae and extensive peripheral anterior synechiae. –– Persistently increased intraocular pressure may lead to disappearance of anterior chamber and eventually to phthisis bulbi. It may occasionally occur in patients with highly frequent recurrence of inflammation or those with the ciliary body dysfunction due to longstanding intraocular inflammation. –– Band keratopathy is very rarely observed in AAU patients with complete posterior synechiae and disappeared anterior chamber (Fig. 12.23).

12.8 Diagnosis • The diagnosis for AAU is generally based on clinical manifestations and history of previous recurrent episodes. • Searching for systemic diseases associated with AAU is very important in view of the different treatment strategies used for various entities.

• Diagnostic evaluations usually include HLA-B27 typing, erythrocyte sedimentation rate (ESR), and C-reactive proteins (CRP). • In cases with suspected systemic diseases, work-up should be done to define or rule out possible underlying diseases.

12.9 Differential Diagnosis • Seronegative spondyloarthropathies associated AAU –– HLA-B27 typing is useful in the differential diagnosis. –– Pelvic X-ray examination, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) are useful in detecting sacroiliitis. –– Measurement of ESR and CRP. • Ocular sarcoidosis –– Chest radiography may show bilateral hilar lymphadenopathy. –– The serum level of angiotensin converting enzyme is elevated in most patients with sarcoidosis.

12.9 Differential Diagnosis

183

a

b

Fig. 12.21  Staining of the optic disc and retinal vascular leakages are disclosed by FFA in a male AAU patient (a). These changes almost disappear at one month following treatment (b)

Fig. 12.22  Serous retinal detachment in association with retinal pigment epithelium detachment detected by optical coherence tomography (OCT) imaging in an AAU patient

–– Serum lysozyme level may also be elevated. –– Transbronchial biopsy is useful in the diagnosis and differential diagnosis. –– Gallium scan of lungs, lacrimal glands, and parotid glands may aid in the diagnosis of this disease.

• Ocular syphilis –– Typical history and variable clinical manifestations are suggestive of the diagnosis. –– Positive nontreponemal tests including venereal disease research laboratory (VDRL) test and rapid plasmin reagin (RPR) suggest an active disease if false-positive result is excluded. –– The main treponemal tests including fluorescent treponemal antibody (FTA-Abs) and treponema pallidum immobilization (TPI) test are positive for whole life if the individual is infected with treponema pallidum. • Behcet’s disease –– No laboratory test is available in the diagnosis of this disease. –– Its diagnosis is mainly based on the features of uveitis (for instance, hypopyon, highly recurrent episodes with short interval, refractory retinal microvasculitis) and extraocular manifestations (oral ulceration, genital ulceration, and multiform skin lesions).

184

12  Acute Anterior Uveitis

Fig. 12.23  Band keratopathy in association with very shallow anterior chamber observed in a patient with recurrent acute anterior uveitis

• Ocular tuberculosis (TB) –– Usually showing granulomatous uveitis. –– Nongranulomatous uveitis occurs occasionally. –– Positive tuberculin skin test. –– Positive interferon-gamma assay tests (QuantiFERON­TB Gold test, QFT-G, T-spot TB test). –– Chest X-ray or chest CT scan. –– Histopathologic examination of the affected tissues. –– Culture from the intraocular fluid. • Tubulointerstitial nephritis and uveitis syndrome –– Increased blood urea nitrogen and creatinine levels. –– Abnormal ESR and CRP. –– Urinalysis showing proteinuria, hematuria, pyuria, and increased β-microglobulin levels. –– Renal biopsy is useful for the diagnosis.

12.10 Treatment • Etiological treatment should be instituted if an infectious agent is defined. • Topical corticosteroids should be administered immediately after the AAU diagnosis is made. For severe anterior chamber inflammation, for instance, hypopyon, intensive fibrin exudates or plastic aqueous, topical corticosteroids, usually dexamethasone phosphate, should be administered every hour for the first 2 or 3 days followed by gradually tapering. • For the moderate inflammation in the anterior chamber, topical corticosteroids are administrated 3 or 4 times each day. • For the mild inflammation in the anterior chamber, topical fluorometholone alcohol or acetate is used 1–3 times each day. • Cycloplegic and mydriatic drops should be absolutely used as they may relieve pain arising from ciliary spasm and break the freshly formed posterior synechiae.

• For the AAU patients with severe anterior chamber inflammation, a low dose of systemic corticosteroids, usually 20–30 mg/day, can be used for 2–4 weeks. • For the AAU patients with corneal epithelial lesions, subconjunctival corticosteroids may be necessary. • For the AAU patients with high frequency of recurrence, systemic corticosteroids in combination with other immunosuppressive agents may be needed.

12.11 Prognosis • Most AAU patients have a good visual prognosis. • In about 1% AAU patients, poor visual prognosis even no light perception may be observed mainly due to disappearance of anterior chamber, detachment of ciliary body and phthisis bulbi.

References 1. Jabs DA, Nussenblatt RB, Rosenbaum JT.  Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140(3):509–16. 2. Singh R, Gupta V, Khairallah M, et al. Anterior non-granulomatous uveitis. In: Gupta A, Gupta V, Herbort CP, et  al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 311–22. 3. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 4. Gueudry J, Bodaghi B.  Anterior uveitis: seronegative spondyloarthropathies. In: Garg SJ, Bodaghi B, Nussenblatt R, et  al., editors. Uveitis. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 36–40. 5. Chang JH, McCluskey PJ, Wakefield D. Acute anterior uveitis and HLA-B27. Surv Ophthalmol. 2005;50(4):364–88. 6. Yang P, Wan W, Du L, et al. Clinical features of HLA-B27-positive acute anterior uveitis with or without ankylosing spondylitis in a Chinese cohort. Br J Ophthalmol. 2018;102(2):215–9.

References

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7. Zierhut M, Pavesio CE, Goldstein DA. Anterior uveitis. In: Zierhut 1 1. Jones N.  Uveitis associated with HLA-B27, arthritis and inflammatory bowel disease. Uveitis. 2nd ed. London: JP Medical Ltd.; M, Pavesio C, Ohno S, et  al., editors. Intraocular inflammation. 2013. p. 129–43. Berlin: Springer; 2016. p. 503–16. 12. Maza MS.  Seronegative spondyloarthropathies. In: Foster CS, 8. Yang P, Fang W, Meng Q, et al. Clinical features of Chinese patients Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. with Behcet’s disease. Ophthalmology. 2008;115(2):312–8. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. 9. Du L, Kijlstra A, Yang P.  Vogt-Koyanagi-Harada disease: novel p. 793–813. insights into pathophysiology, diagnosis and treatment. Prog Retin Eye Res. 2016;52:84–111. 10. Yang P, Ren Y, Li B, et  al. Clinical characteristics of Vogt-­ Koyanagi-­Harada syndrome in Chinese patients. Ophthalmology. 2007;114(3):606–14.

Intermediate Uveitis

13

Contents 13.1   Definition

 187

13.2   Epidemiology

 187

13.3   Etiology and Pathogenesis

 187

13.4   Clinical Manifestations 13.4.1  Symptoms 13.4.2  Signs

 188  188  188

13.5   Complications

 189

13.6   Diagnosis

 189

13.7   Differential Diagnosis

 190

13.8   Treatment

 192

13.9   Prognosis

 192

References

 193

13.1 Definition • Intermediate uveitis (IU) refers to the inflammation mainly concentrated in the vitreous base, pars plana, and peripheral retina. • IU typically manifests as snowballs formed by vitreous inflammatory aggregates and snowbanks formed by inflammatory exudates on the pars plana [1, 2]. • IU is previously described as peripheral uveitis, pars planitis, peripheral cyclitis, posterior cyclitis, hyalitis, and chronic cyclitis in the literatures. • IU usually occurs as an inflammatory disease without underlying systemic diseases or infectious disorders, i.e., idiopathic intermediate uveitis. It may also occur in association with infectious diseases or systemic diseases [2–4].

13.2 Epidemiology • IU predominantly occurs in children and young adults although elderly patients have also been reported. • Males and females are equally affected.

• There is no race predilection. • Bilateral involvement is common. • Percentages of patients with IU in uveitis series vary considerably from 1 to 13%.

13.3 Etiology and Pathogenesis • The exact pathogenesis is not clear. • Idiopathic IU is presumably mediated by immune response. • T cells, macrophages, and B cells are all found in the vitreous of IU patients. • Studies on blood of IU patients have shown an increased ratio of CD4+ T cells to CD8+ T cells and elevated levels of IL-8, IL-2 receptors, intercellular adhesion molecules, IgD, and antiganglioside antibodies. • IU has been reported to be associated with HLA-DR15, HLA-DR17, and HLA-A28. In addition, IU has also been documented to occur in families. These results suggest that genetic factors may be involved in the development of this disease [3].

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13.4 Clinical Manifestations 13.4.1 Symptoms • Most of IU patients complain of floaters and blurred vision at the beginning. • IU patients with aggregated floaters, complicated cataract, cystoids macular edema, vitreous hemorrhage, or retinal detachment may have significant loss of vision [3, 5]. • Pain, photophobia, and tearing occasionally occur as a result of anterior segment involvement.

13  Intermediate Uveitis

• Anterior segment involvement in IU varies greatly among patients. –– Most patients present as mild to moderate anterior chamber reaction. Keratic precipitates, aqueous flare and cells are commonly seen in these patients. –– Posterior synechiae and even angle adhesion may be present (Fig. 13.6). –– Occasionally, red eye, ciliary injection, and substantial anterior chamber reaction are observed at the first onset of IU.

13.4.2 Signs • Vitreous inflammatory aggregates appearing as yellowish white appearance, the so called snowballs, are the characteristic finding (Fig.  13.1). They are mostly distributed inferiorly (Fig. 13.2) [6, 7]. • Vitreous cells are universally present with a range from + to +++ in IU patients. • Yellowish white exudates on the pars plana, the so-called snowbanks, are pathognomonic feature for IU (Figs. 13.3, 13.4, and 13.5). They usually begin with the inferior pars plana and peripheral retina, and may extend to encompass the whole 360°. Active snowbank consists of fibrous tissue with lymphocytic infiltration. • Vasculitis is not uncommon in IU patients and usually presents with subtle sheathing of venules in the peripheral retina. Fig. 13.2  Snowballs distributed in streak adjacent to the retina in a patient with intermediate uveitis

Fig. 13.1  Confluent snowballs in a patient with intermediate uveitis

Fig. 13.3  Snowbank observed inferiorly in a patient with intermediated uveitis. This lesion was previously diagnosed as intraocular tumor in other hospitals. It has been successfully treated by us with immunosuppressive agents

13.6 Diagnosis

Fig. 13.4  Active snowbank observed in an IU patient

189

Fig. 13.6  Goniosynechia observed in an IU patient

• Retinal neovascularization usually at periphery may develop in association with hemorrhage. • Increased intraocular pressure or glaucoma may occur either due to a chronic inflammation or long-term use of corticosteroids. • Epiretinal membrane is a less common complication and may result in retinal breaks and rhegmatogenous retinal detachment. • Optic edema, optic neuritis, optic disc neovascularization, and rarely optic nerve atrophy may develop in certain IU patients.

13.6 Diagnosis

Fig. 13.5  Snowbanks observed in an IU patient

13.5 Complications • Cystoid macular edema (CME) is a common complication and occurs in 12–63% of the IU patients. It is the most common cause of visual impairment in these patients. • Complicated cataract is a common complication and frequently presents as subcapsular opacities. It varies considerably with reports, ranging from 15 to 50%. • Retinal detachment may occur and take the form of either rhegmatogenous or exudative retinal detachment. • Vitreous traction and hemorrhage may develop in a few of IU patients.

• In general, the diagnosis of IU relies on the clinical features. Characteristic snowbanks in the pars plana and vitreous snowballs are highly suggestive of the diagnosis of IU. • As IU may be associated with systemic diseases or infectious diseases, patient’s history, systemic examinations, and laboratory investigations, if necessary, should be taken into consideration in the diagnosis and differential diagnosis of IU (see below). • Fundus fluorescein angiography (FFA) is useful in detection of the involvement of the retinal blood vessels, especially the microvasculitis, in IU patients. • Ultrasound biomicroscopy (UBM) is helpful in detection of the changes around the pars plana and periphery retina, which are not readily detected clinically. Exudates with varying appearances have been documented by UBM (Figs. 13.7 and 13.8). • Optical coherence tomography (OCT) is helpful in detection of macular changes, especially cystoid macular edema which is a common finding in IU patients (Fig. 13.9).

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13  Intermediate Uveitis

Fig. 13.7  Snowbanks with varying appearances detected by UBM in a female IU patient

13.7 Differential Diagnosis • Multiple sclerosis –– Multiple sclerosis is one of the common diseases associated with IU. –– Female and young caucasian patients with multiple sclerosis are apt to develop IU. –– A magnetic resonance imaging scan, examination of the cerebrospinal fluid, and neurological consultation should be performed in the patients with clinical findings suggestive of multiple sclerosis. • Sarcoidosis –– Sarcoidosis may take the form of IU clinically. Snowballs or string of pearls-like vitreous opacities may appear in some patients. Therefore, it should be on the list of differential diagnosis. –– Sarcoidosis frequently affects both anterior and posterior segments. Chorioretinitis and retinal vasculitis with candle wax drippings are typical findings in this disease. –– Bilateral hilar lymphadenopathy, increased angiotensin-­converting enzyme level, increased lymphocytes or CD4+/CD8+ T cells in bronchoalveolar

lavage, and the presence of noncaseating granuloma aid in the diagnosis and differential diagnosis. • Primary intraocular lymphoma –– It may affect the eye and present as infiltration of malignant lymphoid cells into the retinal, uveal tract, vitreous, and optic nerve. –– The vitreous opacities in primary intraocular lymphoma may resemble snowballs seen in IU and therefore should be differentiated from those seen in IU patients. –– Vitreous reaction recalcitrant to immunosuppressive agents or corticosteroids especially in older patients is evocative of primary intraocular lymphoma. –– Vitreal biopsy, cerebrospinal fluid investigation, neurology consultations, and magnetic resonance imaging (MRI) scan should be performed in the suspected patients. • Tuberculosis –– Ocular tuberculosis may present with vitreous opacities resembling those observed in IU. –– Careful taking of history, chest X-ray or computed tomography (CT) scan, Mantoux skin test, interferon gamma assay, histopathologic examination, i­ ntraocular

13.7  Differential Diagnosis

191

Fig. 13.8  Snowbanks detected by UBM in IU patients

fluid culturing, and relevant systemic investigations should be kept in mind for the patients suspected of having intraocular tuberculosis. • Syphilis –– Syphilis frequently causes vitreous opacities in association with retinal vasculitis or retinitis and therefore should be differentiated from IU [8]. –– In patients with unexplainable uveitis or irresponsible to usual treatment in context of the presence of exposure history, the suspicion of syphilis should be highly raised.

–– Serology investigations including nonspecific tests (rapid plasma reagin test and venereal disease research laboratory investigations) and specific tests (fluorescent treponemal antibody absorption test and microhemagglutination assay for T pallidum) should be performed in the patients with suspected syphilis. • Other disorders in differentiation from IU –– Lyme disease –– Cat-scratch disease –– Fuchs syndrome

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13  Intermediate Uveitis

Fig. 13.9  Cystoid macular edema detected by OCT in a male IU patient

–– –– –– –– ––

Toxoplasmosis Toxocariasis Behcet’s disease Eales disease Tubulointerstitial nephritis and uveitis syndrome

13.8 Treatment • • Some authors recommend commencing the treatment for the IU patients with vision lower than 20/40. However, others suggest early treatment for the patients with active inflammation. On the basis of the author’s experience, treatment should be instituted if the inflammation is present no matter how serious it is. Indolent low-grade inflammation may also lead to significant visual impairments. • Corticosteroids are the mainstay for the treatment of IU patients. –– Systemic treatment with corticosteroids commences at varying initial dosages ranging from 20 to 60 mg per day for the patients with bilateral involvement according to the severity of IU. An initial low dose of systemic corticosteroids is used for the patients with mild to moderate inflammation. Gradual tapering is recommended if the inflammation is controlled. –– Periocular injection of corticosteroid, for instance, triamcinolone 20 to 40 mg, is indicated for the patients with unilateral involvement, especially for those with cystoid macular edema. –– Topical corticosteroids in combination with mydriatic and cycloplegic agents are recommended for the patients with anterior segment inflammation. • Cyclosporine is a drug commonly used in the treatment of IU patients. –– The author usually uses cyclosporine at an initial dosage of 3–5 mg/kg/day. This treatment lasts for 3–5 months followed by a gradual tapering to 2 mg/kg/day over 3–5 months. Maintenance therapy with 2 mg/kg/ day usually lasts for 3–6 months.

• •

•

•

–– Cyclosporine is always combined with a low dose of corticosteroids or less commonly with other immunosuppressive agents. –– Side effects and toxicity may develop during therapy including nephrotoxicity, hypertension, central neurotoxicity, and hepatotoxity. Regular monitoring of these side effects is needed especially in patients on long-­ term therapy with this drug. Other immunosuppressive agents have also been used in the treatment of IU. Careful monitoring for the side effects and potentially serious toxicity should be kept in mind during the treatment. –– Azathioprine –– Cyclophosphamide or chlorambucil –– Mycophenolate mofetil –– Methotrexate Cryotherapy has been used to treat neovascularization of the vitreous base. Panretinal laser photocoagulation has been recommended for the treatment of peripheral neovascularization observed in IU patients. Pars plana vitrectomy has been used to treat the complications of IU including tractional or rhegmatogenous retinal detachment, persistent vitreous opacities, vitreous hemorrhage, vitreous traction, and persistent cystoid macular edema unresponsive to conventional immunosuppressive agents in IU patients. Intravitreal injection of anti-VEGF agents is increasingly used to treat retinal vascularization and cystoid macular edema associated with uveitis. The efficacy of these agents in the treatment of IU is expected to be demonstrated in future.

13.9 Prognosis • Adequate and prompt treatment with corticosteroids and immunosuppressive agents may lead to inflammation remission and is associated with a good visual outcome in most IU patients.

References

• A snowbank has been reported to be associated with a poor visual prognosis. • Tractional or rhegmatogenous retinal detachment and persistent cystoid macular edema may lead to a significant visual impairment.

References 1. Schaal S, Sobolewska B, Zierhut M, et al. Intermediate uveitis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 517–32. 2. Nussenblatt RB, Whitcup SM, Palestine AG.  Intermediate uveitis. Uveitis fundamentals and clinical practice. 2nd ed. St. Louis: Mosby-Year Book, Inc.; 1996. p. 279–88.

193 3. Zierhut M, Deuter C, Vitale AT, et al. Intermediate uveitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1169–87. 4. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 5. Biswas J, Sudharshan S.  Intermediate uveitis. In: Gupta A, Gupta V, Herbort CP, et  al., editors. Uveitis test and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 348–62. 6. Birnbaum AD, Goldstein DA.  Intermediate uveitis. In: Garg SJ, Bodaghi B, Nussenblatt R, et  al., editors. Uveitis. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 59–64. 7. Jones N. Intermediate uveitis and idiopathic chronic vitritis, Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 259–64. 8. Yang P, Zhang N, Li F, et  al. Ocular manifestations of syphilitic uveitis in Chinese patients. Retina. 2012;32(9):1906–14.

14

Posterior Uveitis

Contents 14.1   Definition

 195

14.2   Epidemiology

 195

14.3   Etiology and Pathogenesis

 196

14.4   Entities of Posterior Uveitis

 196

14.5   Diagnosis and Differential Diagnosis

 197

14.6   Treatment

 200

14.7   Prognosis

 200

References

 200

14.1 Definition • Posterior uveitis refers to the inflammation occurring in the choroid, retina, retinal pigment epithelium, retinal blood vessels, and the optic disc. In most patients with posterior uveitis, the vitreous is involved, usually manifesting as vitreous cells and opacities [1, 2]. • The posterior uveitis includes choroiditis, retinitis, retinal pigment epitheliitis, retinal vasculitis, chorioretinitis, retinochoroiditis, and papillitis.

14.2 Epidemiology • As posterior uveitis is an umbrella name for the inflammation involving the posterior layers of the eye and includes numerous entities, its incidence or prevalence as a whole is still not exactly known. • A number of posterior uveitis entities have racial or geographic predilections [3–7]. –– Eales disease occurs frequently in the Indian subcontinent and mostly involves healthy young males. –– Ocular tuberculosis is frequently seen in India.

–– Birdshot chorioretinopathy occurs almost exclusively in whites and usually at their middle age. Females are more frequently affected. –– Ocular sarcoidosis is more often seen in African-­ Americans, Japanese, and whites in Europe. It is less common in China, Southeast Asia, India, and New Zealand. –– Multifocal choroiditis and panuveitis mostly affect females in their mid-30s. –– Multiple evanescent white dot syndrome is mainly seen in young females. –– Acute retinal pigment epitheliitis frequently affects young males in the second to fourth decade of life. –– Frosted branch angiitis frequently occurs in children or young adults. Males are more often affected than females. –– Ocular toxoplasmosis is more common in tropical areas, the United States, South America, and Europe, but rare in China. –– Ocular toxocariasis is frequently seen in the Southeastern United States, Argentina and Japan, and predominantly affects children with an average of 7 years old.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_14

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196

• The rates of posterior uveitis range from 1.5 to 31% in total uveitis cases. Based on our previous study in 1752 uveitis patients, 119 cases with posterior uveitis are observed.

14.3 Etiology and Pathogenesis • Infectious posterior uveitis can be caused by direct invasion of infectious agents or by an immune response to these agents. • Noninfectious posterior uveitis is usually caused by an autoimmune response or a complement–immune complex. • A number of malignancies such as intraocular-central nervous system lymphoma, leukemia, malignant melanoma, retinoblastoma, and metastases of systemic malignancies to the eye may cause clinical findings resembling those of posterior uveitis, i.e., masquerade syndrome. • Th17 (IL-23/IL-17) and Th1 cells have been shown to be involved in the development of posterior uveitis seen in Behcet’s disease and Vogt–Koyanagi–Harada (VKH) disease [8–11]. • Genetic factors have been confirmed to be involved in a number of uveitis entities, such as Behcet’s disease (BD), VKH disease, and birdshot chorioretinopathy [5, 9, 12].

14.4 Entities of Posterior Uveitis • Infectious posterior uveitis entities commonly seen in the clinic include syphilitic posterior uveitis, ocular tuberculosis, ocular toxoplasmosis, ocular toxocariasis, acute retinal necrosis syndrome, and cytomegalovirus retinitis [1, 13]. • Noninfectious posterior uveitis includes idiopathic retinitis, idiopathic retinal vasculitis, multifocal choroiditis and panuveitis, birdshot chorioretinopathy, acute posterior multifocal placoid pigment epitheliopathy, multifocal evanescent white dot syndrome, acute retinal pigment epitheliitis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, punctuate inner choroidopathy, papillitis, and neuroretinitis [1]. • Behcet's disease, sympathetic ophthalmia, Vogt– Koyanagi–Harada disease, and ocular sarcoidosis may take the form of posterior uveitis during certain stages or in certain patients, or other form of uveitis [6, 7, 9, 14, 15]. • Although there are numerous posterior uveitis entities, they can be generally divided into three categories: retinitis, retinal vasculitis, and inflammation involving the choroid or retinal pigment epithelium according to the primary location of the inflammation (Table 14.1).

14  Posterior Uveitis Table 14.1  Retinitis, retinal vasculitis, and inflammation involving the choroid or retinal pigment epithelium Categories of inflammation Common entities Retinitis Acute retinal necrosis syndrome Cytomegalovirus (CMV) retinitis Toxoplasmosis Behcet’s disease Ocular syphilis Intraocular lymphoma Leukemias Human immunodeficiency virus (HIV) infection Systemic lupus erythematosus Retinal vasculitis Eales disease Idiopathic retinal vasculitis Acute retinal necrosis syndrome CMV retinitis Juvenile idiopathic retinal vasculitis JIA-associated uveitis Ocular syphilis Behcet’s disease Ocular sarcoidosis Frosted branch angiitis Ocular tuberculosis Blau syndrome Ocular toxoplasmosis Uveitis associated with relapsing polychondritis Sympathetic ophthalmia Inflammation involving Ocular sarcoidosis the choroid, retinal VKH disease pigment epithelium or Ocular tuberculosis both Ocular toxoplasmosis Birdshot chorioretinopathy Multifocal choroiditis and panuveitis Punctate inner choroidopathy Serpiginous choroiditis Subretinal fibrosis and uveitis syndrome Multiple evanescent white dot syndrome Acute posterior multifocal placoid pigment epitheliopathy Acute retinal pigment epitheliitis

• Retinitis is characterized by cellular infiltrates or necrosis of the retina. It may be associated with retinal hemorrhage, retinal edema, retinal vasculitis, and vitreous cells and opacities. • Retinal vasculitis typically shows sheathing of the blood vessels and occlusive retinopathy, presenting as capillary dropout and cotton wool spots [16]. –– It may be associated with retinal hemorrhage, retinal edema, and vitritis. –– Retinal vasculitis is more common than imagined on clinical examination because a large number of patients with capillaritis are not correctly diagnosed due to the absence of visibly apparent manifestations of sheathing of the blood vessels. –– Subclinical retinal vasculitis is frequently observed in pediatric uveitis, Behcet’s disease, and ocular sarcoidosis.

14.5  Diagnosis and Differential Diagnosis

• Choroiditis has been classified into three subtypes by Herbort and Mantovani [17]: primary inflammatory choriocapillaropathies, primary stroma choroiditis, and secondary stromal choroiditis. –– It may present as one focus or multiple foci with varying sizes and configurations. –– Active lesions typically show creamy-white spots whereas old lesions appear pigmented or punched-out. –– It is frequently associated with exudative retinal detachment in severe cases. –– The retinal pigment epithelium may be involved in some cases. • Vitreous changes are quite common in posterior uveitis [1, 7] –– Vitreous inflammatory cells are frequently present in varying numbers in patients with posterior uveitis, especially those with retinitis or retinal vasculitis. –– Vitreous opacities develop as a result of exudates and aggregates of inflammatory cells and vary considerably with posterior uveitis entities. Severe vitreous opacities usually occur in Behcet's disease, fungal or bacterial endophthalmitis, and acute retinal necrosis syndrome. Whereas choroiditis, for instance, Vogt– Koyanagi–Harada disease, rarely causes obvious vitreous opacities. –– Vitreous hemorrhage may occur as a result of retinal neovascularization and is commonly seen in Eales disease. –– Vitreous fibrovascular proliferation may develop in patients with posterior uveitis and can lead to vitreous hemorrhage, tractional retinal detachment, and rhegmatogenous retinal detachment. • Optic disc involvement usually presents either as a primary manifestation of certain posterior uveitis entities or as a secondary manifestation arising from the inflammatory lesions close to it. • Anterior chamber reaction is usually absent in posterior uveitis. However, spillover of inflammatory cells into the anterior chamber is occasionally observed in some patients with posterior uveitis. –– In general, anterior chamber cells are few in number and anterior chamber flare is mild in these patients. Posterior synechiae is rarely observed. –– Acute retinal necrosis syndrome, although considered as one form of posterior uveitis clinically, may cause marked anterior segment inflammation, including mutton fat keratic precipitates, obvious anterior chamber reaction and posterior synechiae.

197

14.5 Diagnosis and Differential Diagnosis • As the clinical evolution, treatment and prognosis of diverse posterior uveitis entities are strikingly different, it is very important to make an accurate diagnosis. The key points for the diagnosis of each form of posterior uveitis are listed below. • Acute posterior multifocal placoid pigment epitheliopathy [17, 18] –– It is an uncommon entity of posterior uveitis and mainly affects young adults. –– Patients usually complain of a sudden drop of vision in both eyes, but occasionally in one eye, frequently associated with central or paracentral scotomata. –– It is characterized by multiple round, yellow-white, circumscribed, flat, placoid lesions at the level of retinal pigment epithelium. These lesions are scattered throughout the posterior pole and vary in size from one to two disc diameters. They are normally well circumscribed and discrete although confluence of these lesions is sometimes observed. –– Fundus fluorescein angiography in the acute stage typically shows early hypofluorescence and late hyperfluorescence. • Acute retinal pigment epitheliitis [19, 20] –– It usually occurs in otherwise healthy young adults. –– Acute visual disturbance is usually associated with metamorphopsia or central scotoma. –– Gray spots surrounded by yellow-white halo are the hallmark of the disease. –– It spontaneously resolves over 6–12 weeks. –– Patients usually enjoy a complete recovery of visual acuity. • Subretinal fibrosis and uveitis syndrome [21, 22] –– It usually occurs in young otherwise healthy female adults with myopia. –– Patients frequently complain about varying degrees of decreased vision, central or multiple scotomas, metamorphopsia, floaters, and photopsia. –– The characteristic findings are multiple, discrete, whitish-­ yellow lesions at the level of the retinal pigment epithelium or inner choroid in the early stage, and irregular or extensive zones of subretinal fibrosis in the late stage. –– It may be the consequence of a number of disorders involving the retinal pigment epithelium and choroid. –– Patient’s visual prognosis varies considerably with the location of the lesions and the response to treatment. • Serpiginous choroiditis [23–25] –– It occurs frequently in male adults and bilateral involvement is common.

198

•

•

•

•

–– Patients usually complain about decreased vision, metamorphopsia, and scotomas. –– Gray-white or cream-yellow subretinal lesions with irregular borders and spreading centrifugally are the hallmark of this disease. –– It often presents as peripapillary choroiditis although macular and multifocal serpiginous choroiditis are also observed. –– Its association with tuberculosis has been reported and therefore work-up for this disease should be performed in these patients. –– Recurrence of choroiditis, choroidal neovascularization, and macular involvement may result in severe visual impairment. Multiple evanescent white dot syndrome [26, 27] –– It usually occurs in young healthy female adults and unilateral involvement is common. –– Patients usually complain about blurred or decreased vision, photopsia, and subjective scotomas. –– Typical manifestations include small, faint white dots deep in the retina or at the level of the retinal pigment epithelium and macular granularity. –– Fundus changes always spontaneously resolve over 2–8 weeks. –– Visual prognosis is good in most patients. Punctate inner choroidopathy [28, 29] –– It usually affects both eyes of the young healthy women with myopia. –– Patients usually complain about blurred vision, floaters, photopsia, scotomas, and metamorphopsia. –– Multiple, small, discrete, and yellow-white lesions at the level of the retinal pigment epithelium and inner choroid scattered throughout the posterior pole are the characteristic feature. –– Choroidal neovascularization or recurrent lesions involving macular regions may lead to a poor visual prognosis. Multifocal choroiditis and panuveitis [22, 30] –– It usually occurs in young healthy female adults. –– Patients may complain about blurred or decreased vision, photopsias, and floaters. –– It is characterized by multiple yellow-gray lesions with 50μm to 350μm in size at the level of retinal pigment epithelium in association with mild to moderate reaction in the anterior chamber and vitreous. –– Permanent cystoid macular edema, choroidal neovascularization, and atrophy of the optic nerve may lead to severe visual impairment. Syphilitic uveitis [13, 31] –– Most patients manifest as posterior uveitis although anterior uveitis, intermediate uveitis, and panuveitis are also observed.

14  Posterior Uveitis

–– Various fundus changes including retinitis, papillitis, and retinal vasculitis have been observed in patients with syphilitic uveitis. –– Multiple infiltration dots associated with hemorrhages and vascular sheathing seem to be characteristic of syphilitic posterior uveitis. –– History of sexual or homosexual contact and serologic tests may aid in diagnosis and differential diagnosis. • Vogt–Koyanagi–Harada disease [6, 9] –– VKH disease often occurs in Chinese, Japanese, Hispanic, Greek, and Native American ancestry. –– In general, VKH disease is classified into panuveitis. However, it begins with posterior uveitis and progresses to the anterior segment. Therefore, it should be on the list of differential diagnosis of posterior uveitis. –– Bilateral diffuse choroiditis in association with serous retinal detachment is the hallmark of the disease in the early stage. However, sunset glow fundus with considerably different appearances in association with pigmentation, Dalen–Fuchs nodules, and chorioretinal atrophy are the typical findings of the posterior segment in the patients with recurrent granulomatous anterior uveitis. –– A number of extraocular manifestations including headache, neck stiffness, nausea, confusion, hearing loss, tinnitus, poliosis, vitiligo, and alopecia may develop in different stages. • Behcet’s disease [7] –– Behcet’s disease frequently occurs in Japan, China, and the mediterranean countries. –– Behcet’s disease mainly manifests as panuveitis or posterior uveitis and therefore should be on the list of differential diagnosis of posterior uveitis. –– Behcet’s disease is characterized by oral ulcerations, uveitis, multiple skin lesions, genital ulcerations, and involvement of other systems. –– Retinal vasculitis is the most common finding in the posterior segment followed by retinitis and papillitis. –– Retinal vasculitis may affect arteries, veins, and capillaries. –– Capillaritis (microvasculitis) disclosed by fundus fluorescein angiography (FFA) is observed in almost all the Behcet’s disease patients with posterior segment involvement. –– Silver-wired retinal vessels (ghost vessels) in association with extensive retinal and optic nerve atrophy are the typical manifestations of Behcet’s disease in the late stage. • Acute retinal necrosis (ARN) syndrome [32] –– ARN syndrome is a necrotizing retinitis presumably caused by herpesviruses. –– Patients usually complain about redness, photophobia, discomfort around eye, decreased vision, and floaters.

14.5  Diagnosis and Differential Diagnosis

–– It is characterized by necrotizing retinitis starting at the peripheral retina, retinal vasculitis mainly affecting the arteries, severe vitritis and rhegmatogenous retinal detachment in the healing stage. –– Anterior segment involvement as evidenced by mutton fat keratic precipitates, aqueous flare and cells, and elevated intraocular pressure is common in the early stage. • Sympathetic ophthalmia [14, 33] –– It is a bilateral granulomatous uveitis following penetrating eye injury or intraocular surgery. –– The typical changes include granulomatous anterior uveitis, diffuse choroiditis, sunset glow fundus and Dalen–Fuchs nodules or chorioretinal atrophy. –– The extraocular manifestations are similar to but less common than those seen in VKH disease. –– A history of penetrating eye injury or intraocular surgery and bilateral granulomatous uveitis are essential to the diagnosis of this disease. • Masquerade syndrome [34, 35] –– A number of malignancies or metastasis of the tumor cells to the eye may cause manifestations resembling the intraocular inflammation. –– Intraocular lymphoma is a common malignancy which causes masquerade syndrome. The common findings include infiltrations around the optic nerve and at posterior pole in association with hemorrhage and vitreous opacities. Lumbar puncture and diagnostic vitrectomy should be performed in the patients with suspected intraocular lymphoma. Brain-­ magnetic resonance imaging (MRI) is also needed to detect the central nervous system (CNS) lesions in these patients. –– Retinoblastoma is a common intraocular tumor occurring in children. It may cause uveitis due to a response to necrotic tumor or manifest as masquerade syndrome. Ciliary congestion, mutton fat-like keratic precipitates, pseudohypopyon, and multiple iris nodules are the main findings. Fundus changes and family history are extremely helpful to the diagnosis. Ultrasonography, computed tomography (CT) scan, MRI of the orbit and head may provide substantial evidences to the diagnosis and differential diagnosis. Pathological examination may confirm diagnosis of the disease although aspiration biopsy is not always recommended.

199

–– Leukemias are malignancies of the hematopoietic stem cells and may invade the eye and manifest as masquerade syndrome. Retinal infiltrations associated with hemorrhages, perivascular sheathing, hard exudates, and cottonwool spots are all observed. Infiltrations of leukemic cells in the uvea tract may cause choroidal masses, serous retinal detachment, retinal pigment epithelium changes, iridocyclitis and, occasionally, hypopyon, pseudohypopyon, or hyphema. A complete work-up on peripheral blood and bone marrow including cytological analysis, immunohistochemistry, immunophenotyping, and molecular investigations should be performed in the patients with suspected leukemia. –– Metastasis to the eye is commonly seen in breast, lung, and renal cancers. Patients may complain about red eye, pain, blurred or decreased vision, floaters, diplopia, metamorphopsia, and exophthalmos. Yellow-white to pink-white subretinal lesions associated with serous retinal detachment, disc edema, vitreous hemorrhage, and opacities are common findings. Involvement of the anterior segment manifests as keratic precipitates, aqueous flare and cells, irregular swelling of the iris and ciliary body. History of malignancy and work-up searching for the primary tumor are essential to the diagnosis. • Ocular sarcoidosis [15, 36] –– Sarcoidosis is a granulomatous inflammatory disease involving multisystem and organs. –– The lung is the most common organ affected, followed by the eye, lymph nodes, skin, liver, central nervous system, bone and join, spleen, salivary glands, and the heart. –– The common ocular findings are uveitis, typically showing mutton fat keratic precipitates, iris nodules, or granuloma in the anterior segment and yellow-gray nodular lesions in the choroid, segmental perivasculitis associated with candle wax dripping, snowball,“strings of pearls,” retinal microvasculitis identified by FFA, and vitritis in the posterior segment. –– The diagnosis of sarcoidosis is mainly based on bilateral hilar lymphadenopathy, granulomatous uveitis, and the manifestations of multiple systems. –– Epithelioid cell granulomas without caseation identified by pathological examination could confirm the diagnosis of sarcoidosis.

200

• Ocular toxoplasmosis [37, 38] –– Toxoplasmosis is common in Europe, Northern America, and South America but rare in China. –– Active retinochoroiditis adjacent to an old chorioretinal scar in the macula forming the so-called satellite lesions is the hallmark of ocular toxoplasmosis. –– Retinal vascular sheathing associated with hemorrhage and retinal edema may also develop. –– In immunocompromised individuals, enlarged retinochoroiditis may masquerade viral retinitis. Other forms of intraocular inflammation including panophthalmitis and orbital cellulitis may also develop. –– The diagnosis of ocular toxoplasmosis is based on clinical manifestations and laboratory tests including Giemsa staining, serological investigations, and deoxyribonucleic acid (DNA) detection by polymerase chain reaction (PCR) technique. • Ocular Toxocariasis [39, 40] –– Ocular toxocariasis is one kind of relatively common posterior uveitis in western countries. –– It usually presents as posterior pole granuloma, peripheral granuloma, and chronic endophthalmitis. –– Posterior pole granuloma is characterized by white or gray and elevated lesion usually located between the macular and the optic nerve. –– Peripheral granuloma manifests as white elevated mass anterior to the equator of the eye. –– Chronic endophthalmitis typically presents as marked vitreous inflammation and exudative retinal detachment. –– The diagnosis is based on the clinical manifestations and serological investigations. • Cytomegalovirus (CMV) retinitis [31, 41] –– CMV retinitis occurs frequently in the patients with HIV infection and immunocompromised individuals. –– Most patients take the form of fulminant CMV retinitis, manifesting as white confluent retinal opacification and necrosis along retinal vessels in association with hemorrhage and vascular sheathing. –– Granular indolent CMV retinitis and frosted branch angiitis are also observed. –– The diagnosis of CMV retinitis is principally based on the typical fundus findings, serological investigations, and the status of immunocompromise in the patients.

14.6 Treatment • Accurate diagnosis of the entity of posterior uveitis is extremely important for adequate treatment of the patients. • Specific treatment including antibiotics, antivirus agents or antifungal agents is used for the patients with relevant infections.

14  Posterior Uveitis

• Most patients with noninfectious posterior uveitis necessitate systemic corticosteroids in conjunction with periocular or intravitreal steroids although no treatment is needed for patients with certain forms of posterior uveitis including multiple evanescent white dot syndrome and punctate inner choroidopathy. • Other immunosuppressive agents including cyclosporine, cyclophosphamide, chlorambucil, azathioprine, methotrexate, and mycophenolate mofetil are also used alone or in combination for the patients with noninfectious posterior uveitis who are unresponsive to corticosteroids alone or do not tolerate their side effects. • Biological agents are increasingly used in the treatment of the vision-threatening or refractory posterior uveitis with beneficial results. • Pars plana vitrectomy is indicated for the patients with dense vitreous opacities or massive hemorrhage, proliferative vitreoretinal membrane, and tractional or rhegmatogenous retinal detachment. • Panretinal laser photocoagulation is indicated for the patients with capillary nonperfusion, retinal neovascularization, and anterior segment neovascularization. • Intravitreal injection of anti-vascular endothelial growth factor agents, such as Conbercept, is recently used for the patients with retinal neovascularization and cystoid macular edema in patients with posterior uveitis.

14.7 Prognosis • Visual prognosis varies considerably with the entities and severity of posterior uveitis. • In general, visual prognosis is associated with macular involvement, severity of the inflammation, and the development of complications. • Prompt and adequate treatment can greatly improve the patient’s visual prognosis.

References 1. Okada AA.  Posterior uveitis. In: Zierhut M, Pavesio C, Ohno S, et al, Intraocular inflammation. Berlin: Springer 2016; pp 533-543. 2. Krishnadev N, Nussenblatt R, Sen HN. Posterior uveitis and collagen vascular diseases: Vogt-Koyanagi-Harada syndrome. In: Garg SJ, Bodaghi B, Nussenblatt R, et  al, Uveitis. Philadelphia: Lippincott Williams & Wilkins. 2012; pp 76-80. 3. Gupta A, Gupta V, Bansal R, et al. Ocular tuberculosis: A. Ocular tuberculosis in endemic areas. B.  Ocular tuberculosis in non-­ endemic areas. In: Gupta A, Gupta V, Herbort CP, et  al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 563–89. 4. Abu El-Asrar AM, Herbort CP, Tabbara KF. Vasculitis; B. Retinal vasculitis. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 363–96.

References 5. Vitale AT.  Birdshot retinochoroidopathy. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 982–1004. 6. Yang P, Ren Y, Li B, et  al. Clinical characteristics of Vogt-­ Koyanagi-­Harada syndrome in Chinese patients. Ophthalmology. 2007;114(3):606–14. 7. Yang P, Fang W, Meng Q, et al. Clinical features of chinese patients with Behcet’s disease. Ophthalmology. 2008;115(2):312–8. 8. Chi W, Yang P, Zhu X, et  al. Production of interleukin-17  in Behcet’s disease is inhibited by cyclosporin A.  Mol Vis. 2010;16(96–98):880–6. 9. Du L, Kijlstra A, Yang P.  Vogt-Koyanagi-Harada disease: novel insights into pathophysiology, diagnosis and treatment. Prog Retin Eye Res. 2016;52:84–111. 10. Chi W, Yang P, Li B, et  al. IL-23 promotes CD4(+) T cells to produce IL-17  in Vogt-Koyanagi-Harada disease. J Allergy Clin Immunol. 2007;119(5):1218–24. 11. Chi W, Zhu X, Yang P, et  al. Upregulated IL-23 and IL-17  in Behcet patients with active uveitis. Invest Ophthalmol Vis Sci. 2008;49(7):3058–64. 12. Hou S, Du L, Lei B, et  al. Genome-wide association analysis of Vogt-Koyanagi-Harada syndrome identifies two new susceptibility loci at 1p31.2 and 10q21.3. Nat Genet. 2014;46(9):1007–11. 13. Yang P, Zhang N, Li F, et  al. Ocular manifestations of syphilitic uveitis in Chinese patients. Retina. 2012;32(9):1906–14. 14. Yang P, Liu S, Zhong Z, et  al. Comparison of clinical features and visual outcome between sympathetic ophthalmia and Vogt-­ Koyanagi-­Harada disease in Chinese patients. Ophthalmology0. 2019;126(9):1297–305. 15. Mochizuki M, Ohno-Matsui K, Takase H, et  al. Sarcoidosis. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 414–29. 16. Ayliffe W.  Retinal vasculitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1136–68. 17. Herbort CP, Mantovani A.  Inflammatory choriocapillaropathies: C.  Acute posterior multifocal placoid pigment epitheliopathy (APMPPE). In: Gupta A, Gupta V, Herbort CP, et  al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 430–511. 18. Pedroza-Seres M, Vitale AT. Acute posterior multifocal placoid pigment epitheliopathy. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1056–66. 19. Pedro BA. Acute retinal pigment epitheliitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1067–76. 20. Neri P, Pirani V, Arapi L.  Acute retinal pigment epitheliitis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 903–7. 21. Rojas B.  Subretinal fibrosis and uveitis syndrome. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. Jaypee Brothers Medical Publishers (P) Ltd.: New Delhi; 2013. p. 1090–103. 22. Terrada C, Bodaghi B. White dot syndromes: multifocal choroiditis/ subretinal fibrosis syndrome. In: Garg SJ, Bodaghi B, Nussenblatt R, et  al, Uveitis. Philadelphia: Lippincott Williams & Wilkins. 2012; pp 135-140. 23. Terrada C, Bodaghi B. White dot syndromes: multifocal choroiditis/ subretinal fibrosis syndrome. In: Garg SJ, Bodaghi B, Nussenblatt R, et  al., editors. Uveitis. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 128–31.

201 24. Moorthy RS, Zierhut M.  Serpiginous choroiditis. In: Zierhut M, Pavesio C, Ohno S, et al, Intraocular inflammation. Berlin: Springer. 2016; pp 1021-1032. 25. Rodriguez-Garcia A. Serpiginous choroiditis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1077–89. 26. Terrada C, Bodaghi B.  White dot syndromes: multiple evanescent white dot syndrome. In: Garg SJ, Bodaghi B, Nussenblatt R, et al, Uveitis. Philadelphia: Lippincott Williams & Wilkins. 2012; pp 132-134. 27. Herbort CP. Multiple evanescent white dot syndrome (MEWDS). In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 997–1005. 28. Terrada C, Bodaghi B.  White dot syndromes: punctuate inner choroidopathy. In: Garg SJ, Bodaghi B, Nussenblatt R, et al., editors. Uveitis. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 141–4. 29. Channa R, Bittencourt M, Ibrahim MA, et al. Punctate inner choroidopathy. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1104–15. 30. Vitale AT, Shakoor A.  Multifocal choroiditis and panuveitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1033–48. 31. Julian K, Bodaghi B, LeHoang P.  Infectious posterior uveitis: syphilis. In: Garg SJ, Bodaghi B, Nussenblatt R, et  al, Uveitis. Philadelphia: Lippincott Williams & Wilkins. 2012; pp 181-187. 32. Julian K, Bodaghi B, LeHoang P. Infectious posterior uveitis: herpetic. In: Garg SJ, Bodaghi B, Nussenblatt R, et al., editors. Uveitis. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 163–71. 33. Sen HN, Nussenblatt R.  Posterior uveitis and collagen vascu lar diseases: sympathetic ophthalmia. In: Garg SJ, Bodaghi B, Nussenblatt R, et  al., editors. Uveitis. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 72–5. 34. Sen HN, Bodaghi B.  Masquerade syndromes: primary intraocular lymphoma. In: Garg SJ, Bodaghi B, Nussenblatt R, et al., editors. Uveitis. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 279–84. 35. Waheed NK, Foster CS. Masquerade syndromes: malignancies. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 705–35. 36. Sen HN, Nussenblatt R.  Posterior uveitis and collagen vascular diseases: sarcoidosis-associated uveitis. In: Garg SJ, Bodaghi B, Nussenblatt R, et  al., editors. Uveitis. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 65–71. 37. Julian K, Bodaghi B, LeHoang P. Infectious posterior uveitis: ocular toxoplasmosis. In: Garg SJ, Bodaghi B, Nussenblatt R, et  al., editors. Uveitis. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 204–7. 38. Oréfice F, Vasconcelos-Santos DV. Toxoplasmosis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 1379–411. 39. Julian K, Bodaghi B, LeHoang P. Infectious posterior uveitis: ocular toxocariasis. In: Garg SJ, Bodaghi B, Nussenblatt R, et al, Uveitis. Philadelphia: Lippincott Williams & Wilkins. 2012; pp 208-211. 40. Oréfice F, Veloso CEDR. Toxocariasis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 1371–7. 41. Capella MJ, Foster CS. Herpesviruses. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 437–60.

Uveitis Associated with Ankylosing Spondylitis

15

Contents 15.1    Definition

 203

15.2    Epidemiology

 203

15.3    Etiology and Pathogenesis

 203

15.4    Systemic Manifestations

 204

15.5    Ocular Manifestations

 205

15.6    Complications

 209

15.7    Diagnosis

 212

15.8    Differential Diagnosis

 212

15.9    Treatment

 214

15.10   Prognosis

 220

References

 220

15.1 Definition • Ankylosing spondylitis (AS) is a systemic disease characterized by a chronic inflammation in the spine and sacroiliac joints [1]. • AS is frequently associated with acute anterior uveitis (AAU) [2, 3]. • AS is the most common systemic disease associated with AAU [4–6].

15.2 Epidemiology • AS is estimated to affect about 1% of the general population. • AS affects both males and females although a severe disease and total spinal fusion are more frequently seen in males [5, 6]. • More than 90% of the AS patients are HLA-B27 positive.

• About 20–30% of the AS patients develop uveitis either before or more frequently after disease onset.

15.3 Etiology and Pathogenesis • The exact mechanisms underlying AS are still unclear [7]. • It has been shown that Gram-negative bacteria including Klebsiella pneumoniae and Shigella flexneri are associated with the pathogenesis of AS [5, 6]. • Our recent study shows that gut microbiota is involved in the development of AAU and AS.  Eight genera such as Roseburia were reduced in AAU patients. Seven fecal metabolites such as 6-deoxy-d-glucose, linoleic acid, and N-acetyl-beta-d-mannosamine 3 were increased in these patients, suggesting a possible role in the development of this disease [8]. • HLA-B27 is strongly associated with AS and AS-­ associated AAU [3, 5–7, 9].

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_15

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• Family accumulation of AS also indicates that genetic factors play an important role in the development of this disease.

15.4 Systemic Manifestations • The main complaints of AS patients are chronic inflammatory back pain and stiffness that are usually worse in the morning and improve with activity or exercise. Fig. 15.1  Spinal deformity observed in patients with both AS and AAU

15  Uveitis Associated with Ankylosing Spondylitis

• Few patients may progress to bamboo spine and spinal deformity although intensive treatment is used (Fig. 15.1). • Peripheral arthritis may occur before or at some point after disease onset. It often affects one or more joints mostly in the lower limbs (Fig. 15.2). • Other systemic manifestations, although less common, include aortic regurgitation, chronic prostatitis, amyloid deposition, and upper lobe pulmonary fibrosis.

15.5 Ocular Manifestations

205

15.5 Ocular Manifestations

Fig. 15.2  Ankle swelling observed in a patient with both AS and AAU

• In our recent study on 581 HLA-B27+ patients with both AS and AAU, male accounts for 75% [3]. • AAU is the most common manifestation of the eye in AS patients. It typically shows unilateral attack although bilateral involvement is common during the course of this disease. • AAU is usually recurrent and alternating. • Patients with both AAU and AS typically experience a sudden onset of the disease, ocular pain, photophobia, and blurry vision. • The main signs include ciliary injection with or without forniceal conjunctiva injection (Fig.  15.3), dust-like keratic precipitates (Fig. 15.4), cells and flare in the anterior chamber (Fig. 15.5). Fibrous exudation (Fig. 15.6) in

Fig. 15.3  Ciliary injection accompanied by forniceal conjunctiva injection observed in a patient with both AS and AAU

Fig. 15.4  Dust-like keratic precipitates observed in a patient with both AS and AAU

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15  Uveitis Associated with Ankylosing Spondylitis

Fig. 15.5  Uniform aqueous microparticles observed under slit-lamp microscopy indicating inflammatory cells in the anterior chamber in patients with both AS and AAU

the anterior chamber or even hypopyon may be observed in the AS patients with severe AAU. • The hypopyon in AAU patients appears fixed and is not prone to change as head moves (Figs. 15.7 and 15.8). It responds well to topical corticosteroids in conjunction with cycloplegic and mydriatic agents. • Residuals of fibrous exudates or pigmentation on the lens surface may be observed when the posterior synechiae is broken by mydriatic and cycloplegic agents (Fig. 15.9). • The posterior segment is generally spared although cells in the anterior vitreous, papillitis (Fig. 15.10), and cystoid macular edema (CME) may be observed in some severe cases [3]. Chorioretinal inflammation is very rare and only observed in one patient in our uveitis center during the past more than 20 years (Fig. 15.11).

• Subclinical involvement of retinal blood vessels is not uncommon and accounts for 36.5% of the 446 patients with both AAU and AS in our recent study [3]. It mainly appears as retinal microvascular leakage of fluorescence on FFA. Staining of the optic disc is also a relatively common finding in AS patients with AAU (Figs. 15.12, 15.13, and 15.14). Staining of retinal vascular walls is occasionally observed in these patients (Fig.  15.15). In very rare conditions, the vascular leakages may last for several years although no obvious inflammation sign is observed clinically. • Granulomatous anterior uveitis is extremely rare in AS patients. • Chronic anterior uveitis may be occasionally observed in AS patients. This inflammation is long-lasting and often results in entire posterior synechiae, extensive anterior synechiae, shallow anterior chamber, band keratopathy, and even phthisis bulbi.

15.5 Ocular Manifestations

207

a

b

c

d

e

f

Fig. 15.6  Fibrous exudates observed on the lens surface in the patients with both AS and AAU (a–d: photographs; e–f: ultrasound biomicroscopy results)

208

15  Uveitis Associated with Ankylosing Spondylitis

Fig. 15.7  Hypopyon in a patient with both AS and AAU seems fixated and takes a long time for its reformulation as head moves. This form of hypopyon is quite different from that observed in Behcet’s disease (BD) (see chapter Behcet’s disease)

Fig. 15.8  Hypopyon associated with fibrous exudates observed in a patient with both AAU and AS

15.6 Complications

209

• Scleritis may occasionally occur in AS patients [10]. Patients usually manifest as diffuse anterior scleritis (Fig. 15.16). • Conjunctivitis is an uncommon finding in AS patients. Patients usually show a self-limited conjunctivitis. It is a bilateral and nonpurulent inflammation.

15.6 Complications

Fig. 15.9  Circular pigmentary deposition on the lens surface observed in a patient with both AS and AAU

• Posterior synechiae is not common if the treatment is instituted immediately after disease onset. However, it may develop as a result of delayed treatment or in the AS patients with chronic uveitis (Fig. 15.17).

Fig. 15.10  Papillitis observed in patients with both AS and AAU

a

b

Fig. 15.11  Multiple chorioretinal lesions observed in a female AS patient. (a: fundus photograph; b: fundus fluorescein angiography result)

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Fig. 15.12  Staining of the optic disc observed in a male patient with both AS and AAU

a

b

c

d

e

f

Fig. 15.13  Staining of the optic disc and vascular leakage observed in a patient with both AS and AAU (a–c) substantially subsides following the resolution of anterior chamber inflammation after treatment (d–f)

15.6 Complications

211

a

b

c

d

e

f

Fig. 15.14  Staining of the optic disc, vascular leakages, and CME (a–c) in a male patient with both AS and AAU are greatly improved at 1 month following treatment (d–f)

Fig. 15.15  Staining of the retinal vessel walls observed in a female patient with both AS and AAU

212

15  Uveitis Associated with Ankylosing Spondylitis

a

b

Fig. 15.16  Diffuse anterior scleritis observed in a patient with both AS and AAU (a: photograph; b: UBM result)

• Cataract is an uncommon complication in AS patients with AAU.  However, it is observed in AS patients with chronic anterior uveitis (Fig. 15.18). • Elevated intraocular pressure is mainly observed in AS patients with chronic anterior uveitis and those with entire posterior synechiae or extensive anterior synechiae. • Band keratopathy, shallow anterior chamber (Fig. 15.19), peripheral anterior synechiae, and even phthisis bulbi may be observed in AS patients with long-lasting or recurrent anterior uveitis.

15.7 Diagnosis • As the attack of AAU does not correlate with the severity of the spinal inflammation, it is very important to take history about AS in patients with this inflammation. • The history should carefully characterize the symptoms with special attention to the inflammatory back pain and stiffness. • The diagnosis of AS is principally based on history, clinical evaluation, and imaging investigations (Figs.  15.20, 15.21, 15.22, and 15.23).

• The criteria for AS used widely is the modified New York criteria (1984 Table 15.1) [1]. • HLA-B27 typing is useful for the diagnosis of AS. However, it should be kept in mind that HLA-B27negative individuals may also develop AS as well as AAU. • UBM is very useful for evaluation of the anterior segment changes in AS patients with AAU. The changes include cells in the anterior and posterior chamber, exudates, hypopyon and posterior synechiae (Fig. 15.24) [11].

15.8 Differential Diagnosis • • • • • • • • •

Idiopathic AAU. AAU associated with reactive arthritis. AAU associated with psoriasis. AAU associated with inflammatory bowel disease. AAU seen in sarcoidosis. Bacterial or fungal endophthalmitis Tubulointerstitial nephritis and uveitis syndrome. Behcet’s disease. Vogt–Koyanagi–Harada disease (anterior uveal involvement stage).

15.8 Differential Diagnosis

Fig. 15.17  Posterior synechiae observed in patients with both AS and AAU

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15.9 Treatment

Fig. 15.18  Complicated cataract in a patient with both AS and chronic anterior uveitis (a relatively rare complication)

• Treatment for AS. –– The treatment of AS is principally based on the severity and activity of the disease and should be referred to the specialists in rheumatology department. –– Systemic nonsteroidal anti-inflammatory drugs may be helpful in relieving inflammatory back pain and slowing down the frequency of the attacks. –– Systemic corticosteroids combined with immunosuppressive agents including cyclosporine, methotrexate, and azathioprine are used for certain cases. –– Biologic agents used in the treatment of refractory AS mainly include anti-TNF-α agents such as infliximab, etanercept, adalimumab, and golimumab.

Fig. 15.19  Band keratopathy and shallow anterior chamber (very rare manifestations) observed in a patient with both AS and AAU

a

b

Fig. 15.20  Erosion, sclerosis, and closure of sacroiliac joint in a patient with both AS and AAU (a, b: computed tomography results; c: X-ray result)

15.9 Treatment

c

Fig. 15.20 (continued)

Fig. 15.21  Changes in the sacroiliac joint width and erosion detected by CT in patients with both AS and AAU

215

216 Fig. 15.22  Sacroiliac joint changes detected by magnetic resonance imaging (MRI) in patients with both AS and AAU

15  Uveitis Associated with Ankylosing Spondylitis

15.9 Treatment

217

Fig. 15.23  Bridging syndesmophytes and “bamboo spine” disclosed by X-ray in an AS patient

Table 15.1 Modified New  York criteria, 1984 for ankylosing spondylitis A. Diagnosis 1.  Clinical criteria (a) Low back pain and stiffness for more than 3 months which improves with exercise, but is not relieved by rest (b) Limitation of motion of the lumbar spine in both the sagittal and frontal planes (c) Limitation of chest expansion relative to normal values corrected for age and sex 2.  Radiologic criteriona Sacroiliitis grade ≥2 bilaterally or sacroiliitis grade 3–4 unilaterally B. Grading 1. Definite ankylosing spondylitis if the radiologic criterion is associated with at least one clinical criterion 2.  Probable ankylosing spondylitis if: (a)  Three clinical criteria are present (b) The radiologic criterion is present without any signs or symptoms satisfying the clinical criteria (Other causes of sacroiliitis should be considered) Reprinted with permission from Linden SV, Valkenburg HA, and Cats A.  Evaluation of Diagnostic Criteria for Ankylosing Spondylitis. A Proposal for Modification of the New  York Criteria. Arthritis and Rheumatism 1984;27:361–368 a Radiologic grading of sacroiliitis: 0, normal; 1, suspicious; 2, minimal abnormality (small localized areas or erosion or sclerosis without alteration in the joint width); 3, unequivocal abnormality (erosions, sclerosis, change in joint width or partial ankylosis); and 4, severe abnormality (total ankylosis)

• Treatment for AS patients with uveitis –– Topical corticosteroids, cycloplegic and mydriatic drops are absolutely necessary for these patients and should be adjusted according to the severity of the inflammation. –– For the patients with severe inflammation, such as extensive fibrous exudates in the anterior chamber and hypopyon or CME, subconjunctival or systemic corticosteroids in a low dose usually 20–30 mg per day are used for a short time (normally 2–4 weeks). • Treatment of the complications –– Phacoemulsification and intraocular lens implantation can be safely performed in most patients with quiescent inflammation. Topical and, if necessary, systemic corticosteroids should be prescribed for a few days before and after surgery. The use of topical corticosteroids should be adjusted according to the postoperative reaction in the anterior chamber. –– Increased intraocular pressure or uveitic glaucoma is usually treated by topical carbonic anhydrase inhibitors, non-selective β-blockers and alpha-­ adrenergic agonists. Laser iridotomy or peripheral iridectomy is

218

Fig. 15.24  Changes disclosed by UBM in patients with both AS and AAU

15  Uveitis Associated with Ankylosing Spondylitis

15.9 Treatment

Fig. 15.24 (continued)

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220

15  Uveitis Associated with Ankylosing Spondylitis

necessary for the patients with pupillary block. Antiglaucoma surgeries including trabeculectomy, cyclophotocoagulation, or aqueous shunts should be performed for the patients with extensive peripheral anterior synechiae.

15.10 Prognosis • The prognosis of AS patients has been greatly improved with early diagnosis and aggressive treatment. • The visual prognosis of AS patients with AAU is generally good if adequate treatment is instituted immediately after disease onset. Optic nerve atrophy due to uveitic glaucoma and phthisis bulbi may lead to persistent visual impairment or even visual loss. • Chronic anterior uveitis is uncommon in AS patients. Patients with this inflammation frequently have recurrent episodes, posterior synechiae, or extensive peripheral anterior synechiae. Complicated cataract and secondary glaucoma in these patients are ominous signs and prognosticators of poor visual prognosis.

References 1. Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27(4):361–8.

2. Accorinti M, Iannetti L, Liverani M, et  al. Clinical features and prognosis of HLA B27-associated acute anterior uveitis in an Italian patient population. Ocul Immunol Inflamm. 2010;18(2):91–6. 3. Yang P, Wan W, Du L, et al. Clinical features of HLA-B27-positive acute anterior uveitis with or without ankylosing spondylitis in a Chinese cohort. Br J Ophthalmol. 2018;102(2):215–9. 4. Chang JH, McCluskey PJ, Wakefield D. Acute anterior uveitis and HLA-B27. Surv Ophthalmol. 2005;50(4):364–88. 5. Maza M.  Seronegative spondyloarthropathies. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 793–813. 6. Wakefield D, Carr G, McCluskey P. Ankylosing spondyloarthropathy. In: Zierhut M, Pavesio C, Ohno S, et al, Intraocular inflammation. Berlin: Springer. 2016; pp 693-702. 7. Wakefield D, McCluskey P.  HLA-B27-associated acute anterior uveitis. In: Zierhut M, Pavesio C, Ohno S, et al, Intraocular inflammation. Berlin: Springer. 2016; pp 967-973. 8. Huang X, Ye Z, Cao Q, et al. Gut microbiota composition and fecal metabolic phenotype in patients with acute anterior uveitis. Invest Ophthalmol Vis Sci. 2018;59(3):1523–31. 9. Brewerton D, Caftrey M, Nicholls A.  Acute anterior uveitis and HL-A 27. Lancet. 1973;2:994–6. 10. Yang P, Ye Z, Tang J, et  al. Clinical features and complica tions of scleritis in Chinese patients. Ocul Immunol Inflamm. 2018;26(3):387–96. 11. Yang P, Meng Q, Huang X, et al. Longitudinal study of anterior segment inflammation by ultrasound biomicroscopy in patients with acute anterior uveitis. Acta Ophthalmol. 2009;87(2):211–5.

Uveitis Associated with Reactive Arthritis

16

Contents 16.1  Definition 

 221

16.2  Epidemiology 

 221

16.3  Systemic Manifestations 

 221

16.4  Ocular Manifestations 

 222

16.5  Diagnosis 

 224

16.6  Differential Diagnosis 

 225

16.7  Treatment 

 225

16.8  Prognosis 

 226

References 

 226

16.1 Definition

16.3 Systemic Manifestations

• Reactive arthritis (ReA), known as Reiter's syndrome previously, typically shows a clinical trait including arthritis, urethritis, and conjunctivitis [1–3]. • Uveitis may occur in ReA patients. • ReA usually develops following genitourinary and gastrointestinal infections [1, 3].

• Arthritis [1, 3, 6] –– Arthritis usually develops within a month after genitourinary or gastrointestinal infections. –– Arthritis may be acute, chronic, or recurrent in nature, usually affecting ankles, knees and toes. –– Arthritis may manifest as monoarticular, pauciarticular, and polyarticular inflammation. –– Sacroiliitis (Fig. 16.1) and spondylitis may develop in the HLA-B27-positive ReA patients. –– Other manifestations include dactylitis (“sausage” digits) (Fig.  16.2), plantar fasciitis, Achilles tendonitis, and calcaneal periostitis. • Constitutional symptoms –– Malaise and fatigue –– Low-grade fever –– Weight loss

16.2 Epidemiology • There are no accurate epidemiologic data about this disease. • ReA usually affects young males between the ages of 30 and 40 years old [1, 3]. • Uveitis associated with ReA is a rare disease [4, 5].

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_16

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Fig. 16.1  Sacroiliitis detected by Pelvic X-ray in a ReA patient with uveitis

Fig. 16.2  “Sausage” digits (arrow) observed in a ReA patient with uveitis

16  Uveitis Associated with Reactive Arthritis

–– It is usually nonspecific and self-limited inflammation, lasting for less than 10 days. –– Bilateral involvement is common. • Uveitis [1, 3, 6] –– Anterior uveitis is a relatively common ocular manifestation, developing in 2.3%~12% of the ReA patients. It is usually acute in nature. Patients usually complain about redness, pain, photophobia, and tearing. It frequently occurs 2–4 weeks after genitourinary and gastrointestinal infections. It frequently occurs in HLA-B27-positive patients, especially in those with sacroiliitis. Bilateral involvement is usual although the initial attack is always unilateral. It usually shows a nongranulomatous inflammation, presenting as ciliary injection, fine dust-­ like keratic precipitates (KPs), flare and cells in the anterior chamber. Intensive fibrous exudates and even hypopyon may appear in severe cases (Fig. 16.3). Posterior synechiae is a common sequela in this disease (Fig. 16.4). Peripheral anterior synechiae and even glaucoma secondary to pupillary block may develop in the patients with recurrent episodes. –– Posterior uveitis or panuveitis may also be observed in certain ReA patients (Figs. 16.5 and 16.6). • Other ocular manifestations –– Episcleritis is a rare manifestation and may be simple or nodular in nature. –– Scleritis, usually manifesting as diffuse anterior scleritis, may occasionally occur at some point following the development of conjunctivitis and AAU. –– Keratitis may develop alone or in association with conjunctivitis or AAU.

• Genitourinary manifestations [1, 3] –– Urethritis is the most common manifestation. –– Other manifestations include prostatitis, epididymitis, seminal vesiculitis, cystitis, orchitis, vaginitis, and cervicitis.

16.4 Ocular Manifestations • Conjunctivitis [1, 3, 6] –– Conjunctivitis is the most common ocular manifestation in ReA patients, accounting for up to 58–74% of the total patients. –– Conjunctivitis frequently occurs a few weeks after arthritis or urethritis onset although it may be the presenting manifestation of this disease.

Fig. 16.3  Descemet’s folds, exudate membrane, iris bombe due to complete posterior synechiae of the iris, and hypopyon observed in a ReA patient with acute anterior uveitis (AAU)

16.4 Ocular Manifestations

223

Fig. 16.4  Entire posterior synechiae observed in a ReA patient with AAU

a

b

c

Fig. 16.5  Attenuation and occlusion of retinal vessels in association with retinal atrophy and pigmentation observed in a male ReA patient with uveitis (a). Optical coherence tomography (OCT) imaging shows retinal atrophy (b, c)

Fig. 16.6  Vascular leakages and nonperfusion of capillaries disclosed by fundus fluorescein angiography (FFA) in the ReA patient with uveitis as described in Fig. 16.5

224

–– Other rare manifestations consist of optic disc edema, macula edema, retinal vasculitis, and retinal microvasculitis (Fig. 16.6).

16.5 Diagnosis • The diagnosis is principally based on history and clinical manifestations. • Bone scanning or magnetic resonance imaging (MRI) is useful in the diagnosis of arthritis [1, 3].

16  Uveitis Associated with Reactive Arthritis

• HLA-B27 testing may provide additional evidence for the diagnosis of ReA, but is not absolutely necessary. • Ultrasound biomicroscopy (UBM) is useful in evaluation of changes in the anterior segment of ReA patients (Figs. 16.7 and 16.8). • Diagnostic criteria for ReA have been proposed by Lee et al. (Tables 16.1 and 16.2) [1]. This system consists of major manifestations including arthritis, conjunctivitis or AAU, arthritis or cervicitis and mucocutaneous lesions, and minor manifestations. Arthritis plus at least two other major manifestations could establish a definite diagnosis.

a

b

c

d

Fig. 16.7  Detachment of the ciliary body (a, b) and exudates in the anterior chamber (c, d) detected by UBM in ReA patients with uveitis

16.7 Treatment

225

a

b

c

d

e

f

g

h

Fig. 16.8  Striking alterations in the anterior segment detected by UBM in a ReA patient with AAU (a–d). These alterations almost completely disappear following a two-month treatment with a low-dose sys-

temic prednisone combined with topical corticosteroids and cycloplegic agents (e–h)

16.6 Differential Diagnosis

–– The patients with systemic manifestations should be recommended to consult relevant specialists. Oral nonsteroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids, methotrexate, and azathioprine are tailored according to the patients’ condition. –– Antibiotic therapy may be necessary for the patients with sexually acquired ReA. • AAU –– Topical corticosteroids and cycloplegic/mydriatic agents should be used once the diagnosis is made. –– A high frequency of topical corticosteroids is needed for the patients with severe AAU. –– A short use of systemic corticosteroids at a low to middle dosage may be necessary for the patients with

• • • • •

Idiopathic AAU. AAU associated with AS. AAU associated with psoriasis. Tubularinterstitial nephritis and uveitis syndrome. Anterior chamber inflammation observed in Behcet’s disease (BD). • AAU associated with inflammatory bowel disease.

16.7 Treatment • Systemic disease

226

16  Uveitis Associated with Reactive Arthritis

Table 16.1  Proposed major and minor criteria for the diagnosis of Reiter’s syndromea Major Joints Polyarthritis

Eyes Conjunctivitis or iridocyclitis Genitourinary Urethritis Skin Keratoderma blennorrrhagica or balanitis circinata

Table 16.2  Likelihood of diagnosing Reiter’s syndrome according to number of proposed criteria presenta

Minor Likelihood of diagnosis Definite

Plantar fasciitis Achilles tendinitis Pain in the lower part of the back Sacroiliitis Spondylitis

a

Keratilis Genitourinary system Cystitis Prostatitis

16.8 Prognosis

Painless oral mucosal involvement Psoriasiform eruptions Nail changes Gastrointestinal Diarrhea associated with other symptoms in the complex Laboratory findings Positive HLA-B27 Leukocytosis Increased α1-, α2-, or γ-globulins on serum protein electrophoresis Inflammation revealed on synovial fluid analysis

severe AAU or with the involvement of the posterior segment, such as optic edema, cystoid macular edema, and retinal vasculitis. –– In general, AAU in ReA patients does not necessitate other immunosuppressive agents. However, they may be necessary for the treatment of systemic disorders in these patients. • Scleritis –– Topical NSAIDs and corticosteroids are required for the patients with scleritis. –– Oral NSAIDs may be needed for the ReA patients with scleritis. –– Systemic corticosteroids and even other immunosuppressive agents are usually needed in the treatment of the patients with severe scleritis or with recurrent episodes.

Probable Possible

No. of Criteria Major ≥3 2 2 2

Minor – ≥3 2 1

Reprinted with permission from Lee DA, et al. The clinical diagnosis of Reiter’s syndrome. Ophthalmology 1986;93:350–356

• Anterior uveitis and anterior scleritis usually respond well to the aforementioned treatments. Most patients have a good visual prognosis. However, recurrent episodes of uveitis may result in the development of glaucoma or cystoid macular edema. • The prognosis of the patients with systemic disease is highly variable. The patients may experience recurrent arthritis or even chronic arthritis. Disabilities may occur in some patients. Mortality may develop in the patients with cardiac involvement or amyloidosis.

References 1. Lee DA, Barker SM, Su WP, et al. The clinical diagnosis of Reiter’s syndrome. Ophthalmic and nonophthalmic aspects. Ophthalmology. 1986;93(3):350–6. 2. Taylor-Robinson D, Gilroy CB, Thomas BJ, et  al. Detection of Chlamydia trachomatis DNA in joints of reactive arthritis patients by polymerase chain reaction. Lancet. 1992;340(8811):81–2. 3. Wakefield D, Carr G, McCluskey P. Reactive arthritis. In: Zierhut M, Pavesio C, Ohno S, et  al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 703–12. 4. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 5. Chang JH, McCluskey PJ, Wakefield D. Acute anterior uveitis and HLA-B27. Surv Ophthalmol. 2005;50(4):364–88. 6. Maza MS.  Seronegative spondyloarthropathies. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 793–813.

Uveitis Associated with Psoriasis

17

Contents 17.1  Definition 

 227

17.2  Epidemiology 

 227

17.3  Etiology and Pathogenesis 

 227

17.4  Systemic Manifestations 

 228

17.5  Ocular Manifestations 

 231

17.6  Complications 

 236

17.7  Diagnosis 

 236

17.8  Differential Diagnosis 

 238

17.9  Treatment 

 238

17.10  Prognosis 

 242

References 

 242

17.1 Definition • Psoriasis is an immunologically mediated systemic disease and characterized by skin lesions, nail changes, arthritis, and ocular involvement [1–3]. • Psoriasis is generally divided into four types: psoriasis vulgaris, psoriatic arthritis (PsA), psoriatic erythroderma, and pustular psoriasis. • All of the four types have been shown to be associated with ocular involvement (mainly uveitis). However, PsA is more likely the most common type to be associated with uveitis [1, 4, 5].

• Psoriasis vulgaris accounts for over 90% of the psoriasis patients. • PsA accounts for 5–7% of the patients with psoriasis. A literature review by Zeboulon et al. shows that about 25% of the patients with PsA develop uveitis [6]. • Psoriasis occurs more frequently in the individuals in the 3rd or 4th decade of life. • Psoriasis affects male more commonly than female. In a recent report, we found that the male to female ratio is 2.6:1 in psoriasis patients with uveitis [5]. • Uveitis associated with psoriasis is relatively uncommon in clinical practice [7].

17.2 Epidemiology

17.3 Etiology and Pathogenesis

• Psoriasis is reported to occur in 1–3% of the world population.

• Psoriasis is presumably caused by innate or acquired immune reactions.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_17

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228

• The involved cells include Th1 cells, Th17 cells, CD8+ T cells, and dendritic cells. Imbalance of Th1, Th17/Th2 cells has been documented in this disease [2, 4]. • A number of cytokines including IFN-γ, TNF, IL-23, IL-6, and IL-8 have been reported to be involved in the development of this disease [2, 4]. • Genetic factors have been shown to be involved in the pathogenesis of psoriasis, especially PsA.  HLA-B27, HLA-Cw∗06, HLA-DRB1∗07, and HLA-DR13 have been identified to be associated with PsA or uveitis in PsA [2, 4].

17  Uveitis Associated with Psoriasis

17.4 Systemic Manifestations • Skin lesions –– Psoriasis vulgaris is the most common form of psoriasis characterized by sharply demarcated and erythematous scaly papules and/or plaques. These lesions are usually covered by dry, slivery, and loosely adherent scales (Fig. 17.1). –– Erythrodermic psoriasis is characterized by generalized erythema and scaling and may affect almost all of the body surface (Fig. 17.2).

Fig. 17.1  Cutaneous changes observed in patients with both psoriasis vulgaris and uveitis

17.4 Systemic Manifestations

229

Fig. 17.2  Skin lesions observed in patients with both erythrodermic psoriasis and uveitis

–– Pustular psoriasis may manifest as erythema and sterile pustules (Fig. 17.3). –– PsA may manifest as mono- or asymmetric oligoarthritis. Inflammation of the interphalangeal joints, both the distal (DIP) and proximal (PIP) of the hands and feet, is the most common form of PsA (Fig. 17.4). Involvement of the PIP or both the DIP and PIP joints can result in the classic “sausage toes” (Fig. 17.5). Exclusive involvement of the DIP joints is a “classic” but not the presentation in PsA.  This variant may develop in association with contiguous nail involvement. In some patients, these joints will become fixed in a flexed position (Fig.  17.6). Rheumatoid arthritis-like presentation may also be

observed. It manifests as symmetric polyarthritis that involves small- and medium-sized joints, especially the PIP, metacarpophalangeal joints (MCP), wrists, ankles, and elbows. Arthritis mutilans, spondylitis, and sacroiliitis may also develop in patients with psoriasis. –– Nail psoriasis The fingernails are more commonly affected than the toenails. Nail changes include thick, brittle, DIP onycholysis, pitting, and “oil spot” phenomenon (Fig. 17.7). –– Psoriasis of the scalp is characterized by plaques over the scalp. Palpation of the scalp gives a “miniature mountain” feeling (Fig. 17.8).

230

Fig. 17.3  Erythema and sterile pustules observed in patients with pustular psoriasis

17  Uveitis Associated with Psoriasis

17.5 Ocular Manifestations

231

Fig. 17.6  Arthritis observed in a male patient with PsA and uveitis shows fixed fingers in a fixed position

17.5 Ocular Manifestations

Fig. 17.4  Skin lesions and arthritis observed in a male patient with PsA, erythrodermic psoriasis, and uveitis

Fig. 17.5  Sausage toes observed in a male patient with both PsA and uveitis

• Psoriasis precedes uveitis in most patients. • Most patients show bilateral ocular involvement. • Intraocular inflammation associated with psoriasis predominantly manifests as anterior uveitis, followed by panuveitis and posterior uveitis. • Anterior uveitis accounts for 56.9% of the patients with both psoriasis and uveitis in our uveitis center. • Anterior uveitis accounts for 80% of the patients with both PsA and uveitis. • Psoriasis appears to be associated with Vogt– Koyanagi–Harada (VKH) disease in few patients (Fig. 17.9) [5]. • Uveitis observed in psoriatic patients is usually nongranulomatous. However, patients with both psoriasis and VKH disease definitely show a granulomatous intraocular inflammation. • Anterior uveitis typically shows acute and nongranulomatous inflammation, especially in patients with PsA or those who are HLA-B27-positive [5]. –– Fine keratic precipitates (KPs), aqueous flare and cells, even fibrous exudates, hypopyon (Fig.  17.10), and occasionally hyphema (Fig.  17.11) are observed in these patients. Very few psoriatic patients may manifest as granulomatous anterior uveitis, showing mutton fat KPs (Fig.  17.12), sago-like Koeppe and Busacca nodules (Fig. 17.13).

232

Fig. 17.7  Nail changes observed in patients with psoriasis and uveitis

Fig. 17.8  Scalp psoriasis observed in patients with both psoriasis and uveitis

17  Uveitis Associated with Psoriasis

17.5 Ocular Manifestations Fig. 17.9  Psoriasis occurring at the areas of vitiligo observed in a patient with VKH disease

Fig. 17.10  Hypopyon observed in patients with both psoriasis and uveitis

233

234

17  Uveitis Associated with Psoriasis

Fig. 17.11  Hyphema observed in a male patient with both psoriasis and uveitis

Fig. 17.12  Mutton fat KPs observed in a female patient with both psoriasis and uveitis

–– Posterior synechiae (Fig. 17.14) is a common manifestation in patients with recurrent anterior uveitis attack. • Posterior segment involvement includes intermediate uveitis, vitreous opacities (Fig.  17.15), retinal vasculitis (mostly microvasculitis), retinitis (Fig. 17.16), and retinal hemorrhage. • Other ocular lesions –– Conjunctivitis occurs in 20% of the psoriasis patients with ocular involvement. –– Episcleritis and scleritis may occur in 1–2% of the psoriasis patients. Scleritis usually presents as anterior scleritis. However, it may also present as posterior scleritis.

17.5 Ocular Manifestations

235

Fig. 17.13  Koeppe and Busacca nodules observed in patients with both psoriasis and uveitis

Fig. 17.14  Posterior synechiae observed in patients with both psoriasis and uveitis

Fig. 17.15  Obvious vitreous opacities observed in a female patient with psoriasis and uveitis

Fig. 17.16  Retinitis observed in a male patient with psoriasis and uveitis (a very rare manifestation)

236

17.6 Complications –– Cataract is the most common complication in psoriatic patients with uveitis. –– Elevated intraocular pressure or secondary glaucoma is another common complication. It is mostly due to complete posterior synechiae and/or extensive anterior synechiae. Persistently elevated intraocular pressure may result in optic nerve atrophy (Fig. 17.17).

Fig. 17.17  Atrophy of the optic nerve observed in a male patient with psoriasis and uveitis

17  Uveitis Associated with Psoriasis

–– Cystoid macular edema (CME) is a common complication in psoriatic patients with retinal microvasculitis. –– The less common complications include retinal neovascularization, retinal detachment, and epiretinal membrane (Fig. 17.18).

17.7 Diagnosis • The diagnosis of psoriasis is principally made based on psoriatic skin lesions and nail changes [1]. • The diagnosis of PsA is made based on psoriatic skin lesions, spondyloarthropathy, or peripheral arthritis. • In the diagnosis of uveitis associated with psoriasis, it is important to take the history about psoriatic skin lesions and psoriatic arthropathy. It is always necessary to recommend the patients to consult relevant specialists for making a definite diagnosis of skin lesions or arthropathy. • Ultrasound biomicroscopy (UBM) is valuable in the evaluation of the anterior segment inflammation and the effectiveness of therapy (Fig. 17.19). • Optical coherence tomography (OCT) imaging has been used in the detection of CME (Fig. 17.20) and other abnormalities (Figs. 17.21 and 17.22) in the posterior pole and their dynamic changes during the course of this disease. • Fundus fluorescein angiography (FFA) is widely applied to evaluate the abnormalities of the retina and retinal vessels. The changes disclosed by FFA in the patients with both psoriasis and uveitis include vascular leakages (Figs. 17.23, 17.24, and 17.25), macular edema, staining of the optic nerve (Fig.  17.26), and neovascularization (Fig. 17.27)

Fig. 17.18  Epiretinal membrane associated with CME observed in the patient as described in Fig. 17.17

17.7 Diagnosis Fig. 17.19  Changes in the anterior segment disclosed by UBM in patients with both psoriasis and uveitis

237

238

17  Uveitis Associated with Psoriasis

a

b

c

d

Fig. 17.20  CME (a, b) in association with detachment of the retinal pigment epithelium (c, d) detected by OCT imaging in patients with both psoriasis and uveitis

Fig. 17.21  Serous retinal detachment in the macular area detected by OCT imaging in a patient with both psoriasis and uveitis

17.8 Differential Diagnosis • As ankylosing spondylitis, reactive arthritis, and PsA may share similar clinical manifestations, it is important to differentiate uveitis associated with psoriasis from that associated with the other two conditions. • Other entities including idiopathic acute anterior uveitis, anterior uveitis observed in Behcet’s disease (BD), sarcoidosis, and tubulointerstitial nephritis should also be differentiated from that seen in psoriatic patients.

17.9 Treatment • Skin lesions and arthritis should be treated by specialists in dermatology department or rheumatology department. • For the patients with uveitis, treatment modalities are as follows [2, 4, 5]. –– Topical cycloplegic/mydriatic and corticosteroids are indicated for anterior uveitis seen in psoriatic patients. –– Periocular injections of triamcinolone (20–40 mg) are recommended for the psoriasis patients with CME or those with inflammation in the posterior segment. –– Oral corticosteroids are useful for posterior uveitis or panuveitis associated with psoriasis. However,

Fig. 17.22  Swelling of the optic disc observed in a patient with both psoriasis and uveitis

they may deteriorate the skin lesions in some patients. A low dose of systemic corticosteroids (usually 20  mg or less prednisone) combined with other immunosuppressive agents are recommended for these patients. –– Immunosuppressive agents are indicated for the psoriasis patients with bilateral involvement, chronic or recurrent uveitis. Methotrexate at a dose of 7.5–15 mg per week is commonly used for these patients. Cyclosporine is used at an initial dose of 2–5 mg each day followed by gradual tapering. Cyclophosphamide, chlorambucil, azathioprine, and mycophenolate mofetil may also be used for these patients in the context of individuals’ conditions. Immunosuppressive agents are usually used in combination with low dose of systemic corticosteroids. –– Biologic agents, such as adalimumab and infliximab, have been used in the patients with severe cutaneous psoriasis or those with both PsA and uveitis. The effectiveness of these agents is expected to be confirmed by randomized controlled trials in Chinese patients. –– Other biologic agents have also been investigated in the treatment of psoriasis [8, 9].

17.9 Treatment

239

Fig. 17.23  Vascular leakages, CME, neovascularization, and staining of the optic disc detected by FFA in patients with both psoriasis and uveitis

240 Fig. 17.24 Vascular leakages disclosed by FFA in a psoriasis patient (a) subside completely following the treatment with cyclosporine and low dose of systemic corticosteroids (b)

17  Uveitis Associated with Psoriasis

a

b

Fig. 17.25  A male psoriasis patient shows no change of the fundus (a), but has obvious vascular leakages on FFA (b, c)

a

b

c

17.9 Treatment

241

Fig. 17.26  Staining of the optic disc and vascular walls, and vascular leakages detected by FFA in patients with psoriatic uveitis

a

b

Fig. 17.27  Retinal vascularization and vascular leakages disclosed by FFA in a psoriasis patient (a) subside following treatment with cyclosporine and low dose of systemic corticosteroid (b)

242

17.10 Prognosis • The visual prognosis varies greatly among psoriatic patients with uveitis. In general, it is worse than that in ankylosing spondylitis patients with uveitis. • Glaucoma, CME, devastating and long-lasting intraocular inflammation may result in severe visual impairment or even visual loss.

References 1. Fraga NA, Oliveira MF, Follador I, et  al. Psoriasis and uveitis: a literature review. An Bras Dermatol. 2012;87(6):877–83. 2. Maza MS. Seronegative spondyloarthropathies. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 793–813.

17  Uveitis Associated with Psoriasis 3. Schön MP, Boehncke WH.  Psoriasis. N Engl J Med. 2005;352(18):1899–912. 4. Sharma SM, Rosenbaum JT.  Psoriasis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 713–8. 5. Yang P, Zheng M, Zhang L, et al. Uveitis in Chinese patients with psoriasis. Ocul Immunol Inflamm. 2017;25(6):855–65. 6. Zeboulon N, Dougados M, Gossec L. Prevalence and characteristics of uveitis in the spondyloarthropathies: a systematic literature review. Ann Rheum Dis. 2008;67(7):955–9. 7. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 8. McInnes IB, Kavanaugh A, Gottlieb AB, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013;382(9894):780–9. 9. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin­12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356(6):580–92.

Uveitis Associated with Inflammatory Bowel Diseases

18

Contents 18.1  Definition 

 243

18.2  Epidemiology 

 243

18.3  Etiology and Pathogenesis 

 243

18.4  Systemic Manifestations 

 244

18.5  Ocular Manifestations 

 244

18.6  Complications 

 245

18.7  Diagnosis 

 245

18.8  Differential Diagnosis 

 246

18.9  Treatment 

 246

18.10  Prognosis 

 247

References 

 247

18.1 Definition • Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis [1, 2]. • Crohn’s disease is a granulomatous transmural inflammation mainly involving the ileum and cecum [2, 3]. • Ulcerative colitis is a chronic diffuse mucosal inflammation limited to the colon, predominantly affecting the rectum [1, 2]. • Both Crohn’s disease and ulcerative colitis are associated with uveitis and other ocular disorders [1–3].

18.2 Epidemiology • Both Crohn’s disease and ulcerative colitis are more commonly seen in North America and Northern Europe. • It occurs mainly in the populations of 25–45 years old. • Males and females are equally affected.

• IBD seems to be prevalent in the developed countries. • Uveitis associated with IBD is an uncommon disease in clinical practice [4].

18.3 Etiology and Pathogenesis • The exact mechanisms underlying both diseases are not completely understood. • Changes of gut microbiome have been recently disclosed and are considered to be involved in the pathogenesis of both diseases. • Genetic susceptibility has been identified in IBD. HLA-­ B27 is strongly associated with IBD-associated sacroiliitis and spondylitis. HLA-DRB1∗0103 is associated with ulcerative colitis with uveitis and arthritis. • Autoimmune response has also been presumably involved in the development of IBD.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_18

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18.4 Systemic Manifestations • Patients with Crohn’s disease usually complain of diarrhea in association with right-lower quadrant colicky pain, nausea, vomiting, anorexia, fever, fatigue, and weight loss. • Patients with ulcerative colitis typically present with intermittent bloody mucoid diarrhea associated with left-­ lower quadrant cramping pain. Patients may also experience fever, anorexia, profuse rectal hemorrhages, anemia, weight loss, dehydration, electrolyte imbalance, and even toxic megacolon. • Arthritis, manifesting as monoarticular or pauciarticular inflammation, sacroiliitis (Fig.  18.1), or spondylitis (Fig. 18.2), may occur in the IBD patients [2, 5]. • Other systemic manifestations include oral ulcerations, erythema nodosum, pyoderma gangrenosum, thrombophlebitis, primary sclerosing cholangitis, urogenital disorders, and hepatobiliary abnormalities.

18  Uveitis Associated with Inflammatory Bowel Diseases

–– Chronic anterior uveitis is also observed in some patients. Posterior synechiae, even seclusion of pupil, may develop (Fig. 18.3). –– Intermediate uveitis, posterior uveitis, and panuveitis may also be observed in IBD patients. –– Granulomatous uveitis is more frequently associated with Crohn’s disease.

18.5 Ocular Manifestations • Uveitis [1, 2, 6] –– It is a common ocular disorder associated with IBD. –– It occurs in 8–17% of the IBD patients. –– Uveitis develops frequently at some point after IBD onset although it may precede gastrointestinal disorder. –– It usually presents as acute and nongranulomatous anterior uveitis in nature. This form of inflammation is mainly observed in HLA-B27-positive patients. Ciliary injection, dust-like keratic precipitates (KPs), large number of aqueous cells, fibrous exudates, and even hypopyon are observed in these patients. Bilateral involvement is common.

Fig. 18.2  Spinal deformity observed in a patient with both ulcerative colitis and uveitis

Fig. 18.1  Sacroiliac alterations detected by computed tomography (CT) in a patient with ulcerative colitis and uveitis

18.7 Diagnosis

245

Fig. 18.3  Complete posterior synechiae (seclusion of pupil) observed in a female patient with both Crohn’s disease and uveitis

It usually develops some years after IBD onset. It is usually associated with arthritis and other extra-intestinal findings. • Corneal involvement –– Various corneal infiltrates may be observed. –– Corneal lesions may lead to astigmatism and visual impairment. • Other ocular findings –– Conjunctivitis. –– Extraocular muscle paresis. –– Orbital cellulitis and orbital pseudotumor.

18.6 Complications Fig. 18.4  Obvious vitreous opacity observed in a patient with both IBD and uveitis

–– Uveitis may be associated with or without gastrointestinal disease activity. –– Retinal vasculitis associated with obvious vitreous opacities (Fig. 18.4), subclinical retinal capillaritis disclosed by fundus fluorescein angiography (FFA) (Fig.  18.5), serous retinal detachment, multifocal inflammatory lesions, subretinal fibrosis and uveitis syndrome, retrobulbar neuritis, and papillitis have been described in IBD patients. • Scleritis and episcleritis [7] –– Scleritis may develop in 2.1–9.8% of the IBD patients. It occurs usually some years after IBD onset. It is usually associated with arthritis and other extra-intestinal findings. It mainly shows diffuse anterior inflammation although necrotizing anterior, nodular anterior and posterior scleritis may also develop. –– Episcleritis tends to develop in Crohn’s disease and the reported incidence is 3.2%.

• Acute anterior uveitis in IBD, like that in other seronegative spondyloarthropathies, is less commonly associated with complications. • Chronic anterior uveitis or posterior segment inflammation in IBD are apt to be associated with various complications such as posterior synechiae, cataract, elevated intraocular pressure or glaucoma, and cystoid macular edema.

18.7 Diagnosis • Tissue biopsy from colonoscopy in the context of clinical manifestations is the gold standard for IBD diagnosis. • Uveitis in IBD patients is readily diagnosed and should be classified according to the clinical manifestations and ancillary investigations. • It should always be kept in mind that various forms of uveitis may be associated with this disease. A careful history taking is necessary to establish the association between uveitis and IBD. • Fundus fluorescein angiography (FFA) is very useful in the detection of the retinal changes in IBD patients.

246

18  Uveitis Associated with Inflammatory Bowel Diseases

Fig. 18.5  Vascular leakages and staining of the optic disc disclosed by FFA in a male patient with ulcerative colitis

• Ultrasound biomicroscopy (UBM) (Fig.  18.6), optical coherence tomography (OCT) imaging, and B-scan ultrasonography are also useful in detection of the ocular abnormalities in IBD patients.

• Ocular tuberculosis and syphilitic uveitis should also be differentiated from the uveitis associated with IBD.

18.8 Differential Diagnosis

• The systemic disorders should be referred to specialists in relevant departments. • Acute anterior uveitis is readily controlled by topical corticosteroids, mydriatic and cycloplegic agents. • For the IBD patients with very severe anterior uveitis, subconjunctival injection of corticosteroid and/or short-­ term use of low-dose systemic corticosteroids (about 20 mg of prednisone each day) may be indicated. • For the IBD patients with posterior segment involvement, systemic corticosteroids are used alone or in conjunction

• Acute anterior uveitis associated with IBD should be differentiated from idiopathic anterior uveitis and that associated with other seronegative spondylarthropathies. • Other forms of uveitis associated with IBD should be differentiated from those associated with or without systemic diseases as well as idiopathic uveitis, such as Behcet’s disease, tubulointerstitial nephritis and uveitis syndrome, and ocular sarcoidosis.

18.9 Treatment

References

a

247

b

Fig. 18.6  Iris bombe due to complete posterior synechiae (a), edema of the ciliary body and exudates adjacent to this tissue (b) detected by UBM in a patient with both ulcerative colitis and uveitis

with other immunosuppressive agents such as cyclosporine, methotrexate, cyclophosphamide, chlorambucil, and mycophenolate mofetil. • Biologic agents such as TNF-α antagonists have been used in the treatment of IBD with a beneficial result. • Scleritis and keratitis are usually treated with topical and systemic corticosteroids. Combination with other ­immunosuppressive agents is indicated for patients with refractory inflammation.

18.10 Prognosis • Most IBD patients with ocular involvement have a good visual prognosis if treatment is instituted promptly. • Persistent cystoid macular edema and prolonged elevated intraocular pressure may result in permanent visual impairment.

References 1. Jones N. Uveitis associated with HLA-B27, arthritis and inflammatory bowel disease, Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 129–43. 2. Pasadhika S, Rosenbaum JT. Crohn’s disease and ulcerative colitis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 719–29. 3. Salmon JF, Wright JP, Murray AD. Ocular inflammation in Crohn’s disease. Ophthalmology. 1991;98(4):480–4. 4. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 5. Gravallese EM, Kantrowitz FG. Arthritic manifestations of inflammatory bowel disease. Am J Gastroenterol. 1988;83(7):703–9. 6. Petrelli EA, McKinley M, Troncale FJ.  Ocular manifestations of inflammatory bowel disease. Ann Ophthalmol. 1982;14(4):356–60. 7. de la Sainz MM, Jabbur NS, Foster CS.  Severity of scleritis and episcleritis. Ophthalmology. 1994;101(2):389–96.

Anterior Uveitis Associated with Herpesviruses

19

Contents 19.1  Definition

 249

19.2  Epidemiology

 249

19.3  Etiology and Pathogenesis

 249

19.4  Clinical Manifestations

 250

19.5  Complications

 261

19.6  Diagnosis

 261

19.7  Differential Diagnosis

 264

19.8  Treatment

 267

19.9  Prognosis

 267

References

 267

19.1 Definition • There are more than 100 herpesviruses, in which eight are found to cause uveitis in human, including herpes simplex virus (HSV) type 1 and 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein–Barr virus (EBV) and HSV-6, 7, and 8 [1]. • Both anterior uveitis and posterior uveitis could be caused by these herpesviruses [1–3]. • Fuchs syndrome and Posner–Schlossman syndrome have been reported to be associated with the infection of these viruses [4, 5]. • The relationship between anterior uveitis and herpesviruses is generally established based on clinical manifestations rather than confirmed by laboratory investigations. Therefore, this disease is named as anterior uveitis associated with herpesviruses or herpesvirus-associated anterior uveitis. Herpetic anterior uveitis is loosely used clinically. Actually and more accurately, it should be named as presumed herpetic anterior uveitis. • Anterior uveitis associated with HSV or VZV is a relatively common form of uveitis in our clinical practice.

Anterior uveitis associated with both viruses is, by and large, similar in clinical manifestations and therefore discussed together in this chapter.

19.2 Epidemiology • The prevalence of herpesvirus-associated anterior uveitis is not known. • There is no racial predilection. • Both males and females are equally affected. • It predominantly occurs at young and adult ages. • Unilateral involvement is usual. • Herpesvirus-associated anterior uveitis has been reported to account for 1.5% of total anterior uveitis patients in a tertiary center for uveitis in China [6].

19.3 Etiology and Pathogenesis • Herpesviruses infect primarily the mucosa and establish their latency in sensory ganglia.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_19

249

250

• Reactivation of the latent HSV due to a wide range of factors may cause various ocular lesions mainly including anterior uveitis. • Immune response induced by the infected herpesviruses may also contribute to the development of anterior uveitis.

19.4 Clinical Manifestations • In general, there is no systemic manifestation during the active stage of anterior uveitis.

19  Anterior Uveitis Associated with Herpesviruses

• Herpes zoster ophthalmicus (Fig.  19.1) may precede the development of anterior uveitis in a few patients [7, 8]. • Patients usually complain about redness, burning, photophobia, tearing, pain, blurred vision, or decreased vision. • Anterior uveitis may be associated with corneal lesions. • The accompanied corneal lesions typically manifest as disciform keratitis or interstitial keratitis (Figs. 19.2 and 19.3) although epithelial dendritic keratitis is considered as the hallmark of the infection of HSV in the literature. The lesions may also involve the peripheral cornea (Fig. 19.4) and corneal endothelium, manifesting as corneal endotheliitis [1, 7, 9].

Fig. 19.1  Skin lesions and scars observed in herpes zoster ophthalmicus patients with uveitis

19.4 Clinical Manifestations

251

Fig. 19.2  Interstitial keratitis associated with anterior uveitis with various appearances observed in patients with herpesvirus-associated uveitis

252

• Ciliary flush with or without forniceal conjunctival congestion is usually present. The congestion may be 360° (Fig.  19.5) or confined to one or more quadrants (Fig. 19.6). • Keratic precipitates (KPs) are usually medium-sized or mutton fat-like in appearance, small in number (although

a

19  Anterior Uveitis Associated with Herpesviruses

a large number of these KPs are occasionally observed), and distributed on the endothelium of the affected areas of the cornea (Fig. 19.7). Mutton fat KPs frequently toned with pigmentation distributed diffusely or inferiorly on the endothelium are characteristic findings in these patients with iridocyclitis (Fig. 19.8) [1, 2, 10].

d

b

e

c

f

Fig. 19.3  Thickening of the cornea detected by anterior segment optical coherence tomography (OCT) imaging in patients with herpesvirus-­ associated interstitial keratitis (a, d: anterior segment OCT imaging

results of normal cornea; b, e: anterior segment OCT imaging results of the affected cornea; c, f: photographs of affected cornea)

19.4 Clinical Manifestations

Fig. 19.4  The lesions observed in the peripheral cornea in patients with herpesvirus-associated uveitis

Fig. 19.5  Ciliary congestion involving 360° observed in patients with herpesvirus-associated anterior uveitis

Fig. 19.6  Localized congestion observed in patients with herpesvirus-associated anterior uveitis

253

254

19  Anterior Uveitis Associated with Herpesviruses

Fig. 19.7  Medium-sized and mutton fat KPs distributed on the endothelium of the affected cornea observed in patients with herpesvirus-­associated anterior uveitis

• Varying degrees of anterior chamber inflammation are observed in these patients. Moderate inflammation is noted in most patients, whereas severe inflammation as evidenced by fibrous exudates, severe cellular and flare reaction, and even hypopyon may be occasionally present (Fig. 19.9). • Iris atrophy [1, 2, 8] –– Iris stromal atrophy is a pathognomonic feature of anterior uveitis associated with herpesviruses.

–– Iris stromal atrophy may be single (Fig.  19.10) but usually multiple (Fig. 19.11) in number. –– Iris stromal atrophy may be round, oval (Fig. 19.11), or irregular in appearance (Fig. 19.12). –– Large areas of iris stromal atrophy associated with varying degrees of depigmentation are observed in the patients with herpesvirus-associated anterior uveitis (Fig. 19.13)

19.4 Clinical Manifestations

255

Fig. 19.8  KPs distributed diffusely or inferiorly on the endothelium of the cornea observed in patients with herpesvirus-associated anterior uveitis

256

19  Anterior Uveitis Associated with Herpesviruses

Fig. 19.9  Hypopyon associated with corneal involvement observed in a patient with herpesvirus-associated anterior uveitis

Fig. 19.10  Single iris atrophy observed in patients with herpesvirus-associated anterior uveitis

–– Sector iris stromal atrophy has been described as a classic finding for this disease (Fig. 19.14). However, it is less commonly seen in our patients. –– Iris stromal atrophy may involve the whole iris, leading to a very large pupil (Fig. 19.15). • Posterior synechiae –– Posterior synechiae are common in anterior uveitis associated with HSV or VZV.

–– Irregular pupil secondary to posterior synechiae is usual and permanent if no surgery is performed in these patients (Fig. 19.16). Irregular pupil in patients with herpesvirus-associated anterior uveitis typically shows a “rigid” appearance (Fig.  19.17), contrary to that observed in other uveitis entities. –– This “rigid” posterior synechiae is considered to be caused by the damage to pupillae sphincter.

19.4 Clinical Manifestations

Fig. 19.11  Multiple iris stromal atrophy lesions observed in patients with herpesvirus-associated anterior uveitis

Fig. 19.12  Iris stromal atrophy showing irregular appearances in patients with herpesvirus-associated anterior uveitis

257

258

19  Anterior Uveitis Associated with Herpesviruses

Fig. 19.13  Iris atrophy accompanied by varying degrees of depigmentation observed in patients with herpesvirus-associated anterior uveitis

19.4 Clinical Manifestations

Fig. 19.14  Sector iris atrophy observed in patients with herpesvirus-associated anterior uveitis

Fig. 19.15  Iris stromal atrophy involving the whole iris in patients with herpesvirus-associated anterior uveitis

Fig. 19.16  A very large pupil has been diminished following operation observed in a patient with herpesvirus-associated anterior uveitis

259

260

19  Anterior Uveitis Associated with Herpesviruses

Fig. 19.17  The pupil displaying a particular “rigid” appearance due to the damage to pupillae sphincter observed in patients with herpesvirus-­ associated anterior uveitis

19.6 Diagnosis

261

Fig. 19.18  Pupillary margin is hardly observed in the affected areas observed in patients with herpesvirus-associated anterior uveitis

development of optic nerve atrophy. However, persistently elevated intraocular pressure may result in enlarged C/D (Cup/Disc) ratio (Fig. 19.19).

19.5 Complications • Corneal lesions may leave scarring and neovascularization in the cornea following treatment. • Prolonged or recurrent iridocyclitis and trabeculitis may be associated with decompensation of the corneal endothelium and result in bullous keratopathy. • Glaucomatous damage to the optic nerve may develop as a result of persistently elevated intraocular pressure. • Complicated cataract may follow in the patients with recurrent or chronic herpetic anterior uveitis.

19.6 Diagnosis Fig. 19.19  An enlarged C/D ratio observed in a herpesvirus-associated anterior uveitis patient with permanently increased intraocular pressure

–– Irregular pupil is usual in these patients. Pupillary margin in the affected area is sometimes not observed due to the extremely dilated pupil (Fig. 19.18). • Elevated intraocular pressure –– It is a quite common sign in this disease and presumably arises from trabeculitis. –– It can last for a few weeks or months even under treatment. –– Unlike patients with acute angle-closure glaucoma, these patients usually tolerate elevated intraocular pressure well for a long time and are not prone to the

• The diagnosis of anterior uveitis associated with HSV or VZV predominantly depends on the clinical features. –– Medium-sized or mutton fat KPs toned with pigmentation are distributed diffusely or inferiorly, which is the hallmark of herpesvirus-associated anterior uveitis. –– Other typical clinical feature includes varying degrees and various appearances of iris stromal atrophy. –– Anterior uveitis frequently associated with elevated intraocular pressure. • Decreased number and abnormal morphological appearances of the endothelial cells are observed in certain patients with herpetic anterior uveitis (Figs.  19.20 and 19.21).

262

19  Anterior Uveitis Associated with Herpesviruses

a

ID. Last Name First Name Date Eye Label

: : : : : :

b

201201389

ID. Last Name First Name Date Eye Label

2012-08-30 Right #1

Number of Cells Minimum Size Maximum Size Average Size Total Size S.D. of Size C.V. for Size

34

73

Hexagonality

201201389 2012-08-30 Left #2 101

Number of Cells

572.9 (um2) 1867.6 (um2) 1100.8 (um2) 37426.1 (um2) 298.3 (um2) 27.1 (%) 908.5

Cell Density

: : : : : :

Minimum Size Maximum Size Average Size Total Size S.D. of Size C.V. for Size

(/mm)

Cell Density

(%)

Hexagonality

20% 0% 10% 0~ 100~ 200~ 300~ 400~ 500~ 600~ 700~ 800~ 900~ 1000~ 1100~ *Above 1200 : 23.5%

30%

40%

148.8 (um2) 718.6 (um2) 379.1 (um2) 38292.1 (um2) 112.6 (um2) 29.7 (%) 2637.6 60

(/mm) (%)

50% 0.0% 0.0% 0.0% 0.0% 0.0% 5.9% 5.9% 0.0% 8.8% 11.8% 20.6% 23.5%

0% 0~ 100~ 200~ 300~ 400~ 500~ 600~ 700~

20%

10%

30%

40%

50% 0.0% 4.0% 20.8% 34.7% 26.7% 9.9% 3.0% 1.0%

Fig. 19.20  Decreased number and morphological abnormalities of corneal endothelium observed in a male patient with herpesvirus-associated anterior uveitis. (a: the affected eye; b: the normal eye)

a

b

ID. Last Name First Name Date Eye Label

: : : : : :

20141583 2014-06-26 Right #1

Number of Cells Minimum Size Maximum Size Average Size Total Size S.D. of Size C.V. for Size Cell Density

798.3 (um2) 1984.4 (um2) 1529.6 (um2) 36710.6 (um2) 282.1 (um2) 18.4 (%) 653.8 67

10%

*Above 1200 : 87.5%

: : : : : :

20141583 2014-06-26 Left #2

Number of Cells

24

Hexagonality

0% 0~ 100~ 200~ 300~ 400~ 500~ 600~ 700~ 800~ 900~ 1000~ 1100~

ID. Last Name First Name Date Eye Label

20%

Minimum Size Maximum Size Average Size Total Size S.D. of Size C.V. for Size

(/mm)

Cell Density

(%)

Hexagonality

30%

40%

112 99.0 (um2) 827.4 (um2) 387.0 (um2) 43344.7 (um2) 140.8 (um2) 36.4 (%) 2583.9 61

(/mm) (%)

50% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 4.2% 0.0% 0.0% 0.0% 8.3%

0% 0~ 100~ 200~ 300~ 400~ 500~ 600~ 700~ 800~

10%

20%

30%

40%

50% 0.9% 6.3% 17.0% 37.5% 20.5% 8.9% 5.4% 1.8% 1.8%

Fig. 19.21  Decreased number and morphological abnormalities of corneal endothelium observed in a female patient with herpesvirus-associated anterior uveitis. (a: the affected eye; b: the normal eye)

19.6 Diagnosis

263

Fig. 19.22  Large number of inflammatory cells detected by UBM in a patient with herpesvirus-associated anterior uveitis

• Ultrasound biomicroscopy (UBM) may detect cells in the anterior chamber. The number of cells varies considerably with patients. Tremendous number of cells is occasionally observed in patients with herpetic anterior uveitis (Fig. 19.22). • Fundus fluorescein angiography (FFA) may occasionally reveal the retinal vascular involvement and cystoid macular edema (CME) (Fig.  19.23) in the patients with herpesvirus-­associated anterior uveitis (Fig. 19.24).

• Visual field changes may also be observed in certain patients with persistently elevated intraocular pressure (Figs.  19.25 and 19.26), although most patients tolerate well this increased intraocular pressure. • In general, laboratory tests are not recommended in the diagnosis of this disease.

264

19  Anterior Uveitis Associated with Herpesviruses

Fig. 19.23  Vascular leakages and CME identified with FFA in a patient with herpesvirus-associated anterior uveitis

Fig. 19.24  Retinal vascular leakages and staining of the optic disc identified with FFA in an 8-year-old female patient with herpesvirus-­associated anterior uveitis

19.7 Differential Diagnosis • Fuchs syndromes –– Diffuse iris depigmentation and mild anterior chamber inflammation. –– Stellate or medium-sized KPs distributed diffusely or centrally. –– No posterior synechiae. –– Elevated intraocular pressure may occur, but is not as common as that seen in anterior uveitis associated with HSV or VZV. • Posner–Schlossman syndrome –– Self-limiting, but episodically recurrent elevated intraocular pressure. –– Smaller mutton fat-like KPs in small number distributed centrally.

–– No posterior synechiae. –– There is no iris atrophy in patients although uneven depigmentation is observed. • Other uveitis entities which should be differentiated from herpetic anterior uveitis are listed below: –– Vogt–Koyanagi–Harada (VKH) disease. –– Sympathetic ophthalmia. –– Anterior uveitis associated with sarcoidosis. –– Idiopathic granulomatous anterior uveitis. –– Intermediate uveitis. –– Uveitis associated with multiple sclerosis. –– Uveitis occurring in granulomatosis with polyangiitis (Wegener’s granulomatosis).

19.7 Differential Diagnosis

265

Fixation Monitor: Gaze/Blind Spot

Stimulus: III, White

Pupil Diameter: 6.5 mm

Date: 2015–04–08

Fixation Target: Central

Background: 31.5 ASB

Visual Acuity:

Time: 12:28

Fixation Losses: 1/10

Strategy: SITA-Fast

RX:

DS

DC X

Age: 40

False POS Errors: 0% False NEG Errors: 0% Test Duration: 03:12 Fovea: OFF

30

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–7 –7 –6 –6

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–3 –3 –5 –3 –3 –4

0 –3

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–4

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0

–3 –4 –5 –5 –5 –5 –6

–5

2

–4 –5 –6 –7 –7 –8 –7 –7

1 0

–6 –6 –6 –8 –6 –3

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–2

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–1

2

0 –1 –1 –1

GHT Borderline/General Reduction VFI

96%

MD

–6.338 dB P < 0.5%

PSD Total Deviation

1.56 dB

Pattern Deviation

< 5% < 2%

CQ Medical University NO.1 Hospital

< 1% < 0.5%

Fig. 19.25  General reduction of sensitivity detected by Humphrey perimetry in a herpesvirus-associated anterior uveitis patient with persistently increased intraocular pressure

266

19  Anterior Uveitis Associated with Herpesviruses

Fixation Monitor: Gaze/Blind Spot

Stimulus: III, White

Pupil Diameter: 7.6 mm

Date: 2014–04–29

Fixation Target: Central

Background: 31.5 ASB

Visual Acuity:

Time: 17:18

Fixation Losses: 1/15

Strategy: SITA-Fast

RX:

DS

DC X

Age: 42

False POS Errors: 2% False NEG Errors: 9% Test Duration: 05:10

14

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–10 –10 –9 –11 –10 –10 –10

–11 –10

–1 –1 –1 –2 –1 –1 –1

–2 –1

–12 –11 –9 –9 –9 –7 –8

–15 –14

–3 –2

–6 –5

–6

–14 –9 –11 –9 –9 –6 –15 –12 –15 –18

0

0

0

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0 –2

0

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–4

–13 –9 –10 –10 –15 –13 –13 –16

0 –1 –1 –6 –4 –4 –7 –5

–14 –9 –16 –12 –12 –12

0 –7 –3 –3 –3 –0 –7 –6

–9 –16 –15 –15

1

–6

GHT General Reduction of Sensitivity VFI

91%

MD

–11.24 dB P < 0.5%

PSD

2.74 dB P < 5%

Pattern Deviation

Total Deviation

< 5% < 2%

CQ Medical University NO.1 Hospital

< 1% < 0.5%

Fig. 19.26  General reduction of sensitivity detected by Humphrey perimetry in a herpesvirus-associated anterior uveitis patient with persistently increased intraocular pressure

References

19.8 Treatment • Systemic antivirals are recommended in the literature to treat the anterior segment inflammation associated with HSV or VZV. • In the author’s experience, systemic antivirals are needed only in the patients with dendritic keratitis or with herpes zoster ophthalmicus. • The anterior chamber inflammation is predominantly treated with topical and systemic corticosteroids although the anterior uveitis is, by definition, caused by HSV or VZV.  We have treated more than 300 patients and achieved good results in most patients. –– Topical corticosteroids, such as prednisolone acetate 1%, are initially given 4–6 times per day and followed by a gradually tapering manner. –– The author usually initiates the systemic corticosteroid treatment at a dose of 20–30  mg/day in a gradually tapering regimen. • Corticosteroid-sparing immunosuppressive agents, such as cyclosporine, are sometimes needed for the patients with chronic or recurrent herpesvirus-associated anterior uveitis. • Cycloplegic agents are not necessarily needed in the treatment of anterior uveitis associated with HSV and VZV although they are universally used for anterior uveitis except for Fuchs syndrome and Posner–Schlossman syndrome. • Elevated intraocular pressure in these patients should be treated with topical corticosteroids and antiglaucoma agents. Antiglaucoma agents alone are usually not sufficient to control the elevated intraocular pressure in these patients. Antiglaucoma surgeries are indicated if the elevated intraocular pressure failed to respond to medical treatment.

19.9 Prognosis • Most patients have a good visual prognosis if adequate treatment is given promptly.

267

• Long-lasting treatment with corticosteroids may be necessary for some patients in controlling chronic inflammation and preventing the recurrences of anterior uveitis in these patients. • Severely impaired vision may arise from bullous keratopathy or optic nerve atrophy secondary to persistently elevated intraocular pressure.

References 1. Capella MJ, Foster CS. Herpesviruses. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 437–60. 2. Jones N. Viral infection, Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 181–209. 3. Julian K, Lehoang P, Bodaghi B. Herpes simplex virus. In: Zierhut M, Pavesio C, Ohno S, et  al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 1165–80. 4. Becker MD, Jakob E, Mackensen F.  Fuchs uveitis syndrome. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 955–65. 5. Ohno S, Namba K, Miyazaki A. Posner-Schlossman syndrome. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 1007–12. 6. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 7. Liesegang TJ. Classification of herpes simplex virus keratitis and anterior uveitis. Cornea. 1999;18(2):127–43. 8. Nussenblatt RB, Whitcup SM, Palestine AG. Other viral diseases, Uveitis fundamentals and clinical practice. 2nd ed. St. Louis: Mosby-Year Book, Inc.; 1996. p. 207–10. 9. Robin JB, Steigner JB, Kaufman HE. Progressive herpetic corneal endotheliitis. Am J Ophthalmol. 1985;100(2):336–7. 10. Rathinam SR, Khairallah M, Hmidi K.  Anterior granulomatous uveitis. In: Gupta A, Gupta V, Herbort CP, et  al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 335–47.

20

Fuchs Syndrome

Contents 20.1  Definition

 269

20.2  Epidemiology

 269

20.3  Etiology and Pathogenesis

 269

20.4  Clinical Manifestations

 270

20.5  Complications

 284

20.6  Diagnosis

 284

20.7  Differential Diagnosis

 285

20.8  Treatment

 285

20.9  Prognosis

 287

References

 287

20.1 Definition

• Unilateral involvement occurs approximately in 90% of the patients. In 104 Chinese patients with Fuchs syn• Fuchs syndrome is generally considered as an unilateral drome reported by our group, 86.5% of the patients show uveitis entity characterized by low-grade, non-­ unilateral involvement [3]. granulomatous iridocyclitis, varying degrees of iris depig- • The prevalence of Fuchs syndrome varies considerably with mentation, stellate or medium-sized keratic precipitates studies reported in different tertiary uveitis centers. It counts (KPs) diffusely distributed on the entire endothelium of for 0.4–13.2% of all uveitis patients. In a total of 1752 uvethe cornea [1–3]. itis patients reported by us, Fuchs syndrome was found in • Vitreous opacity is common and retinal vascular involve100 patients (5.7%) [3]. During the past 10 years, we found ment is found in certain patients [4]. more than 800 patients with Fuchs syndrome out of 16,000 • This disease is also described as Fuchs heterochromic uveitis or scleritis patients coming from all over China. cyclitis, Fuchs heterochromic iridocyclitis, and Fuchs uveitis syndrome.

20.3 Etiology and Pathogenesis

20.2 Epidemiology • • • •

Fuchs syndrome occurs worldwide [1, 2, 5]. There is no racial predilection. Males and females are equally affected. The disease occurs mostly in the third or fourth decades, although it may be observed at any age.

• The exact etiology and pathogenesis are not completely known. • Infection with cytomegalovirus (CMV), rubella virus and toxoplasma gondii has been proposed to be involved in this disease. However, there is no evidence to show amelioration of the disease by antivirus therapy or by anti-­ toxoplasma therapy [1, 2].

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_20

269

270

• Trophic defect in the sympathetic nervous system is presumed to be involved in the development of iris depigmentation in this disease. • Immune response to corneal antigens or retinal S-antigen and increased levels of CD8+ T cells have been found in Fuchs syndrome. These abnormalities may also be one of the mechanisms underlying this disease. • Recent studies have shown that IL23R gene is associated with Fuchs syndrome. These results suggest that genetic predisposition may be involved in the development of this disease.

20.4 Clinical Manifestations • Symptoms –– The patients usually complain of blurred vision or decreased vision and floaters due to vitreous opacities.

20  Fuchs Syndrome

–– A few patients may experience red eye, photophobia, and discomfort around the eye at presentation, but do not have these symptoms anymore during follow-up. –– Some patients may have mild pain, colored haloes around lights, and headache in case of the presence of highly elevated intraocular pressure. –– A severely impaired vision is observed in Fuchs syndrome patients with cataract or secondary glaucoma. • Signs –– Ciliary congestion is occasionally observed in the Fuchs syndrome patients at their first attack. –– Stellate (Fig. 20.1) and medium-sized KPs (Fig. 20.2) are characteristic for Fuchs syndrome. In general, they are distributed diffusely on the entire posterior surface of the cornea (Fig. 20.3). They may also appear on inferior or central corneal endothelium (Fig. 20.4) sometimes during follow-up examination. Medium-sized KPs in large number are occasionally noted in patients with Fuchs syndrome. (Fig. 20.5)

Fig. 20.1  Stellate KPs observed in patients with Fuchs syndrome

Fig. 20.2  Medium-sized KPs observed in a female patient with Fuchs syndrome

20.4 Clinical Manifestations

271

Fig. 20.3  KPs diffusely distributed on the corneal epithelium observed in patients with Fuchs syndrome

Fig. 20.4  KPs distributed on the pupil area observed in a patient with Fuchs syndrome

Medium-sized KPs toned with pigment are occasionally observed in patients with Fuchs syndrome (Fig. 20.6) –– Mild to moderate anterior chamber reaction evidenced by cells and flare is a rule although not all patients have active inflammation signs during each follow-up examinations. Laser flare-cell meter has been used to evaluate the flare and cells in the anterior chamber of the patients with Fuchs syndrome [6]. –– Varying degrees of iris depigmentation are observed in all patients. Diffuse iris depigmentation is the characteristic finding of this disease. As iris depigmentation varies considerably in patients with Fuchs syndrome in pigmented individ-

272

20  Fuchs Syndrome

Fig. 20.5  Large number of medium-sized KPs observed in a patient with Fuchs syndrome. This is a rare sign

Fig. 20.6  Medium-sized KPs toned with pigment observed in patients with Fuchs syndrome

uals, slight depigmentation is readily neglected in this population. A wide spectrum of iris depigmentation is shown in this chapter (Figs.  20.7, 20.8, 20.9, and 20.10) in an attempt to decrease the misdiagnosis rate for this disease.

Gross heterochromia is common in Caucasian patients with Fuchs syndrome but extremely rare in heavily pigmented patients. In more than 800 patients with Fuchs syndrome encountered in our clinic during past ten years, gross heterochromia is found only in less than 10 patients (Fig. 20.11).

20.4 Clinical Manifestations

273

Fig. 20.7  Varying degrees of iris depigmentation observed in patients with Fuchs syndrome. Left: affected eyes; Right: normal eyes in the same individual of the patients

274

20  Fuchs Syndrome

Fig. 20.8  Varying degrees of iris depigmentation observed in patients with Fuchs syndrome. Left: affected eyes; Right: normal eyes in the same individual of the patients

20.4 Clinical Manifestations

275

Fig. 20.9  Varying degrees of iris depigmentation observed in patients with Fuchs syndrome. Left: affected eyes; Right: normal eyes of the same individual of the patients

276

20  Fuchs Syndrome

Fig. 20.10  Varying degrees of iris depigmentation observed in patients with Fuchs syndrome. Left: affected eyes; Right: normal eyes of the same individual of the patients

20.4 Clinical Manifestations

Fig. 20.11  Heterochromia grossly identified in Chinese patients with Fuchs syndrome. Left: affected eyes; Right: normal eyes

277

278

20  Fuchs Syndrome

Iris depigmentation is readily detected through observation of translucent zone around a ­narrow slit-beam. Iris depigmentation is graded by us as 0, I, II, and III which are shown in (Fig. 20.12) according to the translucent zone around the slit-beam in Chinese patients with Fuchs syndrome.

Moth-eaten appearance of the iris due to depigmentation is occasionally observed in patients with Fuchs syndrome (Fig. 20.13). Depigmentation at the pupillary margin is sometimes obvious in patients with Fuchs syndrome (Fig. 20.14).

a

b

c

d

Fig. 20.12  Grading of the iris depigmentation: 0: no iris depigmentation (a); I: Slight iris depigmentation (b); ΙΙ: Obvious iris depigmentation (c); III: Striking iris depigmentation (d)

Fig. 20.13  A moth-eaten appearance of the iris observed in patients with Fuchs syndrome

20.4 Clinical Manifestations

279

Fig. 20.14  Depigmentation at the pupillary margin in patients with Fuchs syndrome. Left: affected eyes; Right: normal eyes of the same individual of the patients

280

–– Both Koeppe nodules and Busacca nodules are observed in patients with Fuchs syndrome. However, they are usually smaller than those observed in granulomatous inflammation and exhibit fluffy appearance (Figs. 20.15 and 20.16). –– Russell bodies, manifesting as small, crystalline, and highly refractile deposits on iris surface, are occasionally noted in the patients.

20  Fuchs Syndrome

–– Iris swelling with spongy appearance is occasionally noted in patients with Fuchs syndrome (Fig. 20.17). –– A slightly larger pupil (Fig. 20.18) may be observed in the affected eye due to involvement of the sphincter pupillae. –– Posterior synechiae do not develop in patients with Fuchs syndrome, but can be occasionally noted in them following cataract surgery.

Fig. 20.15  Koeppe nodules and Busacca nodules with varying appearances observed in patients with Fuchs syndrome

20.4 Clinical Manifestations

Fig. 20.16  Koeppe nodules with varying appearances observed in patients with Fuchs syndrome

281

282

20  Fuchs Syndrome

a

b

c

d

Fig. 20.17  Iris swelling with spongy appearance observed in a patient with Fuchs syndrome (a–c: the affected eye; d: normal eye)

a

b

c

d

Fig. 20.18  A slightly enlarged pupil observed in patients with Fuchs syndrome. (a, c: normal eyes; b, d: affected eyes of the same patients)

20.4 Clinical Manifestations

–– Overt rubeosis and filiform hemorrhage (hyphema following anterior chamber paracentesis) have been reported in the literature. However, they have not been observed in more than 800 Chinese patients with Fuchs syndrome referred to our tertiary uveitis center. –– Varying degrees of vitreous opacities (Figs.  20.19 and 20.20) are observed in most patients with Fuchs

283

syndrome. Severe vitreous opacity which could obscure fundus details is occasionally noted in the patients [3, 4]. –– Peripheral inflammatory chorioretinal lesions have been reported in the literature. However, they are not observed in Chinese patients with Fuchs syndrome.

Fig. 20.19  Opacity dots in the anterior vitreous observed in patients with Fuchs syndrome

Fig. 20.20  Opacities in the anterior vitreous detected by ultrasound biomicroscopy (UBM) in patients with Fuchs syndrome

284

20  Fuchs Syndrome

20.5 Complications • Cataract is the most common complication in Fuchs syndrome, occurring in 23–70.7% of the patients depending on the length of follow-up [1, 2, 7]. • Secondary glaucoma develops in 12–59% of the patients. Persistently elevated intraocular pressure frequently results in permanent visual loss. • Rhegmatogenous retinal detachment is very rarely observed in Fuchs syndrome.

20.6 Diagnosis • The diagnosis of Fuchs syndrome is mainly based on clinical observations. • Careful history taking and slit lamp microscopy examination for both eyes are critical to the diagnosis of Fuchs syndrome. • Insidious onset, chronic and low-grade anterior uveitis are typical clinical findings of Fuchs syndrome.

• Stellate or medium-sized keratic precipitates scattered on the entire corneal endothelium and varying degrees of diffuse iris depigmentation without posterior synechiae are hallmark features for this disease. • There is no laboratory test in the diagnosis of this syndrome. • Fundus fluorescein angiography (FFA) reveals retinal vascular leakages and disc staining in a number of patients (Fig. 20.21). However, these features are not specific to this disease. • There are no universally accepted diagnostic criteria for Fuchs syndrome. The following criteria are proposed by the author based on the clinical features of more than 800 Chinese patients with Fuchs syndrome (Table 20.1). • Decreased number and morphological abnormalities of corneal endothelial cells (Fig. 20.22) are observed in certain patients with Fuchs syndrome although they are not considered as an important parameter in the diagnosis of this disease.

OD, FA 6:12.07 55º [HS]

OD, FA 6:14.35 55º [HS]

OD, FA 6:16.96 55º [HS]

OD, FA 7:55.65 55º ART [HS]

OD, FA 8:02.46 55º ART [HS]

OD, FA 8:15.76 55º ART [HS]

Fig. 20.21  Vascular leakage disclosed by FFA in patients with Fuchs syndrome

20.8 Treatment

285

20.7 Differential Diagnosis

–– Herpetic anterior uveitis may appear with or without corneal involvement. –– Ciliary injection, medium-sized, or mutton fat KPs mostly toned with pigmentation, localized iris atrophy, posterior synechiae, and frequently elevated intraocular pressure are highly evocative of herpesvirus-­ associated anterior uveitis. • Other diseases such as sarcoidosis, intermediate uveitis, tuberculosis (TB), multiple sclerosis, primary intraocular lymphoma at its early stage, and Vogt– Koyanagi–Harada (VKH) disease at its recurrent granulomatous anterior uveitis stage should also be differentiated from Fuchs syndrome.

• Posner–Schlossman syndrome –– It may also manifest with medium-sized KPs. However, these KPs are small in number and distributed centrally or inferiorly. –– In general, there is no diffuse iris depigmentation although an uneven iris depigmentation could be observed in this disease. –– Recurrent elevated intraocular pressure ranging from 30 to 60  mmHg in association with open angle is a hallmark for this disorder. –– In general, there is no vitreous involvement. –– Elevated intraocular pressure is sensitive to topical corticosteroids. • Herpetic anterior uveitis –– Anterior uveitis may be caused by herpes simplex virus (HSV), varicella zoster virus (VZV), and CMV.

20.8 Treatment • A short time of treatment with topical corticosteroid might be indicated if an obvious anterior chamber inflammation is present. • Transient treatment with low dose of systemic corticosteroid is occasionally needed for the patients with heavy vitreous opacities. However, vitreous opacities are not sensitive to corticosteroid in most patients. A high dose of systemic corticosteroids may lead to central serous chorioretinopathy in these patients (Fig. 20.23).

Table 20.1  Diagnostic criteria proposed for Fuchs syndrome 1. Stellate or medium-sized KPs distributed diffusely or centrally 2. Varying degrees of diffuse iris depigmentation with or without heterochromia 3. Absence of posterior synechiae 4. Low-grade anterior chamber reaction 5. Vitreous cells and opacities

a

b

ID. Last Name First Name Date Eye Label

: : : : : :

201601347 2016-04-27 Right #1

Number of Cells Minimum Size Maximum Size Average Size Total Size S.D. of Size C.V. for Size Cell Density

38

42

10%

: : : : : :

201601347 2016-04-27 Left #2

Number of Cells

75.4 (um2) 1529.9 (um2) 907.5 (um2) 34486.8 (um2) 313.3 (um2) 34.5 (%) 1101.9

Hexagonality

0% 0~ 100~ 200~ 300~ 400~ 500~ 600~ 700~ 800~ 900~ 1000~ 1100~

ID. Last Name First Name Date Eye Label

20%

Minimum Size Maximum Size Average Size Total Size S.D. of Size C.V. for Size

(/mm)

Cell Density

(%)

Hexagonality

30%

40%

104 115.9 (um2) 881.4 (um2) 383.7 (um2) 39904.7 (um2) 127.5 (um2) 33.2 (%) 2606.2 56

(/mm) (%)

50% 2.6% 0.0% 2.6% 2.6% 5.3% 0.0% 10.5% 10.5% 13.2% 7.9% 10.5% 15.8%

0% 0~ 100~ 200~ 300~ 400~ 500~ 600~ 700~ 800~

10%

20%

30%

40%

50% 0.8% 5.8% 20.2% 30.8% 26.9% 13.5% 1.0% 1.0% 1.0%

Fig. 20.22  Decreased density and morphological abnormalities of corneal endothelial cells in a patient with Fuchs syndrome. (a: the affected eye; b: the normal eye)

286

20  Fuchs Syndrome

a

b

c

d

e

Fig. 20.23  A female patient with Fuchs syndrome (a: affected eye, b:normal eye) developed central serous chorioretinopathy after oral prednisone at a local hospital (c, d: FFA results; e: optical coherence tomography imaging result)

References

287

• It is not absolutely necessary to use corticosteroid-sparing • A poor visual prognosis is rarely seen in the patients with or immunosuppressive agents for patients with Fuchs refractory secondary glaucoma. syndrome. • Antiviral treatment is not effective although virus infection has been presumed to be involved in this disease. • The effectiveness of topical nonsteroidal anti-­References inflammatory drugs is still controversial. • Secondary glaucoma can be controlled in most patients by 1. Becker M, Jakob E, Mackensen F.  Fuchs uveitis syndrome. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammatopical and systemic antiglaucoma medications. However, tion. Berlin: Springer; 2016. p. 955–66. filtering surgery may be necessary in refractory cases. 2. Livir-Rallatos C, Zafirakis P. Fuchs’ heterochromic iridocyclitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd • Cataract surgery and intraocular lens implantation are ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. well tolerated by patients with Fuchs syndrome. It can be p. 925–34. safely performed at any time even in patients with KPs. 3. Yang P, Fang W, Jin H, et al. Clinical features of Chinese patients • Therapeutic vitrectomy is occasionally indicated for the with Fuchs’ syndrome. Ophthalmology. 2006;113(3):473–80. 4. Herbort CP, Bouchenaki N.  Neglected and unrecognised signs in patients with heavy vitreous opacities.

20.9 Prognosis • The prognosis of patients with Fuchs syndrome is generally good. • Cataract surgery is frequently associated with a good visual prognosis.

Fuchs’ uveitis. Ophthalmic Res. 2005;37S:96. 5. Velilla S, Dios E, Herreras JM, et  al. Fuchs’ heterochromic iridocyclitis: a review of 26 cases. Ocul Immunol Inflamm. 2001;9(3):169–75. 6. Fang W, Zhou H, Yang P, et  al. Aqueous flare and cells in Fuchs syndrome. Eye (London). 2009;23(1):79–84. 7. Fuchs E. Ueber Komplikationen der Heterochromie. Z Augenheilk. 1906;15:191–212.

Posner–Schlossman Syndrome

21

Contents 21.1  Definition

 289

21.2  Epidemiology

 289

21.3  Etiology and Pathogenesis

 289

21.4  Clinical Manifestations

 289

21.5  Complications

 292

21.6  Diagnosis

 292

21.7  Differential Diagnosis

 292

21.8  Treatment

 294

21.9  Prognosis

 294

References

 294

21.1 Definition

21.3 Etiology and Pathogenesis

• Posner–Schlossman syndrome is a self-limiting disease and characterized by recurrent attacks of unilateral elevated intraocular pressure in association with mild nongranulomatous anterior uveitis [1–3]. • Vision, visual field, and optic nerve are usually normal despite episodically increased intraocular pressure.

• The etiology and pathogenesis remain unclear. • Infection with herpes simplex virus, varicella-zoster virus, and cytomegalovirus has been proposed to be associated with this disease [1, 3, 7]. However, there is no evidence to show an effectiveness of antiviral therapy in the treatment of this disease. • Inflammation in the trabecular meshwork is presumably considered as a main cause for the elevated intraocular pressure. • Allergic response, immunogenetic factors, and increased levels of prostaglandin E are also reported to be associated with this disease [1].

21.2 Epidemiology • Posner–Schlossman syndrome occurs worldwide [4–6]. • Although there is no racial predilection, more patients are observed in Shanghai, Jiangsu province, and Zhejiang province in China based on our clinical observation. • There is a male preponderance in this disease. • It mostly occurs in patients at 20–50 years of age. • It usually affects one eye, but occasionally affects another eye in subsequent episodes.

21.4 Clinical Manifestations • Patients with Posner–Schlossman syndrome typically complain of intermittent episodes of blurred vision, colored haloes around lights, and mild discomfort in the affected eye [1, 3].

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_21

289

290

• The frequency of attacks varies considerably with patients, ranging from once every few months to once every 1–3 years. • Mild redness is occasionally noted by patients themselves. • The characteristic findings are significantly elevated intraocular pressure (usually 30–60  mmHg) with a few medium-sized keratic precipitates (KPs) or mutton fat

21  Posner–Schlossman Syndrome

like KPs distributed centrally or on the lower one-third of the corneal endothelium (Fig. 21.1) [1–3]. • The elevated intraocular pressure and mild anterior uveitis are self-limited and usually last for a few weeks to one month. • There is very mild anterior chamber reaction as evidenced by a few cells and minor fare. • The angle is open.

Fig. 21.1  Medium-sized or mutton fat like KPs observed in patients with Posner–Schlossman syndrome

21.4  Clinical Manifestations

• Iris heterochromia has been reported. However, in Chinese patients, we did not see this sign. Iris depigmentation may be seen in these patients. The iris depigmentation in Posner– Schlossman syndrome seems to be uneven or somewhat focal in appearance (Figs.  21.2 and 21.3) and is different from that observed in Fuchs syndrome in appearance.

291

• There is no posterior synechiae. • There are no vitreous cells or retinal involvement although optic nerve atrophy may develop as a result of frequent attacks of elevated intraocular pressure. • Subretinal vasculitis may be occasionally observed in patients with Posner–Schlossman syndrome (Fig. 21.4).

Fig. 21.2  Uneven or somewhat focal iris depigmentation observed in patients with Posner–Schlossman syndrome. Left: normal eye; Right: affected eye

292

a

21  Posner–Schlossman Syndrome

b

Fig. 21.3  Uneven depigmentation observed in a patient with Posner–Schlossman syndrome (a: normal eye; b: affected eye)

Fig. 21.4  Staining of vascular walls disclosed by fundus fluorescein angiography (FFA) in a patient with Posner–Schlossman syndrome

21.5 Complications • Complicated cataract is a rare complication. Patients with Posner–Schlossman syndrome usually tolerate topical corticosteroids well but may develop subcapsular opacities. • Frequent attacks of elevated intraocular pressure may cause visual field defect and enlarged optic disc cup in a few patients.

21.6 Diagnosis • History of recurrent blurred vision with discomfort and the distinct behavior of elevated intraocular pressure is essential to the diagnosis of Posner–Schlossman syndrome [1, 8].

• Three disassociations listed below are highly suggestive of the diagnosis of Posner–Schlossman syndrome –– Disassociation between highly elevated intraocular pressure and symptoms. –– Disassociation between highly elevated intraocular pressure and ciliary injection or corneal edema. –– Disassociation between highly elevated intraocular pressure and anterior chamber reaction. • Medium-sized or mutton fat like KPs without posterior synechiae and uneven iris depigmentation usually raise the suspicions in the diagnosis of this disease.

21.7 Differential Diagnosis • Fuchs syndrome [1, 9] –– Elevated intraocular pressure may also occur in Fuchs syndrome but is quite different from that seen in

21.7  Differential Diagnosis

293

Posner–Schlossman syndrome which occurs episodically. –– The elevated intraocular pressure usually responses well to antiglaucoma medicines in Fuchs syndrome. Whereas the elevated intraocular pressure is usually very high and sensitive to topical corticosteroids in Posner–Schlossman syndrome. –– Stellate or medium-sized KPs distributed diffusely in association with obvious iris depigmentation or

heterochromia are typical in Fuchs syndrome. Whereas a few mutton fat like KPs universally associated with elevated intraocular pressure and the absence of diffuse iris depigmentation are characteristic findings of Posner–Schlossman syndrome. –– Patients with Fuchs syndrome typically show diffuse depigmentation of the iris, which is contrary to uneven or somewhat focal depigmentation (Fig. 21.5).

a

b

c

d

e

f

Fig. 21.5  Comparison of iris depigmentation between Fuchs syndrome and Posner–Schlossman syndrome (a, c, e: Fuchs syndrome; b, d, f: Posner–Schlossman syndrome)

294

–– Vitritis and complicated cataract are common in Fuchs Syndrome. Whereas vitritis is usually not present and complicated cataract is rare in Posner–Schlossman syndrome. • Herpetic anterior uveitis –– Mutton fat KPs mostly toned with pigmentation in association with ciliary injection, moderate or severe anterior chamber inflammation, posterior synechiae, and focal iris atrophy are the characteristic features of herpetic anterior uveitis. –– Herpetic anterior uveitis usually causes a persistently increased intraocular pressure if the inflammation is not well controlled. Whereas the elevated intraocular pressure in Posner–Schlossman syndrome responds dramatically to topical corticosteroids. –– Bullous keratopathy may develop as a consequence of chronic inflammatory damage to the corneal endothelium in herpetic anterior uveitis. In general, there is no corneal complication in Posner–Schlossman syndrome. • Acute angle-closure glaucoma –– The patients with acute angle-closure glaucoma usually have severe symptoms such as pain around the affected eye, headache, and photophobia, which are contrary to the mild symptoms seen in patients with Posner–Schlossman syndrome. –– The increased intraocular pressure is sensitive to antiglaucoma medicines, rather than to topical corticosteroids. • Other ocular inflammations –– Ocular sarcoidosis –– Vogt–Koyanagi–Harada (VKH) disease –– Sympathetic ophthalmia –– Anterior scleritis –– Idiopathic granulomatous anterior uveitis or panuveitis

21.8 Treatment • Topical corticosteroids three or four times a day are usually sufficient to control the anterior chamber inflammation and to reduce the elevated intraocular pressure. • Topical antiglaucoma agents such as beta-blockers are usually used in combination with topical corticosteroids during disease attacks.

21  Posner–Schlossman Syndrome

• Oral carbonic anhydrase inhibitors are needed in patients with highly elevated intraocular pressure. • Glycerin or mannitol is indicated if the highly elevated intraocular pressure is not promptly controlled. • Patients do not necessitate an antiviral treatment although virus infection has been presumably linked with the development of this disease. • It is not necessary to treat patients during the remission stage.

21.9 Prognosis • Visual prognosis in patients with Posner–Schlossman syndrome is generally good although recurrent attacks of elevated intraocular pressure are usual. • It has usually been considered as a benign condition. However, high frequencies of attacks may occasionally lead to optic disc atrophy and varying degrees of visual field loss.

References 1. Ohno S, Namba K, Miyazaki A.  Posner-Schlossman syndrome. In: Zierhut M, Pavesio C, Ohno S, et al, Intraocular inflammation. Berlin: Springer. 2016; pp 1007-1012. 2. Bodaghi B.  Anterior uveitis: Posner-Schlossman Syndrome. In: Garg SJ, Bodaghi B, et  al, Uveitis. Philadelphia: Lippincott Williams & Wilkins. 2012; pp 41-42. 3. Jelliti B, Khairallah M.  Fuchs’ uveitis and Posner-Schlossman Syndrome: B.  Posner-Schlossman Syndrome. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 332–4. 4. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 5. Soheilian M, Heidari K, Yazdani S, et  al. Patterns of uveitis in a tertiary eye care center in Iran. Ocul Immunol Inflamm. 2004;12(4):297–310. 6. Islam SM, Tabbara KF.  Causes of uveitis at the Eye Center in Saudi Arabia: a retrospective review. Ophthalmic Epidemol. 2002;9(4):239–49. 7. Chee SP, Bacsal K, Jap A, et al. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol. 2008;145(5):834–40. 8. Jones N.  Fuchs’ heterochromic uveitis and other anterior uve itis syndromes, Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 145–54. 9. Yang P, Fang W, Jin H, et al. Clinical features of Chinese patients with Fuchs’ syndrome. Ophthalmology. 2006;113(3):473–80.

22

Uveitis in Children

Contents 22.1  Definition

 295

22.2  Epidemiology

 295

22.3  Specific Concerns About Uveitis in Children

 295

22.4  Complications

 296

22.5  Diagnosis

 296

22.6  Treatment

 297

22.7  Prognosis

 299

References

 306

22.1 Definition • Uveitis developing before the age of 16 is named as childhood uveitis or pediatric uveitis [1, 2]. • Almost all of uveitis entities occurring in adults can develop in children although the spectrum of this disease is quite different between them [3, 4].

22.2 Epidemiology • In general, uveitis is not as common in children as in adults. • According to most reports, children account for 5–10% of the total uveitis patients [1, 5, 6]. • During the past 10 years, 1866 children were found to suffer from uveitis in our uveitis center, accounting for 12.4% of the total uveitis patients. • Male and female are equally affected although sexual preponderance has been found in certain forms of uveitis. • Idiopathic uveitis is the main category in children. Toxoplasmosis is the most common infectious disease associated with uveitis in children in the western countries [7, 8]. Juvenile idiopathic arthritis (JIA) is the most common systemic disease associated with uveitis in children according to most studies [8, 9].

22.3 S  pecific Concerns About Uveitis in Children • Diagnosis is difficult in pediatric uveitis –– It is difficult to take history in children as most of them could not tell what happened, when and how the disease occured. This poses the first challenge in the diagnosis of uveitis in children. –– Thorough review of systems is difficult in these patients, posing the second challenge in the diagnosis of uveitis in children. –– Thorough ocular examination is also difficult and sometimes performed under general anesthesia, being an additional challenge in the diagnosis and follow-up of uveitis in children. –– The delay in the diagnosis of pediatric uveitis is present in a relatively large group. In fact, a large number of patients already experience complications, such as posterior synechiae, cataract, elevated intraocular pressure or glaucoma, and band keratopathy at their presentation to uveitis specialists. • Treatment for uveitis in children is difficult and quite complicated. –– Poor compliance exists in most patients with pediatric uveitis.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_22

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296

–– Various side effects occurring during the treatment, including growth retardation due to long-term use of systemic corticosteroids, myelosuppression, and gonadal dysfunction associated with chlorambucil and cyclophosphamide can greatly narrow the selection of drugs used in the treatment of pediatric uveitis. –– The parents of the patients with pediatric uveitis always have great expectations for the therapy effectiveness and visual outcome. These high expectations force a significant impact on the doctors’ decisions in the treatment modality. –– Patients with pediatric uveitis tend to develop subclinical retinal vasculitis that often lasts for a long time and is sometimes refractory to corticosteroids and other immunosuppressive agents. –– Complications, such as posterior synechiae, cataract, and secondary glaucoma are quite common in pediatric uveitis due to long-term or recurrent intraocular inflammation [10–12]. These patients often have exuberant and strong inflammation following surgery and surgery failure is quite commonly seen. This inflammatory response will greatly decrease the effectiveness of the surgery. • Common uveitis entities preferentially affecting children are listed below: –– Idiopathic anterior uveitis –– Idiopathic retinal vasculitis in children –– Uveitis associated with juvenile idiopathic arthritis –– Uveitis associated with Kawasaki syndrome –– Blau syndrome –– Tubulointerstitial nephritis and uveitis syndrome (TINU) –– Ocular toxoplasmosis –– Ocular toxocariasis –– Congenital syphilis –– Masquerade syndrome arising from retinoblastoma –– Masquerade syndrome arising from leukemia • More than 80% of the patients with pediatric uveitis show chronic or recurrent intraocular inflammation. Long-term treatment with a minimized dose of medicines is preferentially recommended in the decision of treatment modality.

22.4 Complications • Complications are more common in pediatric uveitis. • A number of ocular complications have been documented in the literature. • Band keratopathy, posterior synechiae, complicated cataract, and secondary glaucoma are quite common. Other complications include cystoid macular edema (CME), vitreous hemorrhage, proliferative vitreoretinopathy,

22  Uveitis in Children

•

•

•

•

•

•

epiretinal membrane, retinal neovascularization, choroidal neovascularization (CNV), retinal detachment, hypotony, and even phthisis bulbi. Amblyopia may also develop as a result of refractive media opacity. Band keratopathy preferentially occurs in pediatric uveitis (Fig. 22.1). Children are at higher risk to the development of band keratopathy than adults in the context of same uveitis entity. Posterior synechiae is the most common complication in pediatric uveitis, especially in idiopathic chronic anterior uveitis (Fig. 22.2), JIA-associated uveitis and granulomatous anterior uveitis associated with systemic disease. Anterior synechiae is also common in these patients and may take localized (Fig. 22.3) or extensive form. Complicated cataract mainly manifests as posterior subcapsular opacity in the early stage and progresses to total opacity. –– It is usually associated with chronic or recurrent pediatric uveitis. –– Cataract presenting as brown or porcelain white appearance is an ominous sign and always predicts very poor visual prognosis. Secondary glaucoma tends to develop in pediatric uveitis. It arises not only from posterior synechiae, but also from the extensive peripheral anterior synechiae in most patients. Macular edema, usually presenting as cystoid appearance (Fig. 22.4), is common in the children with intermediate uveitis, posterior uveitis, and subclinical retinal vasculitis. Other complications, such as macular hole, epiretinal membrane (Fig. 22.5), serous, tractional or rhegmatogenous retinal detachment, retinal neovascularization, and CNV (Fig. 22.6) may also occur in these patients.

22.5 Diagnosis • Diagnosis of uveitis in children, like in adults, is predominantly based on the medical history, clinical examinations, and investigations. Except for a few systemic diseases associated with uveitis in children as listed above, most patients manifest as idiopathic uveitis. Exclusion of these specific entities seems to be very important in the diagnosis of uveitis in children [1, 8]. • Band keratopathy, complicated cataract, and low degree of anterior chamber reaction have been considered as a triad for idiopathic chronic anterior uveitis in children and JIA-associated uveitis although they may occur in other forms of uveitis. This triad is often suggestive of these two forms of uveitis. • Granulomatous uveitis is common in children. However, nongranulomatous uveitis, acute anterior uveitis (AAU), and even hypopyon may also be observed (Fig. 22.7).

22.6 Treatment

297

Fig. 22.1  Band keratopathy with various appearances observed in patients with pediatric uveitis

• Mutton fat keratic precipitates (KPs) are usually distributed in a base-down pyramidal manner. However, they are occasionally distributed in the pupil area (Fig. 22.8). • Mutton fat KPs may be toned with pigment (Fig. 22.9), especially in the patients with prolonged intraocular inflammation. • Relevant laboratory investigations and systemic examinations are always important in making or excluding diagnosis of uveitis in children (see chapter laboratory investigation). • UBM may disclose a variety of changes in the anterior segment including cells and exudates, posterior and anterior synechiae, permanent membrane, detachment of ciliary body, and disappearance of the anterior chamber (Fig. 22.10). • Fundus fluorescein angiography (FFA) is helpful in the diagnosis of subclinical retinal vasculitis which is quite common in pediatric uveitis. It typically shows diffuse retinal vascular leakages (Figs. 22.11, 22.12, 22.13, and 22.14). Other changes include staining of optic disc and/ or vascular walls, CME, neovascularization, and capillary nonperfusion.

• B-scan ultrasonography is useful in detecting alterations of the posterior segment in pediatric uveitis. The changes include vitreous opacities, proliferative vitreoretinopathy, and retinal detachment. • OCT imaging is particularly helpful in detection of the changes in the posterior fundus. The changes include swelling of the optic disc (Fig. 22.15), CME, serous retinal detachment, and CNV (Figs. 22.16 and 22.17).

22.6 Treatment • Anterior uveitis is treated by topical corticosteroids, mydriatic and cycloplegic agents. As most patients present as chronic or recurrent anterior uveitis, topical treatment is usually not enough to control the intraocular inflammation. Combination of topical treatment with a low dose of systemic corticosteroids and/or other immunosuppressive agents is therefore indicated. • Posterior segment inflammation is treated by, if unilateral and possible, periocular injection. Systemic corticosteroids combined with other immunosuppressive agents are recommended for the patients with recurrent or chronic

298

Fig. 22.2  Posterior synechiae with different ranges and appearances observed in patients with pediatric uveitis

Fig. 22.3  Anterior synechiae observed in a patient with pediatric uveitis

Fig. 22.4  CME detected by optical coherence tomography (OCT) imaging in a patient with pediatric uveitis

22  Uveitis in Children

22.7 Prognosis

299

inflammation. Side effects should be monitored regularly during treatment. • Laser iridotomy or surgical iridectomy is used to prevent the development of secondary glaucoma. Surgical iridectomy has higher success rate as compared with iridotomy. Certain patients may necessitate surgery for several times to establish the channel between anterior and posterior chamber because it is not always successful. • Cataract surgery should be performed with great care as intraocular inflammation is apt to reoccur after operation.

–– In general, cataract surgery is planned usually at least 3 to 6 months after the inflammation is completely quiescent in the patients with idiopathic chronic or recurrent uveitis and those with posterior segment inflammation. –– Preoperative topical corticosteroids, mydriatic and cycloplegic agents and, if necessary, systemic corticosteroids and/or other immunosuppressive agents are usually initiated one week before the surgery. –– Postoperative treatment may last for some periods of time in an attempt to avoid severe postoperative inflammatory reaction as well as recurrence of uveitis. • Secondary glaucoma in pediatric uveitis should be treated according to the mechanisms underlying the disease. –– Elevated intraocular pressure due to trabecular inflammation, exudates, and pigment deposition is treated by topical corticosteroids, mydriatic and cycloplegic agents in combination with antiglaucoma drugs. –– Laser iridotomy or surgical iridectomy is indicated for the patients with complete posterior synechiae. –– Trabeculectomy and other antiglaucoma surgeries are prescribed according to the patients’ conditions.

22.7 Prognosis

Fig. 22.5  Epiretinal membrane observed in a patient with pediatric uveitis

a

• The visual prognosis varies greatly with uveitis entities, severity of the inflammation as well as the patients. • AAU in children is frequently associated with a good visual outcome. • Patients with chronic or recurrent anterior uveitis but without band keratopathy, complete posterior synechiae or extensive anterior synechiae and secondary glaucoma also enjoy a good visual prognosis. • Chronic or recurrent uveitis in association with band keratopathy, entire posterior synechiae, secondary glaucoma, persistent CME, and other severe posterior seg-

b

Fig. 22.6  CNV observed in a patient with pediatric uveitis (a: fundus photograph; b: OCT imaging result)

300

22  Uveitis in Children

a

Fig. 22.7  Hypopyon observed in a patient with pediatric uveitis (a: photograph; b: ultrasound biomicroscopy result)

Fig. 22.8  Mutton fat KPs distributed in the lower pupil area observed in a patient with pediatric uveitis

Fig. 22.9  Pigmentary KPs observed in a patient with pediatric uveitis

b

22.7 Prognosis

Fig. 22.10  Anterior segment changes identified by UBM in patients with pediatric uveitis

301

302 OD, FA 1:49.76 55º ART [HS]

22  Uveitis in Children OD, FA 3:05.82 55º ART [HS]

OD, FA 7:04.23 55º ART [HS]

Fig. 22.11  Diffuse retinal vascular leakages in association with macular edema, and staining of the optic disc disclosed by FFA in a patient with pediatric uveitis

OD, FA 0:45.89 55~ [HS]

OD, FA 1:42.93 55~ [HS]

OD, FA 6:25.07 55~ ART [HS]

Fig. 22.12  Staining of the optic disc and vascular leakages identified by FFA in a patient with pediatric uveitis

a

Fig. 22.13  Retinal vascular leakages and staining of the optic disc disclosed by FFA (a) completely disappeared at 9 months following treatment with a low-dose of systemic corticosteroids and cyclosporine in a patient with pediatric uveitis (b)

22.7 Prognosis

303

b

Fig. 22.13 (continued)

a

b

c

Fig. 22.14  Extensive vascular leakages identified by FFA in both eyes of a patient with pediatric uveitis (a, c) disappeared completely at 9 months following treatment with a low dose of systemic corticosteroids combined with cyclosporine (b, d)

304

d

Fig. 22.14 (continued)

Fig. 22.15  Swelling of the optic disc disclosed by OCT imaging in a patient with pediatric uveitis

Fig. 22.16  CNV detected by OCT imaging in a patient with pediatric uveitis

22  Uveitis in Children

22.7 Prognosis

a

305

b

c

Fig. 22.17  CNV disclosed by OCT imaging (a, b) and angio-OCT imaging (c) in a patient with pediatric uveitis

306

ment complications always result in a worse visual prognosis. • Patients with chronic or recurrent uveitis, especially those who failed to respond to iridectomy for several times may eventually develop phthisis bulbi.

References 1. Cunningham ET.  Uveitis in children. Ocul Immunol Inflamm. 2000;8(4):251–61. 2. Kump L, Vitale A, Foster CS. Pediatric uveitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1214–53. 3. Dajee KP, Rossen JL, Bratton ML, et al. A 10-year review of pediatric uveitis at a Hispanic-dominated tertiary pediatric ophthalmic clinic. Clin Ophthalmol. 2016;10:1607–12. 4. Heiligenhaus A, Heinz C, Walscheid K, et al. Uveitis in children. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 615–32.

22  Uveitis in Children 5. Paroli MP, Spinucci G, Liverani M, et al. Uveitis in childhood: an Italian clinical and epidemiological study. Ocul Immunol Inflamm. 2009;17(4):238–42. 6. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 7. Oréfice F, Vasconcelos-Santos DV.  Toxoplasmosis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 543–68. 8. Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology. 2009;116(8):1544–51. 9. Petty RE, Smith JR, Rosenbaum JT. Arthritis and uveitis in children. A pediatric rheumatology perspective. Am J Ophthalmol. 2003;135(6):879–84. 10. Rosenberg KD, Feuer WJ, Davis JL. Ocular complications of pediatric uveitis. Ophthalmology. 2004;111(12):2299–306. 11. Edelsten C, Reddy MA, Stanford MR, et al. Visual loss associated with pediatric uveitis in English primary and referral centers. Am J Ophthalmol. 2003;135(5):676–80. 12. de Boer J, Wulffraat N, Rothova A. Visual loss in uveitis of childhood. Br J Ophthalmol. 2003;87(7):879–84.

Uveitis-associated with Juvenile Idiopathic Arthritis

23

Contents 23.1   Definition

 307

23.2   Epidemiology

 307

23.3   Etiology and Pathogenesis

 308

23.4   Systemic Manifestations

 308

23.5   Ocular Manifestations

 308

23.6   Complications

 311

23.7   Diagnosis

 312

23.8   Differential Diagnosis

 318

23.9   Treatment

 318

23.10  Prognosis

 322

References

 325

23.1 Definition

23.2 Epidemiology

• Juvenile idiopathic arthritis (JIA) is a systemic autoimmune disease occurring before 16 years old and characterized by arthritis of unknown etiology lasting for at least 6 weeks [1, 2]. • JIA has been divided into three categories according to number of joints affected, i.e., systemic, oligoarticular/ pauciarticular, and polyarticular JIA [3]. • Systemic JIA mainly presents as fever, arthritis, skin rash, lymphadenopathy, and hepatosplenomegaly. • Oligoarticular/pauciarticular JIA predominantly manifests as arthritis of 4 or less joints in the first 6 months of disease. • Polyarticular JIA manifests as arthritis of 5 or more joints in the first 6 months of disease. • JIA is a common disease associated with uveitis in children. • All three forms of JIA can be associated with uveitis. However, oligoarticular /pauciarticular JIA is the most common type associated with uveitis followed by polyarticular form. Systemic JIA is very rarely associated with uveitis [1, 2].

• JIA occurs worldwide [4]. • Uveitis is found to occur in 4–24% of JIA patients. Up to 20% of the patients with oligoarticular/pauciarticular JIA develop uveitis [1]. • About 5% of the patients with polyarticular JIA develop uveitis. • JIA associated with uveitis is one of the most common entities seen in pediatric uveitis [2, 4]. • Early onset of arthritis predisposes the patients to ­uveitis [1]. • Bilateral involvement is usual although unilateral uveitis is observed. • Males and females are equally affected. However, females are usually associated with chronic anterior uveitis. • Uveitis usually develops at some time, mostly within 12 months, after JIA onset although it may precede this disease. Approximate 10% of the patients with JIA ­ develop uveitis 5 or more years after its onset.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_23

307

308

23.3 Etiology and Pathogenesis • The mechanisms underlying JIA and JIA-associated uveitis are still not fully understood. • It has been presumably caused by an autoimmune response. However, the major autoantigens have not been well identified. • Antinuclear antibody has been detected in most patients. However, its targets are still not determined. • Recent studies show that genetic factors are involved in the development of JIA and JIA-associated uveitis [5–7]. HLA-DRB1∗11 and DRB1∗13 are linked with JIA-­ associated uveitis [8]. • A number of genes have been identified to be associated with JIA during recent years. Our recent studies have shown that a number of single nucleotide polymorphisms (SNPs) including PRM1/rs11074967, JAZF1/rs73300638, PSMA3/rs2348071, IRF5/rs2004640, MEFV/rs224217, and PTPN2/rs7234029 are associated with JIA-associated uveitis, but not with idiopathic pediatric uveitis [9]. • B cells, T cells, macrophages, TNF-α, and IL-6 have been shown to be involved in the development of JIA [8].

23.4 Systemic Manifestations • Systemic JIA is characterized by arthritis accompanied by or preceded by daily fevers for at least 2 weeks in association with one or more of the following features: erythematous rash, generalized lymphadenopathy, hepatomegaly or splenomegaly. –– It accounts for about 10% of total JIA patients. –– Both oligoarthritis and polyarthritis are observed. –– Up to 10% of the patients are antinuclear antibody (ANA) positive. –– Most patients are rheumatoid factor (RF) negative. –– In general, these patients rarely suffer from uveitis. • Polyarticular JIA is characterized by arthritis involving 5 or more joints during first 6 months of disease. –– It accounts for 40% of the JIA patients. –– ANA is found in 25–50% of these patients. –– A positive RF is observed only in small minority of the patients. –– Joint deformity develops in 30–50% of the patients. –– It may be associated with uveitis. • Oligoarticular/pauciarticular JIA is characterized by arthritis involving 4 or less joints during first 6 months of disease. –– It accounts for 35–50% of JIA patients.

23  Uveitis-associated with Juvenile Idiopathic Arthritis

–– –– –– ––

Female is more frequently affected than male. Most patients are ANA positive and RF negative. Arthritis may lead to joint deformity (Fig. 23.1). It tends to be associated with uveitis.

23.5 Ocular Manifestations • JIA-associated uveitis typically takes the form of anterior segment inflammation although other forms of uveitis are occasionally observed. • In the literature, JIA-associated uveitis is generally considered as nongranulomatous anterior segment inflammation. • In the JIA patients with uveitis referred to our uveitis center, granulomatous inflammation is quite common. These patients typically present as “white uveitis,” insidious onset, medium-sized or mutton fat keratic precipitates (KPs) (Fig. 23.2), aqueous flare, variable number of aqueous cells, Busacca and Koeppe nodules (Fig. 23.3), and even iris granuloma (Fig. 23.4). • In a few of JIA patients, acute anterior uveitis may develop, showing ciliary congestion, tremendous number of aqueous cells, fibrous exudates, and even hypopyon (Fig. 23.5). • Fibrous membrane may be left permanently in the anterior chamber after anterior uveitis resolves (Fig. 23.6) • Poor vision without any other symptoms is found during a vision screen in a number of patients. • Subclinical retinal microvasculitis is quite common in JIA-associated uveitis patients although classically defined posterior uveitis is uncommon. –– These patients typically show various degrees of anterior chamber reaction in association with a low degree of vitreous reaction. –– In general, there is no any visible fundus change. In few patients, macular edema, epiretinal membrane and choroidal neovascularization may be observed. –– Fundus fluorescein angiography (FFA) shows varying degrees and extents of retinal vascular leakages of fluorescence, macular edema, and staining of the optic nerve (Figs.  23.7 and 23.8). These vascular leakages may disappear after treatment with systemic corticosteroids and/or immunosuppressive agents (Figs. 23.9 and 23.10). However, vascular leakages may be present for a long time without clinically visible signs of inflammation. • Neuroretinitis manifesting as swelling of the optic nerve and macular exudates is occasionally observed. (Fig. 23.11).

23.5 Ocular Manifestations

Fig. 23.1  Joint deformity with various appearances observed in JIA patients with uveitis

309

310

23  Uveitis-associated with Juvenile Idiopathic Arthritis

Fig. 23.2  Mutton fat KPs, some of them toned with pigmentation, observed in JIA patients with uveitis

a

b

c

d

Fig. 23.3  Busacca and Koeppe nodules observed in a female JIA patient with uveitis (a–c: photographs; d: ultrasound biomicroscopy result)

23.6 Complications

a

311

b

Fig. 23.4  Granuloma in the peripheral iris (arrow) and Busacca nodules in a female JIA patient with anterior uveitis (a) disappear following the treatment with systemic corticosteroids and topical corticosteroids eye drops, mydriatic and cycloplegic agent (b)

Fig. 23.5  Severe congestion and hypopyon observed in a JIA patient with anterior uveitis

23.6 Complications • Posterior synechiae is the most common sequelae of chronic or recurrent JIA-associated uveitis and usually results in different appearances of the pupil (Fig. 23.12). Peripheral anterior synechiae is frequently observed in the patients with chronic and recurrent anterior uveitis (Fig.  23.13). Persistent fibrous membrane may be left after anterior uveitis subsides. • Complicated cataract is a very common complication [10]. It usually takes the form of posterior subcapsular opacity at the beginning and gradually becomes complete opacity in the late phase. Cataract in brown or porcelain white appearance (Figs. 23.14 and 23.15) is usually suggestive of the involvement of the posterior segment and poor visual prognosis. • Band keratopathy is one of the most common complications seen in JIA-associated uveitis.

–– It usually initiates at the cornea adjacent to limbus at 3 and 9 o’clock (Fig. 23.16) although it may also occur in the inferior cornea. –– Transcorneal band keratopathy may develop centrally or inferiorly (Fig. 23.17) and is always associated with chronic and recurrent anterior uveitis. –– Localized decalcification zone in band keratopathy may be observed in some JIA patients with uveitis (Fig. 23.18). –– Band keratopathy may reformulate after it is surgically removed. • Secondary glaucoma is a common complication in JIA patients with uveitis. –– It occurs frequently as a result of pupillary block or extensive anterior synechiae. –– It is not readily controlled by medications or surgeries. • Macular edema is a common complication in JIA patients with subclinical retinal vasculitis (Fig. 23.19). It resolves

312

23  Uveitis-associated with Juvenile Idiopathic Arthritis

Fig. 23.6  Fibrous membrane left after inflammation resolution observed in JIA patients with chronic anterior uveitis

frequently following the regression of retinal vasculitis. Other macular abnormalities include serous retinal detachment (Fig.  23.20), choroidal neovascularization (Fig. 23.21), epiretinal membrane and, occasionally, macular hole. • Phthisis bulbi (Fig. 23.22) is the most severe complication and mostly associated with chronic, recurrent anterior uveitis, complete posterior synechiae, extensive anterior synechiae, and ciliary body detachment. • Dense vitreous opacification and proliferative vitreoretinopathy may also develop in the JIA patients with severe posterior segmentation involvement. • Other rare complications include retinal neovascularization, hemorrhages, and tractional retinal detachment.

23.7 Diagnosis • JIA is usually diagnosed by pediatric rheumatologists. However, the collaboration between ophthalmologists and rheumatologists is very important to coordinate actions towards treatment.

• Careful inquiry of history with particular respect to arthritis should be kept in mind in the diagnosis of pediatric uveitis. • As the inflammation of the anterior segment in JIA may present as white uveitis, slit-lamp microscopy should be carefully performed to depict the subtle abnormalities. • JIA patients with positive ANA are at high risk to development of uveitis. Therefore, these patients should be referred to uveitis specialists for regular follow-up. • FFA should be performed, if possible, in JIA patients. Subclinical retinal vasculitis is quite common and may be associated with CME and other complications. • Ultrasound biomicroscopy (UBM) is a very useful tool in evaluating the anterior segment especially in JIA patients who frequently show various changes due to chronic or reluctant intraocular inflammation. The changes disclosed by UBM include cells and exudates in the anterior and posterior chamber, posterior and anterior synechiae, shallow or disappearance of anterior chamber, swelling of the iris and ciliary body, granuloma or nodules in the iris, exudates adjacent to ciliary body, ciliary detachment, atrophy of the iris and ciliary body (Figs. 23.23 and 23.24).

23.7 Diagnosis

313

OS, FA 4:34.23 55° ART[HS]

OS, FA 4:45.93 55° ART[HS]

OS, FA 5:00.50 55° ART[HS]

OD, FA 1:41.53 55° ART[HS]

OD, FA 2:39.04 55° ART[HS]

OD, FA 8:53.42 55° ART[HS]

OD, FA 9:12.42 55° [HS]

OD, FA 9:42.67 55° [HS]

OD, FA 9:45.29 55° [HS]

Fig. 23.7  Vascular leakages and staining of the optic disc detected by FFA in JIA patients with uveitis but without any visible abnormality of the fundus

314 OS, FA 10:17.25 55° [HS]

23  Uveitis-associated with Juvenile Idiopathic Arthritis OS, FA 10:45.67 55° [HS]

OS, FA 10:48.85 55° [HS]

FA 0:25.79 55º ART[HS]

FA 1:44.76 55º ART[HS]

FA 3:16.21 55º ART[HS]

FA 3:53.20 55º ART[HS]

FA 4:04.89 55º ART[HS]

FA 12:25.25 55º ART[HS]

Fig. 23.7 (continued)

Fig. 23.8  Vascular leakages and blockage of fluorescence due to epiretinal membrane detected by FFA in a female JIA patient with uveitis

23.7 Diagnosis OD, FA 9:47.15 55º ART[HS]

315 OD, FA 9:52.15 55º ART[HS]

OD, FA 9:56.25 55º ART[HS]

OD, FA 15:50.45 55º [HS]

OD, FA 15:53.75 55º [HS]

a

OD, FA 15:27.59 55º [HS]

b

Fig. 23.9  Vascular leakages detected by FFA (a) disappear 6 months after treatment with a low-dose of systemic corticosteroids combined with cyclosporine (b) in a 12-year JIA patient with uveitis OD, FA 6:58.76 55º [HS]

OD, FA 7:20.25 55º [HS]

OD, FA 7:29.34 55º [HS]

OD, FA 9:28.95 55º ART[HS]

OD, FA 9:43.50 55º ART[HS]

a

OD, FA 9:08.28 55º ART[HS]

b

Fig. 23.10  Vascular leakages and staining of the optic disc (a) almost resolve 2 months after treatment with systemic corticosteroids and cyclosporine (b)

316

23  Uveitis-associated with Juvenile Idiopathic Arthritis

a

b

c

d

Fig. 23.11  Swelling of the optic nerve in association with macular exudates (a, b) is greatly improved 3 months after treatment with systemic corticosteroids and cyclosporine (c, d) in a female JIA patient

23.7 Diagnosis

Fig. 23.12  Posterior synechiae and deformed pupil with various appearances observed in JIA patients with uveitis

317

318

23  Uveitis-associated with Juvenile Idiopathic Arthritis

Fig. 23.13  Peripheral anterior synechiae observed in JIA patients with uveitis

Fig. 23.14  Complicated cataract with a brown appearance observed in a JIA patient with uveitis

Fig. 23.15  Complicated cataract showing a porcelain white appearance observed in a JIA patient with uveitis

• B-scan ultrasonography is used in JIA patients with opaque media to evaluate the changes of the posterior segment. The changes identified include vitreous opacities, proliferative vitreoretinopathy, and retinal detachment (Fig. 23.25)

• Masquerade syndrome arising from retinoblastoma • Ocular tuberculosis • Ocular syphilis

23.8 Differential Diagnosis

• Collaboration between uveitis specialist and rheumatologist is very important to coordinate the management of JIA patients with uveitis. • Active arthritis should be referred to specialist in rheumatology department for treatment. • JIA patients with uveitis should be treated individually according to the location, severity, and the nature of the intraocular inflammation [1]. • Topical corticosteroids, mydriatic, and cycloplegic agents are used for the patients with anterior uveitis.

• • • • • • • •

Idiopathic pediatric uveitis Idiopathic retinal vasculitis in children Ocular sarcoidosis Idiopathic chronic anterior uveitis. Blau syndrome Vogt–Koyanagi–Harada (VKH) disease in children Uveitis associated with Kawasaki disease Intermediate uveitis

23.9 Treatment

23.9 Treatment

319

Fig. 23.16  Band keratopathy occurring at the cornea adjacent to limbus at 3 and 9 o’clock observed in JIA patients with uveitis

–– Potent topical corticosteroids and high usages are prescribed in patients with severe anterior uveitis. –– As JIA-associated uveitis is often chronic in nature, topical treatment usually lasts for a longer time and does not stop until the aqueous cells completely disappear. –– Side effects of this treatment with particular respect to elevated intraocular pressure and cataract should be monitored, and the application rate should be adjusted according to the amelioration of the inflammation. –– Less potent corticosteroids, such as fluorometholone 0.1% or prednisolone 0.12%, are recommended for the patients with low-grade inflammation in the anterior chamber. • Systemic corticosteroids [1] –– They are usually prescribed for the patients with chronic, reluctant anterior uveitis, and those with dense vitreous opacities, posterior uveitis, and retinal vasculitis associated with CME. –– Dosage of corticosteroids varies greatly with reports worldwide. A higher initial dosage of 1–2 mg/kg/day is recommended by some doctors.

We favor a lower initial dosage, i.e., 0.4–0.8 mg/kg/ day, in the treatment of the patients with pediatric uveitis mainly due to the concerns of their side effects arising from long-term treatment. The patients who necessitate systemic corticosteroids always show a chronic, reluctant uveitis, or highly frequent attacks of uveitis. These forms of inflammation are not able to be controlled by a short-term treatment with a high dosage of corticosteroids. Therefore, the treatment regimen should focus on the long-­lasting control of the intraocular inflammation rather than the inflammation quiescence tomorrow. A minimized dosage of corticosteroids with properly tapering and long-term use has been widely used in our clinic and gained beneficial results without obvious side effects in most patients. Intravenous pulse therapy with methylprednisolone has been used to treat severe uveitis by some doctors. However, the effectiveness and the balance between the beneficial effects and risk need to be warranted in future. Side effects, especially growth retardation, are always the concern for the patients

320

23  Uveitis-associated with Juvenile Idiopathic Arthritis

Fig. 23.17  Transcorneal band keratopathy with various appearances observed in JIA patients with uveitis

on ­prolonged treatment with systemic corticosteroids and should be monitored regularly during treatment. • Non-steroidal anti-inflammatory agents (NSAIDs). –– They have been used in the treatment of pediatric uveitis especially those associated with arthritis or scleritis. –– Their effectiveness on uveitis is still needed to be clarified in future studies. • Immunosuppressive agents –– Immunosuppressive agents are indicated for the JIA patients who have failed to respond well to corticoste-

roids or do not tolerate their side effects during treatment. –– Methotrexate and azathioprine are the two most common medications used for JIA patients in the literature. In terms of the author’s experience, cyclosporine is more effective for these patients. An initial dosage of 2–4 mg/ kg/day is usually recommended in our clinic. Gradual tapering of the dosage follows when uveitis is ameliorated if the initial dosage is more than 2 mg/kg/day. –– Other immunosuppressive drugs such as mycophenolate mofetil, chlorambucil, and cyclophosphamide

23.9 Treatment

321

Fig. 23.18  Decalcification zone observed in band keratopathy in JIA patients with uveitis

Fig. 23.19  Cystoid macular edema (CME) detected by optical coherence tomography (OCT) imaging in a JIA patient with subclinical retinal vasculitis

may also be used in the patients who fail to respond to the immunosuppressive agents as stated above. However, much attention should be paid to the side effects such as myelosuppression, gonadal dysfunction, and even sterility when chlorambucil or cyclophosphamide is used. –– Immunosuppressive agents are usually used in combination with a low dose of systemic corticosteroids. –– Combination of two or more immunosuppressive agents are also recommended in the treatment of JIA

patients with uveitis in an attempt to achieve a synergy effect while minimizing their side effects. –– TNF-α inhibitors are indicated for the patients who fail to respond to the treatment of corticosteroids and other immunosuppressive agents or develop non-tolerable side effects during treatment. Adalimumab (the complete human monoclonal antibodies) is available and has been used for the treatment of pediatric uveitis [1, 8].

322

23  Uveitis-associated with Juvenile Idiopathic Arthritis

Fig. 23.20  Serous retinal detachment detected by OCT imaging in JIA patients with subclinical retinal vasculitis

Fig. 23.21  Choroidal neovascularization detected by OCT imaging in JIA patients with subclinical retinal vasculitis

23.10 Prognosis

Fig. 23.22  Phthisis bulbi observed in a female JIA patient with uveitis

• In general, JIA patients with uveitis are at high risk to development of complications and having a poor visual prognosis as compared to those with only uveitis. • Chronic and reluctant inflammation is always associated with complete posterior synechiae, refractory elevated intraocular pressure, and a poor visual outcome. • CME is frequently associated with subclinical retinal vasculitis and may lead to severely impaired visual acuity. • Recurrent and chronic inflammation may lead to severe damage to the ciliary body or the formation of the cyclitic membrane, and in turn result in phthisis bulbi.

23.10 Prognosis

Fig. 23.23  Various changes of the anterior segment detected by UBM in JIA patients with uveitis

323

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23  Uveitis-associated with Juvenile Idiopathic Arthritis

Fig. 23.24  Nodules or granuloma detected by UBM in a JIA patient with granulomatous uveitis (arrow)

Fig. 23.25  Changes of the posterior segment disclosed by B-scan ultrasonography in JIA patients with posterior uveitis

References

References 1. Heiligenhaus A, Tappeiner C, Heinz C, et  al. Juvenile idiopathic arthritis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 731–48. 2. Lobo AM.  Juvenile idiopathic arthritis. In: Papaliodis GN, editor. Uveitis. Cham: Springer International Publishing AG; 2017. p. 183–8. 3. Petty RE, Southwood TR, Baum J, et al. International League of Associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rhematol. 2004;31(2):390–2. 4. Heiligenhaus A, Heinz C, Edelsten C, et al. Review for disease of the year: epidemiology of juvenile idiopathic arthritis and its associated uveitis: the probable risk factors. Ocul Immunol Inflamm. 2013;21(3):180–91.

325 5. Finkel TH, Li J, Wei Z, et al. Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility. BMC Med Genet. 2016;17:24. 6. Hinks A, Cobb J, Marion MC, et al. Dense genotyping of immune-­ related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet. 2013;45(6):664–9. 7. Reinards THCM, Albers HM, Brinkman DMC, et  al. CD226 (DNAM-1) is associated with susceptibility to juvenile idiopathic arthritis. Ann Rheum Dis. 2015;74(12):2193–8. 8. Macaubas C, Nguyen K, Milojevic D, et al. Oligoarticular and polyarticular JIA: epidemiology and pathogenesis. Nat Rev Rheumatol. 2009;5(11):616–26. 9. Deng J, Tan H, Hu J, et  al. Genetic aspects of idiopathic paediatric uveitis and juvenile idiopathic arthritis associated uveitis in Chinese Han. Br J Ophthalmol. 2020;104(3):443–7. 10. Lam LA, Lowder CY, Baerveldt G, et al. Surgical management of cataracts in children with juvenile rheumatoid arthritis-associated uveitis. Am J Ophthalmol. 2003;135(6):772–8.

24

Blau Syndrome

Contents 24.1  Definition

 327

24.2  Etiology and Pathogenesis

 327

24.3  Systemic Manifestations

 327

24.4  Ocular Manifestations

 327

24.5  Complications

 328

24.6  Diagnosis

 329

24.7  Differential Diagnosis

 329

24.8  Treatment

 331

24.9  Prognosis

 331

References

 331

24.1 Definition

24.3 Systemic Manifestations

• Blau syndrome is a rare autosomal dominant multisystem disease characterized by recurrent uveitis, skin rash, and arthritis [1, 2]. • This disease is reported by Dr. Blau in 1985 and subsequently named as Blau syndrome [1]. • Blau syndrome is also called pediatric granulomatous arthritis and uveitis.

• The typical manifestations of Blau syndrome are the triad including joint, skin, and eye disease [2]. • Arthritis frequently involves the wrists, ankles, and fingers (Fig. 24.1). It usually occurs between 2 and 4 years old. • Skin rashes (Fig.  24.2) appear often between 2 and 4 years old although late onset is observed. • The lung, cranial nerves, and large arteries are also affected in Blau syndrome. Other manifestations including fever, abnormal liver and renal function, lymphadenopathy, hypercalcemia, and hypertension may also occur in these patients.

24.2 Etiology and Pathogenesis • Linkage analysis shows disease locus at chromosomal region 16q12.1–13. • Mutations of the NOD2/CARD15 gene is definitely identified in Blau syndrome [3]. • Nod2 protein could activate a group of proteins which can regulate the synthesis of cytokines such as interleukin-1 beta and therefore are involved in the development of this disease [2].

24.4 Ocular Manifestations • Ocular symptoms usually occur around 4 years old although they may develop in the adults. • The patients usually present with uveitis.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_24

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328

24  Blau Syndrome

Fig. 24.1  Arthritis observed in patients with Blau syndrome

–– Recurrent intraocular inflammation is common. Uveitis may precede the skin lesion and arthritis [4]. –– The changes in the anterior segment include mutton fat keratic precipitates, aqueous flare and cells, and posterior synechiae (Fig. 24.3) [5]. –– The changes in the posterior segment include vitreous opacities (Fig. 24.4), macular edema, swelling of the optic disc (Fig.  24.5), multifocal choroiditis [6], and chorioretinal scarring. Other changes such as retinal vasculitis, peripapillary hyperpigmentation, and optic disc vessel sheathing are also reported. Subclinical retinal vasculitis is common (Fig. 24.6).

24.5 Complications

Fig. 24.2  Skin rashes observed in a patient with Blau syndrome

• • • •

Band keratopathy (Fig. 24.7) Complicated cataract Secondary glaucoma Phthisis bulbi

24.7 Differential Diagnosis

a

329

b

Fig. 24.3  Posterior synechiae observed in a patient with Blau syndrome (a, b)

Fig. 24.4  Vitreous opacities detected by B-scan ultrasonography in a patient with Blau syndrome

24.6 Diagnosis • Classic clinical triad during childhood is critical to the diagnosis of this disease. • Family history of similar disease provides a substantial clue to the diagnosis of this disease. • Noncaseating granulomas identified in skin biopsy strongly support the diagnosis of Blau syndrome if sarcoidosis is excluded. • Mutations in the NOD2 gene should be examined in the suspected patients.

• It should be kept in mind that one of triad may develop alone or one after the other with intervals of some years later.

24.7 Differential Diagnosis • • • • •

Uveitis associated with sarcoidosis Uveitis associated with juvenile idiopathic arthritis Idiopathic pediatric uveitis Vogt–Koyanagi–Harada (VKH) disease Ocular tuberculosis

330

24  Blau Syndrome

Fig. 24.5  Swelling of the optic disc detected by optical coherence tomography (OCT) imaging in a patient with Blau syndrome

Fig. 24.6  Vascular leakages and staining of the optic disc identified by fundus fluorescein angiography (FFA) in patients with Blau syndrome

References

331

Fig. 24.7  Band keratopathy observed in patients with Blau syndrome

24.8 Treatment • Topical corticosteroids in combination with cycloplegic and mydriatic agents are commonly used in patients with anterior uveitis. • Systemic corticosteroids are indicated for the patients with recurrent and chronic anterior uveitis or those with posterior segment involvement. • Corticosteroid-sparing immunosuppressive agents, such as cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil are recommended for the patients who do not respond well to corticosteroids or tolerate the side effects of these drugs. • TNF-α inhibitors, such as adalimumab, may be prescribed for the patients with refractory uveitis [7].

24.9 Prognosis • As patients with Blau syndrome always suffer from recurrent or chronic uveitis and have various complications, visual prognosis varies considerably with the patients.

• Patients with posterior segment involvement, especially with permanent macular edema, usually have a worse visual outcome.

References 1. Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr. 1985;107(5):689–93. 2. Rosenbaum JT, Rosenzweig HL, Martin TM.  Blau syndrome. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 881–3. 3. Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet. 2001;29(1):19–20. 4. Wu S, Zhong L, Sun Z, et al. Ocular features in Chinese patients with Blau Syndrome. Ocul Immunol Inflamm. 2020;28(1):79–85. 5. Sarens IL, Casteels I, Anton J, et al. Blau Syndrome-associated uveitis: preliminary results from an international prospective interventional case series. Am J Ophthalmol. 2018;187:158–66. 6. Latkany PA, Jabs DA, Smith JR, et  al. Multifocal choroiditis in patients with familial juvenile systemic granulomatosis. Am J Ophthalmol. 2002;134(6):897–904. 7. Milman N, Andersen CB, Hansen A, et al. Favourable effect of TNF-­ alpha inhibitor (infliximab) on Blau syndrome in monozygotic twins with a de novo CARD15 mutation. APMIS. 2006;114(12):912–9.

Tubulointerstitial Nephritis and Uveitis Syndrome

25

Contents 25.1  Definition

 333

25.2  Epidemiology

 333

25.3  Etiology and Pathogenesis

 333

25.4  Clinical Manifestations

 333

25.5  Diagnosis

 334

25.6  Differential Diagnosis

 337

25.7  Treatment

 338

25.8  Prognosis

 338

References

 338

25.1 Definition

25.3 Etiology and Pathogenesis

• Tubulointerstitial nephritis and uveitis syndrome (TINU) refers to an intraocular inflammation associated with acute interstitial nephritis (AIN) [1]. • Uveitis may occur concurrently with AIN onset or 2 months before or one year after the onset of the disease [2]. • Uveitis observed in TINU typically shows bilateral nongranulomatous anterior segment inflammation [1, 2].

• The exact etiology and pathogenesis remain unclear. • TINU may occur as an idiopathic disease or in association with infections, immunologic diseases, or drug hypersensitivity [2]. • Histological and immunohistopathologic examination typically shows renal interstitial edema and infiltration mostly of T lymphocytes and plasm cells and less eosinophils and neutrophils. • TINU is caused by T cell mediated delayed-type hypersensitivity. • Recent studies show that HLA-DR1 and HLA-DRB1∗0102 subtypes are strongly associated with TINU [1, 3].

25.2 Epidemiology • TINU is a rare disorder. • TINU usually occurs in children and young adults although it may develop at any age. • There is no racial predilection. • Females seem to be more commonly affected than males [2].

25.4 Clinical Manifestations • Systemic features [1, 2, 4, 5] –– The common findings of AIN include malaise, fatigue, fever, and weight loss.

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334

–– Other findings consist of weakness, anorexia, abdominal and flank pain, nausea, vomiting, arthralgias, and myalgias. –– About 15% of patients with TINU show a concurrent onset of uveitis and interstitial nephritis. –– In the majority of the patients with TINU, uveitis occurs several weeks before and 1 year after the onset of interstitial nephritis. • Uveitis associated with AIN typically shows bilateral iridocyclitis [4, 5]. –– It is characterized by nongranulomatous inflammation. However, granulomatous anterior uveitis is occasionally observed in the TINU patients (Fig. 25.1) –– It usually shows acute onset but may be chronic in course and associated with posterior synechiae (Fig. 25.2)

25  Tubulointerstitial Nephritis and Uveitis Syndrome

–– Usually recurrent –– Uveitis activity varies from mild to moderate anterior segment inflammation although severe inflammation may also be observed. –– In general, anterior uveitis responds well to topical corticosteroids. • Posterior segment inflammation associated with AIN has been reported [1, 5] –– Vitritis associated with or without pars plana exudates –– Retinal vasculitis (Figs. 25.3 and 25.4) associated with hemorrhages, vascular sheathing, and exudates –– Retinitis –– Choroiditis or chorioretinitis –– Papillitis (Fig. 25.5) –– CME (Fig. 25.6) • Recurrent nodular scleritis has been reported in TINU patients [6].

25.5 Diagnosis

Fig. 25.1  An iris granuloma (arrow) is observed in a female patient with TINU

Fig. 25.2  Bilateral posterior synechiae in a patient with TINU

• The diagnosis is mainly based on bilateral anterior uveitis, systemic manifestations, laboratory investigations, and renal biopsy. • Renal biopsy is the gold standard for the diagnosis of AIN. However, patients are not always amenable to this examination. In this case, renal function tests and urinalysis are essential for the diagnosis of this disease. –– Elevated blood urea nitrogen and creatinine. –– Proteinuria, glycosuria, and sterile pyuria. –– Elevated serum levels of β2 microglobulin and Krebs von den Lungen-6 (KL-6).

25.5 Diagnosis

335 OD, FA 15:21.45 102° ART [HS]

OD, FA 13:45.90 102° ART [HS]

Fig. 25.3  Vascular leakage disclosed by fundus fluorescein angiography(FFA) in the periphery retina of a female patient with TINU

Fig. 25.4  Vascular leakage, optic disc staining, and cystoid macular edema (CME) disclosed by FFA in a female patient with TINU

336

25  Tubulointerstitial Nephritis and Uveitis Syndrome

a

b

c

d

e

f

Fig. 25.5  Papillitis in a male patient with TINU (a, b: fundus photographs; c, d: optical coherence tomography results; e–h: FFA results)

25.6 Differential Diagnosis

g

337

h

Fig. 25.5 (continued)

Fig. 25.6  CME detected by OCT imaging in a female patient with TINU

25.6 Differential Diagnosis • AIN should be differentiated from other renal disorders caused by infection or associated with systemic diseases including Behcet’s disease, granulomatosis with polyangiitis and systemic lupus erythematosus.

• Anterior uveitis associated with AIN should be differentiated from idiopathic anterior uveitis, anterior uveitis associated with seronegative spondylarthropathies, Behcet’s disease, sarcoidosis, systemic lupus erythematosus and granulomatosis with polyangiitis.

338

25  Tubulointerstitial Nephritis and Uveitis Syndrome

25.7 Treatment

References

• Patients with active AIN should be referred to the nephrologists. • Topical corticosteroids combined with mydriatic and cycloplegic agents are generally sufficient to control anterior uveitis in the patients with TINU. • Periocular or oral corticosteroids may be indicated for the patients with vitritis or posterior uveitis. • Systemic corticosteroids usually combined with steroid-­ sparing immunosuppressive agents may be adequate for the patients with chronic and posterior segment inflammation.

1. Levinson R.  Tubulointerstitial nephritis and uveitis syndrome. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 873–80. 2. Cerón O, Foster CS.  Tubulointerstitial nephritis and uveitis syndrome. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 973–81. 3. Levinson RD, Park MS, Rikkers SM, et  al. Strong associations between specific HLA-DQ and HLA-DR alleles and the tubulointerstitial nephritis and uveitis syndrome. Invest Ophthalmol Vis Sci. 2003;44(2):653–7. 4. Goda C, Kotake S, Ichiishi A, et al. Clinical features in tubulointerstitial nephritis and uveitis (TINU) syndrome. Am J Ophthalmol. 2005;140(4):637–41. 5. Mandeville JT, Levinson RD, Holland GN.  The tubuloint erstitial nephritis and uveitis syndrome. Surv Ophthalmol. 2001;46(3):195–208. 6. Daniel E, Gangaputra S, Kempen JH, et al. Recurrent nodular scleritis preceding an adult TINU syndrome. Ocul Immunol Inflamm. 2006;14(4):239–40.

25.8 Prognosis • AIN is usually a self-limited disease and often associated with a good prognosis. • Anterior uveitis associated with AIN usually resolves following treatment with topical corticosteroids, mydriatic and cycloplegic agents. • Choroidal neovascularization and macular edema are rare but can lead to poor visual prognosis.

26

Behcet’s Disease

Contents 26.1   Definition 

 339

26.2   Epidemiology 

 339

26.3   Etiology and Pathogenesis 

 340

26.4   Ocular Lesions 

 340

26.5   Extraocular Manifestations 

 349

26.6   Ocular Complications 

 368

26.7   Diagnosis 

 380

26.8   Diagnostic Criteria 

 404

26.9   Differential Diagnosis 

 404

26.10  Treatment 

 404

26.11  Prognosis 

 409

References 

 410

26.1 Definition

26.2 Epidemiology

• Behcet’s disease (BD) is a chronic and recurrent multisystemic inflammatory disease. • BD is characterized by recurrent oral ulcerations, uveitis with recurrent episodes, multiform skin lesions, and genital ulcerations. Many other systems can also be affected [1–3]. • BD is currently considered as an autoinflammatory disease. • BD was also named Adamantiades–Behcet’s syndrome, Behcet’s syndrome, and uveomeningoencephalitic syndrome in previous literature [2]. • As BD is frequently observed in populations along the ancient “silk road,” it is also named as “silk road disease” [1, 4].

• BD is frequently prevalent in Japan, China, and the Mediterranean countries [1, 2, 5, 6]. • The prevalence of BD in the United States is 4 in 100,000 individuals [7] whereas the prevalence of BD is 8–10 and 80–300 in 100,000 population in Japan [8] and Turkey [9, 10] respectively. • The prevalence of BD in Japan is getting lower during recent years based on recent studies. • The prevalence of BD in China remains unchanged based on our experience in clinical practice although there is no epidemic survey in the population. • BD patients account for 16.5% of the total uveitis patients based on a study previously reported by us in a tertiary uveitis center in China [11]. In a recent study, we found that BD patients accounted for 10.6% of the more than 15,000 uveitis patients.

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• BD mostly affects young adults (20–40 years old). • Both males and females are affected. However, most studies show a male predilection and a severer disease in male patients [5]. • About 70% of BD patients have ocular involvement. • Bilateral involvement is usual although unilateral uveitis is common during recurrence.

26.3 Etiology and Pathogenesis • The etiology and pathogenesis are not yet completely known although immune response has been considered as an important mechanism involved in its development [1, 2]. • Viral and bacterial infections have been shown to be associated with BD. However, there is no direct evidence to show their involvement in the pathogenesis of this disease. • Our recent study on fecal samples from active BD patients shows that abnormal gut microbiome is involved in the development of this disease. Transplantation of feces from active BD patients may significantly worsen the severity of experimental autoimmune uveoretinitis, a common uveitis model in animal [12]. • Genetic predisposition has been extensively studied for BD and the results show that BD is strongly associated with HLA-B51 in various races [4]. • A number of genes including IL-23R, STAT4, STAT3, IL-10, CD40, and TLR2 have also been shown to be associated with BD [13–16]. • Activation of Th1 and Th17 cells and their modulating factors including A20, IL-7, IL-22, NOD1, 2, TLR2, 3, 4,

Fig. 26.1  Scleritis observed in BD patients

26  Behcet’s Disease

ROS-NLRP3, IL-37, and IL-27 have been shown to play a role in the development of BD [17–19]. • Overactivation of Th17 and Th1 cells following viral or bacterial infection in genetic susceptible individuals may be an essential mechanism involved in BD development. • Resistance of lymphocytes to Fas-mediated apoptosis has been presumed as one of the mechanisms involved in the pathogenesis of BD [20].

26.4 Ocular Lesions • Ocular involvement occurs in 83–95% of the male BD patients and 67–73% of the female BD patients. • The most common ocular finding is uveitis [1, 2]. Other findings include scleritis (Figs.  26.1, 26.2 and 26.3), episcleritis (Fig. 26.4), keratitis (Fig. 26.5), conjunctival ulcers, and corneal ulcers. • BD patients with intraocular inflammation frequently manifest as generalized uveitis, posterior uveitis, and anterior uveitis although intermediate uveitis is occasionally observed. • BD patients definitely display nongranulomatous uveitis. • Inflammation in the anterior segment. –– It may be present alone (anterior uveitis) or as one part of generalized uveitis. –– Patients may complain about redness, periocular or periorbital pain, photophobia, tearing and blurred vision, or decreased vision. –– Slit-lamp biomicroscopic examination shows ciliary injection (Fig.  26.6), dust-like keratic precipitates (KPs) (Fig. 26.7), aqueous flare and cells (Fig. 26.8).

26.4 Ocular Lesions

341

Fig. 26.2  Diffused anterior scleritis observed in BD patients

Fig. 26.3  Nodular scleritis observed in a male BD patient

Fig. 26.4  Episcleritis observed in a BD patient

–– Cells in the anterior chamber are prone to move freely and quickly. However, fixed aqueous humor is occasionally noted. –– Numerous cells in the anterior chamber are usually associated with mild aqueous flare (Fig. 26.8a) in spite of the occasional presence of severe aqueous flare (Fig. 26.9) and marked fibrous exudates in certain BD patients. –– Hypopyon is common [1, 2] and occurs in 20–44% of ocular BD patients. It is characterized by the following features: Recurrent attacks. Sterile hypopyon. Easy shifting with gravity as head position is changed. Figures 26.10 and 26.11 are two examples to show the rapid shifting of hypopyon with gravity. It may be associated with ciliary injection (the socalled hot hypopyon) (Fig. 26.12) or without apparent ciliary injection (the so-called cold hypopyon) (Fig. 26.13). It may also be associated with fibrous exudates (Fig. 26.14). Trauma or intraocular surgery tends to induce hypopyon recurrence. It is sensitive to corticosteroid eye drops. It usually lasts for 2–4 days. –– Fibrous exudates are usually observed in BD patients with severe anterior segment inflammation (Figs. 26.15 and 26.16). –– Hyphema may be occasionally observed in BD patients, especially in those with rubeosis (Fig. 26.17).

342

26  Behcet’s Disease

Fig. 26.5  Corneal lesions observed in BD patients

Fig. 26.6  Ciliary injection observed in a BD patient

–– Inflammation in the anterior chamber is prone to resolve spontaneously over one or two weeks. However, recurrent attacks with a short interval are relatively common. –– Posterior synechiae is a common consequence of recurrent attacks of inflammation in the anterior cham-

ber especially in the patients who are not treated promptly and properly. Posterior synechiae may lead to deformed pupil in various appearances (Fig. 26.18). Complete posterior synechiae (pupillary seclusion) (Fig. 26.19) may develop and in turn lead to pupillary block and iris bombe (Fig. 26.20). Peripheral anterior synechiae (Fig.  26.21) is less common and observed mainly in BD patients with refractory intraocular inflammation. –– Depigmentation and atrophy of the iris may be observed in BD patients with recurrent anterior uveitis and extensive posterior synechiae. • Inflammation in the posterior segment. –– Involvement of the retina and retinal vessels is the hallmark of BD and may progress to irreversible changes in a few years (Fig. 26.22). –– The most common manifestation in the posterior segment is retinal vasculitis [1, 2, 21, 22]. It typically manifests as retinal microvasculitis (capillaritis) as evidenced by fluorescence leakages from retinal capillaries on fundus fluorescein angiography (FFA) although there is no visible fundus changes in most cases (Figs. 26.23 and 26.24).

26.4 Ocular Lesions

343

Fig. 26.7  Dust-like KPs observed in BD patients

a

b

Fig. 26.8  Aqueous cells with minor (a) or obvious (b) flare observed in BD patients

Fig. 26.9  Severe aqueous flare in association with numerous cells observed in BD patients

344

Fig. 26.10  Hypopyon in a male BD patient rapidly shifts with gravity as the patient changes his head position

26  Behcet’s Disease

26.4 Ocular Lesions

Fig. 26.11  Hypopyon in a female BD patient rapidly shifts with gravity as the patient changes her head position

345

346

Fig. 26.12  Hot hypopyon observed in BD patients

Fig. 26.13  Cold hypopyon observed in BD patients

26  Behcet’s Disease

26.4 Ocular Lesions

Fig. 26.14  Hypopyon associated with fibrous exudates observed in a male BD patient

Fig. 26.15  Fibrous exudates in various appearances observed in BD patients

347

Obliterative and necrotizing vasculitis is the hallmark of the retinal findings. Both the arteries and veins are involved (Fig. 26.25). It may also present as periphlebitis or thromboangiitis obliterans and manifest as soft exudates and retinal or vitreous hemorrhages (Fig. 26.26). In very few patients, frosted branch angiitis may be observed (Fig. 26.27) Ischemic retinal changes due to recurrent severe vasculitis may lead to retinal neovascularization and massive vitreous hemorrhage. Sheathing of the veins, arteries and even silver-­ wired vessels (ghost vessels) (Fig.  26.28) may develop due to relentless inflammatory processes. Widespread ghost vessels associated with retinal atrophy and optic nerve atrophy are the

348

26  Behcet’s Disease

Fig. 26.15 (continued)

a

b

Fig. 26.16  Fibrous exudates observed in a BD patient (a: photograph; b: ultrasound biomicroscopy finding)

typical manifestations in the end stage of this disease [1, 2]. Hard exudates are occasionally observed in BD patients with refractory microvasculitis. They may be observed in macular (Fig. 26.29) or other regions (Fig. 26.30). –– Retinitis [5, 21] It is not as common as retinal vasculitis. It may appear as single or multifocal yellow-­white lesions (Figs. 26.31 and 26.32). Massive necrotizing retinitis similar to CMV retinitis in appearance, frequently associated with marked vitreous inflammation, is occasionally observed in BD patients (Fig. 26.33). Retinitis may leave retinal atrophy after the inflammation resolves (Fig. 26.34).

–– Papillitis is a relatively uncommon manifestation in the posterior segment of BD patients (Fig.  26.35). It may be associated with peripapillary hemorrhage and fluorescence leakage of retinal capillaries (Fig. 26.36). • Vitreous opacity is a common finding in the BD patients with posterior segment involvement. –– It varies greatly with patients. –– Vitreous opacities may manifest as diffuse, mass-like appearances, or veil-like appearances (Fig. 26.37). –– Subclinical retinal vasculitis is often associated with minor vitreous opacity. –– Clinically visible retinal vasculitis is usually associated with obvious vitreous opacity. –– Retinitis is frequently associated with significant vitreous opacity.

26.5 Extraocular Manifestations

349

Fig. 26.17  Hyphema observed in BD patients

26.5 Extraocular Manifestations • Oral aphthae are the most common extraocular manifestation [1, 2, 5], occurring in more than 90% of the BD patients. –– They may occur anywhere in the oral cavity and in varying numbers (Fig. 26.38). –– They usually precede ocular lesions and other extraocular manifestations. –– They tend to relapse with a short interval. Recurrence at least three times each year is the typical feature. –– They are painful and usually last for 5–14 days. • Skin lesions [1, 2, 5, 21]. –– They are one of the common extraocular findings, occurring in about 80% of the BD patients. Fig. 26.18  Plum flower-like pupil observed in a BD patient

350

Fig. 26.19  Complete posterior synechiae of the iris (seclusion of the pupil) observed in BD patients

Fig. 26.20  Iris bombe due to pupillary block observed in BD patients

26  Behcet’s Disease

26.5 Extraocular Manifestations

351

a

b

c

Fig. 26.21  Posterior and anterior synechiae of the iris observed in a BD patient (a: photograph; b, c: UBM findings)

a

b

Fig. 26.22  Ocular fundus changes at first uveitis onset in a male BD patient (a, b). Four years later, obvious fundus changes and even retinal and optic nerve atrophy are observed in this patient (c, d)

352

c

26  Behcet’s Disease

d

Fig. 26.22 (continued)

a

b

c

Fig. 26.23  There is no obvious fundus change in both eyes of a male BD patient (a, b). However, FFA shows diffuse fluorescence leakages from retinal capillaries and staining of the optic disc (c: right eye; d: left eye)

26.5 Extraocular Manifestations

353

d

Fig. 26.23 (continued)

a

b

c

Fig. 26.24  There is no obvious fundus change in both eyes of a male BD patient (a, b). However, FFA reveals extensive vascular leakages, cystoid macular edema (CME), and staining of the optic disc (c: right eye; d: left eye)

354

26  Behcet’s Disease

d

Fig. 26.24 (continued)

a

b

c

Fig. 26.25  Retinal vasculitis affecting both arteries and veins observed in BD patients (a–c)

26.5 Extraocular Manifestations

Fig. 26.26  Retinal vasculitis associated with retinal hemorrhages and soft exudates in various appearances observed in BD patients

355

356

26  Behcet’s Disease

Fig. 26.27  Frosted branch angiitis observed in a male BD patient

Fig. 26.28  Silver-wired retinal vessels (ghost vessels) accompanying retinal and optic nerve atrophy observed in BD patients in the end stage

26.5 Extraocular Manifestations

a

b

Fig. 26.29  Hard exudates and extensive vascular leakage observed in a BD patient (a: fundus photograph; b: FFA results)

Fig. 26.30  Hard exudates in the retina observed in BD patients

357

358

Fig. 26.31  Retinitis in various appearances observed in BD patients

26  Behcet’s Disease

26.5 Extraocular Manifestations

Fig. 26.31 (continued)

Fig. 26.32  Large area of retinitis associated with edema, hemorrhages, and papillitis observed in BD patients

Fig. 26.33  Large area of necrotizing retinitis accompanying retinal hemorrhages observed in BD patients

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360

Fig. 26.34  Large area of retinal atrophy observed in a BD patient

Fig. 26.35  Papillitis observed in BD patients

26  Behcet’s Disease

–– Erythema nodosum (Figs.  26.39, 26.40, and 26.41), papulopustules (Fig. 26.42), and acneiform pseudofolliculitis (Figs. 26.43 and 26.44) are the common skin lesions. Other skin lesions including ulcerations (Figs. 26.45, 26.46, and 26.47), pyoderma, necrotizing lesions, and superficial thrombophlebitis may occasionally develop. –– Skin lesions tend to relapse and disappear spontaneously without scarring or leaving hyperpigment scars. –– Thrombophlebitis, usually occurring at lower limbs, may be observed in certain BD patients. • Genital ulcers. –– It is a relatively common extraocular manifestation, occurring in 30–94% of the BD patients. –– They are painful and can occur on the scrotum, penis, vulva, vaginal mucosa, and perianal areas (Fig. 26.48). –– They usually disappear within 7–14 days. –– Large and deep ulcers may leave scars as they heal (Fig. 26.49). • Arthritis. –– Arthritis occurs in 51–80% of BD patients.

26.5 Extraocular Manifestations

361

a

c

b

d

Fig. 26.36  Papillitis-associated hemorrhages and vascular leakages observed in a BD patient (a: fundus photograph; b–d: FFA results)

362

26  Behcet’s Disease

Fig. 26.37  Various vitreous opacities observed in BD patients

–– Joint involvement may manifest as monoarticular, oligoarticular, or polyarticular arthritis. –– Articulatio genus, podarthrum (Fig.  26.50), articulationes manus, and elbow joint are frequently affected. –– Ankylosing spondylitis or sacroiliitis can also be observed in few BD patients. –– Nonmigrating and nondestructive arthritis are often observed. However, erosive damage may be occasionally observed. • Other extraocular manifestations –– Neurological involvement is uncommon, but it is a severe manifestation in BD.

–– Gastrointestinal involvement is less common and mainly manifests as single or multiple ulcers in esophagus, stomach or intestine. –– Pulmonary involvement is rare and mainly presents as pulmonary arteritis. –– Cardiovascular involvement is rare and may present as arterial occlusion, aneurysms, venous occlusion, varices, endocarditis, myocarditis, pericarditis, endomyocardial fibrosis, and myocardial infarction. –– Epididymitis occurs in about 10% of the BD patients and presents as pain and swelling for some days. –– Acute glomerulonephritis, IgA nephropathy, and amyloidosis are rarely seen in BD patients.

26.5 Extraocular Manifestations

Fig. 26.38  Oral aphthae observed in BD patients

363

364

Fig. 26.39  Erythema nodosum in various appearances observed in BD patients

26  Behcet’s Disease

26.5 Extraocular Manifestations

365

Fig. 26.40  Large erythema nodosums observed in BD patients

Fig. 26.42  Pustules observed in a pediatric BD patient

Fig. 26.41  Scar and pigmentation left after the healing of erythema nodosum observed in a BD patient

366

Fig. 26.43  Furuncles and acne-like lesions observed in BD patients

26  Behcet’s Disease

26.5 Extraocular Manifestations

367

Fig. 26.44  Histological changes of folliculitis in a BD patient

Fig. 26.45  Ulceration in the skin observed in BD patients

a

b

c

d

Fig. 26.46  Ulcerations in the skin (lasting for more than 5 years) of a BD patient from Turkey (a, c) are completely healed following a more than two-month treatment with immunosuppressive agents combined with traditional Chinese medicine (b, d)

368

a

c

26  Behcet’s Disease

b

d

Fig. 26.47  A skin ulcer (a, b) in a female BD patient is completely healed following treatment with immunosuppressive agents combined with traditional Chinese medicine (c, d)

26.6 Ocular Complications • Complicated cataract –– It is frequently seen in the BD patients with highly recurrent episodes of intraocular inflammation. –– Posterior subcapsular opacities (Fig. 26.51) are common in BD patients with recurrent intraocular inflammation. • Secondary glaucoma –– Increased intraocular pressure or secondary glaucoma is a relatively common complication in BD patients. –– It may develop as a result of pupillary block, extensive peripheral anterior synechiae, and occasionally iris neovascularization.

• CME –– CME (Fig. 26.52) occurs frequently as a consequence of retinal vasculitis in BD patients. –– Permanent CME is usually associated with a poor visual prognosis. –– It is usually refractory to therapy although it may resolve in certain BD patients after treatment with c­ orticosteroids combined with other immunosuppressive agents. –– Intravitreous anti-VEGF agents such as Conbercept may be useful in the treatment of CME.  However, repeated injections may be needed. • Retinal neovascularization –– Neovascularization usually develops at or around the optic disc in BD patients with retinal vasculitis (Figs. 26.53, 26.54, and 26.55).

26.6 Ocular Complications

369

Fig. 26.48  Genital ulcers observed in BD patients

–– Retinal neovascularization may occur at any part of the retina (Figs. 26.56 and 26.57). –– Iris neovascularization (Fig. 26.58) is often associated with complete posterior synechiae or retinal ischemia. –– Choroidal neovascularization is rare in BD patients (Fig. 26.59). • Retinal atrophy and optic nerve atrophy [1, 2, 5, 21] –– They usually develop in BD patients with recurrent or permanent retinal vasculitis and papillitis. –– They are the common complications at the end stage of BD. –– Diffuse retinal atrophy accompanying occlusion of retinal vessels (ghost vessels) (Figs. 26.60, 26.61, and 26.62) and optic nerve atrophy (Fig.  26.63) is the pathognomonic feature at the end stage of BD. • Epiretinal membrane –– It is a relatively uncommon complication. Fig. 26.49  Scars left after regression of genital ulcers in a BD patient

370

Fig. 26.50  Swelling of the ankle joint observed in BD patients

Fig. 26.51  Posterior subcapsular opacities in association with pigmentation observed in both eyes of a BD patient

Fig. 26.52  CME detected by optical coherence tomography (OCT) imaging in a BD patient

26  Behcet’s Disease

26.6 Ocular Complications

371

a

b

c

d

e

f

Fig. 26.53  Neovascularization around and on the optic disc observed in a BD patient (a, d: fundus photographs; b, c, e, f: FFA results; b, c: right eye; e, f: left eye)

a

b

Fig. 26.54  Neovascularization around the optic nerve and fluorescence leakages from capillaries identified in a BD patient (a, b: fundus photographs; c, d: FFA results; c: right eye; d: left eye)

372

26  Behcet’s Disease

c

d

Fig. 26.54 (continued)

Fig. 26.55  Retinal hemorrhages associated with retinal neovascularization observed in a BD patient

–– It often occurs in the BD patients with recurrent retinitis or clinically visible retinal vasculitis. –– It may develop at macular area, optic disc, and elsewhere (Figs. 26.64, 26.65, and 26.66). • Macular hole –– It is an uncommon complication. –– It usually occurs in BD patients with refractory posterior uveitis (Fig. 26.67). –– OCT imaging may exactly depict macular hole in these patients. • Retinal detachment –– It is a relatively uncommon complication in BD patients. –– It may be serous, rhegmatogenous, or tractional in nature. –– B-scan ultrasonography and OCT imaging are useful in detecting retinal detachment.

26.6 Ocular Complications

Fig. 26.56  Retinal neovascularization observed in BD patients

Fig. 26.57  Retinal neovascularization detected by FFA in BD patients

373

374

Fig. 26.58  Iris neovascularization observed in BD patients

Fig. 26.59  Choroidal neovascularization detected by OCT imaging in a BD patient

26  Behcet’s Disease

26.6 Ocular Complications

375

a

c

b

d

Fig. 26.60  Diffuse retinal atrophy associated with ghost blood vessels and optic nerve atrophy observed in a BD patient (a, b: fundus photographs; c, d: OCT imaging results)

Fig. 26.61  Severe retinal thinning (retinal atrophy) detected by OCT imaging in both eyes of a BD patient

376

a

26  Behcet’s Disease

b

c

d

Fig. 26.62  Retinal atrophy associated with occlusion and attenuation of the retinal vessels and optic nerve atrophy observed in a BD patient (a, b: fundus photographs; c, d: FFA results; c: right eye; d: left eye)

26.6 Ocular Complications

Fig. 26.63  Optic nerve atrophy associated with occlusion and attenuation of the retinal vessels observed in a BD patient

Fig. 26.64  Epiretinal membrane observed in BD patients

377

378

26  Behcet’s Disease

a

b

c

Fig. 26.65  Epiretinal membrane observed in a BD patient (a: fundus photograph; b, c: FFA results)

• Vitreous hemorrhages –– It is a less common complication in BD patients (Fig. 26.68). –– It often occurs in BD patients with retinal neovascularization.

• Phthisis bulbi –– It is an uncommon complication. –– It mainly occurs in the BD patients with recurrent panuveitis or with permanent intraocular inflammation.

26.6 Ocular Complications

379

Fig. 26.66  Various epiretinal membranes observed in BD patients

a

b

c

Fig. 26.67  Macular hole identified in a BD patient (a, b: fundus photographs; c: OCT imaging result)

380

26.7 Diagnosis The diagnosis of BD is principally based on clinical manifestations. Auxiliary examinations may be helpful in the evaluation of changes in the ocular tissues. There is no specific laboratory test for BD although some are useful for evaluating and monitoring the side effects of drugs used in the treatment. • Typical clinical observations –– Recurrent nongranulomatous uveitis especially in association with hypopyon, diffuse retinal microvasculitis as disclosed by FFA, retinal vasculitis, retinitis and diffuse retinal atrophy, optic nerve atrophy, and silver-wired retinal blood vessels. –– Recurrent and painful oral aphthae with a high frequency. –– Recurrent and painful genital ulcers. –– Multiform skin lesions. –– Other systemic involvement.

Fig. 26.68  Massive vitreous hemorrhages observed in a BD patient

Fig. 26.69  Positive pathergy test result observed in BD patients

26  Behcet’s Disease

• Positive pathergy test is helpful to the diagnosis of BD (Fig. 26.69) • Auxiliary examinations –– FFA It is a very useful technique in detecting retinal and retinovascular changes in BD patients. The changes disclosed by FFA include fluorescence leakage from the retinal blood vessels or the retinal capillaries, CME (Fig.  26.70), fluorescence blockage due to hemorrhages (Figs.  26.71, 26.72, and 26.73), ­nonperfusion of the retinal capillaries (Fig. 26.74), retinal neovascularization (Fig.  26.75), and ­ staining  of the optic disc and vascular wall ­ (Fig. 26.76). Fluorescence leakages from retinal capillaries usually present as “fern-leaf” appearance (Fig. 26.76) Retinal vascular leakages are the most common findings and account for about 80% of BD patients with ocular involvement. A number of BD patients without visible fundus changes may display significant diffuse fluorescence leakage from the retinal capillaries (Figs. 26.77, 26.78, and 26.79). –– OCT imaging It is widely used to determine the changes of the posterior pole in BD patients and other uveitis entities involving posterior segment. It is useful in detecting CME (Fig.  26.80), macular hole (Figs. 26.81 and 26.82), serous retinal detachment (Fig.  26.83), retinal pigment epithelium detachment (Figs.  26.84 and 26.85), thinning of the retina (Fig. 26.86), swelling of the optic nerve, and epiretinal membrane (Figs. 26.87 and 26.88). CME is the most common change in BD patients with retinal vasculitis whereas the retinal thinning is commonly seen at the end stage of the disease.

26.7 Diagnosis

381

OS, FA 6:17.73 55º ART[HS]

Fluo 1:46.2 12/07/2005

Fluo 13:36.7 12/07/2005

Fluo 14:34.4 12/07/2005

Fig. 26.70  CME associated with vascular leakages and staining of the optic disc detected by FFA in BD patients

Fig. 26.71  Hemorrhages due to neovascularization of the optic nerve and retina observed in a BD patient. (a: fundus photograph; b, c: FFA results)

a

382

26  Behcet’s Disease Fluo 2:59.3 26.06.2006 OD

Fluo 3:28.3 26.06.2006 OD

Fluo 3:59.4 26.06.2006 OD

Fluo 0:42.3 26.06.2006 OD

Fluo 2:27.1 26.06.2006 OD

Fluo 2:42.4 26.06.2006 OD

b

c

Fig. 26.71 (continued)

a

b

c

d

Fig. 26.72  Hemorrhages due to neovascularization of the optic nerve, fluorescence blockage, and leakage of retinal capillaries disclosed by FFA in a BD patient (a: fundus photograph; b–d: FFA results)

26.7 Diagnosis

383

a

b

c

Fig. 26.73  Retinal vasculitis associated with hemorrhages observed in a BD patient (a: fundus photograph; b, c: FFA results)

OS, FA 3:57.71 30º ART [HS]

OS, FA 4:32.50 30º ART [HS]

OS, FA 5:02.57 30º ART [HS]

OS, FA 2:26.17 55º ART [HS]

OS, FA 2:54.68 55º ART [HS]

OS, FA 3:03.89 55º ART [HS]

Fig. 26.74  Nonperfusion of the retinal capillaries associated with vascular leakages detected by FFA in BD patients

384

26  Behcet’s Disease

b

a

OD, FA 1:02.71 55° [HS]

OD, FA 4:14.40 55° ART [HS]

OD, FA 10:07.12 55° ART [HS]

OD, FA 0:43.07 55° [HS]

OS, FA 5:12.23 55° ART [HS]

OD, FA 9:03.82 55° ART [HS]

c

d

Fig. 26.75  Retinal neovascularization observed in a BD patient (a, b: fundus photographs; c, d FFA results)

26.7 Diagnosis OD, FA 3:13.56 55º ART [HS]

385 OD, FA 3:18.01 55º ART [HS]

OD, FA 5:54.54 55º ART [HS]

Fig. 26.76  “Fern-leaf” shaped fluorescence leakages from the retinal capillaries and staining of the optic disc observed in a BD patient

a

b

c

d

Fig. 26.77  A male BD patient does not have obvious fundus change in his right eye. However, diffuse fluorescence leakages are detected by FFA (a: fundus photograph; b–d: FFA results)

386

26  Behcet’s Disease

a

b

c

d

Fig. 26.78  There is no visible fundus change in the left eye of a male BD patient. However, FFA discloses diffuse fluorescence leakages and staining of the optic disc (a: fundus photograph; b–d: FFA results)

26.7 Diagnosis

387

a

FA 3:36.59 55~ART [HS]

b

FA 7:03.45 55~ART [HS]

c

Fig. 26.79  A male BD patient does not have visible fundus changes in his left eye (a). However, FFA shows extensive fluorescence leakages and staining of the vascular walls and optic disc (b, c)

388

Fig. 26.80  CME in association with retinal detachment detected by OCT imaging in a BD patient

26  Behcet’s Disease

–– B-scan ultrasonography It is useful to evaluate the changes of the posterior segment in BD patients with opaque media. Common findings disclosed by B-scan ultrasonography include varying degrees of vitreous opacities (Fig. 26.89), proliferative vitreoretinopathy, and retinal detachment (Fig. 26.90). B-scan ultrasonography can also be used to evaluate phthisis bulbi. –– UBM UBM is commonly used in evaluating the changes in the anterior segment.

Fig. 26.81  Macular hole in different appearances detected by OCT imaging in BD patients

Fig. 26.82  Macular hole in association with retinal detachment detected by OCT imaging in a male BD patient

26.7 Diagnosis

389

Fig. 26.83  Serous retinal detachment detected by OCT imaging in both eyes of a BD patient

Fig. 26.84  Retinal detachment and retinal pigment epithelium detachment detected by OCT imaging in a BD patient

Fig. 26.85  Obvious retinal detachment associated with tiny retinal pigment epithelium detachment detected by OCT imaging in a BD patient

The changes disclosed by UBM in BD patients include cells in the anterior chamber (Fig. 26.91) and posterior chamber (Fig.  26.92), fibrous exudates (Fig.  26.93), posterior synechiae (Fig.  26.94), peripheral anterior synechiae (Fig. 26.95), iris atrophy (Fig. 26.96), exudates adjacent to the pars plana (Fig. 26.97), and disorganization and detachment of the ciliary body (Fig. 26.98) –– Multifocal electroretinography (mfERG) It has been used to evaluate the function of the posterior retina in patients with posterior segment involvement. Various mfERG abnormalities have been documented in BD patients (Fig. 26.99).

390

26  Behcet’s Disease

Fig. 26.86  Retinal atrophy detected by OCT imaging in BD patients

Fig. 26.87  Epiretinal membrane and focal thickening of the retina due to the shrinkage arising from this membrane in a BD patient

Fig. 26.88  Epiretinal membrane detected by OCT imaging in a male BD patient

26.7 Diagnosis

Fig. 26.89  Various vitreous opacities detected by B-scan ultrasonography in BD patients

391

392

Fig. 26.90  Proliferative vitreous retinopathy and retinal detachment detected by B-scan ultrasonography in BD patients

Fig. 26.91  Cells in the anterior chamber detected by UBM in BD patients

26  Behcet’s Disease

26.7 Diagnosis

Fig. 26.92  Cells in the anterior and posterior chamber detected by UBM in BD patient

Fig. 26.93  Fibrous exudates and cells in the anterior chamber detected by UBM in a BD patient

393

394

Fig. 26.94  Posterior synechiae and aqueous cells detected by UBM in a BD patient

Fig. 26.96  Iris atrophy detected by UBM in BD patients

26  Behcet’s Disease

Fig. 26.95  Peripheral anterior synechiae detected by UBM in a BD patient

26.7 Diagnosis

Fig. 26.97  Exudates adjacent to the pars plana detected by UBM in a BD patient

Fig. 26.98  Disorganization and detachment of the ciliary body detected by UBM in BD patients

395

396

Fig. 26.98 (continued)

Fig. 26.99  Various abnormalities of mfERG documented in BD patients

26  Behcet’s Disease

26.7 Diagnosis

–– Abnormalities in visual field Abnormalities in visual field are common in BD patients with posterior segment involvement. Various abnormalities in visual field are identified.

397

Examples are given to show abnormalities in visual field in BD patients (Figs.  26.100, 26.101, 26.102, 26.103, 26.104, and 26.105).

Fig. 26.100  General reduction of sensitivity shown on Humphrey perimetry in a BD patient

398

Fig. 26.101  General reduction of sensitivity detected by Humphrey perimetry in a BD patient

26  Behcet’s Disease

26.7 Diagnosis

Fig. 26.102  Residual partial visual islands identified by Humphrey perimetry in a BD patient

399

400

Fig. 26.103  General reduction of sensitivity identified by Humphrey perimetry in a BD patient

26  Behcet’s Disease

26.7 Diagnosis

Fig. 26.104  Residual central island identified by Octopus perimetry in a BD patient

401

402

26  Behcet’s Disease

a

Fig. 26.105  General reduction of sensitivity (a, b) and inferior half visual field defect (b) identified by Humphrey perimetry in a BD patient

26.7 Diagnosis

b

Fig. 26.105 (continued)

403

404

26  Behcet’s Disease

26.8 Diagnostic Criteria

26.9 Differential Diagnosis

• There are several criteria in the diagnosis of BD. The criteria used worldwide are those developed by Behcet’s Disease Research Committee of Japan (Table 26.1) [23] and those proposed by The International Behcet’s disease Study Group (Table 26.2) [24]

• Uveitis associated with BD is absolutely nongranulomatous in nature. • The following diseases or uveitis entities should be differentiated from BD. –– HLA-B27+ acute anterior uveitis –– Acute anterior uveitis associated with seronegative spondyloarthropathies –– Idiopathic nongranulomatous anterior uveitis –– Tubulointerstitial nephritis and uveitis syndrome –– Nongranulomatous anterior uveitis associated with sarcoidosis –– Vogt–Koyanagi–Harada (VKH) disease in anterior uveal involvement stage

Table 26.1 Diagnostic criteria of Behcet’s disease Research Committee of Japana 1. Major symptoms A. Recurrent aphthous ulceration of the oral mucous membrane B. Skin lesions  (a) Erythema nodosum-like lesions   (b) Thrombophlebitis  (c) Folliculitis or acne-like lesions  (d) Cutaneous hypersensitivity C. Ocular symptoms  (a) Iridocyclitis  (b) Retinochoroiditis  (c) Sequelae of a and b D. Genital symptoms 2. Minor symptoms A. Arthritis B. Intestinal lesions (intestinal Behcet’s disease) C. Epididymitis D. Vascular lesions (angio-Behcet’s disease) E. Neuropsychiatric lesions (neuro-Behcet’s disease) 3. Examination Skin prick test 4. Diagnosis A. Complete type: patients with all four major symptoms B. Incomplete type  (a) Patients with three major symptoms  (b) Patients with two major symptoms and two minor major symptoms  (c) Patients with ocular symptoms and one another major symptom  (d) Patients with ocular symptoms and two minor major symptoms Reprinted with permission from Kurokawa MS, Suzuki N.  Behcet’s disease. Clin Exp Med. 2004; 3:10–20

a

Table 26.2  The International Behcet’s Disease Study Group criteriaa These criteria require the presence of two of the four features below: 1. Genital ulcers 2. Eye lesions 3. Pathergy test 4. Skin lesions (folliculitis, papulopustular lesions, acneiform nodules, and/or erythema nodosum) Adapted from Criteria for diagnosis of Behcet’s disease. International Study Group for Behcet’s Disease. Lancet 1990;335:1078–1080

a

26.10 Treatment • Therapy strategies in the management of BD patients. –– Treatment should be individualized according to the activity of intraocular inflammation, frequencies of attack, the systemic disorders as well as patient’s economic condition. –– A long-term treatment with a low dose of drugs is necessary for the permanent controlling of chronic low-­ grade intraocular inflammation, especially for retinal microvasculitis, in most BD patients. –– Combination of a low dose of corticosteroids with one or more immunosuppressive agents is usually recommended in an attempt to improve BD patients’ prognosis and to reduce side effects of drugs used during treatment as maximally as possible. –– Symptomatic treatment is immediately prescribed in acute condition in BD patients with fulminate retinitis, necrotizing retinal vasculitis, or rapidly elevated intraocular pressure. • Corticosteroids and other various immunosuppressive agents have been used for the treatment of BD. The choice of drugs mainly relies on the severity of the disease, frequency of the disease recurrence, and the patients’ response to them [1, 2, 5]. • Anterior uveitis. –– Anterior uveitis alone is not common in BD patients and is mainly seen in female patients. –– Topical corticosteroids, cycloplegics and mydriatics should be prescribed for the BD patients with anterior uveitis. –– Recurrent anterior uveitis with high frequencies may need systemic corticosteroids.

26.10 Treatment

• Panuveitis or posterior uveitis. –– Topical corticosteroids, cycloplegics and mydriatic agents are needed for the patients with anterior chamber reaction. –– Corticosteroids are usually as the first-line agent for the patients with posterior segment involvement. Aggressive treatment with systemic corticosteroids, for instance 50–60 mg prednisone each day, is needed only for the BD patients with fulminate explosive episodes and severe necrotizing retinitis. The dosage of corticosteroids should be rapidly tapered to a maintenance dose, normally 20 mg daily. It has been shown that BD patients will eventually become resistant to corticosteroids and their longterm use at a higher dosage even worsen the patients’ visual prognosis and result in severe side effects. In author’s experience, a low dose of corticosteroids (20 mg prednisone for adult patients) combined with other immunosuppressive agents is useful for most BD patients. The concurrent use of other immunosuppressive agents includes cyclosporine, cyclophosphamide, chlorambucil, colchicine, methotrexate, and mycophenolate. –– Cyclophosphamide It is a widely used alkylating agent in the treatment of BD patients. It is administered orally at an initial dose of 100 mg each day although higher doses have been recommended in the literature. It is usually used in combination with a low dose of corticosteroids and cyclosporine. As a variety of side effects including bone marrow depression, sterile hemorrhagic cystitis, azoospermia, and amenorrhea could occur during a long-term treatment, regular monitoring is definitely necessary. –– Chlorambucil [5] It is an alkylating agent. A variety of dosage regimens are recommended in the literature. The author prefers to use an initial dose of 0.1  mg/kg/day with a gradual tapering to 2  mg/day over 4–6 months. A maintenance dose of 2 mg/day is used for some years if needed. Myelosuppression, azoospermia, and amenorrhea are the main side effects and toxicity. Other side effects including hepatic abnormality, pulmonary fibrosis, CNS stimulation, gastrointestinal distress, rash, postural hypotension, and rarely secondary malignancies may occur in some patients. Regular monitoring of these side effects is needed especially for the patients on long-­term use of this drug.

405

–– Cyclosporine [25–27] It can inhibit the production of IL-2, IL-4, CD4L, γ-interferon, and IL-17, and suppress the ­activation and proliferation of Th1 and Th17 cells. Its effectiveness in the treatment of BD has well been recognized by numerous investigators as well as in our practice. Several dosage regimens are reported in the literature. The author prefers to begin with a dose of 3–5 mg/kg/ day in the treatment of refractory uveitis observed in BD patients for 4–6 months and then gradually reduce the dosage. The treatment lasts usually for more than one year if patients respond to it. In some BD patients, retinal vasculitis could completely subside following the treatment with cyclosporin in combination with low-dose systemic corticosteroids (Figs.  26.106 and 26.107). Combination of cyclosporin with corticosteroids is highly recommended by most uveitis specialists. Combination with other immunosuppressive agents such as cyclophosphamide, chlorambucil, and azathioprine is also suggested according to the patient’s condition. Concomitant use of aminoglycosides, nonsteroidal anti-inflammatory drugs, and drugs which are potentially toxic to the kidney may have synergistic nephrotoxicity and should be, therefore, avoided. The side effects of cyclosporin reported are usually associated with high-dose regimens, but can also occur in the patients on low-dose treatment. The most common and severe side effects are nephrotoxicity, hypertension, central neurotoxicity, and hepatotoxicity. Other side effects include hirsutism, gingival hyperplasia, normochromic and normocytic anemia, increased sedimentation rate, hyperuricemia, gouty arthritis, increased total serum cholesterol, paresthesias, temperature hypersensitivity, nausea, and vomiting. –– Mycophenolate mofetil [1, 2] It can inhibit purine synthesis and therefore suppresses rapidly dividing cells. It also inhibits antibody production and interactions between lymphocytes and vascular endothelial cells. There are few reports as regards the use of mycophenolate mofetil in the treatment of BD patients. The recommended dose is 0.5–1 g twice daily. Side effects include hepatotoxicity, nephrotoxicity, secondary infection, anorexia, nausea, alopecia, leukopenia, and increased risk of malignancies. –– Azathioprine It inhibits T and B lymphocytes through interfering with purine and DNA synthesis.

406

26  Behcet’s Disease

a

b

c

d

e

f

Fig. 26.106  Staining of the optic disc and diffuse fluorescence leakage disclosed by FFA in a male BD patient (a–c). These changes almost completely resolve at 8 months after treatment with cyclosporine and a low dose of systemic corticosteroids (d–f)

Fig. 26.107  Vascular leakages and staining of the vascular walls in a BD patient resolve at one year after treatment with cyclosporine combined with a low dose of systemic corticosteroids

26.10 Treatment

A dose of 2–3 mg/kg/day is recommended by a number of uveitis specialists in the treatment of BD patients. In the author’s experience, the use of azathioprine alone is not sufficient to achieve a good result. Combination with corticosteroids is suggested in most cases. The most common side effects are gastrointestinal discomfort and bone marrow depression with leukopenia and thrombocytopenia. A granulocytosis or aplasia is occasionally observed. Increased liver enzymes, hepatocellular necrosis, intestinal pneumonitis, pancreatitis, alopecia, stomatitis, and secondary infections have also been reported. –– Methotrexate It is a folic acid analogue and inhibits RNA, DNA, and protein synthesis through interfering with purine synthesis. The dosage is usually 7.5–15 mg/week, administered orally as a single dose. Intravitreous injection of methotrexate at a dose of 400  μg in 0.1  mL is used for intraocular lymphoma, persistent CME, and choroidal neovascularization secondary to chronic inflammation in the posterior segment. Combination with corticosteroids is a rule in the treatment of BD patients. The most common side effects are myelosuppression and hepatoxicity. Ulcerative stomatitis, diarrhea, acute pneumonitis, pulmonary fibrosis, alopecia, and dermatitis may also occur during treatment. –– Interferon alpha [1, 2, 28, 29] Interferon alpha is a protein with antiviral and immunomodulatory effects.

407

It has been used in the treatment of noninfectious uveitis, especially BD. A variety of therapy regimens has been suggested in the treatment of BD patients. The author usually initiates the treatment at a dose of daily subcutaneous injection of 3 million IU for 3–5 months and then gradually tapers the dose if a beneficial result is observed. Most BD patients respond well to interferon alpha. However, only in a number of these patients retinal vascular fluorescence leakages can disappear following the treatment (Figs. 26.108 and 26.109). The most common side effect is flu-like symptoms, which occurs in more than 90% of the patients at their first subcutaneous injection. Other side effects include the formation of anti-DNA or antithyroid antibody, mild leukopenia, gastrointestinal discomfort, increased liver enzymes, alopecia, depression, paresthesias, and redness at the site of injection. –– TNF-ɑ blocking agents [1, 30] TNF-ɑ blocking agents exert their effect either through inactivation of its cellular receptors (etanercept) or through interfering with its protein (infliximab, adalimumab, golimumab, and certolizumab). Infliximab and adalimumab are shown to be effective in the treatment of BD and other recalcitrant noninfectious uveitis. A full workup should be performed prior to initiation of TNF-ɑ blocking agents with special attention to exclusion of tuberculosis. There are no standard schedules in the use of these agents. Infliximab is intravenously given at a usual dose of 5  mg/kg at an interval of 1–2 months. Adalimumab is given subcutaneously at a dose of

a

Fig. 26.108  Staining of optic disc and vascular leakages disclosed by FFA in a BD patient (a: right eye; c: left eye). These changes almost completely disappear at 9 months after treatment with interferon alpha (b: right eye; d: left eye)

408

b

c

d

Fig. 26.108 (continued)

26  Behcet’s Disease

26.11 Prognosis

409

OD, FA 10:06.95 55° [HS]

OD, FA 10:26.15 55° [HS]

OD, FA 10:33.87 55° [HS]

OD, FA 9:05.48 55° ART[HS]

OD, FA 9:10.03 55° ART[HS]

OD, FA 9:19.59 55° ART[HS]

a

b

Fig. 26.109  Extensive vascular leakages disclosed by FFA in a BD patient (a) almost disappear at 10 months after treatment with interferon alpha (b)

40 mg, once every other week. Etanercept is administered subcutaneously at a dose of 25 mg twice a week. Etanercept is reported to be less effective than TNF-ɑ antibodies in the treatment of uveitis. Side effects of TNF-ɑ blocking agents include infections and reactivation of latent tuberculosis, neurological lesions, cardiac lesions, lupus-like syndrome, cutaneous or systemic vasculitis, nephritis, and increased risk of developing malignancies.

•

•

26.11 Prognosis • In general, the anterior segment inflammation is easily controlled with topical corticosteroids, mydriatic and cycloplegic agents. However, retinal vasculitis is difficult to be controlled in most patients. Therefore, a long-term

•

•

treatment (even for several years) with a low dose of systemic corticosteroids in combination with one or two immunosuppressive agents is needed in these patients. Subclinical retinal vasculitis may last for a long time even in the patients without obvious clinical symptoms after treatment. Visual prognosis of BD patients varies considerably with the location, severity, and frequency of the ocular inflammation. BD patients with only anterior uveitis usually have a good visual prognosis. Recurrent attacks of posterior segment inflammation or persistent retinal vasculitis are usually ominous prognosticators of poor visual prognosis. Retinal atrophy, optic nerve atrophy, and extensive silver-­ wired retinal blood vessels are generally associated with severely impaired vision or even blindness.

410

Fig. 26.110  Complicated cataract with porcelain white appearance observed in a BD patient

• Complicated cataract with porcelain white (Fig. 26.110) or brown appearance is always associated with a very poor visual prognosis. • A Kaplan–Meier survival analysis by our group estimated that the risk of losing useful vision (0.05) is 6.4%, 24.5%, and 62.2% at 1, 5, and 10 years respectively. The visual prognosis is much better in female BD patients than in male BD patients. The risk of losing vision is 29% and 65% at 5 and 10 years respectively in male BD patients. However, it is 6% and 33% in female BD patients.

References 1. Ohno S, Namba K, Takemoto Y. Behcet’s disease. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 785–95. 2. Zafirakis P, Foster CS. Adamantiades-Behcet’s disease. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 858–86. 3. Nussenblatt R, Whitcup S, Palestine A. Behcet’s disease. In: Uveitis fundamentals and clinical practice. 2nd ed. St. Louis: Mosby-Year Book, Inc.; 1996. p. 334–53. 4. Ohno S, Ohguchi M, Hirose S, et al. Close association of HLA-Bw51 with Behcet’s disease. Arch Ophthalmol. 1982;100(9):1455–8. 5. Yang P, Fang W, Meng Q, et al. Clinical features of Chinese patients with Behcet’s disease. Ophthalmology. 2007;115(2):312–8. 6. Yang P, Du L, Ye Z. How to deal with uveitis patients? Curr Mol Med. 2018;17(7):468–70. 7. O’Duffy JD.  Behcet’s disease. In: Kelly WN, Harris ED, Ruddy S, et  al., editors. Textbook of rheumatology. Philadelphia: WB Saunders; 1985. p. 1174–8. 8. Mishima S, Masuda K, Izawa Y, et  al. The eighth Frederick H.  Verhoeff Lecture. presented by saiichi mishima, MD Behcet’s disease in Japan: ophthalmologic aspects. Trans Am Ophthalmol Soc. 1979;77:225–79. 9. Yazici H. Behcet’s syndrome. In: Klippel JH, Dieppe PA, editors. Rheumatology. London: Mosby; 1994. p. 6.20.1–6.

26  Behcet’s Disease 10. Yurdakul S, Gunaydin I, Tuzun Y, et al. The prevalence of Behcet’s syndrome in a rural area in northern Turkey. J Rheumatol. 1988;15(5):820–2. 11. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 12. Ye Z, Zhang N, Wu C, et al. A metagenomic study of the gut microbiome in Behcet’s disease. Microbiome. 2018;6(1):135. 13. Jiang Z, Yang P, Hou S, et al. IL-23R gene confers susceptibility to Behcet’s disease in a Chinese Han population. Ann Rheum Dis. 2010;69(7):1325–8. 14. Yu H, Zheng M, Zhang L, et  al. Identification of susceptibility SNPs in IL10 and IL23R-IL12RB2 for Behcet’s disease in Han Chinese. J Allergy Clin Immunol. 2017;139(2):621–7. 15. Takeuchi M, Mizuki N, Meguro A, et  al. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behcet’s disease susceptibility. Nat Genet. 2017;49(3):438–43. 16. Kirino Y, Bertsias G, Ishigatsubo Y, et  al. Genome-wide association analysis identifies new susceptibility loci for Behcet’s disease and epistasis between HLA-B∗51 and ERAP1. Nat Genet. 2013;45(2):202–7. 17. Chi W, Zhu X, Yang P, et  al. Upregulated IL-23 and IL-17  in Behcet patients with active uveitis. Invest Ophthalmol Vis Sci. 2008;49(7):3058–64. 18. Liu X, Wang C, Ye Z, et al. Higher expression of Toll-like receptors 2, 3, 4, and 8 in ocular Behcet’s disease. Invest Ophthalmol Vis Sci. 2013;54(9):6012–7. 19. Qi J, Hou SP, Zhang Q, et al. A functional variant of pre-miRNA-­ 196a2 confers risk for Behcet’s disease but not for Vogt-Koyanagi-­ Harada syndrome or AAU in ankylosing spondylitis. Hum Genet. 2013;132(12):1395–404. 20. Yang P, Chen L, Zhou H, et al. Resistance of lymphocytes to Fas-­ mediated apoptosis in Behcet’s disease and Vogt-Koyangi-Harada syndrome. Ocul Immunol Inflamm. 2002;10(1):47–52. 21. Tugal-Tutkun I.  Behcet’s disease. In: Gupta A, Gupta V, Herbort CP, et  al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 397–413. 22. Jones N. Vasculitis: Behcet’s disease, Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 293–301. 23. Kurokawa MS, Suzuki N.  Behcet’s disease. Clin Exp Med. 2004;4(1):10–20. 24. International Study Group for Behcet’s Disease. Criteria for diagnosis of Behcet’s disease. Lancet. 1990;335(8697):1078–80. 25. Deuter CM, Kotter I, Wallace GR, et  al. Behcet’s disease: ocular effects and treatment. Prog Retin Eye Res. 2008;27(1):111–36. 26. Masuda K, Nakajima A, Urayama A, et al. Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behcet’s disease. Lancet. 1989;1(8647):1093–6. 27. Liu X, Yang P, Lin X, et  al. Inhibitory effect of Cyclosporin A and corticosteroids on the production of IFN-gamma and IL-17 by T cells in Vogt-Koyanagi-Harada syndrome. Clin Immunol. 2009;131(2):333–42. 28. Stübiger N, Zierhut M. Interferon Alpha. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 345–53. 29. Yang P, Huang G, Du L, et  al. Long-term efficacy and safety of Interferon Alpha-2a in the treatment of Chinese patients with Behcet’s uveitis not responding to conventional therapy. Ocul Immunol Inflamm. 2019;27(1):7–14. 30. Accorinti M, Zierhut M. TNF-alpha blocking agents. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 293–307.

Vogt–Koyanagi–Harada Disease

27

Contents 27.1   Definition

 411

27.2   Epidemiology

 411

27.3   Etiology and Pathogenesis

 411

27.4   Clinical Manifestations 27.4.1  Ocular Manifestations 27.4.2  Extraocular Manifestations 27.4.3  Manifestations in Different Stages

 412  412  412  413

27.5   Complications

 473

27.6   Auxiliary Examinations

 477

27.7   Diagnosis

 530

27.8   Differential Diagnosis

 531

27.9   Treatment

 533

27.10   Prognosis

 536

References

 537

27.1 Definition

27.2 Epidemiology

• Vogt–Koyanagi–Harada (VKH) disease is a systemic autoimmune disorder typically manifesting as a bilateral granulomatous panuveitis frequently in association with skin, auditory-vestibular and nervous involvement [1]. • VKH disease is formerly termed as uveo-meningitic syndrome, uveo-encephalitis, idiopathic uveo-encephalitis, and VKH syndrome [1]. • VKH disease shows a typical disease progression. It begins with bilateral diffuse choroiditis in the early stage and finally progresses to granulomatous anterior uveitis if this disease is not well controlled [2]. • Harada disease (diffuse choroiditis) and Koyanagi disease (granulomatous anterior uveitis) had been considered as two separate diseases. In fact, they are the manifestations in different stages of VKH disease rather than two diseases [1, 3, 4].

• VKH disease is more frequently seen in Chinese, Japanese, Hispanics, Greeks, and Native American ancestry. It is rarely seen in Caucasians [1]. • It accounts for 15.9% of total uveitis patients in China [5], 6.8–10% in Japan and 1–4% in the United States [6]. • It occurs frequently in the second to fifth decades of life. • Male and female are affected with a slight male preponderance.

27.3 Etiology and Pathogenesis • VKH disease is generally considered as an autoimmune disorder mediated by immune response against melanin associated antigen, retinal S-antigen, and interphotoreceptor retinoid-binding protein [1].

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_27

411

412

• Th1 and Th17 cell overreaction is critical to the development, chronicity, and recurrence of this disease [7, 8]. • A network of modulating molecules has been found to be involved in the regulation of Th17 cells and the development of VKH disease during recent years. –– The molecules promoting Th17 cells including IL-23, osteopontin, leptin, IL-7, IL-21, IL-6, TGF-β, NOD1 and 2 have been identified during recent years. A number of molecules including VitD3, IL-2, IL-4, IL-25, IL-27, IL-35, IL-37, and disabled-2 have been shown to inhibit Th17 cell differentiation or IL-17 production in this disease [1]. –– An increased expression of the positive molecules and decreased expression of the negative molecules have been found in VKH patients and this disturbed expression may result in overreaction of Th17 cells and therefore contribute to the development and recurrence of this disease [9]. • Decreased frequency of CD4+CD25high Treg cells or impaired function of these cells have been implicated in the overreaction of Th17 cells and are in turn involved in the development of this disease. • Fas and Fasl are two important factors involved in the modulation of cellular apoptosis. The disturbed expression of both molecules on CD4+T cells has been found in active VKH patients. This disturbance leads to increased resistance of the activated autoimmune T cells to apoptosis and persistent accumulation of these cells, consequently resulting in chronicity and recurrence of this disease [9]. • It has been shown that HLA-DR4 and HLA-DRw53 are strongly associated with VKH disease in Chinese, Japanese, and Hispanic patients [1]. • Recently two regions, ADO-ZNF365-EGR2 and IL23R-­ C1orf141, are identified by us to be closely associated

a

27  Vogt–Koyanagi–Harada Disease

with VKH disease in Chinese patients using genome-­ wide association study analysis [10]. • Other genes including CTLA-4, STAT4, FGFR1OP, JAK1, miR-146, and TNFAIP3 are also shown to be associated with this disease. • A recent study by our group shows that abnormalities of gut microbiota are involved in the development of VKH disease.

27.4 Clinical Manifestations 27.4.1 Ocular Manifestations [1, 11] • Bilateral diffuse choroiditis develops frequently in association with serous retinal detachment and swelling of the optic disc in the early stage of this disease. • Granulomatous panuveitis, typically showing recurrent granulomatous anterior uveitis, eventually develops if the disease is not well controlled. • Sunset glow fundus accompanied by Dalen–Fuchs nodules or nummular chorioretinal scars is also a typical sign of this disease in recurrent granulomatous anterior uveitis stage. • Diffuse scleritis and necrotizing scleritis may be occasionally noted in VKH patients (Fig. 27.1).

27.4.2 Extraocular Manifestations [1–4] • The extraocular manifestations vary with different stages. • They usually include fever, headache, neck stiffness, nausea, confusion, tinnitus, hearing loss, poliosis, vitiligo, and alopecia as described below. • Psoriatic skin lesions may be occasionally observed in VKH patients.

b

Fig. 27.1  Diffused scleritis (a) and necrotizing scleritis (b) observed in VKH patients

27.4  Clinical Manifestations

413

27.4.3 Manifestations in Different Stages [1, 4, 12]

–– Prodromal stage: 1–2 weeks before uveitis attack. Patients may experience the following symptoms: fever, headache, slight confusion or ataxia, neck stiffness, and hypersensitivity to touch of hair and scalp. A few patients complain about nausea, vomiting, orbital pain, slight photophobia, redness (Fig. 27.2), and even chemosis (Fig. 27.3). Few patients may have tinnitus and hearing loss. –– Posterior uveitis stage: within 2 weeks after disease onset. Patients usually experience a sudden onset of the disease, bilateral decreased vision, or even visual loss during a short time after disease onset, photopsia, and metamorphopsia. Conjunctival congestion is occasionally observed in this stage (Figs. 27.4 and 27.5). Patients usually have diffuse choroiditis, typically manifesting as slight and uneven retinal elevation at the peripapillary and posterior pole as a result of multiple serous retinal detachments (Fig. 27.6).

• Moorthy et  al. have divided VKH disease into four distinct phases: (1) prodromal stage, (2) acute uveitis stage, (3) convalescent stage, and (4) recurrent stage. • Based on clinical process and manifestations of 410 VKH patients, we divide this disease into four stages: (1) prodromal stage, (2) posterior uveitis stage, (3) anterior uveal involvement stage, and (4) recurrent granulomatous anterior uveitis stage. This phasing system precisely describes the evolution of this disease and allows doctors to make a diagnosis at any time after disease onset. It is worthwhile to point out that not all of VKH patients progress through all four stages. Early and appropriate treatment may halt the disease at either the posterior uveitis stage or the anterior uveal involvement stage. The manifestations during the four stages are described below in detail.

Fig. 27.2  Conjunctival congestion observed in a VKH patient in prodromal stage

Fig. 27.4  Conjunctival congestion observed in a VKH patient at posterior uveitis stage

Fig. 27.3  Bilateral chemosis observed in a VKH patient in prodromal stage

414

a

27  Vogt–Koyanagi–Harada Disease

b

Fig. 27.5  Conjunctival injection (a) observed in a VKH patient in posterior uveitis stage subsides after treatment with immunosuppressive agents (b)

Serous retinal detachment is commonly seen in the posterior pole and/or inferior midperiphery (Fig. 27.7). Papillitis, sometimes accompanying hemorrhage (Figs. 27.8 and 27.9), stellate exudate (Fig. 27.10), or retinal striate (Fig. 27.11), is observed in some patients. Dilated and tortuous retinal vessels are occasionally associated with swelling of the optic disc in VKH patients (Fig. 27.12). Patients may have the extraocular manifestations as stated in prodromal stage. –– Anterior uveal involvement stage: 2 weeks to 2 months after uveitis onset. With the use of the corticosteroids and other immunosuppressive agents, choroiditis, although present, gradually subsides. Serous retinal detachment (Fig.  27.13) may be still present although they are usually less obvious. Detachment of the ciliary body may be observed in this stage (Fig. 27.14). Dalen–Fuchs nodules begin to appear at the midperiphery (Fig. 27.15). Mild anterior chamber reaction, including cells and flare, is observed in most patients. However, there are no granulomatous inflammation signs such as mutton fat keratic precipitates (KPs) and iris nodules in this stage. Slight RPE clumping or migration may develop with time (Fig.  27.16). Papillitis may be still observed or greatly improved after adequate treatment (Fig. 27.17). Macular pigmentation is often observed in the patients who are treated properly after disease onset (Fig. 27.18). Macular exudates may still be present in few patients (Fig. 27.19)

––

––

––

––

The extraocular manifestations listed in prodromal stage may also be present in this stage. Tinnitus and hearing loss are somewhat more common in this stage. Poliosis, alopecia, and vitiligo appear to be seen in this stage. Sunset glow fundus usually begins to appear 1–2 months after disease onset and gradually become typical over time (Figs. 27.20, 27.21, 27.22, and 27.23). It may not be present if early and appropriate treatment is given (Figs. 27.24 and 27.25). Recurrent granulomatous anterior uveitis stage: 2 months after uveitis onset. If the disease is not well controlled by medications, it will progress onto this stage. The active choroiditis subsides frequently leaving sunset glow fundus, Dalen–Fuchs nodules (Figs.  27.26 and 27.27), chorioretinal scars and pigmentation (Fig. 27.28). Recurrent anterior uveitis may begin with nongranulomatous inflammation, manifesting as dust-like KPs, Descemet’s folds (Fig. 27.29), aqueous flare and cells, and occasionally fibrous exudates in the anterior chamber. It usually progresses onto granulomatous inflammation in a short time if no adequate treatment is instituted. Granulomatous anterior uveitis evidenced by mutton fat KPs (Fig.27.30), iris swelling (Fig. 27.31), Koeppe (Fig.  27.32) and Busacca nodules (Figs.  27.33 and 27.34) is the hallmark in this stage. Granuloma in the iris may be occasionally observed in this stage (Fig. 27.35) Mutton fat KPs are usually located inferiorly. However, they may be observed at the lower pupil area (Fig. 27.36) at the beginning of the recurrent anterior

27.4  Clinical Manifestations

Fig. 27.6  Diffuse choroiditis observed in VKH patients in posterior uveitis stage

415

416

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

e

f

Fig. 27.7  Serous retinal detachment observed in the posterior pole (a, b) and inferior midperiphery (c–f) observed in VKH patients during posterior uveitis stage

27.4  Clinical Manifestations

417

a

b

c

d

Fig. 27.8  Swelling of the optic disc associated hemorrhages observed in both eyes of a VKH patient during posterior uveitis stage (a, b: fundus photographs; c, d: optical coherence tomography imaging results)

Fig. 27.9  Papillitis in association with hemorrhages observed in both eyes of a VKH patient at posterior uveitis stage

418

27  Vogt–Koyanagi–Harada Disease

Fig. 27.10  Papillitis associated with stellate exudates observed in both eyes of a VKH patient in posterior uveitis stage

Fig. 27.11  Papillitis associated with retinal striate observed in VKH patients in posterior uveitis stage

27.4  Clinical Manifestations

419

a

b

c

d

e

f

Fig. 27.12  Papillitis associated with dilated and tortuous blood vessels observed in the right eye of a VKH patient in posterior uveitis stage (a: fundus photograph; b–h: fundus fluorescein angiography results)

420

27  Vogt–Koyanagi–Harada Disease

g

h

Fig. 27.12 (continued)

a

b

c

d

Fig. 27.13  Slight papillitis (a, b) in association with hemorrhages and retinal pigment epithelium (REP) clumping and migration (c, d) observed inVKH patients in anterior uveal involvement stage

27.4  Clinical Manifestations

421

Fig. 27.14  Bilateral detachment of the ciliary body detected by ultrasound biomicroscopy (UBM) in VKH patients in anterior uveal involvement stage

422

Fig. 27.15  Dalen–Fuchs nodules in association with RPE clumping and migration observed in a VKH patient in anterior uveal involvement stage

27  Vogt–Koyanagi–Harada Disease

––

–– uveitis or in the resolution phase of the anterior uveitis following treatment. –– Posterior synechiae are one of the most common findings in this stage and may be associated with iris neovascularization (Figs. 27.37 and 27.38). Complete posterior synechiae may lead to obvious iris bombe (Fig. 27.39). Other manifestations include peripheral anterior synechiae (Fig. 27.40), iris atrophy (Fig. 27.41), depigmentation (Fig. 27.42), and iris cyst (Fig. 27.43). Peripapillary atrophy secondary to choroiditis and complicated cataract are the main consequences in this stage. –– Depigmentation of the choroid and RPE. Overt depigmentation of the choroid and RPE usually causes typical sunset glow fundus (Fig. 27.44). Depigmentation of the choroid and RPE may be gradually obvious over time although there is no clinically visible inflammation in the posterior segment (Figs. 27.45 and 27.46). Sunset glow fundus develops usually 2 months after disease onset and may show different appearances due to various degrees of depigmentation. Severe depigmentation associated with RPE clumping and migration, and subretinal fibrosis

––

––

may lead to atypical uneven red appearance (Figs. 27.47, 27.48, 27.49, and 27.50) Depigmentation of the RPE and choroid may not be uniform and therefore results in different appearances (Figs. 27.51 and 27.52). Severe depigmentation of the choroids and RPE may allow to see clearly the choroidal blood vessels and the sclera under ophthalmoscopy, leaving an uneven white-red fundus appearance (Fig. 27.53) [13]. In this circumstance, the ocular fundus appears white-red rather than uniform red fundus. This uneven white-red fundus represents a result similar to sunset glow fundus, and therefore is named by the author as sunset glow fundus in proper sense. Sunset glow fundus can be readily observed under slit-­ lamp microscopy when slit beam is placed at pupil area (Fig. 27.54). Sunset glow fundus could be evaluated through a red reflex via the sclera, pupil, peripheral iris hole, or depigmentation areas of the iris (Figs.  27.55, 27.56, 27.57, 27.58, 27.59, and 27.60) under slit-lamp microscopy. Dalen–Fuchs nodules usually begin in the anterior uveal involvement stage and end in atrophic lesions following adequate treatment. Dalen–Fuchs nodules are usually distributed in the midperiphery or periphery although they may occur anywhere. They vary in size, number, and appearance (Fig. 27.61) Dalen–Fuchs nodules usually end in multifocal chorioretinal atrophy (Fig. 27.62) The extraocular manifestations in this stage mainly include vitiligo, alopecia, and poliosis although tinnitus and hearing loss may be occasionally present. Vitiligo (Fig. 27.63), alopecia (Figs. 27.64, 27.65, and 27.66), and poliosis (Fig.  27.67) occur frequently in recurrent granulomatous anterior uveitis stage. However, they may be seen in other stages even some years before VKH disease onset. Psoriatic skin lesions are occasionally observed in VKH patients (Figs. 27.68 and 27.69) [14].

27.4  Clinical Manifestations

423

a

b

c

d

Fig. 27.16  RPE clumping observed in a female VKH patient at anterior uveal involvement stage (a, b: fundus photographs; c, d: FFA results; e, f: OCT imaging results)

424

e

27  Vogt–Koyanagi–Harada Disease

f

Fig. 27.16 (continued)

a

b

c

d

Fig. 27.17  Papillitis is observed in VKH patients in posterior uveitis stage (a, c). These changes almost resolve 1 month after adequate treatment (b, d)

27.4  Clinical Manifestations

Fig. 27.18  Subtle macular pigmentation observed in VKH patients following treatment with systemic corticosteroids and cyclosporine

Fig. 27.19  Subtle macular exudates observed in both eyes of a VKH patient in anterior uveal involvement stage

425

426

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

e

f

Fig. 27.20  The appearances and dynamic changes of sunset glow fundus over time observed in a female VKH patient who is treated properly after disease onset (a, b: 20 days after disease onset; c, d: 1 month after

disease onset; e, f: 2 months after disease onset; g, h: 6 months after disease onset; i, j: 10 months after disease onset; k, l: 22 months after disease onset)

27.4  Clinical Manifestations

427

g

h

i

j

k

Fig. 27.20 (continued)

l

428

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

Fig. 27.21  The appearances and dynamic changes of sunset glow fundus over time observed in a female VKH patient (a, b: 2 months after disease onset; c, d: 5 months after disease onset; e, f: 7 months after disease onset; g, h: 11 months after disease onset)

27.4  Clinical Manifestations

429

e

f

g

h

Fig. 27.21 (continued)

430

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

e

f

Fig. 27.22  The appearances and dynamic changes of fundus over time observed in a VKH patient (a, b: 7 days after disease onset; c, d: 5 months after disease onset; e, f: 7 months after disease onset; g, h: 12 months after disease onset; i, j: 14 months after disease onset)

27.4  Clinical Manifestations

431

g

h

i

j

Fig. 27.22 (continued)

432

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

e

f

Fig. 27.23  The appearances and dynamic changes of sunset glow fundus over time observed in a VKH patient (a, b: 2 weeks after disease onset; c, d: 9 weeks after disease onset; e, f: 4 months after disease onset)

27.4  Clinical Manifestations

433

a

b

c

d

e

f

Fig. 27.24  A male VKH patient shows diffuse choroiditis and serous retinal detachment 5 days after disease onset (a–d). No obvious sunset glow fundus is observed at 12 months after early and proper treatment (e, f)

434

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

e

Fig. 27.25  Diffuse choroiditis (a, b: fundus photographs; c: OCT result of left eye) observed in a female VKH patient completely resolves without leaving any change in the fundus after early and proper treatment (d, e)

27.4  Clinical Manifestations

435

a

b

c

d

e

f

Fig. 27.26  Sunset glow fundus (a–d) in association with Dalen–Fuchs nodules (a–f) and pigmentation (c, d) observed in VKH patients in recurrentgranulomatous anterior uveitis stage. Dalen-Fuchs nodules are mainly distributed in peripheral retina. Local chorioretinal atrophy is observed in (b)

436

27  Vogt–Koyanagi–Harada Disease

Fig. 27.27  Tremendous number of Dalen-Fuchs nodules observed in VKH patients in recurrent granulomatous anterior uveitis stage

Fig. 27.28  Sunset glow fundus in association with RPE clumping and migration observed in VKH patients in recurrent granulomatous anterior uveitis stage

27.4  Clinical Manifestations

437

Fig. 27.28 (continued)

Fig. 27.29  Anterior uveitis presenting as Descemet’s folds, aqueous cells, and fibrous exudates in the anterior chamber observed in VKH patients at the attack of anterior uveitis in recurrent granulomatous anterior uveitis stage

438

27  Vogt–Koyanagi–Harada Disease

Fig. 27.30  Mutton fat KPs observed in VKH patients in recurrent granulomatous anterior uveitis stage

Fig. 27.31  Iris swelling accompanying iris nodules observed in a VKH patient in recurrent granulomatous anterior uveitis stage

27.4  Clinical Manifestations

439

Fig. 27.32  Koeppe nodules observed in VKH patients in recurrent granulomatous anterior uveitis stage. These nodules show sago-like appearance

440

27  Vogt–Koyanagi–Harada Disease

Fig. 27.33  Koeppe and Busacca nodules observed in VKH patients in recurrent granulomatous anterior uveitis stage. These nodules show sagolike appearance

27.4  Clinical Manifestations

441

Fig. 27.34  Busacca nodules observed in a VKH patient in recurrent granulomatous anterior uveitis

a

c

b

d

Fig. 27.35  A granuloma in the iris (a, b: the arrow) completely resolves after a 3-week treatment with corticosteroids and cyclosporine (c, d)

442

27  Vogt–Koyanagi–Harada Disease

Fig. 27.36  Mutton fat KPs distributed at the lower pupil area in VKH patients

Fig. 27.37  Posterior synechiae associated with iris neovascularization observed in a VKH patient in recurrent granulomatous anterior uveitis stage

Fig. 27.38  Posterior synechiae, iris neovascularization, and unusual exudates on the surface of the iris observed in a VKH patient in recurrent granulomatous anterior uveitis stage

27.4  Clinical Manifestations

Fig. 27.39  Iris bombe due to complete posterior synechiae observed in a male VKH patient

Fig. 27.40  Peripheral anterior synechiae observed in VKH patients in recurrent granulomatous anterior uveitis stage

443

444

Fig. 27.41  Iris atrophy in association with irregular iris swelling observed in a male VKH patient

27  Vogt–Koyanagi–Harada Disease

27.4  Clinical Manifestations

Fig. 27.42  Iris atrophy and irregular depigmentation observed in VKH patients with recurrent anterior uveitis

445

446

27  Vogt–Koyanagi–Harada Disease

a

b

c

Fig. 27.43  A large iris cyst identified by UBM in a VKH patient (a, b). A large cyst in the iris associated with iris rubeosis observed in this VKH patient (c)

27.4  Clinical Manifestations

Fig. 27.44  Sunset glow fundus observed in VKH patients showing uniform red fundus

447

448

Fig. 27.44 (continued)

27  Vogt–Koyanagi–Harada Disease

27.4  Clinical Manifestations

449

a

b

c

d

e

f

Fig. 27.45  The dynamic changes of sunset glow fundus observed in a female VKH patient (a, b: 6 months after disease onset; c, d: 30 months after disease onset; e, f: 54 months after disease onset)

450

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

e

f

Fig. 27.46  Evolution of sunset glow fundus over time in a male VKH patient without clinically visible posterior segment inflammation (a, b: 20 months after disease onset; c, d: 44 months after disease onset; e, f: 72 months after disease onset)

27.4  Clinical Manifestations

451

a

b

c

d

e

f

Fig. 27.47  Sunset glow fundus associated with subretinal fibrosis (a–h) and RPE clumping and migration in VKH patients (a–l)

452

27  Vogt–Koyanagi–Harada Disease

g

h

i

j

k

l

Fig. 27.47 (continued)

27.4  Clinical Manifestations

453

a

b

c

d

e

f

Fig. 27.48  Sunset glow fundus associated with subretinal fibrosis and RPE clumping in a VKH patient. The 6 photographs (a–f) show the fundus changes at 2 years after disease onset. The 6 photographs (g–l)

show the fundus changes without obvious red appearance at 8 years after disease onset

454

27  Vogt–Koyanagi–Harada Disease

g

h

i

j

k

l

Fig. 27.48 (continued)

27.4  Clinical Manifestations

Fig. 27.49  Sunset glow fundus in proper sense observed in VKH patients with a long history of the disease

455

456

27  Vogt–Koyanagi–Harada Disease

a

c

e

b

d

f

Fig. 27.50  Dynamic fundus changes observed in both eyes of a VKH patient (a, b: 1 year after disease onset; c, d: 6 years after disease onset; e, f: 7.5 years after disease onset)

27.4  Clinical Manifestations

Fig. 27.51  Uneven sunset glow fundus with different appearances observed in VKH patients

457

458

Fig. 27.51 (continued)

27  Vogt–Koyanagi–Harada Disease

27.4  Clinical Manifestations

Fig. 27.52  Sunset glow fundus in proper sense associated with chorioretinal atrophies or severe depigmentation observed in VKH patients

459

460

Fig. 27.52 (continued)

27  Vogt–Koyanagi–Harada Disease

27.4  Clinical Manifestations

Fig. 27.53  Severe depigmentation of the choroid and RPE results in visible sclera in the VKH patients

461

462

27  Vogt–Koyanagi–Harada Disease

a

b

Fig. 27.54  Obvious red reflex indicating sunset glow fundus observed under slit-lamp microscopy in a female VKH patient (a). No obvious red reflex is noted in the pupil area of the patient’s sister (b)

Fig. 27.55  A red reflex observed via the temporal sclera when a slit beam is placed in the pupil area in VKH patients

Fig. 27.56  Sunset glow fundus observed under slit-lamp microscopy in a VKH patient. Diffused red reflex via the sclera is noted when a slit beam is placed in the pupil area, suggesting striking depigmentation in the choroid as well as ciliary body

27.4  Clinical Manifestations

463

a

b

c

d

Fig. 27.57  Red reflex via peripheral hole or atrophic areas of the iris (a, d) or the posterior sclera (b) is observed when a slit beam is placed in the pupil area of VKH patients with complicated cataract which severely obscures the fundus view (b–d)

Fig. 27.58  Complete synechiae and cataract which completely obscures the view of the ocular fundus in a 25-year-old female VKH patient. A red flex via the sclera is observed when a slit beam is placed in the pupil area

464

a

27  Vogt–Koyanagi–Harada Disease

b

Fig. 27.59  Lateral view of sunset glow fundus under slit-lamp microscopy (a) in a female VKH patient. There is no red reflex via the sclera in the patient’s sister (b)

a

b

c

d

Fig. 27.60  Sunset glow fundus under slit-lamp microscopy in VKH patients. Photographs (a, b) show red reflex via the sclera when slit beam is placed in the pupil area. Photographs (c, d) show red reflex in the pupil area when silt beam is placed on the sclera

27.4  Clinical Manifestations

Fig. 27.61  Dalen-Fuchs nodules or multifocal chorioretinal atrophies observed in VKH patients

465

466

27  Vogt–Koyanagi–Harada Disease

Fig. 27.62  Old Dalen-Fuchs nodules or atrophic chorioretinal lesions with pigmentation observed in VKH patients

27.4  Clinical Manifestations

Fig. 27.63  Vitiligo observed in VKH patients

467

468

Fig. 27.63 (continued)

27  Vogt–Koyanagi–Harada Disease

27.4  Clinical Manifestations

Fig. 27.64  Alopecia observed in VKH patients

469

470

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

Fig. 27.65  Alopecia in a female VKH patient (a, b) is completely cured by a 12-month treatment with immunosuppressive agents (c, d)

Fig. 27.66  Alopecia observed in VKH patients

27.4  Clinical Manifestations

Fig. 27.67  Poliosis observed in VKH patients

471

472

27  Vogt–Koyanagi–Harada Disease

Fig. 27.68  Psoriasis observed in VKH patients

Main manifestations of VKH patients in different stages Stage Prodromal stage (1–2 weeks before uveitis onset)

Ocular manifestations Orbital pain, redness, and photophobia

Posterior uveitis stage (within 2 weeks after uveitis onset)

Diffuse choroiditis, serous retinal detachment, and swelling of the optic disc

Anterior uveal involvement stage (2 weeks to 2 months after uveitis onset)

Diffuse choroiditis, serous retinal detachment, swelling of optic disc, Dalen–Fuchs nodules, aqueous cells and flare, and dust-like KPs Mutton fat KPs, iris nodules, sunset glow fundus, Dalen–Fuchs nodules, multiple chorioretinal atrophy lesions, posterior synechiae, anterior synechiae, secondary glaucoma, complicated cataract, CNV, and macular edema

Recurrent granulomatous anterior uveitis stage (2 months later after uveitis onset)

Fig. 27.69  Psoriasis occurring in the area of vitiligo observed in a VKH patient

Main extraocular manifestations Fever, headache, neck stiffness, confusion, and nausea Fever, headache, neck stiffness, hypersensitivity to touch of hair and scalp, tinnitus, and hearing loss tinnitus, hearing loss, and headache

Alopecia, poliosis, and vitiligo

27.5 Complications

473

27.5 Complications • Complicated cataract [1–3] –– It often occurs in recurrent granulomatous anterior uveitis stage. –– It occurs in 11–89% of the VKH patients based on studies reported previously. The longer uveitis course is, the more commonly cataract develops. –– It occurs as a result of persistent inflammation perhaps in combination with prolonged use of corticosteroid eye drops. –– Phacoemulsification cataract extraction and intraocular lens implantation have been safely and successfully ­performed in the VKH patients with complicated cataract [15]. • Secondary glaucoma –– It is a common complication in VKH patients with recurrent or chronic granulomatous uveitis. –– It occurs in 6–45% of the VKH patients. –– Acute angle-closure glaucoma occasionally occurs in VKH patients in posterior uveitis stage or prodromal stage. In our previous study, we found that 8 out of 486 VKH patients presented with bilateral acute angle cloa

c

sure glaucoma. Female is more commonly affected than male. The patients usually show moderately elevated intraocular pressure, a shallow anterior chamber, and narrow or closed anterior angle. –– Glaucoma usually develops as a result of angle closure from extensive peripheral anterior synechiae or due to pupillary block from complete posterior synechiae. Open-angle glaucoma, though less common, may occur in patients treated with longstanding use of corticosteroid eye drops. • Choroidal neovascularization (CNV) [16] –– It is one of the important causes leading to permanent visual impairment. –– It commonly occurs in the anterior uveal involvement stage and recurrent granulomatous anterior uveitis stage. –– Patients with chronic inflammation and extensive pigmentary derangement are at high risk to the development of choroid neovascularization. –– The obvious inflammatory signs in the posterior segment are usually not observed clinically in this stage. However, CNV (Figs.  27.70 and 27.71) and macular edema may develop in this stage, possibly suggesting the presence of subclinical inflammation. b

d

Fig. 27.70  Bilateral macular CNV observed in a VKH patient with sunset glow fundus and Dalen–Fuchs nodules (a, b: fundus photographs; c, d: OCT imaging results)

474

a

27  Vogt–Koyanagi–Harada Disease

b

Fig. 27.71  Peripapillary CNV observed in a male VKH patient (a) and a female VKH patient (b) in recurrent granulomatous anterior uveitis stage

Fig. 27.72  Macular CNV observed in a VKH patient

–– CNV predominantly occurs in macular (Fig. 27.72) or peripapillary area (Fig. 27.73) although it may develop in other regions (Figs. 27.74 and 27.75). –– Newly developed CNV may be associated with hemorrhage. • Chorioretinal atrophy –– Peripapillary chorioretinal atrophy is common and occurs frequently in recurrent granulomatous anterior uveitis stage (Fig. 27.75). In general, it does not have influence on the visual prognosis. –– Chorioretinal atrophy may also develop in other regions (Fig. 27.76). –– Chorioretinal atrophy develops following resolution of active Dalen–Fuchs nodules (Fig. 27.77). –– Multifocal chorioretinal atrophies are usual. • Band keratopathy –– It is a less common complication in VKH patients (Fig. 27.78). –– It often occurs in the VKH patients with recurrent and chronic uveitis.

Fig. 27.73  Peripapillary CNV in association with an epiretinal membrane observed in a VKH patient

–– Shallow anterior chamber secondary to extensive peripheral anterior synechiae and pupillary seclusion appear to be risk factors for the development of band keratopathy. –– Band keratopathy is frequently associated with complicated cataract.

27.5 Complications

Fig. 27.74  CNV inferior to macular area observed in a VKH patient

Fig. 27.75  Chorioretinal atrophies around the optic nerve with various appearances observed in VKH patients

475

476

27  Vogt–Koyanagi–Harada Disease

Fig. 27.75 (continued)

• Phthisis bulbi –– Phthisis bulbi is a rare complication (Fig. 27.79). –– It occurs as a result of atrophy of ciliary body due to persistent inflammatory damage to this tissue. • Bullous keratopathy –– It is a rare complication. –– It mainly occurs in the VKH patients with recurrent anterior uveitis, extensive anterior synechiae, and persistently elevated intraocular pressure. • Macular alterations [16] –– In general, macular alterations are less common. In our recent study, these changes were found in 8.7% of 1468 VKH patients. –– Macular alterations observed in VKH patients include macular edema, CNV in the macula (Figs. 27.80 and

27.81), epiretinal membrane (Fig. 27.82), and macular hole. –– Macular edema, mostly cystoid macular edema (CME) (Fig.  27.83), is the most common complication in VKH patients with macular abnormalities followed by CNV, epiretinal membrane, and macular hole (Fig. 27.84). –– These abnormalities are often associated with recurrent intraocular inflammation and chronic disease course. –– Macular abnormalities usually lead to severely impaired visual prognosis. • Retinal neovascularization –– It is a rare complication in VKH patients. –– It usually occurs in recurrent granulomatous anterior uveitis stage.

27.6  Auxiliary Examinations

477

Fig. 27.76  Chorioretinal atrophies observed in VKH patients

–– It may develop at posterior pole, around, or on optic disc (Fig. 27.85). • Optic nerve atrophy –– Optic nerve atrophy is a less common complication. –– It is always secondary to persistent intraocular hypertension.

27.6 Auxiliary Examinations

Fig. 27.77  Confluent chorioretinal atrophies associated with pigmentation adjacent to them observed in a VKH patient

• FFA [1–3] –– FFA is very useful in the diagnosis of VKH disease and following the effectiveness of treatment. –– In the acute phase (posterior uveitis stage and anterial uveal involvement stage), FFA typically shows early multiple punctuate hyperfluorescent dots at the level of RPE and subsequent pooling of the dye in the subreti-

478

27  Vogt–Koyanagi–Harada Disease

Fig. 27.78  Band keratopathy observed in a VKH patient in recurrent granulomatous anterior uveitis stage

nal space underlying serous retinal detachment areas (Figs.  27.86 and 27.87). Another common finding is staining of the optic disc (Fig. 27.88). –– In the recurrent granulomatous anterior uveitis stage, FFA findings mainly include multiple hyperfluorescent RPE window defects and blockage of fluorescence due to RPE clumping (Figs. 27.89, 27.90, 27.91, and 27.92). A moth-eaten appearance or salt and pepper pattern due to alternating hyperfluorescent scene and hypofluorescence may be observed in certain patients. –– Retinal vascular leakages are occasionally observed in VKH patients (Fig. 27.93). Fig. 27.79  Phthisis bulbi of the right eye observed in a VKH patient

Fig. 27.80  CNV in the macula area detected by angio-OCT imaging in a female VKH patient

27.6  Auxiliary Examinations

Fig. 27.81  CNV in the macula area detected by angio-OCT imaging in a male VKH patient

479

480

Fig. 27.82  Macular epiretinal membrane detected by OCT imaging in VKH patients

Fig. 27.83  CME detected by OCT imaging in a VKH patient

27  Vogt–Koyanagi–Harada Disease

27.6  Auxiliary Examinations

Fig. 27.84  Macular hole detected by OCT imaging in a VKH patient in recurrent granulomatous anterior uveitis stage

481

–– Multiple chorioretinal atrophies typically show hyperfluorescent dots or areas (Fig.  27.94). Chorioretinal atrophic lesions disclosed by FFA seem more than those observed ophthalmoscopically in number. (Figs. 27.95, 27.96, 27.97, and 27.98). –– CNV usually shows hyperfluorescence in the late phase of FFA (Figs. 27.99 and 27.100). • Indocyanine green angiography (ICGA) [1, 2, 3, 17] –– ICGA has been widely used for investigating choroidal alterations in VKH disease and other choroidal inflammatory diseases.

a

b

c

d

Fig. 27.85  Neovascularization on and around the optic disc in association with hemorrhages, a relatively rare manifestation, observed in a VKH patient (a: fundus photograph; b–d: FFA results)

482

a

27  Vogt–Koyanagi–Harada Disease

b

Fig. 27.86  Bilateral serous retinal detachment observed in a male VKH patient (a, b). FFA reveals early multiple punctuate hyperfluorescent dots and late pooling of the dye in this patient

27.6  Auxiliary Examinations

483

a

b

c

d

e

f

g

h

Fig. 27.87  A female VKH patient presents as bilateral diffuse choroiditis (a, b). Early multiple punctuate hyperfluorescent dots and late pooling of the dye are detected by FFA (c–h) in this patient

484

27  Vogt–Koyanagi–Harada Disease

Fig. 27.88  Staining of the optic disc and RPE window defects disclosed by FFA in a VKH patient on day 40 after disease onset

–– The typical change of ICGA in posterior uveitis stage and anterior uveal involvement stage is hypofluorescent spots (corresponding to choroidal stromal infiltrates or granulomas) or large hypofluorescent areas (corresponding to serous retinal detachment areas) (Figs. 27.101 and 27.102). –– The typical change of ICGA in recurrent granulomatous anterior uveitis stage is multiple hypofluorescent dots or areas corresponding to atrophic chorioretinal areas (Fig. 27.103). –– It is more sensitive than FFA in detecting subtle changes in VKH patients (Figs.  27.104, 27.105, 27.106, and 27.107). • OCT imaging [1–3] –– OCT imaging is a noninvasive technique to provide high-resolution and high-speed imaging of the posterior segment structure.

–– The typical changes revealed by OCT imaging in VKH patients in posterior uveitis stage and anterior uveal involvement stage include serous retinal detachment and swelling of the optic disc. –– OCT imaging may reveal serous retinal detachment (Figs.  27.108, 27.109, 27.110, 27.111, and 27.112), CNV, cystoid macular edema, epiretinal membrane, and macular hole in VKH patients. • B-scan ultrasonography [1–3] –– It is a noninvasive technique to produce a cross-­ sectional image of the eye and orbital structures. –– It may show exudative retinal detachment and thickened choroid in most VKH patients in posterior uveitis stage and anterior uveal involvement stage (Fig. 27.113). –– Vitreous involvement is usually absent or minor. However, severe vitreous capacities even proliferative

27.6  Auxiliary Examinations

485

a

b

c

d

Fig. 27.89  Pooling of dye in the subretinal space (a, b) detected by FFA in the right eye of a VKH patient in posterior uveitis stage. A 2-month treatment with systemic corticosteroids in combination with

cyclosporine leads to significant improvement. RPE window defects, hyperpigmentation, and staining of the optic disc are observed (c, d)

486

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

Fig. 27.90  Similar results are observed in the left eye of the VKH patient as described in Fig. 27.89 before (a, b) and after treatment (c, d)

27.6  Auxiliary Examinations

a

487

b

c

d

Fig. 27.91  FFA shows window defects and blockage of fluorescence in a VKH patient on day 75 after disease onset (a, b: fundus photographs; c, d: FFA results)

488

27  Vogt–Koyanagi–Harada Disease

a

b

c

Fig. 27.92  Sunset glow fundus observed in both eyes of a male VKH patient in recurrent granulomatous anterior uveitis stage (a). FFA reveals extensive RPE damage and blockage of fluorescence (b, c)

27.6  Auxiliary Examinations

Fig. 27.93  Retinal vascular leakages disclosed by FFA in VKH patients. They are rare findings in VKH disease

489

490

a

27  Vogt–Koyanagi–Harada Disease

b

c

d

Fig. 27.94  Multiple Dalen-Fuchs nodules and chorioretinal atrophies observed in a female VKH patient (a, b: fundus photographs; c, d: FFA results)

27.6  Auxiliary Examinations

a

491

b

c

d

Fig. 27.95  Sunset glow fundus in association with Dalen-Fuchs nodules is observed in VKH patients (a, b). FFA reveals more lesions than observed ophthalmoscopically (c, d)

492

a

27  Vogt–Koyanagi–Harada Disease

b

c

d

Fig. 27.96  Sunset glow fundus and a number of Dalen–Fuchs nodules observed in a female VKH patient (a, b). FFA reveals a tremendous number of hyperfluorescent dots (c, d)

27.6  Auxiliary Examinations

a

493

b

c

d

Fig. 27.97  Sunset glow fundus and Dalen–Fuchs nodules observed in a male VKH patient (a, b). FFA shows tremendous number of hyperfluorescent dots (c, d)

494

a

27  Vogt–Koyanagi–Harada Disease

b

c

d

Fig. 27.98  Sunset glow fundus associated with Dalen–Fuchs nodules or atrophies observed in a VKH patient (a, b). FFA reveals numerous atrophic lesions (c, d)

27.6  Auxiliary Examinations

a

495

b

c

d

Fig. 27.99  CNV observed in a VKH patient (a, b: fundus photographs; c, d: FFA results)

496

27  Vogt–Koyanagi–Harada Disease

a

b

c

Fig. 27.100  CNV is observed around inferio-temporal retinal vessels (a) in a female VKH patient. FFA shows early hypofluorescence and late staining of this lesion (b, c)

27.6  Auxiliary Examinations

497

a

b

c

d

Fig. 27.101  Diffuse choroiditis and papillitis observed in the right eye of a male VKH patient 10 days after disease onset (a). Multiple hypofluorescent dots and large areas of hypofluorescence disclosed by ICGA

on day 10 after disease onset (b). Striking improvement of ICGA results observed on day 30 following treatment (c). Abnormal ICGA results almost disappeared 80 days after treatment (d)

498

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

Fig. 27.102  Diffuse choroiditis and papillitis observed on day 10 after disease onset in the left eye of the patient as described in Fig. 27.101 (a). Multiple hypofluorescent dots and large areas of hypofluorescence

observed on day 10 (b). Striking improvement of ICGA results observed on day 30 following treatment (c). ICGA shows no obvious abnormality on day 80 after treatment (d)

27.6  Auxiliary Examinations

499

a

b

c

d

Fig. 27.103  Multiple hypofluorescent dots disclosed by ICGA (a, c) correspond to hyperfluorescent dots (b, d) disclosed by FFA in a VKH patient

500

27  Vogt–Koyanagi–Harada Disease

a

b

c

Fig. 27.104  There are no obvious fundus changes in the right eye of a female VKH patient 14 days after disease onset (a). FFA shows only staining of the optic disc (b). However, ICGA reveals multiple hypofluorescent dots (c)

27.6  Auxiliary Examinations

501

a

b

c

Fig. 27.105  No obvious fundus change of left eye is observed on day 14 after disease onset in the patient as described in Fig. 27.104. However, pooling of the dye and staining of the optic disc are dis-

closed by FFA (b). More striking alterations including multiple hypofluorescent dots and multiple hypofluorescent areas are revealed by ICGA (c)

502

27  Vogt–Koyanagi–Harada Disease

a

b

c

Fig. 27.106  FFA shows a localized area of dye pooling in a female VKH patient (a, c) on day 5 after disease onset. However, ICGA reveals larger areas of hypofluorescence and multiple hypofluorescent dots (b, d)

27.6  Auxiliary Examinations

503

d

Fig. 27.106 (continued)

vitreoretinopathy (Fig.  27.114) and tractional retinal detachment may be occasionally observed in VKH patients in recurrent granulomatous anterior uveitis stage. • Multispectral image analysis (MSI) [18] –– It is a novel noninvasive, coronal imaging technic to evaluate retinal disease. –– It is a sensitive method to monitor the alterations of the RPE layer. –– It can reveal serous retinal detachment and optic disc swelling in VKH patients at posterior uveitis stage. –– It is extremely useful to detect RPE alterations in VKH patients in recurrent granulomatous uveitis stage (Fig. 27.115). Four abnormalities could be characterized by this technic. General pigmentation Clumping of pigment Macular depigmentation and/or hyperpig­ mentation Extensive fine grainy depigmentation mottled with hyperpigmentation

–– An example of MSI on a male VKH patient is shown in Fig. 27.115. • UBM [1, 13] –– It is a very useful technique to disclose the changes in the anterior segment of uveitis patients. –– The changes detected by UBM in the anterior uveal involvement stage include aqueous cells, swelling, and detachment of the ciliary body (Fig. 27.116). –– The changes disclosed by UBM in recurrent granulomatous anterior uveitis stage vary greatly with patients and the severity of the inflammation. The common findings include cells in the anterior chamber (Fig. 27.117), iris nodules (Fig. 27.118) and swelling (Fig. 27.119), swelling of the ciliary body (Fig. 27.120), posterior or anterior synechiae (Fig. 27.121) and iris bombe. The less common findings include iris atrophy, corneal edema (Fig. 27.122), fibrous exudates in the anterior chamber (Fig.  27.123), detachment of the iris posterior pigmented epithelium (Fig. 27.124), iris cysts, exudates adjacent to the ciliary body and peripheral retina (Figs. 27.125 and 27.126), and atrophy of the ciliary body (Fig. 27.127).

504

27  Vogt–Koyanagi–Harada Disease

a

b

c

Fig. 27.107  There is no detectable change of FFA after 6-week treatment with systemic corticosteroids and cyclosporine in the patient as described in Fig. 27.106 (a, c). However, ICGA could still disclose a few hypofluorescent dots (b, d, e)

27.6  Auxiliary Examinations

505

d

e

Fig. 27.107 (continued)

• Multifocal electroretinography (mfERG) [19] –– It is an objective method to assess the local electroretinography from different regions of the posterior retina. –– Striking mfERG abnormalities as evidenced by markedly decreased amplitudes and prolonged latencies of the N1 and P1 waves have been documented in VKH patients. –– The latency of N1 and P1 waves may return to a normal level if early and adequate treatment is instituted. However, persistently decreased amplitude of N1 and P1 waves may be present, suggesting a longlasting impaired function of photoreceptor in VKH patients.

–– Examples are given to show the changes of mfERG in VKH patients (Figs. 27.128 and 27.129). • Abnormalities in visual field –– They are common findings in posterior uveitis stage and anterior uveal involvement stage. –– Various abnormalities in visual field have been documented including entire defect of the visual field, partial visual field defect, concentric contraction of visual field, arcuate scotoma, central scotoma, paracentral scotoma, and enlarged blind spot. –– Examples are given to show the abnormalities in visual field documented in VKH patients (Figs.  27.130, 27.131, 27.132, 27.133, 27.134, 27.135, 27.136, and 27.137)

506

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

Fig. 27.108  Serous retinal detachment disclosed by OCT imaging in the right eye of a male VKH patient on day 10 after disease onset (a, b). This change is greatly improved 30 days after treatment (c) and almost completely recovers 80 days after treatment (d)

a

b

c

d

Fig. 27.109  A similar result is also observed with OCT imaging in the left eye of the VKH patient as described in Fig. 27.108 (a, b: 10 days after disease onset; c: 30 days after treatment; d: 80 days after treatment)

27.6  Auxiliary Examinations

Fig. 27.110  Bilateral serous retinal detachment disclosed by OCT imaging in a female VKH patient

Fig. 27.111  Bilateral serous retinal detachment detected by OCT imaging in a female VKH patient

507

508

27  Vogt–Koyanagi–Harada Disease

Fig. 27.112  Bilateral serous retinal detachment detected by OCT imaging in a male patient

a

b

c

d

e

f

Fig. 27.113  Serous retinal detachment and thickening of the choroid detected by B-scan on day 10 after disease onset (a, b) in the VKH patient as described in Fig. 27.108. Significant improvement is observed

on day 30 after treatment (c, d). There is no change on day 80 after treatment (e, f)

27.6  Auxiliary Examinations

Fig. 27.114  Vitreous opacities and proliferative vitreoretinopathy detected by B-scan in VKH patients

509

510

27  Vogt–Koyanagi–Harada Disease

Fig. 27.115  Alterations detected by MSI in both eyes of a VKH patient in recurrent granulomatous anterior uveitis stage

27.6  Auxiliary Examinations

511

a

b

c

d

Fig. 27.116  Detachment of the ciliary body and anterior choroid detected by UBM in a VKH patient (a, c: right eye; b, d: left eye)

512

27  Vogt–Koyanagi–Harada Disease

Fig. 27.117  Numerous dots (inflammatory cells) in the anterior chamber detected by UBM in a VKH patient

Fig. 27.118  Multiple iris nodules detected by UBM in a VKH patient in recurrent granulomatous anterior uveitis stage

27.6  Auxiliary Examinations

Fig. 27.119  Diffused or localized swelling of the iris detected by UBM in VKH patients

Fig. 27.120  Edema and swelling of the ciliary body detected by UBM in VKH patients

513

514

Fig. 27.121  Posterior and peripheral anterior synechiae of the iris detected by UBM in VKH patients

Fig. 27.122  Corneal edema detected by UBM in VKH patients

27  Vogt–Koyanagi–Harada Disease

27.6  Auxiliary Examinations

Fig. 27.123  Fibrous exudates in the anterior chamber detected by UBM in a VKH patient

Fig. 27.124  Detachment of the iris posterior pigmented epithelium detected by UBM in VKH patients

515

516

27  Vogt–Koyanagi–Harada Disease

Fig. 27.125  Exudates adjacent to the ciliary body and peripheral retina detected by UBM in a VKH patient at recurrent granulomatous anterior uveitis stage

Fig. 27.126  Exudates adjacent to the ciliary body detected by UBM in VKH patients

27.6  Auxiliary Examinations

517

Fig. 27.127  Atrophy of the ciliary body detected by UBM in VKH patients at recurrent granulomatous anterior uveitis stage

a

d

b

e

c

f

Fig. 27.128  Alterations shown on mfERG in a VKH patient. (a–c: right eye, before treatment and, 3 and 6 months respectively after treat-

ment; d–f: left eye, before treatment and, 3 and 6 months respectively after treatment)

518

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

e

f

g

h

Fig. 27.129  Striking abnormality detected by MfERG in a VKH patient before treatment and a gradual improvement after treatment with immunosuppressive agents (a, c, e and g: right eye, before treat-

ment and 3, 7 and 11 months respectively after treatment; b, d, f and h: left eye, before treatment and 3, 7 and 11 months respectively after treatment)

27.6  Auxiliary Examinations

Fig. 27.130  Concentric contraction of visual field detected by Humphrey perimetry in a VKH patient

519

520

27  Vogt–Koyanagi–Harada Disease

Fig. 27.131  General reduction of sensitivity and mottled visual field defect identified by Humphrey perimetry in a VKH patient

27.6  Auxiliary Examinations

a

Fig. 27.132  Residual partial visual island (a) and tubular visual field (b) detected by Humphrey perimetry in a VKH patient

521

522

b

Fig. 27.132 (continued)

27  Vogt–Koyanagi–Harada Disease

27.6  Auxiliary Examinations

Fig. 27.133  Paracentral scotoma detected by Humphrey perimetry in a VKH patient

523

524

Fig. 27.134  Concentric contraction of visual field detected by Humphrey perimetry in a VKH patient

27  Vogt–Koyanagi–Harada Disease

27.6  Auxiliary Examinations

Fig. 27.135  General reduction of sensitivity and concentric contraction of visual field detected by Humphrey perimetry in a VKH patient

525

526

Fig. 27.135 (continued)

27  Vogt–Koyanagi–Harada Disease

27.6  Auxiliary Examinations

Fig. 27.136  Superior concentric contraction of visual field detected by Humphrey perimetry in a VKH patient

527

528

Fig. 27.136 (continued)

27  Vogt–Koyanagi–Harada Disease

27.6  Auxiliary Examinations

Fig. 27.137  Pterygoid visual field defect detected by Humphrey perimetry in a VKH patient

529

530

27.7 Diagnosis • The diagnosis of VKH disease is principally based on typical clinical manifestations and the findings of FFA, OCT, B-scan ultrasonography, and ICGA [1–3]. –– Typical bilateral diffuse choroiditis at first attack and granulomatous anterior uveitis mostly in association with sunset glow fundus at late stage. –– FFA shows multiple pinpoint leakage and dye pooling in the subretinal space in the posterior uveitis stage, and RPE window defects in recurrent granulomatous anterior uveitis stage. –– B-scan ultrasonography reveals diffuse choroidal thickening and serous retinal detachment. –– OCT imaging shows multiple serous retinal detachment in posterior uveitis stage mostly accompanying swelling of the optic disc. –– ICGA shows multiple hypofluorescent dots and large areas of hypofluorescence. –– In general, laboratory tests are not necessary in the diagnosis of VKH disease. However, they should be

27  Vogt–Koyanagi–Harada Disease

preferred to rule out the underlying diseases and to monitor the side effects of drugs used for treatment. • Diagnosis criteria –– The revised diagnostic criteria for VKH disease (RDC) published in Am J Ophthalmol in 2001 (Table 27.1) are widely used in the diagnosis of this disease (Source: Read Rw, Holland GN, Rao NA et  al. Revised Diagnostic Criteria for Vogt-Koyanagi-Harada disease: report of an International Committee on Nomenclature. Am J Ophthalmol) [20]. These criteria highlight the manifestations in different stages and are sensitive and specific as compared with two sets of criteria as published previously. They divide VKH disease into complete, incomplete, and probable disease and do not allow a doctor to make a decision on the patients with pathognomonic ocular findings but without extraocular manifestations. Another problem of the revised diagnostic criteria is that they highlight the presence of fundus alterations. However, they may not be present if early

Table 27.1  Diagnosis criteria for VKH diseasea Complete Vogt-Koyanagi-Harada disease (criteria 1–5 must be present) 1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis 2. No clinical or laboratory evidence suggestive of other ocular disease entities 3. Bilateral ocular involvement (a) or (b) must be met, depending on the stage of disease when the patient is examined  (A) Early manifestations of the disease    (1) There must be evidence of a diffuse choroiditis (with or without anterior uveitis, vitreous inflammatory reaction, or optic disc hyperemia), which may manifest as one of the following (a) focal areas of subretinal fluid or (b) bullous serous retinal detachments    (2) With equivocal fundus findings, both of the following must be present as well: (a) focal areas of delay in choroidal perfusion, multifocal areas of pinpoint leakage, large placoid areas of hyperfluorescence, pooling within subretinal fluid, and optic nerve staining (listed in order of sequential appearance) by fluorescein angiography and (b) diffuse choroidal thickening, without evidence of posterior scleritis by ultrasonography  (B) Late manifestations of the disease    (1) History is suggestive of prior presence of findings from 3A and either both (2) and (3) below or multiple signs from (3)    (2) Ocular depigmentation (either of the following manifestations is sufficient) (a) sunset glow fundus or (b) Sugiura sign    (3) Other ocular signs: (a) nummular chorioretinal depigmented scars or (b) retinal pigment epithelium clumping and/or migration or (c) recurrent or chronic anterior uveitis 4. Neurological/auditory findings (may have resolved by the time of examination)  (a) Meningismus (malaise, fever, headache, nausea, abdominal pain, stiffness of the neck and back, or a combination of these factors: headache alone is not sufficient to meet the definition of meningismus, however) or  (b) Tinnitus or  (c) Cerebrospinal fluid pleocytosis 5. Integumentary finding (not preceding onset of central nervous system or ocular disease). (a) Alopecia, (b) poliosis, or (c) vitiligo Incomplete VKH disease (criteria 1–3 and either 4–5 must be present) 1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis, and 2. No clinical or laboratory evidence suggestive of other ocular disease entities, and 3. Bilateral ocular involvement 4. Neurologic/auditory findings; as defined for complete Vogt-Koyanagi-Harada disease above, or 5. Integumentary finding; as defined for complete Vogt-Koyanagi-Harada disease above Probable Vogt-Koyanagi-Harada disease (isolated ocular disease; criteria 1–3 must be present) 1. No history of penetrating ocular trauma or surgery preceding the initial onset of uveitis 2. No clinical or laboratory evidence suggestive of other ocular disease entities 3. Bilateral ocular involvement as defined for complete Vogt-Koyanagi-Harada disease above Reprinted with permission from Read Rw, Holland GN, Rao NA et al. Revised Diagnostic Criteria for Vogt-Koyanagi-Harada disease: report of an International Committee on Nomenclature. Am J Ophthalmol 2001;131:647–652

a

27.8  Differential Diagnosis

and appropriate treatment is instituted in the early stage or may not be observed due to severe media opacities. –– Recently, we developed a novel set of diagnostic criteria for VKH disease (Table.27.2) [21] using a data mining method (latent class analysis) on the basis of data from 634 VKH patients and 623 patients with other uveitis entities. We also validated this set of diagnostic criteria using data from 537 patients with a definite diagnosis of VKH disease and 525 patients with other uveitis entities. Our diagnostic criteria for VKH disease divide VKH disease into early phase and late phase. The specificity and positive predictive value of our diagnostic criteria are similar to those of RDC. However, the sensitivity and negative predictive value of our criteria are significantly higher than those of RDC. These results indicated that the VKH disease is not readily misdiagnosed as other forms of uveitis or other ocular diseases using the criteria established according to the latent class analysis.

531

Our diagnostic criteria emphasized the usefulness of OCT and enhanced depth imaging optical coherence tomography (EDI-OCT) and excluded the extraocular manifestations as an important parameter in the diagnosis of VKH disease. The influence of treatment with systemic corticosteroids on the FFA results is also taken into consideration in the development of the novel criteria. Early leakage and late dye pooling are often atypical in VKH patients if early and appropriate treatment is given. However, optic disc staining is less influenced by a short period of treatment. Therefore, optic disc staining is considered as an important parameter in the development of these criteria.

27.8 Differential Diagnosis • Sympathetic ophthalmia [22] –– Ocular surgery or ocular trauma to one eye preceding disease onset.

Table 27.2  Chinese diagnostic criteria for VKH diseasea A. No history of penetrating ocular trauma or intraocular surgery preceding the initial onset of uveitis B. Bilateral ocular involvement (time interval between the two eyes should be ≤2 weeks) C. No evidence of infectious uveitis or accompanying systemic rheumatic diseases or evidence suggestive of other ocular disease entitiesb D. Early phase VKH disease  (1) Signs of diffuse choroiditis and exudative retinal detachment  (2) Serous retinal detachment on OCT or B-scan ultrasonography  (3)c Choroidal thickening on EDI-OCT  (4) Early punctate staining and late subretinal dye pooling on FFA  (5) Hyperfluorescence of the optic disc on FFA Definite diagnosis: Variant 1: In patients presenting with A + B + C + D(1) Variant 2: In patients without clinically visible exudative retinal detachment, i.e., A + B + C + D(2) + D(3) or A + B + C + D(4) Variant 3: In patients already treated with systemic corticosteroids or combined with other immunosuppressive agents, a history of typical appearances of variant 1 or 2, and A + B + C + D(5) E. Late phase VKH disease  (1) Signs of definite sunset glow fundus or retinal pigment epithelium clumping/migration  (2) Signs of bilateral recurrent granulomatous anterior uveitis  (3) Signs of Dalen–Fuchs nodules or multifocal chorioretinal atrophy  (4) Window defects/moth-eaten fluorescence on FFA  (5) Previous history of characteristic findings corresponding to diagnosis of early phase VKH disease Definite diagnosis: Variant 1: In patients presenting with A + B + C + E(1) + E(2) Variant 2: In patients without sunset glow fundus or visible pigment alternations due to early and appropriate treatment, i.e., A + B + C + E(2) + E(3) or A + B + C + E(2) + E(4) Variant 3: In patients with significant media opacity, i.e., A + B + C + E(2) + E(5) Abbreviations: OCT optical coherence tomography, EDI-OCT enhanced depth imaging optical coherence tomography; FFA fluorescence fundus angiography a Reprinted with permission from Yang P, Zhong Y, Du L, et al. Development and Evaluation of Diagnostic Criteria for Vogt-Koyanagi-­Harada Disease. Jama Ophthalmol 2018; 136: 1025–1031 b This criterion includes (1) no history nor clinical evidence to show ocular tuberculosis, syphilis, or ocular toxoplasmosis; (2) no underlying systemic rheumatic disease that could explain the form of uveitis these patients have; and (3) no history or clinical evidence to suggest the possibility of a specific entity, for instance intraocular tumors, toxic uveitis, Fuchs syndrome, or Posner–Schlossman syndrome c Ultrasound can be used to detect the choroidal thickening and therefore may serve as an alternative in the examination where the EDI-OCT is not available, although it is less precise

532

–– In general, ocular manifestations are similar to VKH disease. However, unlike VKH disease, sympathetic ophthalmia does not have a typical evolutionary process. –– Patients with sympathetic ophthalmia may also have neurologic, auditory, and integumentary findings similar to those observed in VKH patients. However, these manifestations are less common in sympathetic ophthalmia as compared to VKH disease. • Posterior scleritis [23] –– Unilateral involvement is common in posterior scleritis whereas bilateral involvement is absolutely present in VKH disease although the severity in both eyes may be different. –– Patients frequently show sclera thickening and choroidal thickening on B-scan ultrasonography. –– Deep pain around the affected eye is common. –– Unilateral swelling of the optic disc or choroidal folds. –– Multifocal, serous retinal detachment disclosed by OCT imaging may be present in some posterior scleritis patients. –– B-scan reveals scleral wall thickness and typical T-sign. Subretinal mass is occasionally observed. • Bullous central serous chorioretinopathy –– Unilateral involvement is usual. However, bilateral involvement is also observed. –– There are no fundus inflammatory signs. However, multifocal serous retinal detachment similar to that observed in VKH disease may be present (Fig. 27.138) –– No involvement of the anterior segment. –– OCT imaging may also reveal serous retinal detachment (Fig. 27.139). –– FFA and ICGA are very useful in the diagnosis and differential diagnosis of this disease.

27  Vogt–Koyanagi–Harada Disease

Central serous chorioretinopathy usually shows gradually increased multiple hyperfluorescent dots on FFA (Fig. 27.140). Whereas VKH disease typically shows early multiple punctuate hyperfluorescent dots and late pooling of the dye in subretinal space. ICGA displays gradually increased multiple hyperfluorescent dots in central serous chorioretinopathy (Fig.  27.141). However, multiple h­ ypofluorescent dots and large areas of hypofluorescence are the usual findings on ICGA in VKH patients. • Sarcoidosis [24] –– Patients usually manifest as granulomatous uveitis. There is no characteristic evolution course like VKH disease. –– Retinal vasculitis is common and typically shows perivenous sheathing (candle wax drippings). –– The lymph nodes, lung, liver, and skin are frequently affected. –– Chest radiography or computed tomography (CT) reveals hilar lymphadenopathy. –– Tissue biopsy shows classic noncaseating granulomas. –– The elevated level of angiotensin-converting enzyme is useful in the diagnosis of this disease. • Ocular syphilis [25] –– Unilateral or bilateral involvement. –– Patients typically show nongranulomatous uveitis although granulomatous inflammation is previously considered as a common manifestation in these patients. –– Patients may have the chancre (painless ulceration) at the inoculation site and maculopapular or cutaneous rash.

Fig. 27.138  Serous retinal detachment observed in a patient with central serous chorioretinopathy

27.9 Treatment

533

Fig. 27.139  Serous retinal detachment detected by OCT imaging in the patients with bullous central serous chorioretinopathy as described in Fig. 27.138, which is quite similar to that observed in VKH disease

–– Diagnosis of syphilis is mostly based on clinical manifestations and serological tests. Serological tests include specific tests and nonspecific tests. –– Positive specific tests develop in the individuals with infection by treponema pallidum and last for a whole life. –– Positive nonspecific tests are usually observed in the patients with active disease.

27.9 Treatment • Corticosteroids are the mainstay for VKH patients, especially for those at their first attack. –– High doses of corticosteroids with a gradual tapering are recommended by various uveitis specialists in the treatment of this disease [1–3]. –– We usually use an initial dose of prednisone of 0.5~0.8 mg/kg/day in combination mostly with cyclosporine, sometimes with cyclophosphamide or chlorambucil for the VKH patients at their first attack. The initial dose of corticosteroids is used for 1–2 weeks and then gradually tapered to a maintenance dose, 15–20  mg/day, over 4–6 months. This maintenance dose is usually used for another 4–6 months and then gradually tapered to a stop over 4–6 months [5]. –– For the VKH patients with recurrent uveitis, an initial dose of prednisone, 0.4~0.6 mg/kg per day, is used in

combination with the aforementioned immunosuppressive agents. A schedule for tapering of corticosteroids similar to that described above is also recommended [5]. –– Topical corticosteroids, mydriatic and cycloplegic agents are indicated for the patients with anterior segment inflammation. –– For the VKH patients with marked retinal detachment, posterior sub-tenon’s injection of triamcinolone acetonide (20 mg) is indicated. • Other immunosuppressive agents –– Cyclosporine is a common and effective drug used in the treatment of VKH disease. We usually initiate the treatment at a dose of 2–4 mg/kg/day and keep this dose for 5–6 months. A gradual tapering of the dosage follows if the initial dose is more than 2 mg/kg/day. The maintenance dose is 2 mg/kg/day. It is usually used in combination with systemic corticosteroids and other immunosuppressive agents. Regular monitoring of liver and kidney function and blood pressure is necessary. –– Cyclophosphamide is widely used in the treatment of VKH patients especially those with recurrent and chronic intraocular inflammation. –– Chlorambucil is also very effective in the treatment of VKH disease. We normally use an initial dose of 0.1  mg/kg/day mostly in combination with systemic

534

27  Vogt–Koyanagi–Harada Disease

a

b

c

d

Fig. 27.140  Increased multiple hyperfluorescent dots revealed by FFA (a, c) in the patients with bullous central serous chorioretinopathy as described in Fig. 27.138, almost disappeared following photodynamic therapy (b, d)

27.9 Treatment

535

a

b

c

Fig. 27.141  Multifocal hyperfluorescent dots disclosed by ICGA (a, c) disappeared following photodynamic therapy (PDT) (b, d) in the patient as described in Fig. 27.138

536

27  Vogt–Koyanagi–Harada Disease

d

Fig. 27.141 (continued)

corticosteroids as stated above. It is also recommended in the patients who do not respond well to corticosteroids and cyclosporine. Myelosuppression and gonadal dysfunction are the main side effects and should be monitored regularly during the treatment. • Other immunosuppressive agents used in the treatment of VKH disease include methotrexate, azathioprine, and mycophenolate mofetil. Based on the author’s experience, each of these drugs is usually not sufficient to control the intraocular inflammation in VKH disease. A combination of one or two of these drugs with systemic corticosteroids or other immunosuppressive agents is needed in most cases. • Generally speaking, biologic drugs are not recommended for VKH patients because they usually respond well to conventional treatment. In very rare VKH patients who fail to respond to systemic corticosteroids and immunosuppressive agents, biologic drugs, for instance adalimumab, may be indicated.

27.10 Prognosis • Based on our recent study, the intraocular inflammation could be completely controlled in more than 90% of the VKH patients if regular treatment is instituted. A recurrent intraocular inflammation may be observed in a few patients but is readily controlled by topical corticosteroids, mydriatic and cycloplegic agents in combination with systemic medicines. • In general, the visual prognosis is good if the treatment is instituted promptly and accurately. In our recent study

on 998 VKH patients, visual improvement and stability are observed in more than 90% of these patients. More than 70% of the patients who visit us within 2 months after disease onset achieve a vision ≥20/25 following regular treatment. Up to 63.5% of these total VKH patients achieve a vision ≥20/25 at their final visit. Kaplan–Meier survival analysis reveals that the proportions of patients with visual impairment (lower than 20/40) at 1 year following treatment in patients being referred to our uveitis center within 2 weeks, 2 weeks to 2 months, and more than 2 months after disease onset are 6.2%, 6.0%, and 15.6% respectively. At 2 years after treatment, the proportions in these three groups are 18.5%, 20.9%, and 26% respectively. At 5 years after treatment, the proportions are 3.3%, 33.5%, and 55.9% respectively [5]. • Multivariate analysis has revealed a number of factors including age at onset, complicated cataract, exudative retinal detachment at presentation, integumentary findings, intraocular hypertension, band-shaped keratopathy, vision at presentation and 1 month following treatment, and sunset glow fundus as predictors for final visual prognosis [26–28]. • Our multivariate logistic regression analysis shows that the initiation of treatment immediately after disease onset, vision at presentation and at 1 month after treatment are predicting factors for visual prognosis. • A poor visual prognosis is usually observed in the patients who are not adequately treated or develop refractory glaucoma, subretinal fibrosis, and choroidal neovascular membranes.

References

References

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14. Yang P, Zheng M, Zhang L, et al. Uveitis in Chinese patients with psoriasis. Ocul Immunol Inflamm. 2017;25(6):855–65. 15. Ji Y, Hu K, Li C, et al. Outcome and prognostic factors of phaco 1. Du L, Kijlstra A, Yang P.  Vogt-Koyanagi-Harada disease: novel emulsification cataract surgery in Vogt-Koyanagi-Harada uveitis. insights into pathophysiology, diagnosis and treatment. Prog Retin Am J Ophthalmol. 2018;196:121–8. Eye Res. 2016;52:84–111. 16. Yang P, Ye Z, Xu J, et al. Macular abnormalities in Vogt-Koyanagi-­ 2. Kase S, Rao NA.  Vogt-Koyanagi-Harada disease. In: Zierhut M, Harada disease. Ocul Immunol Inflamm. 2019;27(8):1–8. Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: 17. Herbort CP. Indocyanine green angiography: A. Fundus ICG angiSpringer; 2016. p. 1041–7. ography. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis 3. Ohno-Matsui K, Horie S, Mochizuki M.  Primary stromal chotext and imaging. New Delhi: Jaypee Brothers Medical Publishers roiditis: Vogt-Koyanagi-Harada (VKH) disease. In: Gupta A, (P) Ltd.; 2009. p. 88–144. Gupta V, Herbort CP, et  al., editors. Uveitis text and imaging. 18. Huang G, Peng J, Ye Z, et al. Multispectral image analysis in Vogt-­ New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. Koyanagi-­Harada disease. Acta Ophthalmol. 2018;96(4):411–9. p. 529–40. 19. Yang P, Fang W, Wang L, et al. Study of macular function by mul 4. Yang P, Ren Y, Li B, et  al. Clinical characteristics of Vogt-­ tifocal electroretinography in patients with Vogt-Koyanagi-Harada Koyanagi-­Harada syndrome in Chinese patients. Ophthalmology. syndrome. Am J Ophthalmol. 2008;146(5):767–71. 2007;114(3):606–14. 20. Read RW, Holland GN, Rao NA, et al. Revised diagnostic criteria 5. Yang P, Ye Z, Du L, et  al. Novel treatment regimen of Vogt-­ for Vogt-Koyanagi-Harada disease: report of an international comKoyanagi-­ Harada disease with a reduced dose of corticostemittee on nomenclature. Am J Ophthalmol. 2001;131(5):647–52. roids combined with immunosuppressive agents. Curr Eye Res. 21. Yang P, Zhong Y, Du L, et  al. Development and evaluation of 2018;43(2):254–61. diagnostic criteria for Vogt-Koyanagi-Harada disease. JAMA 6. Tesavibul N. Vogt-Koyanagi-Harada disease. In: Foster CS, Vitale Ophthalmol. 2018;136(9):1025–31. AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: 22. Yang P, Liu S, Zhong Z, et  al. Comparison of clinical features Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1013–32. and visual outcome between sympathetic ophthalmia and Vogt-­ 7. Li B, Yang P, Zhou H, et  al. Upregulation of T-bet expression in Koyanagi-­ Harada disease in Chinese patients. Ophthalmology. peripheral blood mononuclear cells during Vogt-Koyanagi-Harada 2019;126(9):1297–305. disease. Br J Ophthalmol. 2005;89(11):1410–2. 23. Yang P, Ye Z, Tang J, et  al. Clinical features and complica 8. Chi W, Yang P, Li B, et al. IL-23 promotes CD4+ T cells to produce tions of scleritis in Chinese patients. Ocul Immunol Inflamm. IL-17 in Vogt-Koyanagi-Harada disease. J Allergy Clin Immunol. 2018;26(3):387–96. 2007;119(5):1218–24. 24. Capella MJ, Foster CS. Sarcoidosis. In: Foster CS, Vitale AT, edi 9. Yang P, Ji L, Zhou H, et al. Disturbed expression of Fas/FasL on tors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee CD4(+) and CD8(+)T cells in Behcet’s disease, Vogt-Koyanagi-­ Brothers Medical Publishers (P) Ltd.; 2013. p. 951–2. Harada syndrome, and idiopathic anterior uveitis. Ocul Immunol 25. Yang P, Zhang N, Li F, et  al. Ocular manifestations of syphilitic Inflamm. 2001;9(3):185–91. uveitis in Chinese patients. Retina. 2012;32(9):1906–14. 10. Cao S, Chee SP, Yu HG, et al. Investigation of the association of 26. Abu El-Asrar AM, Al Tamimi M, Hemachandran S, et  al. Vogt-Koyanagi-Harada syndrome with IL23R-C1orf141  in Han Prognostic factors for clinical outcomes in patients with Vogt-­ Chinese Singaporean and ADO-ZNF365-EGR2  in Thai. Br J Koyanagi-­Harada disease treated with high-dose corticosteroids. Ophthalmol. 2016;100(3):436–42. Acta Ophthalmol. 2013;91(6):486–93. 11. Fang W, Yang P. Vogt-Koyanagi-Harada syndrome. Curr Eye Res. 27. Chee SP, Jap A, Bacsal K.  Prognostic factors of Vogt-­ 2008;33(7):517–23. Koyanagi-­ Harada disease in Singapore. Am J Ophthalmol. 12. Moorthy RS, Inomata H, Rao NA.  Vogt-Koyanagi-Harada syn2009;147(1):154–61. drome. Surv Ophthalmol. 1995;39(4):265–92. 28. Read RW, Rechodouni A, Butani N, et al. Complications and prog 13. Yang P, editor. Diagnosis and treatment of uveitis. Peking: People’s nostic factors in Vogt-Koyanagi-Harada disease. Am J Ophthalmol. Medical Publishing House; 2009. p. 667–778. 2001;131(5):599–606.

Sympathetic Ophthalmia

28

Contents 28.1  Definition

 539

28.2  Epidemiology

 539

28.3  Etiology and Pathogenesis

 540

28.4  Ocular Manifestations

 540

28.5  Extraocular Manifestations

 547

28.6  Complications

 547

28.7  Diagnosis

 548

28.8  Differential Diagnosis

 553

28.9  Management

 561

28.10  Prognosis

 561

References

 561

28.1 Definition • Sympathetic ophthalmia (SO) is a bilateral granulomatous uveitis induced by penetrating eye injury or surgery to one eye [1–3]. • It is generally considered to be mediated by autoimmune response to ocular antigens exposed following ocular injury or surgery. • The injured eye is known as the inciting or exciting eye while the fellow eye is called the sympathizing eye.

28.2 Epidemiology • Early studies showed a higher incidence of sympathetic ophthalmia. However, a dramatic decrease was reported during the last decades predominantly due to the substantial improvement in the treatment of penetrating eye injury. • In general, penetrating eye injuries are more apt to induce SO as compared to intraocular surgery. • The incidence of SO reported varies significantly with reports and is from 0.06 to 0.5% following penetrating eye injuries.

• SO has also been reported to occur after ocular surgery or intraocular procedures such as cataract surgery, glaucoma filtration surgery, sclera buckling, vitrectomy, peripheral iridectomy, evisceration, paracentesis, iris inclusions, cyclocryotherapy, cyclodialysis, Nd-YAG laser cyclotherapy, helium ion irradiation, or proton beam irradiation [2, 3]. • The incidence of SO is estimated to be 0.01% following routine pars plana vitrectomy [4]. • SO is more frequently observed in males than females, which could be explained by a higher frequency of penetrating eye injuries in this population [2, 3]. • No gender predilection is observed in the patients with SO secondary to the intraocular procedure or ocular surgery. • SO is reported to account for 0.3–1.4% of the uveitis patients in various reports. In our previous report, patients with SO account for 1.6% of 1752 uveitis patients referred to a tertiary center for uveitis in China [5]. In our recent observation, SO is noted in 146 patients out of more than 15,000 patients with uveitis or scleritis.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_28

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28.3

28  Sympathetic Ophthalmia

Etiology and Pathogenesis

• An immune privilege feature, known as anterior chamber-­ associated immune deviation (ACAID), has been well described and considered as an important mechanism for the maintenance of microenvironmental stability within the eye. • Autoimmune response to ocular antigens exposed to the conjunctival lymphatics following penetrating ocular injuries or ocular surgeries is definitely responsible for the development of SO [2, 3]. • Infectious agents may be involved in the initiation of autoimmune response as an adjuvant, which is evidenced by the association between SO and infectious perforating wounds or wound with uveal prolapse. • The typical pathological feature of SO is the non-­ necrotizing granuloma formation. • CD4+T cells and CD8+T cells are found to be involved in the development of this disease. • Genetic predisposition has been shown to be involved in the pathogenesis of SO.  HLA-A11 [6], HLA-DR4 [7], HLA-B40, HLA-DRB1∗04, HLA-DQB1∗04, and DA10D3 [8], and the polymorphisms of IL-10 and PDCD1 [9] have been identified to be associated with this disease.

•

•

• •

•

•

•

28.4 Ocular Manifestations

•

• SO occurs from 2 weeks to 3 months in 80% of the cases following the initial insult although the latent period var- • ies from 5 days to 66 years. • The classic features of this disease include granulomatous anterior uveitis, exudative retinal detachment, yellowish-­ white choroidal lesions (Dalen–Fuchs nodules), papillitis, and sunset glow fundus. These clinical features are gener-

ally similar to those observed in Vogt–Koyanagi–Harada (VKH) disease [1, 2, 10]. A typical evolutionary process is well defined for VKH disease including a prodromal stage, a posterior uveitis stage, an anterior uveal involvement stage, and a recurrent granulomatous anterior uveitis stage. However, this evolutionary process for SO is not described. The patients may complain about photophobia, pain, watering, blurred vision, mild visual disturbance, or severely decreased vision. Exciting eye of the patients may have various changes caused by penetrating eye injury (Fig. 28.1). The patients mostly present with mutton fat keratic precipitates (KPs) (Fig.  28.2), sometimes Koeppe nodules and Busacca nodules (Fig. 28.3) and rarely iris granuloma. In certain patients, they may manifest as nongranulomatous anterior uveitis as evidenced by dust-like KPs and numerous cells in the anterior chamber with or without ciliary congestion (Fig.  28.4). In few patients, fibrous exudates may be observed (Fig. 28.5). Posterior synechiae (Fig. 28.6) is the common consequence of chronic anterior uveitis in SO and may be associated with old fibrous membrane in the pupil area (Fig. 28.7). Peripheral anterior synechiae and goniosynechiae may also develop in a number of patients. SO, like VKH disease, may cause serous retinal detachment either in the posterior pole (Fig. 28.8) or in the inferior periphery (Fig. 28.9). Multiple subretinal white-yellow lesions, known as Dalen–Fuchs nodules, mainly distributed in the mid-­ equatorial and periphery (Fig. 28.10), are observed in up to 50% of the patients. Dalen–Fuchs nodules resolve frequently leaving punch-out chorioretinal atrophic lesions (Fig. 28.11) [1, 2, 10, 11].

Fig. 28.1  Anterior segment changes observed in the excising eye of the SO patients

28.4 Ocular Manifestations

541

Fig. 28.2  Mutton fat KPs observed in SO patients

a

b

Fig. 28.3  Numerous Busacca nodules (a) in a SO patient completely disappear following treatment with immunosuppressive agents combined with topical corticosteroid and cycloplegic agents (b)

Fig. 28.4  Ciliary congestion observed in a SO patient

Fig. 28.5  Fibrous exudates in the pupil area observed in a SO patient

542

28  Sympathetic Ophthalmia

Fig. 28.6  Posterior synechiae observed in SO patients

a

Fig. 28.7  Old fibrous membrane and 360° of posterior synechiae observed in a SO patient

Fig. 28.8  Serous retinal detachment in the macula observed in a SO patient

b

Fig. 28.9  Striking serous retinal detachment (a) disappears following treatment with immunosuppressive agents in a SO patient (b)

28.4 Ocular Manifestations

543

Fig. 28.10  Multiple Dalen-Fuchs nodules observed in SO patients

Fig. 28.11  Multiple punch-out chorioretinal atrophic lesions observed in a SO patient with inactive inflammation

• Papillitis (Fig. 28.12) and mild to moderate vitritis are the common manifestations in the posterior segment. In a few patients, significant vitreous opacities may also be observed. • Sunset glow fundus due to varying degrees of depigmentation in the choroid and retinal pigment epithelium with different appearances is a common finding in the SO patients with a chronic or recurrent uveitis (Fig. 28.13). • Sunset glow fundus with varying degrees of pigmentation is also observed in the patients (Fig. 28.14). • Uneven depigmentation of the retinal pigment epithelium (RPE) and choroid may result in sunset glow fundus with different appearances (Fig. 28.15) [12]. • The sclera and large blood vessels of the choroid may be visible via substantial depigmentation of the choroid and retinal pigment epithelium (Fig. 28.16). • Peripapillary atrophy of the choroid and retina is a common sign in the SO patients with a long history of the disease (Fig. 28.17).

544

Fig. 28.12  Papillitis associated with serous retinal detachment observed in SO patients

Fig. 28.13  Sunset glow fundus observed in a SO patient

28  Sympathetic Ophthalmia

28.4 Ocular Manifestations

Fig. 28.14  Sunset glow fundus-associated pigmentation in SO patients

Fig. 28.15  Sunset glow fundus with irregular depigmentation observed in SO patients

545

546

Fig. 28.16  Sunset glow fundus with visible choroidal blood vessels and the sclera in a SO patient

Fig. 28.17  Peripapillary atrophy observed in SO patients

28  Sympathetic Ophthalmia

28.6 Complications

28.5 Extraocular Manifestations • SO may have extraocular manifestations similar to those seen in VKH disease [13, 14]. • Extraocular manifestations include meningeal signs, auditory disturbance, alopecia, poliosis, vitiligo, and cerebrospinal fluid pleocytosis. • These extraocular manifestations in SO are less common as compared to VKH disease [14].

547

• Band keratopathy may be observed in patients with recurrent intraocular inflammation (Fig. 28.19). • Choroidal neovascularization (CNV) (Fig. 28.20), macular edema, and optic nerve atrophy may develop in the patients with recurrent or chronic intraocular inflammation.

28.6 Complications • Complicated cataract is frequently seen in the patients with recurrent anterior uveitis, mostly showing posterior subcapsular opacity (Fig. 28.18). • Secondary glaucoma occurs usually as a result of complete posterior synechiae or extensive anterior synechiae.

Fig. 28.18  Posterior subcapsular opacity observed in a SO patient

Fig. 28.20  CNV detected by OCT imaging in a SO patient

Fig. 28.19  Band keratopathy observed in SO patients

548

• Iris neovascularization may be observed in very few patients with SO (Fig. 28.21) • Retinal neovascularization is occasionally observed in SO patients (Fig. 28.22) • Phthisis bulbi may be occasionally observed due to severe disorganization.

28  Sympathetic Ophthalmia

28.7 Diagnosis • The diagnosis is principally based on the history of penetrating eye injury or intraocular surgery and typical clinical manifestations [10, 11, 14]. • There is no specific laboratory test to aid in the diagnosis. • FFA and indocyanine green angiography (ICGA) are helpful for the diagnosis of SO [15]. • In the patients with active choroiditis, FFA typically shows pinpoint leakages at the level of retinal pigment epithelium in the early phase and subretinal dye pooling in the area of serous retinal detachment in the late phase (Figs. 28.23 and 28.24) [1, 2, 14]. • Hyperfluorescence of the optic nerve and staining of vascular wall are also observed in certain patients (Figs. 28.25 and 28.26). • Hyperfluorescent dots corresponding to Dalen–Fuchs nodules revealed by FFA may be observed in certain patients in the late phase of angiogram (Fig. 28.27). • In the late stage of the disease, patients usually show window defects (Figs. 28.28 and 28.29).

Fig. 28.21  Swelling of the iris associated with iris neovascularization and posterior synechiae observed in a SO patient

a

b

Fig. 28.22  Neovascularization disclosed by fundus fluorescein angiography (FFA) in a SO patient (a–c). Fundus photograph showing retinal hemorrhage (d)

28.7 Diagnosis

c

549

d

Fig. 28.22 (continued)

a

Fig. 28.23  Photographs (a, c, e, g) are the results disclosed by FFA in an SO patient with active diffuse choroiditis, typically showing pinpoint leakage in the early phase and multiple subretinal dye pooling in the late phase of angiogram. Photographs (b, d, f, h) are the results of

b

ICGA. ICGA shows multiple hypofluorescent dots in the early phase and large dark areas corresponding to serous retinal detachment in the late phase of angiogram

550

28  Sympathetic Ophthalmia

c

d

e

f

Fig. 28.23 (continued)

28.7 Diagnosis

g

551

h

Fig. 28.23 (continued)

Fig. 28.24  Hyperfluorescent dots at early phase and pooling of dye at late phase detected by FFA in SO patients

552

Fig. 28.24 (continued)

Fig. 28.25  Staining of the optic disc and vascular walls identified by FFA in a SO patient

28  Sympathetic Ophthalmia

28.8 Differential Diagnosis

553

Green 27.09.2005

Fluo 0:20.0 27.09.2005

Fluo 1:19.7 27.09.2005

Fluo 6:43.1 27.09.2005

Fig. 28.26  Staining of the optic disc disclosed by FFA in a SO patient

• In a few patients with SO, FFA may show diffuse microvascular leakages and staining of the vascular wall (Fig. 28.30). • ICGA typically shows multiple hypofluorescent dots at the choroid level in active inflammation (Fig. 28.31) and dark areas corresponding to serous retinal detachment (Fig. 28.23b, d, f, h) [15]. • Optical coherence tomography (OCT) imaging may reveal multiple serous retinal detachment (Fig.  28.32), optic nerve swelling, the epiretinal membrane (Fig. 28.33), cystoid macular edema (CME), and CNV (Fig. 28.34) in certain patients [1–3, 14]. • Ultrasonography may aid in the detection of choroidal thickening and retinal detachment (Fig. 28.35).

• Ultrasound biomicroscopy (UBM) may detect the inflammatory cells in the anterior segment, swelling of the iris and ciliary body, and detachment of the ciliary body (Fig. 28.36).

28.8 Differential Diagnosis • VKH disease is an autoimmune bilateral granulomatous uveitis, which is strikingly similar to the inflammation seen in SO. A history of penetrating eye injury or intraocular surgery would distinguish SO from VKH disease. Extraocular manifestations including meningeal signs, auditory disorders, and integumentary changes are less

554

28  Sympathetic Ophthalmia

FA 0:54.68 55º [HS]

FA 5:37.53 55º [HS]

FA 5:47.64 55º [HS]

FA 5:58.09v 55º [HS]

Fig. 28.27  Numerous hyperfluorescent dots corresponding to Dalen–Fuchs nodules detected by FFA in a SO patient

28.8 Differential Diagnosis

Fig. 28.28  Window defects identified by FFA in the late phase of angiogram in SO patients

555

556

Fig. 28.29  Extensive window defects identified by FFA in a SO patient

28  Sympathetic Ophthalmia

28.8 Differential Diagnosis

557

HRA2 2008-01-24, OS, FA 0:18.51 55º

HRA2 2008-01-24, OS, FA 1:59.20 55º

HRA2 2008-01-24, OS, FA 2:29.51 55º

HRA2 2008-01-24, OS, FA 3:05.96 55º

HRA2 2008-01-24, OS, FA 4:07.21 55º

HRA2 2008-01-24, OS, FA 10:41.56 55º

Fig. 28.30  Multifocal hyperfluorescent dots, microvascular leakages, and staining of the vascular wall disclosed by FFA in a SO patient

Fig. 28.31  Multiple hypofluorescent dots disclosed by ICGA in a SO patient

558

Fig. 28.32  OCT imaging shows swelling of the optic nerve and serous retinal detachment in SO patients

Fig. 28.33  Epiretinal membrane detected by OCT imaging in a SO patient

28  Sympathetic Ophthalmia

28.8 Differential Diagnosis

a

559

b

c

Fig. 28.34  CNV observed in a SO patient (a: fundus photograph; b, c: OCT imaging results)

Fig. 28.35  Choroidal thickening and serous retinal detachment detected by B-scan ultrasonography in a SO patient with active diffuse choroiditis

common in SO as compared to VKH disease. VKH disease typically shows an evolution process and most patients have sunset glow fundus, whereas this change is less commonly seen in SO patients. Additionally, intraocular inflammation is more readily controlled in VKH disease as compared to that in SO [13, 14]. • Lens-induced uveitis is a granulomatous inflammation that develops as a result of lens capsule disruption either from trauma or surgery. It typically presents with unilat-

eral inflammation although bilateral involvement is rarely reported. Furthermore, the posterior segment is not involved in this disease. SO usually shows bilateral inflammation and posterior segment involvement [1, 2, 10, 11]. • Posterior scleritis may present with exudative retinal detachment and optic nerve swelling which are similar to those observed in SO.  However, severe pain around the eye, headache, and usually unilateral involvement are the hallmarks for posterior scleritis. Ultrasonography typi-

560

Fig. 28.36  Alterations detected by UBM in SO patients

28  Sympathetic Ophthalmia

References

cally shows choroidal thickening, retrobulbar edema and, rarely, subretinal mass-like lesion [16]. • Sarcoidosis may present with bilateral granulomatous uveitis resembling SO.  Systemic manifestations, the absence of a history of penetrating eye injury or intraocular surgery and relevant investigations may assist in diagnosis and differential diagnosis. • Other uveitis entities including idiopathic granulomatous uveitis, subretinal fibrosis and uveitis, ocular tuberculosis, syphilitic uveitis, and infective endophthalmitis should also be on the list of differentiation.

28.9 Management • The preventive effect of enucleation of the injured eye on the development of SO is presumed in early studies. However, prophylactic enucleation is rarely advocated with widespread use of advanced surgical techniques. Enucleation of the injured eye is suggested only for the severely disorganized eyes without light perception and the possibility to be repaired. Enucleation is usually recommended within 2 weeks after eye injury. • Corticosteroids are the mainstay of treatment for SO [1, 2, 14]. –– A high dose of oral corticosteroids is recommended with an initial dose of 0.7~1.0  mg/kg daily or 0.5~0.8  mg/kg daily for patients referred within 2 months or more than 2 months after disease onset. This dosage is usually used for one or two weeks followed by a gradual tapering to a maintenance dose (15~20 mg/ day) over 3~5 months. –– Corticosteroids with maintenance dose are usually used for 3~5 months and then gradually tapered over 3~5 months. –– Posterior sub-tenon’s injection of triamcinolone acetonide (20–40  mg) is advocated in the patients with severe exudative retinal detachment. –– Intravitreal corticosteroids are useful in treating the patients with severe and refractory inflammation in the posterior segment. The potential side effects including infectious endophthalmitis, increased intraocular pressure, and cataract may occur especially in the patients with repeated injections. –– Topical corticosteroids are used always in combination with mydriatic and cycloplegic agents for the patients with anterior uveitis. • Other immunosuppressive drugs used in the treatment of SO [1–3, 17]. –– Cyclosporine is usually used in conjunction with corticosteroids in the resistant patients or in those with severe involvement of posterior segment. Cyclosporine

561

is used normally at an initial dose of 3~5 mg/kg/day, followed by a gradual tapering to a maintenance dose (2 mg/kg/day). Treatment with this maintenance dose usually lasts for more than 6 months. –– Alkylating agents including cyclophosphamide and chlorambucil have been successfully used in combination with corticosteroid by us to treat SO patients with exudative retinal detachment and those with recalcitrant uveitis. –– Azathioprine has been successfully used in conjunction with a low dose of corticosteroids in the treatment of SO. • Biological agents [3] –– Anti-TNF-alpha agent such as adalimumab has been used for the patients with refractory uveitis. –– Intraocular inflammation is completely controlled after administration of anti-TNF-alpha agent in a patient with SO who does not respond to conventional treatment in our uveitis center.

28.10 Prognosis • Prompt and appropriate treatment with corticosteroids, other immunosuppressive agents, or both have greatly improved SO patient’s prognosis. • Refractory secondary glaucoma and long-lasting intraocular inflammation frequently result in significantly decreased vision or even visual loss. • The visual prognosis of patients with SO is worse than that of patients with VKH disease [14].

References 1. Chang G, Young L. Sympathetic ophthalmia. Semin Ophthalmol. 2011;26(4–5):316–20. 2. Kumaradas M, Rao N.  Sympathetic ophthalmia. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 1033–9. 3. Dhubhghaill SN, Power WJ.  Sympathetic ophthalmia. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1005–12. 4. Gass JD.  Sympathetic ophthalmia following vitrectomy. Am J Ophthalmol. 1982;93(5):552–8. 5. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 6. Reynard M, Shulman IA, Azen SP, et al. Histocompatibility antigens in sympathetic ophthalmia. Am J Ophthalmol. 1983;95(2): 216–21. 7. Davis JL, Mittal KK, Freidlin V, et al. HLA associations and ancestry in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. Ophthalmology. 1990;97(9):1137–42.

562 8. Atan D, Turner SJ, Kilmartin DJ, et  al. Cytokine gene polymorphism in sympathetic ophthalmia. Invest Ophthalmol Vis Sci. 2005;46(11):4245–50. 9. Deng J, Hu J, Tan H, et al. Association of a PDCD1 polymorphism with sympathetic ophthalmia in Han Chinese. Invest Ophthalmol Vis Sci. 2017;58(10):4218–22. 10. Jones N.  Sympathetic uveitis and Vogt-Koyanagi-Harada syn drome, Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 281–92. 11. Marmalidou A, Nwanze C. Sympathetic ophthalmia. In: Papaliodis GN, editor. Uveitis. Cham: Springer International Publishing AG; 2017. p. 540–52. 12. Yang P, editor. Diagnosis and treatment of uveitis. Peking: People’s Medical Publishing House; 2009. p. 780–812. 13. Du L, Kijlstra A, Yang P.  Vogt-Koyanagi-Harada disease: novel insights into pathophysiology, diagnosis and treatment. Prog Retin Eye Res. 2016;52:84–111.

28  Sympathetic Ophthalmia 14. Yang P, Liu S, Zhong Z, et  al. Comparison of clinical features and visual outcome between sympathetic ophthalmia and Vogt-­ Koyanagi-­ Harada disease in Chinese patients. Ophthalmology. 2019;126(9):1297–305. 15. Herbort CP. Indocyanine green angiography: A. Fundus ICG angiography. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 88–144. 16. Yang P, Ye Z, Tang J, et  al. Clinical features and complica tions of scleritis in Chinese patients. Ocul Immunol Inflamm. 2018;26(3):387–96. 17. Patel S, Dodds E, Echandi L, et al. Long-term, drug-free remission of sympathetic ophthalmia with high-dose, short-term chlorambucil therapy. Ophthalmology. 2014;121:596–602.

29

Retinal Vasculitis

Contents 29.1    Definition

 563

29.2    Retinal Vasculitis Associated with Systemic Vasculitis

 563

29.3    Retinal Vasculitis Secondary to Infectious Diseases

 566

29.4    Primary Retinal Vasculitis

 567

29.5    Clinical Manifestation 29.5.1  Symptoms 29.5.2  Signs

 567  567  568

29.6    Complications

 571

29.7    Diagnosis

 572

29.8    Differential Diagnosis

 579

29.9    Management

 579

29.10  Prognosis

 584

References

 586

29.1 Definition • Retinal vasculitis refers to the inflammation involving the retinal blood vessels, including arteries (arteritis), veins (phlebitis), and capillaries (capillaritis) [1, 2]. • Retinal vasculitis may occur alone or as a component of a number of systemic diseases [1–3]. • Primary retinal vasculitis is an umbrella term to denote an idiopathic disease without systemic inflammation or vasculitis [3, 4]. • Secondary retinal vasculitis refers to the disorder associated with systemic diseases or secondary to an infection origin [1, 4].

29.2 Retinal Vasculitis Associated with Systemic Vasculitis • A number of systemic vasculitides or disorders could cause retinal vasculitis or uveitis [1, 2, 4, 5].

• Behcet’s disease (BD) typically presents with oral and genital ulcerations, multiform skin lesions, and ocular involvement. Retinal vasculitis is very common in this disease and frequently manifests as widespread capillaritis identified by fundus fluorescein angiography (FFA) in the early stage (Fig. 29.1), gradually involves the venules and arterioles (occlusive vasculitis), and finally results in frank silver-wiring appearance (Fig. 29.2) [6, 7]. • Granulomatosis with polyangiitis, formerly known as Wegener’s granulomatosis, is a granulomatous necrotizing vasculitis principally involving small vessels. It typically affects the upper (sinuses) and lower respiratory tracts, kidneys, and sometimes, the eyes, the orbits, skin, and joints. Ocular disorders include orbital involvement, recurrent conjunctivitis, episcleritis, scleritis, peripheral ulcerative keratitis, and uveitis [8, 9]. • Sarcoidosis is an idiopathic granulomatous inflammatory disease. It typically presents with hilar lymphadenopathy, pulmonary involvement, arthropathy, skin lesions, central nervous systemic involvement, uveitis, and retinal vascu-

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_29

563

564 OD, FA 7:57.70 55° ART [HS]

29  Retinal Vasculitis OD, FA 8:15.34 55° ART [HS]

OD, FA 8:21.03 55° ART [HS]

Fig. 29.1  Widespread capillaritis disclosed by FFA in a BD patient

Fig. 29.2  Silver-wiring vessels associated with retinal atrophy and macular abnormality observed in a BD patient

litis. Patchy perivenous creamy exudate (candle wax ­drippings or taches de bougie) is considered as a hallmark of this retinal vasculitis [10, 11]. • Systemic lupus erythematosus (SLE) is a chronic inflammation disease. It mainly involves connective tissue but may affect every organ of the body. The most common ocular manifestations are retinal vascular lesions mostly presenting as cotton-wool spots with or without retinal hemorrhages (Fig. 29.3) [12]. • HLA-B27-positive acute anterior uveitis or acute anterior uveitis alone may be associated with vascular leakage on FFA examination although obvious retinal vasculitis is usually not observed. This vascular leakage usually resolves in about 4–6 weeks after disease onset [13].

• Giant cell arteritis is a granulomatous disease. It typically presents with headache, temporal tenderness, and jaw claudication. Ischemic optic neuropathy is the characteristic finding. Other manifestations include iritis, bilateral swelling of the optic disc, and rarely branch retinal artery occlusion [14]. • Polyarteritis nodosa is a rare necrotizing vasculitis mainly affecting small to medium-sized arteries which may result in end-organ infraction as an acute and life-threatening disorder. Retinal vasculitis, necrotizing scleritis, peripheral ulcerative keratitis, and uveitis are common ocular findings in this disease [15]. • Multiple sclerosis is a demyelinating disease of the central nervous system mediated by an immune response

29.2 Retinal Vasculitis Associated with Systemic Vasculitis

565

a

b

c

d

Fig. 29.3  Multiple hypofluorescent spots disclosed by FFA in a patient with systemic lupus erythematosus (a, b). They correspond to the cotton-­ wool spots observed ophthalmoscopically (c, d)

566

29  Retinal Vasculitis

against myelin. Systemic manifestations include fatigue, sensor disturbance, pain, weakness, bladder, bowel and sexual dysfunction, impairment of memory, and swallowing disturbance. Diplopia, optic neuritis, and uveitis (typically intermediate uveitis) are common ocular findings [16]. • Takayasu arteritis is a rare granulomatous inflammatory disease mainly affecting large vessels. Systemic manifestations are caused by gradual stenosis of involved arteries and include transient ischemic attack or stroke, vertebrobasilar dysfunction, limb claudication, renovascular hypertension, and angina. Ischemic neuropathy or the manifestations arising from ocular ischemia such as generalized vasodilation of retinal blood vessels, microaneurysms, neovascularization, vitreous hemorrhage, tractive retinal detachment, and secondary glaucoma may be present [17]. • Churg–Strauss syndrome, also termed as allergic granulomatosis, is a rare systemic vasculitis and mainly affects young adults. Characteristic findings are extravascular necrotizing granulomas and angiitis. It typically occurs in patients with asthma or in those with a history of allergy. Ocular findings, although rare, may appear as retinal vasculitis, anterior or posterior neuropathy, orbital inflammatory pseudotumors, conjunctivitis, scleritis, and uveitis [18]. • Kawasaki disease, also known as mucocutaneous lymph node syndrome, is an idiopathic systemic vasculitis mainly occurring in children from Asian origin. It is characterized by persistent high fever, mucosal inflammation, lymphadenopathy, cutaneous edema, and redness of palms and soles with a later progressive desquamation. Ocular findings include conjunctivitis, acute bilateral anterior uveitis, and rarely posterior segment involvement such as retinal folds, tortuous or dilated retinal blood vessels, and subretinal hemorrhage [19]. OD, FA 8:38.70 55° ART [HS]

• Other systemic diseases associated with retinal vasculitis or uveitis include dermatomyositis, polymyositis, Crohn’s disease, microscopic polyangiitis, urticarial vasculitis, and leukocytoclastic vasculitis [1–4].

29.3 Retinal Vasculitis Secondary to Infectious Diseases • Syphilis is an infectious disease transmitted sexually by the spirochete bacterium treponema pallidum. Ocular involvement is quite common. It presents with a broad spectrum of ocular inflammation. Our recent studies reveal posterior segment involvement in up to 86% of the patients with syphilitic uveitis. Although clinically visible retinal vasculitis is only noted in 4 out of 19 patients with syphilitic vasculitis, FFA shows retinal vascular leakage in 15 out 17 patients, indicating that retinal vasculitis is a common manifestation in this disease (Fig. 29.4) [20, 21]. • Tuberculosis (TB) is an infectious disease caused by mycobacterium tuberculosis. Although ocular TB presents with a wide spectrum of lesions, uveitis is the most common disorder in the eye. Immune response to mycobacterium tuberculosis has been suggested to be involved in the development of Eales disease [22]. • Cytomegalovirus (CMV) retinitis is the most common opportunistic retinal infection in immunocompromised individuals, especially in those with acquired immune deficiency syndrome. Necrotizing retinitis is the hallmark of this disease. Retinal vasculitis and vascular occlusion are an important component of CMV retinitis. Perivenous exudation is sometimes observed in this disease. Occasionally, patients may present as frosted branch angiitis [23]. • Acute retinal necrosis syndrome is one kind of necrotizing retinopathy presumably caused by varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), and

OS, FA 9:14.29 55° ART [HS]

OD, FA 9:44.96 55° ART [HS]

Fig. 29.4  Vascular leakage and staining of the vascular walls and optic disc detected by FFA in patients with syphilis

29.5 Clinical Manifestation

567

Fig. 29.5  Vasculitis and retinal necrosis observed in patients with acute retinal necrosis syndrome

herpes simplex virus type 2 (HSV-2). The characteristic findings are multifocal areas of retinal necrosis, vasculitis (Fig.  29.5), rapidly progressive vitritis, and rhegmatogenous retinal detachment in the healed phase. The vasculitis always affects the arterioles frequently in association with perivascular retinal hemorrhage (Fig. 29.6) [23]. • Ocular toxoplasmosis is an infectious disease caused by toxoplasma gondii. It typically presents as one or more fresh retinal lesions continuous with or close to an old scar. Retinal vasculitis is common in this disease and may affect venules, arterioles, or both. • Other infectious diseases with potential involvement of retinal blood vessels include Lyme disease, candidiasis, coccidioidomycosis, brucellosis, and rickettsia.

29.4 Primary Retinal Vasculitis • Eales disease, also known as idiopathic retinal perivasculitis, mainly occurs in healthy young males. Characteristically, it presents as retinal phlebitis with “cuffing,” perivascular edema, and multiple superficial retinal hemorrhages. Occasionally, there is breakthrough bleeding from the inflamed retinal vessels, resulting in massive vitreous hemorrhage. Retinal vessel obstruction may develop as a result of recurrent attacks and eventually results in frank neovascularization, which in turn leads to recurrent vitreous hemorrhage and tractional retinal detachment [22]. • Frosted Branch angiitis is a rare retinal vasculitis and presents with a widespread translucent sheathing of

r­etinal arterioles and venules. It typically affects healthy children, occasionally immunocompromised individuals, patients with Behcet’s disease, and those with CMV retinitis [24]. • Idiopathic retinal vasculitis is not uncommon in children with intraocular inflammation. Recently, the author found a high frequency of vascular leakage of fluorescence in pediatric uveitis although there is no clinically visible retinal alteration in most cases. This disease usually occurs in the healthy children and may be termed as juvenile idiopathic retinal microvasculitis (Fig. 29.7).

29.5 Clinical Manifestation 29.5.1 Symptoms • Patients usually complain of painless decrease or significant loss of visual acuity and floaters at some time during the course of the disease [25, 26]. • Some patients may experience scotomata due to retinal ischemia, hemorrhage, or infiltration. • Patients with peripheral retinal vasculitis may have mild symptoms or none at all. • Sudden loss of vision may be observed in patients with vitreous hemorrhage, especially those with Eales disease. • Some patients, especially those with acute retinal necrosis (ARN), may report redness and eye pain. Patients with systemic diseases may have systemic symptoms relevant to the involved organs.

568

29  Retinal Vasculitis

Fig. 29.6  Retinal vasculitis associated with retinal hemorrhages observed in patients with acute retinal necrosis syndrome

Fig. 29.7  Retinal vasculitis disclosed by FFA in a patient with pediatric uveitis

29.5.2 Signs • Sheathing of the blood vessels. –– In active inflammation, perivascular sheathing is considered to be caused either by extravasated or by actively migrated inflammatory cells. Perivascular sheathing usually presents as irregular and fuzzy appearance frequently accompanied by vessel caliber changes and tortuosity (Figs.  29.8 and 29.9) [1–4].

–– In the inactive inflammation, the perivascular sheathing usually presents as clearer, smoother, and gliosis appearance (Figs. 29.10 and 29.11). –– An extreme form of perivascular sheathing simulating tree branches in winter is observed in frosted branch angiitis (Fig.  29.12), Behcet’s disease, and CMV retinitis. –– Yellow and dense perivascular exudates resembling “candle-wax drippings” are characteristic findings in sarcoidosis.

29.5 Clinical Manifestation

Fig. 29.8  Vascular sheathing and retinal hemorrhages observed in a patient with retinal vasculitis

Fig. 29.9  Retinal vasculitis associated with hemorrhages observed in a male patient

569

570

29  Retinal Vasculitis

Fig. 29.10  Vascular sheathing observed in patients with inactive retinal arteritis

Fig. 29.11  Occlusion of the affected arteries observed in a patient with retinal arteritis

Fig. 29.12  Fundus alterations observed in a patient with frosted branch angiitis

• Vessel caliber changes [1–4] –– A variety of vessel caliber changes have been observed in the patients with retinal vasculitis including dilation (Figs.  29.13 and 29.14), patchy attenuation, widespread attenuation, and occlusion. –– Total obliteration of the retinal vessels, also known as “ghost vessels,” is commonly seen in BD patients in the end stage (Fig. 29.2). • Cotton wool spots are caused by precapillary retinal arteriolar occlusion and frequently observed in SLE, other retinal vasculitis as well as human immunodeficiency virus (HIV) retinopathy. • Retinal hemorrhages is a common event in the retinal vasculitis (Figs.  29.6, 29.8, and 29.15) especially seen in Eales disease, acute retinal necrosis syndrome, Behcet’s disease, and CMV retinitis [1–3, 7]. • Retinal edema is common in patients with retinal vasculitis, especially in those with retinal capillaritis. • Other changes in the fundus including vascular anastomoses, microaneurysms, macroaneurysms, telangiectasis, and optic disc neovascularization [1, 2, 4]. • Vitritis with varying severities are frequently observed in patients with retinal vasculitis [1, 2]. • Anterior chamber reaction is not uncommon in retinal vasculitis mostly as the expression of “spillover” of frank posterior segment inflammation. Usually, there are minimal flare and a few cells in the anterior chamber. However, an obvious inflammation with keratic precipitates (KPs), moderate to severe anterior chamber reaction is frequently observed in Behcet’s disease, and acute retinal necrosis syndrome. • The optic disc may be hyperemic and swelling in active retinal vasculitis. Optic nerve pallor may develop in patients with recurrent and chronic retinal vasculitis.

29.6 Complications

a

571

b

c

Fig. 29.13  Dilated retinal vessels in association with retinal vasculitis are observed at the first visit to our uveitis center (a). Considerable improvement of the dilated vessels is achieved 70 days after treatment

with systemic corticosteroids and cyclosporine (b). The dilated vessels are normalized 11 months after treatment (c)

29.6 Complications

• Macular hole • Vitreous hemorrhage • Epiretinal membrane mostly occurs in the posterior pole (Fig. 29.18) • Neovascular glaucoma • Widespread retinal atrophy (see Behcet’s disease) • Optic nerve atrophy

• • • • •

Retinal capillary dropout and nonperfusion Retinal and optic disc neovascularization Macular edema or cystoid macular edema (Fig. 29.16) Choroidal neovascularization (Fig. 29.17) Serous retinal detachment (or tractional retinal detachment)

572

29  Retinal Vasculitis

a

b

Fig. 29.14  FFA shows vascular leakage and staining of the vessel walls in the patient as described in Fig. 29.13 (a). There is no abnormality at 11 months following treatment (b)

29.7 Diagnosis

Fig. 29.15  Perivascular sheathing associated with retinal hemorrhages observed in a patient with retinal vasculitis

• A thorough history-taking should be performed in patients with retinal vasculitis, with special respect to oral or genital ulcerations, skin lesions, arthritis, neurologic disorders, and respiratory abnormalities. • Malignancy and infectious diseases such as tuberculosis, syphilis, and toxoplasmosis should be always kept in mind as potential causes of retinal vasculitis. • Meticulous opthalmological examinations may characterize the clinical findings of the affected eye and, therefore, are helpful in making a diagnosis and providing with the evidences for systemic diseases. • Fundus fluorescein angiography is of great importance to the diagnosis of retinal vasculitis. It shows dye leakage (Fig. 29.19), staining of the blood vessel wall (Fig. 29.20), and cystoid macular edema (Fig. 29.21). It is particularly useful in evaluating subclinical vasculitis (Figs. 29.22 and 29.23), nonperfusion, and neovascularization (Fig. 29.24) in the patients with retinal capillaritis that is not found ophthalmoscopically (Fig. 29.25). It is also very useful in

29.7 Diagnosis

573

Fig. 29.16  Cystoid macular edema detected by optical coherence tomography (OCT) imaging in a female patient with retinal vasculitis

evaluating dynamic changes of the subclinical retinal vasculitis (Fig. 29.26) [1–4]. • A tailored laboratory workup should be performed to assist in diagnosis. Laboratory investigations including complete blood count, erythrocyte sedimentation rate, and c-reactive protein should be performed routinely on patients with retinal vasculitis. • Syphilis serology tests should be performed in the patients with homosexual contact, HIV infection, and those with clinical manifestations unexplainable by other disorders. • Tuberculin skin testing, IFN-γ release assay, and chest X-ray or computed tomography (CT) scan are indicated in the patients with a history of exposure, Eales disease

coming from endemic area as well as those with suspected tuberculosis. Unselective screening in the patients may lead to misdiagnosis (see chapter ocular tuberculosis). • Serum angiotensin-converting enzyme (ACE) and chest radiography should be performed in the patients with granulomatous inflammation and retinal vasculitis with patchy perivenous creamy exudates. • Measurement of antinuclear antibodies is suggested in patients with SLE and other connective tissue diseases. • Anti-neutrophil cytoplasmic antibodies have been found to be associated with a number of systemic vasculitis or autoimmune diseases. These antibodies should be measured in patients possibly with underlying systemic diseases.

574 Fig. 29.17 Choroidal neovascularization detected by OCT imaging in patients with juvenile idiopathic retinal microvasculitis

29  Retinal Vasculitis

29.7 Diagnosis Fig. 29.18 Epiretinal membrane observed in patients with retinal vasculitis (a: fundus photograph; b: OCT imaging result)

575

a

b

576

29  Retinal Vasculitis

OD, FA 1:17.67 102° ART [HS]

OD, FA 4:53.55 102° ART [HS]

OD, FA 16:25.78 102° ART [HS]

OS, FA 2:07.67 102° ART [HS]

OS, FA 6:57.29 102° ART [HS]

OS, FA 16:39.81 102° ART [HS]

Fig. 29.19  Vascular leakages, neovascularization, and nonperfusion detected by FFA in both eyes of a patient with retinal vasculitis

a

Fig. 29.20  Staining of the vessel walls observed in a female patient (a). It almost completely resolves at 5 months after treatment with systemic corticosteroids and cyclosporine (b)

29.7 Diagnosis

577

b

Fig. 29.20 (continued)

Fig. 29.21  Neovascularization at and around the optic disc, vascular leakages, and cystoid macular edema disclosed by FFA in a patient with juvenile idiopathic retinal vasculitis

578

29  Retinal Vasculitis

Fig. 29.21 (continued)

a

b

c

Fig. 29.22  A female patient does not have obvious fundus abnormality. However, FFA shows staining of the vascular walls and optic disc, and vascular leakages in both eyes (a, b: photographs; c: FFA results of right eye; d: FFA results of left eye)

29.9 Management

579

d

Fig. 29.22 (continued)

29.8 Differential Diagnosis • Retinal vasculitis should be identified as primary (idiopathic or isolated), secondary disease or as a component of systemic disease. • In the patients with possibly suspected infection origin, a specific laboratory workup for each condition should be performed. • In the patients with possible systemic diseases, specific laboratory investigations as well as relevant auxiliary examinations are recommended. • Retinal vasculitis may be seen in numerous uveitis entities. The specific diagnosis should be made in terms of the history, meticulous examinations, and the accompanying systemic or ocular disorders.

29.9 Management • The treatment of retinal vasculitis is principally based on whether it is infectious or noninfectious, independent or associated with systemic diseases and the severity of the inflammation. • Antibiotics or antiviral agents should be used in the patients with an infectious inflammation (see relevant chapters: syphilis, ocular tuberculosis, and acute retinal necrosis syndrome). • Corticosteroids are the mainstay in the treatment of noninfectious retinal vasculitis [1–3]. • High-dose oral steroids are recommended in the treatment of acute occlusive primary retinal vasculitis. • Corticosteroids at an initial dose of 30 to 50 mg/kg/day with a gradual tapering and long-lasting treatment with maintenance dose are normally used by the author to treat primary retinal vasculitis and usually give rise to a beneficial result in most patients.

–– The treatment with corticosteroids is discontinued usually after complete resolution of retinal vasculitis clinically or disclosed by FFA. –– Long-term therapy with corticosteroids may cause a constellation of side effects. Therefore, the dose should be adjusted according to the response of the patients to treatment as well as the side effects developed during the treatment. • Corticosteroid-sparing immunosuppressive drugs [1–4] –– Immunosuppressive drugs have been used to reduce the dose of corticosteroids by us or in patients who do not respond well to them alone. –– These immunosuppressive drugs are usually recommended to treat patients with systemic diseases. –– Cyclosporine has been effectively used in conjunction with low-dose corticosteroids by us in the treatment of retinal vasculitis with or without systemic disease. The treatment usually lasts for a long time. Therefore, side effects of this drug should be monitored regularly. –– Other immunosuppressive agents such as cyclophosphamide, chlorambucil, methotrexate, azathioprine, and colchicine have been also used in the treatment of retinal vasculitis, especially that in Behcet’s disease. The effectiveness of these drugs has been reported although a uniform result has not been achieved. Patients who respond poorly to one drug may respond well to others. The selection of immunosuppressive drugs is mostly based on the response of the patients as well as the doctor’s experience. –– Mycophenolate mofetil inhibits the pathway of purine synthesis and is increasingly used in the treatment of uveitis including retinal vasculitis. The effectiveness of this drug in Chinese patients is expected to be confirmed in the future study.

580

29  Retinal Vasculitis

Fig. 29.23  There is no obvious fundus abnormality in a patient with retinal vasculitis. However, staining of the vascular walls and vascular leakages are detected by FFA

29.9 Management

581

Fig. 29.24  Neovascularization, nonperfusion, and vascular leakages disclosed by FFA in a female retinal vasculitis patient without obvious fundus abnormality

582

a

29  Retinal Vasculitis

b

c

Fig. 29.25  Staining of the vascular walls and optic disc detected by FFA in a female patient with subclinical retinal vasculitis (a: fundus photograph; b, c: FFA results)

29.9 Management

583

a

b

c

d

Fig. 29.26  Neovascularization and retinal vasculitis disclosed by FFA in a patient with subclinical retinal vasculitis (a, b: fundus photographs; c–f: FFA results; c, e: before treatment; d, f: after treatment)

584

e

29  Retinal Vasculitis

f

Fig. 29.26 (continued)

• Biologic response modifiers –– Antibodies to tumor necrosis factor, such as adalimumab have been used in the treatment of systemic diseases alone or associated ocular lesions and usually give rise to a beneficial result in most patients. –– INFα-2a has been successfully used by others and us to treat the patients with Behcet’s disease that respond poorly to corticosteroids and other immunosuppressive drugs. • Laser treatment –– Laser treatment is recommended for the patients with extensive retinal ischemia, persistent neovascularization, and especially those with recurrent vitreous hemorrhage. • Anti-VEGF agents –– Intravitreal injection of anti-VEGF agents, such as Conbercept, has been used for the treatment of retinal neovascularization and macular edema arising from

uveitis and retinal vasculitis (Figs.  29.27 and 29.28). However, repeated injection may be needed. Repeated intravitreous injection may cause vitreous hemorrhage and increase the risk of developing infection. • Vitrectomy has been used in the patients with persistent vitreous hemorrhage, proliferative vitreoretinopathy, and tractional retinal detachment.

29.10 Prognosis • Most patients with mild or moderate idiopathic retinal vasculitis have a good visual prognosis if appropriate treatment is instituted. • Retinal or optic disc neovascularization, persistent macular edema, neovascularized glaucoma, and tractional retinal detachment usually cause significant loss of vision.

29.10 Prognosis OD, FA 9:15.78 55° ART [HS]

585 OD, FA 9:40.46 55° ART [HS]

OD, FA 9:51.62 55° ART [HS]

OD, FA 7:46.48 55° ART [HS]

OD, FA 7:51.48 55° ART [HS]

a

OD, FA 7:12.01 55° ART [HS]

b

Fig. 29.27  Neovascularization and retinal vasculitis (a) resolve following treatment with systemic corticosteroids and cyclosporine in conjunction with intravitreal injection of Conbercept (b)

a

b

Fig. 29.28  A male patient with idiopathic retinal vasculitis shows retinal neovascularization, which does not response to laser treatment and systemic corticosteroids combined with steroid-sparing immunosup-

pressive agents (a, b). Intravitreous injections of Conbercept for 7 times eventually result in complete regression of the retinal neovascularization (c, d).

586

29  Retinal Vasculitis

c

d

Fig. 29.28 (continued)

References 1. Ayliffe W.  Retinal vasculitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1136–68. 2. El-Asrar A, Herbort CP, Tabbara KF. Retinal vasculitis. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 376–96. 3. Herbort CP, Luca C, El-Asrar A.  Vasculitis: global approach to ocular vasculitis. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 363–76. 4. Jones N.  Vasculitis, Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 293–341. 5. Nussenblatt R, Whitcup S, Palestine A. Retinal vasculitis. Uveitis fundamentals and clinical practice. 2nd ed. St. Louis: Mosby-Year Book, Inc.; 1996. p. 354–63. 6. Ohno S, Namba K, Takemoto Y. Behcet’s disease. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 785–95. 7. Yang P, Fang W, Meng Q, et al. Clinical features of Chinese patients with Behcet’s disease. Ophthalmology. 2008;115(2):312–8. 8. Soukiasian SH.  Granulomatosis with polyangiitis. In: Zierhut M, Pavesio C, Ohno S, et  al, Intraocular inflammation. Berlin: Springer. 2016; pp 829-835. 9. Soukiasian SH. Granulomatosis with polyangiitis (Wegener’s). In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 898–916. 10. Capella MJ, Foster CS. Sarcoidosis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 951–72.

11. Shigeaki O, Kitaichi N, Kitamura M. Sarcoidosis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 863–72. 12. Uy HS, Chan PS.  Systemic lupus erythematosus. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 814–25. 13. Yang P, Wan W, Du L, et al. Clinical features of HLA-B27-positive acute anterior uveitis with or without ankylosing spondylitis in a Chinese cohort. Br J Ophthalmol. 2018;102(2):215–9. 14. Siddique SS, Foster CS. Giant cell arteritis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 836–57. 15. Soheilian M, Ramezani A. Polyarteritis nodosa. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 887–97. 16. Mackensen F, Becker MD.  Multiple sclerosis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 851–61. 17. Matos K, Muccioli C. Takayasu arteritis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 767–71. 18. Stübiger N, Zierhut M.  Churg-Strauss Syndrome. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 761–5. 19. Ohno S, Namba K, Kitamei H. Kawasaki disease. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 755–9. 20. Mauro J, Samson CM, Foster CS.  Syphilis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 337–45. 21. Yang P, Zhang N, Li F, et  al. Ocular manifestations of syphilitic uveitis in Chinese patients. Retina. 2012;32(9):1906–14.

References 22. Biswas J, Davda MD, Parmar VK. Eales’ disease. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 941–9. 23. Capella MJ, Foster CS. Herpesviruses. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 437–60. 24. Jones N. Frosted branch angiitis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 951–4.

587 25. Samuel MA, Equi RA, Chang TS, et  al. Idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis (IRVAN): new observations and a proposed staging system. Ophthalmology. 2007;114(8): 1526–9. 26. Sobolewska B, Khochtali S, Khairallah M, et al. Retinal vasculitis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 575–90.

30

Eales Disease

Contents 30.1   Definition 

 589

30.2   Epidemiology 

 589

30.3   Etiology and Pathogenesis 

 589

30.4   Clinical Manifestations  30.4.1  Symptoms  30.4.2  Signs 

 589  589  590

30.5   Complications 

 590

30.6   Diagnosis 

 590

30.7   Differential Diagnosis 

 590

30.8   Treatment 

 592

30.9   Prognosis 

 596

References 

 596

30.1 Definition

30.3 Etiology and Pathogenesis

• Eales disease, also named as idiopathic perivasculitis, is an idiopathic retinal perivasculitis, more accurately periphlebitis, usually occurring in the peripheral retina [1, 2]. • Characteristic features include inflammation, ischemia and neovascularization.

• The exact aetiology and pathogenesis are not completely known, although hypersensitivity to mycobacterial antigens is presumed to be involved in this disease. • A cell-mediated immune response may play a role in the pathogenesis of Eales disease. • The fact that HLA-B5 (B51) is associated with this disease and its predilection for the people living in Indian subcontinent, raises the possibility that genetic factors may be implicated in this disease [4, 5].

30.2 Epidemiology • Eales disease is mostly observed in the Indian subcontinent [2]. • It usually affects an otherwise healthy individuals in their 20s–30s. • Males are more commonly affected than females. • Bilateral involvement ranges from 50 to 90%. • Eales disease is an uncommon ocular disease in China [3].

30.4 Clinical Manifestations 30.4.1 Symptoms • In general, patients do not have systemic diseases. • Patients usually complain of floaters and blurred vision followed by spontaneous improvement.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_30

589

590

• Sudden impairment or loss of vision may occur as a result of massive vitreous hemorrhage [1, 2]. • These symptoms are usually improved spontaneously and reoccur in an episodic manner.

30  Eales Disease

• Mild to moderate vitreous opacities may be observed. • Mild anterior chamber reaction such as cells and flare may be seen in certain patients.

30.5 Complications 30.4.2 Signs • Eales disease usually presents with active periphlebitis followed by retinal microvascular nonperfusion and retinal neovascularization [1, 2, 6]. • Active periphlebitis mostly starts in the peripheral retina and manifests as sheathing with fluffy and thick appearance frequently associated with retinal hemorrhage (Fig. 30.1). Breakthrough bleeding from the involved vessels may result in massive vitreous hemorrhage and sudden loss of vision [1, 2, 6]. • Active periphlebitis may be associated with ischemic changes and neovascularization (Fig. 30.2). • Recurrent periphlebitis often leads to complete occlusion of blood vessels and varying degrees of retinal microvascular nonperfusion. • Neovascularization frequently occurs as a result of ­retina ischemia due to obliterated vessels. It usually develops at the junction of the avascular and vascular retina and may also occur in the retina elsewhere and the optic disc. Fibrovascular proliferation may lead to recurrent vitreous hemorrhages and tractional retinal detachment. • The larger veins are occasionally affected and a branch retinal vein or a central retinal vein occlusion may be observed.

• • • •

Proliferative vitreoretinopathy (Fig. 30.3) [1, 2, 6]. Tractional retinal detachment [1, 2, 6]. Neovascular glaucoma. Cystoid macular edema (CME).

30.6 Diagnosis • The diagnosis of Eales disease is mainly based on typical clinical manifestations including recurrent periphlebitis with retinal and vitreous hemorrhage, retinal ischemia and neovascularization in the absence of any systemic disorders [1, 2]. • Eales disease is a diagnosis of exclusion. Systemic disorders should be ruled out. • FFA is extremely useful in the evaluation of the activity of Eales disease, capillary non-perfusion as well as in guidance of laser therapy. The findings of FFA are described as below [1, 2, 6]. –– Staining of the vessel wall (Fig. 30.4) –– Staining of the optic disc (Fig. 30.5) –– Non-perfusion of the retinal capillaries (Fig. 30.6). –– Retinal neovascularization (Fig. 30.7). –– Leakages of the retinal blood vessels (Fig. 30.8) • Blockage of fluorescence due to hemorrhages. (Fig. 30.9) • Ultrasonography is used in patients with significant vitreous hemorrhage to detect posterior vitreous detachment, proliferative retinopathy and retinal detachment. • There is no specific laboratory test in the diagnosis of Eales disease.

30.7 Differential Diagnosis

Fig. 30.1  Retinal vascular sheathing and hemorrhages observed in a patient with Eales disease

• A number of uveitis entities with retinal vasculitis, including Behcet’s disease (BD), intermediate uveitis, idiopathic retinal vasculitis and juvenile idiopathic retinal vasculitis should be differentiated from Eales disease [1, 2, 7]. • Retinal vasculitis associated with systemic diseases, including sarcoidosis, multiple sclerosis, systemic lupus erythematosus (SLE), polyarteritis nodosa, etc. should also be distinguished from Eales disease [1, 2]. • Retinal vasculitis is also observed in Lyme’s disease, toxoplasmosis and syphilis. They all should be on the list of differentiation from Eales disease [1–3].

30.7 Differential Diagnosis

591

a

b

c

d

e

f

Fig. 30.2  Alterations including retinal vascular sheathing, hemorrhages, neovascularization, exudates and nonperfusion of retinal capillaries observed in a patient with Eales disease (a, b: fundus photographs; c–f: fundus fluorescein angiography results)

30  Eales Disease

592

Fig. 30.3  Proliferative vitreoretinopathy observed in patients with Eales disease

•

Fig. 30.4  Staining of the vessel wall disclosed by FFA in a patient with Eales disease

•

30.8 Treatment • Antituberculosis treatment should be instituted for the patients with active tuberculosis. • Corticosteroids remain the mainstay of therapy for this disease [1, 2]. –– Systemic corticosteroids usually begin with a dose of 0.6–1  mg/kg/day and in a gradual tapering manner. –– Posterior subtenon injection of triamcinolone is indicated in the patients with CME.

•

•

–– It has been reported that intravitreal corticosteroids may be useful in some patients [8]. –– Topical corticosteroids, mydriatic and cycloplegic agents are suggested in the patients with an anterior chamber reaction. If the patients do not respond well to the corticosteroid or have unacceptable side effects during steroid treatment, other immunosuppressive agents are recommended to be used usually in combination with a low-dose of corticosteroids [1, 2, 6]. –– The common immunosuppressive agents used in treating Eales disease as well as other retinal vasculitides include cyclosporine, chlorambucil, cyclophosphamide and azathioprine. –– Two or more immunosuppressive agents in conjunction with corticosteroids are recommended in the treatment of patients with severe inflammation and recurrent vitreous hemorrhage. Intravitreal injection of Anti-VEGF agents is useful for the patients with retinal or optic disc neovascularization. Laser photocoagulation has been effectively used in the treatment of retinal neovascularization. –– In the patients with optic disc neovascularization or with widespread capillary nonperfusion, panretinal photocoagulation is indicated. –– In the patients with localized retinal neovascularization or with localized capillary nonperfusion, sector laser photocoagulation is recommended. Vitrectomy has been successfully employed in the patients with vitreous hemorrhage, epiretinal membranes and tractional retinal detachment [1, 2, 6].

30.8 Treatment

593

a

OS, FA 0:30.98 55° ART [HS]

OS, FA 10:26.23 55° ART [HS]

OS, FA 11:00.87 55° ART [HS]

b

Fig. 30.5  Fundus changes (a) and staining of the optic disc and neovascularization disclosed by FFA (b) in a male patient with Eales disease

Fluo 2:39.3 11.11.2002 OS

Fluo 2:47.9 11.11.2002 OS

Fig. 30.6  Neovascularization and nonperfusion of retinal capillaries disclosed by FFA in a patient with Eales disease (Courtesy of professor Feng Wen)

594

30  Eales Disease Fluo 3:10.5 11.11.2002 OS

Fluo 11:44.3 11.11.2002 OS

Fig. 30.6 (continued)

Fluo 0:32.1 02.07.2003 OS

Fluo 1:23.4 02.07.2003 OS

Fluo 2:20.3 02.07.2003 OS

Fluo 16:06.0 02.07.2003 OS

Fig. 30.7  Vascular leakage, neovascularization and large zones of nonperfusion of retinal capillaries detected by FFA in a patient with Eales disease (Courtesy of professor Feng Wen)

30.8 Treatment

595 Fluo 3:12.7 01/24/2006 OS

Fluo 4:37.1 01/24/2006

Fluo 12:36.1 01/24/2006

Fluo 13:56.7 01/24/2006

Fig. 30.8  A localized retinal vasculitis evidenced by leakages of the retinal blood vessels and the staining of the vascular walls disclosed by FFA in a patient with Eales disease

596

30  Eales Disease Fluo 0:14.2 10/10/2005

Fluo 1:41.0 10/10/2005

Fluo 1:58.4 10/10/2005

Fluo 2:10.3 10/10/2005

Fluo 2:25.0 10/10/2005

Fluo 2:47.9 10/10/2005

Fluo 8:12.4 10/10/2005

Fluo 9:09.7 10/10/2005

Fluo 9:36.3 10/10/2005

Fig. 30.9  Vascular leakages, nonperfusion of retinal capillaries, blockage of fluorescence due to hemorrhages and staining of the optic disc disclosed by FFA in a patient with Eales disease

30.9 Prognosis • Most patients have a good visual prognosis if early and appropriate treatment is instituted. • Vasculitis affecting the macular area, widespread neovascularization, tractional retinal detachment and neovascular glaucoma may lead to significant loss of vision.

References 1. Ayliffe W.  Retinal vasculitis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 1136–68.

2. Biswas J, Davda M, Parmar K.  Eales’ disease. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 941–50. 3. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 4. Biswas J, Mukesh BN, Narain S, et  al. Profiling of human leukocyte antigens in Eales’ disease. Int Ophthalmol. 1997;21(5): 277–81. 5. Ohno S, Mizuki N.  Molecular genetics of posterior uveitis. Int Ophthalmol Clin. 1995;35(3):21–32. 6. Das T, Pathengay A, Hussain N, et al. Eales’ disease: diagnosis and management. Eye (Lond). 2010;24(3):472–82. 7. Yang P, Fang W, Meng Q, et al. Clinical features of chinese patients with Behcet’s disease. Ophthalmology. 2008;115(2):312–8. 8. Ishaq M, Feroze AH, Shahid M, et al. Intravitreal steroids may facilitate treatment of Eales’ disease (idiopathic retinal vasculitis): an interventional case series. Eye. 2007;21(11):1403–5.

Frosted Branch Angiitis

31

Contents 31.1  Definition 

 597

31.2  Epidemiology 

 597

31.3  Etiology and Pathogenesis 

 597

31.4  Clinical Manifestations 

 598

31.5  Complications 

 599

31.6  Diagnosis 

 599

31.7  Differential Diagnosis 

 609

31.8  Treatment 

 609

31.9  Prognosis 

 609

References 

 609

31.1 Definition

31.2 Epidemiology

• Frosted branch angiitis is a rare retinal vasculitis with widespread sheathing of blood vessels simulating frost on a tree branch [1, 2]. • It almost exclusively affects the veins but occasionally involves the arterioles [1, 2]. • It is mostly idiopathic. However, it has also been reported to occur in cytomegalovirus retinitis, Behcet’s disease, sarcoidosis, systemic herpes simplex infection, toxoplasmosis, Crohn’s disease, systemic lupus erythematosus (SLE), lymphoma, and relapsing acute lymphoblastic leukemia [2, 3]. • In general, this disease without any systemic diseases is classified into primary frosted branch angiitis, whereas that with systemic abnormalities is termed as secondary frosted branch angiitis [1, 4].

• Frosted branch angiitis is more often reported in Japanese. However, it may occur in other countries [1, 2, 5]. There are few patients reported from China [6, 7]. • It mainly occurs in children or young adults. • Males are more frequently affected than females. • Bilateral involvement is common.

31.3 Etiology and Pathogenesis • The exact causes and pathogenesis remain unknown. • The prodromal symptoms like viral illness suggest the involvement of infection in its pathogenesis [3]. • Rapid resolution of primary frosted branch angiitis following treatment with corticosteroids raises the possibility that it is mediated by an immune response [2, 3].

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_31

597

598

31  Frosted Branch Angiitis

31.4 Clinical Manifestations • A number of patients with primary frosted branch angiitis may experience symptoms like viral illness. • Patients usually present with a sudden onset of bilateral blurred vision, floaters, redness, and photophobia. • Patients may experience a rapidly progressive loss of vision, even counting fingers or worse.

• Widespread perivascular exudate with translucent appearance is the pathognomonic feature for this disease (Fig. 31.1) [1–3]. • Other fundus changes include widespread retinal edema, papillitis (Fig.  31.2), macular edema, retinal hemorrhages, and exudative retinal detachment. • Mild to moderate vitritis is observed in most patients. • Anterior uveitis in nongranulomatous nature may present as flare and cells in the anterior chamber.

a

b

c

d

e

f

Fig. 31.1 Extensive retinal vascular sheathing, macular edema observed under ophthalmoscopy in a 5-year-old patient with frosted branch angiitis (a–d). Retinal vascular sheathing completely disappears

following 6-month treatment with systemic corticosteroids combined with cyclosporine (e, f)

31.6 Diagnosis

599

Fig. 31.2  Papillitis and retinal vascular sheathing observed in patients with frosted branch angiitis

31.5 Complications • Complications are rarely observed in patients with primary frosted branch angiitis. • Complications include complicated cataract, secondary glaucoma, posterior vitreous detachment, and retinal neovascularization.

31.6 Diagnosis • Typical widespread perivascular sheathing is pathognomonic for the diagnosis of this disease [1, 2, 4, 5]. • Fundus fluorescein angiography (FFA) typically reveals widespread vascular leakages and staining of the vascular walls (Figs. 31.3 and 31.4).

• Indocyanine green angiography (ICGA) may show multiple hyperfluorescent and hypofluorescent spots (Fig. 31.5). • Optical coherence tomography (OCT) imaging may show serous retinal detachment (Fig.  31.6) and multiple hyper-­ r eflective dots in the outer retina (Fig. 31.7). • Multifocal electroretinography (MfERG) usually shows striking abnormality (Fig. 31.8). • Visual field defect may be present (Figs. 31.9 and 31.10). However, it can almost disappear after treatment (Figs. 31.11 and 31.12) • There is no laboratory test for primary frosted branch angiitis.

600

31  Frosted Branch Angiitis OD, FA 13:40.56 55º ART[HS]

a

OD, FA 9:13.85 55º ART[HS]

c

OD, FA 2:53.79 55º ART[HS]

e

Fig. 31.3  Widespread vascular leakages and staining of the vascular walls detected by FFA in the right eye of the patient described in Fig. 31.2 (a, b). The vascular leakages are greatly improved following

OD, FA 14:43.26 55º ART[HS]

b

OD, FA 9:03.73 55º ART[HS]

d

OD, FA 3:13.46 55º ART[HS]

f

a 2-month treatment (c, d) and disappears almost completely at 9 months after treatment (e, f)

31.6 Diagnosis

601 OS, FA 4:24.54 55º ART[HS]

a

OS, FA 15:36.67 55º ART[HS]

b

OS, FA 4:33.37 55º ART[HS]

c

OS, FA 10:09.21 55º ART[HS]

d

OS, FA 2:03.29 55º ART[HS]

e

OS, FA 7:58.57 55º ART[HS]

f

Fig. 31.4  Widespread vascular leakages and staining of the vascular walls (a, b) detected by FFA in the left eye of the patient described in Fig. 31.2. The vascular leakages are greatly improved following a 2-month treatment (c, d) and disappears at 9 months after treatment (e, f)

602

31  Frosted Branch Angiitis

a

b

c

Fig. 31.5  Multiple hyperfluorescent spots and hypofluorescent spots disclosed by ICGA (a, b: 7 days after disease onset; c, d: 23 days after disease onset)

31.6 Diagnosis

603

d

Fig. 31.5 (continued)

Fig. 31.6  Serous retinal detachment disclosed by OCT imaging in the patient as described in Fig. 31.2 on day 7 after disease onset

a

b

c

d

Fig. 31.7  Multiple hyper-reflective dots disclosed in the outer retina of a patient as described in Fig. 31.2 on day 15 after disease onset (a, b). They completely resolve following a 2-month treatment with systemic corticosteroids and cyclosporine (c, d)

604

31  Frosted Branch Angiitis

a

b

c

d

e

f

g

h

Fig. 31.8  A patient as described in Fig. 31.2 shows striking mfERG abnormalities (a, b) and a gradual improvement after treatment (c, d: 2 months; e, f: 5 months; g, h: 9 months after treatment)

31.6 Diagnosis

605

Fig. 31.9  General reduction of sensitivity, enlarged physiologic blind spot and visual islands detected by Humphrey perimetry in the right eye of a patient with frosted branch angiitis on day 23 after disease onset

606

31  Frosted Branch Angiitis

Fig. 31.10  General reduction of sensitivity and enlarged physiologic blind spot detected by Humphrey perimetry in the left eye on day 23 after disease onset in the patient as described in Fig. 31.9

31.6 Diagnosis

607

Fig. 31.11  Abnormal visual field of right eye detected by Humphrey perimetry is significantly improved at 7 months after treatment with systemic corticosteroids in the patient as described in Fig. 31.9

608

31  Frosted Branch Angiitis

Fig. 31.12  Central scotoma detected by Humphrey perimetry in the left eye at 7 months after treatment in the patient as described in Fig. 31.9

References

31.7 Differential Diagnosis • As a number of disorders may present with retinal vasculitis resembling frosted branch angiitis, they should be considered in the differential diagnosis. Localized frosting of vessels is a rule in these conditions, contrary to the widespread vascular frosting in frosted branch angiitis. • Behcet’s disease (BD) is characterized by oral and genital ulcerations, multiple skin lesions, recurrent uveitis, and occlusive retinal vasculitis. • Ocular sarcoidosis is frequently associated with systemic manifestations, intermediated uveitis, multifocal chorioretinitis, and patchy perivenous creamy exudates (candle wax drippings). • Viral retinitis with vasculitis frequently shows frank necrotizing retinitis and localized frosting of blood vessels. • Multiple sclerosis is often associated with intermediate uveitis and, sometimes, peripheral retinal venous sheathing. Involvement of the central nervous system is helpful for the diagnosis. • Syphilitic uveitis is often associated with retinitis and widespread retinal vascular leakages but rarely perivascular exudates. The systemic manifestations and serologic investigations are useful in the diagnosis. • Ocular toxoplasmosis typically shows focal retinitis frequently occurring in the macular area. Fresh lesions often develop adjacent to a chorioretinal scar. The retinal vascular sheathing is often localized and develops close to the active focus although it may occur at any position of the retina.

31.8 Treatment • Systemic corticosteroids are the mainstay in the treatment of primary frosted branch angiitis [1–3]. • Treatment with corticosteroid commences usually at a dose of 0.6–1mg/kg/day followed by gradual tapering.

609

• Secondary frosted vasculitis should be treated in the context of the causes and associated systemic diseases. • Other immunosuppressive agents such as cyclosporine are also used for patients with primary frosted branch angiitis. Systemic corticosteroids in conjunction with cyclosporine have been used by the author in the treatment of primary frosted branch angiitis with beneficial result.

31.9 Prognosis • Most patients with primary frosted branch angiitis have a good visual prognosis after the disease resolves. • Complications including macular scarring, epiretinal membrane, and optic nerve atrophy may result in persistent visual impairment.

References 1. Jones N.  Vasculitis: frosted branch angiitis. In: Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 307–9. 2. Walker S, Iguchi A, Jones NP. Frosted branch angiitis: a review. Eye (Lond). 2004;18(5):527–33. 3. Jones N. Frosted branch angiitis. In: Zierhut M, Pavesio C, Ohno S, et al., editors. Intraocular inflammation. Berlin: Springer; 2016. p. 951–4. 4. Jones N. Vasculitis. Uveitis. 2nd ed. London: JP Medical Ltd.; 2013. p. 293–314. 5. El-Asrar A, Herbort CP, Tabbara KF. Retinal vasculitis. In: Gupta A, Gupta V, Herbort CP, et  al., editors. Uveitis text and imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. p. 376–96. 6. Luo G, Yang P, Huang S, et  al. A case report of frosted branch angiitis and its visual electrophysiology. Doc Ophthalmol. 1998;97(2):135–42. 7. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8.

32

Ocular Sarcoidosis

Contents 32.1  Definition 

 611

32.2  Epidemiology 

 611

32.3  Etiology and Pathogenesis 

 611

32.4  Systemic Manifestations 

 612

32.5  Ocular Manifestations 

 612

32.6  Diagnosis and Diagnostic Criteria 

 613

32.7  Differential Diagnosis 

 620

32.8  Treatment 

 624

32.9  Prognosis 

 625

References 

 625

32.1 Definition • Sarcoidosis is a multisystem disease typically showing epithelioid cell granulomas without caseation in the affected tissues [1–3]. • Ocular involvement is common, occurring in up to 30–60% of the patients with systemic sarcoidosis. • Definite ocular sarcoidosis refers to the disease having characteristic findings of the eye with the identification of noncaseating granuloma through tissue biopsy [3, 4]. • Presumed ocular sarcoidosis refers to the disease with compatible ocular manifestations in patients with bilateral hilar lymphadenopathy but without identification through tissue biopsy.

32.2 Epidemiology • Sarcoidosis occurs worldwide, but is more commonly seen in African-Americans, Caucasians of Sweden and Irish, and Japanese. However, it is rare in China, Southeast Asia, and India [4].

• In a study performed in a tertiary center for uveitis in China, sarcoidosis accounts for 0.1% of the patients with anterior uveitis and those with posterior uveitis [5]. • Systemic sarcoidosis usually affects young female adults. • Ocular sarcoidosis frequently occurs in adults.

32.3 Etiology and Pathogenesis • The exact etiology and pathogenesis of sarcoidosis are not clear. • Exposure to microbe-rich environments has been suggested to be involved in the pathogenesis of sarcoidosis [1]. • CD4+ T cells are increased in the lung and activated to release IL-2 and other inflammatory mediators [1, 3]. • Immunoregulatory cytokines including IL-12, TNF-α, IL-10, and IL-8 are also involved in the development of this disease [6, 7]. • The familial aggregation has been reported, suggesting the presence of genetic predisposition.

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_32

611

612

• The association of HLA-B8 and HLA-DRB1 with ­sarcoidosis also suggests that genetic susceptibility may be responsible for the development of this disease [8].

32.4 Systemic Manifestations • The lung is the most common organ affected in sarcoidosis, accounting for about 90% of the patients [3, 8]. –– The involvement of hilar and mediastinal lymph nodes, manifesting as adenopathy detected by chest X-ray or computed tomography (CT) scan (Fig. 32.1), is seen in almost all patients with sarcoidosis. –– The most common manifestations include dyspnea, chest pain, and non-productive cough. • The skin is affected in 9–37% of the patients with sarcoidosis [3]. –– Erythema nodosum is common and nonspecific (Fig. 32.2). It usually occurs in acute and benign disease and subsides usually within weeks to months. –– Other cutaneous lesions include lupus pernio, maculopapular eruptions, subcutaneous nodules, and infiltrated plaques. • The nervous system is also affected, accounting for 5–26% of the patients with sarcoidosis.

32  Ocular Sarcoidosis

–– Cranial nerve involvement, frequently showing abnormalities of optic and facial nerves, is the most common finding. –– A wide variety of neurological manifestations arising from the involvement of brain parenchyma, meninges, and spinal cord may also be observed. • Cardiac involvement is not uncommon. –– It may occur at any time point during the course of the disease. –– A variety of manifestations including myocardiopathy, pericarditis, conduction abnormalities, heart failure, and sudden death have been described as cardiac involvement. • Other systemic abnormalities include arthropathy, abnormalities of the bones, hepatic granulomas, and interstitial nephritis.

32.5 Ocular Manifestations • Any part of the eye can be affected. • Ocular involvement is more commonly seen in the female than in the male. • Ocular involvement usually manifests as uveitis [3, 4]. • Anterior uveitis accounts for two-thirds of the patients with ocular sarcoidosis.

Fig. 32.1  Pretracheal, hilar, subcarina, and peripulmonary artery lymph nodes are enlarged in a patient with sarcoidosis (CT findings)

32.6 Diagnosis and Diagnostic Criteria

613

–– Retinal vasculitis is common (Fig. 32.8) and may display periphlebitis with characteristic perivenous creamy white exudation, the so-called candle wax drippings or “taches de bougie” (Figs.  32.9 and 32.10) in association with retinal hemorrhage (Fig. 32.11) [1, 2, 4]. However, this typical periphlebitis is rare in Chinese patients. Most Chinese patients show subclinical vasculitis, manifesting as microvasculitis identified by fundus fluorescein angiography (FFA) (Figs. 32.12 and 32.13). –– Choroidal nodules may appear in some patients. –– Another typical manifestation in the posterior segment is cellular infiltration in the vitreous usually taking the form of snowballs or strings of pearls. –– Exudative retinal detachment and cystoid macular edema (CME), subfoveal, and peripapillary choroidal neovascularization (CNV), epiretinal membrane, and retinal neovascularization may develop in some patients. –– Optic nerve abnormalities may present as papillitis, anterior or retrobulbar optic neuropathy, and optic nerve granuloma. • Other ocular manifestations. –– Conjunctival or subconjunctival granulomas (Fig. 32.14) –– Lacrimal gland enlargement –– Dry eye –– Diplopia –– External ophthalmoplegia –– Scleritis –– Central retinal vein occlusion Fig. 32.2  Erythema nodosum observed in a patient with sarcoidosis (Courtesy of professor James T. Rosenbaum)

32.6 Diagnosis and Diagnostic Criteria

–– It typically shows bilateral and granulomatous inflammation as evidenced by mutton fat keratic precipitates • The diagnosis of ocular sarcoidosis is principally based (KPs) (Fig. 32.3), Koeppe nodules (Fig. 32.4), Busacca on the multisystemic manifestations, relevant auxiliary nodules (Figs.  32.5 and 32.6), and trabecular meshexaminations, and laboratory investigations as listed work nodules. below. –– Few patients may manifest as nongranulomatous ante- • Noncaseating epithelioid cell granulomas identified by rior uveitis. histological examination in couple with clinical manifes–– Posterior synechiae, complicated cataract (Fig. 32.7), tations and radiographic findings may confirm the definite and secondary glaucoma tend to develop in the patients diagnosis of sarcoidosis [3, 4]. with granulomatous anterior uveitis. • Chest radiology is very helpful in the diagnosis of sar–– Band keratopathy is occasionally observed in these coidosis [1, 3, 4]. patients. –– The characteristic finding is bilateral symmetric hilar • Posterior segment involvement is observed in about one-­ lymphadenopathy and mediastinal lymphadenopathy. fourth of the patients with ocular sarcoidosis. –– Other changes identified by chest radiology include –– Posterior segment involvement may take the forms of lung infiltration and pulmonary fibrosis. posterior uveitis, retinal vasculitis, and optic nerve –– High-resolution CT is recommended for these patients abnormalities or constitute one component of the interwith suspected sarcoidosis but without abnormalities mediate uveitis and panuveitis. of chest X-ray.

614

32  Ocular Sarcoidosis

Fig. 32.3  Mutton fat KPs observed in patients with ocular sarcoidosis

Fig. 32.4 Koeppe nodules observed in a patient with ocular sarcoidosis

• A whole body gallium-67 (67Ga) scan has been used to evaluate the inflammation by uptake of the isotope in patients with suspected sarcoidosis.

• An increased number of CD4+ T lymphocytes together with a higher CD4+/CD8+ T cell ratio in bronchoalveolar lavage is highly suggestive of the diagnosis of sarcoidosis. • An increased serum level of the angiotensin-converting enzyme (ACE) is observed in most patients with active sarcoidosis and has been considered as a serum marker for this disease. However, in other diseases such as leprosy, rheumatoid arthritis, primary biliary cirrhosis, chronic pulmonary disease, tuberculosis, histoplasmosis and diabetes mellitus, elevated serum ACE levels may also be present. Therefore, the increased ACE level should be interpreted in the context of clinical manifestations [1, 3, 4]. • An increased serum level of lysozyme is also observed in patients with sarcoidosis. • Pathological confirmation of the presence of noncaseating epithelioid cell granuloma through conjunctival, lacrimal gland, or a skin biopsy is essential to a definite diagnosis of sarcoidosis. • FFA is useful in the dynamic evaluation of the changes in the posterior segment in ocular sarcoidosis patients. The following changes may be noted.

32.6 Diagnosis and Diagnostic Criteria

615

Fig. 32.5  Busacca nodules observed in a patient with ocular sarcoidosis

a

b

c

d

Fig. 32.6  Numerous Busacca nodules (a, b) resolve leaving multifocal iris depigmentation 3 months (c, d) after treatment with systemic corticosteroids in combination with cyclosporine, topical steroids, mydriatic

and cycloplegic agents in the patient with ocular sarcoidosis as described in Fig. 32.5

616

32  Ocular Sarcoidosis

Fig. 32.7  Complicated cataract associated with posterior synechiae observed in a patient with ocular sarcoidosis

Fig. 32.10  The classic “candle wax dripping” (en taches de bougie) (arrow) along the retinal vein observed in a patient with ocular sarcoidosis (Courtesy of professor James T. Rosenbaum)

Fig. 32.8  Retinal vascular sheathing and hemorrhages observed in a patient with ocular sarcoidosis (Courtesy of professor James T. Rosenbaum)

Fig. 32.11  Retinal hemorrhages in a patient with ocular sarcoidosis (Courtesy of professor James T. Rosenbaum)

Fig. 32.9 Periphlebitis with characteristic candle wax drippings around vessels observed in a patient with ocular sarcoidosis

–– Retinal vascular leakages of fluorescence (Figs. 32.15 and 32.16). –– Choroidal granulomas display early blockage and late staining (Fig. 32.17). –– CME. –– Multiple chorioretinal atrophies (Fig. 32.18). –– Retinal vascularization. –– Nonperfusion of capillaries (Fig. 32.19). –– Window defects arising from retinal pigment epithelial damage. • Indocyanine green angiography (ICGA) has been used in detection of choroidal granulomas in the choroid (Fig. 32.20).

32.6 Diagnosis and Diagnostic Criteria

617

Fig. 32.12  A male patient with presumed ocular sarcoidosis does not show obvious fundus changes. However, FFA shows cystoid macular edema and vascular leakages

618

32  Ocular Sarcoidosis

Fig. 32.13  A female patient with presumed ocular sarcoidosis does not have any change in the fundus. However, macular edema, staining of the optic disc and vascular leakages are detected by FFA

32.6 Diagnosis and Diagnostic Criteria

• Ultrasound biomicroscopy (UBM) is employed in the evaluation of the changes in the anterior segment including mutton fat KPs, iris nodules, aqueous cells and exudates in patients with ocular sarcoidosis (Fig. 32.21). • B-scan ultrasonography is very helpful in evaluating the changes in the posterior segment especially in ocular sarcoidosis patients with dense vitreous opacities (Figs. 32.22 and 32.23). • Optical coherence tomography (OCT) imaging is also useful in the evaluation of the changes in the posterior fundus in the ocular sarcoidosis patients (Figs. 32.24 and 32.25). • Diagnostic criteria for ocular sarcoidosis are proposed in the first international workshop on ocular sarcoidosis held in 2006 in Tokyo and published in 2009 (Table 32.1) [9].

619

–– There are seven clinical signs and 5 laboratory tests used for the development of these criteria (Source: Herbort CP, Rao NA, Mochizuki M. International criteria for the diagnosis of ocular sarcoidosis: results of the first International Workshop on Ocular Sarcoidosis (IWOS). Ocul Immunol Inflamm. 2009;17; 160–9) [9]. –– The suggestive clinical signs of the disease Mutton fat KPs (large or small) and/or iris nodules at the pupillary margin (Koeppe) or in the stroma (Busacca) Trabecular meshwork nodules and/or tent-­shaped peripheral anterior synechiae Snowballs/string of pearls vitreous opacities Multiple chorioretinal peripheral lesions (active and atrophic) Nodular and/or segmental periphlebitis (candle wax drippings) and/or microaneurysm in an inflamed eye Optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule Bilaterality (assessed by clinical examination or laboratory tests showing subclinical inflammation) –– The laboratory tests for the suspected patients Negative tuberculin test in a Bacillus Calmette– Guérin-vaccinated patient or having had a positive purified protein-derivative (or Mantoux) skin test previously Elevated serum angiotensin-converting enzyme and/or elevated serum lysozyme

Fig. 32.14  Multiple conjunctival follicles in a patient with ocular sarcoidosis (Courtesy of professor James T. Rosenbaum)

Fig. 32.15  Vascular leakages disclosed by FFA in a patient with ocular sarcoidosis

620

32  Ocular Sarcoidosis

Fig. 32.16  Vascular leakages, CME, and staining of the optic disc disclosed by FFA in a patient with presumed ocular sarcoidosis

Chest X-ray: look for bilateral hilar lymphadenopathy Abnormal liver enzyme tests (Positive when serum levels of alkaline phosphatase are more than three times the upper limit of normal; or when two of the following liver enzymes, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, or γ-glutamyl transpeptidase are more than twice the upper limit of normal) Chest computed tomography scan in patients with negative chest X-ray

32.7 Differential Diagnosis

Fig. 32.17  Late staining of choroidal granulomas detected by FFA in a patient with ocular sarcoidosis (Courtesy of professor James T. Rosenbaum)

• As ocular sarcoidosis may manifest as anterior, intermediate, posterior, and generalized uveitis, and have protean manifestations, other intraocular inflammations should be always kept in mind in the differential diagnosis [1, 3, 10–12].

32.7 Differentiation Fluo 4:00.4 12/21/2005

621 Fluo 4:17.2 12/21/2005

Fluo 11:19.9 12/21/2005

Fig. 32.18  Multifocal chorioretinal atrophies revealed by FFA in a patient with presumed ocular sarcoidosis

Fig. 32.19  Nonperfusion of retinal capillaries disclosed by FFA in a patient with presumed ocular sarcoidosis

Fig. 32.20  Multiple hypofluorescent spots disclosed by ICGA in a patient with ocular sarcoidosis (Courtesy of professor James T. Rosenbaum)

• Anterior uveitis in patients with ocular sarcoidosis should be differentiated from those listed below: –– Vogt–Koyanagi–Harada (VKH) disease (in recurrent granulomatous anterior uveitis stage) –– Sympathetic ophthalmia –– Tuberculosis –– Herpes virus associated with anterior uveitis –– Syphilitic uveitis –– HLA-B27-associated anterior uveitis –– Behcet’s disease (BD) –– Uveitis associated with juvenile idiopathic arthritis (JIA) –– Idiopathic anterior uveitis • Intermediate uveitis in patients with ocular sarcoidosis should be differentiated from the following diseases: –– Idiopathic intermediate uveitis –– Multiple sclerosis –– Lyme disease • Posterior uveitis in ocular sarcoidosis should be differentiated from the following diseases: [1, 3, 11–13]

622

Fig. 32.21  Changes identified by UBM in patients with presumed ocular sarcoidosis

32  Ocular Sarcoidosis

32.7 Differentiation

623

a

b

c

d

Fig. 32.22  Vitreous opacities (a, b) have been greatly improved 2 months after treatment with systemic corticosteroids in combination with cyclosporine (c, d) in a patient with presumed ocular sarcoidosis

–– VKH disease (in posterior uveitis stage and the anterior uveal involvement stage) –– Behcet’s disease –– Tuberculosis –– Syphilitic uveitis –– Intraocular lymphoma –– Serpiginous choroidopathy –– Ocular toxoplasmosis –– Ocular toxocariasis –– Multiple choroiditis

–– Eales disease –– Birdshot chorioretinopathy • Generalized uveitis in ocular sarcoidosis should be differentiated from the following diseases: –– VKH disease (in the recurrent granulomatous anterior uveitis stage) –– Sympathetic ophthalmia –– Behcet’s disease –– Ocular tuberculosis –– Syphilitic uveitis

624

32  Ocular Sarcoidosis

Fig. 32.23  Changes in the posterior segment disclosed by B-scan ultrasonography in patients with presumed ocular sarcoidosis

32.8 Treatment • Corticosteroids are still the mainstay of the treatment for ocular sarcoidosis [1, 3]. –– Systemic corticosteroids with a gradual tapering of dosage are able to control the intraocular inflammation in most patients with ocular sarcoidosis. –– Topical steroids in combination with mydriatic and cycloplegic agents are indicated for the patients with anterior chamber inflammation. • Other immunosuppressive agents such as cyclosporine, methotrexate, cyclophosphamide, chlorambucil, azathio-

prine, and mycophenolate mofetil are used alone or in combination with corticosteroids in the treatment of the patients with refractory uveitis. • Secondary glaucoma can be controlled with medical treatment in most patients. Relevant surgeries are needed in the patients who are unresponsive to medical treatment. • Panretinal photocoagulation has been used for the patients with retinal neovascularization and ischemia. • Phacoemulsification cataract extraction and intraocular lens implantation can be successfully performed in most ocular sarcoidosis patients with inactive intraocular inflammation.

References

Fig. 32.24  Epiretinal membrane arising from the optic disc detected by OCT imaging in a patient with presumed ocular sarcoidosis

625 Table 32.1  Diagnostic criteria for ocular sarcoidosisa All other possible causes of uveitis, in particular tuberculous uveitis, have to be ruled out 1. Biopsy supported diagnosis with a Definite ocularb compatible uveitis sarcoidosis Presumed ocularb 2. Biopsy not done; presence of bilateral hilar lymphadenopathy (BHL) with a compatible sarcoidosis uveitis 3. Biopsy not done and BHL negative; presence Probable ocularb of three of the suggestive intraocular signs sarcoidosis and two positive investigational tests Possible ocularb 4. Biopsy negative, four of the suggestive intraocular signs and two of the sarcoidosis investigations are positive a Reprinted with permission from Herbort CP, Rao NA, Mochizuki, et  al. International criteria for the diagnosis of ocular sarcoidosis: results of the first International Workshop on Ocular Sarcoidosis (IWOS). Ocul Immunol Inflamm 2009;17;160–9 b Used in the sense of intraocular inflammatory lesions both in patients with systemic disease and in patients with disease seemingly limited to the eye without any clinically detectable involvement of another organ

Fig. 32.25  CME identified by OCT imaging in a patient with presumed ocular sarcoidosis

32.9 Prognosis • Most patients have a good visual outcome. • Prolonged and severe inflammation together with CME, subfoveal CNV, persistently increased intraocular pressure may lead to permanent visual impairment or even visual loss.

References 1. Ohno S, Kitaichi N, Kitamura M.  Sarcoidosis. In: Zierhut M, Pavesio C, Ohno S, et al, Intraocular inflammation. Berlin: Springer. 2016; pp 863-872. 2. Nussenblatt R, Whitcup S, Palestine A.  Sarcoidosis. In: Uveitis fundamentals and clinical practice. 2nd ed. St. Louis: Mosby-Year Book, Inc.; 1996. p. 289–98. 3. Capella M, Foster C.  Sarcoidosis. In: Foster CS, Vitale AT, editors. Diagnosis & treatment of uveitis. 2nd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2013. p. 951–72. 4. Pepple KL, Van Gelder RN.  Sarcoidosis. In: Papaliodis GN, editor. Uveitis. Cham: Springer International Publishing AG; 2017. p. 243–54.

5. Yang P, Zhang Z, Zhou H, et al. Clinical patterns and characteristics of uveitis in a tertiary center for uveitis in China. Curr Eye Res. 2005;30(11):943–8. 6. Chan CC, Wetzig RP, Palestine AG, et al. Immunohistopathology of ocular sarcoidosis. Report of a case and discussion of immunopathogenesis. Arch Ophthalmol. 1987;105(10):1398–402. 7. Mitchell DN, Scadding JG, Heard BE, et  al. Sarcoidosis: histopathological definition and clinical diagnosis. J Clin Pathol. 1977;30(5):395–408. 8. Sen HN, Nussenblatt R.  Posterior uveitis and collagen vascular diseases: sarcoidosis-associated uveitis. In: Garg SJ, Bodaghi B, Nussenblatt R, et  al., editors. Uveitis. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 65–71. 9. Herbort CP, Rao NA, Mochizuki M, et al. International criteria for the diagnosis of ocular sarcoidosis: results of the first International Workshop On Ocular Sarcoidosis (IWOS). Ocul Immunol Inflamm. 2009;17(3):160–9. 10. Du L, Kijlstra A, Yang P.  Vogt-Koyanagi-Harada disease: novel insights into pathophysiology, diagnosis and treatment. Prog Retin Eye Res. 2016;52:84–111. 11. Yang P, Liu S, Zhong Z, et  al. Comparison of clinical features and visual outcome between sympathetic ophthalmia and Vogt-­ Koyanagi-­ Harada disease in Chinese patients. Ophthalmology. 2019;126(9):1297–305. 12. Yang P, Fang W, Meng Q, et al. Clinical features of Chinese patients with Behcet’s disease. Ophthalmology. 2008;115(2):312–8. 13. Yang P, Zhang N, Li F, et  al. Ocular manifestations of syphilitic uveitis in Chinese patients. Retina. 2012;32(9):1906–14.

Systemic Lupus Erythematosus

33

Contents 33.1  Definition

 627

33.2  Epidemiology

 627

33.3  Etiology and Pathogenesis

 627

33.4  Systemic Manifestations

 628

33.5  Ocular Manifestations

 628

33.6  Diagnosis

 630

33.7  Differential Diagnosis

 631

33.8  Treatment

 633

33.9  Prognosis

 633

References

 641

33.1 Definition • Systemic lupus erythematosus (SLE) is an autoimmune disease mediated predominantly by immune complexes [1, 2]. • A large number of autoantibodies against the component of the cell nuclei with a wide range of organ involvement is the hallmark of this disease [1, 3]. • Multiple systemic involvements are a feature of this disease. Glomerulonephritis, dermatitis, arthritis, neurologic and hematologic involvement are the common manifestations [1, 3]. • Ocular involvement is also common in SLE patients [1, 3, 4].

33.2 Epidemiology • SLE occurs worldwide. • Females are more frequently affected than males, accounting for 90% of the total cases [1, 3].

• More than 80% of the female patients develop this disease at their childbearing age [1, 3].

33.3 Etiology and Pathogenesis • The exact etiology and pathogenesis are still unknown. • Family aggregation has been found in SLE patients, suggesting the presence of genetic background in the development of this disease. • Infections of microbe, especially viral infections, have been presumably involved in activation of aberrant immunoresponse and development of SLE [1, 3, 4]. • Ultraviolet light is an important trigger for exacerbation of cutaneous and systemic disease. • Antibodies to nucleic acids and nucleic acid-binding proteins are induced in SLE and are of diagnostic value for this disease. • Immune complex formation and complement activation are important mechanisms involved in the pathogenesis of various damages including skin lesion, kidney disorder, heart disease, and cytopenia [1, 3, 4].

© Springer Nature Singapore Pte Ltd. and People’s Medical Publishing House, PR of China 2021 P. Yang, Atlas of Uveitis, https://doi.org/10.1007/978-981-15-3726-4_33

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• Disturbed immune response including B-cell hyperactivity, suppressor T-cell dysfunction, hypergammaglobulinemia has been reported in this disease. • SLE has been shown to be associated with HLA-DR2, HLA-DR3, HLA-B7, and HLA-B8 [3, 5].

33.4 Systemic Manifestations • Fever, fatigue, and weight loss are usually seen in most SLE patients [1, 3]. • Cutaneous lesions [1, 3, 4]. –– They occur in 85% of the SLE patients, typically showing butterfly rash across the nose and cheeks, known as the malar rash. –– Discoid lupus erythematosus, cutaneous ulcers, purpuric lesions, splinter hemorrhages and alopecia are also commonly seen in these patients. –– About 30–40% of the patients develop painless oral lesions. –– Sun exposure is an inducer for the skin lesions. • Arthritis [1, 3, 4]. –– Arthritis is a common manifestation, affecting approximately 85% of the SLE patients. –– Patients may manifest as peripheral arthritis or migratory polyarthritis. • Renal involvement [1, 3]. –– It is common and found in approximately 50% of the SLE patients. –– It may appear as nephrotic syndrome or glomerulonephritis.

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–– Other nephrotic disorders such as focal proliferative nephritis, membranous glomerulonephritis, diffuse proliferative nephritis and mesangial disease may also develop in the SLE patients. • Pericarditis, myocarditis, and Libman–Sacks endocarditis may occur in certain SLE patients [1]. • Neuropsychiatric disturbances, pulmonary lesions, and hematologic abnormalities are also observed in the SLE patients [3].

33.5 Ocular Manifestations • Discoid lupus erythematous may occur in the eyelids. • Secondary Sjogren’s syndrome or keratoconjunctivitis sicca develops in about 20% of the SLE patients. • Scleritis has been reported to be associated with SLE, predominantly manifesting as diffuse anterior inflammation [1, 3]. • Episcleritis can be occasionally observed in SLE patients. • Angle-closure glaucoma may occur as a result of uveal effusion. • Retinal involvement [1, 3, 4]. –– Cotton-wool spots and retinal hemorrhages occur frequently (Fig. 33.1). –– Other retinal abnormalities include retinal vasculitis, branch retinal vein occlusion, central retinal artery occlusion, central retinal vein occlusion, vascular sheathing, occlusion and attenuation of the blood vessels (Fig. 33.2), dilated vessels (Fig. 33.3), proliferative retinopathy, and retinal neovascularization.

Fig. 33.1  Multiple cotton-wool spots in association with retinal hemorrhages observed in a female SLE patient

33.5 Ocular Manifestations

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a

b

c

d

Fig. 33.2  Numerous cotton-wool spots observed in a female SLE patient at her first visit to our hospital (a, b). These changes disappear 7 months after treatment. However, optic nerve atrophy and vascular occlusion developed in this patient (c, d)

–– Optic disc vasculitis and optic nerve atrophy. –– Proliferative retinopathy (Fig. 33.4). • Neuro-ophthalmic involvement [1, 3]. –– Optic neuritis. –– Ischemic optic neuropathy. –– Extraocular muscle abnormality. –– Retrochiasmal tract abnormality.

• Orbital pseudotumor and orbital myositis. • Anterior uveitis. –– It is relatively uncommon. –– Patients may manifest as dust-like keratic precipitates, aqueous flare and cells. –– Posterior synechiae are occasionally observed (Fig. 33.5).

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33.6 Diagnosis • The diagnosis of SLE is predominantly based on characteristic features and laboratory investigations [1, 3]. • Multiple systemic involvements with typical malar rash and discoid rash. • Antibodies to dsDNA and to Smith antigen are specifically useful in the diagnosis of SLE. • Antinuclear antibodies usually act as screening markers for SLE as they also develop in other autoimmune diseases.

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• Careful fundus examinations may provide additional, but very important evidence for SLE diagnosis. • Fundus fluorescein angiography (FFA) may show the following results: –– Nonperfusion of the retinal capillary (Figs.  33.6 and 33.7). –– Retinal neovascularization. –– Retinal microvascular leakages (Fig. 33.8). –– Multiple hypofluorescent spots may be observed corresponding to the cotton-wool spots recognized ophthalmoscopically (Fig. 33.9). • Optical coherence tomography (OCT) imaging may show the following features: –– Cystoid macular edema (CME) (Fig. 33.10) and retinal atrophy (Fig. 33.11). –– Multiple retinal foci (Fig. 33.12). –– Serous retinal detachment (Fig. 33.13). • There are two classification criteria for SLE available in the literature. –– Criteria developed by American College of Rheumatology (Published in 1982, revised in 1997) (Table 33.1) [1, 6, 7]. –– Criteria developed by the Systemic Lupus International Collaborating Clinics (Table 33.2) [1, 8]. • Multifocal electroretinography (mfERG) may show various abnormalities• (Fig. 33.14). • Visual field examination may detect decreased sensitivity (Fig. 33.15).

Fig. 33.3 Vascular dilation associated with multiple hemorrhages observed in a SLE patient

a

b

Fig. 33.4  Multiple cotton-wool spots observed in a female SLE patient at her first visit to our hospital (a). Proliferative retinopathy develops 8 months thereafter (b)

33.7 Differential Diagnosis

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33.7 Differential Diagnosis

Fig. 33.5  Anterior uveitis develops in a female SLE patient. Note the pigmentary circle on the surface of the lens left after application of mydriatic agent

• Behcet’s disease. • Granulomatosis with polyangiitis (Wegner’s granulomatosis). • Polyarteritis nodosa. • Multiple sclerosis. • Uveitis associated with inflammatory bowel disease (IBD). • Takayasu’s disease. • Diabetic retinopathy. • Human immunodeficiency virus (HIV) retinopathy. • Radiation retinopathy. • Syphilitic uveitis. • Cotton-wool sports in hypertension.

Fig. 33.6  Extensive nonperfusion of the retinal capillaries and neovascularization on the optic disc disclosed by FFA in a female SLE patient

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Fig. 33.7  Nonperfusion of the retinal capillaries and neovascularization disclosed by FFA in a female SLE patient

a

b

Fig. 33.8  No visible fundus change is observed in a SLE patient (a, b). However, microvascular leakages are disclosed by FFA in this patient (c, d)

33.9 Prognosis

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FA 0:59.12 55~ [HS] c

FA 3:46.54 55~ [HS]

FA 8:49.42 55~ [HS]

OS, FA 0:52.28 55~ [HS]

OS, FA 3:03.00 55~ [HS]

OS, FA 8:57.62 55~ [HS]

d

Fig. 33.8 (continued)

33.8 Treatment • The treatment is principally based on the involvement of organs and the severity of the disease. • For the patients with photosensitivity, arthritis or serositis, a nonsteroidal anti-inflammatory agent in combination with chloroquine or hydroxychloroquine is usually sufficient to control the disease. If the patients do not respond well to these drugs, systemic corticosteroids and, sometimes, other immunosuppressive agents are needed. As chloroquine and hydroxychloroquine may cause retinal toxicity, it is necessary to monitor these side effects during treatment [1, 3]. • For the patients with multiple organ lesions, high-dose of corticosteroids combined with cyclophosphamide are usually the first choice. Other immunosuppressive agents such as azathioprine and methotrexate are also used in combination with corticosteroids [1, 3].

• For the patients with severely impaired vision and recalcitrant retinopathy, plasmapheresis in combination with immunosuppressive agents may be necessary to restore the patient’s visual acuity [1, 3, 4]. • For the patients with severe vaso-occlusive retinal lesions, laser photocoagulation is indicated to ameliorate these lesions.

33.9 Prognosis • With adequate treatment, the 10-year survival rate is observed in 90% of the SLE patients. • Recurrent and chronic nephritis, cardiovascular disease and central nervous system disorder, onset at younger age and male sex are frequently associated with a poorer prognosis.

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a

b

c

Fig. 33.9  Multiple hypofluorescent spots disclosed by FFA (a, b) in a patient with systemic lupus erythematosus. They correspond to the cottonwool spots observed ophthalmoscopically (c)

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Fig. 33.10  CME detected by OCT imaging in a SLE patient

Fig. 33.11  Retinal atrophy detected by OCT imaging in a SLE patient

Fig. 33.12  Retinal foci detected by OCT imaging corresponding to the cotton-wool spots observed ophthalmoscopically in the SLE patient as described in Fig. 33.9

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Fig. 33.13  Slight serous retinal detachment detected by OCT imaging in the SLE patient as described in Fig. 33.9 Table 33.1  The 1982 revised criteria for classification of systemic lupus erythematosusa Criteria Definition 1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds 2. Discoid rash Erythematosus raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions 3. Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation 4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician 5. Arthritis Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion 6. Serositis (a) Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion  OR (b) Pericarditis—documented by EKG or rub or evidence of pericardial effusion 7. Renal disorder (a) Persistent proteinuria greater than 0.5 grams per day or greater than 3+ if quantitation not performed  OR (b) Cellular casts—may be red cell, hemoglobin, granular, tubular, or mixed 8. Neurologic disorder (a) Seizures—in the absence of offending drugs or known metabolic derangements; e.g. uremia, ketoacidosis, or electrolyte imbalance  OR (b) Psychosis—in the absence of offending drugs or known metabolic derangements; e.g. uremia, ketoacidosis, or electrolyte imbalance 9. Hematologic disorder (a) Hemolytic anemia—with reticulocytosis  OR (b) Leukopenia—less than 4000/mm3 total on 2 or more occasions  OR (c) Lymphopenia—less than 1500/mm3 on 2 or more occasions  OR (d) Thrombocytopenia—less than 100,000/mm3 in the absence of offending drugs 10. Immunologic disorder (a) Positive LE cell preparation  OR (b) Anti-DNA: antibody to native DNA in abnormal titer  OR (c) Anti-Sm: presence of antibody to Sm nuclear antigen  OR (d) False-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test 11. Antinuclear antibody An abnormal titer of antinuclear antibody by immuno-flurescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with “drug-induced lupus” syndrome a Reprinted with permission from Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of Systemic Lupus erythematosus. Arthritis and Rheumatism. 1982; 25:1271–1277 The proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person shall be said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation

33.9 Prognosis Table 33.2  Clinical and immunologic criteria used in the SLICC classification systema Clinical criteria 1. Acute cutaneous lupus, including:    Lupus malar rash (do not count if malar discoid)   Bullous lupus    Toxic epidermal necrolysis variant of SLE    Maculopapular lupus rash    Photosensitive lupus rash   In the absence of dermatomyositis    OR subacute cutaneous lupus (nonindurated psoriasiform and/or annular polycyclic lesions that resolve without scarring, although occasionally with postinflammatory dyspigmentation or telangiectasias) 2. Chronic cutaneous lupus, including:    Classic discoid rash     Localized (above the neck)     Generalized (above and below the neck)    Hypertrophic (verrucous) lupus    Lupus panniculitis (profundus)   Mucosal lupus    Lupus erythematosus tumidus   Chilblains lupus    Discoid lupus/lichen planus overlap 3. Oral ulcers   Palate    Buccal    Tongue    OR nasal ulcers    In the absence of other causes, such as vasculitis, Behcet’s disease, infection (herpesvirus), inflammatory bowel disease, reactive arthritis, and acidic foods 4. Nonscarring alopecia (diffuse thinning or hair fragility with visible broken hairs)   In the absence of other causes such as alopecia areata, drugs, iron deficiency, and androgenic alopecia 5. Synovitis involving 2 or more joints, characterized by swelling or effusion    OR tenderness in 2 or more joints and at least 30 minutes of morning stiffness 6. Serositis    Typical pleurisy for more than 1 day    OR pleural effusions    OR pleural rub    Typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day    OR pericardial effusions    OR pericardial rub     OR pericarditis by electrocardiography    In the absence of other causes, such as infection, uremia, and Dressler’s pericarditis 7. Renal    Urine protein-to-creatinine ratio (or 24-hour urine protein) representing 500 mg protein/24 hour     OR red blood cell casts 8. Neurologic   Seizures   Mononeuritis multiplex    In the absence of other known causes such as primary vasculitis   Myelitis    Peripheral or cranial neuropathy    In the absence of other known causes such as primary vasculitis, infection, and diabetes mellitus    Acute confusional state    In the absence of other causes, including toxic/metabolic, uremia, drugs 9. Hemolytic anemia

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Table 33.2 (continued) Clinical criteria 10. Leukopenia (