The Uveitis Atlas [1st ed. 2020] 978-81-322-2409-9, 978-81-322-2410-5

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Vishali Gupta Quan Dong Nguyen Phuc LeHoang Aniruddha Agarwal Editors

The Uveitis Atlas

The Uveitis Atlas

Vishali Gupta • Quan Dong Nguyen Phuc LeHoang • Aniruddha Agarwal Editors

The Uveitis Atlas With 835 Figures and 35 Tables

Editors Vishali Gupta Advanced Eye Centre Postgraduate Institute of Medical Education and Research (PGIMER) Chandigarh, India

Quan Dong Nguyen Spencer Center for Vision Research Byers Eye Institute at Stanford University Palo Alto, CA, USA

Phuc LeHoang Department of Ophthalmology Pitié-Salpêtrière University Hospital Sorbonne University Paris, France

Aniruddha Agarwal Advanced Eye Centre Postgraduate Institute of Medical Education and Research (PGIMER) Chandigarh, India

ISBN 978-81-322-2409-9 ISBN 978-81-322-2410-5 (eBook) ISBN 978-81-322-2411-2 (print and electronic bundle) https://doi.org/10.1007/978-81-322-2410-5 Library of Congress Control Number: 2019935499 © Springer Nature India Private Limited 2020 This work is subject to copyright. All rights are reserved by the Publisher, 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 publisher, 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 publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature India Private Limited The registered company address is: 7th Floor, Vijaya Building, 17 Barakhamba Road, New Delhi 110 001, India

To my teacher Prof. Amod Gupta, who taught me the basics of uveitis and the art and science of managing uveitis patients. To Mr. Arun Kapil, our Certified Retinal Angiographer (CRA) and Chief Photographer, for his years of dedicated service and perseverance in acquiring the best images. To my residents and students for their untiring efforts in helping me manage our patients. To my family, Rajesh and Sarakshi, for always being there. Vishali Gupta, M.S. To my parents, Dr. and Mrs. Dong So Nguyen; my brothers, Dr. Phong Dong Nguyen, Dr. Chau Dong Nguyen, and Mr. Chuong Dong Nguyen, Esq; and my family for their constant devotion, support, and encouragement in the past, present, and future, and for teaching me much about compassion and humility. To my teachers, colleagues, fellows, residents, students, patients, and Dr. Yasir J. Sepah, and to Professor C. Stephen Foster, who taught me my first lessons in uveitis, for bestowing upon me the confidence to be the best physician to my patients and the most productive clinician scientist in my profession. And . . . to my wife and lifetime companion, Dr. Diana Van Ha Do, and our three loving daughters, Alexandra Anh Thu, Olivia Thu Huong, and Madelyne Mai Anh, for their unconditional love and care, and for their willingness to stand by me throughout the successful as well as the most challenging times. Quan Dong Nguyen, M.D., M.Sc. To my parents, my wife, and two daughters, To my grandparents and family, To my mentors, To my friends, colleagues, and patients, To my enemies who push me forward,

To the readers, particularly to those for whom uveitis is a burden, hoping they will find some help and appeasement with this practical non-comprehensive atlas sharing real-life cases. With gratitude Phuc LeHoang, M.D., Ph.D. To my parents, Dr. K.B. Agarwal and Dr. (Mrs.) Piyush Agarwal, who have been my pillars of support and a constant source of inspiration and love, for teaching me the value of truth and honesty, and above all, for keeping me grounded. To my teachers, Prof. Amod Gupta, Prof. Vishali Gupta, and Prof. Quan Nguyen, who have taught me everything about retina and uveitis, and have been my guiding light at all times. To Prof. Jagat Ram, who provided constant support during different stages of my career. To my wife and soulmate, Dr. Kanika Aggarwal, for her unconditional love and encouragement, and for teaching me compassion and humility. Aniruddha Agarwal, M.S.

Foreword

It is with great pleasure that I write this Foreword to the book The Uveitis Atlas edited by Drs. Vishali Gupta, Quan Dong Nguyen, Phuc LeHoang, and Aniruddha Agarwal, who are currently among the most prolific and recognized authors in the field of ocular inflammations and uveitis. It is a matter of great pride for me personally to write this Foreword since the lead editor, Dr. Gupta, was associated with me for more than 25 years, first as a student and later as a most valued research partner and colleague. The editors of this Atlas are some respected leaders in the field and represent the experience of the three largest continents in the world, namely, America, Europe, and Asia. They also succeeded in recruiting the best available contributing authors in the field to produce a magnificently illustrated treatise on uveitis, one of the most rapidly growing and challenging subspecialities of ophthalmology. While interacting with comprehensive ophthalmologists and uveitis experts during the last several years, I realized that there was an unmet need for a quick and, at the same time, a comprehensive reference book to deal with the myriad ocular inflammatory diseases that present in the clinic. The Uveitis Atlas fills that void admirably well. We, as physicians in our day-to-day clinical practice, tend to relate, remember, and recall individual patients and their images rather than learn from browsing the descriptive terms in the library. The editors, who are also most experienced teachers, realizing the power of crisp images with short case reports, have used this format very effectively in The Uveitis Atlas. What also makes this book unique and a trendsetter is the promise by its editors to keep the Atlas “alive” by regularly updating the chapters and case reports. The Uveitis Atlas is a most valuable addition to the existing literature and should adorn the clinic bookshelves of all those who encounter patients with ocular inflammatory diseases in their practice. This Atlas will go a long way in educating students, residents, fellows, and clinicians in practice. Emeritus Professor and Former Dean Post Graduate Institute of Medical Education and Research (PGIMER) Chandigarh, India

Amod Gupta, M.D.

vii

Foreword

The Uveitis Atlas is a treasure, a fabulous piece of work in the relatively neglected arena of inflammatory eye diseases, with outstanding pictures illustrating all of the entities described and discussed. I attempted to do this a decade ago, with my fellows at the time, “self-publishing” and failing miserably because of the lack of a professional publisher (Foster CS, Bhat P, Yilmaz T, Cervantes, R, Mauro J. Atlas of Ocular Inflammatory Diseases. 2009). Gupta, Nguyen, LeHoang, Agarwal, and associates have now succeeded brilliantly with the superb power of Springer, a world class publisher of medical materials. This Atlas will be a spectacular resource for all residents in ophthalmology training programs and for practicing ophthalmologists around the world. Bravo!! C. Stephen Foster, M.D., FACS, FACR, FARVO Clinical Professor of Ophthalmology Harvard Medical School Boston, MA, USA Founder, Ocular Immunology and Uveitis Foundation Weston, MA, USA

ix

Preface

In the subspecialty of uveitis, there is always something new to learn from every patient. Keen observation skills are the cornerstone of successfully managing a patient with uveitis. It is necessary for every ophthalmologist to be familiar with these skills because of the relative urgency and appropriateness of diagnostic and therapeutic interventions. There are excellent publications and textbooks from masters of uveitis that have served as a resourceful learning base for all of us throughout the years. The idea of this book came from the need for an Atlas that provides a comprehensive, illustrative, and case-based disease description of all the ocular inflammatory conditions. The aim of this Atlas is to stress on the clinical presentation, anterior and posterior segment imaging, systemic features and their appearance, role of radiological tests, and, finally, the descriptions on histology for various uveitic entities. In this Atlas, we have attempted to include all possible etiologies associated with ocular inflammation. Stalwarts of uveitis world over have contributed the best of their cases that typify the disease that serve as a learning resource for all of us. In addition, the book also includes a number of algorithms and role of auxiliary tools such as fluorescein angiography, indocyanine angiography, optical coherence tomography, optical coherence tomography angiography, ultrasonography, and other modern modalities to help reveal the diagnosis and manage the patients appropriately. The most experienced authors from premiere institutions around the globe have generously contributed to this Atlas, which has more than 100 chapters. The presented cases have been handpicked ensuring that a comprehensive evaluation can be demonstrated for the benefits of the readers. One of the highlights of this Atlas is the e-book version, which is available on the Springer website for easy access. We aim to regularly update the e-book as and when newer information becomes available. This Atlas would not have been possible without the tremendous efforts of all the authors who have contributed despite their very busy professional and personal lives. We are thankful to Springer for helping us with our project. We are also indebted to our mentors, Professor Amod Gupta and Professor C. Stephen Foster, who have been the guiding light for this book. Finally, we hope that this Uveitis Atlas will serve as a useful learning tool for uveitis specialists, general ophthalmologists, residents, and fellows alike, now and in the generations to come. We invite all the readers to enjoy the book. Chandigarh, India Palo Alto, USA Paris, France Chandigarh, India September 2019

Vishali Gupta Quan Dong Nguyen Phuc LeHoang Aniruddha Agarwal Editors-in-Chief

xi

Contents

Part I

Normal Anatomy of the Uvea . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

Normal Histology of the Uvea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael Stuntz, Aniruddha Agarwal, Gerald Christensen, and Quan Dong Nguyen

3

Normal Fundus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sameeksha Tadepalli, Aniruddha Agarwal, Mohit Dogra, and Vishali Gupta

7

Normal Fundus Fluorescein Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . Sana Khochtali, Imen Khairallah-Ksiaa, and Salim Ben Yahia

11

Normal Indocyanine Green Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . Atul Arora, Aniruddha Agarwal, and Vishali Gupta

17

Normal OCT and OCT Angiography of Retina and Choroid . . . . . . . . . . . . . Igor Kozak and Aniruddha Agarwal

21

Ocular Ultrasound and its Clinical Applications . . . . . . . . . . . . . . . . . . . . . . Savleen Kaur and Ramandeep Singh

27

Ultrasound Biomicroscopy and its Clinical Applications . . . . . . . . . . . . . . . . Savleen Kaur and Ramandeep Singh

37

Grades of Vitreous Clarity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brian Madow and John H. Kempen

45

Part II

Algorithms and Differential Diagnosis of Uveitis . . . . . . . . . . . . . .

51

Anterior Uveitis: Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aniruddha Agarwal, Kanika Aggarwal, Aman Kumar, and Vishali Gupta

53

Differential Diagnosis of Hypopyon Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . Aniruddha Agarwal, Ilaria Testi, Ankur Singh, and Vishali Gupta

63

Algorithm for Work-Up of Episcleritis and Scleritis . . . . . . . . . . . . . . . . . . . Dinesh Visva Gunasekeran and Rupesh Agrawal

71

Entities That Can Present as IU/Vitritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tripti Chaudhary and Reema Bansal

75

Algorithm for Work-Up of Panuveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Luca Cimino

79

Algorithm for Workup of Retinal Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . Ahmed M. Abu El-Asrar

101

Differential Diagnosis of Choroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alessandro Invernizzi

105

xiii

xiv

Contents

Differential Diagnosis of Infectious Retinitis . . . . . . . . . . . . . . . . . . . . . . . . . André Luiz Land Curi

119

Differential Diagnosis of Noninfectious Retinitis . . . . . . . . . . . . . . . . . . . . . . Sofia Androudi and Anna Dastiridou

123

Part III

Anterior Segment Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . .

127

Fuchs’ Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Koushik Tripathy, Aniruddha Agarwal, and Vishali Gupta

129

HLA B27 Spondyloarthritides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Denis Wakefield

133

Tubulointerstitial Nephritis and Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Muhammad Hassan, Aniruddha Agarwal, Nam V. Nguyen, Yasir J. Sepah, and Quan Dong Nguyen

139

Juvenile Idiopathic Arthritis (JIA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Manfred Zierhut and Sobolewska Bianka

143

Crohn’s Disease-Associated Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Buraa Kubaisi, Laura Kopplin, Aniruddha Agarwal, James T. Rosenbaum, C. Stephen Foster, and Quan Dong Nguyen

147

Nodular Anterior Scleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maite Sainz de la Maza

153

Diffuse Anterior Scleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rupesh Agrawal and Dinesh Visva Gunasekeran

159

Necrotizing Anterior Scleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maite Sainz de la Maza

163

Infectious Scleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Somasheila I. Murthy and Swapnali Sabhapandit

167

Surgically Induced Necrotizing Scleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amit Gupta and Anchal Thakur

173

Rubella Virus Associated Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nikos N. Markomichelakis and Stelios Masselos

179

Herpetic Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aliza Jap, Soon-Phaik Chee, Aniruddha Agarwal, and Vishali Gupta

185

Tubercular Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vishali Gupta and Sarakshi Mahajan

195

Hansen’s Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Radhika T. Manoj and S. R. Rathinam

201

Anterior Segment Manifestations of Lyme Disease . . . . . . . . . . . . . . . . . . . . Muhammad Hassan, Mohammad Ali Sadiq, Aniruddha Agarwal, Bahram Bodaghi, and Quan Dong Nguyen

205

Miscellaneous Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Keegan Harkins, Muhammad Hassan, Aniruddha Agarwal, Ramandeep Singh, Deepta Ghate, Diana V. Do, and Quan Dong Nguyen

207

Contents

xv

The Zebras . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Andrew Baldwin, Aniruddha Agarwal, Jagat Ram, Vishali Gupta, Diana V. Do, and Quan Dong Nguyen

213

Band Shaped Keratopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Elliot S. Crane, May Shum, and David S. Chu

219

Complicated Cataract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aniruddha Agarwal and Jagat Ram

225

Part IV

Infectious Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

229

Bacterial Endophthalmitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sophia L. Zagora, Alex P. Hunyor, and Peter J. McCluskey

231

Fungal Endophthalmitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alessandro Invernizzi

237

Nocardia Endophthalmitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yasir J. Sepah, Mohammad Ali Sadiq, and Quan Dong Nguyen

243

Aspergillus Retinochoroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kalpana Babu, Aditi Parikh, and Vishali Gupta

247

Candida Retinochoroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mohammad Ali Sadiq, Aniruddha Agarwal, Vishali Gupta, Mangat Ram Dogra, Amod Gupta, and Quan Dong Nguyen

251

Blastomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cherie A. Fathy, Gowtham Jonna, and Anita Agarwal

257

Coccidioidomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gowtham Jonna and Anita Agarwal

263

Cryptococcus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Philippe Kestelyn

271

Infectious Panuveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reema Bansal

279

Posterior Segment Manifestations of Tuberculosis . . . . . . . . . . . . . . . . . . . . . Gaurav Gupta, Aniruddha Agarwal, Kanika Aggarwal, and Vishali Gupta

283

Tubercular Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ahmed M. Abu El-Asrar and Marwan Abouammoh

293

Eales’ Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Parthopratim Dutta Majumder and Jyotirmay Biswas

301

Syphilitic Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mohamed Kamel Soliman, Mostafa Hanout, Salman Sarwar, David T. Wong, Diana V. Do, and Quan Dong Nguyen

305

Cat Scratch Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . André Luiz Land Curi

309

Presumed Ocular Histoplasmosis Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . Piergiorgio Neri, Ilir Arapi, Vittorio Pirani, Michele Nicolai, Andrea Saitta, Cesare Mariotti, and Alfonso Giovannini

313

xvi

Contents

Toxocariasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reema Bansal, Vishali Gupta, and Amod Gupta

317

Toxoplasma Retinochoroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aniruddha Agarwal, Kanika Aggarwal, Pooja Bansal, Alessandro Invernizzi, Reema Bansal, and Vishali Gupta

321

Posterior Segment Manifestations of Cysticercosis . . . . . . . . . . . . . . . . . . . . . Muna Bhende and Pramod S. Bhende

329

Posterior Segment Manifestations of Leptospirosis . . . . . . . . . . . . . . . . . . . . Sudheer Bhagya and S. R. Rathinam

335

Rickettsial Infections of Retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nesrine Abroug, Rim Kahloun, Bechir Jelliti, and Moncef Khairallah

339

River Water Granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rajesh Vedhanayaki and S. R. Rathinam

345

Herpes Viral Retinochoroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anne-Laure Rémond, Phuc LeHoang, and Bahram Bodaghi

347

Epstein Barr Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aniruddha Agarwal, Madhuri Akella, Maria Cristina Savastano, Marco Rispoli, Bruno Lumbroso, and Vishali Gupta

359

Chikungunya and the Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Padmamalini Mahendradas

363

Dengue Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aliza Jap, Ranjana Mathur, and Soon-Phaik Chee

369

West Nile Virus Chorioretinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rubbia Afridi, Mohamed Kamel Soliman, Aniruddha Agarwal, Diana V. Do, and Quan Dong Nguyen

387

Rift Valley Fever Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aniruddha Agarwal, Aman Kumar, Moncef Khairallah, and Emad Abboud

393

Subacute Sclerosing Panencephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mohit Dogra and Vishali Gupta

397

HIV Manifestations of Posterior Segment . . . . . . . . . . . . . . . . . . . . . . . . . . . J. Fernando Arevalo, Marwan Abouammoh, and André Luiz Land Curi

401

HIV Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Igor Kozak and Aniruddha Agarwal

409

DUSN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shriji Patel and Anita Agarwal

413

Part V

Noninfectious Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

421

Acute Posterior Multifocal Placoid Pigment Epitheliopathy . . . . . . . . . . . . . . Piergiorgio Neri, Ilir Arapi, Vittorio Pirani, Michele Nicolai, Andrea Saitta, Cesare Mariotti, and Alfonso Giovannini

423

Multiple Evanescent White Dot Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . Alessandro Invernizzi

429

Contents

xvii

Birdshot Chorioretinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arash Maleki, Muhammad Sohail Halim, and Quan Dong Nguyen

441

Multifocal Choroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Muhammad Hassan, Nam V. Nguyen, Yasir J. Sepah, and Quan Dong Nguyen

445

Punctate Inner Choroidopathy (PIC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arash Maleki, Muhammad Sohail Halim, and Quan Dong Nguyen

451

Helioid Choroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shriji Patel and Anita Agarwal

455

Serpiginous Choroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aniruddha Agarwal, Quan Dong Nguyen, and Vishali Gupta

459

Relentless Placoid Choroidopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Francesco Pichi and Careen Y. Lowder

465

Ophthalmic Manifestations Associated with Multiple Sclerosis . . . . . . . . . . . William R. Rhoades, Aniruddha Agarwal, Mohamed Kamel Soliman, Sachin Kedar, Rana K. Zabad, Neil Jouvenat, and Quan Dong Nguyen

471

Pars Planitis (Idiopathic Intermediate Uveitis of the Pars Planitis Type) . . . . Aniruddha Agarwal, Kanika Aggarwal, and Vishali Gupta

475

Posterior Scleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aniruddha Agarwal, Kanika Aggarwal, Muhammad Amir, Ramanuj Samanta, Rupesh Agrawal, and Vishali Gupta

479

Sarcoid Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . John Gonzales

483

Sarcoid Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hiroshi Takase

491

Acute Retinal Pigment Epithelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alessandro Invernizzi

497

Autoimmune Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Karen R. Armbrust, Maggie M. Wei, Brett G. Jeffrey, and H. Nida Sen

501

Behçet’s Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ilknur Tugal-Tutkun

509

Retinal Vasculitis and Perivasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ahmed M. Abu El-Asrar and Marwan Abouammoh

519

Systemic Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aman Sharma, Shankar Naidu, Manish Rathi, and Ritambhra Nada

537

Frosted Branch Angiitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kanika Aggarwal, Aniruddha Agarwal, and Vishali Gupta

543

Idiopathic Retinal Vasculitis, Aneurysms, and Neuroretinitis (IRVAN) . . . . . Mangat Ram Dogra and Deeksha Katoch

547

Blau Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aniruddha Agarwal, Carlos D. Rosé, Carine H. Wouters, Catherine Guly, and Quan Dong Nguyen

555

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Contents

Churg-Strauss Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aman Sharma, Shankar Naidu, Manish Rathi, and Ritambhra Nada

559

Juvenile Xanthogranuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angela Bessette, Francesco Pichi, and Arun Singh

563

Vogt Koyanagi Harada Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Koushik Tripathy, Aniruddha Agarwal, Rohan Bir Singh, Kanika Aggarwal, and Vishali Gupta

569

Sympathetic Ophthalmia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kanika Aggarwal, Aniruddha Agarwal, Ramanuj Samanta, Mohit Dogra, Pallavi Singh, and Vishali Gupta

581

Inflammatory Choroidal Neovascular Membranes . . . . . . . . . . . . . . . . . . . . Reema Bansal, Vishali Gupta, and Amod Gupta

585

Cystoid Macular Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reema Bansal, Vishali Gupta, and Amod Gupta

595

Part VI

Masquerades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

603

Cancer-Associated Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maggie M. Wei, Karen R. Armbrust, Brett G. Jeffrey, and H. Nida Sen

605

Melanoma-Associated Retinopathy (MAR) . . . . . . . . . . . . . . . . . . . . . . . . . . Jose S. Pulido

619

Vitreoretinal Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mary E. Aronow, Ian Yeung, and Chi-Chao Chan

623

Uveal Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mary E. Aronow and Chi-Chao Chan

631

Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jangwon Heo, Jeeyun Ahn, Young Hee Yoon, Joo Yong Lee, Won Ki Lee, and Aniruddha Agarwal

637

Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Harvey S. Uy and Jorge Lo Yao

645

Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) . . . . . . . . . . . . . Rohan Bir Singh, Aniruddha Agarwal, Rupesh Agrawal, Mandeep Sagoo, Kanika Aggarwal, and Vishali Gupta

651

Retinoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Raksha Rao and Santosh G. Honavar

655

Choroidal Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sarakshi Mahajan and Vishali Gupta

665

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

669

About the Editors

Dr. Vishali Gupta is a Professor of Ophthalmology in the Retina and Uveitis Services of Advanced Eye Center, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. She runs a busy uveitis clinic, where nearly 300 uveitis patients are examined per week. Her research interests include addressing the diagnostic challenges involving intraocular tuberculosis, application of molecular biology techniques to diagnose intraocular tuberculosis, describing the phenotypic expression of the disease and the management strategies. Dr. Gupta has over 194 indexed publications and authored more than 76 chapters and 3 books. She is a much sought-after international speaker and delivered several keynote lectures. Dr. Gupta is currently the Vice President of the Uveitis Society of India and the Principal Investigator of the Collaborative Ocular Tuberculosis Study Group (COTS) with over 25 international centers participating in the study.

Dr. Quan Dong Nguyen, M.D., M.Sc., FAAO Born in Saigon, Vietnam, and immigrated to the United States in 1980, Dr. Quan Dong Nguyen is a Professor of Ophthalmology at the Byers Eye Institute, Stanford University School of Medicine. Dr. Nguyen received his baccalaureate from the Phillips Exeter Academy and his bachelor and master of science degrees simultaneously in Molecular Biophysics and Biochemistry from Yale University. Subsequently, he earned his medical degree at the University of Pennsylvania. xix

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He completed an internship in Internal Medicine at the Massachusetts General Hospital and a residency in Ophthalmology at the Massachusetts Eye and Ear Infirmary, Harvard Medical School. Dr. Nguyen also completed fellowships in Immunology and Uveitis at the Massachusetts Eye and Ear Infirmary, Ocular Immunology at the Wilmer Eye Institute, and medical and surgical retina at the Schepens Eye Research Institute and the Massachusetts Eye and Ear Infirmary. After completing his education in 2001, Dr. Nguyen joined the faculty at the Wilmer Eye Institute, Johns Hopkins University, as Assistant Professor and then Associate Professor of Ophthalmology. In 2013, he was appointed as the McGaw Endowed Chair in Ophthalmology, Professor and Chair of the Department of Ophthalmology and the Inaugural Director of the Stanley M. Truhlsen Eye Institute, and Assistant Dean for Translational Research at the University of Nebraska Medical Center. In 2017, Dr. Nguyen was invited to join the faculty at Stanford University. Professor Nguyen is known for his innovative work in early proof-of-concept, first-inhuman clinical trials to evaluate potential pharmacotherapeutic agents for retinal vascular and uveitic diseases.

Dr. Phuc LeHoang, M.D., Ph.D. is Professor of Ophthalmology at La Pitie-Salpetriere Hospital, Sorbonne University (Paris, France). His ophthalmology residency in Paris was completed by a Master of Science in Biochemistry and an education at the Pasteur Institute leading to a Ph.D. in Immunology in 1979. He received his Doctor of Medicine in 1981. He was appointed as Professor of Ophthalmology in 1985 and thereafter spent a sabbatical as Visiting Scientist at the National Eye Institute (Bethesda, USA). Dr. LeHoang has co-authored over 300 articles in peer-reviewed literature as well as numerous book chapters and co-edited a textbook on uveitis with Prof. Bahram Bodaghi. As an investigator on numerous projects dealing with research, medical, and surgical management of ocular inflammation, he has established an effective school in that field in France. He has participated in the organization of several international meetings, served as President of the International Ocular Inflammation Society from 2003 to 2011. Besides, he is serving as colonel (reserve) in the French army and received the Medal of Voluntary Military Services and the Medal of the National Defence. A Member of the French National Academy of Surgery, Dr. LeHoang has been awarded knighthood in the Order of the Academic Palms (Chevalier dans l’Ordre des Palmes Academiques) and in the highest Order of the French Republic (Chevalier dans l’Ordre de la Legion d’Honneur).

About the Editors

About the Editors

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Dr. Aniruddha Agarwal is currently working as an Assistant Professor in the Retina and Uveitis services in the Department of Ophthalmology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. He completed his Clinical Research Fellowship (subspecialty of vitreoretina and uveitis) in the Ocular Imaging Research and Reading Center, Stanley M. Truhlsen Eye Institute, Omaha, Nebraska, USA, between 2014 and 2016. He did his ophthalmology residency at PGIMER, Chandigarh, India. He is a recipient of prestigious awards, such as the Bayer Global Ophthalmology Association Project (GOAP) Fellowship, Carl Camras Best Researcher Award, J.M Pahwa Award by Vitreoretina Society of India (VRSI), Narsing Rao Award by Uveitis Society of India (USI), and the Carl Herbort Award by the USI. In 2015, he was felicitated by the Hon. Prime Minister of India for his excellent contribution. He has authored more than 150 publications and 36 book chapters. His areas of interest include uveitis as well as medical and surgical diseases of the retina. He is an expert in ocular imaging, and has been part of numerous international presentations and collaborations in that field.

Contributors

Emad Abboud Posterior Segment Department, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates Marwan Abouammoh Department of Ophthalmology, College of Medicine, King Saud University, King Abdulaziz University Hospital, Riyadh, Saudi Arabia Nesrine Abroug Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia Ahmed M. Abu El-Asrar College of Medicine, Department of Ophthalmology, King Abdulaziz University Hospital, King Saud University, Riyadh, Saudi Arabia Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Riyadh, Saudi Arabia Rubbia Afridi Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA Aniruddha Agarwal Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Anita Agarwal Vanderbilt Eye Institute, Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA West Coast Retina Medical Group, San Francisco, CA, USA Kanika Aggarwal Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Rupesh Agrawal National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore Department of Medical Retina, Moorfields Eye Hospital NHS Foundation Trust, London, UK Jeeyun Ahn Department of Ophthalmology, Seoul National University, College of Medicine, Seoul, South Korea Department of Ophthalmology, SMG-SNU Boramae Medical Center, Seoul, South Korea Madhuri Akella Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Muhammad Amir National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore Anchal Thakur Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Sofia Androudi Department of Ophthalmology, School of Medicine, University Hospital of Larissa, Larissa, Greece Ilir Arapi University Hospital Mother Teresa, Tirana, Albania xxiii

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J. Fernando Arevalo Retina Division, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Karen R. Armbrust Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA Mary E. Aronow Ophthalmic Oncology/Retina Division, Wilmer Eye Institute, Johns Hopkins, Baltimore, MD, USA Atul Arora Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Kalpana Babu Prabha Eye Clinic and Research Centre, Vittala International Institute of Ophthalmology, Bangalore, India Andrew Baldwin Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA Pooja Bansal Dr. Rajendra Prasad Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India Reema Bansal Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Salim Ben Yahia Department of Ophthalmology, Fattouma Bourguiba University Hospital. Faculty of Medicine, University of Monastir, Monastir, Tunisia Angela Bessette Cleveland Clinic Foundation, Cleveland, OH, USA Sudheer Bhagya Uvea Services, Aravind Eye Hospital, Madurai, Tamil Nadu, India Muna Bhende Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, India Pramod S. Bhende Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, India Sobolewska Bianka Centre for Ophthalmology, University Eye Hospital, Eberhard-Karls University, Tuebingen, Germany Jyotirmay Biswas Uveitis and Ocular Pathology Department, Sankara Nethralaya, Chennai, India Bahram Bodaghi Department of Ophthalmology, DHU Vision and Handicaps, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France Chi-Chao Chan Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA Tripti Chaudhary Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Soon-Phaik Chee Singapore National Eye Centre, Singapore, Singapore Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Duke-NUS Graduate Medical School, Singapore, Singapore Singapore Eye Research Institute, Singapore, Singapore Gerald Christensen Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA

Contributors

Contributors

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David S. Chu Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Doctors Office Center, Newark, NJ, USA Metropolitan Eye Research and Surgery Institute, Palisades Park, NJ, USA Luca Cimino Ocular Immunology Unit, Arcispedale S.M. Nuova IRCCS, Reggio Emilia, Italy Elliot S. Crane Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Doctors Office Center, Newark, NJ, USA André Luiz Land Curi National Institute of Infectious Diseases – INI, Oswaldo Cruz Foundation – FIOCRUZ, Rio de Janeiro, Brazil Anna Dastiridou Department of Ophthalmology, School of Medicine, University Hospital of Larissa, Larissa, Greece Diana V. Do Byers Eye Institute, Stanford University, Palo Alto, CA, USA Mohit Dogra Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Mangat Ram Dogra Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Parthopratim Dutta Majumder Department of Uveitis and Intraocular Inflammation, Sankara Nethralaya, Chennai, India Cherie A. Fathy Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Vanderbilt Eye Institute, Nashville, TN, USA C. Stephen Foster Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA Harvard Medical School, Boston, MA, USA Ocular Immunology and Uveitis Foundation, Weston, MA, USA Deepta Ghate Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA Alfonso Giovannini The Eye Clinic, Università Politecnica delle Marche, Ancona, Italy John Gonzales F.I. Proctor Foundation, University of California San Francisco, San Francisco, CA, USA Catherine Guly University Hospitals Bristol NHS Trust, Bristol, UK Dinesh Visva Gunasekeran Clinical Research, Ophthalmology, Tan Tock Seng Hospital (TTSH), Singapore, Singapore Amit Gupta Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Amod Gupta Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Gaurav Gupta Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Vishali Gupta Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Muhammad Sohail Halim Byers Eye Institute, Stanford University, Palo Alto, CA, USA

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Mostafa Hanout Department of Ophthalmology and Visual Sciences, University of Toronto, St. Michael’s Hospital, Toronto, ON, Canada Keegan Harkins Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA Muhammad Hassan Byers Eye Institute, Stanford University, Palo Alto, CA, USA Jangwon Heo Department of Ophthalmology, Seoul National University Hospital, and Seoul National University College of Medicine, Seoul, South Korea Santosh G. Honavar Ocular Oncology Service, National Retinoblastoma Foundation, Centre for Sight, Hyderabad, India Alex P. Hunyor Save Sight Institute, Sydney Eye Hospital, Sydney, NSW, Australia Alessandro Invernizzi Uveitis and Ocular Infectious Diseases Service - Eye Clinic, Department of Biomedical and Clinical Science, Luigi Sacco Hospital, University of Milan, Milan, Italy Aliza Jap Singapore National Eye Centre, Singapore, Singapore Division of Ophthalmology, Changi General Hospital, Singapore, Singapore Brett G. Jeffrey Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA Retina Consultants of Austin, Austin, TX, USA Bechir Jelliti Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia Gowtham Jonna Vanderbilt Eye Institute, Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA Retina Consultants of Austin, Austin, TX, USA Neil Jouvenat Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA Rim Kahloun Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia Deeksha Katoch Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Savleen Kaur Department of Ophthalmology, Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Sachin Kedar Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA John H. Kempen Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Philippe Kestelyn Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium Moncef Khairallah Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia

Contributors

Contributors

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Imen Khairallah-Ksiaa Department of Ophthalmology, Fattouma Bourguiba University Hospital. Faculty of Medicine, University of Monastir, Monastir, Tunisia Sana Khochtali Department of Ophthalmology, Fattouma Bourguiba University Hospital. Faculty of Medicine, University of Monastir, Monastir, Tunisia Laura Kopplin Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA Igor Kozak Moorfields Eye Hospital, Abu Dhabi, United Arab Emirates Buraa Kubaisi Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA Aman Kumar Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Phuc LeHoang Department of Ophthalmology, Pitié-Salpêtrière University Hospital, Sorbonne University, Paris, France Joo Yong Lee Department of Ophthalmology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, South Korea Won Ki Lee Department of Ophthalmology and Visual Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea Careen Y. Lowder Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA Bruno Lumbroso Centro Italiano Macula, Rome, Italy Brian Madow University of South Florida, Tampa, FL, USA Sarakshi Mahajan Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Padmamalini Mahendradas Uveitis and Ocular Immunology, Narayana Nethralaya Eye Hospital, Bangalore, Karnataka, India Arash Maleki Byers Eye Institute, Stanford University, Palo Alto, CA, USA Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran Radhika T. Manoj Uveitis Service, Aravind Eye Hospital and PG Institute of Ophthalmology, Madurai, Tamil Nadu, India Cesare Mariotti The Eye Clinic, Università Politecnica delle Marche, Ancona, Italy Nikos N. Markomichelakis Ocular Inflammation Institute of Athens, General Hospital of Athens, Athens, Greece Stelios Masselos Ocular Inflammation Institute of Athens, General Hospital of Athens, Athens, Greece Ranjana Mathur Singapore National Eye Centre, Singapore, Singapore Duke-NUS Graduate Medical School, Singapore, Singapore Singapore Eye Research Institute, Singapore, Singapore Peter J. McCluskey Save Sight Institute, Sydney Eye Hospital, Sydney, NSW, Australia

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Somasheila I. Murthy Tej Kohli Cornea Institute, L V Prasad Eye Institute, Hyderabad, Telangana, India Ritambhra Nada Department Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Shankar Naidu Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Piergiorgio Neri The Ocular Immunology Service, Università Politecnica delle Marche, Ancona, Italy The Eye Clinic, Università Politecnica delle Marche, Ancona, Italy Nam V. Nguyen Byers Eye Institute, Stanford University, Palo Alto, CA, USA Quan Dong Nguyen Spencer Center for Vision Research, Byers Eye Institute at Stanford University, Palo Alto, CA, USA Michele Nicolai The Ocular Immunology Service, Università Politecnica delle Marche, Ancona, Italy The Eye Clinic, Università Politecnica delle Marche, Ancona, Italy Aditi Parikh Prabha Eye Clinic and Research Centre, Vittala International Institute of Ophthalmology, Bangalore, India Shriji Patel Department of Ophthalmology, Vanderbilt University Medical Center, Nashville, TN, USA Francesco Pichi Cleveland Clinic Foundation, Cleveland, OH, USA Vittorio Pirani The Ocular Immunology Service, Università Politecnica delle Marche, Ancona, Italy The Eye Clinic, Università Politecnica delle Marche, Ancona, Italy Jose S. Pulido Departments of Ophthalmology and Molecular Medicine, Mayo Clinic, Rochester, MN, USA Jagat Ram Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Raksha Rao Ocular Oncology Service, National Retinoblastoma Foundation, Centre for Sight, Hyderabad, India Manish Rathi Department of Nephrology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India S. R. Rathinam Department of Ophthalmology, Aravind Eye Hospital and PG Institute Ophthalmology, Madurai, Tamil Nadu, India Anne-Laure Rémond Department of Ophthalmology, DHU Vision and Handicaps, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France William R. Rhoades Associated Retinal Consultants, Grand Rapids, MI, USA Marco Rispoli Centro Italiano Macula, Rome, Italy Carlos D. Rosé Department of Pediatric Rheumatology, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA James T. Rosenbaum Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA

Contributors

Contributors

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Swapnali Sabhapandit Tej Kohli Cornea Institute, L V Prasad Eye Institute, Hyderabad, Telangana, India Mohammad Ali Sadiq Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, KY, USA Mandeep Sagoo Department of Medical Retina, Moorfields Eye Hospital NHS Foundation Trust, London, UK UCL Institute of Ophthalmology, London, UK Maite Sainz de la Maza Clinical Institute of Ophthalmology, Hospital Clinic of Barcelona, Central University of Barcelona, Barcelona, Spain Andrea Saitta The Ocular Immunology Service, Università Politecnica delle Marche, Ancona, Italy The Eye Clinic, Università Politecnica delle Marche, Ancona, Italy Ramanuj Samanta Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Salman Sarwar Department of Ophthalmology, University of Missouri, Columbia, MO, USA Maria Cristina Savastano Centro Italiano Macula, Rome, Italy H. Nida Sen Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA Yasir J. Sepah Byers Eye Institute, Stanford University, Palo Alto, CA, USA Aman Sharma Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India May Shum Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Doctors Office Center, Newark, NJ, USA Ankur Singh Advanced Eye Centre, Postgraduate Institute of Medicine and Research (PGIMER), Chandigarh, India Arun Singh Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA Pallavi Singh Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Ramandeep Singh Department of Ophthalmology, Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India Rohan Bir Singh Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA Mohamed Kamel Soliman Department of Ophthalmology, Assiut University Hospital, Assiut, Egypt Michael Stuntz Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA Sameeksha Tadepalli Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

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Hiroshi Takase Department of Ophthalmology and Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan Ilaria Testi Department of Ophthalmology, University of Padova, Padova, Italy Koushik Tripathy Department of Vitreoretina and Uvea, ICARE Eye Hospital and Postgraduate Institute, Noida, Uttar Pradesh, India Ilknur Tugal-Tutkun Department of Ophthalmology, Istanbul faculty of Medicine, Istanbul University, Istanbul, Turkey Harvey S. Uy Ophthalmology and Visual Sciences, University of the Philippines; and, Peregrine Eye and Laser Institute, Makati, Philippines Rajesh Vedhanayaki Uveitis Services, Aravind Eye Hospital & PG. Institute of Ophthalmology, Madurai, Tamil Nadu, India Denis Wakefield School of Medical Sciences and Laboratory of Ocular Immunology, University of New South Wales, Sydney, Australia UNSW, Sydney, Australia Maggie M. Wei Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA David T. Wong Department of Ophthalmology and Visual Sciences, University of Toronto, St. Michael’s Hospital, Toronto, ON, Canada Carine H. Wouters Department of Pediatric Rheumatology, Catholic University of Leuven (KU Leuven), Leuven, Belgium Jorge Lo Yao Emerge Laboratories, Ramsey, NJ, USA Ian Yeung Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA Young Hee Yoon Department of Ophthalmology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, South Korea Rana K. Zabad Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA Sophia L. Zagora Save Sight Institute, Sydney Eye Hospital, Sydney, NSW, Australia Manfred Zierhut Centre for Ophthalmology, University Eye Hospital, Eberhard-Karls University, Tuebingen, Germany

Contributors

Part I Normal Anatomy of the Uvea

Normal Histology of the Uvea Michael Stuntz, Aniruddha Agarwal, Gerald Christensen, and Quan Dong Nguyen

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Iris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Ciliary Body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Choroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Introduction

Iris

The embryological derivation of the uvea is traced to the mesoderm and neural crest tissue. The uvea is contained within the scleral shell and attaches firmly at the scleral spur anteriorly, vortex vein exit points and the optic nerve posteriorly. The posterior uveal tract (choroid) is bound internally by the retina. The uvea functions to supply nutrients to various ocular structures. In addition, muscular elements in the iris and the ciliary body control functions such as accommodation of the crystalline lens and outflow of aqueous humor (Figs. 1 and 2).

The iris divides the anterior segment of the eye into anterior and posterior chambers. It arises from the ciliary body (iris root continuous with the pectinate ligaments of the trabecular meshwork) and forms an anterior diaphragm of the eye. The iris has a central defect, known as the pupil, which functions to regulate the amount of light entering the eye. The pigmented iris epithelium that borders the pupil is known as pupillary ruff. Vascular elements in the iris provide nutrient support to the anterior segment. Increased vascular permeability in uveitis leads to leakage of proteins and cells, resulting in cells and flare which are visible on slit-lamp biomicroscopy (Fig. 3). The gross anatomy of the iris demonstrates two distinct zones – peripheral and pupillary zone – separated by a collarette. The anterior surface of the iris is thrown into numerous folds due to presence of crypts and ridges. On the other hand, the posterior surface appears smooth and uniform. The color of the iris is dependent on the number of melanocytes contained in the superficial layers (Fig. 4). Microscopically, the iris consists of the following layers:

M. Stuntz · G. Christensen Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA A. Agarwal Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected] Q. D. Nguyen (*) Spencer Center for Vision Research, Byers Eye Institute at Stanford University, Palo Alto, CA, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_125

1. Anterior border layer 2. Middle Stroma 3. Posterior Epithelium

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Fig. 1 Histological section of a whole globe (human eye) showing cross-sectional view of various structures

The anterior border layer of the iris consists of loosely arranged connective tissue with numerous interspersed fibroblasts and melanocytes. Collagen fibers are also found in the anterior layers. It is believed that the anterior endothelium, which forms the anterior limit of the iris, is lost during embryogenesis (Fig. 5). The middle stroma consists of the bulk of the tissue and contains loosely arranged connective tissue cells in extracellular matrix. The iris sphincter is a circular muscle surrounding the pupil and innervated by the ciliary nerves (parasympathetic supply). The posterior stroma contains the dilator pupillae muscle which consists of radially arranged fibers innervated by the sympathetic system. The posterior epithelium of the iris consists of two layers of very densely pigmented cells with spur-like projections. These cells consist of rounded nuclei which cannot be normally seen due to heavy pigmentation.

Ciliary Body The ciliary body extends from the iris root and continues posteriorly beyond the ora serrata as the choroid. The ciliary body is divided into two parts: 1. Anterior portion with numerous folds, called pars plicata 2. Smooth posterior portion, called pars plana

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Fig. 2 Hematoxylin and eosin (H&E) staining of the whole globe showing the crystalline lens (L ), detached retina (black arrowheads), subretinal space SRS, and cross-section of the optic nerve (ON)

The pars plicata contains approximately 70–80 radially placed finger-like projections known as ciliary processes. Between ciliary processes are valleys of Kuhnt in which suspensory ligaments of the lens insert (Fig. 6). The innermost layer of the ciliary body is the nonpigmented epithelium, which represents anterior continuation of the photoreceptor layer of the retina. The nonpigmented epithelium continues anteriorly as the posterior pigmented epithelium of the iris. As the cells continue from the iris to the ciliary body the cells become smaller and contain fewer granules of melanin. The outer pigmented epithelium of the ciliary body contains many large melanin granules and is continuous with the retinal pigmented epithelium. The bulk of the ciliary body consists of the ciliary muscle, which is contained in the stroma. The ciliary stroma is continuous with iris stroma anteriorly and choroidal stroma posteriorly. It contains a continuation of the long posterior ciliary arteries and anterior ciliary arteries which anastomose to form the major arterial circle of the iris. The fibers of the ciliary muscle have three components, longitudinal, radial, and circular. They are innervated by both sympathetic and parasympathetic systems, and these nerve fibers can occasionally be seen coursing through the ciliary stroma. Supraciliary lamina is adjacent to the sclera and is the outermost layer of the ciliary body. It is composed of collagen fibers, melanocytes, and fibroblasts. Many of the collagen fibers of the supraciliary lamina are continuous with collagen fibers of the sclera.

Normal Histology of the Uvea

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Fig. 3 Microanatomy of the anterior segment of the human eye. The crystalline lens is denoted by (L ). The iris divides the anterior segment into anterior chamber (AC) and posterior chamber (PC). The angle of the AC is marked by a curved arrow. The black arrowhead indicates the position of the canal of Schlemm. The trabecular meshwork is marked with TM. The ciliary body is marked with an asterisk

Fig. 4 Magnified view of the iris. The anterior border layer (ABL) is the anterior-most limiting layer of the iris. The pigmented posterior epithelium (PE) continues as the pupillary ruff (arrow) at the pupillary border. The stroma of the iris (S) is the bulk of the tissue containing dilator

pupillae muscle (black arrowheads) and the sphincter pupillae (asterisk). The anterior surface of the iris has numerous folds, termed as crypts (C)

Fig. 5 High power magnification of the iris shows the details of the anterior border layer (ABL), pigmented epithelium (PE), and the intervening stroma (S). The stroma consists of loosely arranged matrix with numerous blood vessels (asterisks)

Choroid The choroid is a spongy, thin, highly vascular structure lining the inner surface of the sclera from ora serrata to the optic nerve. Its smooth inner surface is attached to Bruch’s

membrane, which goes on to attach to the retinal pigmented epithelium (Fig. 7). The layers of the choroid from external to internal include the suprachoroidal lamina (lamina fusca), stroma, and the choriocapillaris. The suprachoroidal lamina consists of fibroblasts, melanocytes, and collagen fibers. It overlies the

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Fig. 6 (a) Cross-sectional view of the ciliary body shows the pars plicata (PL) with numerous ciliary processes (asterisk) covered with pigmented epithelium (arrow) and suspensory ligaments (SL). High power view of the ciliary processes (b) and the scleral matrix (M ) is shown in (c)

Fig. 7 Histological section of the choroid and the sclera (S) shows a highly vascular tissue with large blood vessels (BV). The suprachoroidal space (SCS) separates the sclera from the choroidal tissue, which is bound by the suprachoroidal lamina (arrowheads). The region of

choriocapillaris is marked by arrows. The innermost boundary of the choroid is formed by the retinal pigment epithelium – Bruch’s membrane complex (RPE)

suprachoroidal space in which the long posterior ciliary nerves and arteries are contained. Internal to the suprachoroidal lamina is the choroidal stroma. This contains loose connective tissue with multiple layers of vessels. The innermost layer is the choriocapillaris lying next to Bruch’s membrane.

• Breakdown of tight endothelial junctions and increased vascular permeability leads to manifestations of ocular inflammation in various uveitic entities.

Key Points • The uveal tissue is a highly vascular tunic of the eye that supplies nutrients to various ocular structures. • The uveal tissue functions to control entry of light, regulates aqueous outflow, and assists in accommodation of the crystalline lens.

Fine BS, Yanoff M. Ocular histology: a text and atlas. 2nd ed. New York: Joanna Cotler Books; 1979. Heegard S, Grossniklaus H. Eye pathology: an illustrated guide. 1st ed. New York: Springer; 2015. Sassani JW, Yanoff M. Ocular pathology. 6th ed. China: Elsevier; 2009.

Suggested Reading

Normal Fundus Sameeksha Tadepalli, Aniruddha Agarwal, Mohit Dogra, and Vishali Gupta

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Optic Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Area Centralis (Macula) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Peripheral Retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Vascular Arcades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Introduction Normal fundus of an adult comprises of visible part of the retina. Human retina is a transparent structure extending from the optic disc posteriorly to the ora serrata anteriorly. The color of normal fundus may be described as ranging from orange to vermilion, depending on the diffusion spectrum of blood (oxyhemoglobin), the amount of pigment in the choroid, and hexagonal epithelium of the retina. Fundus shows a generalized water-silk reflex corresponding to the light reflecting off the surface of the retina during examination. A fine-stippled reflex (tapetoretinal reflex) due to reflection of light off the pigment epithelial layer may be seen near the macula. The choroid may be deeply pigmented, appearing as dark polyhedral areas between the lighter choroidal vessels, called tessellated fundus (Fig. 1).

The various structures identified on fundus examination include optic nerve, macula, peripheral retina, ora serrata, and retinal vessels.

Optic Nerve Optic nerve head is the well-defined pale circular area about 1.5 mm in diameter corresponding to the area of exit of the nerve fibers of the optic nerve. It is located nasal and superiorly with respect to the macula. At the center of the optic disc is a depression called the physiological cup. It varies in shape, size, position, and depth. The usual ratio of area of the cup and the disc being from 0.2 to 0.5. It is also the point of entry of the retinal vessels (Fig. 2).

Area Centralis (Macula)

S. Tadepalli (*) · A. Agarwal · M. Dogra · V. Gupta Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_2

It is the central area of the retina bound by the optic disc medially and the vascular arcades superiorly, inferiorly, and  laterally. It corresponds to central 15 field of vision. It measures about 5–5.5 mm across and 3.5–4 mm vertically. It is further subdivided as:

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(c) Umbo – It is the central 150–200 μm, corresponding to the foveal light reflex. (d) Foveal avascular zone – It is an area with diameter ranging from 250 to 600 μm from the foveal center where no blood vessels are present. 2. Parafovea – It is the area of the macula up to 0.5 mm beyond the fovea. 3. Perifovea – It is the area from the edge of the parafovea up to 1.5 mm from it.

Peripheral Retina

Fig. 1 Normal fundus photograph obtained using a conventional fundus camera showing the posterior pole and the mid-periphery (approximately 55 view)

Fig. 2 Disc photograph of the left eye of a patient with no known ocular disease showing the physiological cup and healthy neuroretinal rim

1. Fovea centralis. It is the central depressed area which is the most sensitive part of the retina. It measures about 1.85 mm in diameter and  corresponds to central 5 of the visual field. It comprises of:

1. Near periphery – It is a 1.5 mm wide belt beyond the macula. 2. Mid-periphery – It is the area of the fundus, 3 mm wide, from near periphery up to the equator. 3. Far periphery – It extends beyond mid-periphery up to the ora serrata.

Structures observed in the peripheral retina include: Equator – It is the area that divides the eyeball into two equal halves. It is present at the posterior margin of ampullae of vortex veins. The circumferential diameter at the equator of the adult eye averages 69 mm. Ampullae of vortex veins – They are four to eight in number, located at the equator in all four quadrants. There is pigment migration, toward and around the vortex ampullae, which might sometimes be the only indicators of their location. Long ciliary nerves – yellow-to-orange linear structure with variably pigmented borders is observed at approximately 3 and 9 o’clock positions starting at the equator and passing up to the ora serrata. They divide the fundus into superior and inferior halves (Fig. 5). Short ciliary nerves – They are fine, lightly colored branching structures located in the choroid on either side of both vertical meridian (around 1, 5, 7, 11 o’clock positions) present at the equator, for a total of four per eye. Ora serrata – Serrated anterior margin of the retina. Here retina is firmly attached to the vitreous base and the retinal pigment epithelium.

Vascular Arcades (a) Margin – It is situated at about 1.5 mm from foveal center. (b) Foveola – It is the depressed base of the fovea where the highest concentration of cones is present. It measures 0.35 mm in diameter.

The blood supply to the inner retina comes from the central retinal artery that emerges from the optic disc. It has four main branches into supero-nasal, supero-temporal, inferonasal, and infero-temporal. The arteries appear bright red in

Normal Fundus

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Fig. 5 Ultrawide field fundus imaging of a normal fundus showing the long ciliary nerve (white arrow)

Fig. 3 Montage (seven-field) view of a normal fundus obtained using a conventional fundus camera

retina at the optic disc. Veins appear thicker with dark reddish hue. The normal ratio of caliber of arteries to veins is 2:3. Key Points • Normal fundus is the visible part of the retina. It is described according to the landmarks of optic disc, vascular arcades, macula, and ora serrata. • Optic disc is 1.5 mm diameter area marking the location of exit of retinal nerve fibers. • Area centralis is the central part of the retina which includes fovea centralis, parafovea, and perifovea. • Peripheral retina is the area beyond the macula, divided as near, mid, and far periphery. Structures seen include the equator, short and long ciliary nerves, ampullae of vortex veins, and the ora serrata.

Suggested Reading Fig. 4 Ultrawide field fundus imaging of a normal fundus with a camera showing approximately 200 view

color. The temporal branches along with the temporal tributaries of the ophthalmic veins form the boundary of the area centralis. The veins of the retina follow the arteries and finally drain out through the central retinal vein which leaves the

Bowling B, FRCSEd(Ophth), FRCOphth, FRANZCO. Kanski’s clinical ophthalmology. 8th ed. Elsevier: Canada; 2016. Khurana AK, Khurana I. Anatomy and physiology of eye. 3rd ed. CBS publishers and Distributors: New Delhi; 2016). Ryan SJ, MD, Schachat AP, MD, Wilkinson CP, MD, Hinton DR, MD, Sadda SR, MD Wiedemann P, MD. Retina. 5th ed. Elsevier: Canada; 2013. Yanoff M, Duker JS, . Ophthalmology. 4th ed. Elsevier: Canada; 2014.

Normal Fundus Fluorescein Angiography Sana Khochtali, Imen Khairallah-Ksiaa, and Salim Ben Yahia

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Hardware . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 The Dye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Technique of Fluorescein Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Performing the Fluorescein Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Ocular Tissue Response to Fluorescein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Interpreting the Fluorescein Angiogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Introduction Fundus fluorescein angiography (FFA) is a very useful imaging modality for the diagnosis and management of uveitis. It helps in diagnosing specific entities, differentiating active from inactive uveitis, monitoring response to therapy, and evaluating exudative retinal detachment, cystoid macular edema, retinal capillary nonperfusion, choroidal or retinal neovascularisation, and optic disc involvement.

Principle Fluorescence corresponds to the emission of light by cold bodies that have absorbed a particular photon. The glow stops immediately after the exciting light is removed. During FFA, intravenous fluorescein dye that reaches the retinal vessels S. Khochtali · I. Khairallah-Ksiaa · S. Ben Yahia (*) Department of Ophthalmology, Fattouma Bourguiba University Hospital. Faculty of Medicine, University of Monastir, Monastir, Tunisia e-mail: [email protected]; [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_5

will glow with stimulation by blue light at a wavelength varying between 465 and 490 nm and emits a yellowishgreen light between 520 and 530 nm.

Hardware The hardware is essentially the same as for fundus imaging with the addition of appropriate filters (exciter and barrier). The exciter filter is placed in the path of light that allows only blue light of a particular wavelength to stimulate the fluorescein dye. The fluorescein dye emits yellow-green light. In order to accentuate the fluorescence of yellow-green light, a yellow barrier filter placed in front of the film absorbs the unwanted reflected blue light. The images are captured in analog or digital systems. Traditionally, images have been recorded on a photographic film (analog system). Digital images, on the other hand, are composed of pixels. The greater is the number of pixels, the greater is the spatial resolution of the image. The intensity of light detected by each pixel while the fundus is illuminated with a flash lamp is transmitted to the computer where images are stored in a digital format for immediate viewing, manipulation, or storage. 11

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The ideal camera is able to view and photograph variable fundus fields between 20 and 60 . These fundus fields are usually provided in steps of 20 , 35 , 50 , and 60 . The Wider is the field, the lesser is the magnification. Ultra-wide field fundus cameras allow imaging of up to 200 internal degrees of the retina.

The Dye Sodium fluorescein is an orange-red crystalline hydrocarbon with a low molecular weight of 376 Da. The dose used in man for FFA is usually 5 ml in 10–20% concentration corresponding roughly to 15 mg/kg body weight. The dye is excreted in urine and may give false positive testing for sugar in urine. The skin turns yellow for 4–6 h following dye injection. The dye is photosensitive, and exposition to strong sunlight may cause skin burns. Up to 70–80% of the injected dye is bound to albumin and other large protein molecules and 20% remains unbound and produces most of the fluorescence. Both the protein-bound and the unbound portion cannot diffuse through normal retinal vascular endothelium or normal retinal pigment epithelium but can diffuse through the choriocapillaris. The fluorescein is metabolized by liver and excreted by kidney.

Technique of Fluorescein Angiography Precautions Fluorescein angiography is an invasive procedure. It is essential that a selection of emergency drugs is kept readily available for use in case of severe adverse event. The procedure should be explained to every patient, and an informed consent should be obtained.

Patient Selection A full medical history including enquiry for any allergy should be made.

Contraindications – Hypersensibility to fluorescein Cautions – Patients with a history of hypersensibility, asthma, and atopy are at high risk of allergic reactions. – Patients with hepatic failure, renal failure, recent myocardial infarction, and congestive cardiac failure.

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Pregnancy FFA should be avoided as much as possible during pregnancy. It should not be carried out during the first trimester, although there have been no reported fetal complications. Breastfeeding Fluorescein is excreted in breast milk. Nursing mothers may be advised to store breast milk for one or two feedings before injecting fluorescein and to discard the newly secreted milk.

Patient Preparation and Positioning FFA procedure must be explained to the patient to ensure his or her cooperation and obtain good quality photographs. The pupil should be dilated. It is good practice to explain to the patient that imaging will be carried out in the dark and to advise him or her not to move during the session and to follow the instructions regarding the eye movements. In case of a history of undetermined allergic background or previous nausea or reaction, the patient may be given preventively an anti-histaminic agent blocking H1 receptors. The patient is seated in front of the camera. The height of the seat should be adjusted so that the chin rests comfortably on the chin rest, the forehead presses firmly against the forehead bar, and the eye line is adjusted.

Dye Injection A 23-gauge butterfly cannula with a luer-lock system is inserted into an antecubital vein and is held securely by adhesive tape. The dye is rapidly injected (5 ml of 10–20% fluorescein). The cannula should remain in place till the angiography is over as this can be of help during any emergency condition that might arise during the session.

Adverse Reactions Fluorescein is a relatively safe injectable drug.

Mild Adverse Reaction Mild adverse reactions have a rapid and complete resolution without any sequelae. They usually do not require treatment. They mainly include nausea (3–5% of patients undergoing FFA), vomiting, extravasations of dye, sneezing, and pruritis. Moderate Adverse Reaction It is also transient but may require some treatment. The reaction has a complete but gradual recovery. Urticaria,

Normal Fundus Fluorescein Angiography

syncope, other skin eruption, thrombophlebitis, pyrexia, local tissue necrosis, and nerve palsy have been classified as moderate adverse reactions. The overall frequency is 1:63.

Severe Adverse Reaction Severe adverse reactions affect respiratory, cardiac, or neurological system. They include laryngeal edema, bronchospasm, anaphylaxis, circulatory shock, myocardial infarction and arrest, and tonic clonic seizure. Overall frequency of severe reaction is 1:1900. These reactions require prompt intensive treatment and usually leave permanent deficiency in the affected system. Death is a rare complication of FFA with a frequency of 1:222000.

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out of the choroid and choroidal fluorescence returns to insignificant levels several minutes after injection.

Bruch’s Membrane Extracellular fluorescein dye from the choriocapillaris permeates through the Bruch’s membrane, binding to the collagen tissue and to any colloid bodies on it.

Retinal Pigment Epithelium The tight junctions provided by the zonula occludens of healthy retinal pigment epithelium prevent fluorescein dye passing beyond the RPE.

Performing the Fluorescein Angiography Retina Before the injection of the dye, color fundus and red-free photographs are taken and can be completed by additional pictures: – with blue, red filters – infrared imaging – Autofluorescence imaging Both exciter and barrier filters are then inserted. Fluorescein dye is injected intravenously with sufficient speed to produce high-contrast images of the early phases of the angiogram. At the end of the injection, a clock timer is run. Photographs are taken soon after, initially at 0.5 s intervals for the first 6 s, then at 4–10 s intervals for the next few minutes. Late phase photographs should be taken at 10–12 min or later. The dye reaches the eye in 12–15 s and depends upon the “arm-toretina” circulation time and is affected by cardiac output, viscosity of blood, and caliber of nerves in blood vessels.

The endothelial cells of the retinal vessels are impermeable to fluorescein.

Ciliary Body Blood vessels of the ciliary body are freely permeable and allow free movement of fluorescein dye in the ciliary body stroma. Diffusion to the posterior and anterior chambers is however limited by the tight junctions of the ciliary body epithelium.

Vitreous Body It takes several days for the fluorescein dye to clear from the vitreous. The anterior vitreous loses fluorescein through forward diffusion into the aqueous. The posterior vitreous clears through the retinal vessels and by the process of active transport via the retinal pigment epithelium.

Ocular Tissue Response to Fluorescein The anatomical and physiological differences between the ocular tissues lead to different responses to the circulating fluorescein.

Choroid Larger choroidal vessels are impermeable to both proteinbound and unbound fluorescein. However, choriocapillaris vessels are leaky due to multiple fenestrations, allowing egress of both forms of fluorescein. The extra vascular fluorescein stains the choroidal stroma which can however not be seen when the retinal pigment epithelium is intact (the choroidal fluorescence is relatively blocked by the RPE screen). Because fluorescein is a small molecule, it is quickly washed

Optic Nerve Retinal capillaries on the superficial layers of the optic disc are derived from the retinal vessels and are impermeable to fluorescein. However, the peripapillary choroidal plexus leaks, which accounts for the staining of the optic disc seen during the late phase of FFA.

Sclera The inner surface of the sclera stains with fluorescein, which leaks through the choriocapillaris. In case of choroidal atrophy, the sclera appears hyperfluorescent in late frames due to staining with fluorescein that has diffused from adjacent areas.

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Macula The xanthophyll pigment present in the macula lutea masks the background choroidal fluorescence throughout the angiogram. The center of the fovea is completely devoid of blood vessels.

Interpreting the Fluorescein Angiogram An angiogram consists of five phases.

Choroidal Phase (Prearterial) During the first phase, the prearterial phase, the choroid and choriocapillaris fill with dye. Fluorescein usually appears in the choroidal circulation approximately 1 s before it appears in the retinal circulation. This can be clearly demonstrated in patients who have a pale pigment epithelium or in patients with albinism. Even in normal patients the filling pattern of the choriocapillaris is patchy and variable (Shimizu’s sign or Shimizu’s islands). In most angiograms the details of the choriocapillaris are not visible and only choroidal flush will appear on the angiogram (Fig. 1). If there is a cilioretinal artery, it fills along with the choroid as both are supplied by the short posterior ciliary arteries.

Fig. 1 End of the choroidal phase, with beginning of retinal arterial filling

Arterial Phase One to three seconds after choroidal fluorescence, fluorescein dye appears in the arteries pointing the beginning of the arterial phase, which extends until the arteries are completely filled (Fig. 2).

Fig. 2 Arterial phase

Arteriovenous Phase Complete filling of the arteries and capillaries and the first evidence of laminar flow in the veins characterize the arteriovenous phase. The laminar flow is the result of two factors: fluorescein dye entering veins from smaller venules and second the vascular flow being faster in the center of the vessel as compared to the vessel walls (Fig. 3).

Venous Phase The venous phase begins as the arteries are emptying and the veins are filling with dye (Fig. 4). Maximum vessel fluorescence occurs approximately 30 s after the injection of the dye.

Fig. 3 Arteriovenous phase

Normal Fundus Fluorescein Angiography

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Transit Phase

Recirculation Phase

The aggregate of the arterial, arteriovenous and venous phase is commonly referred to as the transit phase of the angiogram. The transit phase represents the first complete passage of fluorescein-containing blood through the retina and choroid. At the end of the transit phase, fluorescein dye remains in the choroid and sclera due to leakage from choriocapillaris vessels. A small amount of fluorescein also remains in the optic nerve head and retinal vessels but without any leakage.

Recirculation phase of the angiogram follows the transit phase and represents the first return of blood containing fluorescein (a small amount) to the eye (Fig. 5). This occurs after the blood has passed through the kidney. The fluorescein dye in the recirculation is very dim in contrast to the transit phase, in which the dye is in a much higher concentration in the blood. The recirculation phase is useful for looking at leaking pathology.

Fig. 4 Venous phase

Fig. 5 Composite fundus fluorescein angiogram during the recirculation phase

Key Points • FFA is a relatively invasive imaging modality. Mild to severe adverse reactions may occur. • Normal retinal pigment epithelium and retinal vascular endothelium are impermeable to fluorescein. • Fluorescein can diffuse through the choriocapillaris but not through large choroidal vessels. • Choroidal fluorescence is relatively blocked by intact retinal pigment epithelium screen. • The angiogram is made of five phases: the choroidal or prearterial phase, the arterial phase, the arteriovenous phase, the venous phase, and the recirculation phase. • FFA gives useful information on optic disc, retinal vessels, retinal pigment epithelium, and choriocapillaris (during the early phases). However, it allows poor evaluation of choroidal involvement.

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Suggested Reading Adl MA, LeHoang P, Bodaghi B. Use of fluorescein angiography in the diagnosis and management of uveitis. Int Ophthalmol Clin. 2012;52 (4):1–12. Berkow JW, Kelly JS, Orth DH. Fluorescein angiography. A guide to the interpretation of fluorescein angiograms. 2nd ed. San Francisco: American Academy of Ophthalmology; 1984. p. 9–16.

S. Khochtali et al. Gupta V, Gupta P, Herbort C, et al. Fluorescein angiography. Uveitis: text and Imaging. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2009. p. 61–87. Patel M, Kiss S. Ultra-wide-field fluorescein angiography in retinal disease. Curr Opin Ophthalmol. 2014;25(3):213–20. Yannuzzi LA, Rohrer KT, Tindel LJ, Sobel RS, Costanza MA, Shields W, Zang E. Fluorescein angiography complication survey. Ophthalmology. 1986;93(5):611–7.

Normal Indocyanine Green Angiography Atul Arora, Aniruddha Agarwal, and Vishali Gupta

Contents History of Indocyanine Green Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Hardware . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 ICG Dye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Precautions and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Precautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Indocyanine Green Angiography Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Dye Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

History of Indocyanine Green Angiography The use of ICG Dye in the field of medicine dates back to mid-1950s when it was initially used in the field of cardiology for measuring cardiac output in valvular heart defects. Still today, it has role in the measurement of cardiac output, hepatic clearance and blood volume. Kogure and Choromokos first demonstrated the use of ICG molecule for infrared absorption fundus angiography. In the initial absorption angiography studies, the ICG dosage used was similar to the amount used for cardiac flow studies (2 mg/kg body weight). This new modality allowed visualization of the normal and abnormal appearance of the choroidal circulation.

Hochheimer and Flower studied the potential role of this new modality for studying choroidal architecture in the aging and glaucomatous eye. Their work resulted in a classic description of ICG angiography performed simultaneously with FA in 1976. The earlier studies were limited largely by inadequate photographic quality, as visualization of the choriocapillaris was not possible due to low resolution. Technological advancements in digital angiography made it possible for ICG angiography to acquire clinically meaningful images. Tokoro and Hayashi first reported the use of the Topcon videoangiography system in ICG angiography. Subsequently, clinical reports of ICG videoangiography with newer techniques having improved temporal resolution were published.

A. Arora · A. Agarwal · V. Gupta (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_10

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In 1989, Scheider combined the use of scanning laser ophthalmoscope with videotape recording to improve spatial resolution.

Principle Fluorescence refers to the property of a substance to emit light after it has absorbed a photon of a particular wavelength. The glow stops immediately after the exciting light is removed. ICG dye fluoresces in near-infrared (845 nm central wavelength) when excited by the illuminating light of 750–800 nm wavelength. These optical characteristics are very important for tissue measurement. Hemoglobin and water are the main optical absorbers in human tissue. Water absorbs visible light above 900 nm wavelength while that below 650 nm is absorbed by hemoglobin. The wavelength between 650 and 900 nm is thus called optical window as is not absorbed by hemoglobin or water.

Hardware ICG dye can be detected only using specialized infrared fundus cameras, a digital imaging system, or a scanning laser ophthalmoscope (SLO). A diode laser illumination system with an output of 805 nm and barrier filters at 500 and 810 nm is used. Because of its longer operating wavelength, ICG fluoresces better through pigment, lipid, fluid, and hemorrhage than fluorescein dye. The images can be captured in analog or digital systems. Earlier imaging systems used analog system to store images. However, digital images are better for immediate viewing, storage, or manipulation. They are composed of pixels. The greater number of pixels results in better spatial resolution of the image.

A. Arora et al.

Precautions and Contraindications As for FFA, ICG angiography is an invasive procedure. Emergency equipment for resuscitation and drugs must be stationed in room where the procedure is being performed. The patient should be explained about the procedure, and an informed consent obtained.

Contraindications Hypersensitivity to ICG.

Precautions Caution should be observed in patients with a history of hypersensitivity, asthma, and atopy as they are at high risk of allergic reactions. History of hepatic/renal failure, recent myocardial infarction, and congestive cardiac failure should be taken. Although there are no reported fetal complications, ICGA should be avoided as much as possible during pregnancy especially during the first trimester.

Indocyanine Green Angiography Procedure Patient Preparation and Positioning The procedure is explained to the patient. This ensures patient’s cooperation in obtaining good quality photographs. The pupils are dilated using Tropicamide-phenylephrine combination. Patients with history of allergic disorders are given an antihistaminic agent blocking H1 receptors preventively.

ICG Dye Dye Injection ICG is a tricarbocyanine dye. It has molecular weight of 775 g/ mol. Being highly protein bound, it does not readily escape from the choriocapillaris. The dye has high first pass metabolism in liver; it has limited recirculation as compared to the fluorescein dye. ICG dye is selectively taken up by hepatocytes and excreted by the hepatobiliary system. Adenosine tri-phosphate-dependent transport process plays a role in its excretion into bile. The compound is not metabolized and does not undergo enterohepatic recirculation. Indocyanine green absorbs light at 805 nm and reflects back at 835 nm. This spectrum renders the retinal pigment epithelium (RPE) invisible allowing visualization of the choroid through hemorrhage or retinal pigmentary deposits. However, the fluorescence of ICG is only 4% (25 times less) as compared to the total fluorescence of fluorescein.

The antecubital vein is cannulated by 23-gauge butterfly cannula and secured by adhesive tape. The dye is rapidly injected (25 mg in 5 ml) followed by 5 ml saline flush. The cannula is kept in place till the angiography is over to provide for IV access in any emergency situations. Fundus and red-free photographs are taken before injecting the dye. Both exciter and barrier filters are then inserted. ICG dye is injected. The speed of injection should be sufficient to produce high-contrast images in the early phases of the angiogram. A clock timer is run at the end of injection. Photographs are taken, initially at 1 min intervals for the first 5 min, then at 10–15 min intervals for the next 30–40 min.

Normal Indocyanine Green Angiography

Interpreting the ICG Angiogram An angiogram consists of four phases.

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Late Mid-Phase (3–15 min) Choroidal vessels start fading but dye still visible in retinal vessels.

Early Phase (0–1 min) Choroidal arteries are filled during early phase.

Late Phase (14–45 min) Choroidal vessels appear hypocyanescent and gradual fading diffuse cyanescence. Early Mid-Phase (1–3 min) The dye reaches choroidal veins and retinal vessels.

It is important to carefully observe ICGA findings and correlate with the clinical findings.

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Lesion Which Appear as Hypercyanescent • Due to choroidal pathology – Leakage: Diffuse hypercyanescense surrounding choroidal hypocyanescent lesion may be seen in any inflammatory disease involving choroid. – Focal hypercyanescense/Tissue staining: Seen in granulomatous choroiditis (sarcoidosis, tuberculosis); syphilis and active multifocal choroiditis. • Due to retinal pathology – Leakage: In case of extensive vascular damage, e.g., Behcet’s uveitis – Pooling: In case of subretinal fluid – Abnormal vessels: Choroidal neovascularization

Adverse Reactions Though a relatively safe procedure, ICGA may show adverse reactions. Mild Adverse Reaction

The procedure may cause nausea, vomiting, sneezing, extravasations of dye, and pruritis. These reactions have a rapid and complete resolution without any sequelae and usually do not require treatment. Moderate Adverse Reaction

They include urticaria, other skin eruption, thrombophlebitis, local tissue necrosis, pyrexia, syncope, and nerve palsy. These are also transient but may require some treatment. There is gradual but complete recovery. Severe Adverse Reaction

Rarely, there may be cardiac, respiratory, or neurological complications such as anaphylaxis, laryngeal edema, bronchospasm, myocardial infarction and arrest, circulatory shock, and tonic clonic seizure. Urgent intensive treatment is required to save life. Key Points • Indocyanine green angiography (ICGA) is a gold-standard imaging technique for visualization of the choroidal anatomy and microcirculation.

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• ICGA is extremely useful in detecting pathologies such as choriocapillaris ischemia/atrophy, choroidal granulomas in conditions such as sarcoidosis and tuberculosis, and other lesions such as choroidal neovascularization. • ICGA helps in the complete assessment of retinochoroidal alterations in various uveitic entities. • ICGA is also extremely useful in the follow-up and management of choroidal lesions in infectious and noninfectious uveitis.

Suggested Reading Bischoff PM, Flower RW. Ten years’ experience with choroidal angiography using indocyanine green dye: a new routine examination or an epilogue? Doc Ophthalmol. 1985;60:235–91. Cherrick GR, Stein SW, Leevy CM, Davidson CS. Indocyanine green: observations on its physical properties, plasma decay, and hepatic extraction. J Clin Invest. 1960;39(4):592–600. Destro M, Puliafito CA. Indocyanine green angiography of choroidal neovascularization. Ophthalmology. 1989;96:846–53. Flower RW. Infrared absorption angiography of the choroid and some observations on the effects of high intraocular pressures. Am J Ophthalmol. 1972;74(4):600–14. Flower RW, Hochheimer BF. Indocyanine green dye fluorescence and infrared absorption choroidal angiography performed simultaneously with fluorescein angiography. Johns Hopkins Med J. 1976;138:33–42. Fox IJ, Wood EH. Indocyanine green: physical and physiologic properties. Proc Mayo Clin. 1960;35:732–44. Guyer DR, Puliafito CA, Mones JM, Friedman E, Chang W, Verdooner SR. Digital indocyanine-green angiography in chorioretinal disorders. Ophthalmology. 1992;99:287–91. Hayashi K, Hasegawa Y, Tokoro T. Indocyanine green angiography of central serous chorioretinopathy. Int Ophthalmol. 1986;9:37–41. Hochheimer BF. Angiography of the retina with indocyanine green. Arch Ophthalmol. 1971;86(5):564–5. Kogure K, Choromokos E. Infrared absorption angiography. J Appl Physiol. 1969;26(1):154–7. Patz A, Flower RW, Klein ML, Orth DH, Fleischman JA, McLeod SM. Clinical applications of indocyanine green angiography. In: de Laey JJ, editor. International symposium on fluorescein angiography: Ghent, 28 March–1 April, 1976. The Hague: Dr W Junk; 1976. p. 245–51. (Doc Ophthalmol Proc Ser 9). Scheider A, Schroedel C. High resolution indocyanine green angiography with a scanning laser ophthalmoscope. Am J Ophthalmol. 1989;108:458–9.

Normal OCT and OCT Angiography of Retina and Choroid Igor Kozak and Aniruddha Agarwal

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 Case 1: Normal OCT in a Young Female . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Case 2: Swept-Source OCT in a Normal Individual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Case 3: OCT Angiography in a Normal Female . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Introduction

Swept-Source Optical Coherence Tomography (SS-OCT)

Optical Coherence Tomography The spectral-domain optical coherence tomography (SD-OCT) has become a gold standard in posterior pole imaging. It uses a broadband light source, split into a reference arm and a sample arm, which reconstructs the microscopic structure of the chorioretinal tissue. The axial resolution of 3–10 μm allows for visualization of individual retinal layers. The swept-source OCT (SS-OCT) uses a wavelength-tunable laser and a dual-balanced photodetector to produce higher imaging speed, higher detection efficiencies, and improved imaging range. The enhanced depth imaging (EDI) system on SD-OCT has improved visualization of the choroidal structure. EDI-OCT can be used to obtain high-quality choroidal images for choroidal thickness and volume measurements including three-dimensional imaging. Additionally, en face imaging of the choroid allows an excellent alternative to histopathologic study of the choroid and can be used to quantify choroidal vascular structures in vivo. I. Kozak (*) Moorfields Eye Hospital, Abu Dhabi, United Arab Emirates e-mail: igor.kozak@moorfields.ae A. Agarwal Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_6

SS-OCT is a newer OCT technology that provides faster image acquisition and processing. SS-OCT can provide a better view of vitreoretinal interface as well as choroid in a single frame. SS-OCT utilizes a narrow light wavelength of 1050 nm and achieves 100,000–400,000 A scan/s. SS OCT with long image range of 7.5 mm clearly delineates the vitreoretinal interface as well as enhanced subretinal pigment epithelium imaging without the application of EDI-OCT. Thus, very high-resolution images are possible with SS-OCT in a short acquisition time.

En Face OCT En face imaging is a new imaging tool that combines OCT with transverse confocal analysis. This results in transverse images of retinal and choroidal layers at a specified depth. It provides an en face view of any given layer within the retina and choroid. En face has many advantages over conventional longitudinal cross-sectional imaging because it can delineate microstructural and morphological changes in coronal view, allowing precise measurements to be made. En face provides an extensive view of the pathological structures in a single image. It also provides a familiar view of the fundus similar to that seen on fundus photography and direct ophthalmoscopy.

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Optical Coherence Tomography Angiography (OCT Angiography) OCT angiography is a groundbreaking technology and is currently a very active area of research. OCT angiography is a new, noninvasive technique that allows the visualization of retinal vasculature without the need for dye injection and thus can be safely used to study retinal vasculature in otherwise normal looking retinas. This helps in picking up the subtle alterations in the retinal vasculature before they manifest clinically. Current gold standard investigations for ophthalmic angiography include fluorescein angiography (FA) and indocyanine green angiography (ICGA). Both investigations require injection of intravenous dye, which is time consuming and carries the risk of allergic reaction. Fluorescein dye injection is a relative contraindication in certain systemic conditions such as pregnancy and renal impairment. Since fluorescein dye cannot diffuse through intact blood-retinal barrier, it serves as an excellent tool for imaging retinal lesions. On the other hand, ICGA enables imaging of the deeper choroidal circulation below the retinal pigment epithelium. However, both FA and ICGA generate two-dimensional images of the retinal or choroidal circulation. This poses difficulty in localizing the depth and extent of lesions, especially in the presence of dye leakage or retinal hemorrhages. OCT angiography is noncontact as well as noninvasive, and avoids dye-related complications such as anaphylaxis. Image acquisition is fast with one scan set of volumetric information obtained within seconds. OCT angiography generates a three-dimensional image set so that vascular plexuses at different depths can be visualized from internal limiting membrane up to choroid.

I. Kozak and A. Agarwal

Decreased retinal vascularity has been reported using OCT angiography in patients with HIV before they develop HIV microangiopathy, diabetes mellitus without any clinical retinopathy, and Takayasu disease in earliest stages of retinopathy. The diagnosis and management of uveitis using OCT angiography are not as well defined as they are in conditions such as age-related macular degeneration. In contrast, uveitis can affect people of any age, be secondary to many possible causes, occur with protean clinical manifestations such as retinal vasculitis, and may or may not be associated with choroidal neovascularization. Because OCT angiography allows us to visualize not only the superficial retinal vasculature but also the deep retinal vasculature, outer retina, and choriocapillaris, it has the potential to reveal new information about the pathophysiology, clinical course, and prognosis of uveitis. In the future, OCT angiography can be improved with new algorithms that maximize signal-to-noise ratio, and new OCT devices with faster scanning speed to expand the field of view may become commercially available. In order for OCT angiography to gain wider acceptance and routine use, large-scale prospective studies are required to establish a normative database and to evaluate the sensitivity and specificity of OCT angiography compared to current standard FA and ICGA.

Case 1: Normal OCT in a Young Female A healthy 33-year-old female patient with 20/20 visual acuity in both eyes underwent nonrevealing clinical ophthalmic examination followed by examination with spectral-domain

Fig. 1 Spectral-domain optical coherence tomography scan of the normal eye. Left panel shows the placement of orientation scan, and the right panel shows B-scan. Please note vitreous condensation (white arrow), normal retinal structure, and foveal contour

Normal OCT and OCT Angiography of Retina and Choroid

Fig. 2 Spectral-domain optical coherence tomography scan of normal eye taken with enhanced depth imaging (EDI) mode. Left panel shows the placement of orientation scan, and the right panel shows B-scan.

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While there is low signal above the retina, the EDI shows more detailed choroidal structure (white arrow) with small lumen choriocapillaris and larger lumen choroidal structure

Fig. 3 SS-OCT scan of the right eye shows a normal retinochoroidal structure. The retinal thickness in the subfoveal region is 213 μm, and subfoveal choroidal thickness measures 359 μm

optical coherence tomography in both eyes. The imaging study showed mild vitreous condensation but normal retinal and foveal structure (Fig. 1). Enhanced depth imaging study of the other eye showed detailed choroidal structure with the absence of any focal pathology or edema (Fig. 2).

Case 2: Swept-Source OCT in a Normal Individual A 45-year-old healthy male presented to the Ophthalmology Department for assessment of the fundus prior to initiation of oral hydroxychloroquine therapy for rheumatoid arthritis. The visual acuity examination revealed 20/20 in both the eyes. The intraocular pressure was within normal limits

(14 mmHg by Goldmann Applanation Tonometry) in both the eyes. As a part of routine ophthalmic screening, he underwent ocular imaging including SS-OCT imaging of both the eyes. The scan did not reveal any retinochoroidal pathology. SS-OCT enabled accurate assessment of retinochoroidal structure and measurement of retinal and choroidal thickness in this patient (Figs. 3 and 4).

Case 3: OCT Angiography in a Normal Female A 32-year-old female presented with mild occasional headaches. She did not report use of glasses. Evaluation of bestcorrected visual acuity revealed a vision of 20/30 (parts) in

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I. Kozak and A. Agarwal

Fig. 4 SS-OCT scan of the left eye of the same patient (case #2) shows a normal retinochoroidal structure. The retinal thickness in the subfoveal region is 286 μm, and subfoveal choroidal thickness measures 293 μm

Fig. 5 OCT angiography of the right eye of the patient (case #3) shows normal appearing arborized pattern of the superficial and deep retinal plexuses (a and b). The outer retina does not normally show any retinal

vasculature and appears dark (c). The signal flow image is shown on the corresponding OCT B-scan (d) which shows colored flow areas (red in the retina and purple in the choroid)

both eyes. Refraction was performed, which showed the presence of simple myopia ( 0.75 diopters) in both the eyes. The patient was advised regular use of eye glasses.

We performed additional fundus imaging, including OCT angiography, for academic purposes. The OCT angiography scans revealed high-quality scans of the superficial and deep

Normal OCT and OCT Angiography of Retina and Choroid

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Fig. 6 The OCT angiography of the same patient (case #3) shows normal choriocapillaris anatomy at the “choroid cap” segmentation slab, which is a 30-μm-thick slab under the retinal pigment epithelium

(a). The image in the panel (b) is the structural en face scan which shows no evidence of signal loss and shadowing effect. The choriocapillaris layer is well visualized

retinal plexuses, as well as the choriocapillaris layer. No areas of flow voids or abnormal nonperfusion were noted in either eye (Figs. 5 and 6).

Agarwal A, Agrawal R, Khandelwal N, Invernizzi A, Aggarwal K, Sharma A, Singh R, Bansal R, Sharma K, Singh N, Gupta V. Choroidal structural changes in tubercular multifocal serpiginoid choroiditis. Ocul Immunol Inflamm. 2018a;26(6):838–44. https:// doi.org/10.1080/09273948.2017.1370650. Agarwal A, Invernizzi A, Singh RB, Foulsham W, Aggarwal K, Handa S, Agrawal R, Pavesio C, Gupta V. An update on inflammatory choroidal neovascularization: epidemiology, multimodal imaging, and management. J Ophthalmic Inflamm Infect. 2018b;8(1):13. https://doi.org/10.1186/s12348-018-0155-6. Review. Agrawal R, Xin W, Keane PA, Chhablani J, Agarwal A. Optical coherence tomography angiography: a non-invasive tool to image end-arterial system. Expert Rev Med Devices. 2016;13(6):519–21. https://doi.org/10.1080/17434440.2016.1186540. Drexler W, Liu M, Kumar A, Kamali T, Unterhuber A, Leitgeb RA. Optical coherence tomography today: speed, contrast, and multimodality. J Biomed Opt. 2014;19(7):071412. Fujimoto JG, Drexler W. Introduction to optical coherence tomography. In: Fujimoto JG, Drexler W, editors. Optical coherence tomography technology and application. Heidelberg: Springer; 2009. p. 1–45. Mrejen S, Spaide RF. Optical coherence tomography: imaging of the choroid and beyond. Surv Ophthalmol. 2013;58(5):387–429. Spaide RF. Choroidal imaging with optical coherence tomography. In: Holz FG, Spaide RF, editors. Medical retina focus on retinal imaging. Berlin: Springer; 2010. p. 169–90. Unterhuber A, Povazay B, Hermann B, Sattmann H, Chavez-Pirson A, Drexler W. In vivo retinal optical coherence tomography at 1040 nm – enhanced penetration into the choroid. Opt Express. 2005;13: 3252–8.

Key Points • Spectral-domain OCT has been widely used to diagnose retinal and some choroidal pathology. • The enhanced depth and en face imaging are preferred methods to visualize the choroidal tissue. • Newer technologies such as swept-source OCT can provide fast, accurate, and good-quality images of the deeper choroid. • OCT angiography is a novel, noninvasive modality that provides noninvasive, high-quality imaging of the retinochoroidal microvasculature and enables quick detection of complications such as choroidal neovascularization.

Suggested Reading Agarwal A, Invernizzi A, Acquistapace A, Riva A, Agrawal R, Jain S, Aggarwal K, Gupta V, Dogra MR, Singh R, OCT ANGIOGRAPHY Study Group. Analysis of retinochoroidal vasculature in human immunodeficiency virus infection using spectral-domain OCT angiography. Ophthalmol Retina. 2017;1(6):545–54. https://doi.org/ 10.1016/j.oret.2017.03.007.

Ocular Ultrasound and its Clinical Applications Savleen Kaur and Ramandeep Singh

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 The Hardware . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 The Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Normal Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Case 1: Granulomatous Panuveitis in a 14-Year-Old Girl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Case 2: Leukocoria with Hypopyon in a 5-Year-Old Girl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Introduction Ultrasound has become a standard diagnostic modality in almost all medical specialties. The use of ultrasound in ophthalmology began in 1956 by the work of Mundt and Hughes. The first use of B scan with the immersion technique was reported by Baum and Greenwood that was later replaced by the contact method by Bronson and Turner. The ultrasound has substantially helped in establishing the diagnosis of several ocular pathologies in the posterior segment. Ultrasound waves have a frequency greater than 20,000 Hz, rendering them inaudible to the human ear. For the practical purposes, commercial probes in ophthalmic practice use frequency of 10 MHz. The 10 MHz probe provides an excellent resolution of 940 μm with a restricted depth of 4 cm, thus imaging the posterior segment of the eye quiet well. The 10 MHz probe can be used to examine low intensity scatterers, such as the vitreous humor. The 20 MHz probes on the other hand have a deeper focus with sharper lateral resolution

S. Kaur · R. Singh (*) Department of Ophthalmology, Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_8

compared with the 10 MHz probe and can be used to better detect details at the posterior pole and in the orbit.

The Hardware The machine consists of a probe with a piezoelectric crystal near its surface, which transmits these high frequency ultrasound waves into the eye. These waves strike the ocular structures and are reflected back. The probe converts these reflected waves into electric signals, which are reconstructed on a monitor. Being relatively superficial, to image the eye, lesser penetration and more resolution is required, provided extremely well by the 10 MHz probe. The eye is relatively a small organ as compared to the rest of the body, as well as superficial, filled with low absorption fluids. Sound travels faster through solids as compared to liquids, an important principle to be kept in mind as the eye has both. Hence velocity of the sound waves in every medium that the wave passes should be known. The A or the Amplitude scan gives a one-dimensional view of the reflected echoes in the form of spikes. The height of the spike is proportional to the reflectance of the structure. It gives information regarding the lesions’ character as well as size (Fig. 1a).

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Fig. 1 (a) The A (Amplitude) scan gives a one-dimensional view of the reflected echoes in the form of spikes. From anterior to posterior (left to right), the highest spikes correspond to cornea, lens, and retina. (b) The

B (Brightness) scan gives a two-dimensional image, composed of dots with brightness proportional to the reflectivity of the tissue

The B or the Brightness scan gives a two-dimensional image, composed of dots with brightness proportional to the reflectivity of the tissue. It gives information about the topography of the lesion (Fig. 1b).

attenuation from the lens hinders the resolution of the scan (Fig. 2a and b). 2. Transverse: It avoids scanning through the lens and provides lateral extent of the lesions. The probe is placed at limbus and as the probe moves from limbus to fornix, it scans the opposite wall posterior to anterior. By convention, the marker is oriented nasally in case of superior and inferior scans and marker is oriented towards 12 o’clock in case of nasal and temporal scans (Fig. 3). 3. Longitudinal: The probe is placed longitudinally from limbus to fornix. By convention the marker is oriented towards the limbus, i.e., each clock hour. It provides an anteroposterior extent of the ocular wall along one meridian only from the peripheral retina above and the optic nerve head below (Fig. 4).

The Technique The procedure should always be explained to the patient. The patient can be seated on a reclining chair or made to lie on a bed. If the examiner is right handed, he/she should be preferably sitting on the right of the examiner. A white line or dot (marker) on the probe indicates the orientation of the probe and represents the upper portion of the display. The B scan requires a coupling medium in the form of gel, which provides an optimal contact between ultrasonic head and tissue to ensure the perfect sound transmission without interference of air. The probe can be placed on the conjunctiva or the cornea.

Type of Scans The basic examination gives information of the topographic data (extent and location), quantitative data (reflectivity and attenuation), as well as the kinetic data (motility and after movement) of any pathology. 1. Axial: The probe is placed on the cornea and the patient fixes in the primary gaze. It displays the optic nerve head in the center in a vertical axial scan with marker facing towards 12 o’clock. For a horizontal axial scan, the marker is oriented nasally and it will show the macula below the optic nerve head. These are the easiest to obtain but sound

Analysis Quantitative analysis includes topographical analysis including reflectivity, internal structure, and sound attenuation. Reflectivity is measured by the height on ‘A’ scan and brightness on ‘B’ scan. Reflectance signals are compared to the highly reflective sclera and very low reflective vitreous cavity (Fig. 5). Sound attenuation implies decline of spikes’ height due to sound absorption. Highly reflective and regularly structured lesions will provide the strongest sound absorption and the maximum decline in spike height. The probe emits oscillating sound waves, which are represented as multitude of dots on a screen. There are various adjustments one can make for a better quality scan.

Gain The amplitude of the display and sensitivity can be altered by adjusting the gain in decibels (db). Higher gain implies

Ocular Ultrasound and its Clinical Applications

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Fig. 2 In the axial scan, the probe is placed on the cornea and the patient fixes in the primary gaze. It displays the optic nerve head in the center in the vertical axial scan (arrow) (a) and above the midline in the horizontal axial scan. (arrow) (b)

Fig. 3 Transverse scan avoids scanning through the lens and it scans the opposite side of the eye

Fig. 4 Longitudinal scan provides an anteroposterior extent of the ocular wall along one meridian only from the peripheral retina above and the optic nerve (ON) head below

weaker signals that are also displayed. Lower gain means weaker signals disappear and stronger signals remain.

Pearls

Scale A variable gray-scale format is used to display the returning echoes as a two-dimensional image. Reducing gray scale increases the contrast.

1. The more perpendicular the probe is held to the surface, more echo is reflected back from the surface into the probe, hence brighter the image. 2. It can be performed on open eye for better images if patient is cooperative.

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Fig. 5 Reflectivity is measured by the height on ‘A’ scan and brightness on ‘B’ scan. Reflectance signals are compared to the highly reflective retina and very low reflective vitreous cavity

3. Begin examination at stronger gain and highest gray scale and decrease it later to delineate pathologies.

Normal Ultrasound A normal 10 MHz scan shows spikes from both anterior and posterior surfaces of cornea, while anterior lens spike and posterior iris usually merge together. The posterior curvature of the lens is clearly demonstrated. The display has posterior pole on the right with the vitreous cavity in the center. Areas that are closest to the probe are imaged to the left of the screen and those farthest away are imaged to the right. The normal vitreous is relatively echolucent and ultrasonographically clear (Fig. 1b). On A scan, there are no echoes between the posterior lens capsule and the retina. Occasional small dots or linear echoes can be seen at the

S. Kaur and R. Singh

Fig. 6 Posterior vitreous separation seen as a mobile and thin low reflective line (arrow). It is less reflective as compared to the retina (arrow in A scan below)

highest gain settings, but they fade rapidly as the gain is reduced. In an aging eye, due to vitreous syneresis, low to medium reflective opacities can be seen. Posterior vitreous separation is seen as a mobile and thin low reflective line on the B scan (Fig. 6). It is less reflective as compared to the retina (Fig. 7) and disappears when the gain is reduced. In cases of vitreous cells, the cavity is seen filled with small dots of low to medium reflectivity (Fig. 8). The choroid is thick echographically. Opposed retina and choroid produce a highly reflective double spike on A scan – one from vitreoretinal interface and the other from retinochoroidal interface (Fig. 9). Retina is seen on B scan as an opaque, smooth, and acoustically opaque surface with high reflectivity echoes inseparable from the choroid-sclera complex. The retinal spike corresponds to 100% on the echo intensity scale if the beam is perpendicular to the retina in A scan (Fig. 7).

Ocular Ultrasound and its Clinical Applications

Fig. 7 Retina seen on B scan as an opaque, smooth, acoustically opaque surface (arrow above) with high reflectivity corresponding to 100% on the echo intensity scale if the beam is perpendicular to the retina in A scan (arrow in figure below)

Strong echoes, such as those seen from sclera or detached retina, are displayed brightly at high instrument gain and remain visible even when the gain is reduced. Weaker echoes, such as those from a vitreous hemorrhage, are seen as a lighter shade of gray that disappear when the gain is reduced. Vertical axial USG B scan is used to measure the retinochoroid thickness (RCT). It is measured with a caliper tool as the distance between outer border of the hypereflective retina and the sclera (Fig. 10). The best area to measure RCT is the peripapillary area. The availability of 20-MHz probe has made the imaging of RCT macula much better with higher resolution (Fig. 11). Highly reflective structures at the back of the eye such as chorioretina, sclera, optic nerve sheaths, and extraocular

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Fig. 8 In a horizontal axial scan, vitreous cavity is seen filled with small dots and lines that give homogenous echoes. On A scan, these have low to medium reflectivity

muscles sheaths are seen at higher resolution with the 20 MHz probe. Optic nerve is seen as a wedge-shaped acoustic void in the retro-orbital region and extraocular muscles seen as echolucent to hyporeflective structures. The episcleral space separates the globe wall from the orbit and is seen as a thin dark line.

Limitations There are certain limitations to ultrasound also. These include operator dependency, contact with the globe which may cause eye pain, interference from overlying bone or air, and inferior spatial resolution when compared with CT or MRI.

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Fig. 10 Retinochoroidal thickness measured with calipers perpendicular to the retinal surface (red arrows). Optic nerve is visible in USG image

Fig. 9 Highly reflective double spike (red arrow) (one from vitreoretinal interface and the other from retinochoroidal interface) on A scan produced by the opposed retina and choroid

Case 1: Granulomatous Panuveitis in a 14-Year-Old Girl A 14-year-old girl presented with decreased vision in both eyes for 1 month with no systemic complaints. At presentation, her best-corrected visual acuity (BCVA) was counting fingers close to face in both eyes. Her intraocular

pressure with Goldmann Applanation tonometery was 26 mmHg in both eyes. Anterior segment examination on slit lamp biomicroscopy revealed bilateral panuveitis with iris bombe, iris neovascularization, iris nodules, and granulomatous keratic precipitates (arrow) (Fig. 12). There was no view of the fundus in both eyes. USG of both eyes showed bilateral no to minimal vitreous echoes with retinochoroidal thickening (Fig. 13). Diagnosis of “Probable Vogt Kayanagi Harada disease” was made in both eyes. She received intensive topical betamethasone and mydriatics drops with intravenous methyl prednisolone 1 g for 5 days followed by oral steroids. After 3 months of tapering doses of steroids and immunosuppression, symptoms resolved (Fig. 14) with bilateral sunset glow fundus (Fig. 15) and her BCVA improved to 20/80 in both the eyes.

Ocular Ultrasound and its Clinical Applications Fig. 11 High-resolution USG with the 20-MHz probe delineates the posterior segment of the eye including the macula (arrow) better than 10-MHz probe

Fig. 12 Anterior segment photograph of both eyes showing mutton fat keratic precipitates on the posterior corneal surface (white arrows) with iris nodules (blue arrow). Note the presence of iris bombe in all quadrants (black arrow)

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Fig. 13 Ultrasonography revealed bilateral retinochoroidal thickening seen as increased thickness between the hyper reflective retina (white arrow) and the posterior layers of choroid (black arrow)

Fig. 14 Anterior segment photograph of the above case showing resolution of inflammation and development of festooned pupil after treatment

Fig. 15 Posterior segment photograph of the above case showing bilateral sunset glow fundus

Ocular Ultrasound and its Clinical Applications

Fig. 16 Anterior segment photograph of the right eye of the patient with total white cataract with ectropion uvea along with large fluffy white cells with hypopyon in the anterior chamber

Case 2: Leukocoria with Hypopyon in a 5-Year-Old Girl A 5-year-old girl presented with a whitish opacity in the right eye. Her parents noticed this opacity 1 month back. At presentation, her best-corrected visual acuity (BCVA) was 20/40 in the right eye and light perception in the left eye. Anterior segment examination on slit lamp biomicroscopy of the left eye revealed a total white cataract with large cells in the anterior chamber with hypopyon (Fig. 16). USG of the left eye was done, as there was no view of the posterior segment. USG revealed mass lesion in the eye along with calcification (Fig. 17). USG helped in clinching the diagnosis of retinoblastoma. Key Points • Ultrasound has become a standard tool in the hands of retina and uvea specialists.

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Fig. 17 Ultrasonography revealed mass lesion in the posterior segment along with calcification (arrow)

• The 10 MHz probe provides an excellent resolution of the posterior segment of the eye quiet well, especially in eyes with poor media. • Ultrasonography is a reliable tool for the diagnosis and evaluation of intraocular inflammatory conditions, especially in cases where media clarity is poor. • Ultrasound studies should be used in conjunction with detailed clinical examination in cases of uveitis.

Suggested Reading Baum G, Greenwood I. The application of ultrasonic locating techniques to ophthalmology. II. Ultrasonic slit lamp in the ultrasonic visualization of soft tissues. Arch Ophthalmol. 1958;60:263–79. Bronson NR. Development of a simple B scan ultrasonoscope. Trans Am Ophthalmol Soc. 1972;70:365–408. Hewick SA, Fairhead AC, Culy JC, Atta HR. A comparison of 10 MHz and 20 MHz ultrasound probes in imaging the eye and orbit. Br J Ophthalmol. 2004;88(4):551–5. Mundt Jr GH, Hughes Jr WF. Ultrasonics in ocular diagnosis. Am J Ophthalmol. 1956;41:488–98.

Ultrasound Biomicroscopy and its Clinical Applications Savleen Kaur and Ramandeep Singh

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 The Hardware . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 The Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Normal Appearance of Iris, Ciliary Body, and Pars Plana on UBM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Case 1: Case of Pediatric Uveitis with Hypotony . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Case 2: Lesion in the Anterior Chamber Angle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Case 3: Unusual Case of Ciliary Body Granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Introduction Pavlin et al. in the 1990s invented high-frequency transducers that helped examine the minor details of the anterior segment of the eye. High frequency meant higher resolution and lesser penetration and was ideal to observe the outer coats of the eye. The subsurface of the eye constituting the anterior segment, till then, was entirely missed while imaging by the conventional 10 MHz ultrasound probe due to its greater penetration. 50 MHz was found to be an ideal compromise between depth and resolution that provided a highly magnified image of the anterior segment. The 50 MHz probe provides real-time imaging of the anterior structures in a noninvasive manner. Though a250nterior segment optical coherence tomography (ASOCT) can obtain higher axial resolution (up to 18 μm), in a noncontact method, it is not able to visualize ciliary body or structures behind the iris, whereas UBM can view these structures very effectively. Advantages of UBM

S. Kaur · R. Singh (*) Department of Ophthalmology, Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_9

include penetration beyond the posterior iris, established reliability of measurements, and good correlation of measurements with histological samples.

The Hardware The UBM consists of a monitor, mouse, probe with the transducer, probe holder, foot switch, the central processing unit, and the printer with accessories such as eye cups (plastic or silicon, PMMA) of various sizes with paradigm machine and clearscan tips or disposable windows with the new model Quantel machines. The transducer is the most important component. It converts the electric current to ultrasonic sound waves, which are transmitted to the ocular structures. The waves when reflected back are again converted by the transducer into electric signals relayed to the amplifier and the monitor. The central processing unit harbors the signalprocessing unit, which processes the radio waves. The standard UBM operates at 50 MHz and provides lateral and axial physical resolutions of approximately

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50 μm and 25 μm, respectively. The depth of penetration is 4–5 mm. A 50 MHz probe means that the piezoelectric crystal produces sound waves at 50 MHz that travel to the tissue and are reflected back. In addition, 25 MHz and 35 MHz probes too are available by some manufacturers. The transducer linear motion technology implicates better image resolution by improving the perpendicularity of the ultrasound beam over the anterior chamber structures. It provides an image resolution of approximately 70 μm. Additional benefits include a lighter design and less vibration when performing an ultrasound, reducing fatigue to the user.

The Technique Scanning is performed with the patient in the supine position using topical anesthesia in the outpatient clinic. A plastic eyecup/open shell of the appropriate size is inserted between the lids. The usually available sizes are 20 mm, 22 mm, 24 mm, and 26 mm in diameter. The cup is filled with normal saline/methylcellulose as coupling medium. Cornea, lens, and anterior chamber create a noise because of close contact with the probe. Medium is required to provide a path for the ultrasound waves to transmit as these cannot travel in air, hence overcoming the acoustic dead zone. It also acts as a barrier to protect the cornea from the moving transducer. Newer products like ultrasound probe covers provide a liquid bath as well as a sterile barrier enabling examination in a sitting position and preventing spread of infection between patients. AVISO A/B machine from Quantel Medical, Bozeman, Montana, uses higher scan rates and more compact handheld probes with a membrane-enclosed tip applied to the eye after topical anesthetic or even through closed lids.

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Radial/Longitudinal: UBM transducer is held over the area to be scanned and moved to and fro across the limbus, with the oscillations perpendicular to the limbus at the specific clock hour to be examined (Fig. 1). The line on the probe faces the cornea. The screen shows the sclera on the left side and the cornea on the right side regardless of the clock hour imaged. This scan is useful to image the angle. While visualizing the nasal angle, the patient is asked to look temporally; whereas while visualizing the superior angle, the patient is directed to look inferiorly and vice versa. Transverse scan: The probe is held at 90 to a radial line at the limbus (Fig. 2). It takes the cross section of the ciliary body when it is placed over it. It can be used as a screening scan to visualize large area of ciliary body in any of the quadrant. Sulcus to sulcus scan (axial): It takes the scan of the anterior segment from front to back. It requires patient cooperation and exact centration of the eye. The probe should be placed in the centre of the cornea with the patient looking in the primary gaze. The marker line pointing in the superior position gives a vertical axial scan and marker in the nasal position gives the horizontal scan (Fig. 3). The real-time image displayed on a video monitor can be recorded on videotape for later analysis.

Pearls 1. Avoid air bubbles in the coupling medium 2. Orient the transducer probe such that the beam strikes the target surface perpendicularly to maximize transmission

Normal Appearance of Iris, Ciliary Body, and Pars Plana on UBM Types of Scans The white line on the side of the probe body indicates the direction of the linear movement of the transducer.

The UBM has an ability to identify normal structures with finer details. Identification of these structural details helps us in identifying and understanding pathogenesis of various

Fig. 1 UBM scan in a normal subject depicting a radial scan, which is acquired when UBM transducer is moved over the specific clock hour (area of interest) with the oscillations perpendicular to the limbus. UBM

shows the sclera on the left side and the cornea on the right side in the picture regardless of the clock hour imaged. The ciliary body can also be well visualized in this picture in this radial scan (arrow)

Ultrasound Biomicroscopy and its Clinical Applications

entities. While dealing with cases of uveitis, one must learn to examine the iris, ciliary body, pars plana, and peripheral retina. The cornea in a normal eye is a multilayered structure, with a highly reflective Bowman’s membrane and Descemetendothelial complex. The stroma shows irregular reflectivity. The cornea-scleral junction or limbus can be differentiated as the junction between the relatively radiolucent cornea and the high-reflectivity sclera. These structures are best seen with sulcus-to-sulcus scan. The anterior chamber is seen as an echo-free space between the posterior surface of the cornea and the anterior surface of iris and lens in the middle. The normal depth of the anterior chamber is 2.5–3.0 mm (Fig. 4). In a normal eye, the iris has a planar configuration with a slight anterior bowing. It has uniform echogenicity. The posterior iris epithelium has higher reflectivity (Fig. 5).

Fig. 2 UBM scan in a normal patient depicting a transverse scan, which is acquired when the probe is held at 90 to a radial line across limbus. The ciliary processes in the form of finger-like projection are seen in this scan (arrow)

Fig. 3 UBM scan in a normal patient depicting sulcus to sulcus scan, which is acquired when the probe is placed over the center of the cornea with the marker line pointing towards the nose. It gives a simultaneous broad view of both the angles

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The reflectivity of posterior iris epithelium membrane helps us in differentiating retroiridial lesions from those that are intra-iridial. Various iris pathologies, cystic or granulomatous, can be picked up with UBM. Retroiridial space is a clear, echo-free space between the posterior surface of iris and anterior capsule of lens (Fig. 5). The anterior chamber angle in a normal eye is seen clearly as wide and clear structure at the periphery of cornea and iris. Anterior chamber angle can be seen in radial scan at the limbus (Figs. 1 and 5). The ciliary body is best visualized using the radial scan. It can be imaged at every clock hour (Fig. 1). It is seen as triangular echo dense area posterior to the area of the iris insertion. The ciliary processes are seen as finger-like projection with the transverse UBM scan (Fig. 2). This transverse scan will produce broader view of ciliary body. Changes seen in the ciliary body in the form of thickening or thinning are very informative for the diagnosis and management of various uveitic entities. The zonules can be visualized as a medium reflective line between the ciliary processes and the lens surface (Fig. 6). Imaging of the pars plana and extreme peripheral retina with the UBM permits study of the morphological alterations in this region. It also allows imaging the peripheral vitreous as well. Imaging of the inferior pars plana area and vitreous with UBM helps us to diagnose intermediate uveitis especially in eyes with poor media and non dilating pupil. However this imaging is gaze dependent and requires a cooperative patient especially for nasal scans (Fig. 7). The sclera and the episclera can be examined in all four quadrants. Scleral thickness can be measured and monitored. The external limit of the sclera can be identified by the deep episcleral vascular plexus, which manifests as a thin hypo reflective space above the solid scleral tissue (Fig. 8). The

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Fig. 4 Sulcus to sulcus UBM scan showing the normal anterior chamber seen as an echo-free space between the posterior surface of the cornea and the anterior surface of iris. The chamber depth can be measured with the caliper tool (yellow arrow)

Fig. 5 Radial UBM scan showing normal iris has a planar configuration with a slight anterior bowing and a highly reflective posterior iris epithelium (red arrow). We can also see clear retroiridial space (green arrow) and anterior chamber angle in this radial scan (blue arrow)

scleral spur is seen as small echogenic dot when the line between the sclera and ciliary body is traced to the anterior chamber.

Case 1: Case of Pediatric Uveitis with Hypotony

Fig. 6 Radial UBM scan showing normal zonules arising for the ciliary body as a medium reflective line between the ciliary processes and the lens

A 7-year-girl, a newly diagnosed case of Juvenile Idiopathic Arthritis (JIA) (oligoarthritis type) presented with painless gradually progressive diminution of vision in both eyes for the last 2 months. She was already on oral methotrexate and oral wysolone for her systemic disease. On clinical examination, visual acuity was counting fingers in the right eye (OD) and 2/60 in the left eye (OS). IOP was 5 mmHg OD and 6 mmHg OS with Goldmann Applanation tonometery. The anterior segment of both eyes revealed complicated cataract with 360 posterior synechiae and keratic

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Fig. 7 Radial UBM scan showing pars plana area and vitreous space below it

Posterior segment showed complete oil fill with no disc edema in both eyes.

Case 2: Lesion in the Anterior Chamber Angle

Fig. 8 UBM scan in a normal patient depicting the solid scleral tissue and a hyporeflective space due to episcleral vessels (yellow arrow)

precipitates (Fig. 9). The posterior segment showed elevated disc suggested of disc edema on B scan ultrasound in both eyes. In view of disc edema and low IOP, UBM was planned to find the cause of hypotony. UBM demonstrated an atrophic ciliary body with cyclitic membrane covering the ciliary body in all quadrants in both the eyes (Fig. 10). Pars plana lensectomy with vitrectomy alongwith cyclitic membrane removal and 5000 cc silicon oil tamponade was done in both eyes (Fig. 11). At 6 months follow-up visit, her BCVA was 20/60 in both the eyes. IOP was 10 mmHg in both eyes with Goldmann Applanation tonometery. She has quiet anterior chamber both eyes except for emulsified oil with inverse hypopyon in the right eye (Fig. 12).

A 28-year-old male presented with a white color lesion in the anterior chamber angle in the right eye. He noticed gradual growth in the lesion size. His best-corrected visual acuity (BCVA) was 20/100 in the right eye and 20/20 in the left eye. Slit lamp examination of the right eye showed translucent white lesion in the angle at 8’o clock in the right eye filling the anterior chamber angle (Fig. 13) along with posterior subscapular cataract. Rest of the anterior segment and posterior segment examination of the right eye and the left eye was within normal limits. UBM was planned to know the posterior extent of the lesion and to know its relation with the iris and ciliary body. UBM of the lesion revealed a mass lesion arising from the ciliary body (Fig. 14). There was no involvement of the iris, pars plana, and sclera seen. After a thorough metastatic work up, the entire tumor was removed with partial iridocyclectomy (Fig. 15). At the last follow-up, his BCVA was 20/20 with pseudophakia and no evidence of recurrence.

Case 3: Unusual Case of Ciliary Body Granuloma A 15-year-old female presented with painful diminution of vision in the right eye for the last 2 months. Her bestcorrected visual acuity was perception of light in the right

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Fig. 9 Anterior segment of both eyes had complicated cataract with 360 posterior synechiae, keratic precipitates, and band-shaped keratopathy

Fig. 10 UBM of both eyes showing atrophic ciliary body (white arrow) and cyclitic membrane imaged as a relatively high-intensity tissue covering iris and the ciliary body (yellow arrow) in both eyes

Fig. 11 Preoperative photograph of the right eye showing thick cyclitic membrane covering the ciliary processes

eye and 20/20 in the left eye. Anterior segment examination revealed 360 posterior synechiae with pigments on lens surface with early complicated cataractous changes (Fig. 16). In view of dense vitritis, ultrasonography was done which demonstrated a lesion in the superonasal periphery with high reflectivity (Fig. 17). UBM of the right eye revealed ciliary body thickening in the superonasal area with hyporeflective area suggestive of abscess within, along with dense pars plana exudates (Fig. 18). Patient was diagnosed with presumed ocular TB based on clinical signs, highly positive mantoux, and UBM findings suggestive of ciliary body thickening with abscess. She was treated with anti-tubercular therapy and had a good outcome.

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Fig. 12 Postoperative photograph showed quiet anterior chamber in both eyes except for emulsified oil with inverse hypopyon in the right eye

Fig. 13 Anterior segment photograph showing translucent white lesion in the angle at 8’o clock in the right eye filling the anterior chamber angle

Fig. 14 UBM of the lesion showing a mass lesion arising from the ciliary body

Fig. 15 Anterior segment photograph after partial iridocyclectomy and complete excision of tumor showing pseudophakia, peripheral iridectomy with no evidence of recurrence

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Fig. 18 UBM of the same area revealed ciliary body thickening in the superonasal area with echolucent area suggestive of abscess (green arrow) within, along with dense pars plana exudates (white arrow)

Fig. 16 Anterior segment examination of the right eye showing posterior synechiae, pigments on lens surface and complicated cataract

• It is a valuable clinical tool, does not require dilatation, and can be used as an adjunct to slit lamp examination. • The standard UBM provides depth of penetration of about 4–5 mm. • It can image the iris, retroiridial structures, ciliary body, and peripheral retina very well to diagnose and monitor cases of uveitis.

Suggested Reading

Fig. 17 Ultrasonography of the right eye showing hyperdense lesion in superonasal area (green arrow)

Key Points • UBM is a noncontact and noninvasive investigation modality, which provides a high resolution, crosssectional, biomicroscopic image of the anterior structures of the eye.

Dorairaj S, Liebmann JM, Ritch R. Quantitative evaluation of anterior segment parameters in the era of imaging. Trans Am Ophthalmol Soc. 2007;105:99–110. Gupta P, Gupta A, Gupta V, Singh R. Successful outcome of pars plana vitreous surgery in chronic hypotony due to uveitis. Retina. 2009;29 (5):638–43. Ishikawa H. Anterior segment imaging for glaucoma: OCT or UBM? Br J Ophthalmol. 2007;91:1420–1. Li H, Leung CKS, Cheung CYL, et al. Repeatability and reproducibility of anterior chamber angle measurement with anterior segment optical coherence tomography. Br J Ophthalmol. 2007;91: 1490–2. Mundt Jr GH, Hughes Jr WF. Ultrasonics in ocular diagnosis. Am J Ophthalmol. 1956;41:488–98. Pavlin CJ, Sherar MD, Foster FS. Subsurface ultrasound microscopic imaging of the intact eye. Ophthalmology. 1990;97:244–50.

Grades of Vitreous Clarity Brian Madow and John H. Kempen

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Vitreous Haze . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Case 1: Severe Vitreous Haze Due to Infectious Uveitis, with Dramatic Clearing After Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Case 2: Severe Bilateral Vitreous Haze Due to Noninfectious Posterior Uveitis with Significant Clearing in Both Eyes After Treatment with Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Introduction The vitreous humor is a transparent gel-like structure occupying the space between the retina, ciliary body, and the lens. The vitreous body forms very early during pregnancy and undergoes rapid transformation in three phases. First, the primary vitreous develops at month one of gestation, representing the vascular structure necessary to support the development of the lens. During the second month of gestation, the vitreous, denoted as secondary vitreous, loses its vascularity and becomes much more transparent. The tertiary vitreous arises in the third month of gestation and surrounds the secondary vitreous. Maximum vitreous clarity is present at term (Fig. 1). The most important function of the vitreous from the sensory standpoint is to allow transmission of visible light to the retina. The clarity required to transmit light appropriately is accomplished not only because of its high water content (approximately 98%) but also because nerves and blood vessels

are absent within the structure of the vitreous. Vitreous clarity and light transmission capabilities also are functions of the index of refraction of the vitreous body reported to be equal to 1.336. This value is very similar to the refractive index of the aqueous humor. Vitreous clarity also depends on the specific structural composition and high level of organization of the collagen fibers with diameter of 10–25 nm. In order to maintain the optical transparency, the vitreous body has a barrier function and buffering properties, both of which prevent cells and proteins from penetrating its structure due to the content of hyaluronic acid. Condensation of the peripheral collagen fibers creates strong transparent boundary membrane or cortex and aids in the barrier function. As a result, the vitreous content of macromolecular solutes, which are known to decrease light scattering, is very low. These properties allow the vitreous body to transmit a very high proportion of visible light, reportedly 90%.

Vitreous Haze B. Madow (*) University of South Florida, Tampa, FL, USA e-mail: [email protected] J. H. Kempen Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_3

Vitreous haze from uveitis is produced by penetration of inflammatory cells and protein exudation into the vitreous from adjacent structures such as the ciliary body, choroid, and retina. The result is a variable degree of obscuration of the fundus details which impacts visual acuity more profoundly than does anterior chamber inflammation (Fig. 2). 45

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The vitreous haze of uveitis presumably is caused by inflammation itself. In an experimental model of uveitis, it was found that the degree of the vitreous inflammation was dependent on the concentration of the protein induced by the inflammation in the vitreous but inversely related to the concentration of the hyaluronic acid. Vitreous opacification from other causes, such as vitreous hemorrhage, also can occur. Cryotherapy application during retinal detachment surgery also has been described to increase vitreous haze, perhaps because of protein seepage from the inflammation induced by cryotherapy. The rate of clearing of the vitreous haze has been studied and was found to be similar in vitrectomized and non-vitrectomized eyes, suggesting that factors external to

Fig. 1 Drawing of the vitreous clarity development

Fig. 2 Drawing of the vitreous haze formation in intermediate (a) and posterior uveitis (b)

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the vitreous are of principal importance. Based on clinical observations, severe vitreous haze tends to clear much slower than the aqueous cells often taking several weeks for significant change with corticosteroid treatment. Complete clearance may take much longer.

Vitreous Clarity Grades Current clinical concepts for measurement or quantitation of the vitreous haze or opacification resemble the methods used by the environmental sciences. The method of turbidimetry has been used widely to determine the level of cloudiness as an inverse measure of clarity of the water in lakes, reservoirs, and channels. It is designed to quantitate the intensity of the transmitted light through a sample of water. A simple device, known since 1864 as a Secchi disk, has been used for quantitation. The disk has black and white sectors on its surface; it is submerged in the tested water until the visibility of the surface sectors is lost. The distance from the surface of the water is recorded and is expressed as a measurement of water transparency. Similarly, when vitreous cavity opacification is measured clinically, the currently accepted methods rely on the determination of the level of visibility of the natural fundus landmarks such as the optic nerve head and the retinal blood vessels. Since the distance from the light source to the focused retina remains approximately constant during the eye examination, it is more practical to determine the degree of obscuration, starting with the smallest perifoveal vessels until the optic nerve head is not visible anymore. The extent of obscuration is transformed into gradations of vitreous haze. The levels need to be characterized precisely

Grades of Vitreous Clarity

and described accurately in order to be useful for clinical grading. The first attempt at grading vitreous haze was described by Kimura et al., in 1959. The authors offer a descriptive five-step scale with levels from 0 to ++++. Level (0) represents a clear view without opacities, level (+) opacities with clear view, level (++) fundus details somewhat obscured, level (+++) opacities with marked blurring of the fundus, and ++++ no view of the fundus. This scale’s gradations are imprecise because not all the factors contributing to vitreous haze are described; hence, the scale was of limited value for clinical use. An improved scale for vitreous haze grading was described in 1985 by Nussenblatt et al. This “NEI” scale not only uses a better description of the vitreous opacification levels but also offers photographic standards for each level (Fig. 3). The NEI scale has six ordinal grades of vitreous opacification ranging from (0) to (4 +). Level (0) represents clear fundus view and level (4+) is full obscuration of the fundus details. Those two extreme grades are similar to those in the Kimura scale. The levels adjacent to these extremes are “trace” (with slight blurring of the optic disk margin) and (3+) (where the optic disk is visible but the retinal vessels are not visible). For grade (2+), some retinal vessels are visible. Level (1+) offers better visibility of the optic disk and the vessels than level (2+). All steps are represented by three standard color film-based photos to account for variations within the levels, except for level (4 +), which is represented by one standard photograph. An expert panel subsequently suggested changing the name of the grade “trace” to “0.5 +.”

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Currently the NEI scale is accepted by the US Food and Drug Administration (FDA) as a surrogate measure of the disease activity in intermediate, posterior, and panuveitis suitable for use as a primary outcome in therapeutic trials. Excellent agreement within 1 grade has been reported for vitreous haze grading in clinical settings. Limitations of the scale include its ordinal rather than quantitative basis (steps are not established to be equal distances from one another) and that the scale offers limited resolution of the vitreous haze grades, especially when low to moderate levels of opacification are present as is typical with uveitis. Because most cases fall in the category of 0.5+ or 1+ haze, the scale does not offer enough discrimination in order to meet reliably the requirement for two-step change as an indicator of treatment effectiveness in clinical trials, unless enrollment is limited to the small subset of cases with 2+ or higher vitreous haze. This limitation creates logistical problems in enrolling sufficient patients and raises generalizability concerns even when this obstacle can be overcome. In order to avoid these limitations, another vitreous haze scale was designed and described in 2010 by Davis and associates. The new “Miami” scale is more photographic and less descriptive and offers more levels of vitreous haze discrimination at the lower end of opacification; it has nine levels (Fig. 4). In this scale, high-quality 30 standard color fundus images were precisely generated to represent the haze levels. Each image was produced by using Bangerter foils17 with designated grade of artificial visual degradation in front of the

Fig. 3 Vitreous haze scale published by Nussenblatt RB, Palestine AG, Chan CC, Roberge F (Reprinted with permission)

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Fig. 4 Photographic vitreous haze scale by J. Davis, B. Madow, J. Cornett, R. Stratton, D. Hess, V. Porciatti, W. Feuer (Reprinted with permission)

camera, when the retina of a normal subject was photographed. The foils were chosen based on their expected correspondence to the visual acuity level. The visual acuity interval between two consecutive foils was selected to represent a difference of approximately 0.3 logMAR units. The scale was validated on the set of photographs from the Multicenter Uveitis Steroid Treatment (MUST) Trial, showing very high intra and interobserver agreement in the reading center setting. In clinical setting, however, a modest exact agreement was reported and excellent agreement within one step for both scales. The recommendations for clinical grading using both of these scales include dark room environment, well-dilated pupil, and conducting indirect ophthalmoscopy using a setting of mid to high level of the light source brightness with a +20.0 or +28.0 diopter aspheric lens. The view from the ophthalmoscope is compared to a printed copy of the scale on non-glossy paper, which is placed in close proximity to the patient.

Case 1: Severe Vitreous Haze Due to Infectious Uveitis, with Dramatic Clearing After Treatment A-52-year-old previously healthy immunocompetent man presented with decreased vision (counting fingers at 2 ft) in his right eye and anterior chamber reaction characterized by the presence of (1+ grade) white cells. The patient had vitreous haze with severity grading of (3+ grade) by the NEI scale and (7+ grade) with Miami scale (Fig. 5). The vitreous had (3+ grade) cells. Large, deep, white confluent retinal plaques were seen in the inferior retinal periphery. The patient was diagnosed with acute retinal necrosis and started on valacyclovir and oral steroids (Fig. 6). One month later his vision recovered to 20/20, and vitreous haze has completely cleared together with resolution of the peripheral retinitis (Fig. 7).

Grades of Vitreous Clarity

Fig. 5 Fundus photograph of the right eye showing vitreous haze with barely visible optic nerve and retinal vessels

Fig. 6 Control fundus reflex photograph of the right eye showing that there are no significant corneal or lens opacities to account for the retinal blurring and that the vitreous haze is solely caused by severe inflammation

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Fig. 7 Fundus photograph of the right eye showing clear retinal vasculature and optic disk after vitreous haze has cleared completely

Fig. 8 Fundus photograph of the right eye showing hazy vitreous with no visible retinal vasculature and barely visible optic nerve before treatment

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Suggested Reading

Fig. 9 Fundus photograph of the right eye showing dramatic vitreous haze clearing after treatment

Case 2: Severe Bilateral Vitreous Haze Due to Noninfectious Posterior Uveitis with Significant Clearing in Both Eyes After Treatment with Corticosteroids Participant in the MUST clinical trial with significant bilateral vitreous haze graded as (8 + grade) on Miami scale and (3+ grade) on the NEI scale in the right eye (Figs. 8 and 9). Key Points • The vitreous is a transparent gel-like structure. • Vitreous clarity develops early in life. • Vitreous clarity depends on the specific structural composition and the high level of molecular organization of the vitreous. • Vitreous haze in patients with uveitis is produced by penetration of inflammatory cells and protein exudation into the vitreous. • Vitreous clarity can diminish in infectious as well as in noninfectious uveitis. • Vitreous haze is accepted as surrogate marker for the disease activity in intermediate posterior and panuveitis, suitable for use as a primary outcome measure in clinical trials. • Current clinical concepts for measurement or quantitation of the vitreous haze or opacification resemble the methods used by the environmental sciences. • Scales for clinical grading have been developed. • Nussenblatt’s (NEI) vitreous haze scale is suitable for clinical use and clinical trials. • Davis’s (Miami) scale – suitable for clinical use, clinical trials, and reading center grading.

Boettner EA, Wolter JR. Transmission of the ocular media. Invest Ophthalmol Vis Sci. 1962;1:776–83. Davis J, Madow B, Cornett JI, et al. Scale for photographic grading vitreous haze. Am J Ophthalmol. 2010;150(5):637–41. Gao Q, Chen X, Ge J, Liu Y, Jiang Z, Lin Z, Liu Y. Refractive shifts in four selected artificial vitreous substitutes based on GullstrandEmsley and Liou-Brennan schematic eyes. Invest Ophthalmol Vis Sci. 2009;50(7):3529–34. Ghosn CR, Li Y, Orilla WC, Lin T, Wheeler L, Burke JA, Robinson MR, Whitcup SM. Treatment of experimental anterior and intermediate uveitis by a dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci. 2011;52(6):2917–23. Hornbeak DM, Payal A, Pistilli M, Biswas J, Ganesh SK, Gupta V, Rathinam SR, Davis JL, Kempen JH. Interobserver agreement in clinical grading of vitreous haze using alternative grading scales. Ophthalmology. 2014;121(8):1643–8. Hultsch E. Peripheral uveitis in the owl monkey: experimental model. Mod Probl Ophthalmol. 1977;18:247–51. 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. Kempen JH, Ganesh SK, Sangwan VS, Rathinam SR. Interobserver agreement in grading activity and site of inflammation in eyes of patients with uveitis. Am J Ophthalmol. 2008;146(6):813–8. Kempen JH, Altaweel MM, Holbrook JT, Jabs DA, Sugar EA. Multicenter uveitis steroid treatment trial research group, the multicenter uveitis steroid treatment trial: rationale, design, and baseline characteristics. Am J Ophthalmol. 2010;149(4):550–61. Kimura SJ, Thygeson P, Hogan MJ. Signs and symptoms of uveitis: II. Classification of the posterior manifestations of uveitis. Am J Ophthalmol. 1959;47(5, Pt 2):171–6. Lowder C, Belfort Jr R, Lightman S, Foster CS, Robinson MR, Schiffman RM, Li XY, Cui H, Whitcup SM. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011;129(5):545–53. Madow B, Galor A, Feuer WJ, Altaweel MM, Davis JL. Validation of a photographic vitreous haze grading technique for clinical trials in uveitis. Am J Ophthalmol. 2011;152(2):170–6. Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology. 1985;92(4):467–71. Odell NV, Leske DA, Hatt SR, Adams WE, Holmes JM. The effect of Bangerter filters on optotype acuity, vernier acuity, and contrast sensitivity. J AAPOS. 2008;12(6):555–9. Ogston AG, Sherman TF. Effects of the hyaluronic acid upon diffusion of solutes and flow of solvents. J Physiol (Lond). 1961;156:67–74. Pelegrín L, de la Maza MS, Molins B, Ríos J, Adán A. Long-term evaluation of dexamethasone intravitreal implant in vitrectomized and non-vitrectomized eyes with macular edema secondary to non-infectious uveitis. Eye (Lond). 2015;29(7):943–50. Secchi Memoria del PA. Relazione delle esperienze fatte a bordo della pontificia pirocorvetta l’Immacolata concezione per determinare la trasparenza del mare. Il Nuovo Cimento. 1864;20 (1):205–38 Swann DA, Constable IJ. Vitreous structure II. Role of hyaluronate. Invest Ophthalmol. 1972;11(3):164–8. Theodossiadis G, Chatzoulis D, Karantinos D, Maguritsas N. Intraocular complications following Custodis-Lincoff operation. Arch Ophtalmol Rev Gen Ophtalmol. 1975;35(8-9):627–38.

Part II Algorithms and Differential Diagnosis of Uveitis

Anterior Uveitis: Differential Diagnosis Aniruddha Agarwal, Kanika Aggarwal, Aman Kumar, and Vishali Gupta

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Classification of Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Workup of a Case of Anterior Granulomatous Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Workup of a Case of Anterior Non-Granulomatous Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Case 1: Tubercular Anterior Granulomatous Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Case 2: Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Case 3: Viral Granulomatous Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Case 4: Juvenile Idiopathic Arthritis (JIA)-Associated Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Case 5: HLA-B27-related Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Case 6: Mobile Hypopyon in a Patient with Behcet’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Introduction The term “anterior uveitis” is used for a group of inflammatory disorders involving primarily the iris and the anterior chamber of the eye including iris, ciliary body, and retroiridal space. It is important to exclude the spillover inflammation in the anterior segment from the posterior segment (intermediate or posterior uveitis), before categorizing it as anterior uveitis. This can be done by ruling out any posterior segment pathology by dilating and examining the fundus. Further, all patients with anterior uveitis should be categorized into granulomatous versus non-granulomatous for listing the differential diagnosis and getting tailored laboratory investigations. It is important to know that this A. Agarwal · K. Aggarwal · A. Kumar · V. Gupta (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_11

classification is not based on histopathology. It is purely based on the clinical characteristics, though some of the etiologies like tuberculosis and sarcoidosis, that may present as granulomatous anterior uveitis, have an underlying granulomatous histopathology. Granulomatous anterior uveitis is characterized by an insidious onset with a long course of symptoms and presence of iris nodules (both Koeppe’s and Busacca’s nodules). Medium-tolarge keratic precipitates (KPs) are seen in patients with granulomatous anterior uveitis in contrast to fine and smaller KPs in non-granulomatous type of anterior uveitis. Non-granulomatous uveitis, on the other hand, is characterized by fine KPs that produce endothelial dusting. KPs in granulomatous uveitis are better individualized compared to non-granulomatous ones. The size of KPs in granulomatous variety of uveitis would depend upon the etiology. Medium-tolarge size granulomatous KPs are called mutton fat KPs. Other features of granulomatous anterior uveitis include presence of Koeppe’s nodules at the pupillary border and/or Busacca’s nodules in the iris stroma. Additionally, hypopyon, 53

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synechiae, anterior segment neovascularization, iris atrophy, complicated (secondary cataract), irregular pupil ( festooned pupil), occlusio pupillae, raised intraocular pressure, hypotony (due to ciliary body atrophy), and neovascular glaucoma (end-stage disease) may be seen in both varieties of anterior uveitis as these are dependent on the amount of inflammation rather than the etiology. The posterior synechiae may be broad-based or filiform. There may be anterior synechiae leading to secondary angle-closure glaucoma. The grading of cellular reaction and flare in the anterior chamber helps in assessing activeness and severity of uveitis. Multiple infective conditions such as tuberculosis (TB), Lyme’s disease, herpes simplex and zoster, cytomegalovirus (CMV), leprosy, toxoplasmosis, as well as noninfective conditions such as sarcoidosis, and multiple sclerosis, among others have been linked with granulomatous anterior uveitis. The common causes of non-granulomatous anterior uveitis include HLA-B27-related uveitis, Behcet’s uveitis, juvenile idiopathic arthritis (JIA), tubulointerstitial nephritis and uveitis (TINU), uveitis associated with scleritis, psoriasis, among others.

Signs and Symptoms of Anterior Uveitis The symptoms of acute anterior uveitis depend upon the onset and severity of disease. Diseases with insidious onset such as TB causing granulomatous anterior uveitis may present with very few symptoms except diminished vision. On the other hand, HLA-B27-related disease causing non-granulomatous type of uveitis will present with acute onset of pain, redness, photophobia, and decreased vision. Signs: 1. Conjunctival Injection: Can be circumciliary congestion that is seen around the limbus or more diffuse. 2. Keratic Precipitates: As mentioned previously, the fine KPs with endothelial dusting is characteristic of nongranulomatous uveitis while moderate to large individualized KPs are seen in granulomatous type of uveitis. Fuchs uveitis has micro-granulomatous stellate KPs. 3. Anterior Chamber Flare: The flare in the normally optically empty anterior chamber is caused by the leakage of plasma proteins due to breakdown of blood aqueous barrier. A very high content of proteins leads to formation of fibrin that is characteristically seen in non-granulomatous anterior uveitis. The flare can be graded on slit lamp using 1 mm  3 mm slit lamp beam (Classification by Proctor Foundation San Francisco). Grade 0: No flare Grade 1: Faint, just detectable Grade 2: Moderate with clear iris details Grade 3: Marked with hazy iris details Grade 4: Intense, fibrin

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The flare in the anterior chamber can be quantified using Laser Flare photometer (LFP). LFP can be used effectively to monitor subclinical flare and to look for recurrence at the earliest. 4. Anterior Chamber Cells: Before one starts grading the cells, it is important to differentiate between inflammatory cells and pigment in anterior chamber that may be mistaken for cells. It is therefore important to grade the cells before pupillary dilation as there may be iris pigment dispersion post mydriasis. The cells are graded on slit lamp with 1  3 mm slit as follows: 0: No cells +: 1–5 cells +: 6–10 cells ++ 11–20 cells +++: 21–50 cells ++++: > 50 cells When cells are 4 + and dense, they settle down at the bottom of anterior chamber causing hypopyon that is commonly seen in non-granulomatous forms of anterior uveitis like HLA-B27-related uveitis or Behcet’s uveitis. 5. Intraocular Pressure (IOP): During the acute stage, IOP is low due to ciliary body shut down. High IOP with inflammation in anterior segment should raise the suspicion of viral anterior uveitis especially herpes simplex and zoster. In the chronic stage of disease like JIA, the eye undergoes hypotony that is mainly due to ciliary body atrophy or cyclitic membrane. Ultrasound biomicroscopy may help to detect ciliary body atrophy or cyclitic membrane.

Classification of Anterior Uveitis Once the anatomical diagnosis of anterior uveitis is confirmed, the presentation must be characterized either as nongranulomatous or granulomatous uveitis in order to narrow down the differential diagnosis and order targeted laboratory investigations. Granulomatous anterior uveitis is characterized by KPs which has a “volume.” Non-granulomatous KPs appear as “dusting” on the corneal endothelial surface. The medium- and large-sized white granulomatous KPs are called mutton-fat KPs. Other characteristic features of granulomatous uveitis are Koeppe’s and Busacca’s nodules at the pupillary margin (Koeppe’s) or within the iris stroma (Busacca’s). Synechiae are common in more pronounced inflammation. In FUS, the KPs are granulomatous in nature as they are medium sized, structured, and usually stellate shaped. The term granulomatous uveitis is in fact a misnomer because a histopathologic term is used to describe clinical conditions based on certain clinical features including specific KPs and iris nodules, among other clinical signs. Originally, the clinical term of granulomatous uveitis was still based on the histopathologic presence of granulomatous lesions which today is no more always the case.

Anterior Uveitis: Differential Diagnosis

Although this clinical distinction between granulomatous and non-granulomatous is a very useful classification, the subdivision is not an absolute one. A granulomatous uveitis may initially present as non-granulomatous before taking its granulomatous aspect. On the other hand, when dusty KPs are very numerous and thick, they may be mistaken as granulomatous. After the initial examination, one should be able to categorize anterior uveitis into granulomatous versus non-granulomatous. The further workup will depend upon this categorization.

Workup of a Case of Anterior Granulomatous Uveitis Prior to obtaining any diagnostic tests, it is important to exclude Fuchs’ uveitis syndrome (FUS) because this granulomatous condition, when sufficiently typical, does not need any workup or treatment (Fig. 1). This condition usually presents with stellate KPs (Fig. 2). Furthermore, corticosteroid treatment should be withheld in FUS to avoid the side effects of a treatment that usually has no impact on the inflammatory process. It is also relevant to exclude posterior segment involvement with spillover anterior segment inflammation. Spillover anterior granulomatous uveitis can occur in very inflammatory conditions such as toxoplasma retinochoroiditis. The most common causes of anterior granulomatous uveitis include sarcoidosis, tuberculosis, and viral etiologies. Raised intraocular pressure should raise the suspicion of possible viral etiology and one should look at other clinical features of viral uveitis including transillumination iris defects, reduced corneal sensations, among other features. In order to differentiate between tuberculosis and sarcoidosis, tuberculin skin test (TST) can be performed which indicates present or past infection with mycobacterium tuberculosis. Among patients with sarcoidosis, the tuberculin skin test may be negative. A negative TST, especially in BCG vaccinated population, is a strong indicator towards sarcoidosis. The additional laboratory tests performed include serum angiotensinconverting enzyme (ACE) and lysozyme. It is important to remember that ACE levels can be normally elevated in children and low in patients taking ACE inhibitors and systemic corticosteroids, and serum lysozyme levels tend to be progressively more elevated in elderly persons. It is therefore important to perform both tests. Contrast-enhanced computerized tomography (CECT) of the chest is useful in these patients to detect hilar lymphadenopathy in sarcoidosis and may be followed by biopsy under the supervision of pulmonologist to establish the histopathologic diagnosis of sarcoidosis. When the Mantoux test (tuberculin skin test) is positive, in the presence of compatible clinical signs such as granulomatous anterior uveitis, broad-based posterior synechiae, and mutton-fat KPs, this should raise the suspicion of a

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tuberculous granulomatous uveitis. An important test performed in addition to tuberculin skin testing is the gamma-interferon releasing assay (QuantiFERON ® TB gold). In these tests, the lymphocytes of patients are tested in vitro in order to detect whether there are lymphocytes reacting in vitro when put in presence with specific proteins coming from mycobacterium tuberculosis. When the patient’s lymphocytes release interferon gamma, it means that the patient has been exposed to the bacteria, and tuberculosis should be actively researched. CECT of the chest is done in these patients to detect presence of old calcified hilar lymph nodes or Ghon’s focus that would indicate past exposure to Mycobacterium tuberculosis. In cases where all these corroborative evidences are equivocal and TB is suspected, PCR from the aqueous humor may be performed. It is relevant to keep in mind other infectious causes of anterior granulomatous uveitis such as viruses. As mentioned previously, high IOP at presentation and iris atrophy should

Fig. 1 A case of Fuchs’ uveitis syndrome with iris nodules, anterior chamber reaction but no evidence of posterior synechiae

Fig. 2 Stellate keratic precipitates in a case of Fuchs’ uveitis syndrome

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raise suspicion of possible viral etiology. Clinical signs that are very suggestive of herpes simplex/zoster uveitis are ocular hypertension, iris atrophy, and hyphema (found both in herpes simplex and varicella-zoster uveitis). Laboratory confirmation of herpes simplex/zoster anterior uveitis can be obtained by the detection of intraocular production of antibodies in the aqueous humor (Goldmann-Witmer coefficient). Aqueous paracentesis can be performed in these cases when in doubt to detect presence of viral DNA using polymerase chain reaction. A negative polymerase chain reaction effectively rules out viral infection. Anterior chamber paracentesis can be performed in uveitis suspected to be herpetic but which does not respond to classical combined systemic antiviral and topical antiviral therapy to search for cytomegalovirus DNA in the aqueous. Syphilis serology is performed either routinely or in case of a positive history among patients with anterior granulomatous uveitis. In case of undefined diagnosis, serology for Lyme borreliosis is performed with the known limitations of the value of a positive serology. There are other rare conditions that can be associated with anterior granulomatous uveitis like multiple sclerosis (MS). Posterior segment findings such as periphlebitis and vitritis are usually present in patients with MS. MS can also present as intermediate uveitis. Although uveitis may be the only presenting feature of MS, a thorough history compatible with MS such as neurological impairment, multiple cranial nerve defects, and neuroimaging including cerebral MRI should be considered.

Workup of a Case of Anterior Non-Granulomatous Uveitis An asymptomatic child presenting with non-granulomatous anterior uveitis is most likely to have JIA or TINU. They must be tested for antinuclear antibody (ANA) to rule out JIS that typically presents in a white eye (inflammatory symptoms absent) and may have associated band-shaped keratopathy. Sometimes, signs of inflammation including hypopyon may be present in a totally asymptomatic eye. Most of these have oligoarticular form of JIA. ANA test must be done and is positive in up to 70% patients. Bilateral non-granulomatous uveitis in children could be a manifestation of TINU syndrome. Urine examination for beta-2 microglobulin, glucosuria, and renal function may be done. In cases where TINU is suspected, renal biopsy may be required to confirm the diagnosis. In case of young-middle aged patient (more commonly men) with acute onset fibrinous anterior uveitis with or without hypopyon, the main investigations are HLA B27 and radiology of sacroiliac spine. HLA B27 positivity helps in predicting the course of disease and also prevents

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investigating for several other etiologies. The disease tends to alternate between two eyes with multiple recurrences. Hypopyon uveitis may also be presenting sign of Behcet’s uveitis. However, fibrin is characteristically absent in patients with Behcet’s uveitis. Mobility of hypopyon is suggestive of Behcet’s disease. It is examine to dilate the fundus in these patients and look for any evidence of a patch of retinitis. In cases with doubt, fundus fluorescein angiography may be performed to look for an evidence of vascular leak especially capillary leak. Corticosteroids are the mainstay in the treatment for both granulomatous and non-granulomatous anterior uveitis along with cycloplegic agents such as topical atropine 1% which helps in reducing the ciliary spasm. In refractory conditions where infectious etiologies have been adequately ruled out, immunomodulatory agents such as adalimumab, infliximab, and other biological agents or immunosuppressive therapies such as azathioprine, cyclosporine, or methotrexate are used to reduce the ocular inflammation.

Case 1: Tubercular Anterior Granulomatous Uveitis Anterior uveitis that occurs due to presumed tubercular etiology has protean clinical manifestations. It usually presents with granulomatous inflammation with large mutton-fat KPs (Fig. 3) and iris nodules which can be either at the pupillary edge (Koeppe’s) (Fig. 4) or at the iris stroma (Busacca’s). Presence of broad-based posterior synechiae is highly predictive of tubercular anterior uveitis (Fig. 5). The sensitivity,

Fig. 3 Mutton-fat keratic precipitates in a patient with tubercular anterior uveitis

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specificity, and predictive values of various clinical signs of anterior segment involvement in tubercular uveitis are listed in Table 1. A 28-year-old female presented with decreased vision in her right eye for the past 2 months. She had no previous episodes in the past. She also complained of pain, redness, and watering. Assessment of best-corrected visual acuity (BCVA) was performed, which showed BCVA of 20/100 in the right eye and 20/20 in the left eye. Ocular examination revealed presence of anterior chamber cells 2+, flare 2+, and presence of posterior synechiae. There were large muttonfat keratic precipitates on the corneal endothelial surface (Fig. 6). Systemic evaluation was performed which revealed a positive Mantoux test of 20 mm induration at 48 h. She had bilateral hilar and paratracheal lymphadenopathy which was suggestive of a previous inflammatory pathology (consistent with tuberculosis). Thus, a diagnosis of presumed tubercular anterior uveitis was made, and the patient was treated with antitubercular therapy with topical and oral corticosteroids.

Case 2: Sarcoidosis Fig. 4 Koeppe’s nodules (at the pupillary edge) in a patient with tubercular anterior uveitis

A 39-year-old female (Asian Indian) presented with disturbance in vision in her left eye for the past 2 months. She had a previous episode of redness and pain in her left eye 10 years ago which was treated with topical corticosteroids. Ocular examination revealed a BCVA of 20/50 in the left eye and 20/20 in the right eye. Slit-lamp biomicroscopy revealed presence of mild anterior chamber reaction (cells 1+, flare 1+) and mutton-fat KPs in the inferior angle seen on gonioscopy (Figs. 7 and 8). At the time of this recurrence, she underwent a complete systemic evaluation. Her Mantoux testing revealed lack of any induration, and contrast-enhanced chest computerized tomography showed bilateral mediastinal lymphadenopathy. A diagnosis of presumed sarcoidosis was made, and the patient was started on oral corticosteroids and counselled regarding the need for systemic methotrexate.

Case 3: Viral Granulomatous Anterior Uveitis

Fig. 5 Broad-based posterior synechiae in a patient with tubercular anterior uveitis

A 28-year-old male presented with painful diminution of vision in the right eye for the past 15 days. He also complained of redness and watering. Examination revealed a BCVA of 20/50. The corneal sensations were slightly decreased in all the quadrants. The mean intraocular pressure measured 30 mm Hg in the right eye. Examination of the left eye revealed a normal visual acuity of 20/20 and intraocular pressure of 15 mm Hg. Slit-lamp examination revealed presence of 1+ cells and 1+ flare and granulomatous KPs (Fig. 9). There was evidence of mild iris atrophy involving the right

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Table 1 Diagnostic accuracy of anterior segment features in tubercular uveitis Clinical signs Mutton-fat keratic precipitates Broad-based posterior synechiae Iris nodules

Sensitivity (%) 7

Specificity (%) 93

Positive predictive value (%) 50

Negative predictive value (%) 53

Overall diagnostic accuracy (%) 53

32

93

79

60

47

2

98

55

53

53

Fig. 6 Large mutton-fat keratic precipitates in a young girl with tubercular anterior uveitis

Fig. 8 Gonioscopic image of the patient in Fig. 7 diagnosed with sarcoidosis shows presence of iris nodules involving the inferior angle

Fig. 7 Presence of iris nodules on the inferior iris angle in a young female with presumed sarcoid-related anterior uveitis

eye compared to the left eye. Anterior chamber paracentesis was positive for herpes virus DNA. The patient was started on oral valaciclovir 1 g three times a day, topical corticosteroids, and cycloplegic agents.

Fig. 9 Pigmented granulomatous keratic precipitates in a young male with herpetic anterior uveitis

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Fig. 10 Anterior segment photographs of a young child (case #4) with JIA-associated uveitis shows presence of peripheral band-shaped keratopathy and posterior synechiae (a). Slit-lamp examination reveals anterior chamber inflammation and iris deposition on anterior lens surface (b)

Fig. 11 Anterior segment photographs of the patient (Case #5) with HLA-B27-associated anterior uveitis shows presence of mild anterior segment inflammation with significant iris pigment deposition on the anterior lens surface (a). The slit-beam evaluation reveals faint flare (b)

Case 4: Juvenile Idiopathic Arthritis (JIA)-Associated Uveitis An 8-year-old boy presented with bilaterally reduced visual acuity, occasional pain, and redness for the past 3 months. There was a systemic history of small joint pains for which he was under evaluation with pediatric rheumatology. Examination revealed a BCVA of 20/100 in both the eyes. There was a

mild peripheral band-shaped keratopathy, and broad posterior synechiae inferiorly. There were 1+ anterior chamber cells and flare, and mild secondary cataract. Few iris pigments were deposited on the anterior lens surface (Fig 10a and b). The posterior segment was within normal limits, and there was no spillover vitritis. The patient was diagnosed with JIA-associated uveitis based on the systemic examination and laboratory findings.

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Fig. 12 Anterior segment photograph of the patient (Case#6) with Behcet’s disease shows presence of significant anterior chamber inflammation with hypopyon uveitis

Case 5: HLA-B27-related Uveitis A 26-year-old male presented with recurrent episodes of redness, pain and watering in both the eyes (alternating episodes) for the past 6 months. He also complained of early morning lower backache and stiffness of joints. Ocular examination revealed a BCVA of 20/30 in both the eyes. The intraocular pressures were normal (16 mmHg in both eyes). The patient had 0.5+ cells and mild flare in both eyes. There was significant pigment deposition on the anterior lens surface (Fig 11). The patient was evaluated by the internist, and his HLA-B27 testing by flow cytometry was positive. Magnetic resonance imaging (MRI) of the sacroiliac joint revealed reduced joint spaces and mild erosion, consistent with the diagnosis of HLA-B27-associated sacroiliitis and uveitis. The patient was initiated on systemic sulfadiazine and topical corticosteroids and cycloplegic agents.

Case 6: Mobile Hypopyon in a Patient with Behcet’s Disease A 24-year-old Asian Indian male presented with painful diminution of vision in the right eye for the past 1 month. There was significant redness, photophobia, and congestion. Examination revealed a BCVA of counting fingers at 2 m. There was significant circumciliary and diffuse conjunctival congestion. The mean intraocular pressure measured 10 mmHg in the right eye and 20 mmHg in the left eye. Slit-lamp examination revealed presence of a white hypopyon in the anterior chamber with 4+ anterior chamber cells

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Fig. 13 Anterior segment photograph of the same patient after lying down in right lateral position shows that the hypopyon is mobile and has tracked temporally

and flare (Fig. 12). The patient was asked to lie in right lateral position for 30 min. Slit-lamp examination after 30 min revealed presence of a mobile hypopyon which had shifted to the right (Fig. 13). The patient underwent detailed systemic examination by a rheumatologist, who determined presence of painful oral and scrotal ulcers. The HLA-B51 testing was positive, and the patient was diagnosed with Behcet’s disease. He was started on intravenous methylprednisolone (1 gm/day) along with intensive topical corticosteroid therapy (one hourly 1% betamethasone drops), cycloplegics, and laboratory workup was initiated prior to starting the patient on biological therapy.

Conclusion Granulomatous uveitis is a well-defined group of entities determined by a set of clinical signs including small to large/mutton-fat granulomatous KPs, Koeppe’s and Busacca’s nodules, iris infiltration, and often increased intraocular pressure, which differentiates it clearly from non-granulomatous uveitis and orients toward specific clinical entities. Key Points • An elaborate history taking and clinical workup is the cornerstone of differentiating a case of granulomatous from non-granulomatous anterior uveitis. • Recurrent chronic course and presence of mutton-fat keratic precipitates and nodules in anterior chamber are suggestive of granulomatous type uveitis. • Non-granulomatous anterior uveitis is characterized by fine keratic precipitates (KPs) no larger than dust may have associated fibrin or hypopyon.

Anterior Uveitis: Differential Diagnosis

• The differentiation is important to lead the investigations. • In the initial stages, granulomatous anterior uveitis can sometimes present itself as non-granulomatous. • Corticosteroids (mainly topical) are the mainstay of therapy along with cycloplegic agents and antiglaucoma drugs (if required). • Specific therapy needs to the added depending upon the etiology.

Suggested Reading Baarsma GS, La Hey E, Glasius E, de Vries J, Kijlstra A. The predictive value of serum converting enzyme and lysozyme levels in the diagnosis of ocular sarcoidosis. Am J Ophthalmol. 1987;104:211–7. De Schryver I, Rozenberg F, Cassoux N, Michelson S, Kestelyn P, LeHoang P, Davis JL, Bodaghi B. Diagnosis and treatment of cytomegalovirus iridocyclitis without retinal necrosis. Br J Ophthalmol. 2006;90:852–5. Herbort CP, Guex-Crosier Y, de Ancos E, Pittet N. Use of laser flare photometry to assess and monitor inflammation in uveitis. Ophthalmology. 1997;104:64–72.

61 Hogan MJ, Kimura SJ, Thygeson P. Signs and symptoms of uveitis: 1: anterior uveitis. Am J Ophthalmol. 1959a;47:155–70. Hogan MJ, Kimura SJ, Thygeson P. Signs and symptoms of uveitis. 1 Anterior uveitis. Am J Ophthalmol. 1959b;47:155–70. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130(4):492–513. James DG, Williams WJ. Immunology of sarcoidosis. Am J Med. 1982;72:5–8. Lim JI, Tessler HH, Goodwin JA. Anterior granulomatous uveitis in patients with multiple sclerosis. Ophthalmology. 1991;98:142–5. Mackensen F, Smith JR, Rosenbaum JT. Enhanced recognition, treatment and prognosis of tubulointerstitial nepritis and uveitis syndrome. Ophthalmology. 2007;114:995–9. McCannel CA, Holland GN, Helm CJ, Cornell PJ, Winston JV, Rimmer TG. Causes of uveitis in the general practice of ophthalmology. UCLA Community-Based Uveitis Study Group. Am J Ophthalmol. 1996;121(1):35–46. Tran VT, Auer C, Guex-Crosier Y, Pittet N, Herbort CP. Epidemiological characteristics of uveitis in Switzerland. Int Ophthalmol. 1995;18:293–8.

Differential Diagnosis of Hypopyon Uveitis Aniruddha Agarwal, Ilaria Testi, Ankur Singh, and Vishali Gupta

Contents Introduction: Why Is Hypopyon Uveitis Relevant? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Pathology and Pathogenesis of Hypopyon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Etiologies of Hypopyon Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Case 1: Toxic Hypopyon Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Case 2: Behcet’s Disease with Hypopyon Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Case 3: Post-traumatic Endophthalmitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Approach to a Case of Hypopyon Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Introduction: Why Is Hypopyon Uveitis Relevant? Hypopyon is defined as an inflammatory leukocytic exudate that sediments in the dependent part of the anterior chamber. Since it is not a general inflammatory response of the eye but it tends to occur in association with systemic conditions ranging from infectious or autoimmune diseases to neoplastic processes, detection of hypopyon is a valuable clinical sign not to be underestimated that can act as an alarm bell for the diagnosis of systemic diseases potentially leading to serious sequalae for

A. Agarwal · V. Gupta (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; [email protected] I. Testi Department of Ophthalmology, University of Padova, Padova, Italy e-mail: [email protected] A. Singh Advanced Eye Centre, Postgraduate Institute of Medicine and Research (PGIMER), Chandigarh, India e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_123

the patient. A careful questioning and a detailed examination of the eye with review of systems is hence mandatory to guide the differential diagnosis, identify the causative agent, and promptly start the most appropriate treatment.

Pathology and Pathogenesis of Hypopyon By definition hypopyon is a purulent exudative process of the anterior chamber, formed by cells and products derived from inflammatory response towards both exogenous and endogenous initiating factors. The response first consists of changes in blood flow with an increased permeability of iris vessels allowing migration of fluid, blood proteins, and recruited leukocytes out of the capillaries in the anterior chamber. Hypopyon consists of degenerated polymorphonucleocytes and macrophages, serum proteins including albumin, globulins, and fibrin, together with tissue destruction debris. Viable or nonviable microorganisms may be present if the inflammatory response is secondary to an infective intraocular process, while large amount of malignant cells may be found in neoplasia associated hypopyon. Causes can include infections, immune response to a trigger agent in a 63

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Conditions commonly causing hypopyon are divided according to the main etiology in infectious, noninfectious, masquerade, and iatrogenic. Among infectious uveitis (Fig. 1), toxocariasis, syphilis, leprosy, and brucellosis have been reported to be more frequently associated with hypopyon, but also severe herpetic iridocyclitis can induce an exudative process in the anterior chamber. Intraocular tuberculosis can present as hypopyon uveitis in extremely rare cases; thus, suspicion must be raised especially in endemic area. In the presence of sign of endophthalmitis, disease resulting from hematogenous spread of microorganism from a remote primary source is listed as endogenous or metastatic endophthalmitis, whereas if it occurs after traumatic or surgical continuity solutions of ocular coats are classified as exogenous. In endogenous endophthalmitis, patients often report history of surgical procedure elsewhere in the body or have an

associated medical condition as diabetes mellitus, renal failure, malignancies, or acquired immunodeficiency syndrome that predisposes to the development of the disease often characterized by purulent exudation in the anterior chamber most often caused by bacteria (Bacillus cereus, Klebsiella pneumoniae, and Fusarium among the Gram negative; Neisseria meningitidis, Listeria monocytogenes, or Hemophilus influenzae among the Gram positive) or fungi (most commonly Candida, Cryptococcus neoformans, Aspergillus, or Histoplasma capsulatum). The first site to be reached via central retina and ciliary arteries is the retina with a subsequent involvement of vitreous and eventually anterior chamber thorough blood ocular barrier crossing; less commonly the anterior segment of the eye is the primary site of inflammation. Ocular surgical procedures or trauma may lead microorganisms to enter the eye through the injury resulting in exogenous endophthalmitis, more commonly caused by Gram positive bacteria as Staphylococcus, Streptococcus, or Pneumococcus in postsurgical cases and Gram negative or fungi in traumatic ones. Cataract surgery, vitrectomy, and all other type of ocular surgery may be complicated by the an intraocular infective process characterized by hypopyon. Among systemic inflammatory non0infectious causes (Fig. 2), HLA B27-related uveitis, especially in association with spondyloarthropathy, and Behcet’s disease have an increased incidence of developing hypopyon due to severe anterior chamber inflammation. In particular HLA B27 acute anterior uveitis is the most common form of hypopyon uveitis, characterized by sudden onset of unilateral redness, blurring vision, pain, and photophobia associated with severe anterior chamber exudation with fibrin and hypopyon formation.

Fig. 1 Figure enlists the most common causes of infections that present with a hypopyon uveitis.

Fig. 2 The figure shows various causes of noninfectious entities, as well as neoplastic conditions that present with hypopyon uveitis

genetically susceptible individual or malignancies. All the conditions are able to induce the activation of the inflammatory pathway resulting in vascular damage, recruitment, and extravasation of leukocytes and inflammatory by-products due to production of chemotactic molecules and vasodilators as leukotrienes or bradykinin and tissue damage (Ramsay and Lightman 2001). Aqueous becomes cloudy with subsequent formation of a level of exudative sediment layered in the anterior chamber, whose consistency, appearance, and color depend on its causative agent and constituents.

Etiologies of Hypopyon Uveitis

Differential Diagnosis of Hypopyon Uveitis

Masquerade syndromes are a well-known cause of hypopyon uveitis. Leukemia, lymphoma, retinoblastoma, melanoma, and metastasis may cause hypopyon due to both the inflammatory response secondary to the disease and the direct invasion of malignant cells in the anterior chamber. In case of masquerades definition of pseudo-hypopyon would be more appropriate, since the material is not purulent but mainly consists of tumoral cells. Among malignant clonal disorders, acute lymphoblastic leukemia (ALL) is the most common and usually induces hypopyon uveitis in children between 2 and 10 years while Hodgkin’s lymphoma affected elderly population. Both the disorders may present as initial feature of an unknown underlying malignant condition or as a sign of recurrence. Masquerade syndromes should always be suspected by the presence of hypopyon failing to respond to corticosteroid treatment in a susceptible population. The presence of hypopyon uveitis with leukocoria in a child should always be awarded of retinoblastoma and differentiated from toxocariasis through diagnostic modalities as ultrasound or computerized tomography. Among medical agents, Rifabutin for M. Avium prophylaxis in HIV patients has been reported to be a causative agent of hypopyon uveitis, while the use of traditional eye medicines in the developing countries as leaf and root extracts or plant juice, sometime mixed with milk and black powder, is associated to an increase risk of hypopyon due to both the alkaline/acid effect and the lack of hygienic conditions and sterility. Among iatrogenic causes lens associated uveitis, retained surgical products or Nd-YAG capsulotomy/iridotomy and panretinal coagulation can induce an hypopyon uveitis. Lens associated uveitis is due to inflammation reaction caused by the release of lens proteins occurring days to weeks after surgical but includes also traumatic disruption of lens capsule or spontaneously due to a hypermature cataract acting through both a toxic and immuno-mediated process. Not all postoperative inflammation is infective but could simply be related to the surgical manipulation that itself induces a fibrinous anterior chamber exudation with formation of hypopyon. Usually the presence of clear posterior media makes you lean for a sterile hypopyon.

Case 1: Toxic Hypopyon Uveitis A 56-year-old male presented with painful diminution of vision in the right eye since 15 days. He has a history of instillation of topical drops (Herbal/Ayurvedic formulation) in both the eyes. The patient was seen elsewhere and diagnosed with hypopyon uveitis and started on oral

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steroids (oral prednisone 60 mg/day) which was stopped within 1 week. Due to lack of improvement, he was referred to our center. At the time of initial presentation, he had corneal edema, endothelial plaques, and hypopyon (Fig. 3). He was started on topical moxifloxacin, tobramycin, frequent topical steroids, atropine, dilators, and intravenous (IV) antibiotics. Anterior chamber paracentesis was negative for gram staining, potassium hydroxide 1% mount (KOH), polymerase chain reaction (PCR) for bacteria, fungi, and viruses. PCR for acanthamoeba was also negative. Cytology revealed polymorphs and macrophages, and parasitic infection was ruled out. After three doses of IV methylprednisolone, the hypopyon decreased. The patient was shifted to oral steroids and oral antibiotics. After a week of therapy, he has minimal hypopyon, corneal endothelial plaque (similar to presentation), and endothelial deposits. The hypopyon and inflammation resolved in 3 weeks.

Case 2: Behcet’s Disease with Hypopyon Uveitis A 25-year-old North-African male presented with complaint of progressive visual loss in both eyes over the last 1 year associated with episodes of redness and photophobia. He reported a history of recurrent bilateral unspecified panuveitis, discontinuously treated with systemic and topical corticosteroids with multiple exacerbations of disease, associated with intermittent migratory arthralgias and recurrent oral ulcers. His did not report any other symptoms and his past medical and familiar history was unremarkable. On examination, his best correct visual acuity was 20/100 in the right eye and counting fingers in the left eye. Anterior segment evaluation showed perilimbal hyperemia, anterior chamber reaction corresponding to 2+ cells and 4+ cells in the right and left eye, respectively, with hypopyon in the left eye (Fig. 4). Posterior segment showed 3+ vitreous haze with multiple inferior vitreous exudates in both eyes (Fig. 5). Fluorescein angiography revealed a bilateral diffuse fern-like appearance vasculitis not complicated by cystoid macular edema (Fig. 6). Laboratory investigations included complete blood count, ESR, liver and renal function test, Tuberculin Skin Test, VDRL, and TPHA. Topical corticosteroids (1 drop/h while awake with a slow gradual tapering) and cycloplegic eye drops were started. Tests were negative or within normal limits. Considering the presence of bilateral panuveitis characterized by fern-like pattern retinal vasculitis and unilateral hypopyon in a young male coming from the Mediterranean area with a history of recurrent oral ulcers and arthralgias, the patient was diagnosed with Behcet’s disease and started on systemic corticosteroids (prednisone 50 mg/day with a slow

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Fig. 3 The figure shows anterior segment photographs of the patient (case #1) who developed toxic hypopyon uveitis due to the use of herbal topical medication. There is presence of hypopyon and fibrin in the anterior chamber, along with significant corneal edema (a and b)

Fig. 4 Anterior segment photographs of the patient with Behcet’s disease (case #2) are shown (a and b). The examination of the right eye shows conjunctival hyperemia and chemosis, cells, and flare (a).

Examination of the left eye reveals conjunctival hyperemia and chemosis, anterior chamber reaction, mobile hypopyon with pupil fibrinous exudate (b)

tapering) and Azathioprine (started at 50 mg/day and progressive increased to 150 mg/day). There was an improvement in anterior and posterior segment inflammation, with the resolution of both hypopyon and vitritis and a complete regression of vasculitis in a 3 week time.

left eye. On anterior segment examination, right eye showed mucopurulent discharge, conjunctival hyperemia and chemosis, corneal ulceration with epithelial defect, anterior chamber 4+ cells, hypopyon with pupil fibrinous exudate, and a streak hypopyon (Fig. 7). Ultrasound B-scan of the right eye confirmed the presence of exudates in the vitreous cavity. Comprehensive examination of the left eye was normal. On suspicion of acute endophthalmitis following trauma was made (exogenous endophthalmitis). Patients were started on empirical topical and systemic broad spectrum antibiotic treatment (topical vancomycin 50 mg/ml and amikacin 20 mg/ml along with atropine sulfate 1% and prednisolone acetate 1%; systemic vancomycin (1 mg) plus ceftazidime

Case 3: Post-traumatic Endophthalmitis A 60-year-old man presented with complaints of pain, redness, and photophobia in the right eye associated with progressive visual loss for the last 3 days. He suffered trauma from a wire while working near a construction site. Best corrected visual acuity was 20/200 in the right, 20/20 in the

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Fig. 5 Fundus imaging of the patient #2 with Behcet’s disease shows presence of vitritis in both eyes (left eye more than right eye – a and b) along with multiple inferior vitreous exudates (c and d)

(2 mg)). Culture was positive for Staphylococcus epidermidis and antibiotic therapy was modified according to the antibiotic sensitivity profile of the cultured microorganism. At 1 week follow-up, patient’s vision had improved to 20/50, with residual 1+ cells in anterior chamber and resolution of hypopyon. The corneal ulcer showed signs of healing.

Approach to a Case of Hypopyon Uveitis Since hypopyon uveitis is mainly associated with underlying systemic diseases or predisposing medical conditions and risk factors, a careful questioning and a detailed physical examination with review of all the systems is mandatory for a correct diagnostic approach. Ophthalmic clinical signs must be correlated with a comprehensive ocular and systemic medical history to guide the physician in the differential diagnosis through a stepwise approach leading to

identification of the causative agent. Ancillary tests and investigations are ordered accordingly to preliminary clinical and ocular evaluation. Appearance and color of hypopyon can help in the differential diagnosis since depending on causative agents and constituents. Pigmented hypopyon is usually related to infective processes associated with intraocular tuberculosis and Listeria monocytogenes endophthalmitis or to malignant melanoma, while hemorrhagic hypopyon may be a presenting feature of lymphoma or leukemia. Several disorders most commonly affect certain age, sex, origin, or ethnicity groups. HLA B27 associated uveitis typically affects Caucasian man, while Bechet’s disease has a geographic distribution mostly involving Mediterranean areas and Japan. These findings together with a careful investigation about skin, mucous, joint, gastrointestinal, genitourinary, or neurological symptoms together with a detailed evaluation of ocular disease comprehensive of onset and

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Fig. 6 Fluorescein angiography of the patient #2 with Behcet’s disease shows diffuse fern-like vasculitis in both eyes which increases in the late phase. There is significant optic nerve head and macular leakage as well (a–d)

Fig. 7 Anterior segment photograph of the right eye of the patient with traumatic endophthalmitis (case #3) is shown. There is presence of a corneal ulcer with yellowish exudates and fibrin in the anterior chamber. A streak hypopyon was noted. The details of the anterior chamber are obscured due to the inflammation

duration of uveitis, unilateral involvement, and clinical features can help in reaching the diagnosis in case of underlying systemic disorders. Eyes with pseudo-hypopyon masquerading a malignancy are relatively quiet, with less pain, hyperemia, and visual loss if compared to HLA B27 associated uveitis or endophthalmitis. Leukemia and lymphoma should be suspected in hypopyon uveitis that fail to respond to corticosteroid treatment in children and elderly, respectively. A careful questioning about associated symptoms like fatigue, fever, or weight loss and detailed past medical examination is mandatory since the disorders may represent the first manifestation of an unknown underlying disease or the sign of its relapse. Once hypopyon with associated signs of endophthalmitis is established, ocular and systemic examination is required to search for the primary source of the infection and evaluate patient’s immunocompetence. Patient should investigate about history of trauma or surgery and conditions associated with endogenous endophthalmitis as immunocompromised

Differential Diagnosis of Hypopyon Uveitis

states (organ transplantation, leukemia, neutropenia, metastatic neoplasia, pharmacological, nutritional/alcoholic states), intravenous drug abuse, diabetes mellitus, cardiac valve disease, hepatobiliary infection, or invasive procedures (hemodialysis, endoscopy, catheterization). Details including foreign travel, pets, occupation, recreational activities, or sexual habits can help in the diagnosis of infectious uveitis as syphilis, toxocara, brucellosis, or leprosy. Drugs, dosage, and use of traditional eye medicines must be recorded. History taking and examination are followed by investigations and eventually microbiological and/or cytological sampling. A timely identification of the cause is mandatory for establishing a prompt and appropriate treatment and avoid poor visual prognosis. Treatment consists of topical corticosteroids and/or antibiotic treatment with or without an associated systemic therapy depending on the causative agent and underlying conditions. In case of drugs induced hypopyon uveitis, medications must be stopped. Masquerade syndromes require a multidisciplinary approach to timely initiate the most appropriate therapeutic strategy.

Conclusions Hypopyon may be the result of an inflammatory process incited by different causative agents as infective, autoimmune, neoplastic, or iatrogenic conditions. A correct diagnostic management involved a stepwise approach based on detailed history taking and examination, followed by investigations ordered accordingly to preliminary clinical and ocular results. Differentiating infective causes from autoimmune and neoplastic disorders is crucial for a correct therapeutic management and to avoid serious sequelae for the patients in terms of visual prognosis and life expectancy. Key Points • HLA B27 associated uveitis and Behcet’s disease are the most common noninfectious uveitis causing hypopyon; recognizing the typical features of ocular disease and the systemic conditions associated is essential for an early detection. • In the presence of hypopyon with features of endophthalmitis always enquire about history of trauma or surgery and patient’s associated systemic comorbidities and risk factors together with a thorough general examination. • Foreign travels, pets, occupation, recreational activities, or sexual habits should always be investigated on suspicion of infectious uveitis.

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• Consider possibility of masquerade conditions in presence of inflammation that fails to respond to conventional steroid therapy in population at risk. • Drugs, dosage, and use of traditional medications should always be investigated.

Suggested Reading Accorinti M, Pesci FR, Pirraglia MP, Abicca I, Pivetti-Pezzi P. Ocular Behçet’s disease: changing patterns over time, complications and longterm visual prognosis. Ocul Immunol Inflamm. 2017;25(1):29–36. Ahn SJ, Ryoo NK, Woo SJ. Ocular toxocariasis: clinical features, diagnosis, treatment, and prevention. Asia Pac Allergy. 2014;4 (3):134–41. Alkatan HM, Al-Dhibi HA, Edward DP, Al-Rajhi AA. Pigmented hypopyon in association with Listeria monocytogenes endopthalmitis: an interesting case report following refractive surgery procedure with literature review. Middle East Afr J Ophthalmol. 2014;21(1):40–3. Alten F, Ehlert K, Böhm MR, Grenzebach UH. Leukemic hypopyon in acute myeloid leukemia. Eur J Ophthalmol. 2013;23(2):252–4. Bronner A, Risse JF, Philippot J, Gerhard JP, Flament J. Hypertensive uveitis with hemorrhagic hypopyon revealing chronic lymphoid leukemia (discussion of a case). Bull Soc Ophtalmol Fr. 1976;76 (2):201–4. Cunningham C, Widder J, Raiji V. Endophthalmitis. Dis Mon. 2017; 63(2):45–8. D’Alessandro LP, Forster DJ, Rao NA. Anterior uveitis and hypopyon. Am J Ophthalmol. 1991;112(3):317–21. Dawson CR, Togni B. Herpes simplex eye infections: clinical manifestations, pathogenesis and management. Surv Ophthalmol. 1976;21:121–35. Durand ML. Endophthalmitis. Clin Microbiol Infect. 2013;19(3):227–34. Durand ML. Bacterial and fungal endophthalmitis. Clin Microbiol Rev. 2017;30(3):597–613. Endophthalmitis Study Group, European Society of Cataract & Refractive Surgeons. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg. 2007;33 (6):978–88. Garg P, Roy A, Sharma S. Endophthalmitis after cataract surgery: epidemiology, risk factors, and evidence on protection. Curr Opin Ophthalmol. 2017;28(1):67–72. Kopplin LJ, Mount G, Suhler EB. Review for disease of the year: epidemiology of HLA-B27 associated ocular disorders, ocular immunology and inflammation. Ocul Immunol Inflamm. 2016;24 (4):470–5. London NJ, Garg SJ, Moorthy RS, Cunningham ET. Drug-induced uveitis. J Ophthalmic Inflamm Infect. 2013;3(1):43. https://doi.org/ 10.1186/1869-5760-3–43 Papaliodis GN, Montezuma SR. Pseudo-hypopyon as the presenting feature of recurrent B-cell lymphoma. Ocul Immunol Inflamm. 2008;16(3):121–2. Pathanapitoon K, Dodds EM, Cunningham Jr ET, Rothova A. Clinical spectrum of HLA-B27-associated ocular inflammation. Ocul Immunol Inflamm. 2017;25(4):569–76. Petrowski JT. Uveitis associated with rifabutin therapy: a clinical alert. J Am Optom Assoc. 1996;67(11):693–6. Ramsay A, Lightman S. Hypopyon uveitis. Surv Ophthalmol. 2001; 46(1):1–18. Review.

70 Rathinam S, Prajna L. Hypopyon in leprosy uveitis. J Postgrad Med. 2007;53(1):46–7. Rosselet E, Gailloud C, Verrey F. Retinoblastoma and hypopyon. Ophthalmologica. 1970;161(2):139–44. Searl SS, Moazed K, Albert DM, Marcus LC. Ocular toxocariasis presenting as leukocoria in a patient with low ELISA titer to Toxocara canis. Ophthalmology. 1981;88(12):1302–6. Shetty SB, Devulapally SH, Murali S, Walinjkar JA, Biswas J. Tuberculous uveitis presenting as pigmented hypopyon – a case report. Am J Ophthalmol Case Rep. 2017;12(7):1–3. Sheu SJ. Endophthalmitis. Korean J Ophthalmol. 2017;31(4):283–9. Sinha MK, Narayanan R, Chhablani JK. Hypopyon uveitis following panretinal photocoagulation in a diabetic patient. Semin Ophthalmol. 2014;29(3):166–8. Sudharshan S, Kumari A, Biswas J. Bilateral hypopyon as the presenting feature of chronic myeloid leukemia. Ocul Immunol Inflamm. 2008;16(5):244–6. Touitou V, Bodaghi B, Thepot S, Chapiro E, Nguyen-Khac F, Charlotte F, LeHoang P, Maloum K. When the eye gives it all: diagnosis of relapsing acute myeloblastic leukemia with anterior chamber tap of a chronic hypopyon. Am J Hematol. 2014;89(8): 858–9.

A. Agarwal et al. Tugal-Tutkun I, Onal S, Ozyazgan Y, Soylu M, Akman M. Validity and agreement of uveitis experts in interpretation of ocular photographs for diagnosis of Behçet uveitis. Ocul Immunol Inflamm. 2014; 22(6):461–8. Tyagi M, Ambiya V, Rani PK. Hypopyon uveitis following panretinal photocoagulation. BMJ Case Rep. 2016;2016: bcr2016215949. Tyagi M, Govindhari V, Pappuru RR, Ambiya V. Bilateral hypopyon uveitis in chronic myeloid leukemia. Ocul Oncol Pathol. 2017; 4(1):12–5. Velu J, Agarwal S, Gupta V, Sharma K, Sharma A, Gupta A. Hypopyon uveitis-a rare presentation of intraocular tuberculosis. Ocul Immunol Inflamm. 2013;21(3):251–3. Winegarner A, Hashida N, Koh S, Nishida K. Hemorrhagic hypopyon as presenting feature of intravascular lymphoma, a case report. BMC Ophthalmol. 2017;17(1):195. https://doi.org/10.1186/s12886017-0591-3 Wormald RP, Harper JI. Bilateral black hypopyon in a patient with selfhealing cutaneous malignant melanoma. Br J Ophthalmol. 1983; 67(4):231–5. Zaidi AA, Ying GS, Daniel E, et al. Systemic immunosuppressive therapy for eye diseases cohort study. Hypopyon in patients with uveitis. Ophthalmology. 2010;117(2):366–72.

Algorithm for Work-Up of Episcleritis and Scleritis Dinesh Visva Gunasekeran and Rupesh Agrawal

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 General Approach to the Patient Presenting with a Red Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Clinical Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Introduction The sclera and episclera are the external layers of the eye composing of vascular and connective tissue and can be involved in inflammatory disease. One of the most vivid symptoms of an ophthalmic patient is an acute red eye. Acute conjunctivitis, episcleritis, scleritis, acute iritis, and acute angle closure glaucoma form important differential diagnosis for this clinical presentation. While the intensity of acute presentation in affected patients can be alarming, most cases are amenable to timely and appropriate therapy. Clinically the two entities can be difficult to differentiate, and yet they have distinct differences particularly in terms of etiology and prognosis. This was first outlined by Watson PG and Hayreh SS, who described the two entities and proposed a classification for scleritis in the 1970s that is still used today. Episcleritis is generally a benign and potentially recurring condition, with minimal associated complications such as mild keratitis. Furthermore, episcleritis is often selflimiting and resolves spontaneously or with minimal medical

D. V. Gunasekeran Clinical Research, Ophthalmology, Tan Tock Seng Hospital (TTSH), Singapore, Singapore R. Agrawal (*) National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore

therapy. Conversely, scleritis is strongly associated with systemic autoimmune or infectious diseases and can result in severe visual or anatomical abnormalities. Therefore, it is of paramount importance for the ophthalmologist to differentiate between the two entities to direct appropriate work-up and management of patients to avoid complications of inappropriate treatment which can lead to loss of the eye.

General Approach to the Patient Presenting with a Red Eye See Fig. 1.

Clinical Assessment Patients present with red eye and characteristic dilatation of surface vessels of the eye, without clinical features such as raised intraocular pressure or photophobia which may suggest other differentials of the red eye. Eye pain is generally not a prominent feature and would be more suggestive of scleritis particularly of infectious etiology if pain is severe. Eyes affected with episcleritis generally present with straight dilated vessels radiating posteriorly from the limbus

Department of Medical Retina, Moorfields Eye Hospital NHS Foundation Trust, London, UK e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_106

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Fig. 1 Alogrithm for a patient with red eye

on a bright red background, whereby vessels can be displaced over the sclera with a cotton tip applicator. On the other hand, eyes affected with scleritis characteristically have vessels in a crisscross pattern that cannot be displaced on the sclera, on a bluish red/violaceous background when viewed under sunlight. Perhaps the most useful method to differentiate the two entities is application of topical phenylephrine (10%) eye drops, which would cause significant blanching of the vessels in episcleritis but not in scleritis. Episcleritis and scleritis generally do not overlap except in some cases of herpes zoster. Half of patients with scleritis may have clinical features of systemic autoimmune or infectious etiologies (5–10%). Autoimmune diseases can vary from connective tissue to vasculitic disorders such as rheumatic arthritis most commonly sarcoidosis and Behcet’s disease. Infectious scleritis is most commonly of bacterial origin including tuberculosis, with fungal/parasitic etiologies being uncommon except in patients from developing countries with tropical climates and soil exposure. Pseudomonas aeruginosa is the commonest implicated agent, in up to 85% of bacterial scleritis.

Risk factors for patients to develop infectious scleritis include ocular surgery, particularly pterygium surgery and augmentation with adjunctive therapies such as mitomycin C and beta-radiation. Trauma and immunosuppression have also been implicated as risk factors. Clinical features that suggestive of infectious scleritis are a latent interval (up to 1 month) after inciting event, painful red eye with epiphora, and AC flare greater than 1+ on initial presentation. Pain can be severe and out of proportion to clinical signs, with a necrotizing type of scleritis with poor response to immunosuppression. Other suggestive signs include a scleral ulcer with calcified plaque at the site of penetrating injury, satellite abscess lesions, and extension with involvement of extraocular muscles. The attending ophthalmologist should be alert for features of complications, particularly in infectious scleritis. These include extension to surrounding structures such as keratitis/endophthalmitis, glaucoma, posterior scleral thickening, and retinal/choroidal detachments in posterior scleritis. Investigations are generally not required in episcleritis, as it is generally self-limiting. However, they can be useful in patients with scleritis to identify underlying causes in order to

Algorithm for Work-Up of Episcleritis and Scleritis

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Fig. 2 Algorithm for approach to a patient with scleritis

direct specific treatment. Investigations include serial inflammatory markers such as ESR or CRP which may return to normal levels with appropriate treatment for autoimmune or infectious causes accordingly. Markers of systemic diseases can be used as directed by clinical presentation, such as rheumatic factor to exclude rheumatoid arthritis (RA) in patients with symmetrical distal polyarthritis and HLA-B51 to exclude Behcet’s disease in patients with oral/genital ulcers. Ultrasound biomicroscopy (UBM) can reveal suggestive signs such as thickening of affected episcleral/scleral/ choroidal tissues or other features such as anterior ciliary body rotation in supraciliary effusion, elimination of ciliary sulcus, and diffuse choroidal thickening with lacy appearance. Optical coherence tomography (OCT) may also be useful to identify vitreoid opacities or subretinal deposits representing lipofuscin-laden macrophages in infectious scleritis. Both imaging modalities can also help identify complications such as retinal and choroidal detachments (See Figs. 2, 3, and 4).

Fig. 3 Left eye of a 40-year-old female with presence of sectoral congestion of the episclera. The patient had mild pain and discomfort and visual acuity was 20/20, N6 with normal anterior segment, posterior segment, and intraocular pressure. The condition resolved with a short course of topical nonsteroidal anti-inflammatory eye drops without any sequelae

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Key Points • Scleritis and episcleritis are similar on presentation but important to differentiate in order to guide appropriate management and avoid severe complications of inadequately treated scleritis. • Clinical features and investigations highlighted in this chapter may be useful in this regard. • The attending ophthalmologist should ensure potential reversible complications are monitored for and addressed early (Table 1).

Suggested Reading

Fig. 4 Slit lamp photograph of a 47-year-old gentleman with congested sclera of the left eye and had severe dull aching pain in the affected eye. There was presence of nodular lesion of the sclera with scleral edema. On systemic investigation, patient was found to have rheumatoid arthritis with markedly raised erythrocyte sedimentation rate (ESR). This patient required long-term systemic immunotherapy and follow-up for both ocular and systemic condition

Table 1 Tabular presentation of key features of episcleritis and scleritis Pain Orientation of vessels Color and appearance in sunlight Movement of vessels with cotton tip applicator Application of topical phenylephrine 10% Edema Systemic disease association

Episcleritis Nil to mild pain Straight, radiate posteriorly from limbus Bright red color

Scleritis Moderate to severe pain Crisscross pattern

Vessels can be moved over the sclera Episcleral vessels will blanch Episcleral edema Negligible to rare

Vessels cannot be moved over the sclera

Systemic immunosuppression

Not needed

Complications

Nil

Bluish red hue or violaceous hue

Scleral vessels will not blanch Episcleral and scleral edema Autoimmune disease present in significant proportion of cases May need systemic corticosteroids or steroidsparing immunosuppressive therapy and, in selected cases, may require biologic therapy Glaucoma, severe recalcitrant scleritis with risk of blindness

Berchicci L, Miserocchi E, Modorati G, et al. Clinical features of patients with episcleritis and scleritis in an Italian tertiary referral center. Eur J Ophthalmol. 2014;24(3):293–8. Heron E, Gutzwiller-Fontaine M, Bourcier T. Scleritis and episcleritis: diagnosis and treatment. Rev Med Interne. 2014;35(9):577–85. Homayounfar G, Nardone N, et al. Incidence of scleritis and episcleritis: results from the Pacific Ocular Inflammation Study. Am J Ophthalmol. 2013;156(4):752–8. Homayounfar G, Borkar DS, Acharya NR, et al. Clinical characteristics of scleritis and episcleritis: results from the pacific ocular inflammation study. Ocul Immunol Inflamm. 2014;22(5):403–4. Honik G, Wong IG, Gritz DC. Incidence and prevalence of episcleritis and scleritis in Northern California. Cornea. 2013;32(12):1562–6. Nguyen P, Yiu SC. Imaging studies in a case of infectious scleritis after pterygium excision. Middle East Afr J Ophthalmol. 2012;19 (3):337–9. Okhravi N, Odufuwa B, McCluskey P, et al. Scleritis. Surv Ophthalmol. 2005;50:351–63. Ramenaden ER, Raiji VR. Clinical characteristics and visual outcomes in infectious scleritis: a review. Clin Ophthalmol. 2013;7:2113–22. Sainz-de-la-Maza M, Jabbur NS, Foster CS. Severity of scleritis and episcleritis. Ophthalmology. 1994;101:389–96. Sainz de la Maza M, Molina N, Foster CS, et al. Clinical characteristics of a large cohort of patients with scleritis and episcleritis. Ophthalmology. 2012;119(1):43–50. Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol. 1976;60(3):163–91.

Entities That Can Present as IU/Vitritis Tripti Chaudhary and Reema Bansal

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Case 1: Sarcoidosis Presenting as Intermediate Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Case 2: Tuberculosis Presenting as Intermediate Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Case 3: Primary Vitreoretinal Lymphoma Presenting as Intermediate Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . 77 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Introduction Intermediate uveitis (IU) denotes an inflammatory syndrome, mainly involving the anterior vitreous, peripheral retina, and the ciliary body with minimal or no anterior segment or chorioretinal signs. While pars planitis refers to that subset of IU where there is snow bank or snowball formation occurring in the absence of an associated infection or systemic disease, the term IU is used if there is an associated infection or systemic disease. These entities (infectious or noninfectious) include sarcoidosis, tuberculosis (TB), Lyme disease, and multiple sclerosis. To describe the inflammation restricted over the vitreous base, different other terminologies have also been used, such as cyclitis, vitritis, pars planitis, and peripheral uveitis. Majority of patients are young adults and children, although the age of onset of disease is difficult to comment upon due to its mild onset and chronic nature. Usually bilateral, it may present as unilateral disease, with asymmetric or sequential involvement. At the onset, the patient has mild visual symptoms like floaters, or blurred vision. The eyes are usually quiet and white with no pain. Visual loss at a later stage is due to cystoid macular edema (CME) or complications like posterior subcapsular cataract,

and glaucoma. Presence of keratic precipitates or posterior synechiae rule out pars planitis. The diagnosis is often clinical, as most of the laboratory work up is noncontributory. As etiopathogenesis is not clear, the treatment remains nonspecific with corticosteroids (systemic or periocular). Immunosuppressive therapy is reserved for recurrent or recalcitrant cases. Pars plana vitrectomy helps in cases not responding to medical therapy or those requiring vitreous samples for diagnostic tests.

Case 1: Sarcoidosis Presenting as Intermediate Uveitis A 31-year-old male presented with decreased vision in both eyes (right followed by left eye) since 2 years. The visual acuity was 6/6 in right and 6/12 in left eye. The intraocular pressures (IOP) were 8 mm Hg and 14 mm Hg in right and left eyes, respectively. The anterior segments were unremarkable except for some few cells. Both eyes had vitreous cells 3+ and snowballs (Fig. 1). Fluorescein angiography (FA) revealed diffuse peripheral vascular leak, disc hyperfluorescence, and mild perifoveal leak in both eyes (Fig. 2). The tuberculin skin test (TST) was negative, and CT chest revealed mediastinal and hilar lymphadenopathy.

T. Chaudhary · R. Bansal (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_90

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76 Fig. 1 Fundus photograph of case-1 with sarcoidosis showing bilateral vitritis and snowballs

Fig. 2 Fluorescein angiography of case-1 showing diffuse peripheral vascular leak and perifoveal leak in both eyes

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Fig. 3 Fundus photograph (top panel) of case-2 with tuberculosis showing bilateral vitreous membranes and fluorescein angiography (bottom panels) showing peripheral vascular leak with perifoveal leak in left eye

Histopathological examination of transbronchial and endobronchial biopsies showed epitheloid cell granulomas and spare lymphomononuclear cell infiltrate, suggesting granulomatous inflammation consistent with sarcoidosis. He received oral prednisolone (1 mg/kg/day). At 3 months follow up, the visual acuity was 6/6 in both eyes, and IOP 9 and 11 mm Hg in right and left eyes, respectively. The vitritis had decreased significantly in both eyes.

48 h, and CT chest showed nodules in right lung with areas of cavitation, suggesting TB. She received oral corticosteroids for 2 months, and antitubercular therapy for 9 months. At last visit, her visual acuity was 6/6 in both eyes.

Case 3: Primary Vitreoretinal Lymphoma Presenting as Intermediate Uveitis A 75-year-old male presented with blurred vision in both

Case 2: Tuberculosis Presenting as Intermediate eyes for 6 months. His visual acuity was 6/24 in right and 6/36 in left eye. The IOP was 16 mm Hg in both eyes. Both Uveitis A 53-year-old woman presented with floaters, predominantly in the left eye. Her visual acuity was 6/9 in right and 6/24 in left eye. The IOP was 19 and 18 mm Hg in right and left eyes, respectively. The anterior segment was unremarkable in both eyes. She had vitreous cells 1+ in right eye and 3+ in left eye, with vitreous membranes in both eyes (Fig. 3). There was diffuse peripheral vascular leak, disc hyperfluorescence, and perifoveal leak in left eye on FA. Her TST was 12  14 mm at

eyes anterior segment showed few cells. Posterior segment had bilateral dense vitritis, which precluded detailed fundus evaluation (Fig. 4). The FA was inconclusive. Laboratory investigations including hemogram, TST, CT chest, HIV, Treponema pallidum hemagglutination (TPHA), and liver and renal function tests were normal. Systemic examination was normal. He underwent diagnostic pars plana vitrectomy (PPV) in left eye. On cytological examination, the vitreous smears were acellular and showed atypical

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Fig. 4 Fundus photograph of case-3 with primary vitreoretinal lymphoma showing dense vitritis in both eyes, precluding fundus details

lymphoid cells showing high N:C ratio, coarse chromatin, and scanty basophilic cytoplasm, suggestive of NonHodgkin’s Lymphoma (NHL). On immunocytochemistry, the atypical cells were strongly positive for CD20 and negative for CD3 and panCK, suggesting B-cell NHL. Neurology consultation was unremarkable with normal MRI and cerebrospinal fluid cytology. He has received intravitreal methotrexate in left eye and has been planned for right eye PPV. Key Points • Intermediate uveitis (IU) is an anatomical classification of uveitis that denotes an inflammatory syndrome of the anterior vitreous, ciliary body, and peripheral retina, with minimal or no inflammation of the anterior or posterior segment. • Pars planitis is an idiopathic subset of IU with vitreous cells and exudates in pars plana (snow balls and snow banks). Vitritis, cyclitis, peripheral uveitis, etc. have been used synonymously with IU. • While the cause is unknown in majority of cases, several entities can present as IU or vitritis, such as sarcoidosis, tuberculosis, Lyme disease, multiple sclerosis, and primary vitreoretinal lymphoma.

• It begins with mild visual symptoms like floaters or blurred vision. The commonest cause of visual loss in later stage is due to CME, cataract, glaucoma, etc. • Prognosis is variable. While some cases may be selflimiting, majority need treatment with corticosteroids (systemic or periocular). Immunosuppressive therapy or vitrectomy are helpful in recurrent or recalcitrant cases.

Suggested Reading Bloch-Michel E, Nussenblatt RB. International Uveitis Study Group recommendations for the evaluation of intraocular inflammatory disease. Am J Ophthalmol. 1987;103:234–5. Breeveld J, Rothova A, Kuiper H. Intermediate uveitis and Lyme borreliosis. Br J Ophthalmol. 1992;76:181–2. Jabs DA, Nusenblatt 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;140:509–16. Jain R, Ferrante P, Reddy GT, Lightman S. Clinical features and visual outcome of intermediate uveitis in children. Clin Exp Ophthalmol. 2005;33:22–5. Malinowski SM, Pulido JS, Folk JC. Long-term visual outcome and complications associated with pars planitis. Ophthalmology. 1993;100:818–24. Zierhut M, Foster CS. Multiple sclerosis, sarcoidosis and other diseases in patients with pars planitis. Dev Ophthalmol. 1992;23:41–7.

Algorithm for Work-Up of Panuveitis Luca Cimino

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Introduction Uveitis can occur either as a co-manifestation of various autoimmune disorders and infections or as a side effect of medications and toxins, or it can arise as a purely idiopathic ocular inflammation (Table 1). The term panuveitis (PU) should be reserved for those situations in which there is no predominant site of inflammation, but where it is distributed among the anterior chamber, vitreous, and retina and/or choroid (i.e., retinitis, choroiditis, or retinal vasculitis). A comprehensive ocular and systemic history is the most important component of the PU clinical approach. The review of systems should be oriented toward identifying systemic signs or symptoms of general diseases. For example, sarcoidosis can cause lymphadenopathy and skin changes, Vogt-Koyanagi-Harada (VKH) is associated with meningism, and Behçet’s disease (BD) includes oral and/or genital aphthous ulcers, skin lesions (erythema nodosum), and reactive arthritis (Fig. 1). Demographic information such as gender, age at presentation, and ethnic group (people from Silk Route in Behçet’s, blacks in sarcoidosis, Asians in VKH) may suggest certain types of uveitis.

It is essential to rule out infectious etiology, especially in acute, unilateral PU. In fact, do not hesitate to repeat the work-up (even if negative before) in cases of strictly unilateral disease; in cases of chronic, long-standing, and recalcitrant uveitis; and in case of resistance to the therapy. A temporary, intermittent, or incomplete response to steroids should raise also suspicion of masquerade syndromes (neoplastic or nonneoplastic) that may clinically simulate PU, such as necrotic tumors, retinoblastoma, Coats’ disease, tapetoretinal degenerations, disease leukemia, juvenile xanthogranuloma, lymphoma, and others. If the standard work-up for infectious and noninfectious panuveitis is negative, the diagnosis of idiopathic PU is made. Patients with PU may follow an acute (sometimes hyperacute) course, while others may have a slowly progressive debilitating course. For this reason it is important to obtain information regarding the integrity of the immune system and/or to evaluate some predisposing conditions (e.g., recent major gastrointestinal surgery, indwelling catheters, organ transplantation, and undergoing chemotherapy – see association with Candida endogenous endophthalmitis).

L. Cimino (*) Ocular Immunology Unit, Arcispedale S.M. Nuova IRCCS, Reggio Emilia, Italy e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_92

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Laboratory Tests Extensive work-up is not necessary. We propose the following tests: Full blood cells; serum AST-ALT, creatinine, and glucose, serum angiotensin-converting enzyme (ACE) and lysozyme, and serology (IgM and IgG) for herpes simplex 1–2, VZ, CMV Serology (IgM and IgG) for Toxoplasma, QuantiFERONTB Gold and/or Mantoux skin test

Table 1 IUSG clinical classification of uveitis Infectious

Noninfectious Masquerade

Bacterial Viral Fungal Parasitic Others Known systemic associations No known systemic associations Neoplastic Nonneoplastic

Fig. 1 Flowchart of clinical approach to patient with panuveitis

Serology for syphilis: specific (TPHA) and nonspecific (RPR). “Always include HIV serology”. When suspected: human leukocyte antigen (HLA) typing B51 for Behçet’s disease (BD), A29 for birdshot retinochoroiditis, and DR4 for VKH syndrome. Always bear in mind the pretest probability: for example, around 20% of the Italian general population is HLA-B51 positive. Do not hesitate to repeat the work-up in cases where laboratory tests are negative or not supportive for the suspected clinical diagnosis. Also consider revaluation in monolateral disease; in chronic, long-standing, and recurrent uveitis; and in case of resistance to therapy. Suspect infection when the uveitis remains strictly unilateral during its course. Choose the correct evaluation criteria for monitoring and prognosis. Recognize and treat in emergency, according to clinical suspicion, when you are faced with acute retinal necrosis (ARN) or in other critical situations (infectious endophthalmitis). In selected cases, anterior chamber paracentesis can provide important diagnostic evidence to support a specific infective diagnosis. In fact, polymerase chain reaction (PCR) is a molecular technique for evaluation of very

Algorithm for Work-Up of Panuveitis

small amounts of DNA in anterior chamber fluids. It can be a simple, rapid, sensitive, and specific tool for the diagnosis of infection and also to monitor the efficacy of treatment (including Goldmann-Witmer coefficient or antibody index). Cultures of intraocular fluids (especially vitreous) in conjunction with bloods are important to diagnose endogenous endophthalmitis.

Scenario After having reviewed the clinical, laboratory, and other exams, we propose here a list of possible scenarios that we might face in panuveitis, along with the most appropriate work-up for that scenario (Fig. 2). In some cases there are no specific clinical manifestations useful to diagnosis. For this reason a comprehensive, multifactorial assessment is necessary that takes into consideration the clinical history, clinical presentation, any extraocular clinical signs, clinical course, and diagnostic work-up (laboratory, instrumental ocular, and systemic tests) (Table 2).

Unilateral Panuveitis (UPU) For UPU with occlusive vasculitis and +/ vitreous involvement, accompanying with anterior chamber inflammation, consider the differential diagnosis (DD) between Behçet’s disease (see extraocular signs, HLA-B51, always non-granulomatous PU), tuberculosis (see positive Mantoux and/or QuantiFERON-TB Gold), sarcoidosis (negative Mantoux and/or QuantiFERON-TB Gold, presence of

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elevated serum ACE and/or lysozyme), and syphilis (presence of specific and nonspecific tests) (Fig. 3). For UPU with diffuse retinochoroidal lesions with vitreous involvement, consider DD between sarcoidosis, tuberculosis, and syphilis (Figs. 4 and 5). UPU: In patients with atypical forms of uveitis (presumed autoimmune), nonresponsive to conventional therapy (corticosteroid-resistant forms) is important to exclude viral origin. Molecular analysis (PCR and local antibody production for HSV-1–2, VZ, CMV, EBV) can confirm the diagnosis of non-necrotizing herpetic retinopathies (Fig. 6). Sometimes, the more frequent granulomatous PU (sarcoidosis, TBC, syphilis) could be non-granulomatous at presentation. Before starting a systemic steroid therapy, you must ensure to exclude an infectious etiology. Acute UPU with Hypopyon • Information regarding the integrity of immune system • Risk factors: recent major surgery, indwelling catheters, organ transplantation, intravenous drug abuse • Look at systemic symptoms: fever, malaise • Eye involvement: mono-/bilateral • Acute onset (blurred vision) Differential Diagnosis: 1. Severe HLA-B27 uveitis can mimic infection (look at history, vitreous involvement, including eco B-scan for better evaluation; see the patient after 1 day of intense topical therapy with steroids and mydriatic agents). 2. Behçet’s disease with retinal infiltrates and hemorrhages.

Fig. 2 Most frequent clinical presentations of panuveitis. Blue mostly unilateral, yellow bilateral, or green mono- or bilateral

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Table 2 Targeted approach to the diagnosis Clinical setting Mono- or bilateral, usually non-granulomatous panuveitis History and immune status Clinical findings: hypopyon, vitreous infiltration, retinitis foci Monolateral often granulomatous panuveitis History and immune status Clinical findings: acute retinal necrosis  vitreitis Monolateral granulomatous panuveitis History and immune status Clinical findings: vitreitis + retinochoroiditis adjacent to a pigmented scar Non-granulomatous panuveitis with retinal vasculitis history of oral and/or genital aphthous, skin lesions Clinical findings: recurrent anterior uveitis with or without hypopyon Cellular infiltration and opacification of vitreous retinal infiltrates and hemorrhages, cystoid macular edema, disc hyperemia Retinal vasculitis and recurrent vasoocclusive episodes are the major cause of visual morbidity Bilateral granulomatous panuveitis with exudative retinal detachment associated with neurological and auditory signs (more evident in acute phase) and vitiligo, alopecia, poliosis (frequently in convalescent phase) Clinical findings: hallmark, in acute, is bilateral multifocal exudative retinal detachments and papillitis. Peripheral wellcircumscribed yellow-white lesions (clinical equivalent of Dalen-Fuchs nodules, a histological term) In convalescent phase, the fundus exhibits an orange-red discoloration (“sunset glow”) Bilateral granulomatous panuveitis insidious onset, history of ocular penetrating trauma or intraocular surgery (exciting eye) Clinical findings: similar to VKH Bilateral granulomatous panuveitis, with multisystem disease, mediastinal lymphadenopathy, skin lesions (erythema nodosum) Clinical findings: presence of endothelial large mutton-fat keratic precipitates, choroiditis and/or retinal vasculitis, vitreitis, retinal vasculitis (“candle-wax” vascular sheathing) Bilateral panuveitis characterized by posterior segment with dual, independent retinal, and choroidal inflammation The disease has no known extraocular inflammation sites Adjunctive clinical findings: vitreous involvement and possible presence of granulomatous endothelial precipitates Reemerging multisystem granulomatous infectious disease with ocular involvement Clinical findings: bilateral panuveitis (often asymmetric), partially steroid responsive, diagnostic delay, usually old scars Peculiarity of multifocal lesions noncontiguous to the optic disc showing serpiginous spread Chronic bilateral panuveitis (often asymmetric) due to Treponema pallidum (sexually transmitted infection), skin lesions (e.g., hand palm), neurological signs Diagnostic findings: intraocular inflammation is considered to be a risk factor for the presence of asymptomatic neurosyphilis

Instrumental exams B-scan echography

Diagnosis suspicion Endogenous endophthalmitis

Targeted investigation Vitreous and blood culture

Herpes virus (including CMV)

Anterior TAP (PCR and I/A) Anti-herpes IgM and IgG HS 1–2, VZ, EBV, CMV Anti-Toxoplasma IgG and IgM Anterior chamber TAP (PCR)

OCT, fundus color image, FA OCT, fundus color image, FA-ICGA

Behçet’s disease

HLA-B51

OCT, fundus color image, FA

VKH

Lumbar puncture: pleocytosis (mostly lymphocytes) in cerebrospinal fluid HLA-DR4

OCT EDI-OCT FA-ICGA

Sympathetic ophthalmia

Retinal imaging

OCT EDI-OCT FA-ICGA

Sarcoidosis

Serum ACE and lysozyme, skin test for anergy to tuberculin

OCT EDI-OCT FA-ICGA

Birdshot retinochoroiditis

HLA-A29 (100% presence)

OCT FA-ICGA VF

TBC, often presumed Intraocular TB

TBC tests (Mantoux and/or IGRA tests)

OCT EDI-OCT FA-ICGA Similar to sarcoidosis

Syphilis Three stages: primary, secondary, and tertiary syphilis

Syphilis serology (specific and nonspecific) CFS analysis

Color picture OCT FAF FA-ICGA

Toxoplasmosis

(continued)

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Table 2 (continued) Clinical setting Bilateral eye involvement resembling panuveitis (masquerade syndrome) History, immune status, and partially steroid responsive Clinical findings: sheets of cells and dense vitreitis + subretinal infiltrates

Diagnosis suspicion Vitreoretinal lymphoma

Targeted investigation Diagnostic vitrectomy including cytology, cytokines, gene rearrangements, biopsy

Instrumental exams Color picture FAF OCT

TAP anterior chamber paracentesis, FA fluoroangiography, ICGA indocyanine green angiography, FAF fundus autofluorescence, OCT optical coherence tomography, EDI-OCT enhanced depth imaging optical coherence tomography, VFT visual field test, ACE angiotensin-converting enzyme, HRCT high-resolution chest tomography, RPE retinal pigment epithelium, CSF cerebrospinal fluid

• Consider immunodeficiency in atypical case (intraocular fluid analysis including PCR and GW coefficient) (Figs. 9 and 10). Unilateral acute granulomatous panuveitis with a retinochoroidal lesion: • Look at Toxoplasma etiology. • Focal necrotizing retinitis resulting in characteristic atrophic scars. • Reactivation frequently situated adjacent to an old scar. • Anterior uveitis (may be granulomatous) and secondary rise in IOP. Retinal vasculitis near to or distant from focus of active retinochoroiditis (Figs. 11, 12 and 13) Fig. 3 UPU with dense vitreitis and retinal vasculitis in Behçet’s disease

Bilateral Non-granulomatous Panuveitis with Retinal Vasculitis Exclude Acute Endogenous Endophthalmitis • Blood culture • Vitreous tap for microbiology • Cardiological investigation (echocardiography) (Figs. 7 and 8)

Unilateral Acute Granulomatous Panuveitis With retinal necrosis, recognize and treat in emergency: • Immunocompetent patients. Known to occur also in immunocompromised individuals. • Impaired cellular immunity in apparently immunocompetent ARN patients suggesting that it may develop in association with an imbalance of immune system. • Sometimes no typical presentation. • Positive serum-specific serology is only confirmatory. • Anterior TAP for herpes virus (PCR for HSV-1–2, VZ, EBV, CMV).

Remember that sometimes even classical, more frequent granulomatous panuveitis in sarcoidosis, tuberculosis, and syphilis may be non-granulomatous at onset or during follow-up! Always keep in mind the differential diagnosis (looking at the diagnostic work-up) between these three entities and Behçet’s disease: • Most frequently panuveitis with involved predominantly veins • Behçet’s disease, tuberculosis, sarcoidosis Discrimination between infectious (Tb) and noninfectious etiology is important. Behçet’s Disease (Looking at Diagnostic Criteria) • Italy: HLA-B51 positive in 18% of normal controls and in 60% of BD patients. • Extraocular involvement: oral and genital aphthae, erythema nodosum, others.

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Fig. 4 UPU with vitreitis and diffuse chorioretinal scars in sarcoidosis

Fig. 5 UPU with diffuse, peripapillary infiltrate involving the optic nerve (neuroretinitis): (a, b) acute phase, (c, d) convalescent phase

• Laser flare photometry (LFP) is a method used to detect flare in the anterior chamber (AC). LFP results should always be interpreted in conjunction with the usually clinical observations. There is some evidence that worsening of the flare on two consecutive visits is predictive of a relapse, especially in patients with Behçet’s disease.

• Pathognomonic of Behçet’s disease: transient white patches of retinitis, small adjacent hemorrhages in patients with active uveitis, silent on FA. • FA is more sensitive than clinical examination. • Active vasculitis: leakage of dye due to breakdown of inner blood-retinal barrier and staining of blood vessel wall.

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Fig. 6 UPU with non-necrotizing retinitis due to HSV-2 (PCR positive in aqueous humor): (a) acute, (b, c) post-acute phase

Fig. 7 Acute endogenous endophthalmitis due to Candida albicans: (a) intense vitreitis, in acute phase, (b) inferior dense vitreous infiltrates, (c) after vitrectomy + silicone oil

Fig. 8 (a) Acute endogenous endophthalmitis with hypopyon, (b) intense and diffuse vitreitis in acute phase, (c) convalescent phase after systemic and local therapy

• Leakage may be focal or more frequently diffuse. • Diffuse capillary leakage (Figs. 14, 15, 16 and 17). Bilateral panuveitis with papillitis and serous retinal detachment:

• • • •

Not always bilateral serous retinal detachment Differential diagnosis of choroidal folds + papillitis Vogt-Koyanagi-Harada disease (see diagnostic criteria) If previous ocular penetrating trauma or intraocular surgery: sympathetic ophthalmia (SO)

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Fig. 9 Granulomatous PU after a severe bronchial pneumonia, at presentation (a-c); note the possible DD between HSV and Toxoplasma (anterior chamber TAP showed PCR positive for HSV-1): (a) anterior

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granulomatous uveitis, (b) retinal active lesion, (c, d) FA showing retinal ischemic lesion, (e, f, g) follow-up visits after 7, 14 (acyclovir i.v.), and 40 days (oral valacyclovir)

Fig. 10 Bilateral acute retinal necrosis in pt. HIV+. LE anterior TAP confirmed a positive PCR for Toxoplasma. Importance of intraocular fluid analysis when the clinical diagnosis is not clear (in this case the possible DD with CMV)

Fig. 11 (a, b) LE acute retinochoroidal lesion in UPU: typical toxoplasmosis (see the new lesion adjacent the old scar). (c) The same healed lesion after 1 month of anti-Toxoplasma therapy. The diagnosis is confirmed by fundus exam

Algorithm for Work-Up of Panuveitis Fig. 12 Peridiscal toxoplasmic lesion (see the utility of OCT during the follow-up) first episode in 42 y.o.

Fig. 13 (a) Toxoplasma retinochoroidal lesion, active phase, (b) healed lesion after specific therapy, (c) progressive improvement of visual field test (VFT) during the follow-up

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Fig. 14 Mobile hypopyon (seeing with the head movement) to differentiate with HLA-B27 hypopyon

Fig. 15 Attention to the extraocular signs: erythema nodosus, oral and genital aphthae

Fig. 16 Behçet’s disease-related bilateral PU in 24 M with full visual acuity and therapy incomplete control. In optic nerve neovessels (color photos), FA is more sensitive than fundus exam

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Fig. 17 The same case after 1 month of more aggressive systemic therapy

Fig. 18 Posterior scleritis (confirmed by ultrasound B-scan) with papillitis and after the resolution of the acute phase

• Posterior scleritis (looking at eco B-scan showing sclera thickening and pain during eye movement) (Fig. 18) VKH: chronic, bilateral, granulomatous panuveitis associated with central nervous system, auditory, and integumentary manifestations: • Always treat VKH aggressively (preventing sunset glow fundus). • Importance of ICGA EDI-OCT: to monitor choroidal thickness. • FA-ICGA: disc hyperfluorescence (acute phase). • FA in acute: diffuse hyperfluorescent, pinpoints, and dye pooling (late phase); chronic phase, window and blocking effect due to RPE disorders. • ICGA in acute: fuzzy and indistinct choroidal vessels, diffuse hyperfluorescent dots (granuloma), hyperfluorescent pinpoints (exudation) (Figs. 19, 20 and 21). Sympathetic Ophthalmia (SO) Rare bilateral granulomatous panuveitis that occurs as a complication of a penetrating injury that involves the uvea of one eye:

• Major sight-threatening disorder. • High index of suspicion must be maintained whenever inflammation occurs in fellow eye (sympathizing eye) of an eye (exciting eye) that has suffered penetrating trauma or intraocular surgery. • Infection should be carefully ruled out. • Diagnosis is made clinically: histological proof is not required. • Injured eye which has potential vision should not be enucleated in an attempt to prevent or lessen SO or to provide confirmatory pathology (Figs. 22, 23 and 24).

Bilateral Panuveitis Often Granulomatous Sarcoidosis and tuberculosis, similar instrumental work-up: Multimodal imaging: nonspecific signs may be helpful in establishing the diagnosis but are useful for assessing the extent of inflammation. FA: retinal vasculitis, disc hyperfluorescence, and cystoid macular edema ICGA: diffuse hypofluorescent dark dots (granuloma), fuzzy choroidal vessels in intermediate phase, and diffuse hyperfluorence due to choroidal staining in the late phase

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Fig. 19 To confirm the diagnosis, lumbar puncture to obtain the presence of pleocytosis (mostly lymphocytes)

Fig. 20 (a) Bilateral PU with papillitis and serous retinal detachment in acute phase, (b) quasi-complete resolution of inflammation after 1-month therapy

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Algorithm for Work-Up of Panuveitis Fig. 21 Sometimes, in recurrent bilateral PU, we can see bilateral papillitis (a) without serous retinal detachment. Consider the extraocular signs (e.g., vitiligo) (b) and headache. Perform FA (c) and ICGA (d) to see more specific lesions

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Fig. 22 Perforating trauma

Fig. 23 Sympathetic ophthalmia: active inflammation in a case with diagnostic delay. The right eye is the exciting (past perforating trauma), and the left eye is the sympathizing. Note the presence of bilateral vitreitis and papillitis. In the left eye, the more inflamed eye, are visible

diffuse small yellow lesions (Dalen-Fuchs nodules). In the right eye are present depigmented scars (representing the loci of previous DalenFuchs nodules)

Sarcoidosis Elevated serum lysozyme and angiotensin-converting enzyme (ACE). Attention: the children show normally elevated serum ACE. Radiology: high-resolution (HR) CT scan better than chest X-ray to detect hilar and mediastinal lymphadenopathy. Lesion biopsy: when possible, mediastinal lymph nodal biopsy is important to have a specific diagnosis of

sarcoidosis (in differential diagnosis with TBC or lymphoma when the clinical manifestations and work-up are not exhaustive) and also to ensure a good therapeutic approach, avoiding potential side effects (e.g., regarding the use of anti-TNF agents not recommended in case of TBC). Exclude birdshot retinochoroiditis (vitreitis, retinal vasculitis, stromal choroiditis that can show granulomatous keratic precipitates, presence of HLA-A29) (Figs. 25 and 26).

Algorithm for Work-Up of Panuveitis

Fig. 24 The sympathizing eye (a–c) in acute phase looking at ICGA (hyperfluorescence of optic disc and diffuse hypofluorescent dots indicating active inflammation) is more sensitive than FA (A). OCT (c)

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shows exudative retinal detachment. Figures (d, e) resolution of inflammation after therapy

Fig. 25 High-resolution CT scan is more sensitive to show lymphadenopathy chest X-ray

Tuberculosis This can be due to direct infection or indirect immunemediated hypersensitivity response to mycobacterial antigens. • In recent years, ocular involvement due to TB has reemerged associated with an increasing prevalence of TB. • High index of clinical suspicion is essential for early diagnosis.

• Diagnosis should be considered when unexplained chronic uveitis with the characteristic clinical signs occurs that promptly recurs upon tapering corticosteroid and/or immunosuppressive therapy. • Most patients with ocular involvement have no history of pulmonary or other systemic forms. • The absence of clinically evident pulmonary TB does not rule out the possibility of ocular TB as about 60% of

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Fig. 26 Choroidal granuloma well seen at EDI-OCT at the beginning and during the follow-up

• • • • •

patients with extrapulmonary TB has no evidence of pulmonary TB. In most cases diagnosis of intraocular TB is only presumptive. Diagnostic criteria for presumed tuberculosis uveitis. Ocular findings consistent with possible TB with no other causes of uveitis suggested by history, symptoms, or ancillary testing. QuantiFERON-TB positive and/or a strongly positive tuberculin skin test result. Response to antituberculosis therapy with the absence of recurrences (Fig. 27).

Syphilis • Extraocular manifestations. • Serology: nonspecific and specific tests. • Specific tests are more sensitive in all stages than nonspecific tests. • Nonspecific type of uveitis.

• Considerations: partially steroid responsive, diagnostic delay. Therapy of choice is penicillin (Figs. 28 and 29).

Bilateral Chronic Panuveitis with Moderate Response to Steroids: Vitreoretinal Lymphoma (VRL) Suspect in cases of uveitis in which infectious forms have been ruled out and which do not respond completely to steroid therapy. In fact, in the presence of dense vitreal involvement with diffuse subretinal infiltrates, suspicion of VRL is strong. Intraocular lymphomas are one of the most critical entities to take into consideration in the differential diagnosis of patients with panuveitis. Careful ophthalmic examination, appropriate consideration of past medical history, and a diagnostic

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Fig. 27 Bilateral granulomatous panuveitis in ocular TBC. (a–d) acute phase: (a) color fundus, (b) FA, (c) OCT. (e, f) Convalescent phase: (e) color fundus, (f) OCT

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Fig. 28 Attention at extraocular signs: maculopapular eruption on the palm in a patient with secondary syphilis

Fig. 29 Placoid choroidal infiltration in syphilis. (a) Color fundus, (b) FAF, (c) FA, (d) ICGA early phase, (e) ICGA late phase, (f) OCT acute phase, (g) OCT convalescent phase

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Fig. 30 Vitreoretinal lymphoma: (a, b) dense cellular infiltration in the vitreous, (c) the same case after chemotherapy (local and systemic)

Fig. 31 Large multifocal but coalescing subretinal masses and dense cellular vitreous infiltration are typical for vitreoretinal lymphoma

vitrectomy timely performed could lead to the correct (early) diagnosis of intraocular lymphoma. (Figs. 30, 31, 32 and 33) Key Points • Diagnostic evaluation should be focused guided by history and ophthalmic and physical examinations. • A detailed history, review of systems, and physical examination allow for a differential diagnosis. • The absence of any diagnostic clues from history makes idiopathic panuveitis most likely. • If medical history, review of systems, or ocular examination suggests an underlying systemic disease, then diagnostic work-up should be tailored for that disease. • Discrimination between infectious and noninfectious etiology is important.

• Possibility of a masquerade syndrome (malignancy) should be kept in mind. • Specific antimicrobial therapy is indicated for infectious causes. • Specific immunosuppressive agents may be useful in immunologic-mediated disorders but contraindicated in infectious causes without specific antimicrobial treatment. • Malignancy must be ruled out. It should be considered if disease becomes refractory to treatment after an initial improvement. Not only sight threatening but could be the first sign of potentially lethal systemic disease. • Prompt diagnosis and institution of appropriate therapy will help to control ocular disease and systemic disease. • PU often involves an interdisciplinary approach, essential in evaluation and treatment and laboratory investigation.

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Fig. 32 Secondary choroidal lymphoma: patient with choroidal involvement secondary to marginal lymphoma in the lung. In (a) color picture, you can appreciate vitreitis, (b) B-scan ultrasonography:

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choroidal thickening, (c) OCT showing irregularly choroidal profile due to lymphoma infiltration, (d) lung histology

Fig. 33 The same case after radiotherapy. The (a) color fundus, (b) eco B-scan, (c) OCT photos show the complete resolution of lymphoma choroidal infiltration

Algorithm for Work-Up of Panuveitis

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Algorithm for Workup of Retinal Vasculitis Ahmed M. Abu El-Asrar

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Fundus Fluorescein Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Identification of the Involved Retinal Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Cotton-Wool Spots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 Intraretinal Infiltrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Necrotizing Retinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Aneurysmal Dilatations of the Retinal and Optic Nerve Head Arterioles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Frosted Branch Angiitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Retinal Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Diagnostic Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Introduction In this chapter, a practical approach to the diagnosis of retinal vasculitis is discussed based on ophthalmoscopic and fundus fluorescein angiographic findings (Tables 1 and 2).

wall with fluorescein. Such leakage may be focal as seen in sarcoidosis or multiple sclerosis or more diffuse as seen in Behçet’s disease and retinal vasculitis associated with tuberculoprotein hypersensitivity. Diffuse capillary leakage is also a common finding in many conditions such as Behçet’s disease and birdshot chorioretinopathy.

Fundus Fluorescein Angiography Identification of the Involved Retinal Vessels Intravenous fluorescein angiography is an essential component of the evaluation and management of retinal vasculitis. Characteristic features seen with fluorescein angiography in active vasculitis include leakage of dye due to breakdown of the inner blood-retinal barrier and staining of the blood vessel A. M. Abu El-Asrar (*) College of Medicine, Department of Ophthalmology, King Abdulaziz University Hospital, King Saud University, Riyadh, Saudi Arabia

Retinal vasculitis affecting predominantly the veins (phlebitis) has been described in association with Behçet’s disease, tuberculosis, sarcoidosis, multiple sclerosis, pars planitis, retinal vasculitis associated with tuberculoprotein hypersensitivity, and human immunodeficiency virus infection. Retinal arteritis is more commonly seen in acute retinal necrosis; idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN); and systemic vasculitides such as systemic

Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Riyadh, Saudi Arabia e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_78

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102 Table 1 Disorders associated with retinal vasculitis Infectious Disorders Bacterial disorders: tuberculosis, syphilis, Lyme disease, Whipple’s disease, brucellosis, cat scratch disease, endophthalmitis, post-streptococcal syndrome. Viral disorders: human T cell lymphoma virus type 1, cytomegalovirus, herpes simplex virus, varicella zoster virus, Epstein-Barr virus, Rift Valley fever virus, hepatitis, acquired immunodeficiency syndrome, West Nile virus infection, Dengue fever virus. Parasitic disorders: toxoplasmosis. Rickettsial disorders: Mediterranean spotted fever, Rocky Mountain spotted fever. Neurologic Disorders Multiple sclerosis Microangiopathy of the brain, retina, and cochlea (Susac syndrome) Malignancy Paraneoplastic syndromes Ocular lymphoma Acute leukemia Systemic Inflammatory Disease Behçet’s disease Sarcoidosis Systemic lupus erythematosus Granulomatosis with polyangiitis (GPA) Polyarteritis nodosa Churg-Strauss syndrome Relapsing polychondritis Sjögren’s A antigen Rheumatoid arthritis HLA-B27-associated uveitis Crohn’s disease Postvaccination Dermatomyositis Takayasu’s disease Buerger’s disease Polymyositis Ocular Disorders Frosted branch angiitis Idiopathic retinal vasculitis, aneurysms, and neuroretinitis Pars planitis Birdshot chorioretinopathy Modified from Abu El-Asrar et al. (2010)

lupus erythematosus (SLE), polyarteritis nodosa, and granulomatosis with polyangiitis (GPA); Churg-Strauss syndrome; and cryoglobulinemia.

Cotton-Wool Spots Cotton-wool spots representing microinfarcts of the retina due to precapillary retinal arteriolar occlusion are most often found in association with systemic vasculitides such as SLE, polyarteritis nodosa, granulomatosis with polyangiitis (GPA),

A. M. Abu El-Asrar Table 2 Differential diagnosis of retinal vasculitis based on ophthalmoscopic findings Ophthalmoscopic finding Phlebitis

Arteritis

Cotton-wool spots

Intraretinal infiltrates Necrotizing retinitis Aneurysmal dilatations of the retinal and optic nerve head arterioles Frosted branch angiitis

Retinal ischemia

Inflammatory branch retinal vein occlusion Retinal arterial occlusions

Possible diagnoses Behçet’s disease, tuberculosis, sarcoidosis, multiple sclerosis, pars planitis, human immunodeficiency virus infection Acute retinal necrosis, idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN), systemic vasculitides such as systemic lupus erythematosus (SLE), polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA), Churg-Strauss syndrome, and cryoglobulinemia Systemic vasculitides such as SLE, PAN, granulomatosis with polyangiitis (GPA), Churg-Strauss syndrome, and cryoglobulinemia and Susac syndrome Behçet’s disease, rickettsial infection, cat scratch disease Ocular toxoplasmosis, acute retinal necrosis, cytomegalovirus retinitis IRVAN, sarcoidosis

Idiopathic, infiltration with malignant cells (lymphoma or leukemia), SLE, Crohn’s disease, toxoplasmic retinochoroiditis, human T cell lymphoma virus type 1 infection, acquired immunodeficiency syndrome, human immunodeficiency virus infection, herpes simplex virus infection, Epstein-Barr virus infection Tuberculosis, Behçet’s disease, multiple sclerosis (rare), sarcoidosis (rare) Behçet’s disease, tuberculosis, sarcoidosis (rare) SLE, PAN, granulomatosis with polyangiitis (GPA), ChurgStrauss syndrome, Crohn’s disease, Susac syndrome, cat scratch disease, Mediterranean spotted fever, ocular toxoplasmosis

Modified from Abu El-Asrar et al. (2010)

Churg-Strauss syndrome, and cryoglobulinemia. Susac syndrome is a rare disease of unknown pathogenesis. It is also caused by microangiopathy affecting the arterioles of the brain, retina, and cochlea, giving the classic triad of encephalopathy, branch retinal arterial occlusions, and sensorineural hearing loss. The underlying process is believed to be a small vessel vasculitis causing microinfarcts of the retina, brain, and cochlea.

Algorithm for Workup of Retinal Vasculitis

Intraretinal Infiltrates Intraretinal infiltrates are characteristic of infectious processes, but in the absence of these, they are pathognomonic of Behçet’s disease. These transient white patches of retinitis often with small adjacent hemorrhages are almost always seen in patients with active posterior Behçet’s uveitis. Typically, they are silent on fundus fluorescein angiography.

Necrotizing Retinitis Retinal vasculitis may be associated with necrotizing retinitis due to ocular toxoplasmosis, acute retinal necrosis, cytomegalovirus (CMV) retinitis, and rarely human T cell lymphoma virus type 1 (HTLV-1) associated uveitis.

Aneurysmal Dilatations of the Retinal and Optic Nerve Head Arterioles IRVAN is a rare clinical entity characterized by bilateral retinal arteritis, numerous aneurysmal dilatations of the retinal and optic nerve head arterioles, peripheral retinal vascular occlusion, neuroretinitis, and uveitis. Visual loss is due to exudative maculopathy and neovascular sequelae of retinal ischemia. Arterial macroaneurysms, occurring in elderly female patients with sarcoidosis associated with peripheral multifocal chorioretinitis, have been described. These patients had severe cardiovascular disease.

Frosted Branch Angiitis The retinal findings include swelling of the retina and severe sheathing of the retinal venules, creating the appearance of frosted tree branches. Additional findings include intraretinal hemorrhages, hard exudates, and serous exudative detachments of the macula and periphery. Fluorescein angiography demonstrates leakage of dye from the vessels, but no evidence of decreased blood flow or occlusion. Patients who have the appearance of frosted branch angiitis are classified into three subgroups. First are patients with lymphoma or leukemia whose disease is due to infiltration with malignant cells (frosted branch-like appearance). Second is the group of patients who have associated viral infections or autoimmune disease. Frosted branch angiitis was reported in patients with systemic lupus erythematosus, Crohn’s disease, toxoplasmic retinochoroiditis, human T cell lymphoma virus type 1 infection, AIDS associated with small patches of retinitis, HIV without CMV retinitis, herpes simplex virus

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infection, and Epstein-Barr virus infection. In these patients, frosted branch angiitis is a clinical sign, possibly of immune complex deposition (secondary frosted branch angiitis). Finally, there is the group of otherwise healthy young patients (acute idiopathic angiitis).

Retinal Ischemia Ischemic retinal vasculitis is frequently seen secondary to tuberculosis and retinal vasculitis associated with tuberculoprotein hypersensitivity. Ischemic retinal vasculitis may also be secondary to Behçet’s disease and multiple sclerosis. Retinal periphlebitis associated with sarcoidosis is usually nonocclusive, sometimes subclinical, and only visible on fluorescein angiography, associated with typical segmental cuffing or more extensive sheathing and perivenous exudates, which are usually indicated as “candle wax drippings.” Development of capillary nonperfusion and subsequent neovascularization as well as branch and central retinal vein occlusions have been described.

Diagnostic Evaluation The search for a cause in patients with retinal vasculitis often involves a multidisciplinary approach and laboratory investigation (Table 3). Discrimination between infectious or noninfectious etiology of retinal vasculitis is important because treatment is different. In cases of diagnostic doubt, malignancy must be ruled out and should certainly be considered if, after an initial improvement with therapy, the patient’s disease rapidly becomes refractory to treatment. The laboratory workup of a patient with retinal vasculitis should be based on differential diagnosis derived from a detailed history, review of systems, and physical examination. If the patient’s medical history, review of systems, or ocular examination suggests an underlying systemic disease, then the diagnostic workup should be tailored for that disease. Key Points • Differential diagnosis of retinal vasculitis is based on ophthalmoscopic and fluorescein angiographic findings. • Multidisciplinary team approach is essential in evaluation and treatment. • Thorough history, review of systems, and physical examination are essential. • The diagnostic workup should be tailored according to the patient’s medical history, review of systems, and physical examination.

104 Table 3 Diagnostic studies performed on patients with retinal vasculitis A. Laboratory Tests: Complete blood count with differential Erythrocyte sedimentation rate C-reactive protein Serum chemistry panel with tests for renal and liver functions Blood sugar Urinalysis Venereal Disease Research Laboratory (VDRL) test, Fluorescent treponemal antibody absorption (FTA-ABS) test Tuberculin skin testing Interferon-γ release assays for tuberculosis Toxoplasmosis serology Lyme disease serology Dengue virus serology Cat scratch disease serology Rickettsial serology Human immunodeficiency virus, human T cell lymphoma virus type 1, cytomegalovirus, herpes simplex virus, varicella zoster virus, hepatitis virus, and West Nile virus serology Polymerase chain reaction to identify pathogens in ocular specimens Serum angiotensin-converting enzyme Rheumatoid factor Antinuclear antibody Anti-dsDNA Antineutrophil cytoplasmic antibody Antiphospholipid antibodies (lupus anticoagulants and anticardiolipin antibodies) Serum complement, CH50, AH50 Extractable nuclear antigen Serum protein electrophoresis Serum cryoglobulins Human leukocyte antigen testing Vitreous biopsy Cerebrospinal fluid cytology and cell count B. Imaging Fluorescein angiography Indocyanine green angiography Optical coherence tomography Ultrasonography Chest x-ray Chest CT scanning Magnetic resonance imaging Gallium scan Sacroiliac x-ray Modified from Abu El-Asrar et al. (2010)

A. M. Abu El-Asrar

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Differential Diagnosis of Choroiditis Alessandro Invernizzi

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 The Choroid: Primary Target or Accidental Host? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 How to Find Out the Correct Diagnosis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 The Importance of the Medical History “Who is the Host?” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 The Main Role Played by the Clinical Picture: “How Does It Look Like?” . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 Multi-Imaging: A Useful Tool to Better Understand the Choroidal Involvement . . . . . . . . . . . . . . . . . . . . . 110 Systemic Investigations: Is It Just in the Eye? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Intraocular Specimens Analysis: The Final Proof . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Introduction Choroiditis can be defined as an inflammatory process affecting the choroid. The main cause of inflammation can range from an autoimmune reaction targeting specific ocular antigens to an immune response against an exogenous agent infecting the eye. However, regardless the underlying trigger, the inflammatory status can result in similar clinical pictures in the choroid, making the proper diagnosis a real challenge. On the other hand, an immunosuppressive therapy, essential to save the eye in case of an autoimmune disease, could be devastating in the presence of a misdiagnosed infectious entity. Thus, to discriminate between infectious and noninfectious conditions is the first step of the diagnostic process

A. Invernizzi (*) Uveitis and Ocular Infectious Diseases Service - Eye Clinic, Department of Biomedical and Clinical Science, Luigi Sacco Hospital, University of Milan, Milan, Italy e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_32

while facing these entities. The second goal that must be achieved, especially in case of an infectious disease, is to identify the pathogen which is causing the choroiditis, in order to start the specific treatment. The aim of this chapter is hence to provide clinicians a schematic algorithm based on simple hints and general rules for the work-up of infectious choroiditis, in order to differentiate them from noninfectious forms and to identify the causative agent.

The Choroid: Primary Target or Accidental Host? Inflammatory processes involving the choroid can be divided according to their location into choriocapillaritis when the inflammation involves the choriocapillaris and stromal choroiditis when the inflammatory foci are located deep in the Haller and Sattler layers. When the inflammation is sustained by an autoimmune reaction targeting the choriocapillaris or the retinal pigment epithelium (RPE), we classify the disease as a 105

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primary inflammatory choriocapillaropathy. On the other hand, the choriocapillaris can show inflammatory signs when contiguous structures such as the retina or the deep choroid are inflamed. These entities can have an infectious etiology and are classified as secondary choriocapillaropathies. Stromal choroiditis can also be divided into two groups according to the underlying inflammatory process. When the inflammation is sustained by an autoimmune reaction targeting the choroid, the diseases are classified as a primary obligatory choroiditis. On the contrary, when the choroid represents the hosting tissue of a systemic infectious/inflammatory condition accidentally located in the eye, the disease is considered a secondary choroiditis. A list of the diseases commonly causing choroiditis classified according to the principles above is reported in Table 1.

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It is important to notice how the three main consecutive steps, allowing the filtering process that brings us from the global set of diseases we know to the final diagnosis, are linked by two-way arrows. This means that they can influence each other creating a dynamic, self-developing process. To give an example, a specific sign detected by funduscopic examination (second step) can raise the clinical suspect of precise entities, and consequently bring the clinician back to the medical history (first step), in order to enquire for more focused questions. The same could happen during the interpretation of test results.

The Importance of the Medical History “Who is the Host?”

When we try to reach a diagnosis, we basically compare the clinical history and picture of the patient with several compatible diseases we know. We then select the entities that better fit with the signs and symptoms of the subject we are examining, and we finally perform some tests to isolate the cause of the pathological condition among the others. A schematic representation of this process is reported (Fig. 1).

Most of the time, it is useless and even self-defeating to put the patient through a too detailed, and possibly embarrassing, questionnaire on his/her lifestyle and previous medical history. Nevertheless, we cannot avoid considering details of the patient’s history that could make us include rare diseases or unusual clinical pictures. Despite the quite large number of entities possibly affecting the choroid, we can assess the conditions that could shape our list of diseases by a simple scheme, based on just four main questions (Fig. 2). The pool of diseases that need to be considered along the diagnostic process will then include specific rare entities in addition to the main conditions commonly causing choroiditis (Table 1).

Table 1 Inflammatory conditions frequently affecting the choroid are divided according to the mainly involved choroidal layer (choriocapillaris or stroma). Diseases directly targeting the eye tissues are listed as “primary,” whereas ocular involvement occurring as a manifestation of a systemic disease is classified as “secondary.” Serpiginoid

tuberculosis is classified in between the two categories since it is caused by an immune reaction against the retinal pigment epithelium (RPE) when the RPE cells present tubercular antigens on their surface after being affected by mycobacteria. Infectious diseases are reported in bold

How to Find Out the Correct Diagnosis?

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The proposed questionnaire is just a basic scheme and should be modified according to clinicians’ experience and the geographic/social contexts. Furthermore, as mentioned before, the detection of specific signs during the clinical exam, the imaging examination, or the laboratory tests, could make the clinician suspecting an initially ignored disease and lead back to the medical history collection step in order to ask for targeted questions.

The Main Role Played by the Clinical Picture: “How Does It Look Like?” Fig. 1 The diagnostic process (scheme)

The clinical exam is the most important part of the diagnostic process: it can help in understanding the disease appearance and distribution, in perceiving the disease progression

Fig. 2 Simplified scheme for Medical history collection. Testing the reported four main fields of interest allows to include a large number of rare entities that need to be considered in the differential diagnosis when specific risk factors are present

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pathway, and in evaluating the surrounding structures involvement.

Choroidal Lesions In case of a solitary choroidal lesion, the infectious etiology should always be considered as a front-runner. A primary localization of pathogens in the choroid due to hematogenous spread as well as secondary to septic embolization is responsible of such lesions in most of the cases. Nevertheless neoplastic conditions either primitive or metastatic must be ruled out. On the contrary, multiple choroidal lesions, especially when involving both eyes, could be related both to autoimmune and infectious diseases. For this reason a bilateral involvement always needs for further investigations, including a multi-imaging approach, to be properly studied. It is almost impossible to differentiate infectious from autoimmune diseases by the sole appearance of choroidal lesions; however, there are some features detectable by the simple funduscopic examination that can address the diagnostic process towards the correct direction: – Similar size and shape for all the lesions is suggestive of an autoimmune disease. – Symmetrical and evenly distributed lesions are more likely autoimmune rather than infectious. – Sign of “penetration” from the choroidal district through the RPE into the subretinal/retinal/vitreous compartment is strongly suggestive of an infectious condition.

Associated Findings: Do the Surrounding Structures Look Involved? It is always important to carefully examine the whole eyeball searching for inflammatory alterations accompanying choroidal lesions. Being the RPE and the retina contiguous to the choroid, these are the most commonly involved structures secondary to choroidal diseases. In case of infectious pathologies, the RPE and the retina can be either directly targeted by the infective microorganism or indirectly damaged by the inflammatory process occurring within the underlying choroid. On the contrary, in case of autoimmune choroiditis, an accompanying retinitis is more rare, and the retinal lesions are more often the expression of secondary ischemic or inflammatory damage. Chorioretinal scars often represent the sign of a previous choroiditis episode. Although non-active, these lesions can be very useful in the differential diagnosis since their shape,

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distribution, size, and pigmentation differ from a disease to the other. Multiple pigmented scars along the vessels’ course are suggestive of TB (Fig. 3a), whereas small round-shaped yellowish atrophic dots in the mid-periphery with a prevalence in the inferior sectors are more frequent in sarcoidosis (Fig. 3b). A pigmented scar with an active retinochoroiditis along one border strongly supports the diagnosis of reactivate toxoplasmic retinochoroiditis (Fig. 3c). Finally, looking at a serpiginoid scar, pigment clumping at the center of the lesion is suggestive for infectious etiology (Fig. 3d), whereas autoimmune disease usually gets pigmented along the borders. Intraocular inflammation, regardless of the etiology, is often characterized by a breakdown of the inner blood retinal barrier; however, specific vasculitic alterations can help in developing a diagnostic hypothesis. Although an occlusive vasculitis can be found in several uveitis conditions, including autoimmune diseases such as Behçet disease or systemic lupus erythematosus, in case of choroiditis, an accompanying occlusion of the retinal vessels can be suggestive of infectious etiologies (Fig. 4a). An exudative segmental phlebitis on the contrary, is more likely related to autoimmune conditions such as sarcoidosis (Fig. 4b). Two exceptions to this general rule are represented by the retinal artery occlusions that can be found along with choroidal infarcts mimicking choroiditis in polyarteritis nodosa (Fig. 5) on one side, and the focal exudative vasculitis that often occurs along retinal vessels crossing a choroidal lesion in TB (Fig. 6). A careful evaluation of the vitreous involvement can also add useful information. First of all, vitritis is itself a sign of inflammatory reaction and can hence be considered as a direct representation of the immune status of the patient. Thus, the absence of vitreous involvement should always make the clinician doubtful about the diagnosis of a proper choroiditis, and rather consider alternative conditions mimicking choroidal inflammation such as choriocapillaritis or choroidal infarcts. In case the clinical picture is suggestive of an infectious etiology, vitritis should always be present, and its lack should raise the suspect of immunodeficiency, thus inducing the inclusion of unusual pathogens in the differential diagnosis. Furthermore some specific diseases, typically presenting with choroidal lesions, are associated with particular vitritis features: vitreous aggregates disposed with a “string of pearls” fashion are suggestive of fungal etiology, a dense vitreal reaction overlying a chorioretinal lesion is common in toxoplasmosis, and a dense vitritis organized in parallel sheets is typical of intraocular lymphomas. Anterior segment is less frequently involved in case of choroiditis being the most far district of the eye from the

Differential Diagnosis of Choroiditis

Fig. 3 Chorioretinal scars caused by different diseases. (a) Chorioretinal pigmented scars along the vessels’ course in a patient affected by tubercular choroiditis. (b) Multiple small round-shaped atrophic lesions in the mid-periphery in a patient affected by sarcoidosis. (c) An active retinitis focus (gray arrowhead) along the border of a

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chorioretinal scar (white arrowhead) and a more pigmented (older) scar (black arrowhead) in a patient affected by toxoplasmic retinochoroiditis. (d) Serpiginoid choroiditis with pigment clump at the center of the lesion in a patient affected by serpiginoid tuberculosis

Fig. 4 Retinal vasculitis as an associated finding of choroidal inflammatory conditions. (a) Occluded vessels (black arrowheads) in a patient affected by intraocular tuberculosis. (b) Vascular sheathing (white arrowheads) as a sign of exudative vasculitis in a patient affected by sarcoidosis

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Fig. 5 Funduscopic findings in a patient affected by panarteritis nodosa (PAN), a systemic condition causing multiple vascular occlusions that can mimic choroiditis lesions. A whitening of the retina along the papillomacular bundle (white arrowhead) is visible at funduscopic

examination (a) as a sign of retinal ischemia. Multiple yellowish deep lesions (black arrowheads) could be misdiagnosed as choroiditis but actually represent choroidal infarcts, a typical finding in PAN. Retinal ischemia is confirmed by fluorescein angiography (b)

Fig. 6 Segmental exudative vasculitis in a patient affected by intraocular tuberculosis. Tuberculosis usually causes occlusive vasculitis. However focal vascular leakage (white arrowhead) can be noted in some patients on fluorescein angiography (a) as a sign of exudative

vasculitis. Associated indocyanine green angiography (b) reveals an underlying choroidal granuloma (black arrowhead) likely causing the inflammatory process secondary involving the retinal leaking vessel

choroid. Despite this, observing granulomatous keratic precipitates can be useful in considering granulomatous rather than nongranulomatous uveitis as causative agent.

the contrary, can allow a better visualization of the alterations occurring within the choroid, differentiating them according to their location, their perfusion, and the relationships they have with the surrounding structures.

Multi-Imaging: A Useful Tool to Better Understand the Choroidal Involvement Fundus Autofluorescence (FAF) Being the choroid a deep structure, overlaid by other tissues, different lesions can have a similar appearance at funduscopic examination. A multi-imaging study, on

FAF images are generated by stimulating the retinal pigment epithelium with a specific wavelength and collecting

Differential Diagnosis of Choroiditis

the light consequently generated by the fluorophores contained in the RPE cells. Being the choroid located beyond the RPE, in many choroidal lesions FAF looks normal. However, once a deep lesion alters the overlying structures inducing exudative or atrophic changes at the RPE or the retina, FAF can change. As a general rule, an increased autofluorescence can be consequent to atrophic changes of the retina with preserved RPE, whereas a decreased FAF can result either from RPE atrophy or a masking effect secondary to material or fluid accumulated over the RPE. Specific patterns of FAF are associated with certain pathologic entities such as multiple evanescent white dot syndrome (MEWDS) or serpiginous/serpiginous-like choroiditis and can be useful in the differential diagnosis as well as in the activity assessment of these forms.

Fluorescein Angiography (FA) FA is commonly used to study the retinal rather than the choroidal perfusion. Nevertheless it can be really useful in collecting additional informations about the retinal involvement and the inflammatory status of the posterior segment in the presence of a choroiditis. As already mentioned, the identification of a retinal vascular alteration and its characterization as occlusive or exudative can be really helpful in differentiating the etiology of an underlying choroiditis (Fig. 7). In addition, a staining of dye can be visualized by FA in the areas of retina overlying an active choroidal lesion, whereas a window defect is visible in correspondence with retinal scars following the resolution of a preexisting choroiditis. Finally FA represents the gold

Fig. 7 Fluorescein angiography showing vascular alterations in the retina accompanying choroidal inflammation. (a) Retinal ischemic areas (black arrowheads) as a consequence of occlusive vasculitis in a patient affected by intraocular tuberculosis. A retinal neovascularization

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standard technique to identify retinal or choroidal neovascularization that can complicate some cases of choroiditis.

Indocyanine Green Angiography (ICGA) Due to their chemical and physical features, the indocyanine green molecules do not get out of the choriocapillaris fenestrations hence allowing a good visualization of the choroidal vasculature. As a consequence, ICGA is the gold standard technique to visualize and study choroidal alterations. ICGA hyper-fluorescence can have two main causes: the presence of choroidal vessels leaking in the late phases of the angiogram as an a-specific sign of inflammation, or the leakage of dye through RPE disruptions occurring in case of choroidal thickening associated with outer retinal blood barrier alteration such as in Vogt-Koyanagi-Harada disease. ICGA hypo-fluorescence is frequently associated with choroiditis, and its features throughout the angiogram allow the identification of different choroidal lesions (Fig. 8). A schematic interpretation of ICGA hypo-fluorescence and its association with possible etiologies is represented in Fig. 9.

Spectral Domain Optical Coherence Tomography (SD-OCT) SD-OCT provides in vivo quasi histological sections of the eye structures. Intraretinal fluid and subretinal fluid can be easily detected as a sign of inflammation associated with choroidal disease. Retinal alterations occurring in the areas of tissue overlying a choroidal lesion, either

is visible on the left side of the image (gray arrowhead). (b) Segmental leakage along main vessels (white arrowheads) as a sign of exudative vasculitis in a patient affected by sarcoid-related uveitis

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Fig. 8 Schematic interpretation of the hypofluorescent alterations on indocyanine green angiography (ICGA) according to their shape and appearance throughout the different phases of the exam. ICGA can visualize more choroidal lesions than any other imaging technique.

Furthermore a correct interpretation of hypofluorescent findings allows to identify the exact choroidal layer involved in the inflammatory process (i.e., choriocapillaris, full-thickness choroidal stroma, partial thickness choroidal stroma)

caused by a direct invasion of the retinal cells by the microorganisms such as in retinitis or secondary to an inflammatory or ischemic damage, can also be detected. SD-OCT features suggestive for specific choroiditis etiologies are reported (Fig. 10).

increased the importance of EDI-OCT in the management of posterior uveitis, especially choroiditis. Changes in choroidal thickness reflecting disease activity have been reported in several inflammatory entities and are nowadays used for monitoring the inflammatory status and the response to therapy. In contrast to the proved usefulness of EDI-OCT in monitoring choroiditis activity, its use as a diagnostic tool is still poorly explored. Few papers have reported the possibility to visualize choroidal lesions (e.g., granulomas) by the use of EDI-OCT. However a differential diagnosis among the causative agents based on EDI-OCT characteristics of the

Enhanced Depth Imaging Optical Coherence Tomography (EDI-OCT) EDI-OCT is an advanced OCT technique that allows the visualization of structures deeper than the RPE, hardly reached by the standard SD-OCT. The possibility to image the choroid and to measure its thickness has

Differential Diagnosis of Choroiditis

Fig. 9 Indocyanine green angiography (ICGA) hypofluorescent alterations and their association with choroidal inflammatory diseases. After the first differentiation between choriocapillaris inflammation/hypoperfusion and stromal choroiditis, a further classification of the ICGA hypofluorescent alterations according to their localization, shape, and associated findings can help in identifying the underlying disease. A

choroidal granulomas is still impossible although certain features show a higher prevalence in TB-related lesions (Fig. 11). EDI-based structural analysis of the choroidal sublayers has also showed Sattler’s layer enlargement in sarcoidosis, not detectable in TB-related uveitis. Finally, EDI-OCT features of several entities other than uveitis have been described, making this technique really useful in differentiating these entities from choroiditis. Several neoplastic entitles such as intraocular lymphoma, for example, show specific EDI-OCT signs that can help in confirming or excluding this masquerading syndrome from the possible differential diagnosis.

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schematic algorithm to correlate the ICGA findings with the presumed causative agent is reported. It has to be underlined that ICGA can support an etiological hypothesis or guide the diagnostic process, but the definitive diagnosis cannot be made just on these technique’s findings

Systemic Investigations: Is It Just in the Eye? Being infectious choroiditis the expression of a systemic disease in most cases, clinicians dealing with such entities cannot avoid extending their investigations beyond the eye. Nevertheless, it is almost impossible to list all the tests that could be performed to investigate a patient affected by a choroidal infectious disease, considering the prominent number of possible etiologies. Among the most common choroiditis entities, two infectious diseases should always be considered as possible causative agents until otherwise proven: syphilis and

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Fig. 10 Spectral domain optical coherence tomography (SD-OCT) findings suggestive for specific uveitis entities associated with choroidal inflammation. (a) Subretinal fluid pockets (white asterisk) with multiple septa (white arrowheads) in a patient affected by VogtKoyanagi-Harada disease (Ishihara et al. 2009). (b) Retinal thickening and hyperreflectivity as a sign of active retinitis (black asterisk) in a patient affected by toxoplasmic retinochoroiditis. The inflammatory involvement of the underlying choroid is visible as a huge thickening

(white segment) (Goldenberg et al. 2013). (c) Photoreceptor outer segment and outer retinal layer alterations (black arrowheads) in a patient affected by syphilitic placoid chorioretinitis (Pichi et al. 2014). (d) A pre-retinal hyperreflective deposit (dotted circle) in a case of toxoplasmic retinochoroiditis. This sign has been reported in about 30% of cases and strongly supports toxoplasmic etiology. Accompanying vitritis (grey arrowheads) is also visible (Goldenberg et al. 2013)

tuberculosis. For both of them, the systemic involvement can be assessed by several tests with different levels of sensitivity and specificity. In the suspect of intraocular TB, it has been demonstrated that a combination of Mantoux intradermal reaction (PPD) and an IGRA test (e.g., QuantiFERON TB Gold) offers a higher specificity and sensitivity as compared to each of the two tests alone. In regard to syphilis, the presence of specific antibodies offers the strongest evidence of disease presence. When such assay is not available, a combination of treponemic and non-treponemic tests should be performed. In order to avoid time and resource wasting, other tests should only be performed under the strong suspect, based on the medical history and the clinical picture, for a specific entity. Regardless the systemic investigation we ask for, a careful interpretation of the results is mandatory. In fact, a systemic ‘positivity’ means that the subject is affected or has been affected by the tested disease, but does not prove that infectious agent to be responsible for the ongoing choroiditis. On the other hand, false negatives are frequent in case of immunocompromised hosts.

Only the experience of the clinician and the combined evaluation of the medical history and the clinical picture allow a proper interpretation of the tests results.

Intraocular Specimens Analysis: The Final Proof Although a correct diagnosis can be reached in most of the cases without collecting any intraocular sample, this is the only way to really prove the intraocular localization of a specific infectious agent. In fact, blood test positivity can only demonstrate a subject has been infected by a certain pathogen, but the connection with the choroidal involvement can only be supposed. As a consequence, when the clinical picture remains unclear or there is need for a stronger evidence of intraocular involvement, the collection and the analysis of intraocular samples are mandatory. The choroid is hard to be reached; thus, a choroidal biopsy, although used for the management of certain

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Fig. 11 Enhanced depth imaging optical coherence tomography (EDIOCT) of choroidal granulomas. (a) A sarcoid-related choroidal granuloma (white dotted line) appearing as a hyporeflective round-shaped lesion with distinct margins and a homogeneous intralesional pattern. (b) A tubercular granulomatous lesion (black dotted line) appearing lobulated in shape and isoreflective as compared to the surrounding choroid. Margins are difficult to be determined, and the intralesional

pattern is dishomogeneous. The choroidal lesion as frequently happens in TB is located beneath retinal vessels (white arrowheads). Contrary to reflectivity and internal pattern that does not show prevalence variations in different diseases, undefined margins and lobulated shape are more frequently observed and consequently suggestive for tubercular etiology (Invernizzi et al. 2015)

intraocular tumors, is not routinely adopted in choroiditis diagnosis due to the related surgical difficulties and complications. On the contrary, vitreous specimens are easily collected, and most of the times, their examination allow to perform several lab tests including polymerase chain reaction (PCR), cultures, and slice analysis in order to identify the infecting pathogen and exclude neoplastic entities mimicking uveitis (e.g., intraocular lymphoma). Vitrectomy is also useful to allow the visualization of posterior structures (i.e., retina and choroid) in case of dense vitritis obscuring the fundus. On the contrary, when the disease is confined to the choroidal space only, with no sign of retinal or vitreal involvement, vitreous specimens can result negative since the pathogens have not yet reached the vitreal compartment. In such cases an invasive approach should be carefully evaluated.

In most of the cases, a prompt therapy is mandatory to avoid sight-treating complications, but the proper treatment strictly depends on a correct diagnosis. With this purpose clinicians should focus on two main targets: (1) to differentiate autoimmune from infectious diseases first and (2) to identify the causative agent in case of infection. Following a schematic algorithm such as the one purposed in this chapter can help in searching for the correct diagnosis, avoiding time and resource wasting. However, a book will never be able to describe the complexity of the clinic, and only a passionate clinical practice and a trained experience will allow clinicians to properly interpret the whole data and to reach the correct diagnosis.

Conclusions Despite the improvements in diagnostic techniques and the increased scientific knowledge we reached in the last decades, uveitis are still a difficult conditions to be managed, with choroidal involvement representing the hardest challenge.

Key Points • The differential diagnosis of choroiditis is challenging. • Differentiating autoimmune from infectious etiology is mandatory in order to start a specific treatment. • The medical history and the clinical picture are the main elements to select the possible differential diagnosis. • A multi-imaging study with ICGA as a leading technique is helpful. • Only the experience allows clinicians to properly interpret the whole picture and to reach the correct diagnosis.

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Ocular Toxoplasmosis: The Choroidal Involvement

Ocular toxoplasmosis traditionally manifests as an active retinitis, and this sign is such characteristic to allow the disease diagnosis in most of cases. Nevertheless, the retinal pigment epithelium (RPE) and the choroid can be involved in the inflammatory process as well (Atmaca et al. 2006). A focal choroidal thickening, visible beneath the areas of retinitis, is the expression of the inflammatory response against the parasite, actively duplicating into the overlying retinal lesion. However, choroidal involvement in toxoplasmosis can extend far more from what is clinically visible. Indocyanine green angiography (ICGA) in fact, reveals multiple satellite hypofluorescent dots in most of the patients, invisible at funduscopic examination due to the absence of an associated alteration in the overlying retina. The nature of these lesions is still unclear since they could represent choroidal granulomas containing the parasites as well as the expression of focal inflammatory reaction. Regardless of their pathophysiology, these lesions are the proof of diffuse choroidal involvement justifying the classification of ocular toxoplasmosis as a chorioretinitis, and supporting the use of ICGA in the management of this condition (Auer et al. 1999).

RPE is supposed to be the target of the immune reaction: against RPE self-antigens in the serpiginous form or against exogenous antigens expressed on the infected RPE cells in the serpiginoid form. Patient history, clinical feature, and systemic tests can help in differentiating between serpiginous choroiditis and tubercular multifocal serpiginoid choroiditis as reported below. However, only intraocular specimen analysis can definitively prove or exclude the infectious etiology. Serpiginous choroiditis (likely autoimmune) Born/raised in non-endemic areas Non-multifocal Bilateral Absence of vitreous/anterior chamber inflammatory reaction Lesions starting from the peripapillary area No response to anti-TB treatment Pigment clumping at the border of healed lesions TB systemic tests negative Chest X-ray normal

Serpiginous Choroiditis Versus Infectious Multifocal Serpiginoid Choroiditis (Nazari Khanamiri and Rao 2013)

One of the most impressive similarities between an autoimmune and an infectious choroiditis is represented by the serpiginous choroiditis and the infectious multifocal serpiginoid choroiditis. Serpiginous choroiditis is a posterior uveitis manifesting with ameboid inflammatory lesions spreading from the peripapillary region throughout the fundus with a primary involvement of the choroid and the overlying retinal pigment epithelium (RPE). The pathogenesis is still unclear, but a favorable response to immunosuppressive therapy along with the absence of a proven infectious etiology supports the hypothesis of an autoimmune disease. On the contrary, a similar clinical picture named as “serpiginous-like” or “multifocal serpiginoid” choroiditis has been associated with several infectious conditions with tuberculosis as a front-runner. In both the conditions, infectious and autoimmune, the inflammatory process is mainly focused at the level of the RPE and the choriocapillaris with typical hypoperfusion signs on indocyanine green angiography. The (continued)

Tubercular multifocal serpiginoid choroiditis Lived in endemic areas Multifocal Unilateral/bilateral Vitreous/anterior chamber inflammatory reaction Lesions starting from the posterior pole without primary involvement Improved with anti-TB treatment Pigment clumping usually at the center of lesions TB systemic tests positive Chest X-ray usually negative

Suggested Reading Adl MA, LeHoang P, Bodaghi B. Use of fluorescein angiography in the diagnosis and management of uveitis. Int Ophthalmol Clin. 2012;52 (4):1–12. Aguilar GL, Blumenkrantz MS, Egbert PR, McCulley JP. Candida endophthalmitis after intravenous drug abuse. Arch Ophthalmol. 1979;97(1):96–100. Ang M, Wong W, Ngan CC, Chee SP. Interferon-gamma release assay as a diagnostic test for tuberculosis-associated uveitis. Eye (Lond). 2012;26(5):658–65. Atmaca LS, Simsek T, Atmaca Sonmez P, Sonmez K. Fluorescein and indocyanine green angiography in ocular toxoplasmosis. Graefes Arch Clin Exp Ophthalmol. 2006;244(12):1688–91. Auer C, Bernasconi O, Herbort CP. Indocyanine green angiography features in toxoplasmic retinochoroiditis. Retina. 1999;19(1):22–9. Bourdin C, Busse A, Kouamou E, Touafek F, Bodaghi B, Le Hoang P, Mazier D, Paris L, Fekkar A. PCR-based detection of Toxoplasma gondii DNA in blood and ocular samples for diagnosis of ocular toxoplasmosis. J Clin Microbiol. 2014;52(11):3987–91. Butler NJ, Furtado JM, Winthrop KL, Smith JR. Ocular toxoplasmosis II: clinical features, pathology and management. Clin Experiment Ophthalmol. 2013;41(1):95–108. Cunningham Jr ET, van Velthoven ME, Zierhut M. Spectral-domainoptical coherence tomography in uveitis. Ocul Immunol Inflamm. 2014;22(6):425–8.

Differential Diagnosis of Choroiditis Davis JL. Ocular syphilis. Curr Opin Ophthalmol. 2014;25(6):513–8. Deuter CM, Kötter I, Wallace GR, Murray PI, Stübiger N, Zierhut M. Behçet’s disease: ocular effects and treatment. Prog Retin Eye Res. 2008;27(1):111–36. Goldenberg D, Goldstein M, Loewenstein A, Habot-Wilner Z. Vitreal, retinal, and choroidal findings in active and scarred toxoplasmosis lesions: a prospective study by spectral-domain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2013;251 (8):2037–45. Gupta V, Gupta A, Rao NA. Intraocular tuberculosis – an update. Surv Ophthalmol. 2007;52(6):561–87. Herbort CP, Mantovani A, Bouchenaki N. Indocyanine green angiography in Vogt-Koyanagi-Harada disease: angiographic signs and utility in patient follow-up. Int Ophthalmol. 2007;27(2–3):173–82. Herbort CP, Rao NA, Mochizuki M. Members of Scientific Committee of First International Workshop on Ocular Sarcoidosis. 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. Herbort CP, Papadia M, Mantovani A. Classification of choroiditis based on inflammatory lesion process rather than fundus appearance: enhanced comprehension through the ICGA concepts of the iceberg and jellyfish effects. Klin Monbl Augenheilkd. 2012;229(4):306–13. Hsu CT, Kerrison JB, Miller NR, Goldberg MF. Choroidal infarction, anterior ischemic optic neuropathy, and central retinal artery occlusion from polyarteritis nodosa. Retina. 2001;21(4):348–51. Invernizzi A, Mapelli C, Viola F, Cigada M, Cimino L, Ratiglia R, Staurenghi G, Gupta A. Choroidal granulomas visualized by enhanced depth imaging optical coherence tomography. Retina. 2015;35(3):525–31. Ishihara K, Hangai M, Kita M, Yoshimura N. Acute Vogt-KoyanagiHarada disease in enhanced spectral-domain optical coherence tomography. Ophthalmology. 2009;116(9):1799–807. Margolis R. Diagnostic vitrectomy for the diagnosis and management of posterior uveitis of unknown etiology. Curr Opin Ophthalmol. 2008;19(3):218–24.

117 Mehta H, Sim DA, Keane PA, Zarranz-Ventura J, Gallagher K, Egan CA, Westcott M, Lee RW, Tufail A, Pavesio CE. Structural changes of the choroid in sarcoid- and tuberculosis-related granulomatous uveitis. Eye (Lond). 2015;29(8):1060–8. Nazari Khanamiri H, Rao NA. Serpiginous choroiditis and infectious multifocal serpiginoid choroiditis. Surv Ophthalmol. 2013;58 (3):203–32. Pichi F, Ciardella AP, Cunningham Jr ET, Morara M, Veronese C, Jumper JM, Albini TA, Sarraf D, McCannel C, Voleti V, Choudhry N, Bertelli E, Giuliari GP, Souied E, Amer R, Regine F, Ricci F, Neri P, Nucci P. Spectral domain optical coherence tomography findings in patients with acute syphilitic posterior placoid chorioretinopathy. Retina. 2014;34(2):373–84. Sagoo MS, Mehta H, Swampillai AJ, Cohen VM, Amin SZ, Plowman PN, Lightman S. Primary intraocular lymphoma. Surv Ophthalmol. 2014;59(5):503–16. Sen HN, Bodaghi B, Hoang PL, Nussenblatt R. Primary intraocular lymphoma: diagnosis and differential diagnosis. Ocul Immunol Inflamm. 2009;17(3):133–41. Sharma K, Gupta V, Bansal R, Sharma A, Sharma M, Gupta A. Novel multi-targeted polymerase chain reaction for diagnosis of presumed tubercular uveitis. J Ophthalmic Inflamm Inf. 2013;3(1):25. Shields CL, Manalac J, Das C, Saktanasate J, Shields JA. Review of spectral domain-enhanced depth imaging optical coherence tomography of tumors of the retina and retinal pigment epithelium in children and adults. Indian J Ophthalmol. 2015a;63(2):128–32. Shields CL, Manalac J, Das C, Saktanasate J, Shields JA. Review of spectral domain enhanced depth imaging optical coherence tomography of tumors of the choroid. Indian J Ophthalmol. 2015b;63 (2):117–21. Silpa-Archa S, Lee JJ, Foster CS. Ocular manifestations in systemic lupus erythematosus. Br J Ophthalmol. 2015;100(1):135–41. Yeh S, Forooghian F, Wong WT, Faia LJ, Cukras C, Lew JC, Wroblewski K, Weichel ED, Meyerle CB, Sen HN, Chew EY, Nussenblatt RB. Fundus autofluorescence imaging of the white dot syndromes. Arch Ophthalmol. 2010;128(1):46–56.

Differential Diagnosis of Infectious Retinitis André Luiz Land Curi

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Case 1: Ocular Toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Case 2: Acute Retinal Necrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Case 3: CMV Retinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Introduction

Case 1: Ocular Toxoplasmosis

Toxoplasmic retinochoroitis is characterized by a whitish foci of retinitis with poorly defined margins associated with vitreous inflammation. Anterior segment involvement is secondary to posterior inflammmation. Although it may present as a single lesion, the gold standard is the presence of an active lesion close to an old hyperpigmented scar. Acute retinal necrosis is a syndrome characterized by retinitis, vitritis and vasculitis. This condition is usually secondary to herpes virus infection. Multiple areas of peripheral retinitis spread from the periphery to the posterior pole and are associated with vascular oclusions and significant vitreous haze. Optic disc involvement and retinal detachment are common. Cytomegalovirus retinitis occurs in association of host immunossupression in situations such as HIV positive patients, solid organ transplantation, and leukemia, among others. The retinitis usually stars in the periphery with a granular pattern in the borders and presents with minimal to mild vitreous inflamation. Anterior segment involvement is uncommon

A 24-year-old man from Rio de Janeiro was referred with a 3-week history of blurred vision in one eye. He had no significant medical history and no known allergies. The patient reported a similar previous episode of blurred vision when he had been treated with oral antibiotics and topical medication with recovery of visual acuity. Ophthalmological examination revealed visual acuity 20/20 and 20/60. Biomicrospcopy showed keratic precipitades and 4+ cells in the anterior chamber. Fundocscopy revealed a whitish lesion close to a hyperpigmented scar (Fig. 1). There was 4+ vitreous haze. The diagnosis of toxoplasmosis retinochoroiditis was made and he was put on specific treatment. He was treated with sulfadiazine + pyrimetamine + folinic acid and oral steroids for 30 days. After treatment, the lesion was completely healed and the visual acuity returned to nomal.

A. L. L. Curi (*) National Institute of Infectious Diseases – INI, Oswaldo Cruz Foundation – FIOCRUZ, Rio de Janeiro, Brazil e-mail: andre.curi@ini.fiocruz.br © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_31

Case 2: Acute Retinal Necrosis A 34-year-old woman from Rio de Janeiro was referred to Ophthalmology Clinic at Fiocruz complaining of blurred vision in the left eye for 3 weeks. Visual acuities were 20/20 in the right eye (RE) and 22 mmHg) at presentation and three of them (8.6%) had glaucoma. Nineteen patients (54,3%) had secondary cataract at presentation and other two (5,7%) patients were pseudophacic (Table 1). Key Points • Rubella virus can cause congenital or acquired infections and has a clinical presentation resembling Fuchs’ uveitis syndrome. • Rubella virus has been postulated as one of the agents responsible for Fuchs’ uveitis syndrome; however, this association has not been confirmed yet. • Common clinical features include small-sized stellate keratic precipitates, vitreous opacities, iris signs, and secondary glaucoma.

N. N. Markomichelakis (*) · S. Masselos Ocular Inflammation Institute of Athens, General Hospital of Athens, Athens, Greece e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_22

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Fig. 1 Typical keratic precipitate (KP) distribution and configuration in two patients with RV-associated uveitis. Note that the KPs are small and distributed throughout the entire extent of the corneal endothelium and that many of them have a stellate shape

Fig. 2 The absence of posterior synechiae is a typical characteristic in RV-associated uveitis. In the retroillumination photo we can see clearly the stellate shape of KP’s

Fig. 3 Even if posterior synechiae is extremely uncommon, the anterior synechiae may be seen in 20 % of cases with RV-associated anterior uveitis

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Fig. 4 RV uveitis can cause atrophy and depigmentation of anterior border layer and stroma. The atrophy is defuse and not sector as seen in herpes infection. (a, b) a female patient of 26 years and (c, d) of a male 38 years with RV-associated uveitis. Note the loss of iris substance in the anterior layers of the iris (a, c) compared to the different appearance of the normal eye (b, d). Note also the anisocoria caused by atrophy of the sphincter pupillae. The affected pupil is larger than the unaffected side (a, b)

Fig. 5 A young patient with RV-associated uveitis and heterochromia. The right eye is the affected eye. Heterochromia occurs in light colored irides

Fig. 6 Gonioscopic photograph of a patient with RV-associated uveitis. Note the very subtle vascular abnormalities in the angle (a) as well as the blood in the Schleems canal (b). Abnormal vessels bridging the anterior chamber angle occur in about 80 % of patients

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Fig. 7 The fragile blood vessels in the iridocorneal angle and the iris may be responsible for the occurrence of hyphema after anterior chamber paracentesis (Amsler’s sign)

Fig. 8 Iris nodules in RV-associated uveitis can be either pupillary (Koeppe) (a) or stromal (Busacca) (b). These nodules are small and transparent and therefore may be overlooked

Fig. 9 Cataract formation is a common complication of RV-associated uveitis and occurs in about 60 % of cases. Many patients with RV-associated uveitis are unaware of their disease until their vision

decreases due to cataract formation. It usually commences as posterior subcapsular cataract that progress to maturity with variable speed

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Fig. 10 Vitreous opacification to some degree is seen in the majority of patients with RV-associated uveitis. In general, profound cellular activity in the vitreous is not a feature of the disease and the opacity is usually concentrated in the anterior vitreous Table 1 Clinical and demographic characteristics of our 35 patients proved to be affected with Rubella virus associated uveitis following the analysis of aqueous humor samples with positive Goldman-Witmer coefficient (>3) and/or the presence of rubella RNA Clinical characteristics Male Age at diagnosis years median (range) Diagnosis during a routine eye examination Diagnosis by PCR GWC Both Symptoms Redness Floaters Blurred or decreased vision Unilateral involvement IOP mmHg mean (range) Anterior chamber inflammation None Mild (1+) Moderate (2+) Severe (3+) Keratic precipitates None Small scattered over the endothelium Posterior synechiae Anterior synechiae Heterochromia Iris atrophy Iris nodules Koeppe Busacca Abnormal angle vessels Vitreous inflammation 1+ cells 2+ cells Opacities Cataract Glaucoma

Patients N(%) 18(51) 38(4–65) 20(57) 6(17) 24(69) 5(14) 15(43) 4(11) 14(40) 8(23) 35(100) 15(7–60) 5(14) 21(60) 8(23) 1(3) 4(11) 31(89) 0(0) 7(20) 13(37) 10(29) 5(14) 3(8) 2(6) 28(80) 28(80) 22(63) 5(14) 20(57) 21(60) 3(9)

Suggested Reading Damasceno N, Damasceno E, Souza E. Acquired unilateral rubella retinopathy in adult. Clin Ophthalmol. 2011;5:3–4. de Groot-Mijnes JDF, de Visser L, Rothova A, et al. Rubella virus is associated with Fuchs heterochromic iridocyclitis. Am J Ophthalmol. 2006;141:212–4. De Visser L, Braakenburg A, Rothova A, de Boer JH. Rubella virus–associated uveitis: clinical manifestations and visual prognosis. Am J Ophthalmol. 2008;146:292–7. Hara J, Fujimoto F, Ishibashi T, et al. Ocular manifestations of the 1976 rubella epidemic in Japan. Am J Ophthalmol. 1979;87:642–5. Hayashi M, Yoshimura N, Kondo T. Acute rubella retinal pigment epithelitis in an adult. Am J Ophthalmol. 1982;93:285–8. Lanzieri TM, Parise MS, Siqueira MM, et al. Incidence, clinical features and estimated costs of congenital rubella syndrome after a large rubella outbreak in Recife, Brazil, 1999–2000. Pediatr Infect Dis J. 2004;23:1116–22. Quentin CD, Reiber H. Fuchs heterochromic cyclitis: rubella virus antibodies and genome in aqueous humor. Am J Ophthalmol. 2004;138:46–54. Ruokonen PS, Metzner S, Ücer A, et al. Intraocular antibody synthesis against rubella virus and other microorganisms in Fuchs’ heterochromic cyclitis. Graefes Arch Clin Exp Ophthalmol. 2010;248:565–71. Suzuki J, Goto H, Komase K, et al. Rubella virus as a possible etiological agent of Fuchs heterochromic iridocyclitis. Graefes Arch Clin Exp Ophthalmol. 2010;248:1487–91. Vijayalakshmi P, Rajasundari TA, Prasad NM, et al. Prevalence of eye signs in congenital rubella syndrome in South India: a role for population screening. Br J Ophthalmol. 2007;91:1467–70. Wolff SM. The ocular manifestations of congenital rubella. A prospective study of 328 cases of congenital rubella. J Pediatr Ophthalmol. 1973;10:101–41.

Herpetic Anterior Uveitis Aliza Jap, Soon-Phaik Chee, Aniruddha Agarwal, and Vishali Gupta

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 Cytomegalovirus Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 Case 1: Chronic Anterior Uveitis Mimicking Postoperative Endophthalmitis . . . . . . . . . . . . . . . . . . . . . . . . . 186 Case 2: Development of Glaucomatous Optic Neuropathy with Recurrent Episodes . . . . . . . . . . . . . . . . . 186 Case 3: Aqueous Sampling May Be Negative Initially . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Case 4: CMV Anterior Uveitis May Maintain a Benign Course Despite Long Duration and Frequent Attacks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 Case 5: Optimal Modality of Treatment of CMV Anterior Uveitis Remains to Be Determined . . . . . . 187 Case 6: Progression of CMV Anterior Uveitis to Endotheliitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 Herpes Simplex Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Case 7: A Case of Herpes Simplex Anterior Uveitis with Pigmented Keratic Precipitates . . . . . . . . . . . 191 Varicella Zoster Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Case 8: Varicella Granulomatous Anterior Uveitis with High Intraocular Pressure and Corneal Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Introduction A. Jap Singapore National Eye Centre, Singapore, Singapore Division of Ophthalmology, Changi General Hospital, Singapore, Singapore e-mail: [email protected] S.-P. Chee (*) Singapore National Eye Centre, Singapore, Singapore Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Duke-NUS Graduate Medical School, Singapore, Singapore Singapore Eye Research Institute, Singapore, Singapore e-mail: [email protected]

The common viruses from the herpes family associated with anterior uveitis include herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV). Usually, viral anterior uveitis is suspected in the setting of anterior uveitis with granulomatous keratic precipitates (KPs), anterior chamber cells and flare, iris atrophy, and elevated intraocular pressure (IOP). HSV and VZV are the most common causes of viral anterior uveitis. HSV anterior uveitis can be caused by serotype 1 which affects both males and females in their fourth or fifth decades of life. Serotype 2 may also be associated with anterior uveitis in younger population. VZV

A. Agarwal · V. Gupta Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_21

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is more often seen in an elderly population (sixth or second decade of life) since this virus can remain latent in neural sensory ganglia for several years. Patients with viral anterior uveitis may have a preceding history of viral exanthem or skin blisters. There may be low-grade fever and malaise several days prior to development of anterior uveitis. The inflammation associated with VZV is usually more severe compared to HSV infections. Reduction in corneal sensations and other manifestations such as interstitial keratitis may also be observed in viral anterior uveitis caused by herpetic viruses. CMV infection in immunocompetent individuals typically manifests as an anterior uveitis in contrast to immunosuppressed patients where posterior involvement predominates. CMV anterior uveitis is usually a unilateral event and may manifest as an acute episodic hypertensive uveitis or as a chronic uveitis associated with ocular hypertension. The acute episodic clinical phenotype is more commonly seen in younger patients with mean age of 37 years. Characteristically, they present with recurrent episodes of headache, mild blurring of vision, and seeing haloes. The conjunctival injection is usually mild, with corneal epithelial edema and severely elevated intraocular pressure (IOP) being the most significant findings. The anterior chamber (AC) inflammation is similarly minimal with few granulomatous keratic precipitates (KPs) located centrally or inferiorly and less than 2+ cells. The iris may show areas of patchy atrophy. These episodes are usually transient and the IOP elevations are easily managed with a short course of glaucoma medications. On the other hand, the chronic anterior uveitis phenotype tends to involve older patients (mean age of 65 years). The KPs are classically described as being fine, filiiform, or stellate and are frequently pigmented, much greater in number, and are distributed throughout the cornea. The iris often has a moth-eaten appearance due to diffuse atrophy. The IOP is also often elevated. Posterior synechiae (PS) is not a feature of CMV anterior uveitis. The main causes of visual loss from CMV anterior uveitis are cataract formation (14–60%) especially in the chronic type, glaucomatous optic neuropathy (GON) (13–60%), and endothelial damage. While each virus from the herpes family may have a distinct phenotypic presentation, there may be similarities in the clinical presentation due to overlapping features, and it may be challenging to identify the causative virus based on the clinical examination alone. Other etiologies of anterior uveitis such as syphilis, toxoplasmosis, and chikungunya must be excluded. Other causes such as sarcoidosis may also result in hypertensive anterior uveitis.

A. Jap et al.

Cytomegalovirus Anterior Uveitis Clinical Features Cytomegalovirus (CMV) anterior uveitis is usually unilateral, mild, and may present as an acute recurrent episode or as a chronic iritis associated with ocular hypertension and iris atrophy. Visual loss may occur as a consequence of cataract formation, glaucomatous optic neuropathy, or endothelial damage. The endothelial cell loss may be from a direct result of the CMV infection, a consequence of repeated episodes of inflammation, or from the hypertensive crises. Antiviral therapy with systemic ganciclovir or its prodrug valganciclovir or topical ganciclovir, in combination with topical anti-inflammatory agents results in resolution of the inflammation in about 80% of cases but the relapse rate is also high and long-term therapy of at least 1 year may be required. Control of the IOP with glaucoma medications and/or surgery is a critical component in the management of these eyes in order to minimize visual loss from GON.

Case 1: Chronic Anterior Uveitis Mimicking Postoperative Endophthalmitis A 75-year-old Chinese male who had undergone uncomplicated bilateral phacoemulsification with intraocular lens (IOL) implant 5 years ago was seen for tearing and floaters OS of 3 weeks duration which was associated with mild pain. His visual acuity was 20/20 OU. The left eye was mildly injected with pigmented granulomatous KPs, some of which are arranged in a ring pattern, nodular endothelial lesions, 2+ AC cells, and inflammatory deposits on the IOL (Fig. 1). There was no PS, fibrin, or flare. There were 2+ retrolental cells (Fig. 2) but the deep vitreous was clear and the retina was normal. The IOP was 20 mmHg. Aqueous sampling to exclude a delayed onset exogenous endophthalmitis was positive for CMV and negative for other infectious agents.

Case 2: Development of Glaucomatous Optic Neuropathy with Recurrent Episodes A 61-year-old Chinese male first presented in 1994 with an acute episode of iritis with few granulomatous KPs and odd AC cells and elevated IOP of 41 mmHg in his left eye (Fig. 3). He responded rapidly to glaucoma medications and topical steroids and his cup disc ratio then was 0.4 OU. However, he continued to have such episodes, occurring about twice a year every year for which he was treated elsewhere. He presented again 16 years later when the cup disc ratio in his left eye was noted to be enlarged at 0.6 and automated perimetry showed a possible early nasal step (Fig. 4). Aqueous tap was positive for CMV, and he

Herpetic Anterior Uveitis

Fig. 1 Slit lamp photograph of the left eye showing pigmented granulomatous keratic precipitates of varying sizes, some of which are arranged in a ring pattern (black arrow), nodular endothelial lesions (white arrow)

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Fig. 3 Slit lamp photograph of the left eye showing a few granulomatous KPs

and cells were seen, her IOP was 9 mmHg. Aqueous sampling was negative for viral etiology and the AC inflammation resolved within a week with topical steroids and nonsteroidal anti-inflammatory drugs. She was subsequently well till July 2014 when she again presented a few days after onset of symptoms. This time her IOP was 30 mmHg and repeat tap was positive for CMV.

Case 4: CMV Anterior Uveitis May Maintain a Benign Course Despite Long Duration and Frequent Attacks

Fig. 2 Slit lamp photograph of the same eye showing the presence of retrolental cells

was treated with ganciclovir gel 0.15% and glaucoma medications. However, he was lost again to follow-up, during which he continued to have recurrences, till 3 years later when he returned with progressive cupping and visual field loss (Fig. 5).

A 40-year-old Chinese lady had been having almost monthly episodes of acute recurrent hypertensive uveitis in her left eye since 1990 with a highest recorded IOP of 45 mmHg. Slit lamp examination showed a few granulomatous KPs inferiorly some of which are arranged in a linear fashion adjacent to the limbus, occasional AC cells, and mild iris atrophy (Fig. 7). There was no relative afferent pupillary defect. The cup disc ratios were 0.3 OU and automated perimetry was normal. Aqueous tap was positive for CMV. Her endothelial cell counts were 2273 cells/mm2 OD and 3003 cells/mm2 OS.

Case 3: Aqueous Sampling May Be Negative Initially

Case 5: Optimal Modality of Treatment of CMV Anterior Uveitis Remains to Be Determined

A 65-year-old Chinese female has been having recurrent episodes of acute hypertensive anterior uveitis in her right eye since 2003 with few granulomatous KPs (Fig. 6) and her IOP is typically above 50 mmHg at onset. In April 2013, she presented 9 days after onset of symptoms and although KPs

A gentleman had been treated by other ophthalmologists for hypertensive uveitis in his left eye since 2010. By the time he was first seen at the Singapore National Eye Centre, he already had advanced GON with extensive visual field defects. Slit lamp examination showed numerous fine- to

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Fig. 4 Automated perimetry of the left eye 16 years after onset showing a possible early nasal step

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Fig. 5 Automated perimetry of the same eye 19 years after onset showing progressive field loss

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Fig. 6 Slit lamp photograph of the right eye showing a few granulomatous KPs of varying sizes

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Fig. 8 Slit lamp photograph of the left eye showing numerous fine- to medium-sized pigmented KPs diffusely distributed throughout the entire endothelium

2 weeks. His IOP was 44 mmHg with recurrent KPs and AC cells. Aqueous tap was positive for CMV and he was commenced on ganciclovir gel 0.15% 5 times daily and underwent repeat bleb needling which resulted in lowering the IOP to the low teens and resolution of the AC activity. However, 7 months later, he had another recurrent episode with KPs and AC cells and elevated IOP of 39 mmHg despite being maintained on ganciclovir gel 0.15% 5 times daily. Oral valganciclovir was commenced in combination with ganciclovir drops every 2 h which resulted in a satisfactory reduction in IOP although there were still occasional AC cells.

Fig. 7 Slit lamp photograph of the left eye showing a few inferior granulomatous KPs, linear KPs (black arrow), and mild stromal iris atrophy

medium-sized pigmented KPs diffusely distributed throughout the entire endothelium which are characteristic of chronic CMVanterior uveitis (Fig. 8). He had been receiving topical nonsteroidal anti-inflammatory drugs and his IOP was 32 mmHg on four medications. Aqueous tap at this point was negative for viral cause and he underwent glaucoma filtering surgery with mitomycin C. Postoperatively, he received topical prednisolone acetate 1% which was slowly tapered according to the bleb function. He was quiescent and his IOP was in the low teens till 8 months later when he required needling for bleb failure and the topical prednisolone acetate 1% was increased from twice daily to q3H for 3 months. On the day of review, he complained that the vision in his left eye had deteriorated over the past

Case 6: Progression of CMV Anterior Uveitis to Endotheliitis A 71-year-old Chinese male with left chronic anterior uveitis and GON underwent trabeculectomy with mitomycin C in 2010. Aqueous sampling at the time of surgery was negative and the eye became quiescent with good IOP control and the topical corticosteroids were stopped 6 months postoperatively. Four years later, he again noticed blurring of his left vision for 3 months. His visual acuity was 20/70, the IOP was 14 mmHg, and there was a well demarcated area of edematous cornea superonasally with few small to medium KPs (Fig. 9). The tap was positive for CMV with a count of 281,000 copies. Despite treatment with oral valganciclovir and ganciclovir gel, the corneal edema progressed to involve the entire cornea (Fig. 10), and his visual acuity became further reduced to count fingers at 1 m although the repeat tap at 7 months showed a significant reduction in the viral counts to 453 copies.

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VZV anterior uveitis but not very commonly in HSV anterior uveitis. Pigmented KPs are also a feature of HSV anterior uveitis. The disease is unilateral in 80% cases. Hypopyon may be present in a few cases, and approximately 40% patients may present with posterior synechiae. Spillover vitritis may be seen in 43% cases.

Case 7: A Case of Herpes Simplex Anterior Uveitis with Pigmented Keratic Precipitates

Fig. 9 Slit lamp photograph of the left eye showing a well-demarcated area of edematous cornea superonasally

A 27-year-old male presented with decreased vision in the right eye for the past 2 weeks. BCVA was 6/24 and intraocular pressure was 34 mmHg. Slit lamp examination showed 2+ cells and flare, and pigmented KPs in the lower half (Fig. 11). Polymerase chain reaction (PCR) analysis of aqueous humor was positive for HSV DNA. He received topical corticosteroids, cycloplegic, and antiglaucoma drugs with oral Acyclovir. Three weeks later, KPs resolved completely and the eye was quiescent (panel B). BCVA at 5 months was 6/6 and IOP 12 mmHg. Besides granulomatous KPs, high IOP, and sectoral iris atrophy, pigmented KPs are characteristic of HSV-associated anterior uveitis.

Varicella Zoster Anterior Uveitis Clinical Features

Fig. 10 Slit lamp photograph of the same eye 7 months later showing progression of the edema to involve the entire cornea

Herpes Simplex Anterior Uveitis

VZV-related anterior uveitis occurs in nearly 40–50% patients with herpes zoster ophthalmicus. The disease is usually seen in elderly individuals in the sixth or seventh decade of life. Similar to HSV-associated anterior uveitis, VZV is unilateral in 95% cases. Anterior uveitis is usually granulomatous acute condition with medium-sized KPs, cells and flare, and posterior synechiae in approximately 40% cases. Spillover vitritis in VZV is more common than in patients with HSV anterior uveitis (incidence approximately 83%). The loss of corneal sensations is also profound in these patients.

Clinical Features HSV anterior uveitis is seen in both males and females with equal incidence. The virus stays dormant in the trigeminal sensory ganglion. When the virus which is latent in the trigeminal ganglia reactivates, it is transported down the axon, resulting in lesions of the skin and intraocular inflammation. The typical clinical features include small- to medium-sized KPs, anterior chamber cells and flare, high IOP, and sectoral iris atrophy. High IOP may result in mild corneal edema. Diffuse iris atrophy is seen more often in

Case 8: Varicella Granulomatous Anterior Uveitis with High Intraocular Pressure and Corneal Edema A 25-year-old male presented with painful lesions involving the left side of the face for the past 8 days, along with painful decrease in vision in the left eye for the past 5 days. The patient was seen by a dermatologist 1 day ago and was diagnosed with varicella zoster involving one side of the face and tip of the nose (Fig. 12). Ocular examination

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Fig. 11 (a) Slit lamp photograph of a patient with herpes simplex anterior uveitis reveals few anterior chamber cells (0.5+), flare, posterior synechiae, and pigmented KPs. The pigmented KPs are better seen on the red free anterior segment photograph

Fig. 13 Anterior segment photograph of a patient with varicella zosterrelated anterior uveitis shows presence of significant anterior chamber cells (3+), flare, and mild corneal edema. There are pigments on the anterior lens surface and posterior synechiae Fig. 12 The figure shows lesions of varicella zoster involving the left side of the face and the nose in a patient with varicella zoster anterior uveitis

(1% betamethasone one hourly), cycloplegic agents (2% atropine), and topical ganciclovir gel. revealed BCVA of 20/100 in the left eye with intraocular pressure of 38 mmHg. Slit lamp examination showed 3+ cells and flare, corneal edema, and medium-sized KPs. Iris pigments were found on the anterior lens surface (Fig. 13). The patient underwent anterior chamber paracentesis which was subjected to PCR analysis. The PCR report revealed positive results for VZV. The patient was started on systemic antiviral therapy (valacyclovir) and topical corticosteroids

Key Points • Herpes simplex and varicella zoster anterior uveitis may present as acute granulomatous anterior uveitis with cells, flare, small- to medium-sized keratic precipitates (KPs), iris atrophy, and high intraocular pressure. • Cytomegalovirus (CMV) anterior uveitis may present as an acute recurrent episodic hypertensive uveitis with few

Herpetic Anterior Uveitis

• •

• •

granulomatous KPs and severely elevated intraocular pressure or as a chronic anterior uveitis with numerous diffusely distributed fine pigmented stellate KPs. Initial aqueous samples may be negative and become positive only after repeated taps. Glaucomatous optic neuropathy is a sight-threatening complication that may occur after long duration of repeated recurrences in some eyes but in others the disease may have a benign course. Some eyes may develop irreversible endothelial damage. Optimal therapy with ganciclovir in its various formulations remain uncertain.

Suggested Reading Accorinti M, Gilardi M, Pirraglia MP, Amorelli GM, Nardella C, Abicca I, Pesci FR. Cytomegalovirus anterior uveitis: long-term follow-up of immunocompetent patients. Graefes Arch Clin Exp Ophthalmol. 2014;252(11):1817–24. Chan NS, Chee SP. Demystifying viral anterior uveitis: a review. Clin Exp Ophthalmol. 2019;47(3):320–33. https://doi.org/10.1111/ ceo.13417.

193 Chee SP, Jap A. Presumed fuchs heterochromic iridocyclitis and PosnerSchlossman syndrome: comparison of cytomegalovirus-positive and negative eyes. Am J Ophthalmol. 2008;146(6):883–9. Chee SP, Jap A. Cytomegalovirus anterior uveitis: outcome of treatment. Br J Ophthalmol. 2010;94(12):1648–52. Koizumi N, Inatomi T, Suzuki T, Shiraishi A, Ohashi Y, Kandori M, Miyazaki D, Inoue Y, Soma T, Nishida K, Takase H, Sugita S, Mochizuki M, Kinoshita S, Japan Corneal Endotheliitis Study Group. Clinical features and management of cytomegalovirus corneal endotheliitis: analysis of 106 cases from the Japan cornealendotheliitis study. Br J Ophthalmol. 2015;99(1):54–8. Miyanaga M, Sugita S, Shimizu N, Morio T, Miyata K, Maruyama K, Kinoshita S, Mochizuki M. A significant association of viral loads with corneal endothelial cell damage in cytomegalovirus anterior uveitis. Br J Ophthalmol. 2010;94(3):336–40. Su CC, Hu FR, Wang TH, Huang JY, Yeh PT, Lin CP, Wang IJ. Clinical outcomes in cytomegalovirus-positive Posner-Schlossman syndrome patients treated with topical ganciclovir therapy. Am J Ophthalmol. 2014;158(5):1024–31. Wong VW, Chan CK, Leung DY, Lai TY. Long-term results of oral valganciclovir for treatment of anterior segment inflammation secondary to cytomegalovirus infection. Clin Ophthalmol. 2012; 6:595–600.

Tubercular Anterior Uveitis Vishali Gupta and Sarakshi Mahajan

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Case 1: Granulomatous Anterior Uveitis with Mutton-Fat KPs and Busacca Nodules . . . . . . . . . . . . . . . 195 Case 2: Granulomatous Anterior Uveitis with Koeppe’s Nodules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Case 3: Tubercular Anterior Uveitis Presenting as Iris Mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Case 4: Tubercular Anterior Uveitis Presenting as Hypopyon Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . 196 Case 5: Tubercular Uveitis Presenting as Acute Nongranulomatous Anterior Uveitis . . . . . . . . . . . . . . . . 198 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

Introduction Tubercular anterior uveitis most commonly presents as granulomatous anterior uveitis characterized by the presence of low-grade chronic uveitis with mutton-fat keratic precipitates (KPs), broad-based posterior synechiae, and iris nodules (Koeppe’s and/or Busacca’s nodules) with mild to moderate anterior segment inflammation. Inflammation may be restricted only to anterior segment, or patient may have associated posterior segment involvement (discussed elsewhere). Rarely, however, TB anterior uveitis may present with hypopyon- or endophthalmitis-like picture.

Case 1: Granulomatous Anterior Uveitis with Mutton-Fat KPs and Busacca Nodules A 42-year-old healthy man presented with granulomatous anterior uveitis in the right eye characterized by the presence of mutton-fat keratic precipitates and iris nodules

(Fig. 1). Gonioscopy showed granuloma in the inferior angle (Fig. 2). The basic workup included PPD skin test, chest x-ray, and TPHA to rule out syphilis. His PPD skin test was 16 mmHg, and x-ray chest showed old calcified parahilar lymphadenopathy.

Case 2: Granulomatous Anterior Uveitis with Koeppe’s Nodules A 32-year-old woman was seen with chronic granulomatous uveitis and nodules at the papillary border. Her best-corrected visual acuity was 20/100. Anterior segment had moderate inflammation with prominent Koeppe’s nodules at the papillary border (Fig. 3). Her PPD skin showed induration of 15  14 mm at 72 h. X-ray chest was normal, and PCR from aqueous humor was positive for Mycobacterium tuberculosis.

Case 3: Tubercular Anterior Uveitis Presenting as Iris Mass V. Gupta (*) · S. Mahajan Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_13

A 36-year-old woman presented with complaints of intermittent redness, floaters, and blurred vision in the right eye. Anterior segment examination revealed mild anterior segment 195

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Fig. 1 Anterior segment photograph of right eye showing mutton-fat keratic precipitates on the posterior corneal surface (blue arrows) with Busacca’s nodules on the iris surface (white arrows)

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Fig. 3 Anterior segment photograph showing Koeppe’s nodules (arrows) in patient with tubercular anterior uveitis

Fig. 2 Gonioscopy showing granulomas in the inferior angle (arrows) Fig. 4 Anterior segment photograph showing iris mass (arrow)

inflammation with an iris mass seen temporally (Fig. 4). Her PPD skin was strongly positive with an induration of 14  7 mm at 72 h. Her chest x-ray, serum angiotensinconverting enzyme levels, and Treponema pallidum hemagglutination tests were normal. The biopsy of iris mass showed granulomatous inflammation with no acid-fast bacilli (Fig. 5). Multi-targeted polymerase chain reaction (PCR) using three targets specific for Mycobacterium tuberculosis, i.e., IS6110, MPB64, and protein b, was positive (Fig. 6).

Case 4: Tubercular Anterior Uveitis Presenting as Hypopyon Anterior Uveitis A 40-year-old woman complained of blurred vision in her left eye of 15 days duration. Slit-lamp biomicroscopy showed granulomatous uveitis with cells (4+ grade), intense flare

(4+ grade), hypopyon of 2 mm in the anterior chamber with mutton-fat keratic precipitates, iris nodules, posterior subcapsular cataract, and broad-based posterior synechiae (Fig. 7). She was suffering from end-stage renal failure. Mantoux skin test, interferon gold test for TB, and Elisa for HIV were negative. Her sedimentation rate was elevated (70 mm/1 h); Hb was low (5 g%); and serum creatinine (15.53 mg%) and blood urea (251.23 mg%) were elevated. Aqueous tap for TB PCR was positive for Mycobacterium tuberculosis. Biopsy from right-side cervical lymph node stained positive for acidfast bacilli (Fig. 8) suggestive of tuberculous cervical adenitis along with the presence of granuloma, multinucleate giant cells, and degenerated inflammatory cells with necrosis (Fig. 9). PET scan showed an intense uptake in right cervical and supraclavicular lymph nodes and mildly increased uptake in inferior aspect of globe.

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Fig. 5 Histopathology of the iris mass showing nonspecific granulomatous inflammation

Fig. 6 L1 shows the 100 bp molecular marker, L2 is H 37 RV PC, L3 NC, L4–L8 clinical samples, L9 MM, L10–L16 clinical samples

Fig. 7 Anterior segment photograph left eye at presentation showing the presence of Koeppe’s nodules at the pupillary border, broad-based posterior synechiae, and hypopyon

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Fig. 8 Histopathology section from cervical lymph node showing acidfast bacilli (arrows)

Fig. 10 Anterior segment photograph showing resolution of hypopyon

Fig. 9 Cervical node biopsy showing granuloma with multinucleate giant cells, degenerated inflammatory cells, and necrosis

Fig. 11 Anterior segment photograph of left eye showing acute nongranulomatous uveitis with severe fibrinous reaction

Case 5: Tubercular Uveitis Presenting as Acute Nongranulomatous Anterior Uveitis

His best-corrected visual acuity in the left eye was hand motions close to face. Anterior segment left eye showed acute fibrinous nongranulomatous uveitis (Fig. 11). CT scan of the chest showed cavitary lesion (Fig. 12) and sputum was positive for acid-fast bacilli (Fig. 13). The patient was diagnosed with tubercular anterior uveitis and was treated with topical corticosteroids and cycloplegics in addition to systemic ATT to which he responded with resolution of inflammation. The eye remained free of inflammation over 5 years follow-up (Fig. 14)

A 56-year-old man complained of decreased vision in his left eye. He had lost his right eye 5 years back due to inflammation. He was also diagnosed with pulmonary tuberculosis 1 week earlier for which he was started on four-drug antituberculosis treatment (ATT) by pulmonologist 3 days back.

Key Points • Tuberculosis may present as anterior uveitis only. • Systemic disease may not be manifested, and the disease may be localized only to eye without any manifestation of extraocular tuberculosis.

The patient received antituberculosis therapy with concomitant systemic and topical corticosteroids. One week later, the anterior chamber showed improvement with disappearance of hypopyon, and the media clarity improved to grade 2 (Fig. 10).

Tubercular Anterior Uveitis

Fig. 12 CT scan of chest showing a cavity due to pulmonary TB (arrow)

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Fig. 14 Anterior segment photograph of left eye showing resolution of inflammation with development of complicated cataract

• Rarely, TB may present as nongranulomatous form of anterior uveitis with hypopyon or fibrinous reaction. • The diagnosis is based on the clinical signs combined with PPD skin test, QuantiFERON-TB Gold test, and PCR from aqueous humor. • Extraocular biopsy may be helpful if there is an extraocular focus, e.g., cervical lymph node. • Addition of antituberculosis treatment helps in reducing the recurrence rates.

Suggested Reading

Fig. 13 Sputum examination showing acid-fast bacillus (arrow)

• Anterior granulomatous uveitis is typical presentation characterized by mutton-fat KPs, Koeppe’s or Busacca nodules, granulomas in the anterior chamber, and broadbased posterior synechiae.

Bansal R, Gupta A, Gupta V, Dogra MR, Bambery P, Arora SK. Role of anti-tubercular therapy in uveitis with latent/manifest tuberculosis. (original article). Am J Ophthalmol. 2008;146:772–9. Gupta V, Gupta A, Rao NA. Intraocular tuberculosis-an update. Major review. Surv Ophthalmol. 2007;52:561–87. Gupta A, Bansal R, Gupta V, Sharma A, Bambery P. Ocular signs predictive of tubercular uveitis. Am J Ophthalmol. 2010;149(4): 562–70.

Hansen’s Uveitis Radhika T. Manoj and S. R. Rathinam

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Case 1: Granulomatous Anterior Uveitis in Leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Case 2: Lepromatous Conjunctival Nodule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202 Case 3: Iris Atrophy and Anterior Uveitis in Hansen’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

Introduction Leprosy (Hansen’s disease) is a chronic granulomatous infectious disease affecting skin, peripheral nerves, mucous membranes, and ocular structures. It is caused by Acid Fast bacillus Mycobacterium leprae. Ocular complications are due to nerve damage or infiltration by mycobacterium. The effective management of ocular leprosy depends on early diagnosis and appropriate treatment. Hence it is imperative for ophthalmologist to recognize the ocular clinical signs associated with leprosy. Ocular manifestation includes: Lids – Madarosis, lagophthalmos Sclera – Scleritis, nodular episcleritis Conjunctiva – Conjunctival leproma Cornea – Interstitial keratitis Uvea – Chronic granulomatous iridocyclitis with iris atrophy

Choroid is usually spared as the bacillus prefers cooler environment.

Case 1: Granulomatous Anterior Uveitis in Leprosy Fifty nine-year-old man presented with recurrent granulomatous anterior uveitis with white deposits on the iris like “iris pearls” in the right eye. Figure 1, Basic workup which included purified protein derivative, treponema pallidum haem agglutination assay and chest x-ray were normal. Erythrocyte sedimentation rate was elevated 88 mm. A few months later, he presented with granulomatous anterior uveitis and hypopyon in the left eye. Left eye Anterior Chamber tap, and smear demonstrated lepra bacillus using Fite-Faraco staining technique viewed under oil immersion (Fig. 2).

R. T. Manoj (*) Uveitis Service, Aravind Eye Hospital and PG Institute of Ophthalmology, Madurai, Tamil Nadu, India e-mail: [email protected] S. R. Rathinam Department of Ophthalmology, Aravind Eye Hospital and PG Institute of Ophthalmology, Madurai, Tamil Nadu, India e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_14

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Fig. 1 Slit lamp photograph of right eye showing iris atrophy and iris pearls

Fig. 3 Digital photo face of patient with lepromatous leprosy showing conjunctival nodule – left eye

Fig. 2 Smear of anterior chamber fluid showing leprabacilli using FiteFaraco stain, viewed under oil immersion

Case 2: Lepromatous Conjunctival Nodule Seventy-three-year-old man presented with conjunctival nodule in his left eye (Fig. 3). He had taken irregular treatment for Hansen’s disease for 1 year. Biopsy of the nodule revealed, foam cells with lepra bacilli confirming the diagnosis of conjunctival leproma (Fig. 4).

Case 3: Iris Atrophy and Anterior Uveitis in Hansen’s Disease Fifty-six-year-old man presented with bilateral granulomatous anterior uveitis with iris atrophy (Fig. 5). He had been diagnosed with Hansen’s disease 25 years back, but had not completed full course of treatment.

Fig. 4 Histopathological examination of conjunctival nodule showing leprabacilli by Fite-Faraco method of staining

Key Points • Ocular leprosy occurs in majority of patients with past history of Hansen’s disease. • Nodular scleritis, episcleritis may be either due to direct bacillary invasion or immune modulated. • Granulomatous anterior uveitis with characteristic iris atrophy is the commonest uveitic manifestation. • Neurotropic corneal ulcer can progress to blindness.

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Suggested Reading Nepal BP, Shrestha UD. Ocular findings in leprosy patients in Nepal in the era of multi drug therapy. Am J Ophthalmol. 2004;137(5): 888–92. Rathinam SR. Leprosy uveitis in the developing world. Int Ophthalmol Clin. 2010;50(2):99–111. Singhi MK, Kacchawa D, Ghiya BC. Ocular involvement in leprosy. Indian J Ophthalmol. 2002;50:355–6.

Fig. 5 Digital images of right eye showing granulomatous keratic precipitates with iris atrophy

Anterior Segment Manifestations of Lyme Disease Muhammad Hassan, Mohammad Ali Sadiq, Aniruddha Agarwal, Bahram Bodaghi, and Quan Dong Nguyen

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 Case 1: Borrelia-Associated Granulomatous Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

Introduction Lyme disease is a multisystem infection caused by a spirochete (Borrelia species), which is transmitted by the bite of an infected Ixodes tick. It is the most common tick-borne disease in the United States. Southern Sweden and surrounding areas are among the other regions of high incidence. Lyme-related uveitis is an important manifestation associated with the disease that often presents as a diagnostic challenge due to its protean clinical features. Intraocular inflammation may present with anterior, intermediate, posterior, or panuveitis. In addition, ocular involvement may occur in Lyme neuroborreliosis resulting in optic neuropathy, neuroretinitis,

M. Hassan Byers Eye Institute, Stanford University, Palo Alto, CA, USA M. A. Sadiq (*) Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, KY, USA e-mail: [email protected] A. Agarwal (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected] B. Bodaghi (*) Department of Ophthalmology, DHU Vision and Handicaps, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France e-mail: [email protected] Q. D. Nguyen (*) Spencer Center for Vision Research, Byers Eye Institute at Stanford University, Palo Alto, CA, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_18

and cranial nerve palsies, among others. Intermediate uveitis is the most common clinical manifestation of Lyme disease. Anterior uveitis commonly presents as granulomatous iridocyclitis characterized by posterior synechiae, iris nodules, and tiny mutton-fat keratic precipitates (KPs) over the endothelial surface alongside anterior chamber flare and cells. Other anterior segment manifestations include episcleritis, follicular conjunctivitis, and interstitial keratitis.

Case 1: Borrelia-Associated Granulomatous Anterior Uveitis A young male was referred to the ophthalmology clinic with complaints of ocular pain and photophobia in both eyes. The visual acuity was 20/50 in both eyes. Slit lamp examination demonstrated granulomatous anterior uveitis with 2+ anterior chamber cells and flare. Circumcorneal injection was also noted. There was the presence of iris nodules, posterior synechiae, and pigment deposition on the lens surface (Fig. 1a, b). Extensive work-up was performed to rule out etiologies for granulomatous anterior uveitis including both infectious and noninfectious causes. Laboratory tests for tuberculosis, sarcoidosis, and syphilis were negative. The patient had an equivocal Lyme serology. Diagnostic anterior chamber paracentesis was done. Polymerase chain reaction was performed on the aqueous sample, which was positive for B. burgdorferi-specific DNA. The diagnosis of Lyme disease was confirmed.

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Fig. 1 (a) Anterior segment photograph of the right eye showing irregular pupil with posterior synechiae (black arrows), Koeppe’s nodules (white arrows), and (b) pigment deposits over the lens surface

Key Points • Borrelia-associated anterior uveitis, though uncommon, should be suspected among patients with granulomatous anterior uveitis in endemic regions. • Anterior uveitis in Lyme disease may have nonspecific clinical features of granulomatous inflammation such as iris nodules and mutton-fat KPs. • Investigations such as serum immunoblot assay and polymerase chain reaction of serum and aqueous humor are highly sensitive and specific and can be very helpful in the diagnosis.

Suggested Reading Bodaghi B. Ocular manifestations of Lyme disease. Med Mal Infect. 2007;37(7–8):518–22. Mikkila HO, Seppala IJ, Viljanen MK, Peltomaa MP, Karma A. The expanding clinical spectrum of ocular lyme borreliosis. Ophthalmology. 2000;107(3):581–7. Mora P, Carta A. Ocular manifestations of Lyme borreliosis in Europe. Int J Med Sci. 2009;6(3):124–5. Winterkorn JM. Lyme disease: neurologic and ophthalmic manifestations. Surv Ophthalmol. 1990;35(3):191–204.

Miscellaneous Anterior Uveitis Keegan Harkins, Muhammad Hassan, Aniruddha Agarwal, Ramandeep Singh, Deepta Ghate, Diana V. Do, and Quan Dong Nguyen

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Case 1: Ocular Lymphoma Presenting as Pseudohypopyon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207 Case 2: Sjögren’s Syndrome-Associated Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Case 3: Drug-Induced Uveitis (Rifabutin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Case 4: Uveitis-Glaucoma-Hyphema (UGH) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 Case 5: Immune Recovery Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

Introduction The index chapter will describe several noninfectious causes of anterior uveitis or masquerade syndromes that do not fit into prior, previously described categories, but can present as diagnostic and therapeutic challenges, including: Sjögren’s syndrome, lymphoma, uveitis-glaucoma-hyphemia (UGH)

K. Harkins · D. Ghate Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA M. Hassan · D. V. Do Byers Eye Institute, Stanford University, Palo Alto, CA, USA e-mail: [email protected] A. Agarwal Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected] R. Singh Department of Ophthalmology, Advanced Eye Centre, Postgraduate institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected] Q. D. Nguyen (*) Spencer Center for Vision Research, Byers Eye Institute at Stanford University, Palo Alto, CA, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_30

syndrome, drug-induced uveitis, and immune-recovery uveitis. Sjögren’s syndrome is more often associated with external disease, but has been associated with uveitis presenting most frequently with keratic precipitates (KPs). Masquerade syndromes should always be kept in the differential diagnoses of uveitis as a potential life-threatening etiology of anterior chamber reaction and can present as a recurrent or chronic anterior uveitis. UGH presents with the classic triad of elevated intraocular pressure (IOP), hyphema, and uveitis and is typically caused by dislocated or misplaced single piece intraocular lens (IOLs) located in the sulcus causing lens iris touch and chaffing. Drug-induced uveitis can masquerade as uveitic entities such as HLA-B27 associated uveitis and can lead to a diagnostic challenge, especially when it presents with hypopyon.

Case 1: Ocular Lymphoma Presenting as Pseudohypopyon A 58-year-old Caucasian male was referred for blurred vision in the right eye. He had a history of systemic mantle cell lymphoma treated with chemotherapy and an autologous peripheral bloodstem cell transplantation and had been in remission for several years. Examination revealed counting fingers vision in the right

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eye with 4+ anterior chamber cell, a 50% layered pseudohypopyon (Figs. 1 and 2), and 3+ vitreous cells. Anterior chamber paracentesis was performed. Cytology showed monoclonal B-cell population expressing CD5, CD20, and CD23 consistent with the phenotype of his previous systemic lymphoma. The patient was treated with alternating intravitreal injections of rituximab and methotrexate. After 6 months, the hypopyon cleared and his vision improved to 20/100 OD (Fig. 3).

Case 2: Sjögren’s Syndrome-Associated Anterior Uveitis A 61-year-old Caucasian male presented with recurrent episodes of pain and photophobia in the right eye. He had been treated at outside facility several times with topical steroids. On presentation, he was noted to have mildly decreased vision (20/25 OD and 20/20 OS). On examination, he had 2 + cells and 1+ flare in the anterior chamber, and diffuse stellate keratic precipitates (KPs) (Fig. 4). Laboratory workup included negative Lyme titer, QuantiFERON test, antinuclear antibody (ANA) titers, Treponema Pallidum Hemagglutination Assay (TPHA), HLA-B27, anterior chamber cultures, and viral polymerase chain reaction (PCR). The

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patient had a history of Sjögren’s syndrome with positive SSA and SSB titers. He was diagnosed with primary Sjögren’s syndrome-associated anterior uveitis.

Case 3: Drug-Induced Uveitis (Rifabutin) A 43-year-old female presented with gradual-onset decrease in visual acuity, pain, and redness OS. Examination using slit-lamp biomicroscopy revealed decreased visual acuity to 20/125 OS (20/20 OD), 2+ anterior chamber cell and flare, and a layered hypopyon (Fig. 5). There was no evidence of posterior segment inflammation. Laboratory work-up revealed elevated C-reactive protein (CRP) (16) and erythrocyte sedimentation rate (ESR) (72), but negative antinuclear cytoplasmic antibodies (ANCA), ANA, and herpes simplex virus (HSV) IgM. The patient has known pulmonary tuberculosis and was recently started on rifabutin. She underwent diagnostic anterior chamber (AC) paracentesis to determine the etiology of the acute onset ocular inflammation. Aerobic, anaerobic, and fungal cultures showed no growth; viral PCRs were negative; and cytology/ pathology was negative for malignancy. Drug-induced inflammation was suspected and rifabutin was withheld. The patient was also started on topical steroids (prednisolone acetate 1% frequently). Within 2 days, the ocular inflammation dramatically reduced. The patient was diagnosed with rifabutininduced uveitis and started on alternative antitubercular therapy.

Case 4: Uveitis-Glaucoma-Hyphema (UGH) Syndrome

Fig. 1 Anterior segment photograph showing pseudohypopyon composed of malignant cells

An 89-year-old African American male presented with 2 months of blurred vision in his left eye. He had a past ocular history of cataract extraction in both eyes with posterior chamber single-piece IOLs. On examination, his visual acuity was 20/30 in OD and 20/100 in OS. His IOP was 13 OD and 39 OS on latanoprost once a day, timolol/ brimonidine twice a day, and dorzolamide three times a day in the left eye. He was found to have 1+ pigmented cells in the anterior chamber in the left eye. The posterior chamber IOL could not be well visualized in the left eye due to poor

Fig. 2 Anterior segment optical coherence tomography showing anterior chamber debris composed of malignant cells

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dilation. Ultrasound biomicroscopy revealed a single-piece IOL with one haptic dislocated in the sulcus (Fig. 6). The patient was diagnosed with UGH syndrome and underwent IOL exchange and a short course of topical steroid treatment. The IOP improved to 13 mm Hg within 4 weeks.

Case 5: Immune Recovery Uveitis

Fig. 3 Anterior segment photograph showing clearance of the pseudohypopyon after treatment with intravitreal rituximab and methotrexate

A 32-year-old Indian female was being treated for cytomegalovirus (CMV) retinitis associated with HIV infection with monthly intravitreal ganciclovir injections. She had received five injections and her CD counts had recovered to 350 (from a previous value of 129) when she developed photosensitivity and pain in OS. Anterior segment examination revealed 2+ cell and flare with a single KP (Fig. 7). Dilated fundus examination revealed loss of foveal reflex and vitritis

Fig. 4 Anterior segment photographs (slit-illumination) showing diffuse stellate keratic precipitates

Fig. 5 Anterior segment photograph (a) showing anterior chamber reaction with a layered hypopyon (black arrowheads). Slit illumination shows presence of dense vitritis (b)

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Fig. 6 Ultrasound biomicroscopy showing dislocation of the single piece IOL into the sulcus. The arrowheads mark the area of IOL-iris contact, which gives rise to an inflammatory response

Fig. 7 Anterior segment photo showing central posterior subcapsular cataract (PSC) and one keratic precipitate (KP)

Fig. 8 Color fundus photograph showing loss of foveal light reflex

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Fig. 9 Macular spectral domain optical coherence tomography (SD-OCT) showing center-involved cystoid macular edema (CME)

suggestive of macular edema (Fig. 8). Optical coherence tomography of the macula revealed the present of cystoid macular edema (Fig. 9). The patient was diagnosed with immune recovery uveitis and treated with topical steroids. Key Points • Metastatic lesions involving the iris and ciliary body, such as lymphoma, may present as anterior uveitis with hypopyon. • Certain drugs such as rifabutin, amphotericin, among others, may be associated with ocular inflammation that mimics infectious conditions such as endophthalmitis. It is important to obtain a thorough clinical history to rule out drug-induced uveitis. • Immune-recovery uveitis (IRU) is a relatively new entity that occurs secondary to recovery of the systemic

immunity in conditions such as AIDS and immunosuppression among patients with malignancies or who are recipients of organ transplants.

Suggested Reading Davis JL. Intraocular lymphoma: a clinical perspective. Eye. 2013;27:153–62. Sagoo MS, Mehta H, Swampillai AJ, Cohen VM, Amin SZ, Plowman PN, Lightman S. Primary intraocular lymphoma. Surv Ophthalmol. 2014;59:503–16. Urban B, Bakunowicz-Łazarczyk A, Michalczuk M. Immune recovery uveitis: pathogenesis, clinical symptoms, and treatment. Mediators Inflamm. 2014;2014:971417.

The Zebras Andrew Baldwin, Aniruddha Agarwal, Jagat Ram, Vishali Gupta, Diana V. Do, and Quan Dong Nguyen

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Case 1: Parasitic Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Case 2: Anterior Chamber Abscess from Intraocular Parasite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 Case 3: Intralenticular Bacterial Abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 Case 4: Posner-Schlossman Syndrome in a Patient with Cytomegalovirus Infection . . . . . . . . . . . . . . . . . 215 Case 5: Toxic Anterior Segment Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 Case 6: Bilateral Acute Iris Depigmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

Introduction Parasitic infections of the external ocular adnexal structures such as the eyelids can result in a localized anterior chamber (AC) reaction, while intraocular invasion results in a much more robust inflammatory AC reaction with a poorer prognosis. Posner-Schlossman syndrome is one of a handful of conditions that results in elevated IOP in the setting of uveitis. In the past, it was thought to be an idiopathic disorder;

A. Baldwin Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA A. Agarwal (*) · J. Ram (*) · V. Gupta (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; [email protected]; [email protected] D. V. Do Byers Eye Institute, Stanford University, Palo Alto, CA, USA e-mail: [email protected] Q. D. Nguyen (*) Spencer Center for Vision Research, Byers Eye Institute at Stanford University, Palo Alto, CA, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_24

however, with the advent of PCR testing, Posner-Schlossman syndrome likely has an infectious etiology (cytomegalovirus). Finally, chronic, refractory postoperative inflammation can be secondary to contaminated surgical instruments or ophthalmic viscosurgical devices (OVDs) that often require aggressive management to prevent permanent visual loss.

Case 1: Parasitic Anterior Uveitis A 38-year-old farmer presented to the emergency room with a 2-day history of foreign body sensation and discharge in his left eye following an accident where manure fell into the effected eye. His visual acuity was 20/20. Examination revealed an edematous upper eyelid, temporal conjunctival injection with associated engorgement of the temporal limbal vessels, and a mild AC reaction (1+ cell and flare with no keratic precipitates). Upon eversion of his upper eyelid, a maggot was visualized on the upper palpebral conjunctiva (Fig. 1). Following instillation of topical anesthetic, the maggot was removed and entomological evaluation identified it as early-stage housefly larva, Musca species (Fig. 2). Ocular myiasis is common in developing countries, and a localized

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Fig. 3 External photograph demonstrating an organized fibrinous anterior chamber abscess with diffuse conjunctival injection. (Reproduced from Joshi G, Parchand S, Dogra MR, et al. Live juvenile strobilate tapeworm in the anterior chamber of the human eye. Arch Ophthalmol. 2012; 130:1464–6. Permission obtained) Fig. 1 External photograph showing eversion of the left upper eyelid. Mobile larva on the upper palpebral conjunctiva (black arrowheads) with associated localized inflammatory reaction

Case 2: Anterior Chamber Abscess from Intraocular Parasite A 48-year-old male from the rural North India (Himalayan foothills) presented with a 4-month history of left eye pain, redness, and progressive vision loss. His visual acuity was 20/20 in his right eye and light perception in his left eye. He was noted to have an organized fibrinous abscess in the inferior anterior chamber of his left eye (Fig. 3). Due to concern for a parasitic infection, a systemic workup was performed and did not reveal any etiology. Specific testing included CBC with differential which showed no anemia or eosinophilia, stool studies that were negative for cysts/parasites, and CT brain/orbit which was normal. He subsequently underwent a limbal-based surgical excision of the abscess. During the procedure, the abscess was firmly adherent to the iris, and a sectoral iridectomy was performed, followed by anterior chamber washout and antibiotic injection. Cytological examination was performed and revealed a juvenile tapeworm, Taenia solium, with its scolex firmly attached to the respective iris section (Fig. 4). Figure 5 provides another view of the live worm in the anterior chamber. The eye developed phthisis bulbi despite intensive therapy. This case demonstrates that parasitic uveitis must be kept in mind in cases of patients at risk presenting with refractory uveitis.

Fig. 2 Photomicrograph of the removed Musca species larva showing two distinct black suckers on the head, no limbs, and a tapering body

Case 3: Intralenticular Bacterial Abscess

AC reaction can be observed if the larva incites an inflammatory reaction near the corneal surface. The prognosis is good provided the eyeball is not invaded.

A 24-year-old male presented with decrease in visual acuity in the right eye (OD) 2 weeks after penetrating trauma with a thorn. Ocular examination revealed visual acuity of light

The Zebras

Fig. 4 Photomicrograph of the surgically removed Taenia solium, juvenile tapeworm, showing the scolex (head) with four large suckers and a rostellum surrounded by hooks between the two sets of suckers (Reproduced from Joshi G, Parchand S, Dogra MR, et al. Live juvenile strobilate tapeworm in the anterior chamber of the human eye. Arch Ophthalmol. 2012; 130:1464–6. Permission obtained)

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perception (LP) in OD. Slit lamp biomicroscopy revealed the presence of shallow anterior chamber and opacified crystalline lens full of exudates in OD (Fig. 6a). There was presence of vascularization in all quadrants of the lens capsule at the periphery. Examination of the iris also revealed growth of new vessels. Examination of the sclera revealed diffuse congestion and tortuosity of superficial vessels (Fig. 6b). There was presence of an inferior scleral abscess with central thinning corresponding to the site of trauma. The patient underwent pars plana vitrectomy, lensectomy, and intravitreal antibiotic injections. The culture from the vitreous grew Staphylococcus epidermidis. However, postoperatively, the visual acuity continued to remain LP. Intralenticular abscess is a unique manifestation of intraocular infection and endophthalmitis. The outcome may be poor even after aggressive treatment with antibiotics and surgery.

Case 4: Posner-Schlossman Syndrome in a Patient with Cytomegalovirus Infection An 18-year-old male presented with unilateral raised intraocular pressure (IOP) and mild anterior chamber inflammation (Fig. 7). His visual acuity was 20/20 in both eyes. He had unilateral ocular hypertension with an intraocular pressure (IOP) of 32 mmHg in the right eye and 19 mmHg in the left eye. Due to concern for a possible infectious uveitis, workup for an infectious etiology, including AC tap, was performed. AC paracentesis was positive for cytomegalovirus (CMV) infection. Following treatment with topical/oral ganciclovir and topical steroid therapy, the IOP decreased and the flare improved.

Case 5: Toxic Anterior Segment Syndrome Fig. 5 Anterior segment photograph showing the presence of a worm in the anterior chamber (Reproduced from Joshi G, Parchand S, Dogra MR, et al. Live juvenile strobilate tapeworm in the anterior chamber of the human eye. Arch Ophthalmol. 2012; 130:1464–6. Permission obtained)

A 56-year-old lady underwent phacoemulsification for mature nuclear cataract in her right eye. During the surgery, dispersive as well as cohesive ophthalmic viscosurgical devices (OVDs)

Fig. 6 Anterior segment imaging of a patient diagnosed with staphylococcal abscess of the crystalline lens

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Fig. 7 Anterior segment photograph of the right eye shows old keratic precipitates on the posterior cornea surface. Anterior segment

photograph shows fresh as well as old keratic precipitates, corneal edema, and anterior chamber inflammation

were used to protect the corneal endothelium. The surgery was uneventful and the intraocular lens was placed in the capsular bag. The patient complained of unusual postoperative discomfort. Ocular examination 18 h after surgery revealed circumcorneal congestion and the presence of fibrinous material in the anterior chamber in the pupillary area (Fig. 8a). There was no evidence of hypopyon. Ultrasound B-scan did not reveal significant vitreous echoes. Postoperative toxic anterior segment syndrome (TASS) was suspected. The patient received intravitreal vancomycin and ceftazidime (due to the concern of infective endophthalmitis). The patient also received frequent topical prednisolone acetate 1% (every 15 min). Within 2 h, the fibrinous material started to organize and decrease in extent (Fig. 8b). The patient was aggressively treated with topical steroids and mydriatics, resulting in complete resolution of inflammation within 1 week following surgery.

dispersion in the iridocorneal angle iris transillumination. However, BADI has acute onset and patient in symptomatic in contrast to pigment dispersion syndrome that progresses slowly. Also, pupillary reactions will be normal in pigment dispersion syndrome, and these patients would also have pigment deposition on anterior lens surface and iris stroma. Pseudoexfoliation syndrome is seen in older patients, usually unilateral at the time of presentation and will have characteristic fibrillar material accumulation on lens surface and iris sphincter. BADI was reported earlier than bilateral acute iris illumination (BAIT) and is characterized by stromal iris depigmentation (without iris transillumination) mimicking bilateral uveitis. The initial presentation is similar in in both BADI or BAIT with patients complaining of photophobia with bilateral conjunctival congestion and eye pain and patients may notice change in iris color. In BADI, there is atrophy and depigmentation of the iris stroma, resulting in change in iris color but no transillumination. Clinical picture in BADI is characterized by geographic or diffuse granular depigmentation, with no visible transillumination. BAIT syndrome, on the other hand, shows loss of the epithelial iris pigment with iris transillumination. BADI is seen in relatively younger women in their 30s compared to BAIT that is seen in women in their 40s. Intraocular pressure may be elevated in both. It is important to look for use of antibiotics especially moxifloxacin that may be discontinued as well as new use of fluoroquinolones avoided. IOP may be refractory to medical treatment and photophobia may persist for long time. A 29-year-old male was diagnosed with pulmonary tuberculosis and initiated on standard four-drug antitubercular therapy (ATT) consisting of isoniazid, rifampin, ethambutol, and pyrazinamide. Due to likely hepatotoxicity, his ATT was

Case 6: Bilateral Acute Iris Depigmentation Bilateral acute iris depigmentation (BADI) is a recently described entity that is characterized by acute dispersion of pigment in the anterior chamber, transillumination of iris and dilated pupil that is poorly responsive or unresponsive to light due to sphincter paralysis. The etiology remains unknown though few agents including moxifloxacin, viral infections of upper respiratory tract, clarithromycin have been considered as possible etiologic agents. It is important to know about this entity as it can be mistaken for acute iridocyclitis, pigment dispersion, or pseudoexfoliation syndrome. BADI can be differentiated from acute iridocyclitis by the absence of posterior synechiae which is an important sign in iridocyclitis. BADI and pigment dispersion syndrome resemble more closely as both affect young people, with pigment

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Fig. 8 Anterior segment photograph of a patient with toxic anterior segment syndrome shows the presence of anterior chamber inflammation, flare, and fibrin in the pupillary region 18 h after surgery (a).

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Following topical steroid therapy, clearing of fibrin and decrease in the flare are noted (b)

Fig. 9 Both eyes of the patient showing peripheral patchy loss of iris pigmentation suggestive of BADI (a and b)

Fig. 10 Both eyes of the patient 8 weeks later showing iris atrophy patches

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suspended for a period of 2 weeks. However, the patient developed multidrug resistant (MDR) TB and was reinitiated on appropriate therapy for the same. Within 2 months, he developed redness and blurring of vision in the right eye. Examination revealed multiple pigmented cells and flare, and no evidence of keratic precipitates or posterior synechia (Fig. 9). A diagnosis of BADI was considered and the patient was given no treatment. Follow-up after 6 weeks showed resolution of the cells and flare. At 2 months, there was significant iris atrophy and transillumination (Fig. 10). Key Points • Parasitic infection of the ocular tissues can masquerade as uveitis and may be associated with severe ocular inflammation and loss of vision. • Ocular inflammation may be associated with a number of infectious agents such as bacteria, viruses, and fungi and may have protean manifestations, leading to diagnostic and management challenges.

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• Sterile inflammation needs to be carefully differentiated from infectious etiologies since the treatment paradigms vary significantly. • BADI and BAIT are mostly seen in women with acute onset. History of antibiotic use especially fluoroquinolones should be ruled out. Viral etiology too has been postulated

Suggested Reading Marticorena J, Romano V, Gómez-Ulla F. Sterile endophthalmitis after intravitreal injections. Mediat Inflamm. 2012;2012:928123. Moorthy RS, London NJ, Garg SJ, Cunningham Jr ET. Drug-induced uveitis. Curr Opin Ophthalmol. 2013;24:589–97. Rathinam SR, Annamalai R, Biswas J. Intraocular parasitic infections. Ocul Immunol Inflamm. 2011;19:327–36. Tugal-Tutkun I, Onal S, Garip A, et al. Bilateral acute iris transillumination. Arch Ophthalmol. 2011;129(10):1312–9. Wefers Bettink-Remeijer M, Brouwers K, van Langenhove L, et al. Uveitis-like syndrome and iris transillumination after the use of oral moxifloxacin. Eye (Lond). 2009;23(12):2260–2.

Band Shaped Keratopathy Elliot S. Crane, May Shum, and David S. Chu

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Case 1: Unilateral BSK Secondary to Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Case 2: BSK Secondary to Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Case 3: Early BSK Secondary to Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 Case 4: Residual BSK After Neutral Disodium Ethylenediaminetetra-Acetic Acid (EDTA) Chelation in Girl with Juvenile Rheumatoid Arthritis (JRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 Case 5: Idiopathic BSK Chelated for Cataract Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

Introduction Band-shaped keratopathy (BSK) describes a band of calcium salt precipitated across the Bowman layer of cornea. Calcium precipitation is thought to be favored by interpalpebral tear evaporation, systemic hypercalcemia, and elevated pH (e.g., with uveitis). BSK is associated with various conditions including uveitis, corneal edema, phthisis bulbi, end stage glaucoma, and systemic hypercalcemic states but is often idiopathic. Patients may complain of ocular irritation or blurry vision. Diagnosis is based on slit-lamp examination showing a central gray-white corneal plaque that sometimes spares the periphery. BSK may be treated with EDTA chelation with or without debridement when it causes visual disturbance, obstructs intraocular view required for examination

or surgery, or is symptomatic. The underlying cause should be sought and treated first to prevent recurrence.

Case 1: Unilateral BSK Secondary to Uveitis A 57-year-old woman with rheumatoid arthritis sustained open globe trauma to the RE complicated by RE retinal detachment, cystoid macular edema, sympathetic ophthalmia of both eyes, and BSK of RE. Her uveitis was controlled with prednisone and remained stable on methotrexate and folic acid for many years. Her RE BSK can be seen 10 years later in Fig. 1.

Case 2: BSK Secondary to Sarcoidosis E. S. Crane · M. Shum Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Doctors Office Center, Newark, NJ, USA D. S. Chu (*) Institute of Ophthalmology and Visual Science, New Jersey Medical School, Rutgers University, Doctors Office Center, Newark, NJ, USA

A 30-year-old African-American woman with recently diagnosed sarcoidosis presented with chronic decreasing visual acuity bilaterally. Slit-lamp examination revealed bilateral

Metropolitan Eye Research and Surgery Institute, Palisades Park, NJ, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_112

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Fig. 1 Anterior segment photograph showing a dense area of BSK (arrows) in the RE of a patient with uveitis

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Fig. 3 Anterior segment photograph showing two areas of peripheral early BSK (arrows) and posterior synechiae (arrowhead) in the LE of a girl with uveitis

Fig. 4 Anterior segment photograph showing two areas of peripheral BSK (arrows) in the LE Fig. 2 Anterior segment photograph of LE showing BSK running horizontally in the interpalpebral area of the cornea (arrows). Also present are thickened areas of calcium deposition (double arrowhead), melanosis (single arrowhead), and a displaced anterior chamber intraocular lens (IOL, unlabeled)

BSK and mild anterior uveitis but no other findings from uveitis. Figure 2 demonstrates BSK from chronic uveitis associated with sarcoidosis.

Case 3: Early BSK Secondary to Uveitis A 12-year-old girl with a history of systemic lupus erythematosus has bilateral uveitis that has been controlled and stable for many years on methotrexate, infliximab, and prednisolone acetate ophthalmic. She has early BSK in her left eye (LE) (Fig. 3). Figures 4 and 5 show other examples of early peripheral BSK.

Fig. 5 Anterior segment photograph showing two areas of peripheral BSK (arrows) in the right eye (RE)

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Case 4: Residual BSK After Neutral Disodium Ethylenediaminetetra-Acetic Acid (EDTA) Chelation in Girl with Juvenile Rheumatoid Arthritis (JRA) A 13-year-old African-American girl with JRA developed right-sided uveitis complicated by uveitic glaucoma, cataract, corneal edema, and BSK. RE EDTA chelation was performed to improve visualization for the cataract surgery that followed. Residual peripheral band keratopathy can still be seen over 3 years later (Fig. 6). Her uveitis has been stable on methotrexate and prednisolone acetate ophthalmic suspension for years.

Case 5: Idiopathic BSK Chelated for Cataract Surgery

Fig. 7 Surgeon’s view showing dense central BSK (arrow) on LE about to undergo EDTA chelation and debridement

A 60-year-old man with a 6 year history of diabetes mellitus complicated by end-stage renal disease treated with dialysis presented with bilateral decreased visual acuity. He was found to have bilateral BSK (Fig. 7), a right-sided posterior chamber (PC) IOL, right-sided proliferative diabetic retinopathy, and a mature cataract in the LE obstructing a fundoscopic exam. B-scan revealed no retinal detachment. To provide an adequate view for cataract surgery, he underwent left-sided EDTA chelation (Fig. 8) with EDTA soaked in an ocular cellulose sponge. Chelation may take from a few to 30 min depending on calcium layer thickness. In this case, chelation alone was insufficient to clear the calcium plaque, so simultaneous debridement was performed (Figs. 9, 10, and 11) with sutured amniotic membrane graft Fig. 8 Surgeon’s view showing EDTA-soaked sponge (arrow) atop the dense central BSK in the LE

Fig. 6 Anterior segment photograph of a RE showing residual areas of peripheral BSK (skinny arrows) and an area of new calcium deposition inferiorly (thick arrow) 3 years after EDTA chelation

Fig. 9 Surgeon’s view showing a surgical blade (skinny arrow) debriding the markedly reduced area of BSK (thick arrow) in the LE

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Fig. 13 Surgeon’s view showing resolved RE BSK Fig. 10 Surgeon’s view showing that a burr (skinny arrow) was used in addition to EDTA chelation (thick arrow) for this remarkably dense BSK (arrowhead) on the LE

Fig. 11 Surgeon’s view showing resolution of BSK after EDTA chelation and debridement of the LE. An amniotic membrane graft was sutured on afterwards

Fig. 14 Hematoxylin-eosin stain of the cornea in an eye with BSK and bullous keratopathy. (1) Corneal epithelium, (2) calcium deposits, (3) corneal stroma, (4) corneal endothelium. Photo credit: Tatyana Milman, MD, Perelman School of Medicine at the University of Pennsylvania

placement. Five months later, he underwent left-sided cataract extraction with placement of a PC IOL. Also shown is another eye with idiopathic BSK before (Fig. 12) and after (Fig. 13) EDTA chelation. Excimer laser phototherapeutic keratectomy can also be used to remove BSK in select cases. Figure 14 shows histopathologic examination of an enucleated eye with BSK.

Fig. 12 Anterior segment photograph showing dense BSK (arrows point to the four corners of the band) that obstructed the visual axis in the RE and also caused foreign body sensation

Key Points • BSK describes a band of calcium salt precipitated across the central, subepithelial cornea. • It is associated with various conditions including uveitis, corneal edema, phthisis bulbi, end stage glaucoma, and systemic hypercalcemic states but is often idiopathic.

Band Shaped Keratopathy

• Symptoms include ocular irritation, foreign body sensation, or blurry vision. • Diagnosis is based on slit-lamp examination showing a gray-white corneal plaque. • BSK may be treated with EDTA chelation with or without debridement. • Indications for treatment include when it: causes visual disturbance, obstructs intraocular view required for examination or surgery, or is symptomatic. • The underlying cause should be sought and treated first to prevent recurrence.

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Suggested Reading Anderson DF, Prabhasawat P, Alfonso E, Tseng SCG. Amniotic membrane transplantation after the primary surgical management of band keratopathy. Cornea. 2001;20(4):354–61. Jhanji V, Rapuano CJ, Vajpayee RB. Corneal calcific band keratopathy. Curr Opin Ophthalmol. 2011;22(4):283–9. Johnston RL, Stanford MR, Verma S, Green WT, Graham EM. Resolution of calcific band keratopathy after lowering elevated serum calcium in a patient with sarcoidosis. Br J Ophthalmol. 1995;79:1050–6. Najjar DM, Cohen EJ, Rapuano CJ, Laibson PR. EDTA chelation for calcific band keratopathy: results and long-term follow-up. Am J Ophthalmol. 2004;137(6):1056–64.

Complicated Cataract Aniruddha Agarwal and Jagat Ram

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Case 1: Chronic Anterior Uveitis with Complicated Cataract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Case 2: Cataract Associated with Fuchs’ Uveitis Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 Case 3: Childhood Uveitis with Secondary Cataract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 Case 4: Outcomes of Cataract Surgery in a Patient with Idiopathic Panuveitis . . . . . . . . . . . . . . . . . . . . . . . 227 Case 5: Complicated Cataract in a Patient with Vogt-Koyanagi-Harada Syndrome . . . . . . . . . . . . . . . . . . 227 Case 6: Ocular Inflammation and Phacolytic Glaucoma in a Patient with Hypermature Liquefied Cataract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

Introduction Among patients with uveitis, chronic inflammation of the ocular tissues and therapy with agents such as corticosteroids leads to the development of lenticular opacification. Cataracts in patients with uveitis occur due to an imbalance in the intraocular milieu and may have a characteristic morphological appearance, described in literature as breadcrumb appearance (polychromatic luster). In addition, the patients may have other ocular features such as miotic pupils, floppy/atrophic iris, posterior synechiae, pupillary membranes, and band-shaped keratopathy, which make the surgical management of such cases very challenging. Management of such cases requires a thorough ocular and systemic evaluation and adequate control of inflammation for at least 3 months prior to surgical intervention. A number of surgeons employ therapy with high-dose corticosteroids prior to surgery and continue them postoperatively to minimize flare-up of inflammation. Similar to the advancement in immunosuppressive drugs for the control of uveitis, surgical management of

complicated cataracts has significantly advanced in the recent years. With improvements in surgical instrumentation, and newer intraocular lens designs such as hydrophobic acrylic and squareedged designs, satisfactory visual outcomes may be obtained in skilled hands among patients with uveitis.

Case 1: Chronic Anterior Uveitis with Complicated Cataract A 45-year-old male presented with complaints of chronic progressive diminution of vision and glare in both eyes. His visual acuity was counting fingers at 2 m. The patient was diagnosed with sacroiliitis on radiography. HLA-B27 was positive. Slitlamp biomicroscopic examination revealed the presence of mild AC reaction (1+ cell and flare), 360 posterior synechiae, and a complicated cataract (Fig. 1a). The patient was started on anti-inflammatory therapy with oral corticosteroids, and Nd: YAG synechiolysis was performed to release the iridolenticular adhesions. Two days following synechiolysis, the visual acuity improved to 20/200 (Fig. 1b). After 3 months of quiescence,

A. Agarwal (*) · J. Ram (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_114

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Fig. 1 Anterior segment photographs demonstrating complicated cataract with total peripheral synechiae in a patient with HLA-B27-associated anterior uveitis (a). The patient underwent laser synechiolysis (b)

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followed by phacoemulsification with IOL implantation with a satisfactory visual outcome (c)

Fig. 2 Anterior segment photographs of a patient with Fuchs’ uveitis syndrome and secondary cataract (a). Following an uncomplicated phacoemulsification and in-thebag IOL implantation, the visual acuity improved to 20/20 from an initial value of 20/60

the patient underwent phacoemulsification with implantation of polymethyl methacrylate (PMMA) intraocular lens (IOL). Postoperatively, the visual acuity improved to 20/30 with 1+ anterior chamber cells and flare (Fig. 1c). The IOL was well centered, and anti-inflammatory therapy was continued postoperatively to maintain adequate control of inflammation.

Case 2: Cataract Associated with Fuchs’ Uveitis Syndrome A 35-year-old Asian Indian female presented with complaints of glare and photophobia in the right eye. Her visual acuity was 20/60 in the right eye and 20/20 in the left eye. After adequate laboratory work-up, and exclusion of other uveitic entities, the patient was diagnosed with Fuchs’ uveitis syndrome (FUS). Slit-lamp examination revealed the presence of 2+ anterior chamber cells and flare. There were no iris nodules or heterochromia. Visually significant posterior subcapsular cataract was noted in the right eye (Fig. 2a). The patient underwent uncomplicated phacoemulsification with implantation of a hydrophobic acrylic IOL (single piece)

in the capsular bag. Three months after the procedure, the patient had a clear visual axis and best-corrected visual acuity of 20/20 in both the eyes (Fig. 2b).

Case 3: Childhood Uveitis with Secondary Cataract An 11-year-old male presented with diminution of vision, blurring, and photophobia since 2 years in both the eyes. Ocular examination revealed a best-corrected visual acuity of 20/100. Slit-lamp biomicroscopy revealed the presence of band-shaped keratopathy, obscuring a detailed examination of the anterior chamber. There was presence of a dense cataract. The patient was started on immunosuppression and oral corticosteroids in order to control the inflammation. Following 3 months of quiescence, the patient was scheduled for phacoemulsification and implantation of IOL. At the time of surgery, removal of band-shaped keratopathy was performed using EDTA. Pupillary dilation was ensured using two Y hooks. Phacoaspiration was performed and IOL was implanted in the capsular bag. Three weeks following surgery, the visual acuity improved to 20/50 in the right eye (Fig. 3).

Complicated Cataract

Fig. 3 Postoperative anterior segment photograph of a young child with band-shaped keratopathy and uveitic cataract who underwent phacoemulsification and IOL implantation. Note the opacification of the peripheral anterior capsule and an irregular pupil

Case 4: Outcomes of Cataract Surgery in a Patient with Idiopathic Panuveitis A 45-year-old male was diagnosed with idiopathic panuveitis and a complicated cataract. The patient was on therapy with 5 mg oral prednisone and immunosuppression consisting of azathioprine. The patient developed a complicated cataract in the left eye which was visually significant (visual acuity was 20/100 in the left eye and 20/40 in the right eye). Since the patient had adequate control of inflammation, cataract surgery was planned in the left eye. The dose of oral corticosteroids was increased and the patient underwent extracapsular cataract surgery (ECCE). One month after surgery, the visual acuity improved to 20/40 in the left eye. The IOL was present in the capsular bag. There was opacification and contraction of the anterior capsule. Posterior synechiae were observed and the patient developed posterior capsular opacification. Following Nd: YAG capsulotomy, the patient had a clear visual axis and visual acuity of 20/30 in the left eye (Fig. 4).

Case 5: Complicated Cataract in a Patient with Vogt-Koyanagi-Harada Syndrome A 10-year-old male child, with a known case of VogtKoyanagi-Harada syndrome, presented with complaints of slowly progressive diminution of vision in the left eye for the past 3 months. He was also diagnosed with intractable glaucoma and received a glaucoma drainage device 6 months prior to presentation. On examination, there was mild flare in the left

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Fig. 4 Postoperative anterior segment photograph of the left eye of a patient who underwent extracapsular cataract surgery for idiopathic panuveitis-related cataract followed by Nd:YAG laser capsulotomy. Corneal sutures are noted at the sites of incision. An irregular pupil with opacification of peripheral anterior capsule is noted

eye (no cellular reaction), broad-based posterior synechiae (leading to an irregular pupil), and visually significant posterior subcapsular cataract (Fig. 5a). There was a characteristic sunset glow fundus on retinal examination. The patient was scheduled for phacoemulsification and IOL implantation. During surgery, synechiolysis was performed with the help of a viscoelastic cannula. Phacoaspiration was performed using standard parameters, and hydrophobic acrylic IOL was implanted in the capsular bag (Fig. 5b). Postoperatively, the pupil was regular, IOL was well centered in the capsular bag, and intraocular pressure was under control.

Case 6: Ocular Inflammation and Phacolytic Glaucoma in a Patient with Hypermature Liquefied Cataract A 70-year-old male from rural India presented with pain, redness, and decrease in vision in the left eye for the past 3 days. The patient was seen elsewhere and diagnosed with endophthalmitis. He did not have any history of trauma or prior complaints. The patient was never seen by an ophthalmologist in the past decade. The best-corrected visual acuity was hand motions close to face in the left eye. On examination, there was diffuse and circumcorneal congestion and lid and corneal edema. There was significant haze and anterior chamber inflammation precluding a view of the iris and the lens (Fig. 6a, b). Detailed evaluation, including ultrasound B-scan and ultrasound biomicroscopy (UBM), revealed disrupted crystalline lens. Phacoemulsification was performed. At the time of

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Fig. 5 Preoperative anterior segment photograph of a child with VogtKoyanagi-Harada syndrome showing posterior synechiae and posterior subcapsular cataract (a). Postoperatively (b), a round pupil with well-

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centered IOL and clear visual axis can be observed (Image courtesy: Uveitis and Glaucoma Clinics, Advanced Eye Center, Postgraduate Institute of Medical Education and Research, Chandigarh, India)

Fig. 6 Pre- (a, b) and postoperative (c) anterior segment photographs of a patient with hypermature liquefied cataract resulting in severe intraocular inflammation. During phacoemulsification, the liquefied lens matter was aspirated and a small hyperpigmented nucleus was found

surgery, hypermature liquefied cataract was found. After removal of all the lens matter and anterior chamber irrigation, IOL was implanted in the capsular bag. Postoperatively (Fig. 6c), the patient had an uneventful course with resolution of inflammation and well-centered IOL in the bag.

implants to ensure long-term control of postoperative inflammation and prevention of macular edema. • A close postoperative follow-up is necessary to ensure control of inflammation and prevention of ocular complications.

Suggested Reading Key Points • The diagnosis and surgical management of complicated cataracts can be very challenging among patients in uveitis. • Adequate control of inflammation (usually quiescence of at least 3 months) must be ensured prior to cataract surgery, except in cases such as Fuchs’ heterochromic uveitis or phacolytic uveitis. • Prior to cataract surgery, the dose of steroids must be increased and continued postoperatively with slow taper to ensure adequate control of inflammation. In addition, mydriatics such as atropine/homatropine may be required to prevent development of synechiae. • Patients with complicated cataract may be also treated with intravitreal sustained-release dexamethasone

Gupta A, Ram J, Gupta A, Gupta V. Intraoperative dexamethasone implant in uveitis patients with cataract undergoing phacoemulsification. Ocul Immunol Inflamm. 2013;21(6):462–7. Jancevski M, Foster CS. Cataracts and uveitis. Curr Opin Ophthalmol. 2010;21(1):10–4. Leung TG, Lindsley K, Kuo IC. Types of intraocular lenses for cataract surgery in eyes with uveitis. Cochrane Database Syst Rev. 2014;3, CD007284. Mehta S, Linton MM, Kempen JH. Outcomes of cataract surgery in patients with uveitis: a systematic review and meta-analysis. Am J Ophthalmol. 2014;158(4):676–92.e7. Ram J, Gupta A, Kumar S, Kaushik S, Gupta N, Severia S. Phacoemulsification with intraocular lens implantation in patients with uveitis. J Cataract Refract Surg. 2010;36(8):1283–8. Van Gelder RN, Leveque TK. Cataract surgery in the setting of uveitis. Curr Opin Ophthalmol. 2009;20(1):42–5.

Part IV Infectious Uveitis

Bacterial Endophthalmitis Sophia L. Zagora, Alex P. Hunyor, and Peter J. McCluskey

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Case 1: Chronic Post-cataract Surgery Endophthalmitis Secondary to Propionibacterium acnes . . . 231 Case 2: Bacterial Endophthalmitis Secondary to Intravitreal Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Case 3: Endogenous Endophthalmitis Secondary to Liver Abscess with Klebsiella pneumoniae . . . . . 232 Case 4: Endogenous Endophthalmitis Secondary to Bacterial Endocarditis with Staphylococcus aureus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Case 5: Endogenous Endophthalmitis Secondary to Streptococcus gordonii in an Immunocompromised Male . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

Introduction

Case 1: Chronic Post-cataract Surgery Endophthalmitis Secondary Bacterial endophthalmitis is infection of the vitreous and/or to Propionibacterium acnes aqueous humour of the eye. It occurs most commonly after eye surgery or penetrating ocular trauma (exogenous endophthalmitis) and may also occur secondary to hematogenous seeding during bacteremia (endogenous endophthalmitis). The presentation is usually acute, with eye pain and decreased vision. In exogenous endophthalmitis, infection is confined to the eye. There is no fever and minimal, if any, peripheral leukocytosis. Treatment includes direct injection of antibiotics into the vitreous and vitrectomy in more severe cases. Systemic antibiotics are indicated in endogenous endophthalmitis; their role in exogenous endophthalmitis is controversial. Visual outcome depends on the virulence of the bacterial pathogen and the speed with which treatment is given. Acute bacterial endophthalmitis is a medical emergency, because delay in treatment may result in vision loss.

A 77-year-old man was otherwise well presented with left blurred vision. He had had routine left cataract surgery 8 months prior and had had low-grade persistent anterior uveitis following surgery that was incompletely controlled with topical corticosteroids. There was no prior history of uveitis. His visual acuity was 6/15. On examination there were keratic precipitates on the cornea, granulomatous precipitates on the lens, and cells in the anterior chamber. There was a PC IOL in the capsular bag. There were cells in the vitreous and mild cystoid macular edema (see Fig. 1). A vitreous tap and injection of vancomycin 1 mg/0.1 ml and ceftazidime 2.25 mg/0.1 ml was performed. He was then commenced on hourly topical steroids and sixth hourly topical antibiotics. Propionibacterium acnes was grown on the vitreous sample. The uveitis subsequently relapsed, therefore the IOL and the bag were removed, and a sutured PCIOL was placed 6 months later. His cystoid macular edema resolved, and his final vision was 6/9.

S. L. Zagora · A. P. Hunyor · P. J. McCluskey (*) Save Sight Institute, Sydney Eye Hospital, Sydney, NSW, Australia e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_33

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Fig. 1 Granulomatous precipitates on the lens of a patient with Propionibacterium acnes Fig. 2 Day-one post intravitreal injection of ranibizumab – presentation with hypopyon and conjunctival injection

Case 2: Bacterial Endophthalmitis Secondary to Intravitreal Injection A 76-year-old lady having ranibizumab injections for a subfoveal CNV presented day one after her sixth injection with poor vision and pain (see Fig. 2). Her visual acuity prior to intravitreal treatment was 6/18 and had returned to 6/6 after the five prior injections. She was on a treat-and-extend regime. At presentation, she had a 1 mm hypopyon and vitreous cells. Her pressure was 16 mmHg. She was treated initially with a vitreous tap and an injection of vancomycin 1 mg/0.1 ml and ceftazidime 2.25 mg/0.1 ml. She was commenced on hourly topical steroids. Her vitreous sample was culture negative, and she regained 6/6 vision. The most common organisms involved in acute bacterial endophthalmitis are day-two-to-four Staphylococcus aureus (10%) and Streptococcus (10%). Staphylococcus epidermidis usually presents on days five to seven and is the most common (70%) but the least severe organism in terms of visual complications. Culture-negative cases have the best visual prognosis.

Case 3: Endogenous Endophthalmitis Secondary to Liver Abscess with Klebsiella pneumoniae A 43-year-old Chinese gentleman presented with a 2-day history of bilateral ocular pain, photophobia, and rapidly progressing worsening vision. Ten days prior to presentation, he had developed abdominal pain, nausea, fevers, and myalgias. He was reviewed by his local doctor and commenced on metronidazole 400 mg TDS. Prior to this he had no significant medical history – he had moved to Australia from China in September 2014 and had no known TB exposure. His

ocular examination revealed both right and left visual acuity being Count Fingers and IOP 12 mmHg. He had extensive chemosis, limited eye movement, and hypopyons in both eyes. He also had a large amount of vitreous debris on B scan (see Fig. 3a and b). MRI of the brain and orbits showed marked hyperintensity and contrast enhancement of intraorbital fat and extraocular muscles consistent with inflammation. There was no extraocular collection (see Fig. 4a and b). On physical examination he was febrile and had a mildly distended abdomen with hepatomegaly, tenderness, and rigidity in his right upper quadrant. His bloods showed an elevated WCC (29.7) with a neutrophilia (24.1) and an elevated GGT (138). He was initially treated with a bilateral vitreous tap and injection of intravitreal vancomycin 1 g/0.1 mL and ceftazidime 2.25 mg/0.1 mL. He was commenced on hourly topical steroids and sixth hourly topical antibiotics. In consultation with the infectious diseases team, he was commenced on intravenous triple therapy: gentamicin 320 mg, ampicillin 2 g, and metronidazole 750 mg. He subsequently had a CT chest that revealed a large heterogeneous enhancing lesion in the left lobe of the liver (67 mm x 93 mm) consistent with an evolving hepatic abscess and localized perforation of the abscess medial to the gallbladder (see Fig. 5). He also had a lesion in the right upper lobe consistent with an area of infective consolidation with early abscess formation. His blood cultures and vitreous sample grew Klebsiella pneumoniae. CT-guided hepatic abscess drainage of the left liver abscess (20 mL pus) and perihepatic collection adjacent to the gallbladder (50 mL pus) was performed. Further ophthalmic management included bilateral anterior chamber washout of fibrin, repeat vitreous taps, core vitrectomies, and repeat intravitreal vancomycin 1 g/0.1 mL and

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Fig. 3 (a) and (b) B scan of the right and left eyes showing dense vitreous debris

Fig. 4 (a) and (b) MRI of the brain and orbits showing marked hyperintensity and contrast enhancement of intraorbital fat and extraocular muscles consistent with inflammation

ceftazidime 2.25 mg/0.1 mL injections. He retains light perception in both eyes.

Case 4: Endogenous Endophthalmitis Secondary to Bacterial Endocarditis with Staphylococcus aureus

Fig. 5 CT abdomen showing localized abscess in the left lobe of the liver

A 47-year-old Caucasian male with ankylosing spondylitis for 10 years treated with infliximab 6 weekly, last injection 5 weeks prior, presented with acute-onset severe loss of vision in his left eye. This was preceded by abdominal pain and myalgia. Visual acuity in his left eye was hand movements and IOP 12 mmHg. Vision in his unaffected right eye was 6/9 and IOP 6 mmHg. He had left corneal edema, 3+ cells in his anterior chamber, flare, and severe vitreous haze.

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A vitreous tap and injection of vancomycin 1 mg/0.1 ml, ceftazidime 2.25 mg/0/1 ml, and voriconazole 50 mcg/0.05 ml was performed. Intravenous clindamycin and valganciclovir were also commenced. On day four the patient underwent a vitrectomy where further intravitreal antibiotics were injected (see Fig. 6). Blood cultures grew Staphylococcus aureus. During investigations for a source of this, echocardiography revealed a tricuspid aortic valve with a 10 x 11 mm vegetation on the noncoronary cusp, mild to moderate aortic regurgitation, and thickening of the trigone indicating an early abscess (Fig. 7).

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A diagnosis of subacute bacterial endocarditis was made, and an aortic valve replacement was performed on day seven. Histopathology from the valve revealed myxoid degeneration, fibrin, inflammatory exudate, and colonies of Staphylococcus aureus. The patient was discharged from the hospital on day 14. He further received IV flucloxacillin 2 g q4hr for 6 weeks via a PICC line, warfarin anticoagulation, g.Maxidex TDS, g. Chlorsig TDS, and g.Atropine daily. Figure 8 shows his left fundus 10 days after admission, and Fig. 9 shows his OCT. His final left eye visual acuity was 6/18 (see Fig. 10).

Case 5: Endogenous Endophthalmitis Secondary to Streptococcus gordonii in an Immunocompromised Male

Fig. 6 Left fundus photograph showing the temporal subretinal abscess 2 x 3 mm, overlying hemorrhage, subretinal exudates, retinitis, and choroidal infiltrate post vitrectomy (note the air bubble in superior vitreous cavity)

Fig. 7 Trans-esophageal echocardiogram showing tricuspid aortic valve 10 x 11 mm vegetation, noncoronary cusp. Mild to moderate aortic regurgitation. Thickening of the trigone indicating early abscess

An 81-year-old man presented with a sudden onset of floaters and loss of vision in his left eye. There was no associated pain or redness (see Fig. 11). He had a past ocular history of two retinal detachments in this eye 5 years prior. Past medical history included multiple myeloma (IgG type) on chemotherapy, osteoarthritis of the knees (recent hyaluronic acid, steroid injections, and aspiration 1 week prior), prostate cancer, and atrial fibrillation. At presentation his right visual acuity was 6/9, and his left visual acuity was hand movements. He had an elevated IOP in the left eye of 38 mmHg (normal in the right 14 mmHg). His left pupil was fixed with an absent red reflex. Topical antiglaucoma therapy and oral acetazolamide were given to lower the IOP prior to an intravitreal tap and injection of vancomycin 1 mg/0.1 ml, ceftazidime 2.25 mg/0/1 ml,

Bacterial Endophthalmitis

Fig. 8 Left fundus photo on day 10 of admission showing some resolution of the retinitis and hemorrhages. The choroidal infiltrate is still present

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Fig. 11 Admission photo of the left eye showing hypopyon with a clear cornea. Note that there is minimal conjunctival injection

Fig. 9 Day 10 admission shows subretinal fluid

Fig. 12 Left knee with osteoarthritis and aspirate of synovial fluid which grew Streptococcus gordonii. Note that the knee does not look inflamed or infected

Fig. 10 Six months post discharge, the OCT shows resolution of previous subretinal fluid

foscarnet 2.4 mcg/0.1 ml, and amphotericin 5 mcg/0.1 ml. He was then commenced on hourly topical steroids, atropine 1% BD, oral ciprofloxacin 750 mg BD, oral prednisone 80 mg daily, and intravenous ampicillin 2 g daily. A knee aspirate was then performed which grew Streptococcus gordonii (see Fig. 12). Left vitrectomy and anterior chamber washout were also performed. Serial blood cultures and the vitreous samples all grew Streptococcus gordonii. On discharge the

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patient’s left visual acuity was 6/60, pinholing to 6/18. It was assumed that the Streptococcus had gained entry into the patient’s knee and bloodstream during the initial injection into the knee. Key Points • Always take a thorough history and examination. • Always take a vitreous tap and inject antibiotics. • Always cover for everything unless you are really sure. • If there are fevers, suspect sepsis and take blood cultures. • When a patient is immunosuppressed, signs and symptoms may be masked. • Early vitrectomy improves outcomes in selected cases. • Involve medical teams early; a multidisciplinary approach is crucial to good outcomes.

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Suggested Reading Braga-Mele R, Chang DF, An Henderson B, Mamalis N, Talley-Rostov A, Vasavada A, ASCRS Clinical Cataract Committee. Intracameral antibiotics: safety, efficacy, and preparation. J Cataract Refract Surg. 2014;40:2134–42. ASCRS and ESCRS. Dossarps D, Bron AM, Koehrer P, Aho-Glélé LS, et al. Endophthalmitis after intravitreal injections: incidence, presentation, management, and visual outcome. Am J Ophthalmol. 2015;160 (1):17–25. Gupta A, Orlans HO, Hornby SJ, Bowler ICJW. Microbiology and visual outcomes of culture-positive bacterial endophthalmitis in Oxford, UK. Graefes Arch Clin Exp Ophthalmol. 2014;252:1825–30. Jackson TL, Paraskevopoulos T, Georgalas I. Systematic review of 342 cases of endogenous bacterial endophthalmitis. Surv Ophthalmol. 2014;59:627–35.

Fungal Endophthalmitis Alessandro Invernizzi

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 Case 1: Vitrectomy is the Key . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 Case 2: Opportunistic Fungal Endophthalmitis should Rise the Suspect of HIV Infectious . . . . . . . . . 239 Case 3: Optical Coherence Tomography can Assess the Chorioretinal Lesions Regression and Confirm the Therapy Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 Case 4: Fungal Etiology Should Always be Suspected in Case of Late Onset Post-surgical Endophthalmitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

Introduction Endophthalmitis is defined as the intraocular presence of infectious microorganisms (bacteria or fungi), involving the vitreous and/or the aqueous humors, accompanied by a variable degree of inflammatory reaction. Endophathalmitis can be exogenous, when the infectious agents penetrate the bulb from outside the body (following eye surgery or trauma), or endogenous when it occur as a result of hematogenous spread of microorganisms into the eye. The epidemiology of fungal endophthalmitis is highly influenced by the environment, the climate, and people living conditions. In developed countries, where eye surgery is performed with highly standardized aseptic procedures, fungal endophthalmitis are mainly endogenous, usually related to prolonged hospitalization, indwelling catheters, or immunosuppressive treatments. On the contrary, in hot-climates developing countries, traumatic wounds are frequent and

A. Invernizzi (*) Uveitis and Ocular Infectious Diseases Service - Eye Clinic, Department of Biomedical and Clinical Science, Luigi Sacco Hospital, University of Milan, Milan, Italy e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_19

eye surgery, as well as after care, are often characterized by poor quality control measures, especially in rural settings, making exogenous endophthalmitis the more frequent cause of fungal intraocular infectious in these areas. Although several agents have been demonstrated in fungal endophthalmitis and the prevalence of single species can widely vary among different climatic areas, endogenous endophthalmitis are predominantly caused by yeasts (candida spp), whereas exogenous infectious are mainly sustained by molds (aspergiulls spp.). Symptoms and clinical features widely vary depending on the causing agent and the infectious location within the eye, ranging from an indolent low grade inflammation to a devastating necrotizing process. Endogenous invasion of the eye usually begins with the localization of microorganisms carried by the bloodstream at the level of the choroid or, more rarely, the retina (fungal chorioretinitis). At this time, symptoms are usually mild, but can range from a severe vision loss when posterior pole is involved to a completely silent condition, in case of peripheral lesions alone. As the fungi penetrate the eye structures and get into the vitreous, the inflammatory reaction increases and multiple whitish fluffy balls (typically disposed in a string of pearls fashion) can be detected, floating in the posterior chamber (Fig. 1). These aggregates are formed by a mixture of white cells and infectious microorganisms and represent the most characteristic sign of fungal endophthalmitis sustained by 237

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A. Invernizzi Table 1 Risk factors for fungal endophthalmitis Risk factors for fungal endophthalmitis Endogenous Exogenous Immunosuppression (iatrogenic) Ocular traumatic wound Prolonged hospitalization Eye surgery Indwelling catheters Retained intraocular foreign Diabetes body Overuse of Antibiotics Wood/vegetables/soil debris Hyperalimentation penetrating the eye Neutropenia Acquired Immunodeficiency Syndrome (AIDS) Recent intra-abdominal surgery Intravenous Drug Abuse

Fig. 1 Whitish fluffy vitreal aggregates in a patient affected by endogenous fungal endophthalmitis

candida spp. On the contrary, Aspergillus grows preferentially along subretinal pigment epithelium and subretinal space and the resulting clinical picture is characterized by large areas of retinitis or chorioretinitis. At this stage a severe vitreous haze can be present, along with anterior chamber reaction (acqueous cells, hypopyon, synechiae), leading to decreased vision, miodesopsias, and pain. Post-surgical fungal endophthalmitis usually show a delayed onset and a less aggressive behavior as compared to bacterial, thus they should be suspected in case of indolent post surgical chronic uveitis. An exception is represented by Aspergillus spp., the most frequently isolated agents in post traumatic fungal endophthalmitis, which often show a rapid progression that may lead to early onset endophthalmitis and presentation similarly to bacterial endophthalmitis. The use of imaging investigations does not result really helpful in the diagnosis of fungal endophthalmitis for the laking of pathognomonic signs. Nevertheless optical coherence tomography (OCT) can be used while monitoring the disease progression as well as the alterations induced from the inflammatory and healing process in the retinal tissue. In addition, fluorescein angiography (FA) is useful to assess the possible presence of choroidal neovascularization as well as fibrovascular epiretinal membranes that can occur as a consequence of the prolonged inflammatory stimulus. The diagnosis of fungal endophthalmitis is hence mainly based on clinical findings and should be suspected every time a patient presents with intraocular inflammation associated with a known risk factor (Table 1). Extra ocular findings interpretation is difficult during the diagnostic process. For example the presence of fungemia is not necessarily related to ocular infection as well as

endophthalmitis can occur along with negative blood coltures. Intraocular demonstration of the fungal agent is hence the only technique that allows to confirm the presumptive clinical diagnosis. To reach this target, vitrectomy is the preferable procedure since it allows to collect samples, remove a large amount of microorganisms from the posterior chamber and deliver antifungal agents into the infected eye. On the contrary, aqueous taps has showed a low sensitivity in detecting fungal microorganisms. Once collected, the specimens can be analyzed by direct slides observations, culture or PCR assays. The treatment of fungal endophthalmitis is based on a combination of systemically and intravitreally administered antimycotic drugs (amphotericin B, triazole compounds) associated with pars plana vitrectomy in more severe cases. The visual outcome is variable ad depends on a correct management of the disease as well as on the lesions location, the causative agent and the stage at presentation.

Case 1: Vitrectomy is the Key A 55 years old patient was referred to our unit for decreased vision in his right eye from the abdominal surgery department. He had underwent surgical asportation of a gastric cancer 1 month earlier and since then he was on parenteral nutrition. Blood tests revealed a mild neutropenia. Blood cultures for fungi or bacteria were negative. At first observation, best correct visual acuity (BCVA) was hand motion in the right eye and 20/20 in the left. Right eye slit-lamp examination revealed anterior chamber severe inflammation, posterior synechiae and lens opacities. The fundus was not clearly visible because of an intense vitritis. Despite this a yellowish large lesion involving the whole posterior pole could be appreciated, left eye anterior segment and retina were within normal limits. Considering the presence of multiple risk factors such as recent abdominal surgery and indwelling catheter, endogenous fungal endophthalmitis was immediately suspected. However bacterial etiology as well as a toxoplasmic

Fungal Endophthalmitis

Fig. 2 (a) Because of the multiple posterior synechiae induced by the severe inflammation phacoemulsification and IOL implant needed iris mechanical retractors. Despite cataract extraction, fundus was barely

retinochoroiditis reactivation could not be excluded. In such a sight treating condition, a prompt diagnosis and an early therapy onset are mandatory, thus vitrectomy was performed the same day. After cataract removal and intraocular lens implant (Fig. 2a) some vitreous specimens were collected randomly through the posterior chamber and more posteriorly directly from the pre retinal space above the lesion (Fig. 2b). Cultures and PCR require time thus some material was directly prepared for slices observation. Candida pseudohyphae were visualized at the microscope (Fig. 3) and realtime diagnosis of fungal endophthalmitis was made. Surgery was hence completed with cleaning of the vitreous chamber and intravitreal amphotericin B injection. A systemic antimycotic therapy was also started. The endophthalmitis resolved in a couple of weeks and no other fungal lesions were detected in the patient’s body. Unfortunately, the lesion healed with a scar in the macular region thus right eye BCVA at last examination was still poor (20/200). This case demonstrates the key-role vitrectomy plays in the management of fungal endophthatlmitis, not only for posterior chamber cleaning but also for samples collection and diagnosis confirmation.

Case 2: Opportunistic Fungal Endophthalmitis should Rise the Suspect of HIV Infectious A 33 years old man was visited during a screening program for homeless people. His visual acuity was good in both eyes. However, at fundus examination, multiple round-shaped small-yellowish lesions were visible (Fig. 4). No signs of intraocular inflammation were detectable.

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visible due to the intense vitritis. (b) Collection of vitreous specimens from the pre retinal area just above the posterior pole lesion

Fig. 3 Vitreous specimens slice analyzed by optical microscopy. Candida pseudohyphae are clearly visible between the vitreous debris

In case of an intraocular spread of microorganisms, in absence of an inflammatory reaction, immunodeficiency should always be suspected. The patient was hence hospitalized for further investigations. Blood tests revealed the patient was affected by Acquired Immunodeficiency Syndrome (AIDS) complicated by a systemic criptoccosis. Specific treatments were started. Fungal endophthalmitis can appear completely different in patients with a compromised immune system, the course can be faster while symptoms can be delayed for the lacking of vitreous inflammatory opacification. Moreover, some pathogens as Criptococcus neoformans are unable to infect immunocompetent hosts thus their identification is a landmark for immunodeficiency.

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Case 3: Optical Coherence Tomography can Assess the Chorioretinal Lesions Regression and Confirm the Therapy Efficacy A young diabetic patient complained of decreased vision in his left eye 2 weeks after abdominal surgery. At presentation his BCVA was 20/400 in the left eye and 20/20 in the right eye. At slit-lamp examination of left eye, anterior chamber

A. Invernizzi

showed a mild inflammatory reaction (cells ++), and anterior vitritis was detectable (Fig. 5a). Fundus examination revealed a yellowish lesion infiltrating the posterior pole and multiple fluffy vitreous aggregates (Fig. 5b). Optical coherence tomography allowed to assess the position and the extension of the lesion penetrating the retina and spreading into the vitreous. (Fig. 6a) Suspecting fungal endophthalmitis a systemic + intravitreal anti-fungal therapy was started. At 3 days from the therapy onset, anterior chamber inflammation worsened and hypopyon was detectable (Fig. 7). However, the OCT showed a clear regression of the chorioretinal lesion (Fig. 6b). On the base of these data, the anterior chamber worsening, firstly considered as a negative prognostic sign, was reinterpreted as a JarischHerxheimer reaction, indicating treatment efficacy. Thus the antifungal therapy was continued and topical steroids were administrated. Ten days later the anterior chamber was quite, the vitritis was resolving and the chorioretinal lesion was healed (Fig. 6c).

Case 4: Fungal Etiology Should Always be Suspected in Case of Late Onset Post-surgical Endophthalmitis

Fig. 4 Yellowish round-shaped lesion in a patient affected by Cryptococcus Neoformans. Note the absence of vitreous inflammatory reaction, suggestive for immunodeficiency

A 76 years old lady was referred to our center for decreased vision in her right eye since 2 weeks. She had undergone epiretinal membrane peeling 2 months earlier for a macular pucker and 1 month after surgery the eye was quiet. However at presentation she was still on topical steroids.

Fig. 5 (a) Anterior chamber mild reaction (cells ++). (b) A yellowish lesion infiltrating the posterior pole is visible at fundus examination along with Vitritis and fluffy vitreous aggregates

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Fig. 7 Three days after the therapy onset anterior chamber presented an increased inflammatory reaction. Firstly considered as a negative prognostic sign, after the demonstration by OCT of lesion regression in the retina, the presence of hypopyon (black arrowheads) was reinterpreted as a Jarisch-Herxheimer reaction, indicating treatment efficacy

At slit-lamp examination, right eye showed a mild anterior chamber inflammation (cells ++), a fibrinous reaction on the IOL surface and a mild vitritis. The fundus didn’t show significant alterations. Left eye was within normal limits. Suspecting a late onset endophthalmitis, steroids were stopped and an antibiotic therapy with fortified antibiotics eyedrops was started. The day after the endophthalmitis worsened, hypopyon was visible at slit lamp examination (Fig. 8a) and multiple fluffy aggregates appeared in the vitreous (Fig. 8b). Vitrectomy was performed and pan fungal PCR resulted positive for the presence of fungal elements. Intravitreal + systemic antifungal therapy was started with good response. A delayed onset after surgery and a worsening after steroids drops discontinuation are both suggestive signs for fungal exogenous endophthalmitis.

Fig. 6 (a) At presentation SD-OCT demonstrated a lesion located at the posterior pole involving the foveal region. The focus (white harrowheads) starts from the choroid, extends into the sub retinal space and, infiltrating the retina reaches, the vitreous cavity. (b) Three days after the therapy onset, despite the apparent worsening of the inflammatory reaction in the anterior chamber, the lesion is clearly regressing on OCT scans. (c) Ten days after OCT demonstrates healing of the infiltrating fucus and residual retinal layers alteration

Key Points • Fungal endophthalmitis can be endogenous or exogenous. • Symptoms and signs can widely vary according to the causative agent, the immune system status of the host, the lesions location, and the stage at presentation. • The presence of intraocular inflammation associated with known risks factors should always rise the suspect for fungal endophthalmitis. • Vitrectomy plays a main role in the diagnosis and management of these forms.

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Fig. 8 (a) The day after antibiotics therapy onset and steroids discontinuation, the inflammatory reaction worsened and hypopyon was visible at slitlamp examination. (b) Multiple fluffy aggregates were detectable in the vitreous chamber

Suggested Reading Aguilar GL, Blumenkrantz MS, Egbert PR, McCulley JP. Candida endophthalmitis after intravenous drug abuse. Arch Ophthalmol. 1979;97(1):96–100. Beebe WE, Kirkland C, Price J. A subretinal neovascular membrane as a complication of endogenous Candida endophthalmitis. Ann Ophthalmol. 1987;19(6):207–9. Brooks RG. Prospective study of Candida endophthalmitis in hospitalized patients with candidemia. Arch Intern Med. 1989;149(10):2226–8. Callanan D, Scott IU, Murray TG, Oxford KW, Bowman CB, Flynn Jr HW. Early onset endophthalmitis caused by Aspergillus species following cataract surgery. Am J Ophthalmol. 2006;142:509–11. Chakrabarti A, Shivaprakash MR, Singh R, Tarai B, George VK, Fomda BA, Gupta A. Fungal endophthalmitis: fourteen years’ experience from a center in India. Retina. 2008;28(10):1400–7. Cho M, Khanifar AA, Chan RV. Spectral-domain optical coherence tomography of endogenous fungal endophthalmitis. Retin Cases Brief Rep. 2011;5(2):136–40. https://doi.org/10.1097/ICB.0b013e3181cc2146. Essman TF, Flynn Jr HW, Smiddy WE, Brod RD, Murray TG, Davis JL, Rubsamen PE. Treatment outcomes in a 10-year study of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers. 1997;28(3): 185–94. Henderson DK, Edwards Jr JE, Ishida K, Guze LB. Experimental hematogenous Candida endophthalmitis: diagnostic approaches. Infect Immun. 1979;23(3):858–62. Jaeger EE, Carroll NM, Choudhury S, Dunlop AA, Towler HM, Matheson MM, Adamson P, Okhravi N, Lightman S. Rapid detection and identification of Candida, Aspergillus, and Fusarium species

in ocular samples using nested PCR. J Clin Microbiol. 2000;38(8): 2902–8. Rao NA, Hidayat AA. Endogenous mycotic endophthalmitis: variations in clinical and histopathologic changes in candidiasis compared with aspergillosis. Am J Ophthalmol. 2001;132(2):244–51. Riddell J, Comer GM, Kauffman CA. Treatment of endogenous fungal endophthalmitis: focus on new antifungal agents. Clin Infect Dis. 2011;52(5):648–53. https://doi.org/10.1093/cid/ ciq204. Epub 2011 Jan 16. Shen X, Xu G. Vitrectomy for endogenous fungal endophthalmitis. Ocul Immunol Inflamm. 2009;17(3):148–52. https://doi.org/10.1080/ 09273940802689396. Smiddy WE. Treatment outcomes of endogenous fungal endophthalmitis. Curr Opin Ophthalmol. 1998;9(3):66–70. Stern WH, Tamura E, Jacobs RA, Pons VG, Stone RD, O’Day DM, Irvine AR. Epidemic postsurgical Candida parapsilosis endophthalmitis. Clinical findings and management of 15 consecutive cases. Ophthalmology. 1985;92(12):1701–9. Vaziri K, Schwartz SG, Kishor K, Flynn Jr HW. Endophthalmitis: state of the art. Clin Ophthalmol. 2015;9:95–108. https://doi.org/10.2147/ OPTH.S76406. eCollection 2015. Weissgold DJ, D’Amico DJ. Rare causes of endophthalmitis. Int Ophthalmol Clin. 1996;36(3):163–77. Wykoff CC, Flynn HW Jr, Miller D, Scott IU, Alfonso EC. Exogenous fungal endophthalmitis: microbiology and clinical outcomes. Ophthalmology. 2008;115(9):1501–7, 1507.e1–2. https://doi.org/10.1016/ j.ophtha.2008.02.027. Zhang YQ, Wang WJ. Treatment outcomes after pars plana vitrectomy for endogenous endophthalmitis. Retina. 2005;25(6):746–50.

Nocardia Endophthalmitis Yasir J. Sepah, Mohammad Ali Sadiq, and Quan Dong Nguyen

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Case: Nocardia Chorioretinitis in an Elderly Male . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

Introduction Nocardia species are gram-positive, catalase-positive, rod shaped bacteria. Some species may be pathogenic and may cause a wide spectrum of infections including ocular involvement. Ocular involvement is usually rare and cases may be acquired endogenously or exogenously. Most cases are seen in immunocompromised individuals. In the retina, Nocardia infection usually presents as a localized granulomatous-like lesion which is yellowish in color. Overlying hemorrhage and exudative detachment may also be seen.

Case: Nocardia Chorioretinitis in an Elderly Male A 78-year-old Caucasian man from Switzerland presented with confusion, fever, and redness in the left eye. The patient was recently diagnosed with advanced Hodgkins lymphoma. The patient had also had a resection of a prostate adenocarcinoma 8 months prior to ocular symptoms. Ophthalmic examination

Y. J. Sepah Byers Eye Institute, Stanford University, Palo Alto, CA, USA M. A. Sadiq Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, KY, USA e-mail: [email protected] Q. D. Nguyen (*) Spencer Center for Vision Research, Byers Eye Institute at Stanford University, Palo Alto, CA, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_43

revealed paresis of vertical gaze and a fixed dilated left pupil. Best corrected visual acuity (BCVA) was 20/20 in the right eye and hand motion in the left eye. Anterior segment examination revealed a quiet anterior chamber in the right eye and 4+ injection in the left eye. The patient was pseudophakic bilaterally. Fundus examination showed 4+ vitritis and 4+ haze in the left eye along with a yellow-white mass in the temporal paramacular region along with a few superficial hemorrhages (Fig. 1). Fundus examination in the right eye was unremarkable. The patient had a vitreal biopsy 1 week prior to presentation for the mass in his left eye. Smears, cultures, PCR, cytology, and serologies were all reported to be negative. Computed tomography (CT) scan of the brain revealed a 1-cm lesion in the left superior colliculus, along with annular enhancement and perilesional edema. Subsequent cerebrospinal fluid (CSF) analysis revealed pleocytosis of polymorphonuclear neutrophils and lymphocytes, normal glucose, and increased total proteins. No organism could be identified in the CSF. A magnetic resonance imaging (MRI) scan of the brain revealed six additional punctate lesions distributed in both hemispheres. The patient was started on systemic therapy with intravenous ceftriaxone and clarithromycin along with prednisone and granulocyte colony stimulating factor 1 (GSF-1). The patient was also given topical dexamethasone. No improvement was seen in the next 3 days. Therefore, a retinectomy of the entire lesion along with aspiration of the abscess was performed. Intracameral injection of 40 μg amikacin and 100 μg vancomycin was also given. Retinal smears stained positive with hematoxylin-eosin (Fig. 2a) and gram positive branching rods of Nocardia species were seen on gram stain (Fig. 2b). Therefore, treatment with intravenous trimethoprim-sulfamethaxozole at high dosage (10 mg kg/day 243

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Fig. 1 Fundus photograph from a 78-year-old Caucasian man with history of Hodgkin’s lymphoma and hand-motion vision in the left eye showing dense vitreous haze and vitritis

Fig. 2 (a) Hematoxylin-eosin staining (20X) of the retinal aspirate. (b) Gram positive branching rods of Nocardia species (40X)

Fig. 3 Fundus photographs from the same patients: (a) 3 weeks and (b) 3 months posttreatment showing marked resolution of vitritis in the left eye

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TM and 50 mg/kg/day SMZ) was initiated. Examination 3 weeks (Fig. 3a) and 3 months following treatment (Fig. 3b) demonstrated significant improvement of vitritis in the left eye. Vision in the left eye improved from hand motion at presentation to 20/25 3 months after initiation of therapy.

• Definitive diagnosis of a choroidal abscess generally requires subretinal or choroidal biopsy, which is necessary for therapy with appropriate anti-infectious agents.

Key Points • Nocardia chorioretinitis commonly presents in patients who are immunocompromised secondary to different etiologies. It may be acquired both endogenously and exogenously. • Typical presenting features include a large granulomatouslike yellowish lesion with accompanying hemorrhage and exudative retinal detachment. • Nocardia is the most common bacterium isolated from a subretinal abscess.

Suggested Reading Garg P. Fungal, mycobacterial, and Nocardia infections and the eye: an update. Eye (Lond). 2012;26(2):245–51. Meyer SL, Font RL, Shaver RP. Intraocular nocardiosis. Report of three cases. Arch Ophthalmol. 1970;83(5):536–41. Silva RA, Young R, Sridhar J. NOCARDIA CHOROIDAL ABSCESS: risk factors, treatment strategies, and visual outcomes. Retina. 2015;35(10):2137–46.

Aspergillus Retinochoroiditis Kalpana Babu, Aditi Parikh, and Vishali Gupta

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 Case 1: Aspergillus Endogenous Endophthalmitis Diagnosed with Pars Plana Vitrectomy . . . . . . . . . . 247 Case 2: Aspergillus Endogenous Endophthalmitis Following Intravenous Infusions . . . . . . . . . . . . . . . . . 248 Case 3: Vitreous Exudates in Aspergillus Endophthalmitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

Introduction Aspergillosis is a mycotic infection usually seen in patients who are intravenous drug abusers, post organ transplantation, granulocytopaenia and cardiac surgeries and have undergone organ transplantation, associated with granulocytopenia or cardiac surgery. Symptoms may include subacute vision loss, redness, or pain. The preferential localization of the fungus in the sub-retinal pigment epithelium and sub-retinal space along with its tendency for retinal and choroidal vascular invasion contributes to the extensive retinal necrosis and hemorrhage seen in aspergillosis in contrast to Candida infections. Deep retinal or chorioretinitis with progressive horizontal enlargement is characteristic of Aspergillus infection. Sub-retinal exudation, hemorrhagic retinal vasculitis, intraretinal hemorrhages, fluffy, and large, vitreous exudates are other intraocular signs. These findings are consistent with the relative poor prognosis in aspergillosis. Treatment

K. Babu (*) · A. Parikh Prabha Eye Clinic and Research Centre, Vittala International Institute of Ophthalmology, Bangalore, India e-mail: [email protected] V. Gupta Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_36

includes vitrectomy and systemic azoles like fluconazole, voriconazole, and posconazole. Intravitreal injections of voriconazole are used as an adjunct to systemic therapy.

Case 1: Aspergillus Endogenous Endophthalmitis Diagnosed with Pars Plana Vitrectomy A 25-year-old male with an h/o gastroenteritis presented with a sudden loss of vision in the right eye of 4 days duration. He had received intravenous fluids a week ago. On examination, his BCVA was hand movements in the right eye and 20/20 in the left eye. Slit lamp examination showed an anterior chamber reaction 2+ and intense vitritis. Fundus examination of the right eye showed plenty of fluffy, vitreous exudates and areas of retinitis (Fig. 1a). The disk was hazily seen. Left eye examination was normal. Anterior chamber tap and vitreous biopsy were negative for bacteria or fungi. Laboratory investigations including the routine, random blood sugar, ELISA for HIV, and urine routine were negative. The undiluted vitreous sample during pars plana vitrectomy was positive (KOH stain and culture) for Aspergillus fumigatus (Fig. 1b). He received oral itraconazole 200 mg bd for 3 months with multiple intravitreal injections of amphotericin B (5 μ). He regained a vision of 20/60 at the end of 2 months after the pars plana vitrectomy (Fig. 1c, d).

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Fig. 1 (a) Fundus photograph of the right eye of case 1, showing fluffy, white, vitreous exudates and extensive retinitis. (b) Microphotograph showing multiple, long, septate fungi of Aspergillus species from the vitreous of case 1 (H& E  20). (c) Fundus photograph of the right eye of case 1, 5 days after pars plana vitrectomy and intravitreal injection of

Case 2: Aspergillus Endogenous Endophthalmitis Following Intravenous Infusions A 56-year-old lady presented to us with floaters and diminution of vision in the right eye of 1 week duration. She had a history of hospital admission for pyrexia of unknown origin for which she had received intravenous fluids 3 weeks ago. On examination her BCVA was 20/200 in the right eye and 20/30 in the left eye. Slit lamp examination showed an

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amphotericin B showing retinochoroidal abscess and string of exudates in the vitreous. (d) Fundus photograph of the right eye of case 1, 2 months after the pars plana vitrectomy showing a large chorioretinal scar at the posterior pole

anterior chamber reaction of 2+ with vitritis in the right eye. Fundus examination of the right eye showed areas of retinitis, sub-retinal infiltrates, retinal hemorrhages, and dense vitritis (Fig. 2a). Left eye examination was normal. AC tap and vitreous biopsy were positive for a pan-fungal genome (identified as Aspergillus species) (Fig. 2b). Laboratory investigations including ELISA for HIV and random blood sugars were normal. She received multiple intravitreal injections of voriconazole and oral fluconazole 200 mg bd (Fig. 2c). Her last follow-up was 1 month after the first intravitreal injection. Her BCVA was 20/120 in the right eye.

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Fig. 2 (a) Fundus photograph of the right eye of case 2, showing marked vitritis, retinitis, and retinal hemorrhages prior to the intravitreal injection of voriconazole. (b) Microphotograph showing long, septate, branching fungi of Aspergillus species from the vitreous of case 2 (GMS  20). (c) Fundus photograph of the right eye of case 2, 1 month post multiple intravitreal injections of voriconazole showing reduction in the vitritis and early signs of resolution of the retinitis

Case 3: Vitreous Exudates in Aspergillus Endophthalmitis

At the end of 1 year, she had a large chorioretinal scar at the site of the prior infection (Fig. 3e), and her BCVA was 20/60 in the left eye.

A 32-year-old lady presented with a history of diminution of vision and floaters in the left eye of 1 month duration. She had received an intravenous infusion for a minor illness 2 weeks ago. On examination her BCVA was 20/20 and perception of light with accurate projection in the right and left eyes, respectively. Right eye examination was normal. Left eye examination showed an anterior chamber reaction 2+; marked vitritis with dense, fluffy, vitreous exudates; and no view of the retinal details (Fig. 3a). Laboratory investigations did not reveal any systemic abnormality. AC tap and vitreous biopsy were positive for Aspergillus fumigatus (Fig. 3b). She received multiple intravitreal injections of amphotericin B (5 μg) and oral fluconazole 200 mg bd for 3 months. Resolution of infection was noted in subsequent visits (Fig. 3c, d).

Key Points • Aspergillosis can occur in intravenous drug users, post organ transplantations, granulocytopenia, and cardiac surgeries. • Aspergillus unlike Candida has a predilection for the subretinal pigment epithelium and sub-retinal space. It has a tendency for retinal and choroidal vascular invasion. • Unlike Candida which forms multiple small abscesses in the vitreous, Aspergillus causes large vitreous abscess. • Aspergillus has a poorer prognosis in comparison to Candida infections. • Treatment includes pars plana vitrectomy with intravitreal and systemic azoles.

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Fig. 3 (a) Fundus photograph of the left eye of case 3 showing marked vitritis with fluffy, white exudates in the vitreous with no visualization of the retinal details. (b) Microphotograph showing multiple, long, septate, branching fungi of Aspergillus fumigatus species from the vitreous of case 3 (H& E  20). (c and d) Fundus photograph of the left eye of case 3, 3 days after the pars plana vitrectomy showing the debulked vitreous (c) and 1 week later (d) showing the chorioretinal infiltration and a hazily seen optic nerve head. (e) Fundus photograph of the left eye of case 3 showing a large chorioretinal scar in the posterior pole with sclerosed retinal blood vessels at the end of 1 year

Suggested Reading Adam CR, Sigler EJ. Multimodal imaging findings in endogenous aspergillus endophthalmitis. Retina. 2014;34(9):1914–5. Jampol L, Dyckman S, Maniates V, et al. Retinal and choroidal infarction from aspergillus: clinical diagnosis and clinicopathologic correlations. Trans Am Ophthalmol Soc. 1988;86:422–40. Rao NA, Hidayat AA. A comparative clinicopathologic study of endogenous mycotic endophthalmitis: variations in clinical and histopathologic

changes in candidiasis compared to aspergillosis. Trans Am Ophthalmol Soc. 2000;98:183–93. Rao NA, Hidayat AA. Endogenous mycotic endophthalmitis: variations in clinical and histopathologic changes in candidiasis compared with aspergillosis. Am J Ophthalmol. 2001;132(2):244–51. Saffra NA, Desai RU, Seidman CJ, et al. Endogenous fungal endophthalmitis after cardiac surgery. Ophthalmic Surg Lasers Imaging. 2010;28:41. Vila Arteaga J, Suriano MM, et al. Intravitreal voriconazole for the treatment of aspergillus chorioretinitis. Int Ophthalmol. 2011;31(4):341–4.

Candida Retinochoroiditis Mohammad Ali Sadiq, Aniruddha Agarwal, Vishali Gupta, Mangat Ram Dogra, Amod Gupta, and Quan Dong Nguyen

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Case 1: Posterior Segment Features of Candida Endophthalmitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Case 2: Candida Endogenous Endophthalmitis in a Renal Transplant Recipient . . . . . . . . . . . . . . . . . . . . . 252 Case 3: Postoperative Candida Endophthalmitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 Case 4: Candida Endophthalmitis in an HIV-Positive Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

Introduction Fungal endophthalmitis due to Candida species can occur following trauma, surgery (exogenous endophthalmitis), or, more commonly, due to hematogenous spread from other infectious foci in the body (endogenous endophthalmitis). Endogenous infection is more frequently seen in patients with intravenous drug abuse, hyperalimentation, diabetes, bone marrow transplantation, malignancy, and other immunocompromised states. Candida retinochoroiditis most often presents with focal white lesions in the superficial retina along with vitritis and characteristic vitreous cotton ball opacities. Multiple hemorrhages surrounding the

M. A. Sadiq (*) Kentucky Lions Eye Center, Department of Ophthalmology, University of Louisville, Louisville, KY, USA e-mail: [email protected]; [email protected] A. Agarwal (*) · V. Gupta (*) · M. R. Dogra (*) · A. Gupta (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]

chorioretinitis may also be seen. It is important to differentiate Candida retinochoroiditis from other causes of retinitis that present with a similar picture, as the treatment options may be vastly different depending on the diagnosis.

Case 1: Posterior Segment Features of Candida Endophthalmitis A 57-year-old woman diagnosed with type 2 diabetes presented with sudden-onset progressive decreased vision in both eyes for 2 days. The best-corrected visual acuity (BCVA) was 20/100 in the right eye and 20/120 in the left eye. Fundus photographs revealed multiple, raised, white chorioretinal lesions in both eyes. There was significant vitreous inflammation, and posterior hypopyon was also noted in the left eye (Fig. 1). The patient underwent vitreous tap and the sample was sent for microbiological analysis. The potassium hydroxide mount was positive for Candida sp. The patient was started on antifungal treatment with intravenous amphotericin B and intravitreal voriconazole in both eyes.

Q. D. Nguyen (*) Spencer Center for Vision Research, Byers Eye Institute at Stanford University, Palo Alto, CA, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_35

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Fig. 1 Fundus photographs (at presentation) showing multiple raised white chorioretinal lesions in both eyes (white arrows). A posterior hypopyon is also seen in the left eye inferiorly (black arrow)

Fig. 2 Fundus photographs 2 weeks post treatment showing a reduction in the size of the chorioretinal lesions

The retinochoroidal lesions decreased in size following therapy. Two weeks after the initial visit (Fig. 2), fundus photography was performed which demonstrates an interval reduction in the vitreous haze and the size of the chorioretinal lesions. Six weeks after initiation of therapy, complete resolution of the lesions was seen in both eyes (Fig. 3). The patient was started on strict glycemic control. Two months following therapy, the BCVA improved to 20/50 in both eyes.

Case 2: Candida Endogenous Endophthalmitis in a Renal Transplant Recipient A 28-year-old immunocompromised woman presented with unilateral decreased vision in the right eye. The patient had previously received a renal transplantation and was on treatment with oral mycophenolate mofetil. BCVA in the right eye

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Fig. 3 Fundus photographs from both eyes 6 weeks post treatment showing complete resolution of the lesions

Fig. 4 Fundus photographs from a 28-year-old immunocompromised woman with unilateral decreased vision: (a) – at presentation, showing multiple white chorioretinal lesions and vitritis; (b) – 4 weeks post treatment, showing a reduction in the size of the chorioretinal lesions

and resolution of the vitritis; and (c) – 6 weeks post treatment, showing complete resolution of the chorioretinal lesion and residual scar in the central macula

was 20/200. On examination, anterior segment inflammation was noted with 1+ cells and 1+ flare. Fundus photographs revealed large whitish chorioretinal lesions in the central and inferior macula along with vitritis (Fig. 4a). A diagnosis of

Candida endophthalmitis was made following a positive vitreous biopsy. The patient was given intravenous as well as intravitreal amphotericin (along with intravitreal dexamethasone). The dose of systemic mycophenolate mofetil

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was decreased. Fundus photographs after 4 weeks showed substantial reduction in the size of the chorioretinal lesions and decrease in the severity of vitritis (Fig. 4b). Complete resolution of the macular lesion with formation of a residual scar was seen 6 weeks after initiation of treatment (Fig. 4c).

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patient was started on intravitreal amphotericin B. Subsequent visits demonstrated decrease in the vitreous inflammation. The foci of retinitis also decreased in size.

Case 4: Candida Endophthalmitis in an HIV-Positive Patient Case 3: Postoperative Candida Endophthalmitis A 47-year-old woman presented with decreased vision, pain, and redness in the left eye 72 h post-cataract surgery. BCVA was 20/200 in the left eye at presentation. On further evaluation using slit-lamp biomicroscopy, the main corneal incision appeared to gape and Seidel’s test was positive for aqueous leakage. Significant anterior segment inflammation was noted with anterior chamber cells (3+) and flare (3+). Fundus photographs of the left eye revealed significant vitritis and the presence of whitish chorioretinal lesions in the central macula (Fig. 5a). Vitreous tap was performed and intravitreal vancomycin and ceftazidime were injected. Vitreous tap was positive for Candida sp. and, therefore, the

A 47-year-old HIV-positive woman presented with decreased vision in the left eye. BCVA was hand motion at face. On examination, there were significant anterior chamber cells and flare (3+). Examination of the posterior segment revealed large confluent chorioretinal lesions with dense vitritis, vitreous exudates, and membranes. Both macular and peripheral involvements were seen (Fig. 6). The patient was admitted for further evaluation and management of her systemic comorbidities. Vitreous tap was positive for Candida sp., and the patient was started on intravitreal and intravenous amphotericin B. Highly active antiretroviral therapy was also initiated. Unfortunately, the patient passed away within the next few weeks due to multiple organ failure.

Fig. 5 Fundus photographs from a 47-year-old woman with unilateral decreased vision; (a) – at presentation, showing severe vitritis and the presence of active chorioretinal lesions in the central macula; (b) –

2 weeks post treatment showing reduction in the vitritis; and (c) – 4 weeks post treatment, demonstrating clearing of the vitreous but the presence of dense vitreoretinal membranes

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Key Points • Candida retinochoroiditis may present in patients with immunocompromised status, hyperalimentation, or those with history of intravenous drug abuse. • Typical presenting features include focal, superficial, white chorioretinal lesions along with white “cotton balls” in the vitreous, which is often accompanied by vitritis. • Early diagnosis and treatment are necessary to salvage the vision and improve visual outcomes.

Suggested Reading

Fig. 6 Fundus photograph demonstrates dense vitreous inflammation and the presence of vitreous exudates and membranes in a patient who developed Candida endophthalmitis amid setting of systemic HIV infection

Chakrabarti A, Shivaprakash MR, Singh R, Tarai B, George VK, Fomda BA, Gupta A. Fungal endophthalmitis: fourteen years’ experience from a center in India. Retina. 2008;28(10):1400–7. Sallam A, Lynn W, McCluskey P, Lightman S. Endogenous Candida endophthalmitis. Expert Rev Anti Infect Ther. 2006;4(4):675–85. Shah CP, McKey J, Spirn MJ, Maguire J. Ocular candidiasis: a review. Br J Ophthalmol. 2008;92(4):466–8. Vinekar A, Dogra MR, Avadhani K, Gupta V, Gupta A, Chakrabarti A. Management of recurrent postoperative fungal endophthalmitis. Indian J Ophthalmol. 2014;62(2):136–40.

Blastomycosis Cherie A. Fathy, Gowtham Jonna, and Anita Agarwal

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 Case Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

Introduction Blastomycosis is a systemic pyogranulomatous infection caused by the thermally dimorphic fungus Blastomyces dermatitidis. It is endemic to the Southeastern and South Central United States between the Mississippi and Ohio Rivers, the Midwestern United States, and Canadian provinces bordering the Great Lakes and the St. Lawrence River. Most cases of blastomycosis are reported in Mississippi, Arkansas, Kentucky, Tennessee, and Wisconsin. Outside of the United States, blastomycosis has been reported in Africa, the Middle East, India, and Poland. Persons with exposure to wooded sites, such as farmers, forestry workers, hunters, and campers, are at increased risk of blastomycosis. Immunocompromised individuals, such as those on

C. A. Fathy (*) Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Vanderbilt Eye Institute, Nashville, TN, USA e-mail: [email protected] G. Jonna (*) Vanderbilt Eye Institute, Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA Retina Consultants of Austin, Austin, TX, USA e-mail: [email protected] A. Agarwal (*) Vanderbilt Eye Institute, Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA

chronic corticosteroid therapy, organ transplant recipients, and patients with human immunodeficiency virus (HIV), are also at increased risk. The annual incidence in endemic areas is estimated to be less than 1 case per 100,000 people and up to 40 cases per 100,000 people in hyperendemic regions. Initial infection most commonly originates from the inhalation of conidia (spores), resulting in pulmonary disease after a 3–6week incubation period. Pulmonary lesions can resolve, leaving no signs of past infection. Blastomycosis can range from being completely asymptomatic to presenting as acute or chronic pneumonia or disseminated disease. Extrapulmonary or disseminated disease occurs in up to 40% of patients, and most commonly involves the skin, bones, and/or male urogenital tract. Skin lesions may be the first sign of infection. Disseminated disease occurs more often in immunocompromised individuals. Central nervous system involvement is rare, occurring in 3–10% of cases, but has been noted in up to 40% of patients with acquired immunodeficiency syndrome (AIDS). Ophthalmic involvement is uncommon, occurring either by direct extension or hematogenous dissemination, and has been frequently misdiagnosed in the past (Figs. 1 and 2). With its predilection for facial skin, periorbital and eyelid involvement are more common than intraocular infection. Lesions present in either verrucous or ulcerative forms. In the verrucous form, it begins as a papule or nodule that subsequently enlarges and develops irregular, encrusted borders with possible microabscess formation around the lesion. The ulcerative form is slightly raised, tends to bleed, and is potentially painful.

West Coast Retina Medical Group, San Francisco, CA, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_42

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Fig. 1 Fundus photographs of the right (a) and left (b) eye of a patient with choroidal blastomycosis demonstrating multiple choroidal lesions in the posterior pole and midperiphery. The left eye has a subfoveal chorioretinitis lesion (b). (permission obtained from: Successful

treatment of choroidal blastomycosis with oral administration of voriconazole. Almony A, Kraus CL, Apte RS. Can J Ophthalmol. 2009 Jun;44(3):334–5.)

Fig. 2 Fundus photographs of the patient with right (a) and left (b) eyes demonstrating involution of choroidal lesions after treatment. (permission obtained from: Successful treatment of choroidal blastomycosis

with oral administration of voriconazole. Almony A, Kraus CL, Apte RS. Can J Ophthalmol. 2009 Jun;44(3):334–5.)

Ophthalmic blastomycosis requires prompt diagnosis, as untreated infections can result in rapid and complete vision loss. However, given its rarity, intraocular infection is commonly misdiagnosed as other infectious, inflammatory, or neoplastic etiologies. A definitive diagnosis requires sputum culture, bronchial washing, tissue or exudate biopsy, or aqueous and vitreous aspirates, which may not always be available. Microscopic examination can identify the fungus with the aid of potassium hydroxide preparation and calcofluor white, methenamine silver, hematoxylin-eosin, and periodic acid-Schiff

(PAS) stains. Fine-needle aspiration cytologic analysis may also identify the pathogen. B. dermatitidis grows well on Sabouraud agar, producing white to tan colonies. Given its protean manifestations, blastomycosis should be considered in any patient with a history of active or previous pulmonary lesions presenting with choroidal lesions and/or uveitis. Moreover, any questionable lung or skin lesions should be biopsied to aid in the diagnosis. Since the first report of eyelid blastomycosis by Gilchrist and Stokes in 1896, there have only been about 40 publications describing ophthalmic disease, the majority of which involve

Blastomycosis

the eyelids and periorbita. Though conjunctivitis, keratitis, and iris and choroidal masses have been reported, the most common ocular manifestations are that of uveitis – specifically iridocyclitis, choroiditis, endophthalmitis, and panophthalmitis. Histopathologic examination of enucleated eyes with blastomycosis has revealed acute and chronic, suppurative granulomatous changes with multinucleated foreign-body giant cells containing characteristic broad-based B. dermatitidis yeast forms with a thick refractile wall and finely granular cytoplasm. Pathology may also demonstrate subretinal pigment epithelium granulomas with organisms and abscesses. The role of commercial tests for the diagnosis, including testing for antigens in the urine, blood, and other fluids, has yet to be established. Furthermore, serological testing also lacks sensitivity and specificity at this time. Patients with evidence of extrapulmonary disease or those who are immunocompromised will require antifungal therapy. Infectious Diseases Society of America Clinical Practice Guidelines recommend that any patient with central nervous system (CNS) involvement receives a lipid formulation of amphotericin B (AmB) at 5 mg/kg per day over 4–6 weeks followed by oral azole therapy. Lifelong suppressive therapy of oral itraconazole 200 mg per day should be considered in immunocompromised patients. Though there is no clear consensus on treatment for ocular blastomycosis, efficacy has been demonstrated with intravenous amphotericin B and oral azole therapy. The following review of case reports highlights the variable presentations of ocular blastomycosis and treatment options. Ultimately, the focus should be on early, correct diagnosis and prompt therapy given the fulminant course of the disease. With early recognition and treatment, patients can experience full resolution of intraocular lesions with improvement in vision.

Case Reports Ocular involvement in blastomycosis was first reported by Churchill and Stober in 1914. Since then, blastomycosis has been found to involve the eyelid, orbit, cornea, uvea, retina, vitreous, and meningeal sheaths of the optic nerve. Pariseau et al. documented eight cases of intraocular blastomycosis. Case reports describe common initial systemic symptoms including productive cough, low-grade fever, and weight loss. Ophthalmic symptoms may include pain, photophobia, decreased visual acuity, central scotomata, and metamorphopsia. Pupillary exam may reveal a relative afferent pupillary defect or a sluggish response. Elevated intraocular pressure may also be present. Slit-lamp examination may reveal injection, anterior chamber reaction, iris mass or abscess, corneal opacification, and clouding of the lens. Funduscopic examination may reveal vitreous haze and yellow or yellow-white, elevated choroidal lesions measuring from 0.125 to 8 disc diameters in case reports. There may also

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be subretinal fluid and retinal striae as well as edema of the overlying neurosensory retina and congestion of the involved vasculature. It is possible for choroidal involvement to be the only ocular manifestation. There is currently no definitive serologic, skin, or other laboratory test for the diagnosis of blastomycosis outside of culturing or demonstrating the organisms from the affected site, making the diagnosis difficult. Ocular blastomycosis has been incorrectly diagnosed as tuberculosis, histoplasmosis, cryptococcosis, coccidioidomycosis, bacterial infections, idiopathic orbital inflammation, sarcoidosis, posterior scleritis, or a primary or metastatic neoplasm. Diagnostic testing must be tailored to the individual. Echography may reveal homogenous choroidal lesions with medium internal reflectivity. Fluorescein angiography may demonstrate early hypofluorescence of choroidal lesions with hyperfluorescence in the venous phase and late staining. Pooling of fluorescein is noted in the context of neurosensory retinal detachment. Computerized tomography and/or magnetic resonance imaging of the orbits with and without contrast is useful to assess for abscess formation or optic nerve involvement. Ancillary testing also includes complete blood count, cerebrospinal fluid culture, and imaging to evaluate for pulmonary lesions, including chest X-ray or computed tomography scan. Treatment has evolved since intraocular blastomycosis was first identified. Traditionally, patients were treated with intravenous amphotericin B, which remains the first-line choice in patients with CNS involvement. However, the standard of care for the treatment of systemic fungal infections is currently changing to the use of oral azoles such as voriconazole, which has a 96% bioavailability when taken orally. Voriconazole is better tolerated than amphotericin B, especially for patients with compromised renal function or systemic comorbidities. The most common side effect reported with voriconazole is transient visual disturbances. Hariprasad et al. demonstrated that the oral administration also achieves a mean vitreous and aqueous minimum inhibitory concentration for 90% of isolates against many yeast forms, including blastomycosis. Other case reports have also demonstrated efficacy with the use of 200–400 mg/day of itraconazole for 6 months. Subconjunctival and topical miconazole have also been used, but their efficacy is unknown at this time. Miconazole is tolerated by subconjunctival injection at a daily dose of 5 mg and topically as a 1% solution administered every hour. Topical amphotericin B as 0.15% solution may also be utilized for corneal involvement, but the optimal dosing frequency is not known. Topical corticosteroids and ocular hypotensives may be used to control inflammation and ocular hypertension, respectively. Pars plana vitrectomy and intravitreal antifungal therapy (e.g., amphotericin B 5–10 micrograms/ 0.1 mL) must be considered if significant vitreous inflammation is present. The use of systemic corticosteroids and antibacterial agents without antifungal coverage may actually worsen outcomes, as the fungi are allowed to grow uninhibited.

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The mortality rate of untreated systemic blastomycosis can be as high as 60%. However, with appropriate treatment, that rate is reduced to 10%. Patients who receive a correct diagnosis early are more likely to experience improved visual acuity after treatment with involution of choroidal masses and resolution of subretinal fluid and retinal striae, though choroidal lesions may leave scars. Persistent, chronic macular edema may limit visual potential. Incorrect treatment or diagnosis often leads to worsening of symptoms with patients experiencing total vision loss and developing proptosis, secondary glaucoma, postinflammatory cataract, cicatricial ectropion, and dense, vascularized leukoma. A case report by Li et al. documented the natural progression of untreated blastomycosis of the eye. One month after initial presentation, the globe became deformed by a necrotic mass, prompting enucleation. Histopathologic examination revealed synechial angle-closure, iris abscess, diffuse rubeosis iridis, extensive uveal and retinal thickening with intense granulomatous inflammation, and necrosis extending to the optic nerve head. The retina was totally detached, diffusely thickened, and disorganized. Incorrect or unsuccessful treatment may eventually result in enucleation or the disease progress resulting in a patient’s demise. The prognosis of uveitis secondary to blastomycosis is guarded and dependent on location, extent, and severity of inflammation. With isolated iridocyclitis, one would expect less destructive sequelae and better preservation of vision. With more posterior involvement, especially with neuroretinitis, dense vitritis, and/or fovea-involving macular edema/neurosensory retinal detachment, worse visual outcomes are expected depending on time to initiation of therapy. Though rare, the most feared and potentially devastating presentation is panophthalmitis, which may be difficult to control, especially if the correct diagnosis is not formulated initially. Death may ensue in disseminated disease. Key Points • Blastomycosis is a rare infection with an annual incidence of less than 1 case per 100,000 people. Immunocompromised individuals and those with exposure to wooded areas are at increased risk. • The most common ocular manifestations are that of uveitis – specifically iridocyclitis, choroiditis, endophthalmitis, and panophthalmitis. • Blastomycosis should be considered in any patient with a history of active or previous pulmonary lesions now presenting with choroidal lesion(s) and/or uveitis. • A high index of suspicion and a low threshold to initiate local and systemic antifungal therapy is critical to protect vision.

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• Untreated or incorrectly treated intraocular blastomycosis infection can result in proptosis, secondary glaucoma, corneal opacification, post-inflammatory cataract, retinal detachment, and total vision loss, frequently requiring enucleation.

Suggested Reading Almony A, Kraus CL, Apte RS. Successful treatment of choroidal blastomycosis with oral administration of voriconazole. Can J Ophthalmol. 2009;44(3):334–5. Altman JS, Tonelli DG, Bukhalo M. Red, scaly lesion on the upper eyelid. Am Fam Physician. 2007;76(10):1533–4. Arevalo JF. Retinal and choroidal manifestations of selected systemic diseases. New York: Springer; 2013. p. 185–6. Bond WI, Sanders CV, Joffe L, Franklin RM. Presumed blastomycosis endophthalmitis. Ann Ophthalmol. 1982;14(12):1183–8. Cassady JV. Uveal blastomycosis. Arch Ophthal. 1946;35:84–97. Chapman SW, Bradsher RW, Campbell GD, Pappas PG, Kauffman CA. Practice guidelines for the management of patients with blastomycosis Infectious Diseases Society of America. Clin Infect Dis. 2000;30(4):679–83. Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008;46 (12):1801–12. Churchill FSA. A case of systemic blastomycosis. Arch Intern Med. 1914;13:568. Font RL, Spaulding AG, Green WR. Endogenous mycotic panophthalmitis caused by blastomyces dermatitidis. Report of a case and a review of the literature. Arch Ophthalmol. 1967;77 (2):217–22. Garg A. Ocular therapeutics. New Delhi: Jaypee Brothers Medical Pub; 2013. p. 229–30. Gilchrist TC, Stokes WR. The presence of an Oidium in the tissues of a case of pseudo-lupus vulgaris. Bull Johns Hopkins Hosp. 1896;7:129. Gonyea EF. The spectrum of primary blastomycotic meningitis: a review of central nervous system blastomycosis. Ann Neurol. 1978;3(1):26–39. Gottlieb JL, McAllister IL, Guttman FA, Vine AK. Choroidal blastomycosis. A report of two cases. Retina. 1995;15(3):248–52. Hariprasad SM, Mieler WF, Holz ER, et al. Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans. Arch Ophthalmol. 2004;122(1):42–7. Klein BS, Vergeront JM, Davis JP. Epidemiologic aspects of blastomycosis, the enigmatic systemic mycosis. Semin Respir Infect. 1986;1 (1):29–39. Lewis H, Aaberg TM, Fary DR, Stevens TS. Latent disseminated blastomycosis with choroidal involvement. Arch Ophthalmol. 1988;106(4):527–30. Li S, Perlman JI, Edward DP, Weiss R. Unilateral Blastomyces dermatitidis endophthalmitis and orbital cellulitis. A case report and literature review. Ophthalmology. 1998;105(8):1466–70. Lopez R, Mason JO, Parker JS, Pappas PG. Intraocular blastomycosis: case report and review. Clin Infect Dis. 1994;18(5):805–7. McKee SH. Blastomycosis of the eye. Can Med Assoc J. 1930;22 (4):501–3. Pariseau B, Lucarelli MJ, Appen RE. Unilateral Blastomyces dermatitidis optic neuropathy case report and systematic literature review. Ophthalmology. 2007;114(11):2090–4.

Blastomycosis Patel AJ, Gattuso P, Reddy VB. Diagnosis of blastomycosis in surgical pathology and cytopathology: correlation with microbiologic culture. Am J Surg Pathol. 2010;34(2):256–61. Phelps PO, Seagrave Z, Williams KM. Blastomycosis in the eyelid of a native Chicagoan. Ophthalmology. 2015;122(5):1015. Rodriguez RC, Cornock E, White VA, Dolman PJ. Eyelid blastomycosis in British Columbia. Can J Ophthalmol (J Can d’Ophtalmol). 2012;47(3):e1–2. Roy FH, Fraunfelder FT. Roy and Fraunfelder’s current ocular therapy. Philadelphia: PA Saunders Elsevier; 2008. p. 14–5.

261 Safneck JR, Hogg GR, Napier LB. Endophthalmitis due to Blastomyces dermatitidis. Case report and review of the literature. Ophthalmology. 1990;97(2):212–6. Sinskey RM, Anderson WB. Miliary blastomycosis with metastatic spread to posterior uvea of both eyes. AMA Archi Ophthalmol. 1955;54(4):602–4. Vida L, Moel SA. Systemic North American blastomycosis with orbital involvement. Am J Ophthalmol. 1974;77(2):240–2.

Coccidioidomycosis Gowtham Jonna and Anita Agarwal

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268

Introduction Coccidioidomycosis or the San Joaquin Valley fever or valley fever is a granulomatous disease caused by the soil-dwelling dimorphic fungus Coccidioides immitis or Coccidioides posadasii. Coccidioides exists as a filamentous mold with septate hyphae in soil and in culture and as a nonbudding spherule in host tissue. Ocular involvement occurs secondary to dissemination and is considered rare. Though the eyelids and conjunctiva are the most common sites of involvement, the uvea is the most common site of intraocular disease. Coccidioidal uveitis should be considered in any patient with apparent idiopathic iridocyclitis or choroiditis (Fig. 1) who has lived or traveled through endemic areas, including Arizona, New Mexico, west Texas, parts of Central America, Argentina, northwest Mexico, and the San Joaquin Valley in California.

G. Jonna Vanderbilt Eye Institute, Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA Retina Consultants of Austin, Austin, TX, USA e-mail: [email protected] A. Agarwal (*) Vanderbilt Eye Institute, Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA

The true incidence of ocular coccidioidomycosis is unknown. Coccidioidomycosis is prevalent in the Southwestern United States, parts of Northern Mexico, and Central and South America. In the United States, most cases of coccidioidomycosis occur in the San Joaquin Valley of California and in Arizona. In 2007, the incidence rate has more than tripled in California compared to 2001, increasing from 2.4 to 8.0 per 100,000 and Arizona accounts for 60% of all cases reported in the United States. Individuals of Filipino, Native American, Mexican and African ancestry, women in their third trimester of pregnancy, and immunocompromised individuals are at increased risk for progressive pulmonary disease, disseminated disease (Figs. 2, 3, and 4), and meningitis. Immunocompromised individuals include neonates, elderly, those infected with human immunodeficiency virus (HIV), and patients receiving immunosuppressive therapy for inflammatory diseases or postorgan transplantation. Coccidioides forms 5-micron-sized, segmented, barrelshaped cells called arthroconidia. Infection typically occurs after inhalation of airborne arthroconidia dislodged from the soil, such as following dust storms. The arthroconidia enlarge to form unique, thick-walled, spherical structures with internal septations called spherules inside the lungs of the host. The spherules enlarge and eventually rupture, releasing endospores that spread locally and disseminate. These endospores grow to form new spherules and perpetuate the cycle. In semiarid climates, winters with heavy rain followed by hot, dry, dusty periods favor rapid multiplication of arthroconidia. In line with its mode of transmission, cases of coccidioidomycosis predominate during summer and fall in the Southwestern United States, corresponding to the dusty period of

West Coast Retina Medical Group, San Francisco, CA, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_38

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Fig. 1 A 42-year-old Californian woman with prior history of coccidioidomycosis pneumonia and meningitis presents with focal chorioretinal lesions in the right eye. (Courtesy: Dr. Hua Gao. Also in Gass Atlas of Macular Diseases, 2011, Ed. Anita Agarwal. Permission obtained from Elsevier)

Fig. 2 Fluorescein angiogram showed late staining of the lesions. Her symptoms improved after 6 weeks of antifungal treatment. (Courtesy: Dr. Hua Gao. Also in Gass Atlas of Macular Diseases, 2011, Ed. Anita Agarwal. Permission obtained from Elsevier)

the year. No documented cases of animal-to-human or human-to-human transmission have occurred. Systemic Coccidioidomycosis has five different clinical presentations: acute pneumonia, chronic progressive pneumonia, pulmonary nodules and cavities, disseminated disease, and meningitis. Sixty percentage of infected individuals are completely asymptomatic and the remaining 40% have symptoms secondary to pulmonary infection. The most common presentation is an influenza-like acute pulmonary illness characterized by fever, malaise, night sweats,

G. Jonna and A. Agarwal

Fig. 3 A month after a trip to Arizona, a 48-year-old man developed flu like illness that resolved over 2 weeks. Three months later, he developed back pain caused by a ring-enhancing abscess on MRI. (Courtesy: Dr. Mathew MacCumber & Dr. Sachin Mudvari. Also in Gass Atlas of Macular Diseases, 2011, Ed. Anita Agarwal. Permission obtained from Elsevier)

Fig. 4 Biopsy of the abscess revealed thick-walled spores within granulomas consistent with coccidioidomycosis. (Courtesy: Dr. Mathew MacCumber & Dr. Sachin Mudvari. Also in Gass Atlas of Macular Diseases, 2011, Ed. Anita Agarwal. Permission obtained from Elsevier)

nonproductive cough, and pleuritic chest pain occurring 1–3 weeks after inhalation of arthroconidia. Coccidioidomycosis may simulate community-acquired bacterial pneumonia and thus a high index of suspicion is necessary for the presentation of lobar infiltrates and hilar adenopathy in endemic areas. Erythema nodosum typically affecting the lower extremities or erythema multiforme typically in a

Coccidioidomycosis

necklace distribution may occur anywhere from 3 days to 3 weeks after symptom onset. Disseminated disease occurs in less than 1% of infected individuals and may follow symptomatic or asymptomatic infection. The most common sites of dissemination are skin, bone (Fig. 2), soft tissues, and meninges. The first cases of coccidioidomycosis affecting the external eye and orbit were reported in agricultural workers of Central California in 1896. It was a fatal, diffuse, progressive skin disease primarily involving the head and neck. In 1937, an acute respiratory illness named valley fever was found to be caused by the same organism that caused the skin disease. In 1948, Levitt reported a case of intraocular coccidioidomycosis in a patient with pulmonary coccidioidomycosis. It was not until 1967 that Hagele et al. confirmed a case of intraocular coccidioidomycosis by histopathology and culture prior to enucleation. Coccidioidomycosis may present with: (1) intraocular disease including anterior uveitis, posterior uveitis, or endophthalmitis and (2) external eye disease including blepharitis, granulomatous conjunctivitis, phlyctenular conjunctivitis, keratoconjunctivitis, episcleritis, and scleritis; orbital cellulitis, extraocular nerve palsies, and optic atrophy have also been reported. Uveitis secondary to coccidioidomycosis tends to involve the anterior or posterior uveal tract but rarely both concomitantly. However, retinal seeding from anterior segment disease is possible after vitrectomy surgery. The anterior hyaloid likely serves as a barrier to posterior segment spread from anterior disease. A common presentation of this rare entity is granulomatous iridocyclitis with “mutton-fat” keratic precipitates and anterior chamber reaction. Iris or anterior chamber nodules may coexist with anterior uveitis. Posterior segment involvement can be segregated into four broad categories. First, a diffuse choroiditis that generally spares the retina appears to be associated with widely disseminated, preterminal coccidioidomycosis and has a poor systemic prognosis. Secondly, a common mode of posterior involvement is juxtapapillary chorioretinitis, which presents with large, elevated choroidal infiltrates (100–400 microns; up to three disc diameters in size). Adjacent areas of retinal involvement may demonstrate edema, hemorrhage, and exudate. The third presentation type is whitish-yellow, medium-sized (approximately 0.25–1 disc diameter or 100–400 microns) opacities at the level of Bruch’s membrane and sensory retina (Fig. 1); they appear scattered but with a predilection for the posterior pole and macula. These lesions can be slightly elevated and edematous and resolve more slowly than that in the choroid alone. Lastly and likely most commonly, small, 100–200-micron-sized peripheral chorioretinal scars may be observed, usually detected during an inactive state of the disease. They appear with central hypopigmentation and variable elevation and pigmentation. They represent resolution of lesions as they

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shrink and take on a more “punched-out” appearance. There is no correlation between the scarring and the extent of systemic disease. Although the eye is one of the least common sites of dissemination, up to 10% of patients with coccidioidal pneumonia have visually asymptomatic chorioretinal scars, which may suggest that ocular involvement is more common than clinically recognized. Vitreous cell and perivascular sheathing may also be present with posterior segment disease. Although ocular coccidioidomycosis typically occurs in disseminated disease, there are multiple reports of intraocular coccidioidomycosis in otherwise healthy, apparently immunocompetent individuals. Differential diagnoses to consider include histoplasmosis, candidiasis, sarcoidosis, tuberculosis, herpes simplex virus, blastomycosis, cryptococcosis, syphilis, aspergillosis, and actinomycosis, among others. The peripheral chorioretinal scars are similar in size, shape, and configuration to the lesions found in presumed ocular histoplasmosis (POHS). However, the lesions in coccidioidomycosis are deeper with more pigmentation, choroidal vessels are not visible, and there may be gliosis at the base of the lesions. Importantly, vitritis and perivascular sheathing rarely occur in coccidioidomycosis but have not been observed in POHS. Coccidioidal infection usually spares the adjacent vitreous, representing a clear distinction from Candida infection. Patients living in endemic areas who demonstrate characteristic chorioretinal lesions even in the absence of active intraocular inflammation or present with apparent idiopathic granulomatous iridocyclitis, choroiditis, or endophthalmitis should be suspected of having the disease. Given the protean manifestations of coccidioidomycosis, the clinical diagnosis may be difficult. Ancillary ophthalmologic testing is unlikely to help in identification of the diagnosis. If performed, fluorescein angiography (Fig. 5) may demonstrate late staining of active choroidal lesions. B-scan ultrasonography may demonstrate vitreous opacities in endophthalmitis. Chest roentgenogram is useful to identify pulmonary disease including pneumonitis and/or hilar adenopathy. Biopsy of skin lesions may identify the causative organism. Confirmation of the diagnosis is generally based on serologic, histopathologic, and culture evidence of Coccidioides. In tissue specimens, a mature spherule with endospores is pathognomonic of infection. The spherules stain with hematoxylin and eosin (H&E) and periodic acid-Schiff, but their morphology is best demonstrated with Grocott’s methenamine silver (GMS) stain. Coccidioides grows within 3–4 days at most temperatures on any artificial medium. The clinical laboratory must be informed of the possible diagnosis because culturing the organism poses risk to laboratory staff if the mycelial form is inadvertently inhaled. Aqueous and vitreous biopsies can be examined directly for the organism by means of the

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Fig. 5 Methanamine silver stain shows black coccidioidomycosis spherules. (Courtesy: Dr. Mathew MacCumber & Dr. Sachin Mudvari. Also in Gass Atlas of Macular Diseases, 2011, Ed. Anita Agarwal. Permission obtained from Elsevier)

Papanicolaou stain. Biopsy of iris nodules can also help to establish the diagnosis. If necessary, a chorioretinal biopsy may be considered though it is an invasive procedure. There are a variety of serologic and skin tests that confirm exposure to Coccidioides-related antigen but not specifically intraocular disease. In an immunocompetent patient, serial testing with complement fixation provides a useful measure of response to treatment and prognosis. A complement fixation titer of 1:16 or greater is typically associated with disseminated disease although more severe and life-threatening disease may be associated with a low complement fixation titer even in the immunocompetent patient. Negative serologic tests do not rule out coccidioidal disease. Approximately 5% of patients with AIDS and coccidioidomycosis are seronegative as well as some other immunocompromised patients. A real-time polymerize chain reaction (PCR) assay to detect Coccidioides directly from clinical specimens may provide a rapid, safe means of diagnosis even in infected patients with negative serology while decreasing risk of exposure to laboratory staff. Coccidioidomycosis is treated with Amphotericin B or azoles such as fluconazole, itraconazole, and voriconazole. Amphotericin B is used when patients are rapidly deteriorating and are hospitalized because of coccidioidal infection. It is administered intravenously at a dose of 1 mg/kg body weight per day. A total dose of 500–1500 mg can be given. Intravitreal amphotericin B 5 μg/0.1 mL may be administered for suspected fungal endophthalmitis. Systemic amphotericin B has poor ocular and central nervous system penetration and is associated with high risk, dose-limiting adverse effects including bone marrow suppression and nephrotoxicity. Intravitreal Amphotericin B carries a significant risk of retinal toxicity.

G. Jonna and A. Agarwal

An azole can be used for less severe illness and prolonged maintenance therapy. A large, randomized trial demonstrated similar efficacies of fluconazole and itraconazole in the treatment of progressive, non-meningeal coccidioidomycosis. Fluconazole is effective in treating progressive pulmonary and disseminated coccidioidomycosis. Oral administration results in high concentrations in the aqueous, vitreous, choroid, and retina. Intraocular disease has been successfully treated using oral fluconazole primarily. The usual oral dose of fluconazole is 400 mg/day but up to 1200 mg/day can be used. The role of itraconazole is not clear, but it has been successfully used to treat uveitis in a patient with iris biopsyconfirmed coccidioidomycosis. The usual oral dose of itraconazole is 400–600 mg/day. Though specifically not approved by the United States Food and Drug Administration (FDA) for the treatment of coccidioidomycosis, voriconazole has demonstrated in vitro efficacy against Coccidioides immitis with lower 90% minimum inhibitory concentrations than fluconazole. Resistant strains and treatment failures have been reported with fluconazole. Voriconazole has been used to successfully treat intraocular coccidioidomycosis that progressed despite standard therapy. In one of these cases, the patient developed bilateral, multifocal choroidal lesions while on treatment with high-dose (800 mg) fluconazole daily but responded well with switch to oral voriconazole. One case report demonstrated very good visual outcome with vitrectomy, systemic azole therapy, and multiple intravitreal injections of voriconazole and amphotericin B. The dose for voriconazole is typically 200 mg twice daily, although doses up to 400 mg twice daily have been used. Acute treatment of coccidioidomycosis should always be followed by long-term maintenance therapy, given the significant risk of reactivation and recurrent disease. Antifungal therapy is given until clinical manifestations resolve and serologic testing shows a decrease to a negative finding or a titer of 1:2. Patients with meningitis and those with AIDS (or other immune compromise) and progressive or disseminated coccidioidomycosis should continue lifelong maintenance therapy. Therapeutic vitrectomy may be performed in conjunction with biopsy depending on the severity of the vitreous involvement. Since ocular coccidioidomycosis often represents disseminated disease, obtaining a thorough systemic evaluation in conjunction with an infection diseases specialist is critical. This is especially important if neurologic impairment is suspected. Infectious diseases consultation is also helpful in discerning length of therapy and if and when systemic therapy may be discontinued. Intraocular coccidioidomycosis can be complicated by posterior synechiae, seclusio pupillae, cataracts, scleral thinning, staphyloma formation, and secondary glaucoma. Posterior segment involvement of the macula and optic nerve can cause severe vision loss. Epiretinal membranes,

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Fig. 6 Four months later, he developed chorioretinal lesions in his left eye one of which had secondary CNVM. (Courtesy: Dr. Mathew MacCumber & Dr. Sachin Mudvari. Also in Gass Atlas of Macular Diseases, 2011, Ed. Anita Agarwal. Permission obtained from Elsevier)

Fig. 7 Late staining of the CNVM in left macula that responded to intravitreal bevacizumab with vision improving to 20/50 from 20/80. (Courtesy: Dr. Mathew MacCumber & Dr. Sachin Mudvari. Also in Gass Atlas of Macular Diseases, 2011, Ed. Anita Agarwal. Permission obtained from Elsevier)

chorioretinal scarring, choroidal neovascularization (Figs. 6 and 7), and serous retinal detachment can develop as sequel. Despite systemic antifungal therapy, Coccidioidal meningitis carries a grave prognosis. Coccidioidomycosis in AIDS previously had a very high mortality rate but this has improved significantly with the institution of highly active antiretroviral therapy. Final visual acuity ranges from 20/20 to no light perception. This is variable depending on the location of ocular disease, severity, initial visual acuity, time to diagnosis, time to initiation of therapy, and patient adherence with medical therapy and follow-up. Even with aggressive therapy, the eye may become hypotonous and painful, requiring enucleation. The prognosis for patients with isolated anterior segment coccidioidomycosis is worse than that of posterior segment disease, with the majority requiring enucleation secondary to blindness and pain. Timely diagnosis with institution of appropriate systemic and local antifungal therapy can be life and vision-saving.

• The absence of systemic manifestations and serologic evidence does not rule out the diagnosis of coccidioidal infection. • Biopsies of intraocular lesions and evaluation of aqueous and vitreous specimens may provide rapid diagnosis and are currently the most efficient methods for facilitating appropriate treatment. Real-time PCR assay for detecting Coccidioides from clinical specimens may become of greater value in the future. • Suspicious skin lesions may be biopsied to aid in the diagnosis, especially in cases where acquiring ocular specimens pose greater risk or morbidity. • Amphotericin B should be reserved for more severe disease given its toxicity. Azoles such as fluconazole have a proven efficacy for treating coccidioidomycosis. Emerging evidence suggests that voriconazole may represent a comparable or better first-line agent than fluconazole, given resistance and treatment failures. • Intravitreal voriconazole and/or amphotericin B must be considered in the management of severe posterior segment inflammation. • Vitrectomy may be beneficial for diagnostic and therapeutic purposes, especially in cases with severe vitritis. • Prompt diagnosis and early, aggressive therapy is critical to ensure the best outcomes in cases of uveitis secondary to coccidioidomycosis. • Patients may require prolonged systemic therapy to prevent relapse and azoles are good agents to this end. • Ocular involvement tends to occur in the context of disseminated coccidioidomycosis; it is critical to collaborate

Key Points • The incidence of coccidioidomycosis is increasing in United States and the diagnosis must be considered in the setting of ocular inflammation in patients traveling or living in highly endemic areas. • It is likely under recognized and if not promptly and correctly diagnosed and treated, portends a very poor prognosis.

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closely with the infectious diseases team to ensure that appropriate therapy is administered and for the appropriate duration. • Secondary choroidal neovascularization in a scar from disseminated coccidioidomycosis requires anti-VEGF therapy.

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Cryptococcus Philippe Kestelyn

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 Ocular Manifestations of Cryptococcal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Diagnostic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Treatment Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Induction Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Consolidation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Maintenance Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Outcome of Cryptococcal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Prevention of Cryptococcal Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

Introduction Cryptococcosis is an infectious disease caused by pathogenic encapsulated yeasts of the genus Cryptococcus. Only two species of this genus of basidiomycetous fungi are known to cause human disease: Cryptococcus neoformans and Cryptococcus gattii. Cryptococcus neoformans has a worldwide distribution and is associated with excreta of certain birds (pigeons), with environmental scavengers such as amoeba and woodlice, and with a variety of tree species in their hollows. Cryptococcus neoformans is able to cause disease in immunocompetent and in immunocompromised patients. Cryptococcus gattii is associated with eucalyptus trees in tropical and subtropical climates and with firs and oaks in areas with temperate climates. Although C. gattii has historically been associated with disease in immunocompetent patients, immunodeficiency is also a risk factor for infection

P. Kestelyn (*) Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_41

with this species. Approximately 95% of cryptococcal infections worldwide are caused by C. neoformans, mainly in AIDS patients. However, in immunocompetent patients with cryptococcal infection, C. gattii is more likely to be isolated than C. neoformans. Cryptococcosis was considered a rare disease before the AIDS era. Risk factors then included malignancy, organ transplantation, and immunosuppressive treatments. The incidence of the disease rose dramatically in the mid-1980s with the spread of the AIDS pandemic. Especially persons with CD4+ cell counts 25 cm
H2O). Massive elevation of ICP is often seen in HIV-associated cryptococcal meningitis and results from the impairment of cerebrospinal fluid (CSF) resorption at the level of the arachnoid villae due to mechanical obstruction by cryptococcal polysaccharide capsule. Elevated ICP is thought to be an important risk factor for mortality and vision loss. Optic neuropathy due to inflammation or fungal invasion may lead to optic atrophy and blindness and is probably the more common mechanism in immunocompetent patients with disease caused by C. gattii. Other neuro-ophthalmic manifestations include 3rd nerve pals, nystagmus, internuclear and supranuclear ophthalmoplegia, and chiasmatic and suprachiasmatic visual Table 1 Ocular manifestations of cryptococcosis reported in the literature

Papilledema Diplopia Optic atrophy Intraocular invasion

Kestelyn et al. (1993) n = 80 (prospective) 26/80 (32.5%) 7/80 (9%) 2/80 (2.5%) 2/80 (2.5%)

Mao et al. (2015) n = 40 (retrospective) 19/40 (47.5%) 3/40 (7.5%) 6/40 (15%) 2/40 (5%)

field defects due to ischemic, inflammatory, or space occupying lesions (cryptococcoma) in the brain. Hematogenous dissemination to the eye is a less common occurrence and leads to multifocal choroiditis, chorioretinitis, cryptococcoma, vitritis, and eventually endophthalmitis. Intraocular invasion was exceedingly rare before the AIDS era. In his textbook on ocular mycosis published in 1968, François mentions only about 12 cases of intraocular infection in the world literature. With the advent of HIV, a plethora of reports on intraocular cryptococcosis from all parts of the world has been published. The fact that most authors describe only one or two cases despite the fact that cryptococcal disease is a common opportunistic infection is indicative of the low frequency of metastatic eye disease, not unlike what is observed in tuberculosis. Multifocal choroiditis presents as bilateral yellow nodules in the posterior pole and mid-periphery. This manifestation was already reported in the pre-AIDs era by Hiles and Font who described two cases of choroiditis in 12 patients with intraocular cryptococcosis and described the fundus appearance as “lesions not unlike choroidal tubercles”. In the AIDS era, multiple case report confirmed this finding. A recent report using multimodal imaging confirmed the location of the cryptococcal granulomata at the level of the inner choroid. The retina was normal and the pigment epithelial layer intact. Indocyanine green was superior over fluorescein angiography to detect more hypofluorescent spots than clinically evident. OCT showed a slight hyperreflectivity at the level of the photoreceptor layer probably related to a secondary inflammatory response to the underlying choroidal lesion. The most common intraocular form of cryptococcosis is a focal chorioretinitis that appears initially as a yellowish whitish chorioretinal lesion with minimal or no associated vitreous inflammation. Histopathologic examination reveals a granulomatous chorioretinitis. Cryptococcal endophthalmitis is much rarer and is probably secondary to direct extension in the vitreous from preexisting chorioretinitis. The transition from bilateral chorioretinitis to full blown endophthalmitis has been documented in a case report. Cryptococcal endophthalmitis is characterized by ciliary injection, anterior chamber cells and flare, mutton fat keratic precipitates, and posterior synechiae at the level of the anterior segment; fundus examination may show yellow-white chorioretinal lesions, vasculitis and sheathing, subretinal exudates or localized serous detachment, and severe vitreous inflammation with fluffy exudates; further in the evolution abscess formation, retinal detachment and finally phthisis of the eye may be observed. The rarity of the disease is underscored by the fact that Pettit and coworkers, using strict criteria to define cryptococcal endophthalmitis, narrowed the number of cases reported in the world literature before 1990 up to 15. Bilateral involvement was present in 6 patients, but 3 of them had endophthalmitis

Cryptococcus

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in one eye and chorioretinitis in the other, a further argument that one condition probably precedes the other. A few case reports mention the presence of a cryptococcoma in the eye. These lesions are bulky, subretinal granulomata that may mimic mass lesions such as choroidal melanoma on echography, but unlike melanomas they are accompanied by moderate to severe vitreous inflammation and in fact represent a variant of cryptococcal endophthalmitis. Lesions of the outer eye and the anterior segment due to cryptococcal disease are very rare. Only single case reports describe a palpebral nodule, a limbal mass, a bulbar conjunctival lesion, and a case of iritis. These lesions simply herald disseminated infection and show that virtually any vascularized tissue may be affected.

induction, consolidation, and maintenance is standard care. Longer courses of both induction and consolidation have been proposed in C. gattii infection owing to the severity of neurologic disease in these patients, irrespective of host immune status.

Diagnostic Considerations

Fluconazole (400 md/d) for 8 weeks.

When the ophthalmologist observes papilledema in a patient with headache, low grade fever, and HIV seropositivity in an area where C. neoformans is endemic, cryptococcal meningitis should be high on the list of the differential diagnosis. Neck stiffness is often absent in patients with profound immune suppression as their immune system is no longer able to mount a vigorous inflammatory response. A lumbar puncture should be ordered as the majority of eye infections occurs in the presence of central nervous system infection. The definite diagnosis of cryptococcal disease is made by direct detection or by culture and identification from body fluids. The most rapid method for diagnosis of cryptococcal meningitis is direct microscopic examination for encapsulated yeasts by India ink preparation of CSF. Cryptococcus can be cultured on routine fungal and bacterial media with a positive yield of 90% in HIV-positive adults with cryptococcal meningitis. The organism can be identified with special stains (mucicarmine, PAS, Alcian blue, calcofluor, Gomori methenamine silver) in tissue biopsies. Serology has improved significantly with the development of serologic tests for the presence of cryptococcal polysaccharide capsular antigen (CrAg). The recently introduced lateral flow assay has a sensitivity and specificity >98% in both serum and CSF. This test is simple, rapid, requires minimal infrastructure, is stable at room temperature, and performs also well in settings with low HIV seroprevalence and high rates of C. gattii infection. Therefore, it is an attractive option for point-of-care testing in both rich and poor settings.

Treatment Considerations With few exceptions, the treatment of cryptococcal eye disease will be the treatment of cryptococcal meningoencephalitis: irrespective of host risk factors, a 3-stage regimen of

Induction Therapy Amphotericin B deoxycholate (0.7–1 mg/kg/d) plus flucytosine (100 mg/kg/d) for 2 weeks.

Consolidation Therapy

Maintenance Therapy Fluconazole (200 mg/d) for >1 year. Although this regimen offers the best chances for cure, flucytosine is not always available or affordable in those areas with the highest burden of disease and mortality. Management of intracranial pressure. Elevated ICP is characterized by headaches, vomiting, papilledema, reduction of visual acuity, diplopia often as a result of 6th nerve palsy, confusion, altered mental state, and coma. Significant elevated ICP that is not addressed causes increased mortality in the first 2 weeks of the disease. Therefore, current guidelines stress the importance of monitoring elevated ICP control by daily lumbar punctures until pressures have decreased or symptoms have resolved.

ART Therapy in Patients with Cryptococcal Disease and Immune Reconstitution Inflammatory Syndrome (IRIS) A recent randomized trial demonstrated improved survival in patients with cryptococcal meningitis in whom ART was deferred up to 5 weeks after diagnosis as compared with immediate treatment. Delaying treatment probably reduces subclinical manifestations of cryptococcal IRIS with a positive influence on survival. IRIS develops in up to 30% of patients with cryptococcal meningitis, manifesting as clinical deterioration a few weeks or months after initiating ART. This syndrome is thought to be an aberrant inflammatory response to cryptococcal antigens during recovery of the host immune system. IRIS can be fatal and is associated with a higher mortality. The first report on ocular findings of IRIS in patients with cryptococcal meningitis identified the

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presence of papilledema with dense peripapillary hemorrhages in 4 cases. The authors emphasize the ophthalmologist’s key role in the early diagnosis of this condition to prevent visual complications. Another case report described recurrent chorioretinitis and vitritis after initial improvement 8 weeks after initiation of antifungal therapy and ART, highly suggestive of IRIS.

in-patients. In Papua New Guinea, the case fatality rate in a series of 88 immunocompetent patients with CM was 34% patients. The greatest difference in survival however is noted between resource-rich and resource-limited settings: over half of patients die within 10 weeks of diagnosis in low-income countries compared to as few as 10% of patients from industrialized countries.

Role of Adjuvant Glucocorticoids

Visual Prognosis

Adjunctive glucocorticoids have shown benefit in certain central nervous system infections, such as acute bacterial meningitis and tuberculous meningitis. Given the similarities between tuberculous and cryptococcal meningitis, a randomized trial comparing antifungal therapy with placebo versus antifungal therapy with dexamethasone was conducted in patients with HIV-associated cryptococcal meningitis. It was expected that dexamethasone would improve outcomes by reducing ICP and inflammatory complications and by decreasing the incidence of IRIS. Unfortunately, adjunctive dexamethasone did not reduce mortality and was associated with more adverse events and disability than placebo.

The etiology of visual loss in patients with CM is often multifactorial and different conditions such as pressure induced optic neuropathy, optic neuritis, arachnoiditis, ischemia alone, or in combination may give rise to optic atrophy and blindness. A clear bimodal pattern was described in AIDS patients: rapid and dramatic loss in the first days of admission versus slow gradual loss over several weeks. There seems to be a difference in the pattern and in the prevalence of visual loss between immunocompetent patients mostly infected with C. gattii and AIDS patients infected with C. neoformans. Table 2 summarizes the data for blindness from cryptococcal meningitis in different countries and different patient populations (immunocompetent vs. AIDS patients). The highest prevalence of blindness is noted in patients with normal immunity, and this is especially striking in the series of immunocompetent patients infected with C. neoformans var gattii from Papua New Guinea. According to the authors, the bimodal pattern was not observed in their patients, and they suggested that the high rate of visual loss in these immunocompetent patients may reflect immunemediated optic nerve dysfunction caused by either compression due to arachnoid adhesions or edema and inflammatory cell-mediated damage. The beneficial effect of repeated lumbar punctures in AIDS patients is indirect proof that increased ICP more than intrinsic optic nerve inflammation is the main culprit these patients.

Specific Therapeutic Considerations in Ophthalmic Manifestations of Cryptococcal Disease By and large the treatment applied to cryptococcal meningitis as outlined above will take care of most ophthalmic manifestations, including the neuro-ophthalmologic involvement as well as the choroiditis and the chorioretinitis. Specific ophthalmic treatment should be considered for cryptococcal endophthalmitis/cryptococcoma. In this cases pars plana vitrectomy with removal of the bulk of the infectious mass lesions and intraocular injection of amphotericin B should be considered.

Table 2 Summary of blindness resulting from cryptococcus infection

Outcome of Cryptococcal Disease Although survival has considerable improved with the advent of ART and better antifungal treatment regimens, the prognosis for patients with CM is still grim. In the adjunctive dexamethasone trial at 6 months, the estimated risk of death was 57% in the dexamethasone group and 49% in the placebo group. In the COAT trial (Cryptococcal Optimal Art Therapy), the 6-month mortality was 45% in the earlier ART group versus 30% I the deferred-ART group. The prognosis in HIV uninfected patients is somewhat better. In a series of 57 patients from Vietnam without HIV 11 (20%) died while

Chau et al. (2010) Seaton et al. (1997) Kestelyn et al. (1993) Mao et al. (2015) Loyse et al. (2015)

Number of patients 36 57

Number blind (%) 3 (8%) 9 (16%)

82

33 (40%)

80

Country USA Vietnam

HIV status Negative Negative

4 (5%)

Papua New Guinea Rwanda

Negative Positive

40

6 (15%)

China

Positive

87

8 (9%)

South Africa

Positive

Cryptococcus

Prevention of Cryptococcal Meningitis The best prevention of cryptococcal meningitis is of cause early diagnosis of HIV infection and prompt initiation of ART therapy, as cryptococcal meningitis only occurs in patients with advanced immunosuppression. This ideal scenario is far from reality as cryptococcal meningitis still claims up to 300,000 lives every year, mainly in sub-Saharan Africa. Therefore, it makes sense to screen patients with late HIV disease for the presence of CrAg. CrAg is detectable in serum a median of 3 weeks before the onset of symptoms and is highly predictive of incident cryptococcal meningitis. Patients testing positive should start prophylactic fluconazole, an effective and cost-effective treatment to prevent cryptococcosis in patients with advanced HIV infection in endemic areas. Therefore, as of 2010, the World Health Organization recommends CrAg screening and preemptive fluconazole treatment in ART-naïve adults with a CD4 count of less than 100 cells/mm3 patients in endemic settings (Figs. 1, 2, 3 and 4). Key Points • The incidence of cryptococcal disease has increased with the global increase in the HIV/AIDS burden. • The most common manifestation of cryptococcal disease is papilledema due to meningoencephalitis caused by Cryptococcus neoformans. • Intraocular invasion by cryptococcus is rare, and can present as vitritis, chorioretinitis, and endophthalmitis.

Fig. 1 Disc hemorrhages in a patient with cryptococcal meningitis

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The choroiditis can be multifocal (multiple bilateral yellowish nodules over posterior pole and mid-periphery) or focal (chorioretinitis lesion with minimal or no vitritis). • Cryptococcal endophthalmitis is a rare presentation seen in patients with AIDS and presents with multiple

Fig. 2 Disc edema and hyperemia in cryptococcal meningitis

Fig. 3 Active choroiditis lesions in cryptococcal meningitis

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Fig. 4 Healed choroidal scars in the periphery

chorioretinal lesions with exudative detachment, severe vitreous inflammation with fluffy exudates, retinal abscesses, and detachments. • Direct microscopic examination using India ink preparation of cerebrospinal fluid provides the most rapid diagnosis. • Patients with cryptococcal disease require prolonged systemic antifungal therapy consisting of induction and consolidation therapy. Usually, maintenance therapy with oral fluconazole is required for more than 1 year.

Suggested Reading Abassi M, Boulware DR, Rhein J. Cryptococcal meningitis: diagnosis and management update. Curr Trop Med Rep. 2015;2:90–9. Avendaño J, Tanishima T, Kuwabara T. Ocular cryptococcosis. Am J Ophthalmol. 1978;86:110–3. Baillif S, Delas J, Asrargis A, Gastaud P. Multimodal imaging of cryptococcal choroiditis – photo essay. Retina. 2013;33:249–51. Beardsley J, Wolbers M, Kibengo FM, The CryptoDex Investigators, et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med. 2016;374:542–54. Boulware DR, Meya DB, Muzoora C, The COAT Trial Team, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014;370:2487–98. Carney MD, Combs JL, Waschler W. Cryptococcal choroiditis. Retina. 1990;10:27–32. Charles NC, Boxrud CA, Small EA. Cryptococcosis of the anterior segment in AIDS. Ophthalmology. 1992;99:813–6.

P. Kestelyn Chau TTH, Mai NH, Phu NH, et al. A prospective descsriptive study of cryptococcal meningitis in HIV uninfected patient in Vietnam – high prevalence of Cryptococcus neoformans var grubii in the absence of underlying diseae. BMC Infect Dis. 2010;10:199. Coccia L, Calista D, Boschini A. Eyelid nodule: a sentinel lesion of disseminated cryptococcosis in a patient with AIDS. Arch Ophthalmol. 1999;117:271–2. Ehrhorn J, Groose G, Staib F, Wollensak J. Intraocular cryptococcosis. Klin Monatsbl Augenheilkd. 1976;168:577–83. [in German]. Fine HF, Chang MA, Dunn Jr JP. Bilateral cryptococcal choroidtis. Arch Ophthalmol. 2004;122:1726–7. François J, Elewaut-Rysselaere M, De Vos E. Les mycoses oculaires. Paris: Masson & Cie; 1968. p. 266–74. Gandhi SA, McMeecking AA, Friedberg D, Holzman RS. Cryptococcal choroiditis in a patient with AIDS: case report and review. Clin Infect Dis. 1996;23:1193–4. Hiles DA, Font RL. Bilateral intraocular cryptococcosis with unilateral spontaneous regression. Am J Ophthalmol. 1968;65:98–108. Kaplan J, Vallabhaneni S, Smith R, et al. Cryptococcal antigen screening and early antifungal treatment to prevent cryptococcal meningitis: a review of the literature. J Acquir Immune Defic Syndr. 2015;68:S331–9. Kestelyn P, Taelman H, Bogaerts J, et al. Ophthalmic manifestations of infections with Cryptococcus neoformans in patients with the acquired immune deficiency syndrome. Am J Ophthalmol. 1993;116:721–7. Khurana RN, Javaheri M, Rao N. Ophthalmic manifestations of immune reconstitution inflammatory syndrome associated with Cryptococcus neoformans. Ocul Immunol Inflamm. 2008;16:185–90. Kresch ZA, Espinosa-Heidmann D, Harper T, Jamie-Miller G. Disseminated Cryptococcus with ocular cryptococcoma in a HIV-negative patient. Int Ophthalmol. 2012;32:281–4. Loyse A, Moodley A, Rich P, et al. Neurological, visual, and MRI brain scan findings in 87 South African patients with HIV-associated cryptococcal meningoencephalitis. J Infect. 2015;70:668–75. Mao F, Sun H, Li D. Ophthalmic manifestation in AIDS patients with cryptococcal meningitis. Zhonghua Yan Ke Za Zhi. 2015;51:364–8. [Article in Chinese]. Maziarz EK, Perfect JR. Cryptococcosis. Infect Dis Clin N Am. 2016;30:179–206. Meya DB, Manabe YC, Boulware DR, Janoff EN. The immunopathogenesis of cryptococcal immune reconstitution inflammatory syndrome: understanding a conundrum. Curr Opin Infect Dis. 2016;29:10–22. Morinelli EN, Dugel PU, Riffenberg R, Rao NA. Infectious multifocal choroiditis in patients with AIDS. Ophthalmology. 1993;100:1014–24. Muccioli C, Belfort Jr R, Neves R, Rao N. Limbal and choroidal Cryptococcus infection in the acquired immunodeficiency syndrome. Am J Ophthalmol. 1995;120:539–40. Pappas PG. An expanded role for therapeutic lumbar punctures in newly diagnosed AIDS-associated cryptococcal meningitis? Clin Infect Dis. 2014;59:1615–7. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Disease Society of America. Clin Infect Dis. 2010;50:291–322. Pettit TH, Edwards JE, Purdy EP, Bullock JD. Endogenous fungal endophthalmitis. In: Pepose JS, Holland GN, Wilhelmus KR, editors. Ocular infection & immunity. St. Louis: Mosby; 1996. p. 1262–86. Rex JH, Larsen RA, Dismukes WE, Cloud GA, Bennet JE. Catastrophic visual loss due to Cryptococcus neoformans meningitis. Medicine. 1993;72:209–24. Seaton RA, Verma N, Naraqi S, Wembri JP, Warrell DA. Visual loss in immunocompetent patients with Cryptococcus neoformans var. Trans R Soc Trop Med Hyg. 1997;91:44–9.

Cryptococcus Sheu SJ, ChenYC KNW, Waang JH, Chen CJ. Endogenous cryptococcal endophthalmitis. Ophthalmology. 1998;105:377–81. Shields JA, Wright DM, Augsburger JJ, Wolkowicz MI. Cryptococcal chorioretinitis. Am J Ophthalmol. 1980;89:210–7. Shulman J, de la Cruz EL, Latkany P, Milman T, Iacob C, Sanjana V. Cryptococcal chorioretinitis with immune reconstitution inflammatory syndrome. Ocul Immunol Inflamm. 2009;17(5):314. Tenforde MW, Wake R, Leeme T, Jarvis JN. HIV-associated cryptococcal meningitis: bridging the gap between developed and resource-limited settings. Curr Clin Microbiol Rep. 2016;3: 92–102.

277 Waddell KM, Lucas SB, Downing RG. Case reports and small case series: conjunctival cryptococcosis in the acquired immunodeficiency syndrome. Arch Ophthalmol. 2000;118:1452–3. Weinstein JM. Fungi and mycotic disease. In: Miller NR, Newman NJ, editors. Walsh and Hoyt’s clinical neuro-ophthalmology. 6th ed. Philadelphia: Lippicott, Williams & Wilkins; 2005. p. 2817–52. World Health Organization. Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children. Geneva: World Health Organization; 2011. Wykoff C, Albini TA, Couvillion SS, Dubovy SR, Davis JL. Intraocular cryptococcoma. Arch Ophthalmol. 2009;127:700–2.

Infectious Panuveitis Reema Bansal

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Case 1: Panuveitis in a Case of Ocular Toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 Case 2: Panuveitis in a Case of Acute Retinal Necrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 Case 3: Panuveitis in a Case of Ocular Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

Introduction The International Uveitis Study Group (IUSG) in 1987 defined panuveitis as a generalized inflammation of all parts of uveal tract (iris, ciliary body, and choroid). This also simultaneously involves adjacent vitreous and retina, without any predominant site of inflammation. This anatomical classification was followed by an etiological classification of uveitis by IUSG in 2008 as infectious, noninfectious, and masquerade. While a detailed history (ocular and systemic) and ocular examination are essential in any uveitis work-up, an anatomical and etiological approach is critical for the application of relevant investigations. Once identified as panuveitis, nearly all modalities (including slit-lamp examination, fundus autofluorescence, fluorescein/indocyanine green angiography, optical coherence tomography) play a vital role in diagnosing and monitoring the disease. Certain noninfectious (or autoimmune) entities causing panuveitis, such as VKH disease, sympathetic ophthalmia, or Behcet’s disease, can be ruled out by clinical signs before ordering or requiring any confirmatory laboratory tests. In many of the infectious causes too, clinical signs provide clues to the diagnosis and appropriate antibiotics can be started

empirically and immediately to prevent visual loss. These include toxoplasmic retinochoroiditis, acute retinal necrosis (ARN) or progressive outer retinal necrosis, and endogenous endophthalmitis (fungal or bacterial), which cause acute sight-threatening posterior or panuveitis and should be treated as ocular emergencies. The diagnosis may be corroborated by serum antibodies tests, or confirmed by polymerase chain reaction (PCR) of the intraocular fluids (aqueous or vitreous). For intraocular tuberculosis (IOTB), certain clinical signs are predictive such as broad-based posterior synechiae, retinal vasculitis with/without perivascular choroiditis scars, and/or serpiginouslike choroiditis. While tuberculin skin test and chest radiological findings provide corroborative evidence to support the diagnosis of IOTB, the PCR provides molecular evidence to confirm the diagnosis. Toxocariasis, spirochetal uveitis, and Ebola virus panuveitis are other but less common causes of infectious panuveitis. Specific antimicrobial therapy (antiviral, antifungal, antitoxoplasmic or anti-tubercular) is administered for appropriate duration, along with topical and systemic corticosteroids. Additionally, cycloplegics are administered for anterior uveitis. Immunosuppressive therapy is needed for recalcitrant or recurrent cases. Complications include macular edema, choroidal or retinal neovascularization, cataract, glaucoma, etc.

R. Bansal (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_95

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Fig. 1 Fundus photograph (left) of case-1 with toxoplasmic panuveitis showing vitritis and a pigmented scar with an active retinochoroiditis lesion adjacent to the scar (satellite lesion) in the macula. The fluorescein angiography (right) demonstrated an active leak from the lesion

Case 1: Panuveitis in a Case of Ocular Toxoplasmosis A 13-year-old male presented with decreased vision in right eye for 3 months. The visual acuity was counting fingers in right eye and 6/6 in the left eye. The intraocular pressure (IOP) was 14 mm Hg in both eyes. The left eye was normal. The right eye had cells 2+ in anterior chamber, and a single posteror synechia. Posterior segment had vitreous cells 2+, and a pigmented scar with an active retinochoroiditis lesion adjacent to the scar (satellite lesion) in the macula (Fig. 1). The fluorescein angiography demonstrated an active leak from the lesion, and optical coherence tomography (OCT) showed full thickness retinitis. The patient received antitoxoplasmic therapy (intravitreal clindamycin with oral prednisolone and trimethoprim-sulphamethoxazole). The lesion healed, and the right eye visual acuity was 6/60 at 3 months follow up.

Case 2: Panuveitis in a Case of Acute Retinal Necrosis A 28-year-old female presented with pain, redness, and decreased vision in right eye for 1 month. The left eye was normal. She gave a history of chicken pox 10 days prior to developing ocular complaints. The visual acuity was 6/60 and IOP 10 mm Hg in the right eye. The right eye had cells 2+, flare 2+, and pigmented mutton fat keratic precipitates (Fig. 2). Fundus examination revealed vitritis 2+, and acute

Fig. 2 Slit-lamp photograph of case-2 showing pigmented mutton fat keratic precipitates

retinal necrosis temporal periphery (Fig. 3). She received intravenous anti-viral therapy (acyclovir) therapy with oral corticosteroids for acute retinal necrosis that led to resolution of retinitis and vitritis. At 1 year follow up, the eye was quiescent with healed peripheral scars and no recurrence of uveitis.

Case 3: Panuveitis in a Case of Ocular Tuberculosis A 28-year-old male presented with pain and decreased vision in both eyes for 2 months. The visual acuity was 6/6 and IOP 14 mm Hg in both eyes. Both eyes had mutton

Infectious Panuveitis

fat keratic precipitates, cells 2+ and flare 2+. Fundus examination showed bilateral vitritis 2+, and healed choroiditis scars in inferior periphery. The left eye also had snowballs with active retinal vasculitis and perivascular cuffing superiorly, that was evident on fluorescein angiography (Fig. 4). The tuberculin skin test was positive after 48 h. Chest CT showed necrotic mediastinal lymphadenopathy, with nodules in bilateral lungs likely tuberculosis (TB). Fine needle aspiration cytology of smears from enlarged cervical lymph nodes showed extensive necrosis with degenerating inflammatory cells comprising of histiocytes, lymphocytes, and polymorphs. Stain for acid-fast bacilli was positive, suggesting TB. He received oral prednisolone (1 mg/kg/ day) with antitubercular therapy, leading to resolution of

Fig. 3 Fundus photograph of case-2 showing vitritis and acute retinal necrosis in temporal periphery

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paunveitis. At 12 months of follow up, the visual acuity was 6/6 and IOP 14 mm Hg in both eyes. The fundus was quiescent. Key Points • Panuveitis is an anatomical classification of uveitis that involves a generalized inflammation of all parts of uveal tract (iris, ciliary body, and choroid), without any predominant site of inflammation. This also simultaneously and invariably involves adjacent vitreous and retina too. • An anatomical and etiological (infectious, noninfectious, or masquerade) approach is critical for identification of panuveitis and application of relevant investigations. • Infectious panuveitis is a devastating form of uveitis with acute sight-threatening complications. • In many of the infectious causes (toxoplasmic retinochoroiditis, acute retinal necrosis (ARN) or progressive outer retinal necrosis, and endogenous endophthalmitis), clinical signs provide clues to the diagnosis and appropriate antibiotics can be started empirically and immediately to prevent visual loss. • The diagnosis may be corroborated by serum antibodies tests, or confirmed by polymerase chain reaction (PCR) of the intraocular fluids (aqueous or vitreous). • For intraocular tuberculosis, tuberculin skin test and chest radiological findings provide corroborative evidence to support the diagnosis of IOTB, and PCR confirms the diagnosis. • Toxocariasis, spirochetal uveitis, and Ebola virus panuveitis are other but less common causes of infectious panuveitis.

Fig. 4 Fundus photograph of case-3 with tubercular panuveitis showing active retinal vasculitis and perivascular cuffing superiorly, that was evident on fluorescein angiography

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• Specific antimicrobial therapy (antiviral, antifungal, antitoxoplasmic, or antitubercular) is administered for appropriate duration, along with topical and systemic corticosteroids. • Immunosuppressive therapy is needed for recalcitrant or recurrent cases. Complications include macular edema, choroidal or retinal neovascularization, cataract, glaucoma, etc.

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Suggested Reading Bansal R, Gupta V, Gupta A. Current approach in the diagnosis and management of panuveitis. Indian J Ophthalmol. 2010;58:45–54. Gupta A, Bansal R, Gupta V, Sharma A, Bambery P. Ocular signs predictive of tubercular uveitis. Am J Ophthalmol. 2010;149:562–70. Lin P. Infectious uveitis. Curr Ophthalmol Rep. 2015;3:170–83. Mandelcorn ED. Infectious causes of posterior uveitis. Can J Ophthalmol. 2013;48:31–9.

Posterior Segment Manifestations of Tuberculosis Gaurav Gupta, Aniruddha Agarwal, Kanika Aggarwal, and Vishali Gupta

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 Case 1: A Young Male with Tubercular Serpiginous-like Choroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 Case 2: Tubercular Multifocal Serpiginoid Choroiditis in a Young Male . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 Case 3: Serpiginous-like Choroiditis: Indocyanine Green Angiography and Optical Coherence Tomography Angiography in a Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 Case 4: Tubercular Choroidal Granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 Case 5: Choroidal Tubercles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 Case 6: Tubercular Retinal Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

Introduction A protean set of ocular manifestations can be caused by acidfast bacillus, Mycobacterium tuberculosis, which may or may not be associated with systemic tuberculosis (TB). Ocular TB is not an uncommon disease, especially in endemic countries such as India. Posterior segment involvement is the most common intraocular manifestation of TB. Tubercular posterior segment involvement may occur either by direct spread of M. tuberculosis bacillus through hematogenous route into the choroid as high oxygen tension in this region promotes the growth of the organism or it may be the result of delayed hypersensitivity or immunological reaction in the absence of actual organism within the eye. Ocular TB may be unilateral or bilateral disease. It may present with varied presentations including serpiginous-like choroiditis (either multifocal or placoid type), retinal vasculitis, choroidal granuloma, and tubercles. Definitive diagnosis G. Gupta · A. Agarwal · K. Aggarwal · V. Gupta (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_119

of ocular TB is established by the combination of clinical signs and direct demonstration of the M. tuberculosis bacillus either by culture or DNA amplification using polymerase chain reaction (PCR) of ocular samples (aqueous or vitreous). Presumptive diagnosis can be established by the combination of clinical signs with positive immunological testing or any evidence of pulmonary or extrapulmonary tuberculosis once other causes of uveitis have been ruled out. Various ocular ancillary investigations such as wide-field imaging of the fundus, fluorescein angiography (FA), fundus autofluorescence (FAF), optical coherence tomography (OCT), and OCT angiography play an important role in the diagnosis and management. Systemic investigations that play a role in the management include Mantoux test, interferon (IFN)-γ release testing (QuantiFERON TB GOLD ®), and radiography (preferably contrast-enhanced computed tomography (CECT) of the chest). Conventional treatment for ocular TB is usually systemic steroids in these cases in association with antitubercular therapy. Steroid-sparing immunosuppressive therapy may be needed in patients who show suboptimal response or have steroid responsiveness. Biological agents such as TNF-α inhibitors are the upcoming new treatment modalities in these cases. 283

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Fig. 1 Fundus photograph of the right (a) and left eye (b) shows the presence of active choroiditis lesions in posterior pole. Few lesions have fuzzy and indistinct margins suggestive of active lesions (shown with

Case 1: A Young Male with Tubercular Serpiginous-like Choroiditis A 32-year-old male presented with multifocal choroiditis lesions on posterior pole in both the eyes. These lesions were in different stages of disease; few were fuzzy with ill-defined margins suggestive of active lesions (Fig. 1) which were better appreciated on autofluorescence, in which hyper-autofluorescence of the lesions was suggestive of activity (Fig. 2). Other lesions were flat and well-defined seemed to be inactive on autofluorescence (because they appeared as hypo-autofluorescent). Swept-source OCT was done which showed the presence of choriocapillaris involvement and outer retinal hyper-reflectivity (Fig. 3). Systemic investigations such as Mantoux test and CECT chest were performed. Syphilis was ruled out with negative serology. Mantoux test came out to be strongly positive. Patient was started on oral prednisone 50 mg/day along with standard four-drug antitubercular therapy.

Case 2: Tubercular Multifocal Serpiginoid Choroiditis in a Young Male A 23-year-old male presented diminution and blurring of vision in the right eye for the past 15 days. On examination, his best-corrected visual acuity was 20/30 in the right eye and

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yellow arrow). There are other lesions which are more well-defined and have distinct margins. These lesions have variable pigmentation and appear clinically to be healed choroiditis lesions

20/20 in the left eye. There was no evidence of anterior segment inflammation. Examination of the posterior segment revealed the presence of active multifocal choroiditis lesions in the macula extending to the mid-periphery inferiorly and nasally (Fig. 4). These lesions can be better appreciated on FAF imaging (Fig. 5), in which hyper-autofluorescence denotes activity and dark areas denote inactivity. Laboratory investigations in this patient revealed a positive Mantoux test with an induration measuring 30 mm. The CECT chest was reported normal by the pulmonologist. The patient was started on antitubercular therapy and oral prednisone (1 mg/ kg) followed by a good healing response.

Case 3: Serpiginous-like Choroiditis: Indocyanine Green Angiography and Optical Coherence Tomography Angiography in a Patient A 34-year-old Asian Indian female presented with history of blurring of vision and scotomas in the left eye for the past 3 months. The patient did not have any significant systemic or medical history. There was history of pulmonary tuberculosis in her younger brother 10 years ago, who was treated with appropriate course of anti-tubercular therapy and had healed completely. Examination revealed a best-corrected visual acuity of 20/200 in the left eye, and 20/20 in the right eye. Fundus examination revealed presence of

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Fig. 2 Fundus autofluorescence (FAF) photo of the right (a) and left eye (b), showing choroiditis lesions involving the posterior pole. Few lesions are hyperfluorescent (shown with yellow arrows) suggestive of

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active lesions, and the other lesions are hypofluorescent or dark suggestive of inactive lesions

Fig. 3 Swept-source optical coherence tomography of the right eye shows the presence of choroiditis lesions nasal to the fovea with the presence of localized loss of photoreceptors and retinal pigment epithelium. There is choriocapillaris involvement as well

serpiginous-like choroiditis lesions in the left eye, which showed mild activity on fundus autofluorescence imaging (Fig. 6). The combined FA and indocyanine green angiography (ICGA) revealed mild fuzzy hyperfluorescent leak in the nasal macular lesion on FA, which corresponded to hypofluorescence on ICGA imaging (Fig. 7). The optical coherence tomography angiography (OCTA) imaging revealed choriocapillaris flow void lesions in the area corresponding to the active lesions, and atrophy of the choriocapillaris and visible underlying large choroidal vessels in the healed area at baseline. The patient received systemic corticosteroid therapy along with anti-tubercular drugs and showed complete

healing at 3 months (Fig. 8). The FAF imaging revealed predominant hypo-autofluorescence, and follow-up FA and ICGA showed healed lesions. The OCTA scan performed at 3 months showed improved choriocapillaris perfusion with areas of choriocapillaris atrophy (Fig. 9).

Case 4: Tubercular Choroidal Granuloma A 43-year-old male with a history of choroiditis (treated elsewhere with a short course of oral corticosteroids) presented with a subretinal mass lesion in the inferotemporal

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detachment (Fig. 11a). Detailed laboratory work-up of the patient revealed a positive Mantoux test (18 mm). The CECT chest was reported normal. The patient was initiated on standard four-drug antitubercular therapy along with oral corticosteroids (1 mg/day/kg body weight oral prednisone). The choroidal granuloma was resolved within 4 weeks with a decrease in the subretinal fluid (Fig. 10b). There was a marked reduction in the intraretinal cystoid spaces (Fig. 11b).

Case 5: Choroidal Tubercles

Fig. 4 Fundus photograph of the right eye shows the presence of multiple flat, choroiditis lesions in the posterior pole as well as inferior and nasal part of retina

An 18-year-old female with a history of tubercular meningitis was referred to our center for routine fundus evaluation. On fundus examination, multiple yellowish-white dense subretinal lesions were noted (Fig. 12) in mid-peripheral part of the retina suggestive of tubercles. Tubercles are foci of granuloma in the choroid due to hematogenous dissemination of the tubercular bacilli. These are mostly seen in association with tubercular meningitis. Treatment is as per the primary foci.

Case 6: Tubercular Retinal Vasculitis

Fig. 5 Fundus autofluorescence imaging of the right eye shows a few areas of hyper-autofluorescence within the placoid lesions suggestive of activity, and the remaining areas are hypo-autofluorescent suggestive of inactive healed scarred lesions

quadrant. The lesion measured approximately 4 disc diameters in size. The margins of the lesions were fuzzy (Fig. 10a). The clinical appearance of the lesions gave an impression of a large choroidal granuloma. The lesion was associated with the presence of subretinal fluid and retinal thickening. Spectral-domain OCT (SD-OCT) showed the presence of intraretinal cystic spaces with associated neurosensory retinal

A 46-year-old male presented with vitreous hemorrhage in the right eye and hyperemic disc with sheathed vessels and perivascular exudation in the left eye. The exudation was more along the inferior arcade and few in the nasal part of the retina (Fig. 13a). There were few old laser photocoagulation scars in the periphery. On FA, there was a presence of disc staining with leakage along vessels seen in the late phase and capillary non-perfusion areas in the periphery. Mantoux test was positive with an induration of 16 mm. On CECT chest, there were fibrotic opacities in both the lung apices and presence of axillary lymph node enlargement. Lymph node biopsy from the enlarged lymph nodes was done. The biopsy was suggestive of TB (Fig. 14). Pars plana vitrectomy with 360 endolaser photocoagulation was performed in the right eye, and scatter laser photocoagulation was done in the left eye. Additionally, patient was started on antitubercular therapy. Key Points • Tubercular posterior uveitis can have protean manifestations. The most characteristic and distinctive phenotype is serpiginous-like choroiditis (TB SLC). However, it can also present as placoid choroiditis, choroidal granuloma (solitary or multiple), tubercles, retinal vasculitis with perivascular choroiditis scars, and other rare phenotypes such as those resembling acute posterior multifocal placoid pigment epitheliopathy (APMPPE).

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Fig. 6 Figure at baseline shows fundus photograph (a) of a patient with tubercular serpiginous-like choroiditis (case #3). (b) shows presence of active lesions nasal to the macula, which appear hyper-autofluorescent

on autofluorescence imaging (white arrowheads). There are subretinal fibrotic bands (black arrows) (a) which appear hypo-autofluorescent on autofluorescence imaging (b)

Fig. 7 Combined fluorescein angiography (FA) and indocyanine green angiography (ICGA) at baseline (early phase: a; late phase: b) shows fuzzy hyperfluorescence of active lesions on FA (yellow dashed square), which appears hypofluorescent on ICGA (yellow dashed square).

Optical coherence tomography angiography (OCTA) (3  3 mm: c; 6  6 mm: d) shows hyporeflective areas suggestive of choriocapillaris flow deficit in the areas of active lesions (white arrowheads)

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Fig. 8 Follow-up fundus photography of the same patient (case #3) shows complete healing of the tubercular serpiginous-like choroiditis lesions (a) and predominant hypo-autofluorescence on autofluorescence imaging (b)

Fig. 9 Follow-up combined fluorescein angiography (FA) and indocyanine green angiography (ICGA) (early: a; late: b) shows healing of the lesions with no leakage and only staining on FA, and discreet hypofluorescence on ICGA suggestive of choriocapillaris atrophy.

Optical coherence tomography angiography (OCTA) (3  3 mm: c; 6  6 mm: d) shows healing of the flow deficit areas with visible underlying choroidal vessels due to choriocapillaris atrophy (white arrows)

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Fig. 10 (a) Ultrawide-field fundus photograph of the left eye shows a large subretinal lesion in the inferotemporal quadrant (red circle) suggestive of a choroidal granuloma with associated macular edema and

subretinal fluid (red arrow). (b) The fundus photograph obtained after 6 weeks of therapy shows resolution of the granuloma and retinal edema

Fig. 11 (a) Spectral-domain optical coherence tomography of the same patient in Fig. 10 shows the presence of intraretinal cystoid spaces associated with neurosensory retinal detachment. (b) The optical

coherence tomography imaging at 6 weeks of therapy shows marked resolution of the fluid. There is a presence of an epiretinal membrane leading to traction

• TB SLC presents with yellowish-white choroiditis lesions with an active progressive edge with a healing center. Such patients should be investigated for tuberculosis and treated with corticosteroids and anti-tubercular therapy.

• The lesions of TB SLC shows choriocapillaris ischemia on retinal imaging which tends to heal with variable degree of choriocapillaris atrophy. • Tubercular choroidal granulomas appear as single large or multiple small choroidal stromal nodules with subretinal

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Fig. 12 Fundus photograph of the right eye showing multiple subretinal yellowish-white lesions suggestive of tubercles (yellow arrows)

Fig. 13 (a) Ultrawide-field fundus photograph showing sheathed vessel and perivascular exudation along the inferior arcade. (b) Late phase of FA shows the presence of disc staining, leakage along the inferior

arcade and in the nasal part of the retina. Capillary nonperfusion areas can also be seen in the superior and temporal peripheral retina

Fig. 14 (a) Histopathological examination of the lymph node biopsy showed a large central area of caseous necrosis and peripherally epithelioid cell granulomas with Langerhans’ type of giant cells; (b) acid-fast staining showing positive result for acid-fast bacilli

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fluid and exudation. These lesions respond well to antitubercular therapy with corticosteroids with/without antiVEGF therapy. • Retinal vasculitis can be associated with tuberculosis. These patients often present with occlusive disease and perivascular choroiditis scars, which have a high positive predictive value for the diagnosis of tuberculosis.

Suggested Reading Agarwal A, Agrawal R, Khandelwal N, Invernizzi A, Aggarwal K, Sharma A, Singh R, Bansal R, Sharma K, Singh N, Gupta V. Choroidal structural changes in tubercular multifocal serpiginoid choroiditis. Ocul Immunol Inflamm. 2017a;11:1–7. Agarwal A, Mahajan S, Khairallah M, Mahendradas P, Gupta A, Gupta V. Multimodal imaging in ocular tuberculosis. Ocul Immunol Inflamm. 2017b;25(1):134–45.

291 Aggarwal K, Agarwal A, Deokar A, Singh R, Bansal R, Sharma A, Sharma K, Dogra MR, Gupta V. Ultra-wide field imaging in paradoxical worsening of tubercular multifocal serpiginoid choroiditis after the initiation of anti-tubercular therapy. Ocul Immunol Inflamm. 2017;11:1–6. Agrawal R, Gunasekeran DV, Grant R, Agarwal A, Kon OM, Nguyen QD, Pavesio C, Gupta V, Collaborative Ocular Tuberculosis Study (COTS)–1 Study Group. Clinical features and outcomes of patients with tubercular uveitis treated with antitubercular therapy in the collaborative ocular tuberculosis study (COTS)-1. JAMA Ophthalmol. 2017;135(12):1318–27. Gupta A, et al. Classification of intraocular tuberculosis. Ocul Immunol Inflamm. 2014;14:1–7. Gupta V, et al. Clinics of ocular tuberculosis. Ocul Immunol Inflamm. 2015;23(1):14–24. Gupta B, et al. Ocular manifestations of tuberculosis: an update. Expert Rev Ophthalmol. 2016;11(2):145–54.

Tubercular Vasculitis Ahmed M. Abu El-Asrar and Marwan Abouammoh

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Case 1: Retinal vasculitis with positive tuberculin skin test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Case 2: Occlusive retinal vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Case 3: Fluorescein angiographic findings in tubercular retinal vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Case 4: Features of optic nerve leakage and vascular anastomosis in tubercular retinal vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Case 5: Perivenous sheathing in tubercular retinal vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Case 6: Occlusive retinal vasculitis with positive tuberculin skin test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294 Case 7: Neovascularization of iris in tubercular retinal vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Case 8: Laser photocoagulation for tubercular retinal vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Case 9: Vitreous hemorrhage in tubercular retinal vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 Case 10: Tractional retinal detachment in tubercular retinal vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

Introduction Ischemic retinal vasculitis is frequently seen secondary to tuberculosis and retinal vasculitis associated with tuberculoprotein hypersensitivity. Tuberculous retinal vasculitis is typically an obliterative periphlebitis affecting the retina in multiple quadrants, starting at or anterior to the equator and progressing posteriorly. Occasionally, it can begin close to the optic nerve head, mimicking a vein

A. M. Abu El-Asrar (*) College of Medicine, Department of Ophthalmology, King Abdulaziz University Hospital, King Saud University, Riyadh, Saudi Arabia Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Riyadh, Saudi Arabia e-mail: [email protected]; [email protected] M. Abouammoh Department of Ophthalmology, College of Medicine, King Saud University, King Abdulaziz University Hospital, Riyadh, Saudi Arabia © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_84

occlusion. Ophthalmoscopic findings vary and depend on the stage of the disease. Initially, it presents as active retinal periphlebitis with thick exudates around the retinal veins associated with retinal hemorrhages and hemorrhagic infarctions of the retina. Healed periphlebitis results in sclerosed white venules and abnormal vascular anastomosis. The periphlebitis may cause nonperfusion of a substantial portion of the retina that may lead to proliferative vascular retinopathy with sequelae such as recurrent vitreous hemorrhage, traction retinal detachment, rubeosis iridis, and neovascular glaucoma. The management of active tuberculous retinal vasculitis or retinal vasculitis associated with tuberculoprotein hypersensitivity requires the use of systemic steroids and appropriate antituberculous therapy. New vessel formation associated with capillary closure responds to scatter laser photocoagulation. It is important to identify the presence of retinal ischemia in patients with tuberculous retinal vasculitis because scatter laser photocoagulation should be considered when angiographic evidence of widespread retinal 293

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nonperfusion is present and before (or shortly after) the development of neovascularization. Early vitrectomy and adequate endolaser photocoagulation should be considered in eyes with non-resolving vitreous hemorrhage associated with active fibrovascular proliferation. Tuberculous retinal vasculitis should be suspected in the presence of florid retinal periphlebitis with marked capillary closure with a relatively mild degree of vitreous cellular infiltrate, particularly in patients of Asiatic origin: Genetic predisposition may account for the propensity to develop retinal vasculitis in these patients. Most patients have no history of pulmonary or other systemic forms making a definitive diagnosis difficult. It should be emphasized that the absence of clinically evident pulmonary tuberculosis (TB) does not rule out the possibility of ocular TB, as about 60% of patients with extrapulmonary TB have no evidence of pulmonary TB. In most studies, the diagnostic criteria for presumed tuberculous uveitis are: 1. Ocular findings consistent with possible intraocular TB with no other cause of uveitis suggested by history of symptoms, or ancillary testing 2. Strongly positive tuberculin skin test results (15 mm area of induration/necrosis) 3. Response to antituberculous therapy with the absence of recurrences Tuberculin skin test is of great importance for making the diagnosis of ocular TB. The specificity of the tuberculin skin test for Mycobacterium tuberculosis increases with larger skin reactions and with a history of exposure to an active case of TB. It is important to note that the effect of neonatal vaccination with bacilli Calmette-Guérin (BCG) on tuberculin skin test declines over the first 7 years of life. In addition, it was demonstrated that an induration greater than 14 mm is unlikely to be due to prior BCG vaccination.

Case 1: Retinal vasculitis with positive tuberculin skin test A 26-year-old male with strongly positive tuberculin skin test (24 mm area of induration/necrosis) (Fig. 1). Fundus examination showed thick perivenous sheathing (Fig. 2).

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Fig. 1 A strongly positive Mantoux test with necrosis and ulceration

Case 3: Fluorescein angiographic findings in tubercular retinal vasculitis A 24-year-old man with strongly positive tuberculin skin test. Fundus examination demonstrated thick perivenous sheathing and intraretinal hemorrhages (Fig. 5). Fluorescein angiography showed peripheral capillary nonperfusion (Fig. 6).

Case 4: Features of optic nerve leakage and vascular anastomosis in tubercular retinal vasculitis A 28-year-old man with strongly positive tuberculin skin test. Fundus examination demonstrated thick perivenous sheathing and with intraretinal hemorrhages and preretinal hemorrhage above optic nerve head (Fig. 7). Fluorescein angiography showed leakage from the retinal veins and neovessels on optic nerve head, telangiectasia, abnormal vascular anastomosis, and retinal nonperfusion (Fig. 8).

Case 5: Perivenous sheathing in tubercular retinal vasculitis A 24-year-old man with strongly positive tuberculin skin test. Fundus examination demonstrated preretinal hemorrhage, intraretinal hemorrhages, and thick perivenous sheathing (Fig. 9).

Case 2: Occlusive retinal vasculitis A 25-year-old man with strongly positive tuberculin skin test. Fundus examination demonstrated thick perivenous sheathing with intraretinal hemorrhages and hemorrhagic infarction (Fig. 3). Fluorescein angiography showed leakage and staining of the involved veins (Fig. 4).

Case 6: Occlusive retinal vasculitis with positive tuberculin skin test A 27-year-old man with strongly positive tuberculin skin test. Fundus examination demonstrated sclerosed white retinal vessels in the periphery and neovessels (Fig. 10). Fundus

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Fig. 2 Fundus examination showing the presence of thick perivenular sheathing

Fig. 3 Fundus showing thick perivenular sheathing with hemorrhages

Fig. 5 Fundus showing thick perivenular sheathing and hemorrhages

Fig. 4 Fluorescein angiography showing vasculitis (leakage) and blocked fluorescence due to hemorrhages

Fig. 6 Fluorescein angiography showing vasculitis with capillary nonperfusion areas

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Fig. 7 Exuberant retinal sheathing with hemorrhages and neovascularization at the optic nerve head

Fig. 8 Fluorescein angiography showing active vasculitis with blockage due to overlying hemorrhages and capillary nonperfusion

Fig. 9 Fundus photograph showing preretinal hemorrhage and active vasculitis in the peripheral frames

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Fig. 10 Fundus photograph showing sclerosed vessels and peripheral neovascularization

Fig. 11 Fluorescein angiography showing peripheral vascular tortuosity and capillary nonperfusion areas

fluorescein angiography showed peripheral capillary nonperfusion, telangiectasia, abnormal vascular anastomosis, and leakage from neovessels (Fig. 11).

Case 7: Neovascularization of iris in tubercular retinal vasculitis A 30-year-old man with strongly positive tuberculin skin test. Anterior segment examination showed extensive rubeosis iridis. This patient had, in addition, vitreous hemorrhage, retinal ischemia, and retinal neovessels (Fig. 12).

Case 8: Laser photocoagulation for tubercular retinal vasculitis A 25-year-old man with strongly positive tuberculin skin test. Fundus examination demonstrated perivenous sheathing with intraretinal hemorrhages (Fig. 13) and neovessels nasal to optic nerve head (Fig. 14). Fluorescein angiography showed retinal nonperfusion (Fig. 15). Optical coherence tomography showed macular edema (Fig. 16). Fundus photographs after treatment with systemic steroids, appropriate antituberculous therapy, and scatter laser photocoagulation (Fig. 17) showed

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Fig. 12 Intense neovascularization at the iris

Fig. 14 Fundus examination showing peripheral vascular sheathing with retinal neovascularization Fig. 13 Fundus photograph showing retina sheathing and preretinal hemorrhages

resolution of perivenous sheathing, intraretinal hemorrhages and involution of neovessels. Optical coherence tomography showed normal anatomy of the macula (Fig. 18).

Case 9: Vitreous hemorrhage in tubercular retinal vasculitis A 32-year-old man with strongly positive tuberculin skin test. Fundus examination showed vitreous hemorrhage and active fibrovascular tissue on the optic nerve head and along the vascular arcades (Fig. 19). Fundus photograph after pars plana vitrectomy and endolaser photocoagulation (Fig. 20) showed clear vitreous cavity and involution of neovessels.

Fig. 15 Fluorescein angiography showing capillary nonperfusion areas

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Fig. 16 Optical coherence tomography showing the presence of cystoid macular edema

Fig. 17 Fundus photograph showing therapy with scatter laser photocoagulation

Fig. 18 Optical coherence tomography showing resolution of cystoid macular edema

Case 10: Tractional retinal detachment in tubercular retinal vasculitis A 35-year-old man with strongly positive tuberculin skin test. Fundus examination showed severe traction retinal detachment (Fig. 21). Fundus photograph after pars plana

vitrectomy and endolaser photocoagulation (Fig. 22) showed flat retina. Key Points • Tuberculous retinal vasculitis is an obliterative periphlebitis. • Nonperfusion of the retina may lead to proliferative vascular retinopathy with sequelae including recurrent

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Fig. 19 Fundus examination showing tractional retinal detachment

Fig. 20 Follow-up fundus photograph after pars plana vitrectomy and endolaser photocoagulation

vitreous hemorrhage, traction retinal detachment, rubeosis iridis, and neovascular glaucoma. • The management of active retinal vasculitis requires the use of systemic corticosteroids and appropriate antituberculous therapy. • New vessel formation associated with capillary closure responds to scatter laser photocoagulation. • Early vitrectomy and endolaser photocoagulation should be considered in eyes with vitreous hemorrhage associated with active fibrovascular proliferation.

A. M. Abu El-Asrar and M. Abouammoh

Fig. 21 Fundus examination showing tractional retinal detachment with extensive neovascularization and proliferation

Fig. 22 Follow-up fundus photograph after pars plana vitrectomy and endolaser photocoagulation

Suggested Reading Abu El-Asrar AM, Al-Kharashi SA. Full panretinal photocoagulation and early vitrectomy improve prognosis of retinal vasculitis associated with tuberculo-protein hypersensitivity. Br J Ophthalmol. 2002;86:1248–51. Abu El-Asrar AM, Abouammoh M, Al-Mezaine HS. Tuberculous uveitis. Int Ophthalmol Clin. 2010;50:19–39. Gupta A, Gupta V, Arora S, Dogra MR, Bambery R. PCR-positive tubercular retinal vasculitis. Clinical characteristics and management. Retina. 2001;21:435–44.

Eales’ Disease Parthopratim Dutta Majumder and Jyotirmay Biswas

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Fundus Fluorescein Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 Ultrasonography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

Introduction

Clinical Features

Eales’ disease was first described by Henry Eales, a British ophthalmologist, who thought that it as a noninflammatory condition. The exact cause of Eales’ disease is unknown. Of the several etiologies proposed, the most favored are tuberculosis and hypersensitivity to tuberculoprotein. Several studies have shown positive for one or more Mycobacterium species tested by polymerase chain reaction (PCR) from specimen like vitreous, epiretinal membrane (ERM), and eyeball. Few studies have showed association with human leukocyte antigen (HLA) predominantly HLAB5, DR1, and DR4.

Eales’ disease most predominantly affects healthy young adults between 20 and 40 years. The disease, for unknown reasons, is more prevalent in Indian subcontinent than in the rest of the world. Patients are often asymptomatic in the initial stages of the disease. Common symptoms are floaters, blurring of vision, and sometimes pain-free gross diminution of vision due to massive vitreous hemorrhage. Bilaterality is quite common, 50 to 90% of patients develop bilateral involvement. Classically three basic pathological changes are observed, which are manifested in clinical picture of the disease: inflammation of the retinal veins (peripheral retinal perivasculitis) (Fig. 1); ischemic changes (peripheral retinal capillary nonperfusion); and neovascularization of the retina or disk, which often leads to vitreous hemorrhage (Fig. 2). Anterior uveitis and vitritis are uncommon in Eales’ disease. Typically, active perivasculitis with exudates around the retinal veins and midperipheral venous dilation with superficial retinal hemorrhages are seen involving one or more quadrants. Vascular sheathing ranges from thin white lines limiting the blood column on both sides to segmental heavy exudative sheathing. Sheathing of the veins, sclerosed cord of vessels, pigmentation along venules, kinky venules, and abnormal vascular anastomosis are also

P. Dutta Majumder (*) Department of Uveitis and Intraocular Inflammation, Sankara Nethralaya, Chennai, India e-mail: [email protected] J. Biswas Uveitis and Ocular Pathology Department, Sankara Nethralaya, Chennai, India e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_83

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seen. Neovascularization of retina (NVE) or disk (NVD) is seen in up to 80% of patients. NVEs are usually located at the junction of the perfused and nonperfused retina (Figs. 5 and 6).

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fundus fluorescein angiogram and leak in the late venous phase. Neovascularization, when located in the far periphery, can be missed on routine/ conventional FFA. Ultra-wide field fundus fluorescein angiography can be of practical value in such cases (Figs. 3 and 4).

Fundus Fluorescein Angiography Active vasculitis is characterized by staining of the vessel wall in the early venous phase with extravasation of the dye in the late phase. In the healed stage of vasculitis, only the staining of the vessel wall occurs without any leak in the late phase. Fundus fluorescein angiogram is a valuable tool for precisely delineating the extent and location of neovascularization. Neovascularization usually shows intense hyperfluorescence in the early arteriovenous phases of the

Ultrasonography Ultrasonography is required in cases with vitreous hemorrhage where view of fundus is to rule out any associated retinal detachment, either tractional, rhegmatogenous, or combined, in an eye with opaque media. Early vitreous surgery is indicated if such association is demonstrated.

Treatment

Fig. 1 Fundus photograph of Eales’ disease with active periphlebitis

The main aim of treatment in Eales’ disease is to reduce the inflammation of the retinal vessels and to minimize the risks of vitreous hemorrhage resulting from neovascularizations. Corticosteroids, with or without antitubercular treatment, photocoagulation, and vitrectomy are the currently used treatment modalities. Oral corticosteroid remains mainstay of the treatment in acute inflammatory stage of Eales’ disease. Many believe that antitubercular treatment is helpful as hypersensitivity to tuberculoproteins is considered an important cause of Eales’ disease. Retinal periphlebitis with strong evidence of tuberculosis responds to systemic steroids and appropriate antituberculous therapy. Laser photocoagulation reduces risks of vitreous hemorrhage from new vessels on the retina and/or the optic nerve head. Photocoagulations of areas of capillary dropout have been found beneficial in proliferative Eales’ retinopathy, leading to regression of retinal

Fig. 2 Fibrovascular proliferation and vitreous hemorrhage in a case of Eales’ disease

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Fig. 5 Veno-venous shunt in a patient of Eales’ disease

Fig. 3 Active retinal vasculitis with cystoid macular edema

Fig. 6 Neovascular frond seen in a patient with retinal ischemia due to Eales’ disease Fig. 4 Area of capillary nonperfusion in temporal retina

neovascularization. Vitreous hemorrhage is the prime cause for impaired vision in Eales’ disease and recurrent, nonresolving vitreous hemorrhages may lead to formation of traction bands and membranes in the vitreous and subsequent complications. The main indications for vitrectomy include nonresolving vitreous hemorrhage, tractional retinal detachment involving the posterior pole, multiple vitreous membranes with or without tractional retinal detachment, and combined tractional and rhegmatogenous retinal detachment.

Key Points • Eales’ disease is characterized by occlusive retinal venular inflammation in young healthy male adults (20–40 years) mostly prevalent in the Indian subcontinent. • The exact etiology of this condition is unknown. However, a strong association with tuberculosis has been reported. • Apart from retinal vasculitis, this entity is characterized by anterior uveitis, vitritis, and complications of retinal

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ischemia including neovascularization, vitreous hemorrhage, tractional detachments, and neovascular glaucoma. • The management consists of control of inflammation, and treatment of neovascular complications with laser therapy or vitrectomy.

Suggested Reading Biswas J, Therese L, Madhavan HN. Use of polymerase chain reaction in detection of Mycobacterium tuberculosis complex DNA from vitreous sample of Eales’ disease. Br J Ophthalmol. 1999;83:994. Biswas J, et al. Eales disease – an update. Surv Ophthalmol. 2002;47:197–214. Cai S, Su G, Li H, Xie B, Luo J. Profiling of human leukocyte antigens in Eales disease and tuberculosis. Int Ophthalmol. 2013;33:475–9.

P. Dutta Majumder and J. Biswas Das T, Pathengay A, Hussain N, Biswas J. Eales’ disease: diagnosis and management. Eye Lond Engl. 2010;24:472–82. El-Asrar AMA, Al-Kharashi SA. Full panretinal photocoagulation and early vitrectomy improve prognosis of retinal vasculitis associated with tuberculoprotein hypersensitivity (Eales’ disease). Br J Ophthalmol. 2002;86:1248–51. Madhavan HN, Therese KL, Gunisha P, Jayanthi U, Biswas J. Polymerase chain reaction for detection of Mycobacterium tuberculosis in epiretinal membrane in Eales’ disease. Invest Ophthalmol Vis Sci. 2000;41:822–5. Shanmugam MP, Badrinath SS, Gopal L, Sharma T. Long term visual results of vitrectomy for Eales disease complications. Int Ophthalmol. 1998;22:61–4. Shukla D, Kanungo S, Prasad NM, Kim R. Surgical outcomes for vitrectomy in Eales’ disease. Eye Lond Engl. 2008;22:900–4. Verma A, Biswas J, Dhanurekha L, Gayathri R, Lily Therese K. Detection of Mycobacterium tuberculosis with nested polymerase chain reaction analysis in enucleated eye ball in Eales’ disease. Int Ophthalmol. 2015. https://doi.org/10.1007/s10792-015-0144-9.

Syphilitic Uveitis Mohamed Kamel Soliman, Mostafa Hanout, Salman Sarwar, David T. Wong, Diana V. Do, and Quan Dong Nguyen

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 Case 1: Peripheral Chorioretinitis with Bilateral Papillitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 Case 2: Acute Syphilitic Posterior Placoid Chorioretinitis (ASPPC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 Case 3: Syphilitic Panuveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 Case 4: Syphilitic Chorioretinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

Introduction Syphilis is caused by the spirochete Treponema pallidum. The most common ocular manifestation of syphilis is uveitis, accounting for approximately 10% and 5% of cases of secondary and tertiary syphilis, respectively. Ocular involvement is bilateral in more than 50% of cases and it is believed to occur more often during the secondary or latent stages of infection. Ocular inflammation can be granulomatous or nongranulomatous and virtually all ocular structures can be affected. Posterior uveitis followed by panuveitis is the most commonly reported presentations of ocular syphilis.

M. K. Soliman Department of Ophthalmology, Assiut University Hospital, Assiut, Egypt M. Hanout · D. T. Wong Department of Ophthalmology and Visual Sciences, University of Toronto, St. Michael’s Hospital, Toronto, ON, Canada S. Sarwar Department of Ophthalmology, University of Missouri, Columbia, MO, USA D. V. Do Byers Eye Institute, Stanford University, Palo Alto, CA, USA

Other findings include anterior uveitis, vitritis, vasculitis, focal or diffuse necrotizing retinitis, chorioretinitis, papillitis, and neuroretinitis. High index of suspicion is warranted for early diagnosis and prompt treatment.

Case 1: Peripheral Chorioretinitis with Bilateral Papillitis A 39-year-old healthy female presented with blurring of vision in both eyes. Examination revealed bilateral panuveitis characterized by nongranulomatous anterior uveitis and papillitis in both eyes and peripheral chorioretinitis in the right eye (Fig. 1). Fluorescein angiography highlighted leakage from the optic nerve head, hyperfluorescence of the peripheral chorioretinal lesion, and perivascular leakage (Fig. 2). Anterior chamber paracentesis was performed; infectious work-up has revealed positive rapid plasma regain (RPR) and fluorescent treponemal antibody absorption (FTA-Abs). Spectral-domain optical coherence tomography (SD-OCT) of the peripheral chorioretinal lesion showed thickening of the chorioretinal complex, retinal inflammation, and numerous inflammatory cells in the posterior vitreous (Fig. 3).

Q. D. Nguyen (*) Spencer Center for Vision Research, Byers Eye Institute at Stanford University, Palo Alto, CA, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_15

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Fig. 1 Wide-field fundus photograph of both eyes. (a) Ill-defined and slightly elevated optic nerve head margin of the right eye. (b) Blurred disc margin and chorioretinal ground glass opacification in the superior periphery of the left eye

Fig. 2 Wide-field fluorescein angiography of both eyes. (a) Hyperfluorescence and leakage from the optic nerve head of the right eye in the midphase of the angiogram. (b) Peripheral hyperfluorescence of the

Case 2: Acute Syphilitic Posterior Placoid Chorioretinitis (ASPPC) A 47-year-old Caucasian man presented with a chief complaint of central visual deficit in his right eye. Slit-lamp examination revealed no signs of inflammation in the anterior chamber or the vitreous cavity. A large placoid whitish lesion in the temporal part of the macula was observed on fundus examination. Serological tests for syphilis were positive and hence the patient was treated with intravenous penicillin G which resulted in improvement of his visual problems (Fig. 4).

Case 3: Syphilitic Panuveitis A middle-age healthy white male presented with diminution of vision and redness in the right eye. Ocular examination revealed nongranulomatous panuveitis in the form of anterior uveitis and 3+ vitritis. (Fig. 5a, b). Palmar erythema of the

chorioretinal lesion with mild perivascular leakage (vasculitis) and hyperfluorescence of the optic disc in late frames in the left eye

right hand was detected on comprehensive systemic examination (Fig. 6). Basic uveitis workup was conducted and serological tests for syphilis were positive.

Case 4: Syphilitic Chorioretinitis A 34-year-old Caucasian male with a history of HIV infection presented with flashes, floaters, and blurring of vision in the left eye. In addition, the patient was suffering from dizziness, fluctuating hearing loss, and vestibular imbalance; he was relying on a cane as a walking aid. Anterior segment examination revealed 4+ cells and flare with pigment deposition on the crystalline lens. Vitreous haze with 3+ cells and snow balls in the inferior periphery were seen on fundus examination (Fig. 7b). Perivascular whitish plaques similar to those seen in necrotizing viral retinitis were found at the vascular arcade, superior to the optic disc and extending to the periphery (Fig. 7a and b). Ocular examination of right eye was unremarkable except for hyperemia and subtle elevation of the optic disc (Fig. 7c).

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Fig. 3 Spectral domain optical coherence tomography (SD-OCT) of the chorioretinal lesion: (a, b) Thickening of the chorioretinal complex with distorted retinal contour. Retinal layers show thickening and marked infiltration with hyperreflective spots. The posterior hyaloid is thickened and exerting traction on the retinal surface. There are numerous moderately reflective spots in the posterior vitreous (vitritis)

Fig. 4 Fundus photograph (a), fluorescein angiogram (b), and fundus autofluorescence (c) of the right eye. (a) Large placoid whitish lesion in the temporal part of the macula. (b) Leopard spots represented by the hypofluorescent dots in the temporal macula which is a characteristic

feature in acute syphilitic posterior placoid chorioretinitis (ASPPC). (c) Hyperautofluorescence of the leopard’s spots that were seen in the fluorescein angiogram (Reproduced with permission from Ocular Immunology and Inflammation: Burkholder et al. 2014 Jan 27; 4(1):2)

Fig. 5 (a) Color image of the right eye demonstrating ciliary and conjunctival injection and posterior synechiae with iris pigment on the lens. (b) Color fundus photograph of the right eye showing 3+ vitreous haze obscuring view of the fundus

Anterior chamber paracentesis and hematological evaluation revealed positive syphilis serology; intravenous penicillin therapy was initiated without delay. Treatment resulted in marked improvement of retinal lesions and resolution of dizziness, hearing, and neurologic symptoms. The patient was able to walk unaided during subsequent visits.

Key Points • Syphilis, also known as the great masquerader, can virtually affect any ocular tissue and can mimic any inflammatory ocular disease. • Ocular syphilis, particularly uveitis, may be the presenting feature of syphilis.

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Fig. 6 Color photograph of the right hand showing palmar erythema Fig. 7 Fundus photograph (a, b) of the left eye and (c) the right eye. (a) Hyperemic optic disc with multiple, confluent, yellowish white areas of chorioretinal inflammation along the vascular arcades and superior to the optic disc mimicking necrotizing retinitis. Retinal hemorrhage is also seen superior to the disc. (b) Snowballs in the inferotemporal periphery. (c) Hyperemic optic nerve head with subtle edema

• Posterior uveitis is the most common manifestation of ocular syphilis. • Ground glass retinal inflammation and acute syphilitic posterior placoid chorioretinitis (ASPPC) are distinctive features described in patients with syphilitic uveitis. • Ocular syphilis is considered a manifestation of neurosyphilis and thus should be treated with intravenous penicillin. • Diagnosis of syphilis is based on high index of suspicion, clinical signs, and serological tests. • Early diagnosis and prompt treatment can result in dramatic improvement of ocular manifestations.

Suggested Reading Amaratunge BC, Camuglia JE, Hall AJ. Syphilitic uveitis: a review of clinical manifestations and treatment outcomes of syphilitic uveitis in human immunodeficiency virus-positive and negative. Clin Exp Ophthalmol. 2010;38(1):68–74. Margo CE, Hamed LM. Ocular syphilis. Sur Oophthalmol. 1992;37 (3):203–20. Mauro J, Samson CM, Stephen Foster C. Syphilis. Diagnosis and treatment of uveitis. New Delhi/London: Jaypee Brothers; 2013. p. 1276.

Cat Scratch Disease André Luiz Land Curi

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Case 1: Cat Scratch Disease with Small Foci of Retinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Case 2: Cat Scratch Disease in HIV + Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Case 3: OCT Findings in Cat Scratch Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312

Introduction The systemic condition is characterized by fever associated to regional lymphadenopathy, generally near the site of the scratch. The systemic condition is subject to differential diagnosis against febrile diseases such as infectious mononucleosis and systemic toxoplasmosis. The ocular symptoms are extremely variable. The disease was originally described as a granulomatous conjunctivitis associated to necrosis and preauricular lymphadenopathy. The classic manifestation of intraocular cat scratch disease is neuroretinitis; however, other ocular alterations have also been reported, including retinitis, retinal infiltrates, vascular occlusions, intermediary uveitis, angiomatous lesions, unifocal helioid choroiditis, inflammatory mass, and serous detachment. Diagnosis is based on a positive serology for Bartonella henselae. Doxycycline has been shown effective for intraocular involvement.

Case 1: Cat Scratch Disease with Small Foci of Retinitis An 18-year-old woman from Niterói, Rio de Janeiro, presented with a 7 days history of very intense headache and blurred vision. Due to her headache she was hospitalized for investigation. During hospitalization, lumbar puncture was performed and the diagnosis of aseptic meningitis was made. Ophthalmological examination showed mild disc edema (Fig. 1), discrete hard exudates in the macula and two small foci of superficial retinitis in the nasal to the optic disc. Patient confirmed contact with cats and a cat scratch 2 weeks before. Serology for Bartonella henselae was performed and became positive 1/512 IgG. She was put on doxycycline for 1 month with complete recovery.

Case 2: Cat Scratch Disease in HIV + Patient A 27-year-old homosexual HIV + patient from Niterói, Rio de Janeiro, complained of blurred vision in both eyes. He was diagnosed with CMV retinitis and was started on intravenous A. L. L. Curi (*) National Institute of Infectious Diseases – INI, Oswaldo Cruz Foundation – FIOCRUZ, Rio de Janeiro, Brazil e-mail: andre.curi@ini.fiocruz.br; andre.curi@ipec.fiocruz.br © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_45

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Fig. 1 Fundus photograph of a patient with cat scratch disease shows presence of optic nerve head edema and small nasal foci of retinitis superiorly and inferiorly

Fig. 2 Fundus photograph of a patient with cat scratch disease initially diagnosed with cytomegalovirus retinitis. The fundus shows optic nerve head edema, macular exudation, and abnormal looking vasculature

ganciclovir. Patient did not show any improvement. He also presented with headache and fever. Since he showed no improvement he was referred to Fiocruz for investigation. His CD4 counts were 43 cells/mm and he reported cat exposure. Fundoscopy revealed abnormal vascular network, and

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Fig. 3 Fundus photograph of the right eye of a patient with cat scratch disease shows three foci of retinitis

Fig. 4 Serial photography of the right eye (magnified) shows presence of abnormal vasculature and sheathing of vessels

the diagnosis of cat scratch disease was considered (Fig. 2). Bartonella henselae serology was positive 1/256 and he was put on oral doxycycline. Patient was treated for 3 months and presented complete resolution on the retinal lesions. Doxycycline was discontinued and 1 month later lesions relapsed. Doxycycline was started again until CD4+ reached 250 cells/mm.

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Fig. 5 Fundus photograph of the left eye of the same patient shows foci of retinitis suggestive of cat scratch disease

Fig. 6 Optical coherence tomography scan of the same patient (Case III) shows presence of superficial retinal thickening due to retinitis related to cat scratch disease

Case 3: OCT Findings in Cat Scratch Disease A 21-year-old woman from Rio de Janeiro was referred to the Ophthalmology Research Laboratory in Infectious Diseases at the National Institute of Infectious Diseases complaining of blurred vision in both eyes. Visual acuities were 20/30 RE and 20/80 LE. There was no inflammation in

the anterior chamber of both eyes and intraocular pressures were within normal limits. Fundoscopy revealed three small foci of retinitis in the RE (Figs. 3 and 4) and two foci of retinitis with mild disc edema and hard exudates in the LE (Fig. 5). Patient reported history of cat scratch in the right arm and leg 3 weeks before symptoms started. Bartonella henselae serology was ordered and became positive 1/512 IgG.

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Optical coherence tomography (Fig. 6) showed superficial retinal thickening related to focal retinitis in both eyes and hard exudates in the nuclear layer in the macula region. Patient was started on oral doxycycline 100 mg BD and showed complete resolution after 1 month therapy. Visual acuities returned to 20/20 in both eyes. Key Points • History of cat contact is important for the diagnosis. • Small foci of retinitis are the most common ocular finding. • Treatment with doxycycline has been shown effective. • Prognosis is good.

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Suggested Reading Cunningham ET, Koehler JE. Ocular bartonelosis. Am J Ophthalmol. 2000;130:340–9. Curi ALL, Machado DO, Heringer G, et al. Ocular manifestation of cat-scratch disease in HIV+ patients. Am J Ophthalmol. 2006;141 (2):400–1. Rolain JM, Brouqui P, Koehler JE, et al. Recommendations for treatment of human infections caused by Bartonella species. Antimicrob Agents Chemother. 2004 Jun;48(6):1921–33. Solley WA, Martin DF, Newman NJ, et al. Cat-scratch disease-posterior segment manifestations. Ophthalmology. 1999;106:1546–53.

Presumed Ocular Histoplasmosis Syndrome Piergiorgio Neri, Ilir Arapi, Vittorio Pirani, Michele Nicolai, Andrea Saitta, Cesare Mariotti, and Alfonso Giovannini

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Case 1: Paediatric POHS Complicated by Peripapillary CNV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 Case 2: Accidental Finding of POHS Lesions in an Asymptomatic Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316

Introduction Presumed ocular histoplasmosis syndrome (POHS) is a subset of multifocal choroiditis that occurs secondary to infection with the yeast form of Histoplasma capsulatum, a dimorphic fungus commonly found in bird and bat fecal material. The peculiarities of the disease are the following: atrophic chorioretinal scars, peripapillary atrophy (PPA), absence of vitritis, and choroidal neovascularization (CNV), which represents the most dangerous sequela. The disease can be unilateral or bilateral. The word “presumed” reflects the considerable controversy over the cause of POHS. Although POHS has been described in endemic areas such as Ohio and Mississippi river valleys, this disease has been reported in a few non-US countries including Mexico, India, the UK, and the Netherlands also. Recently, this clinical entity has been

included in the list of the so-called idiopathic multifocal choroiditis. It seems to be carried on the feathers of blackbirds, pigeons, and chickens, as well as in the droppings from infected bats. The way of infection in humans is due to the inhalation of the spore or conidia form, followed by hematogenous spread of the fungus to the choroidal tissue. Epidemiological studies have postulated the correlation between H. capsulatum and POHS, since those patients were positive to histoplasmin skin antigen test. On the other hand, all patients with clinical features of POHS were histoplasmin skin antigen test negative in a European study conducted in the Netherlands. HLA haplotypes DRw2 and B7 were correlated to POHS, and very recently some authors have hypothesized that the disease could also be the expression of an autoimmune inflammatory process triggered by H. capsulatum as well as

P. Neri (*) · V. Pirani · M. Nicolai · A. Saitta The Ocular Immunology Service, Università Politecnica delle Marche, Ancona, Italy The Eye Clinic, Università Politecnica delle Marche, Ancona, Italy e-mail: [email protected]; [email protected]; piranivittorio@virgilio. it; [email protected]; [email protected] I. Arapi University Hospital Mother Teresa, Tirana, Albania e-mail: [email protected] C. Mariotti · A. Giovannini The Eye Clinic, Università Politecnica delle Marche, Ancona, Italy e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_40

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Fig. 1 Confluent atrophic chorioretinal scars in a linear pattern (a) and random atrophic spots (b) observed in the mid-periphery of the left eye

other infective agents. In the medical literature, higher concentrations of HLA DRw2 were found in those patients that developed disciform and peripheral scars. In addition, most of patients with clinical POHS and macular disciform scars in at least one eye are positive for HLA-B7.

Case 1: Paediatric POHS Complicated by Peripapillary CNV A 7-year-old Caucasian female patient presented with blurred vision in her left eye associated with metamorphopsia. The best corrected visual acuity (BCVA) was 20/20 and 20/50 in her right (RE) and left eye (LE), respectively. The examination of the anterior chamber (AC) did not show cells and flare, as well as keratic precipitates (Kps). The vitreous was clear in both eyes, and the binocular indirect ophthalmoscope (BIO) score was 0+ in both eyes. The fundus examination of the right eye was unremarkable, while the left eye revealed confluent atrophic chorioretinal scars in a linear pattern with variable pigmentation in the mid-periphery (Fig. 1a), as well as random atrophic spots (Fig. 1b). The posterior pole presented PPA and a yellowish sub-retinal lesion located at the temporal side of the optic nerve head, compatible with a choroidal neovascularization (CNV, Fig. 2). The optical coherence tomography (OCT) revealed a hyper-reflective area surrounded by intra-/sub-retinal fluid that threatened the foveal region (Fig. 3a), confirming the active stage of the CNV. The patient underwent a full screening for posterior uveitis that was unremarkable. The parents of the young patient denied travels to Histoplasma capsulatum-endemic areas, and the histoplasmin skin antigen test was negative.

Fig. 2 Peripapillary area characterized by atrophic spots (white arrows) and yellowish sub-retinal lesion located in the temporal side of the optic nerve head (black arrow)

Considering the clinical findings and the tests performed, the diagnosis of POHS complicated by peripapillary CNV was made. The patient received systemic prednisone (1 mg/Kg) gradually tapered, associated with two intravitreal 1.25 mg bevacizumab monthly injections. At 3-month follow-up the OCT revealed an evident reduction of CNV thickness and the absorption of the intraretinal fluid with an improvement of BCVA that was 20/25 (Fig. 3b). At 12-month follow-up the CNV remained stable as well as the other clinical findings with a BCVA of 20/25. No further treatments were required up to date.

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Fig. 3 OCT scan at base-line showing a hyper-reflective lesion (white arrow) compatible with a peripapillary CNV, surrounded by hypo-reflective area typical of sub-/intra-retinal fluid (a) threatening the fovea. The same scanned area after treatment showed an evident reduction of the hyper-reflective area and the drying of the retinal tissue (b)

Case 2: Accidental Finding of POHS Lesions in an Asymptomatic Patient A 42-year-old Caucasian man was referred to the ocular immunology service for the accidental finding of retinal lesions that were described during a standard yearly ophthalmological examination. The BCVA was 20/20 in both eyes. The examination of the AC showed neither cells nor flare, and Kps were not observed. The vitreous was clear in both eyes, with a BIO score of 0+ in both eyes. The posterior pole was characterized by peripapillary scars in the RE (Fig. 4) without anomalies in the contralateral one. The mid-periphery of the RE showed confluent yellowish atrophic chorioretinal scars in a linear pattern as well as random atrophic spots (Fig. 5a). All tests performed were negative. No evidence of active inflammation was observed during the examination. The patient denied travels to Histoplasma capsulatum-endemic countries, and he was negative to the histoplasmin skin antigen test. Therefore, the patient was followed up at 3, 6, and 12 months without any treatment, showing a stable BCVA and still no evidence of inflammatory activity up to the last follow-up. The only remark was the progressive change of the pigmentation of the atrophic spots, which has become darker progressively (Fig. 5b).

Fig. 4 Optic nerve head of the RE showing peripapillary atrophic spots

The patient underwent several visits up to date, without showing any sign of recurrence of posterior uveitis, with stable BCVA, and without symptoms. Key Points • POHS can be present in non-US countries. • The peculiar clinical findings are: (a) Peripapillary scars

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Fig. 5 Confluent yellowish atrophic chorioretinal scars in a linear pattern associated with random atrophic spots in the mid-periphery of the RE (a). Pigmented atrophic spots observed in the same region of the mid-periphery after 12-month follow-up (b)

(b) Confluent atrophic chorioretinal scars in a linear pattern associated with random atrophic spots in the mid-periphery of the retina (c) CNV with variable location (peripapillary, sub-foveal) • CNV can progress to a disciform scar with sub-retinal fibrovascular tissue. • Systemic steroids associated with intravitreal anti-vascular endothelial growth factor (VEGF) can be an effective treatment for those cases complicated by CNV. • In those cases without neovascular complications, followups are recommended without any treatment. • Chorioretinal scars can change their pigmentation during the time.

Suggested Reading Cionni DA, Lewis SA, Petersen MR, Foster RE, Riemann CD, Sisk RA, Hutchins RK, Miller DM. Analysis of outcomes for intravitreal bevacizumab in the treatment of choroidal neovascularization secondary to ocular histoplasmosis. Ophthalmology. 2012;119(2):327–32. Diaz RI, Sigler EJ, Rafieetary MR, Calzada JI. Ocular histoplasmosis syndrome. Surv Ophthalmol. 2015;60(4):279–95. Essex RW, Wong J, Jampol LM, Dowler J, Bird AC. Idiopathic multifocal choroiditis: a comment on present and past nomenclature. Retina. 2013;33(1):1–4. Neri P, Lettieri M, Fortuna C, Manoni M, Giovannini A. Inflammatory choroidal neovascularization. Middle East Afr J Ophthalmol. 2009;16(4):245–51.

Toxocariasis Reema Bansal, Vishali Gupta, and Amod Gupta

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 Case 1: Ocular Toxocariasis with Peripheral Granuloma and Subretinal Fibrosis . . . . . . . . . . . . . . . . . . . 317 Case 2: Ocular Toxocariasis with Disc Granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 Case 3: Ocular Toxocariasis with Disc Granuloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

Introduction Toxocariasis is a parasitic disease of the humans caused by the larvae of Toxocara canis (dog or fox roundworm) or Toxocara cati (cat roundworm). The eggs from these roundworms are shed in dog and cat faeces and infect the local environment. The humans may get accidentally infected by eating food contaminated with soil or uncooked food. This condition usually affects children in close contact with pets. Ocular toxocariasis may present with three clinical manifestations: Covert toxocariasis (subclinical febrile illness in children), visceral larva migrans (caused by migration of second-stage larvae through internal human organs) and ocular larva migrans (ocular toxocariasis). Ocular toxocariasis is an isolated disease and is typically unilateral. Diagnosis is largely clinical and is characterized by three forms: a peripheral granuloma, posterior pole granuloma and endophthalmitis. The migration of the larvae into the retina causes granuloma formation, seen as a dense yellowish-white mass in the periphery or posterior pole, accompanied by dense vitritis. A radial fold is often seen extending from the granuloma to the optic disc. Other rare manifestations may include optic neuritis, vasculitis, or neuroretinitis. Visual loss occurs due to tractional

retinal detachment. Other complications include epiretinal membrane, cataract, and choroidal neovascular membrane. Oral or periocular steroids are recommended for severe inflammation. The role of anti-helminthic drugs is not clear. Small granulomas without vitritis may be left alone. Pars plana vitrectomy is indicated in eyes with tractional complications such as retinal detachment or epiretinal membrane.

Case 1: Ocular Toxocariasis with Peripheral Granuloma and Subretinal Fibrosis A 12-year-old boy presented with decreased vision in left eye since 7 months. The visual acuity was 6/6 in right eye and counting fingers in left eye. The right eye was normal and there was a relative afferent pupillary defect in left eye. Fundus examination of left eye revealed dense vitritis, a peripheral granuloma, and a fibrous band extending from granuloma to the disc (Fig. 1). He underwent pars plana vitrectomy in left eye. The media improved but the vision remained counting fingers at 3 months follow up with atrophy of retina and subretinal fibrosis (Fig. 2).

R. Bansal (*) · V. Gupta · A. Gupta Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_47

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Fig. 1 Fundus photograph of left eye showing dense vitritis, a peripheral granuloma and a fibrous band extending from granuloma to the disc Fig. 3 Fundus photograph showing dense vitritis and a granuloma lying nasal to the disc causing tractional retinal detachment

Fig. 2 Fundus photograph at 3 months following vitrectomy showing the residual retinal fold extending from peripheral granuloma to the disc with atrophy of retina and subretinal fibrosis

Case 2: Ocular Toxocariasis with Disc Granuloma A 19-year-old female presented with counting fingers vision in left eye since 6 months. The right eye was normal. Left eye had vitreous cells, and a granuloma lying nasal to the disc causing tractional retinal detachment (Fig. 3). Pars plana vitrectomy with cyst excision led to visual improvement to 6/12 at 8 months follow up. The retinal fold flattened significantly (Fig. 4). Cytological examination of the vitreous fluid

Fig. 4 Fundus photograph following pars plana vitrectomy and cyst excision showing flattening of the retinal fold

revealed numerous eosinophils, macrophages, lymphocytes, and degenerated cells.

Case 3: Ocular Toxocariasis with Disc Granuloma A 13-year-old girl presented with diminution of vision in right eye since 15 days. She had 6/60 vision in right eye. The left eye was normal. The right eye had a relative afferent pupillary defect,

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Fig. 5 Fundus photograph showing dense vitritis and a granuloma over the optic disc with peripapillary tractional retinal detachment

Key Points • Ocular toxocariasis is typically unilateral with significant visual loss, usually affecting children. • Accidental ingestion of eggs of Toxocara roundworms by humans causes this disease. • Retinal invasion leads to granuloma formation and significant vitreous inflammation. • Typically, the granuloma forms in the periphery or posterior pole. Rarely, endophthalmitis may occur due to intraocular death of larvae. • A radial fold of retina between the disc and granuloma is highly characteristic of toxocariasis. • Vitrectomy is indicated for tractional retinal detachment or epiretinal membrane.

Suggested Reading Fig. 6 Fundus photograph following pars plana vitrectomy showing resolution of tractional retinal detachment

vitreous cells, and a granuloma over the optic disc with peripapillary tractional retinal detachment (Fig. 5). Pars plana vitrectomy led to resolution of tractional retinal detachment (Fig. 6). The visual acuity was 6/18 in right eye at 1 year of follow up.

Belmont JB, Irvine A, Benson W, et al. Vitrectomy in ocular toxocariasis. Arch Ophthalmol. 1982;100:1912–5. Biziorek B, Herbort CP. Ocular toxocariasis. In: Gupta A, Gupta V, Herbort CP, Khairallah M, editors. Uveitis: text and imaging. 1st ed. New Delhi: Jaypee; 2009. p. 682–6. Molk R. Ocular toxocariasis: a review of literature. Ann Ophthalmol. 1983;15:216–31. Shields JA. Ocular toxocariasis: a review. Surv Ophthalmol. 1984;28:361–81.

Toxoplasma Retinochoroiditis Aniruddha Agarwal, Kanika Aggarwal, Pooja Bansal, Alessandro Invernizzi, Reema Bansal, and Vishali Gupta

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Case 1: Toxoplasma Retinochoroiditis in a Young Male . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 Case 2: Observation Can Be the Proper Choice for Peripheral Lesions in an Immunocompetent Host . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 Case 3: Toxoplasma Chorioretinitis Mimicking Viral Necrotizing Retinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 324 Case 4: Macular Lesions in Toxoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

Introduction Toxoplasmosis is a common infectious cause of posterior uveitis. The causative organism is a parasite, Toxoplasma gondii, a single-cell intracellular protozoan. While cats serve as the definite host for the organism, mammals including humans can act as intermediate host. The active infectious form is the tachyzoite. It is estimated that more than one billion individuals worldwide are infected with this organism.

A. Agarwal (*) · K. Aggarwal (*) · R. Bansal (*) · V. Gupta (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected] P. Bansal (*) Dr. Rajendra Prasad Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India e-mail: [email protected] A. Invernizzi (*) Uveitis and Ocular Infectious Diseases Service – Eye Clinic, Department of Biomedical and Clinical Science, Luigi Sacco Hospital, University of Milan, Milan, Italy e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_44

The hallmark of ocular toxoplasmosis is necrotizing retinochoroiditis that is often associated with dense vitreous inflammation (headlight-in-fog appearance). Lesions are typically located in the posterior pole and adjacent to previous pigmented scars/atrophic areas suggestive of congenital toxoplasma infection. Primary acquired toxoplasmosis is associated less frequently with ocular disease. More than 85% cases can have bilateral involvement. Classic findings of ocular toxoplasmosis include whitish focal area of retinochoroiditis with accompanying anterior chamber inflammation (non-granulomatous or associated with stellate keratic precipitates). Atypical disease can present with peripheral tongue-shaped lesions mimicking viral retinitis, optic neuritis, retinal vasculitis, retrobulbar neuritis, or occlusive vasculitis. Due to the widespread prevalence of the disease, qualitative serology has certain limitations in establishing the diagnosis. Quantitative serology and polymerase chain reaction of aqueous/vitreous fluid are considered to be superior with higher sensitivity and specificity. The mainstay of therapy includes anti-toxoplasma antibiotics such as clindamycin (administered orally and/or intravitreally), azithromycin, and sulfamethoxazole + trimethoprim. Intravitreal therapy with clindamycin

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may avoid systemic side effects such as pseudomembranous colitis due to oral administration of the drug. In the index chapter, various cases of ocular toxoplasmosis along with their imaging characteristics have been illustrated.

Case 1: Toxoplasma Retinochoroiditis in a Young Male A 29-year-old male presented to the ophthalmology clinic with complaints of decreased vision in the left eye for the past 10 days. There was no history of prior ocular or systemic complaints. The best-corrected visual acuity (BCVA) was counting fingers at 1 m in the left eye and 20/20 in the right eye. Intraocular pressure was recorded as 44 mmHg in the left eye. Anterior segment examinations revealed 3+ cells and 2+ flare in the left eye. There was presence of corneal edema in the left eye. Fundus examination of the left eye showed 3+ vitreous haze, dense vitritis (headlight-in-fog appearance), and a yellowish-white lesion in the superior macula (Fig. 1). Fluorescein angiography revealed early hypofluorescence followed by late hyperfluorescence and leakage (Fig. 2). Optical coherence tomography (OCT) revealed the presence of intraretinal fluid. Since the clinical presentation was suspicious for toxoplasma retinochoroiditis, serology Fig. 1 Color fundus photographs of a patient with toxoplasma retinochoroiditis. Examination of the right eye was unremarkable (a). In the left eye, there is dense vitritis (“headlight-in-fog” appearance) along with a retinochoroiditis lesion in the superior macula and superotemporal to the optic disk (b)

Fig. 2 Fluorescein angiography of the left eye shows early hypofluorescence (a) and late hyperfluorescence with leakage (b) in the region of toxoplasma retinochoroiditis lesion

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was performed and other infectious etiologies were ruled out. Toxoplasma serology (IgM and IgG) was strongly positive. The patient received intravitreal clindamycin (1 mg/0.1 ml) and dexamethasone (4 mg/0.1 ml) along with oral sulfamethoxazole + trimethoprim and topical corticosteroids. Antiglaucoma therapy (oral acetazolamide and topical brimonidine) was initiated along with topical corticosteroids and atropine. After 3 weekly intravitreal injections of clindamycin + dexamethasone, there were clinical improvement and reduction in the retinal thickness on OCT (Figs. 3 and 4).

Case 2: Observation Can Be the Proper Choice for Peripheral Lesions in an Immunocompetent Host A 14-year-old boy was referred for decreased vision in his left eye since 5 days. At presentation his BCVA was 20/20 in the right eye and 20/40 in the left eye. At slit-lamp examination the right eye did not show any relevant finding. In the anterior chamber of the left eye, a mild inflammatory reaction (1+ cells) was detected. Intraocular pressure measured 14 mmHg in both eyes. Funduscopic examination was normal in the right eye. There were 2+ vitreous cells in the left eye mostly localized in the superior quadrants of the posterior

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Fig. 3 Follow-up color fundus photography of the left eye at 2 weeks (a) and 4 weeks (b) after intravitreal clindamycin + dexamethasone and oral sulfamethoxazole + trimethoprim therapy. There are resolution of vitritis and decrease in the size of the retinochoroiditis lesion

Fig. 4 Optical coherence tomography (OCT) at baseline (a), 2 weeks (b), and 4 weeks (c) of the left eye in the region of the toxoplasma retinochoroiditis lesion. At baseline, there is retinal thickening,

intraretinal fluid, and disruption of the retinal layers. At 2 weeks, there is an interval decrease in the retinal edema. At 4 weeks, there are disruption and atrophy of the retinal layers and scar formation

chamber. In the same region, a one papillary diameter large active chorioretinal lesion was visible. Margins of the focus appeared ill defined and multiple signs of vasculitis were detected (Figs. 5, 6, and 7). Toxoplasma serology was positive for disease reactivation (IgG+, IgM ), and other laboratory evaluation revealed that the subject was not immunocompromised. Since the infectious focus was not considered to be sight threatening, no specific antibiotic treatment was initiated. Mydriatic drops and mild topical steroids were started to control anterior chamber inflammation and prevent formation of synechiae. A strict follow-up consisting of two visits/week was scheduled in order to shift the approach from observational to interventional

in case of worsening. After a couple of weeks, the vision was restored to 20/20 and the anterior chamber was quiet. One month after the initial presentation, the vitreous haze was resolved and the active focus appeared to be completely healed. The lesion appeared as a small pigmented scar along a vessel aside the recently healed lesion (Fig. 8). This older focus likely represented the first localization of the parasite during the primary infection and the origin of the reactivation process. Careful observation and a strict follow-up can allow the physician to monitor the disease activity. In case of small peripheral lesions not threatening the vision in immunocompetent hosts, observation can be done to allow spontaneous resolution of inflammation.

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Case 3: Toxoplasma Chorioretinitis Mimicking Viral Necrotizing Retinitis

Fig. 5 Peripheral fundus photograph of the left eye showing an active chorioretinal lesion and vasculitis Fig. 6 A combined imaging (OCT + fluorescein angiography + indocyanine green angiography) confirmed the presence of a chorioretinitis accompanied by multiple breakdowns of the blood retinal barrier along the inflamed vessels

Fig. 7 A combined imaging (OCT + fluorescein angiography + indocyanine green angiography) confirmed the presence of a chorioretinitis accompanied by multiple breakdowns of the blood retinal barrier along the inflamed vessels

A patient was referred for a second opinion after uveitis worsening in response to local steroid injection in his right eye. At presentation, BCVA was hand movements in the right eye and 20/20 in the left eye. The right eye showed conjunctival injection, corneal edema, 3+ cells in the anterior chamber, and intraocular pressure of 26 mmHg. Examination of the left eye was within normal limits. Funduscopic examination revealed a large area of necrotizing chorioretinitis involving the whole posterior pole (Fig. 9). The patient had received a local injection of steroids for an ocular inflammation about 1 week earlier. Due to the absence of pigmented scars that suggest the toxoplasma etiology, clinical picture was highly suggestive for a viral retinitis in the form of progressive outer retinal necrosis. Nevertheless, immunocompromised hosts often develop unusual disease forms, thus a diagnostic vitrectomy was immediately performed in order to initiate the proper therapy. To our surprise, PCR performed on the vitreous tap was negative

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Fig. 8 Fundus photograph of the periphery shows the presence of healed chorioretinal lesion

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Fig. 10 Fundus photograph of the right eye shows healing of the toxoplasma lesion

healed although the vision did not improve due to extensive central retinal pathology (Fig. 10). Toxoplasma retinochoroiditis can have protean manifestations especially in immunocompromised hosts, or in case of local administration of steroids, it can resemble a viral retinitis. Extensive laboratory analysis in such challenging cases is essential in order to find the correct diagnosis and start proper therapy.

Case 4: Macular Lesions in Toxoplasmosis

Fig. 9 Fundus photograph of the right eye shows the presence of a large necrotizing retinochoroiditis lesion involving the posterior pole

for viruses and strongly positive for Toxoplasma gondii. Serology for toxoplasma was positive (IgG+ and IgM+). Considering the severity of the clinical picture and previous local steroid administration, a combined approach was used that included systemic therapy with pyrimethamine and sulfadiazine boosted by a single intravitreal injection of clindamycin. After 2 weeks, the lesion was completely

A 44-year-old female presented with complaints of decreased vision and floaters in the right eye for the past 2 months. There was no history of previous ocular complaints or trauma. Systemic evaluation was within normal limits. The BCVA in the right eye was counting fingers at 2 m and 20/20 in the left eye. Intraocular pressure measured 18 mmHg in both eyes. Slit-lamp biomicroscopy revealed the presence of 0.5+ cells in the anterior chamber of the right eye. Posterior segment examination of the right eye showed the presence of 1+ vitritis and a hypopigmented ill-defined area around the fovea. There were two noncontiguous lesions in the upper temporal retina. One of the lesions appeared as a chorioretinal scar with hyperpigmentation. The other lesion showed discrete edges and barring of choroidal vessels (Fig. 11). Fluorescein angiography showed the presence of hyperfluorescence in the macula (late phase) corresponding to the retinal opacification (Fig. 12). Laboratory

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Fig. 11 Color fundus photographs of a patient with toxoplasma retinochoroiditis. At initial presentation, examination of the right eye revealed the presence of opacification and whitening of the macula in the right eye (a). Examination of the periphery revealed the presence of a pigmented scar and a noncontiguous inactive retinochoroiditis lesion (b). Examination of the left eye was unremarkable (c)

Fig. 12 Fundus fluorescein angiography of the right eye in early phase (a) shows subtle pinpoint leakage at the macula in the right eye. In the late phase, there is evidence of multifocal areas of hyperfluorescence in the macula along with retinal periphlebitis (b)

investigations revealed negative tuberculin test, syphilis, and HIV. Serum toxoplasma serology was equivocal. Due to the high clinical suspicion of toxoplasmosis, vitreous paracentesis was performed which was positive for toxoplasma polymerase chain reaction (Fig. 13). The patient received intravitreal clindamycin (1 mg/0.1 ml) and dexamethasone (4 mg/0.1 ml) along with oral sulfamethoxazole + trimethoprim and topical corticosteroids. After 2 weeks, there were resolution of anterior segment inflammation and healing of the macular lesions (Fig. 14). The BCVA improved to 20/60.

Key Points • Ocular toxoplasmosis is an emerging disease in endemic as well as non-endemic areas as an important cause of infectious retinochoroiditis. • Toxoplasma retinochoroiditis presents with necrotizing retinochoroiditis adjacent to a retinochoroidal scar along with vitritis, vasculitis, and optic neuritis. • The diagnosis of ocular toxoplasmosis is mainly clinical. However, serology and intraocular fluid analysis using polymerase chain reaction may be very helpful in atypical cases.

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Fig. 13 Polymerase chain reaction showing positive toxoplasmosis from the vitreous sample of the patient. Asterisk indicates negative control. Dagger (†) indicates positive control. The result of the index case is indicated by a double dagger (‡)

Fig. 14 Follow-up color fundus photographs of the right eye after intravitreal clindamycin + dexamethasone therapy at 2 weeks. (a) There is resolution of macular whitening (b)

• Treatment of ocular toxoplasmosis consists of specific antibiotic therapy given either systemically or intravitreally. Commonly used antibiotics include sulfamethoxazole/trimethoprim, clindamycin, and sulfadiazine/pyrimethamine (along with folinic acid).

Suggested Reading Bonfioli AA, Orefice F. Toxoplasmosis. Semin Ophthalmol. 2005;20 (3):129–41.

Furtado JM, Winthrop KL, Butler NJ, Smith JR. Ocular toxoplasmosis I: parasitology, epidemiology and public health. Clin Experiment Ophthalmol. 2013;41(1):82–94. Kim SJ, Scott IU, Brown GC, Brown MM, Ho AC, Ip MS, Recchia FM. Interventions for toxoplasma retinochoroiditis: a report by the American Academy of Ophthalmology. Ophthalmology. 2013;120(2):371–8. Maenz M, Schlüter D, Liesenfeld O, Schares G, Gross U, Pleyer U. Ocular toxoplasmosis past, present and new aspects of an old disease. Prog Retin Eye Res. 2014;39:77–106. Vasconcelos-Santos DV. Ocular manifestations of systemic disease: toxoplasmosis. Curr Opin Ophthalmol. 2012;23(6):543–50.

Posterior Segment Manifestations of Cysticercosis Muna Bhende and Pramod S. Bhende

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 Case 1: Extensive Intraocular Inflammation with Subretinal Cysticercosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 Case 2: Subretinal Cysticercosis with Macular Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 Case 3: Subretinal Cysticercosis in the Inferonasal Quadrant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 Case 4: Live Cysticercosis Cyst in Vitreous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

Introduction Human cysticercosis is a parasitic infection caused by Cysticercus cellulosae, the encysted larval form of the pork tapeworm, Taenia solium. Infection with tapeworm is called Taeniasis whereas infection with cysticercus (cysticercus cellulosae) is called cysticercosis. This condition is contracted by ingestion of cysticercus larvae in raw or inadequately cooked pork, contaminated vegetables (food), or drinking polluted water. Acute infection may rarely occur by vomiting or antiperistaltic movements whereby proglottids may be forced from the upper bowel to the stomach and then digested. The sites of predilection include the central nervous system, subcutaneous tissue, skeletal muscles, heart muscles, eye, lung, and peritoneum. Ocular involvement occurs in 13–46% of infested patients. Cysticercosis is endemic to all continents except Australia. It is commonly found in Mexico, Central and South America as well as Africa, China, Pakistan, and India. Soemmering reported the first case of ocular cysticercosis in the anterior chamber in 1830. The same larva was extracted by Schott in 1836. Von Graefe (1854) first

noted the parasite ophthalmoscopically in the vitreous and was the first to extract it from that location. The adult worm, around 3 m in length, inhabits the small intestine of a human, the definitive host. It has a globular scolex and around 1000 proglottids. Segments of gravid proglottids pass out of the host daily, each enclosing thousands of eggs. When these eggs are eaten by a pig, the natural intermediate host, they hatch after reaching the intestine, pass through the mucosal wall, reach the blood or lymph circulation, and finally get lodged in various organs and tissues, where in 2–3 months, they develop into larvae (cellulosae). When infected pork is eaten by a human, a cysticercus, on reaching the intestine evaginates its scolex and anchors itself to the mucosal wall. In 2–3 months, it grows into an adult worm and life cycle is completed. Occasionally, humans act as intermediate host by eating fecally contaminated food or by auto-infestation (due to reverse peristalsis and regurgitation). The ova hatch in the upper intestinal tract, penetrate the intestinal wall, and enter the circulatory system. In the eye, the cyst can lodge in any tissue ranging from lids, lacrimal gland, and subconjunctival space to the subretinal space or optic nerve head, the commonest location

M. Bhende · P. S. Bhende (*) Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, India e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_120

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being submacular region. Involvement of extraocular muscle has also been well described. Neurocysticercosis may be associated with ocular cysticercosis. In the posterior segment, access of the parasite to the subretinal space is presumably, through the posterior ciliary arteries. From this location, they usually pass through a break in the retina into the vitreous. A rhegmatogenous retinal detachment may develop or the perforation may be sealed by an inflammatory reaction which leaves a chorioretinal scar. In rare cases, the parasite may pass from the vitreous, through the pupil, into the anterior chamber. Presence of the cyst on the disc may indicate entry through the central retinal artery. Infestation of the ocular adnexa occurs probably through the anterior ciliary arteries. Intraocular cysticercosis may be asymptomatic in the early stage. As the parasite increases in size, it can cause a gradual, painless, progressive loss of vision. Patients may describe a roundish or irregularly shaped, dark mobile mass (intravitreal location) or may experience visual field defect (subretinal or optic nerve location). Patient may present with exudative or rhegmatogenous retinal detachment. The cyst is well tolerated while the larva is alive. However, when the parasite dies, it elicits a marked inflammatory response and may lead to a blind, painful eye. Infection can sometimes present with a subconjunctival cyst and in rare instances as a subconjunctival abscess or a painless, subcutaneous nodular mass. Intraocular cysticercosis can be easily diagnosed by ophthalmoscopy. The translucent white cyst with a dense white spot formed by the invaginated scolex is characteristic and can be easily recognized. The scolex can be seen to move rapidly within the cyst when exposed to the bright light of an indirect ophthalmoscope. In eyes with media opacity, highresolution ultrasonography displays the characteristic echolucent cyst with well-defined high-reflective walls. The presence of a characteristic central, highly reflective, curvilinear structure within the cyst suggestive of scolex helps to narrow the differential diagnosis to cysticercosis. It is important to rule out involvement of other systems in ocular cysticercosis, most importantly the central nervous system. It is not uncommon to have associated neurocysticercosis which needs to be managed medically hence involvement of an internist is recommended. No effective antihelminthic drug is available for treatment of intraocular cysticercosis, probably because of insufficient penetration of the drug inside the eye. The treatment for intraocular cysticercosis is always surgical. Early surgery should be advocated in all the cases. The approach depends on the location of the cyst. Subretinal cysts can be removed by an intravitreal or transscleral approach. Pars plana vitrectomy has been proved to be an ideal procedure for removal of intravitreal cysticercosis. The cyst can be removed intact or can be cut and removed with a vitreous cutter without compromising the anatomical and functional outcome.

M. Bhende and P. S. Bhende

Case 1: Extensive Intraocular Inflammation with Subretinal Cysticercosis A 39-year-old male presented with complaints of reduced vision and pain in the right eye of 2 months duration. The left eye was asymptomatic and normal in all respects. BCVA in the right eye was 20/80, anterior segment showed pigments on the lens and early cataract with intraocular pressure of 10 mm of

Fig. 1 Preoperative fundus picture showing extensive vitreous inflammation around the subretinal cyst

Fig. 2 Post-operative fundus picture showing a clear vitreous cavity and scarring at the cyst site, sparing the posterior pole

Posterior Segment Manifestations of Cysticercosis

Hg. Fundus showed vitreous membranes, partial retinal detachment, and a subretinal cysticercus cyst (Fig. 1). The patient underwent pars plana vitrectomy, encirclage, cyst removal through a retinotomy, and extraction through the sclerotomy with the help of an endocryo probe. This was followed by endolaser and silicone oil tamponade. BCVA improved to 20/40 6 months after surgery, with a quiet eye and attached retina with scarring at the site of the cyst (Fig. 2). He later underwent uneventful silicone oil removal with phacoemulsification and intraocular lens implantation after 1 year.

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Case 2: Subretinal Cysticercosis with Macular Involvement A 35-year-old male presented with diminution of vision in the right eye. Ophthalmoscopy demonstrated presence of a subretinal cysticercosis cyst in the superotemporal region of the retina involving the macula (Fig. 3). Pars plana vitrectomy and removal of the cyst was planned. Preoperative visual acuity was counting fingers close to face. Fundus after successful vitrectomy with cyst removal showed

Fig. 3 Subretinal cyst involving the macula, with significant pigment epithelial changes around the lesion

Fig. 5 Subretinal cyst in the inferonasal quadrant

Fig. 4 Post-operative photograph showing extensive scarring at the posterior pole, accounting for the poor visual outcome

Fig. 6 Fundus picture post surgery showing scarring at the location of the cyst but with a healthy posterior pole

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Fig. 7 Fundus picture showing vitreous haze

Fig. 9 Cysticercus cyst with a scolex, seen in the vitreous cavity surrounded by inflammatory debris. Change in the cyst contour with increased illumination is seen, signifying a live cyst

Fig. 8 Cysticercus cyst with a scolex, seen in the vitreous cavity surrounded by inflammatory debris. Change in the cyst contour with increased illumination is seen, signifying a live cyst

Fig. 10 B-scan ultrasonography of an intravitreal cysticercus cyst. Note the smooth walled cyst which is echolucent except for a localized area of high reflectivity representing the scolex. This feature distinguishes it from intraretinal cysts seen in long standing detachments

extensive scarring at the site of the cyst which limited the vision improvement to 20/400 (Fig. 4).

inferonasal quadrant (Fig. 5) that stabilized after pars plana vitrectomy and cyst removal at 20/20 (Fig. 6).

Case 3: Subretinal Cysticercosis in the Inferonasal Quadrant

Case 4: Live Cysticercosis Cyst in Vitreous

A 30-year-old male presented with mild diminution of vision in the left eye. Ocular examination did not reveal significant anterior or posterior segment inflammation. Fundus examination of the macula was unremarkable. Due to the absence of significant inflammation and sparing of the posterior pole, the visual acuity was recorded to be 20/30. There was presence of a large subretinal cysticercosis lesion in the

A patient presented with significant vitreous inflammation (Fig. 7) and a live cyst in the vitreous cavity which changed in contour with increased illumination (Figs. 8 and 9). Ultrasonography findings of the cyst are illustrated in Fig. 10. The patient underwent successful vitrectomy with cyst removal and later cataract surgery with IOL implantation. Final BCVA was 20/50 with an attached retina and epiretinal membrane at the macula.

Posterior Segment Manifestations of Cysticercosis

Key Points • Ocular involvement in cysticercosis may occur in a significant proportion of patients infested with the organism and may include various tissues such as conjunctiva, adnexa, anterior and posterior segments, as well as extraocular muscles. • Posterior segment manifestations include cyst involving the retina or the optic nerve head with vitritis, exudative retinal detachment, scarring, and membranes or associated pigment epithelial changes. • Management of ocular cysticercosis must include search for extraocular disease such as neurocysticercosis which requires medical management to prevent complications of the condition. • Intraocular cysts are removed surgically using pars plana vitrectomy.

Suggested Reading Ament CS, Young LH. Ocular manifestations of helminthic infections: onchocersiasis, cysticercosis, toxocariasis, and diffuse unilateral subacute neuroretinitis. Int Ophthalmol Clin. 2006;46:1–10. Arciniegas A, Gutierrez F. Our experience in the removal of intravitreal and subretinal cysticerci. Ann Ophthalmol. 1988;20:75–7.

333 David S, Mathai E. Ocular cysticercosis-a review of 25 cases. J Assoc Physicians India. 2000;48:704–7. Gupta A, Gupta R, Pandav SS, et al. Successful surgical removal of encapsulated subretinal cysticercus. Retina. 1998;18:563–6. Kaliaperumal S, Rao VA, Parija SC. Cysticercosis of the eye in South India – a case series. Indian J Med Microbiol. 2005;23:227–30. Lerdvitayasakul R, Lawtiantong T. Removal of submacular cysticercosis: a case report. J Med Assoc Thai. 1991;74:675–8. Luger MH, Stilma JS, Ringens PJ, et al. In-toto removal of a subretinal Cysticercus cellulosae by pars plana vitrectomy. Br J Ophthalmol. 1991;75:561–3. Natarajan S, Malpani A, Kumar Nirmalan P, et al. Management of intraocular cysticercosis. Graefes Arch Clin Exp Ophthalmol. 1999;237:812–4. Sharma T, Sinha S, Shah N, et al. Intraocular cysticercosis: clinical characteristics and visual outcome after vitreoretinal surgery. Ophthalmology. 2003;110:996–1004. Steinmetz RL, Masket S, Sidikaro Y. The successful removal of a subretinal cysticercus by pars plana vitrectomy. Retina. 1989;9:276–80.

Posterior Segment Manifestations of Leptospirosis Sudheer Bhagya and S. R. Rathinam

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 Case 1: Hypopyon Uveitis in Leptospirosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 Case 2: Complicated Cataract in Leptospirosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 Case 3: Disc Edema in Leptospirosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

Introduction

Case 1: Hypopyon Uveitis in Leptospirosis

Leptospirosis is a zoonotic water borne illness in tropical countries caused by a spirochete of genus Leptospira. It presents in the initial phase as an acute febrile illness followed by an asymptomatic latent period, and uveitis is a late complication of leptospirosis. The incidence being 10–45%. The most common anatomical location is either anterior or panuveitis. Leptospirosis frequently presents as a nongranulomatous anterior uveitis. It is one of the important causes of hypopyon uveitis in leptospiral endemic areas. Early onset, rapid progression, and spontaneous absorption of cataractous lens is a unique feature in this uveitis; however, it is seen only in 10% of leptospiral uveitis. Dense vitreous inflammation with the formation of veil-like membranes is commonly seen in posterior segment. Exudative retinal vasculitis with perivascular sheathing of the vein is frequently seen in leptospiral uveitis, although occlusion and neovascularisation are uncommon. Disc hyperemia and edema can also be seen.

A 34-year-old male farmer by occupation presented with pain, redness, and blurred vision in right eye (RE) for one week. On examination his right eye showed nongranulomatous anterior uveitis with 2–3 mm hypopyon (Fig. 1). Fundus examination showed vitritis with exudative retinal vasculitis (Fig. 2). The basic workup included purified protein derivative (PPD) test, Treponema pallidum hemagglutination test, and erythrocyte sedimentation rate. The test results were inconclusive. Microagglutination test for leptospirosis (Lepto MAT) was positive. Patient was treated with oral doxycycline and steroids with complete resolution of uveitis.

S. Bhagya (*) Uvea Services, Aravind Eye Hospital, Madurai, Tamil Nadu, India e-mail: [email protected] S. R. Rathinam Department of Ophthalmology, Aravind Eye Hospital and PG Institute Ophthalmology, Madurai, Tamil Nadu, India e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_118

Case 2: Complicated Cataract in Leptospirosis A 56-year-old lady presented with defective vision in RE for 2 months which was painless and gradually progressive. She gave a history of contact with rats and had high grade fever with severe myalgia 6 months back. On examination her right eye showed total cataract (Fig. 3). Her blood investigations: PPD, erythrocyte sedimentation rate, and blood counts were within normal limits. Microagglutination test for leptospirosis (Lepto MAT) was positive (Fig. 4). She was operated for cataract and regained good vision postoperative.

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Fig. 1 Slit lamp photograph of the right eye showing nongranulomatous anterior uveitis with hypopyon in leptospiral uveitis in a young male

Fig. 4 Positive microagglutination test for leptospirosis (Lepto MAT)

Case 3: Disc Edema in Leptospirosis

Fig. 2 Fundus picture of the patient showing vitritis and exudative retinal vasculitis

Fig. 3 Slit lamp photograph of right eye with complicated cataract following leptospiral uveitis

A 23-year-old girl came with pain, redness, and defective vision in the right eye for 5 days. She gave history of developing high grade fever with myalgia and headache after taking bath in a pond near her village 2 weeks back. On examination her eye showed nongranulomatous KP’s with 1+ cells and flare. Her fundus showed disc hyperemia with flame-shaped hemorrhages in the superotemporal quadrant and free floating vitreous membranes and vitritis (Fig. 5). Her routine blood investigations and PPD provided no definitive diagnosis but her microagglutination test for leptospirosis (Lepto MAT) was positive. She was started on oral doxycycline and steroids in tapering doses and showed good improvement. Key Points • Uveitis is a late complication of leptospirosis that presents after an asymptomatic latent period. • In a patient coming with uveitis who resides in an endemic area, a past history of exposure to animal urine contaminated environment and a past febrile illness could raise a suspicion of leptospiral etiology. • Commonly presents as unilateral or bilateral acute, nongranulomatous pan uveitis with or without hypopyon,

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optic disc edema, retinal vasculitis, and membranous vitreous opacities. • Although the systemic morbidity is high, leptospiral uveitis carries good visual prognosis.

Suggested Reading

Fig. 5 Fundus photograph of the right eye showing disk hyperemia and flame-shaped retinal hemorrhages in superotemporal quadrant with free floating veil-like vitreous membranes

Durski KN, Jancloes M, Chowdhary T, Bertherat E. A global, multidisciplinary, multi-sectorial initiative to combat leptospirosis: Global Leptospirosis Environmental Action Network (GLEAN). Int J Environ Res Public Health. 2014;11:6000–8. Rathinam SR. Ocular leptospirosis. Curr Opin Ophthalmol. 2002;13:381–6. Rathinam SR, Rathnam S, Selvaraj S, Dean D, Nozik RA, Namperumalsamy P. Uveitis associated with an epidemic outbreak of leptospirosis. Am J Ophthalmol. 1997;124:71–9. Rathinam SR, Namperumalsamy P, Cunningham ET. Spontaneous cataract absorption in patients with leptospiral uveitis. Br J Ophthalmol. 2000;84:1135–41.

Rickettsial Infections of Retina Nesrine Abroug, Rim Kahloun, Bechir Jelliti, and Moncef Khairallah

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339 Case 1: Multifocal Rickettsial Retinitis with Retinal Vascular Occlusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339 Case 2: Rickettsial Infection Presenting as Neuroretinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

Introduction Rickettsial infection of the retina is frequent but usually asymptomatic and easily overlooked. It most commonly presents as bilateral or unilateral unifocal or multifocal superficial retinitis associated with mild vitritis. Retinal vascular involvement is common including focal or diffuse vascular sheathing, vascular leakage, retinal hemorrhages, and asymptomatic or rarely symptomatic vaso-occlusive events. Optic nerve involvement also is common including optic disc edema, optic disc staining, optic neuritis, neuroretinitis, and anterior ischemic optic neuropathy.

Case 1: Multifocal Rickettsial Retinitis with Retinal Vascular Occlusion A 32-year-old-male patient with a 1-week history of febrile illness presented with blurred vision in the left eye (LE). On examination, best-corrected visual acuity (BCVA) was 20/20 in the right eye (RE) and 20/32 in the LE. There were no anterior chamber or vitreous cells on slit lamp

biomicroscopy. Dilated fundus examination of the LE revealed multiple white retinal lesions of different sizes adjacent to retinal vessels (Fig. 1a). Fluorescein angiography showed early hypofluorescence and late staining of large lesions and focal retinal vascular leakage (Fig. 1b and c). Optical coherence tomography (OCT) section acquired through the inferotemporal retinal lesion disclosed increased inner retinal reflectivity with posterior shadowing and associated serous retinal detachment (Fig. 1d). Two days after initial presentation, fundus examination showed a triangular area of ischemic retinal whitening in the macular area (Fig. 2a). Fluorescein angiography confirmed the diagnosis of occlusion of a small macular branch retinal artery (Fig. 2b). OCT section acquired through the superotemporal retinal white lesions showed hyperreflectivity of the inner retinal layers with posterior shadowing corresponding to the area of superficial retinitis and increased reflectivity in the nerve fiber layer zone corresponding to the ischemic retinal whitening area seen clinically (Fig. 2c). The indirect immunofluorescence antibody test was positive for Rickettsia conorii, and the patient was treated with doxycycline (100 mg twice a day) for 10 days with subsequent improvement of visual acuity and gradual resolution of abnormal ocular findings (Fig. 3).

N. Abroug · R. Kahloun · B. Jelliti · M. Khairallah (*) Department of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_52

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Fig. 1 (a) Color fundus photograph of the LE shows multiple juxtavascular superficial white retinal lesions of variable sizes. (b) Early-phase fluorescein angiogram of the same eye shows hypofluorescence of large lesions. (c) Late-phase fluorescein angiogram of the same eye shows staining of the retinal lesions and associated focal

Case 2: Rickettsial Infection Presenting as Neuroretinitis A 44-year-old-female patient with a 1-month history of febrile illness with skin rash presented with vision loss in the RE. On examination, her BCVA was 20/200 in the RE and 20/20 in the LE. There was a relative afferent pupillary defect in the RE. Slit lamp examination revealed 1+ vitreous cells in the RE. Dilated fundus examination of the RE revealed optic disc swelling with macular star, retinal hemorrhages, and peripapillary serous retinal detachment consistent with a diagnosis of neuroretinitis (Fig. 4a). Fundus examination of the LE showed a white retinal lesion superior to the optic disc (Fig. 4b). Fluorescein angiography showed leakage from the optic disc with no evidence of macular abnormality in the RE (Fig. 5a) and late hyperfluorescence of the white retinal lesion in the LE (Fig. 5b). OCT confirmed the presence of peripapillary serous retinal detachment involving the fovea in the RE (Fig. 6). It also showed increased

N. Abroug et al.

retinal vascular leakage and mild optic disc hyperfluorescence. (d) Horizontal optical coherence tomography section acquired through the inferotemporal retinal lesion shows increased inner retinal reflectivity with posterior shadowing and associated serous retinal detachment

reflectivity within the inner retinal layers at the superficial retinal lesion in the LE (Fig. 7). Serological testing was negative for Bartonella henselae and positive for Rickettsia conorii. The patient was treated with doxycycline (100 mg twice a day) for 10 days. One month after initial examination, visual acuity was 20/32 in the RE and 20/20 in the LE. The optic disc edema and serous retinal detachment had completely resolved, with development of peripapillary hard exsudates in the RE (Fig. 8a and b). The white retinal lesion in the LE had almost completely resolved (Fig. 8c). Key Points • Systemic rickettsial disease usually presents as a self limited febrile illness with skin rash. • Ocular involvement is frequent but usually asymptomatic. • Rickettsial infection of the retina: unilateral or bilateral, focal or multifocal superficial retinitis, mild vitritis, retinal vasculitis, and optic nerve involvement. • The diagnosis is based on epidemiological data, systemic manifestations, and the pattern of ocular involvement.

Rickettsial Infections of Retina

Fig. 2 (a) Color fundus photograph of the same eye, two days later, shows the presence of a triangular area of ischemic retinal whitening adjacent to inflammatory lesion (arrowhead). (b) Early-phase fluorescein angiogram confirms the diagnosis of occlusion of a small macular branch retinal artery (white arrow). (c) OCT section of the same eye

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taken through the superotemporal white lesions reveals infiltration of the inner retinal layers with posterior shadowing corresponding to the area of superficial retinitis (white arrow) and increased reflectivity in the nerve fiber layer zone consistent with the diagnosis of branch retinal arterial occlusion (white arrowhead)

Fig. 3 Color fundus photograph of the same eye, taken two weeks after initial presentation, shows an almost complete resolution of the white retinal areas. Note the occurrence of a partial macular star

Confirmation of diagnosis relies on positive serology and PCR in selected cases. • Management: Doxycycline. Other antibiotics: macrolides and fluoroquinolones.

• Prognosis of ocular disease: usually self-limiting and rarely persistent visual loss. • Prevention: Personal protection against tick bites and improvement of sanitary conditions.

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Fig. 4 (a) Color fundus photograph of the RE shows a marked optic disc edema, retinal hemorrhages, and a macular star consistent with a diagnosis of neuroretinitis. (b) Color fundus photograph of the LE shows a white retinal lesion superior to the optic disc

Fig. 5 Late-phase fluorescein angiograms of the same patient shows leakage from the optic disc with no evidence of macular abnormality in the RE (a) and late hyperfluorescence of the white retinal lesion in the LE (b)

Fig. 6 Horizontal OCT section of the RE shows peripapillary serous retinal detachment involving the fovea

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Fig. 7 Horizontal OCT section through the white retinal lesion of the LE shows increased reflectivity of the inner retinal layers (white arrow) corresponding to the area of superficial retinitis

Fig. 8 (a) Color fundus photograph and (b) OCT of the RE in the same patient taken one month after initial presentation show a complete resolution of the optic disc edema and serous retinal detachment with

Suggested Reading Khairallah M, Ladjimi A, Chakroun M, Messaoud R, Ben Yahia S, Zaouali S, Ben Romdhane F, Bouzouaia N. Posterior segment manifestations of Rickettsia conorii infection. Ophthalmology. 2004;111 (3):529–34.

development of peripapillary hard exsudates. (c) Color fundus photograph of the LE shows an almost complete resolution of the white retinal lesion with no obvious chorioretinal scarring Khairallah M, Ben Yahia S, Jelliti B, Ben Romdhane F, Loussaief C, Attia S, Toumi A, Messaoud R, Chakroun M. Diagnostic value of ocular examination in Mediterranean spotted fever. Clin Microbiol Infect. 2009;15 Suppl 2:273–4. Khairallah M, Chee SP, Rathinam SR, Attia S, Nadella V. Novel infectious agents causing uveitis. Int Ophthalmol. 2010;30:465–83. Lukas JR, Egger S, Parschalk B, Stur M. Bilateral small retinal infiltrates during rickettsial infection. Br J Ophthalmol. 1998;82:1215–8.

River Water Granuloma Rajesh Vedhanayaki and S. R. Rathinam

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 Case 1: Granuloma in the Anterior Chamber in a Young Boy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 Case 2: River Water Granuloma Presenting as a Sub-conjunctival Nodule . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

Introduction Ocular infection secondary to trematodes are considered to be rare. River water granuloma is a graulomatous anterior uveitis caused by trematode in children with a preceding history of taking bath in village ponds. The snail in the muddy ponds hosts the trematode larva and when children take bath in these ponds, they are infected with the parasite. The suggested life cycle:

Currently the preferred practice pattern is topical and oral corticosteroids for smaller granulomas and aspiration for larger granulomas.

Case 1: Granuloma in the Anterior Chamber in a Young Boy

Snails act as first intermediate host for this trematode. They release the cercarial larvae to infect the fish, which are the second intermediate host. The infected fish then transmits the trematode to the birds. Fish eating birds are the definite hosts while infected children become an accidental host. Previously the cause for such uveitis was attributed to mycobacterium tuberculosis and these patients were treated with anti tubercular agents with limited to no success.

8 year old boy presented with redness and pain in his right eye after taking bath in his village pond. On evaluation he had diffuse conjunctival congestion and an anterior chamber granuloma. He had 1+cells and flare in his left eye with minimal retrolental flare. His posterior segment was normal. Purified protein derivative (PPD) test, Erythrocyte Sedimentation Rate (ESR), Serum Angiotensin Converting Enzyme (ACE) and X-Ray chest were done to rule out other granulomatous uveitis like tuberculosis and sarcoidosis. The granuloma (Fig. 1) was aspirated through a paracentesis wound and was sent for Real time PCR (RT- PCR) (Fig. 2). Post operatively the patient was started on topical steroids and he responded well.

R. Vedhanayaki (*) Uveitis Services, Aravind Eye Hospital & PG. Institute of Ophthalmology, Madurai, Tamil Nadu, India e-mail: [email protected]

Case 2: River Water Granuloma Presenting as a Sub-conjunctival Nodule

S. R. Rathinam Department of Ophthalmology, Aravind Eye Hospital and PG Institute Ophthalmology, Madurai, Tamil Nadu, India e-mail: [email protected]

12 year old boy presented with history of redness and growth in his right eye for a month after a history of taking bath in pond. On evaluation, he had diffuse congestion and a smooth

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Fig. 1 Picture shows photograph of anterior chamber granuloma with diffuse conjunctival congestion in an eight year old boy Fig. 4 Haematoxylin and eosin staining of subconjunctival granuloma tissue of the patient, the centre square region showing a zonal granulomatous inflammation consisting of necrotizing granuloma with degenerated tegument like features surrounded by epithelioid cells, histiocytes, and lymphocytes in 40 X magnification

nodular elevation in his conjunctiva suggestive of subconjuctival granuloma. Figure 3 shows subconjunctival granuloma. The granuloma was excised and sent for histopathology which confirmed the parasitic etiology (Fig. 4). The wound healed well with topical and oral steroids.

Fig. 2 Picture showing Real Time PCR amplified DNA checked on 2% agarose gel. Lane 1- 100bp DNA ladder, Lane 2- Negative control, Lane 3- Positive control (Fasciola gigantica – DNA), Lane 4- Granuloma DNA and Lane 5- Cercaria DNA

Key Points • River water or trematode granuloma is commonly seen in children where river/pond water is contaminated with trematode-infected snails. • There is always a preceding history of taking part in water activities in contaminated water. • Usually smaller lesions respond well to topical steroids, while larger lesions may need surgical intervention.

Suggested Reading Lalitha P, Rathinam SR, Srinivasan M. Ocular infections due to non-tuberculous mycobacteria. Indian J Med Microbiol. 2004;22:231–7. Rathinam SR, TR F, Srinivasan M, et al. An outbreak of trematodeinduced granulomas of the conjunctiva. Ophthalmology. 2001;108:223–1229. Rathinam SR, Usha K, Rao NA. Presumed trematode-induced granulomatous anterior uveitis: a newly recognized cause of intraocular inflammation in children from South India. Am J Ophthalmol. 2002;133:773–9. Rathinam SR, Arya LK, Usha KR, et al. Novel etiological agent: molecular evidence for trematode-induced anterior uveitis in children. Arch Ophthalmol. 2012;130:1481–4.

Fig. 3 Digital photograph showing subconjunctival granuloma in an otherwise quiet eye

Herpes Viral Retinochoroiditis Anne-Laure Rémond, Phuc LeHoang, and Bahram Bodaghi

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347 Acute Retinal Necrosis (ARN) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348 Nonnecrotizing Herpetic Retinopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351 Other Necrotizing Viral Retinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356

Introduction The viral retinitis entity includes a set of clinical presentations, depending on the immune status of the host, particularly the efficiency of cell-mediated immunity. The main risk factors are immunosuppression (HIV, diabetes, advanced age, cancer, corticosteroids, immunosuppressive therapies) and congenital infection. Recent designs individualized two different forms (Fig. 1): The viral necrotizing retinitis with: – Acute retinal necrosis syndrome or ARN syndrome – Progressive outer retinal necrosis or PORN, (or Progressive retinal necrosis: PRN) – Cytomegalovirus (CMV) retinitis

A.-L. Rémond (*) · B. Bodaghi Department of Ophthalmology, DHU Vision and Handicaps, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France e-mail: [email protected]; [email protected]

The nonnecrotizing viral retinopathy. Acute retinal necrosis syndrome was first described in 1971 by Urayama et al., as a unilateral panuveitis with retinal periarteritis progressing to diffuse necrotizing retinitis and ultimately, rhegmatogenous retinal detachment. It is a rare disease, also known as Kirisawa uveitis. In 1982, Culbertson et al. reported on the association between herpesviruses and ARN. Apart from ARN syndrome, other necrotizing forms of viral retinitis have been described but remain exceptional and are more often due to different members of the herpes virus family. Our knowledge of ARN has recently improved. Two studies, published in 2007 and 2012, estimated the incidence of 1 case per two million people per year. Epidemiological and genetic studies have revealed predisposing characteristics. New diagnostic tools have been developed to quickly identify the virus. Progress in treatment strategies with improvement of systemic antiviral drugs and use of local therapy has significantly decreased the rate of complications. Other types of retinal involvement due to herpesviruses have been more recently identified, deserving prompt diagnosis and therapy.

P. LeHoang Department of Ophthalmology, Pitié-Salpêtrière University Hospital, Sorbonne University, Paris, France e-mail: [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_54

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Herpetic retinopathy

Non-necrotizing retinopathy

Necrotizing retinopathy

Immunocompetent

ARN

Immunosuppressed

PRN/PORN

CMV

Fig. 2 Anterior chamber cells and keratic precipitates HHV6, HHV7, HHV8

Fig. 1 Different clinical presentations of herpetic retinitis according to patient’s immune status

Acute Retinal Necrosis (ARN) Syndrome Definition ARN is a clinical entity consisting of acute, mostly unilateral panuveitis with retinal vasculitis, rapidly progressive peripheral circumferential necrotizing retinitis, and ultimately rhegmatogenous retinal detachment. Viral agents were identified on pathologic examinations of several enucleated eyes. Members of the herpesvirus family were present in all segments of the affected retina, demonstrating an infectious cause. Vitreous tap showed the presence of HSV and VZV. Lesions are due to active viral replication, classically in an immunocompetent host. BARN (or bilateral ARN) was formulated by Young and Bird in 1978. ARN requires prompt diagnosis followed by specific antiviral therapy. Secondary anti-inflammatory drugs may be necessary when viral replication has been controlled.

Clinical Presentation Comorbidity ARN syndrome is a diagnostic and therapeutic emergency. It typically occurs in middle-aged patients (variable average from 36.04 to 43.4 yrs; with extremes 6–85 years), without particular medical history, immunocompetent and more often male (M/F: 2,53). HSV-2 retinitis occurs in younger patients, while HSV-1 or VZV retinitis occurs later, with two

Fig. 3 HSV-associated acute retinal necrosis syndrome with a peripheral white lesion with vasculitis and hemorrhages

frequency peaks: 20–30 years and 50–60 years, respectively. Retinitis is isolated. Nevertheless, it is possible to observe HSV-1, HSV-2 meningitis, or encephalitis. The Von Szily reaction explains some cases of contralateral necrotizing retinitis occurring in patients with a history of ipsilateral herpetic keratitis.

Symptoms and Physical Examination Acutely, a patient may present with a red eye, periorbital pain, photophobia, and/or vision loss. The second eye involvement can occur in one third of patients, typically within 6 weeks (6 weeks–7 months). Anterior segment examination is nonspecific, with flare and cells (1–4 +) and typical keratic precipitates (Fig. 2). Other signs, such as episcleritis, scleritis, keratitis, hypopyon (Fig. 3), hyphema, iris atrophy, and ocular hypertension, may be observed.

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Fig. 4 Fundus photography (OD) of an immunocompetent patient with acute retinal necrosis syndrome due to VZV infection

Table 1 Diagnostic parameters of early-stage ocular findings in acute retinal necrosis (Holland 1994) 1 2 3 4 5

One or more foci of retinal necrosis with discrete borders located in the peripheral retina, with circumferential spread Occlusive vasculitis Variable inflammatory reaction in the anterior chamber Variable inflammatory réaction in the vitreous Papilledema

Posterior segment examination may reveal signs described by Holland et al. in 1994: retinal necrosis (Fig. 4), occlusive vasculitis, vitritis, and papillitis (Table 1). Vasculitis can be contiguous, remote, and sometimes extensive. Clinical examination has to search for headache and a stiff neck. Other neuro-ophthalmic manifestations may occur.

Investigations Laser flare photometry quantifies and monitors AC flare during the course of the disease. The visual field can localize the functional loss related to necrosis and reveal optic nerve involvement. Optical coherence tomography (OCT) may show macular edema as a secondary complication. Recent devices (spectral domain-OCT: SD-OCT) show hyper reflectivity and loss of the normal retinal architecture within necrotic areas. Fundus photography is often difficult to achieve due to vitritis. Fluorescein angiography reveals necrotic areas (Fig. 5), ischemia, occlusive vasculitis, and papillitis. Fundus autofluorescence imaging (FAF) can help monitoring the progression of the disease. Anterior chamber tap can identify the virus and allows treatment monitoring. Complete laboratory tests should be performed to assess the patient’s immune status and exclude differential diagnosis.

Diagnostic Parameters Acute retinal necrosis was first described as a unilateral panuveitis with retinal periarteritis progressing to diffuse necrotizing retinitis (Fig. 2) and ultimately, rhegmatogenous retinal detachment. In 1994, Holland and the Executive Committee of the American Uveitis Society defined 5 diagnostic criteria: anterior chamber inflammation; vitreous cellular response; one or more foci of necrosis with limits localized at the periphery; vasculitis with occlusive arterial involvement; papillitis. BARN (bilateral ARN) means an initial or secondary bilateral involvement. Secondary bilateralization occurs in one third of cases. The longest delay reported is 46 years. The main characteristics are listed in Table 2. Causative viruses are members of the herpesvirus family, especially VZV. In 2015, Takase et al. revisited previous diagnostic criteria, always based on the initial clinical presentation, but also integrating the clinical course and the results of molecular tools applied to ocular fluids (Table 3).

Pathophysiology Acute retinal necrosis occurs in immunocompetent patients due to high virulence of VZV and HSV, explaining the sudden and rapidly progressive nature of infection despite effective defense system. Retina is infected by neurogenic transmission of viral particles. Blood transmission does not appear to be involved. In animal models, an injection of a viral preparation into the anterior chamber induces a retinitis in the contralateral eye, with a transmission via the optic chiasm.

Diagnosis Diagnosis is predominantly clinical, supported by a favorable response to antiviral treatment. Ocular samples (anterior

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Fig. 5 Fluorescein (left fig) and indocyanine green (right fig) angiograms of the same right eye disclosing superior vasculitis, extensive ischemia, and papillitis

Table 2 Main ARN syndrome characteristics Immune status Retinitis Inflammation

Virus

Immunocompetent Necrotising peripheral lesions, with circumferential spread AC flare and cells, granulomatous keratic precipitates Hyphema, hypopyon Hypertony Hyalitis, vasculitis, papilledema VZV > HSV 1 and 2 >> CMV >>> EBV

Table 4 Virologic testing of intraocular fluid characteristics

Principle

Characteristics Fuids Sensitivity Specificity

Polymerase chain reaction Viral DNA detection and quantifying the number of copies Direct method Aqueous humor Vitreous 80%–95% 97%

Goldmann Witmer coefficient Relationship between specific or total antibody levels in aqueous and serum Indirect method Aqueous humor Vitreous 57%–90%

Table 3 Diagnostic parameters of early-stage ocular findings in acute retinal necrosis versus control uveitis (Hiroshi Takase et al. 2015) Ocular findings in the early stage 1a. Anterior chamber cells or mutton-fat keratic precipitates 1b. Yellow-white lesion(s) in the peripheral retina (granular or patchy in the early stage, then gradually merging) 1c. Retinal arteritis 1d. Hyperemia of the optic disc 1e. Inflammatory vitreous opacities 1f. Elevated intraocular pressure Clinical courses 2a. Rapid expansion of retinal lésion(s) circumferentially 2b. Development of retinal break or retinal detachment 2c. Development of retinal vascular occlusion 2d. Development of optic atrophy 2e. Good response to antiviral agents Virologic testing of intraocular fluids Positive by either PCR or Goldmann-Witmer coefficient for HSV-1, HSV-2, or VZV Positive by PCR for HSV-1, HSV-2, or VZV Positive by Goldmann-Witmer coefficient for HSV-1, HSV-2, or VZV

Table 5 Necrotizing retinitis risk factors HSV 1 Concomitant or past encephalitis Past neurosurgical history

VZV Shingles Concomitant chickenpox or recent history

HSV 2 History or current meningitis Neonatal herpes Neurosurgery history Ocular trauma Chorioretinal scars

(Table 4). In case of a negative result, a second sample may be positive even after treatment initiation. In case of immunosuppression, local immunoglobulin synthesis is absent.

Risk Factors chamber tap and/or vitreous biopsy) are important but should not delay therapy. ARN is a therapeutic emergency and antivirals must be initiated as soon as possible. The anterior chamber tap has an excellent diagnostic yield. PCR is highly efficient and superior to Goldmann Witmer coefficient

The two major risk factors are immunosuppression and congenital infection. A history of herpes zoster promotes VZV-associated necrosis and neurosurgery HSV1-associated necrosis (Table 5).

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Clinical Course and Prognosis

Complications

The final prognosis is poor without prompt diagnosis and efficient therapy. Retinal detachment occurs in 25–75% of cases and 65% of patients have a final visual acuity below 20/200. The contralateral eye is affected in 10–20% of cases at initial presentation. Poor prognostic factors include: retinal detachment, VZV infection, low initial visual acuity, involvement of zone 1, or 3000 μ around the fovea or 1500 μ around the optic disc, and optic nerve damage, the extent of the affected area or the time before treatment. Necrosis area inferior to 90% has a better prognosis than total involvement, and the extension of the necrotic area in the absence of treatment promotes retinal detachment. Prophylactic vitrectomy is not correlated with prognosis. These results suggest that severe retinal or optic nerve involvement before treatment affects the visual prognosis. Long-term prognosis is mainly dependent on the occurrence of complications. VZV is the most common but also the most aggressive viral agent. The risk of retinal detachment is high. Primary infection with VZV causes the production of specific antibodies by the immune system. These antibodies are sometimes present despite the absence of clinical signs of chickenpox, indicating a possible subclinical infection. Patients with agammaglobulinemia are less sensitive than those with altered cell-mediated immunity, and the reactivation of VZV is a known marker of HIV infection. All studies show an increase of shingles with age, but some particularly show an increase in the incidence adjusted for age. This can be explained by the use of vaccination and therefore a decrease in exposure to the virus and the ability to stimulate the immune system.

Complications are frequent and occur in the absence of a rapid and appropriate treatment. They include bilateral involvement, extension of retinal necrosis (Fig. 2); ipsilateral recurrence (very rare); optic nerve atrophy; macular edema (55%) and epiretinal membrane (Fig. 6); retinal tears and retinal detachment (67%); cataract; retinal vein occlusion (42%); glaucoma; hypotony (39%); phthisis bulbi; and CNS involvement (3%). Retinal detachment (Fig. 7) is a common complication and may be rhegmatogenous or rarely exudative. Early detachment, sometimes already present at onset, rather exudative and later rhegmatogenous, is favored by dehiscence, adhesions, and vitreous proliferation. Retinal dehiscence may be present in the necrotic area and/or normal retina or at the junction of the two zones. The contralateral involvement can be initial (10%) or secondary (33%). The longest interval reported is 46 years. Systemic corticosteroids administration can sometimes trigger the involvement of the contralateral eye.

Fig. 6 Epiretinal membrane of the right eye in the same patient, visible in monochromatic photograph (left) and OCT (right), associated with cystoid macular edema and parafoveal serous retinal detachment

Nonnecrotizing Herpetic Retinopathy Definition Nonnecrotizing retinitis means a viral infection with posterior segment inflammation without necrotizing lesions. Inflammation is the result of the immune response to viral replication. Clinical signs are the same except necrotic lesions. The same herpesvirus may cause either an acute retinal necrosis, a progressive retinal necrosis, or a posterior uveitis or panuveitis with vasculitis without necrotic lesions (Fig. 8). These developments are dependent on the host.

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Fig. 7 Exudative retinal detachment, visible on the fundus photograph (top) and hypofluorescent area (bottom)

Cystoid macular edema is the main complication of nonnecrotizing viral retinopathy.

Presentation This entity is often observed in severe posterior uveitis not responding to conventional therapy. In order to exclude a viral infection, the aqueous humor is analyzed. Systematic analysis of aqueous humor in 37 immunocompetent patients with steroid resistant posterior uveitis found a virus in 5 cases (13.5%). Clinical entities include birdshot-like retinochoroidopathy, bilateral occlusive vasculitis, inflammatory cystoid macular edema, serpiginous-like choroiditis. Antiviral therapy has improved the clinical course in these patients.

Diagnosis Molecular tools applied to the aqueous humor allow diagnostic confirmation. Sampling is indicated in cases of severe posterior uveitis unresponsive to treatment.

Other Necrotizing Viral Retinopathies Cytomegalovirus Retinitis Cytomegalovirus retinitis usually occurs in immunosuppressed patients, especially those with HIV or induced by immunosuppressors, and exceptionally in immunocompetents. Progression of retinitis is usually slower than other virulent herpesviruses.

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Varicella Zoster Virus Retinitis

necrotizing retinitis, especially at the retinal periphery with a possible extension to the posterior pole.

Zoster retinitis occurs exceptionally during chickenpox or shingles, usually in the form of exudative retinitis or focal

Retinitis Associated with Epstein-Barr Virus Retinal disorders associated with Epstein-Barr virus are rare and occur during infectious mononucleosis or in immunosuppressed patients. Patients usually present with external punctuate retinitis or multifocal choroiditis.

Differential Diagnosis All symptomatic white lesions of the retina should be considered as a differential diagnosis of necrotizing retinitis. The main forms are nonviral necrotizing retinitis masquerading as ARN, described by Balansard et al. in 2005 on a series of 16 patients. The main characteristics are summarized in Table 6.

Infectious Retinitis

Fig. 8 Fluorescein angiography of the left eye in a patient with VZV nonnecrotizing retinopathy (Positive PCR), disclosing capillary diffusion, and occlusive vasculitis

Toxoplasmic Retinochoroiditis In the elderly and/or immunosuppressed patient, toxoplasmic retinochoroïditis is often extensive and may masquerade as ARN, especially if the immune status is unknown at the onset (Fig. 9). The prognosis is often guarded.

Table 6 Clinical features and diagnosis of differential diagnosis of necrotizing herpetic retinopathy

Toxoplasmosis Elderly IS++

Syphilis Homosexual HIV+

Fundus

Variable gray to white or pale yellow Thick layer of inflammatory swelling, superficial spreading form Size: usually small récurrence at edge of scar ; may take aypical in appearance

Yellow to orange Outer retina and choroid Size: temporal macula or patchy

Diagnosis

PCR +/ GWC +

RPR-VDRL FTA-ABS PCR + ; LP +

Background

Candida IS++ NID 2 Intensive care unit i.v. drug abuse White subretinal base with small base May be solitary or multiple penetration through retina vitreous focal opacities and vitreous extension

Blood cultures, microbiological samples (vitrectomy)

Aspergillus IS++ NID 2 Intensive care unit Yellow white Vasculitis Chorioretinal plaque with macula Size: predilection to involve Intense inflammation and intravascular spread Blood cultures, microbiological samples (vitrectomy)

Primary vitreoretinal lymphoma Elderly Lymphoma

Behçet’s disease Male Mediteranean

Vitreous cells haze striking cells in clumps or in sheets Creamy retinal and subretinal lesions, white to orange infiltrates

Occlusive vasculitis , Hemorrhages

IL-10>IL-6 lymphoma cells

Clinical parameters of international group study

IS immunosuppressed, HIV human immunodeficiency virus, NID non-insulin-dependent diabetes, PCR polymerase chain reaction, GWC Goldmann Witmer coefficient, TPHA Treponema pallidum hemagglutination, VDRL veneral disease research laboratory, FTA-ABS fluorescent Treponema antibody absorption, IL-10 interleukin 10

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Fig. 9 Fundus photography (left) and fluorescein angiography (right) of the left eye in a patient with posterior uveitis and extensive retinal necrosis. Toxoplasma gondii DNA was detected in ocular fluids. Fluorescein angiogram shows extensive necrotizing retinitis and papillitis. The diagnosis of HIV infection was confirmed simultaneously

Syphilitic Chorioretinitis Syphilis is capable of mimicking all types of retinal infections. The most typical lesion is acute syphilitic chorioretinitis, rarely mimicking ARN syndrome. Endogenous Fungal Endophtalmitis They may be due to Candida or Aspergillus species. Risk factors are important to determine in order to confirm the diagnosis promptly.

Noninfectious Retinitis Primary Vitreoretinal Lymphoma Primary vitreoretinal lymphoma carries mostly retinal infiltration that can take the appearance of a retinal necrosis with perivascular infiltration. Dense vitritis is frequently associated. The disease is sight and also life-threatening. Behçet’s Disease Behçet’s disease can sometimes presents itself as true retinal foci of necrosis associated with occlusive vasculitis.

Treatment Acute retinal necrosis is a medical emergency and specific treatment should not be delayed. It is necessary to conduct biological tests simultaneously, looking for immunosuppression, particularly HIV infection, blood cell count, and creatininemia, especially if systemic antivirals are proposed. Anterior chamber paracentesis may be performed after the induction of antivirals. Treatment is based on four points: antivirals to limit replication; anti-inflammatory drugs to limit complications; antiplatelets to limit ischemia; and prevention of retinal detachment.

ARN Syndrome Antiviral Treatment Induction Regimen Acyclovir is the gold standard, but the last decades have seen introduction of many alternatives, both orally, such as valaciclovir, famciclovir, and valganciclovir, or intravenously, such as foscarnet and ganciclovir (Table 7). In the absence of consensus, it is still recommended to start intravenous acyclovir in severe cases of viral retinitis. Duration of induction therapy varies from 1–3 weeks. Acyclovir is effective on HSV1–2 and VZV. The typical induction dose is 10 mg/kg twice a day, even though some clinicians increase the dose up to 15 mg/kg twice a day if the renal function allows it. Oral acyclovir (800 mg five times a day) will follow i.v. therapy for 3 months. Newer oral agents such as valacyclovir (prodrug of acyclovir) and famciclovir (prodrug to penciclovir) have greater bioavailibility than oral acyclovir, especially if used with high dosages, and can produce systemic concentrations nearly equal to those obtained with intraveinous acyclovir, thus achieving systemic levels above the in vitro 50% inhibitory concentration for most isolates of VZV, HSV-1, and HSV-2. Foscarnet is used to treat CMV retinitis particularly in immunosuppressed patients or to intensify treatment of HSV and VZV retinitis, in case of resistance. The administration route is intravenous. Doses depend on the virus: 180 mg/kg/day in 2 or 3 infusions for CMV and 120 mg/kg/day in 3 infusions for HSV. Foscarnet injected intravitreally has been used to treat ARN caused by both HSV and VZV, in ARN associated acyclovir-resistant VZV. Intravitreal foscarnet can be administrated at a dose of 2.4 mg/0.1 ml. Ganciclovir is 10–15 times more effective than acyclovir against CMV and has a comparable effect on HSV and VZV. The intravenous induction dose is 5 mg/kg twice a day.

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Table 7 Drugs commonly used in the treatment of herpetic retinitis

Valacyclovir

Route of administration IV: 10–15 mg/kg q8h PO: 800 mg x5/day PO: 1000–2000 mg q8h

Same as acyclovir

Famciclovir

PO: 500 mg q8h

GI symptoms, rash, headache

Ganciclovir

IV: 500 mg q12h IVT: 2–5 mg/0.05 ml, x2–3/ week PO: 900 mg q12h; 3 weeks, then 450 mg q12h IV: CMV: 90 mg/kg q12h or 60 mg/kg q8h; HSV: 40 mg/kg x3/day IVT: 2.4 mg/0.1 ml x1/week

Anemia, granulocytopenia, thrombocytopenia, liver dysfunction RD, endophthalmitis

Predicted relative efficacy HSV1HSV2 > VZV HSV1HSV2 > VZV HSV1 > HSV2 > VZV HSV1CMV > HSV2, VZV

Headache, GI symptoms, anemia, neutropenia, thrombopenia, bone marrow suppression, renal dysfunction Headache, GI symptoms, renal/CNS toxicity RD, endophthalmitis

HSV1CMV >> HSV2, VZV CMV/VZV/ HSV1-2

Drug Acyclovir

Valganciclovir Foscarnet

Adverse events GI symptoms, rash, headache, renal/CNS toxicity

CNS central nervous system, IV intravenous, PO per os, IVT intravitreal, RD retinal detachment

Intravitreal ganciclovir injections represent a common and efficient treatment modality of herpes viruses retinitis (CMV, VZV, HSV1/2) particularly when combined with i.v. Foscarnet. Valganciclovir has a better oral bioavailability than ganciclovir (60% vs. 6%). With an induction dose of 900 mg twice a day, valganciclovir is as effective as intravenous ganciclovir, without disadvantages of the intravenous route. Famciclovir is effective against HSV1, HSV2, and VZV and can be used for treatment of necrotizing viral retinitis as described. Because of many benefits, oral antivirals (valacyclovir and famciclovir) were evaluated for induction therapy. They seem effective but are mostly prescribed for mild forms of the disease. Further studies are needed to determine whether these molecules are efficient enough to allow their use on a routine basis. Antiviral treatment is initiated parenterally, with acyclovir or foscarnet, depending on comorbidity and history, for 2 or 3 weeks. This treatment is associated with intravitreal injections initially: foscarnet or ganciclovir. VZV has the worst prognosis amid all ARN syndromes. Foscarnet injections decreased by 40% the risk of retinal detachment in case of VZV infection. Maintenance Regimen Maintenance therapy is started after intravenous induction treatment and can be kept for months or years, especially in immunosuppressed patients to prevent recurrences and a possible attack of the contralateral eye. The prophylactic oral treatment dosage depends on the virus: acyclovir (4 g/day) or valacyclovir (3 g/day) for HSV and VZV; and valganciclovir (900 mg/day) for CMV. There is no consensus on the duration of the maintenance phase.

Anti-Inflammatory Treatment Systemic This option is important to counter an inflammatory reaction but may be hazardous. This can be initiated once retinitis is stabilized by antiviral treatment and with close monitoring. High doses of methylprednisolone may be initiated and then relayed by oral prednisone (1 mg/kg/day), with progressive tapering over a period of 4 to 6 weeks. The risk of worsening is important to consider if viral replication has not been controlled previously. Subtenon injection of triamcinolone and intravitreal injection of dexamethasone implant remain at high risk due to the same reason.

Antiplatelet Agents The use of oral antiplatelet agents, to help preventing retinal vascular occlusions, has been suggested as well, although the use of such agents remains controversial. Prevention and Treatment of Retinal Detachment Prophylactic Laser Treatment The use of confluent laser photocoagulation in patients with ARN is controversial. Some authors believe that prophylactic laser treatment delivered posterior to active retinitis may help preventing occurrence or progression of retinal detachment. But others have contested this theory. Retinal Surgery Rhegmatogenous retinal detachment, often complicated by proliferative vitreoretinopathy, may occur in up to

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75% of patient with ARN, especially if antiviral therapy has not been aggressive enough or initiated late after the onset. There are often both rhegmatogenous and tractional components that must be surgically adressed. The benefit of early surgery to prevent retinal detachment is controversial. Systematic vitrectomy is also a controversial issue.

Monitoring Clinical The complete clinical examination should be performed regularly, early and over a very long period, with visual acuity, Biomicroscopic examination in search of inflammatory reaction, rubeosis, extensive retinal ischemia with complications, vitritis, papilledema, macular edema, occlusive vasculitis, and retinal detachment. Explorations Imaging Explorations depend on the initial status and accessibility to the posterior segment. Noninvasive OCT is often performed, especially looking for secondary macular edema. Autofluorescence may predict the extension of active viral lesions. Angiography may be performed to evaluate the degree of retinal ischemia. Viral Load It is important to perform and repeat anterior chamber paracentesis several times: the first tap will identify the causative virus and determine the viral load. It is then possible to monitor viral replication, which is slowly decreasing, even when the treatment is effective. Laboratory tests should be performed regularly because of side effects of various antiviral and anti-inflammatory treatments. In summary, herpetic retinitis is a diagnostic and therapeutic emergency. In the absence of an appropriate treatment, visual prognosis is extremely poor with a significant morbidity. Aggressive antiviral therapy is preferable in severe cases. Complications occuring both during the acute phase and after control of viral replication are disastrous. Monitoring should last for many years, with low-dose, long-term antiviral treatment, because of the risk of recurrence and involvement of the second eye. Herpetic viruses can also cause nonnecrotizing retinitis. It is therefore necessary to exclude an infectious etiology in the presence of any posterior or panuveitis. Some atypical presentations of serpiginous choroiditis, multifocal choroiditis, and macular edema can be related to a viral infection. Antiviral therapy may improve the final prognosis in this group of patients.

A.-L. Rémond et al.

Key Points • Viral retinochoroiditis can present either as sight-threatening necrotizing lesions, which include acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN), and cytomegalovirus retinitis (CMV retinitis), or as non-necrotizing viral retinopathy. • ARN presents acutely with redness and pain, anterior uveitis, and tongue-shaped retinitis lesions (typically in the periphery) with occlusive vasculitis, hemorrhages, and occasionally papillitis. • ARN is usually diagnosed clinically. Virologic testing of intraocular fluids may be performed. • While antiviral therapy is mandated for ARN, retinal detachment is one of the most feared complications. • Non-necrotizing viral retinitis usually presents with severe posterior uveitis unresponsive to therapy, and can have bilateral occlusive vasculitis with retinochoroiditis. • Other vision-threatening viral infections include CMV retinitis (common in immunosuppressed or organ transplant recipients). • Viral retinochoroiditis must be differentiated from other entities including toxoplasmosis, vitreoretinal lymphoma, and Behcet’s disease.

Suggested Reading Aizman A, Johnson MW, Elner SG. Treatment of acute retinal necrosis syndrome with oral antiviral medications. Ophthalmology. 2007;114:307–12. Almeida DR, Chin EK, Tarantola RM, et al. Long-term outcomes in patients undergoing vitrectomy for retinal detachment due to viral retinitis. Clin Ophthalmol Auckl NZ. 2015;9:1307–14. Atherton SS. Acute retinal necrosis: insights into pathogenesis from the mouse model. Herpes J IHMF. 2001;8:69–73. Azumi A, Cousins SW, Kanter MY, Atherton SS. Modulation of murine herpes simplex virus type 1 retinitis in the uninoculated eye by CD4+ T lymphocytes. Invest Ophthalmol Vis Sci. 1994;35:54–63. Balansard B, Bodaghi B, Cassoux N, et al. Necrotising retinopathies simulating acute retinal necrosis syndrome. Br J Ophthalmol. 2005;89:96–101. Bodaghi B, Le Hoang P. Uvéite. Paris: Elsevier; 2009. 394 p. Bodaghi B, Rozenberg F, Cassoux N, Fardeau C, LeHoang P. Nonnecrotizing herpetic retinopathies masquerading as severe posterior uveitis. Ophthalmology. 2003;110:1737–43. Culbertson WW, Blumenkranz MS, Haines H, Gass DM, Mitchell KB, Norton EW. The acute retinal necrosis syndrome. Part 2: histopathology and etiology. Ophthalmology. 1982;89:1317–25. Culbertson WW, Blumenkranz MS, Pepose JS, Stewart JA, Curtin VT. Varicella zoster virus is a cause of the acute retinal necrosis syndrome. Ophthalmology. 1986;93:559–69. Cunningham ET, Wong RW, Takakura A, Downes KM, Zierhut M. Necrotizing herpetic retinitis. Ocul Immunol Inflamm. 2014;22:167–9. Emerson GG, Smith JR, Wilson DJ, Rosenbaum JT, Flaxel CJ. Primary treatment of acute retinal necrosis with oral antiviral therapy. Ophthalmology. 2006;113:2259–61. Figueroa MS, Garabito I, Gutierrez C, Fortun J. Famciclovir for the treatment of acute retinal necrosis (ARN) syndrome. Am J Ophthalmol. 1997;123:255–7.

Herpes Viral Retinochoroiditis Han DP, Lewis H, Williams GA, Mieler WF, Abrams GW, Aaberg TM. Laser photocoagulation in the acute retinal necrosis syndrome. Arch Ophthalmol Chic Ill 1960. 1987;105:1051–4. Holland GN. Standard diagnostic criteria for the acute retinal necrosis syndrome. Executive committee of the American uveitis society. Am J Ophthalmol. 1994;117:663–7. Iwahashi-Shima C, Azumi A, Ohguro N, et al. Acute retinal necrosis: factors associated with anatomic and visual outcomes. Jpn J Ophthalmol. 2013;57:98–103. Knox CM, Chandler D, Short GA, Margolis TP. Polymerase chain reaction-based assays of vitreous samples for the diagnosis of viral retinitis. Use in diagnostic dilemmas. Ophthalmology. 1998;105:37–44, 45. Kuo A, Ziaee SM, Hosseini H, et al. The great imitator: ocular syphilis presenting as posterior uveitis. Am J Case Rep. 2015;16:434–7. La Cava M, Abbouda A, Restivo L, Zito R. Delayed onset of bilateral acute retinal necrosis syndrome: a 46-year interval. Semin Ophthalmol. 2015;30:146–9. Labetoulle M, Kucera P, Ugolini G, et al. Neuronal pathways for the propagation of herpes simplex virus type 1 from one retina to the other in a murine model. J Gen Virol. 2000;81:1201–10. Lau CH, Missotten T, Salzmann J, Lightman SL. Acute retinal necrosis features, management, and outcomes. Ophthalmology. 2007;114:756–62. Matsubara S, Atherton SS. Spread of HSV-1 to the suprachiasmatic nuclei and retina in T cell depleted BALB/c mice. J Neuroimmunol. 1997;80:165–71. McDonald HR, Lewis H, Kreiger AE, Sidikaro Y, Heckenlively J. Surgical management of retinal detachment associated with the acute retinal necrosis syndrome. Br J Ophthalmol. 1991;75:455–8. Muthiah MN, Michaelides M, Child CS, Mitchell SM. Acute retinal necrosis: a national population-based study to assess the incidence, methods of diagnosis, treatment strategies and outcomes in the UK. Br J Ophthalmol. 2007;91:1452–5. Ohtake-Matsumoto A, Keino H, Koto T, Okada AA. Spectral domain and swept source optical coherence tomography findings in acute retinal necrosis. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Für Klin Exp Ophthalmol. 2015;253:2049–51. Raymond LA, Wilson CA, Linnemann CC, Ward MA, Bernstein DI, Love DC. Punctate outer retinitis in acute Epstein-Barr virus infection. Am J Ophthalmol. 1987;104:424–6.

357 Reddy AK. Peripheral vascular occlusion in acute retinal necrosis. JAMA Ophthalmol. 2015;133:e152157. Roy R, Pal BP, Mathur G, Rao C, Das D, Biswas J. Acute retinal necrosis: clinical features, management and outcomes – a 10 year consecutive case series. Ocul Immunol Inflamm. 2014;22:170–4. Smith LK, Kurz PA, Wilson DJ, Flaxel CJ, Rosenbaum JT. Two patients with the von Szily reaction: herpetic keratitis and contralateral retinal necrosis. Am J Ophthalmol. 2007;143:536–8. Takase H, Okada AA, Goto H, et al. Development and validation of new diagnostic criteria for acute retinal necrosis. Jpn J Ophthalmol. 2015;59:14–20. Tibbetts MD, Shah CP, Young LH, Duker JS, Maguire JI, Morley MG. Treatment of acute retinal necrosis. Ophthalmology. 2010;117:818–24. Tiedeman JS. Epstein-Barr viral antibodies in multifocal choroiditis and panuveitis. Am J Ophthalmol. 1987;103:659–63. Tran THC, Rozenberg F, Cassoux N, Rao NA, LeHoang P, Bodaghi B. Polymerase chain reaction analysis of aqueous humour samples in necrotising retinitis. Br J Ophthalmol. 2003;87:79–83. Tran THC, Stanescu D, Caspers-Velu L, et al. Clinical characteristics of acute HSV-2 retinal necrosis. Am J Ophthalmol. 2004;137:872–9. Usui Y, Takeuchi M, Goto H, et al. Acute retinal necrosis in Japan. Ophthalmology. 2008;115:1632–3. Ward TS, Reddy AK. Fundus autofluorescence in the diagnosis and monitoring of acute retinal necrosis. J Ophthalmic Inflamm Infect. 2015;5:19. Wensing B, de Groot-Mijnes JDF, Rothova A. Necrotizing and nonnecrotizing variants of herpetic uveitis with posterior segment involvement. Arch Ophthalmol Chic Ill 1960. 2011;129:403–8. Winterhalter S, Stuebiger N, Maier A-K, et al. Acute retinal necrosis: diagnostic and treatment strategies in Germany. Ocul Immunol Inflamm. 2016;24(5):537–43. Wong R, Pavesio CE, Laidlaw DAH, Williamson TH, Graham EM, Stanford MR. Acute retinal necrosis: the effects of intravitreal foscarnet and virus type on outcome. Ophthalmology. 2010;117:556–60. Wong RW, Jumper JM, McDonald HR, et al. Emerging concepts in the management of acute retinal necrosis. Br J Ophthalmol. 2013;97:545–52. Yawn BP, Gilden D. The global epidemiology of herpes zoster. Neurology. 2013;81:928–30.

Epstein Barr Virus Aniruddha Agarwal, Madhuri Akella, Maria Cristina Savastano, Marco Rispoli, Bruno Lumbroso, and Vishali Gupta

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 Case 1: Punched Out Retinal Lesion in EBV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

Introduction Viral infections have been a long recognized cause of uveitis. Most commonly implicated ones include members of the Herpes virus family, namely Herpes simplex virus (HSV), Varicella Zoster virus (VZV), Cytomegalovirus (CMV). With improved diagnostic testing many of the causes of previously termed “idiopathic uveitis” are coming into light. Epstein Barr Virus (EBV), also known as Type 4 Herpes virus, is a member of the same double-stranded DNA virus family. It has been implicated to cause infectious mononucleosis characterized by sore throat and lymphadenopathy. Its association with Burkitt’s lymphoma, nasopharyngeal carcinoma has also been proven. Primary infection is usually asymptomatic following which the virus is induced in a state of latency in B lymphocyte cells with subsequent reactivation during phases of immunosuppression. In the eye, EBV has been documented to cause conjunctival mass, scleritis, stromal keratitis, dacryoadenitis, optic neuritis, papilledema, and nerve palsies with unilateral follicular conjunctivitis being the most common finding. Uveal tract manifestations ranging from anterior to posterior to

panuveitis are more common in chronic EBV infections. Unilateral or bilateral anterior granulomatous uveitis characterized by keratic precipitates, anterior chamber cells, flare, raised intraocular pressure, decreased corneal sensations are indistinguishable from other viral causes. Rare manifestations such as posterior uveitis present as unilateral or bilateral multifocal retinochoroiditis with or without vasculitis and disc swelling. Differential diagnosis for retinochoroiditis includes toxoplasma, tuberculosis, and syphilis. Sequelae involve iris tissue atrophy, secondary glaucoma, cataract, and retinal scars in cases of posterior pole involvement. Diagnosis is mainly through serological tests. Elevated antibodies to viral capsid antigen (VCA), early antigen subset D (EA-D), and EBV nuclear antigen (EBNA) are indicative of chronic infection with raised IgM antibodies to VCA being a marker of acute infection. Ocular samples are not specific as EBV DNA is present in 20% normal individuals. Treatment is mainly supportive with topical steroids and cycloplegic agents. Role of oral antivirals is controversial as the disease is usually self-limiting. The aim of treatment is to reinduce a state of latency of the activated virus. There have been recent reports of successful use of oral valganciclovir 450 mg twice a day for a month to induce remission. EBV

A. Agarwal · M. Akella · V. Gupta (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; [email protected]; [email protected] M. C. Savastano · M. Rispoli · B. Lumbroso Centro Italiano Macula, Rome, Italy e-mail: [email protected]; [email protected]; [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_53

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Fig. 1 (a) Optical Coherence Tomography (OCT) B-scan shows the “punched-out” defect of the retinal pigment epithelium (RPE) and choriocapillaris. The retinal stroma, particularly including the outer layers, appeared to come down into the excavation with disappearance of the ellipsoid layer and external limiting membrane. The outer nuclear layer and the outer plexiform layers follow the precipitation of the

retinal stroma in the excavation (b) OCT near-infrared (IR) image shows the position of the lesion and the line scan position. (c) The en face scan shows the defect corresponding to the Haller’s layer. It appears well defined with the hyperreflectivity of the limit profile. (d) 3D image shows the RPE alteration defect in the juxta-foveal region

should hence be considered a differential diagnosis and testing should be offered in cases of “atypical” idiopathic uveitis.

down into the excavation with loss of the ellipsoid layer and external limiting membrane. The outer nuclear layer and the outer plexiform layers follow the drop down of the retinal stroma in the excavation. OCT near-infrared (IR) image shows the position of the lesion and the line scan position (Fig. 1b). The en face scan shows the defect corresponding to the Haller’s layer. It appears well defined with the hyperreflectivity of the limit profile (Fig. 1c). 3D image shows the RPE alteration defect in the juxta-foveal region (Fig. 1d). The serological tests showed evidence of EBV infection, with positive results for the presence of both VCA and EBNA. The positivity of the IgG antigen profile suggests previous contact with the virus. Tests for Cytomegalovirus (CMV) and Human Herpes virus (HHV) revealed normal values of both IgG and IgM. Details of the serological testing for viral etiology are reported in Table 1.

Case 1: Punched Out Retinal Lesion in EBV Infection A 32-year-old female with best-corrected visual acuity (BCVA) of 20/30 reported symptoms of metamorphopsia and focal blurring of vision in her left eye. The fundus observation showed a focal spot of RPE alteration in the juxta-foveal region with a pigment deposit. Optical coherence tomography (OCT) cross-sectional B-scan shows the “punched-out” defect of the retinal pigment epithelium (RPE) and choriocapillaris (Fig 1a). The retinal stroma, including the outer layers, appeared to fall

Epstein Barr Virus

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Table 1 Details of serological testing for coexistent viral infection in examined patient Epstein Barr Virus (EBV) VCA IgG (PV > IgM (PV >40 20 IU/mL) IU/mL) 750 10

EBNA IgG (PV > 20 IU/mL) 243

IgM (PV >20 IU/mL) 13

Cytomegalovirus (CMV)

Human Herpes virus (HHV)

IgG (PV >1.1 IU/mL) 0.95

IgG (PV >1.1 IU/mL) 0.6

IgM (PV >0.8 IU/mL) 0.33

IgM (PV 1.1 IU/mL) 0.5

VCA virus capsid antigen, EBNA Epstein Barr nuclear antigen, PV positive value, IU international unit

Key Points • Epstein Barr Virus is a ubiquitous virus belonging to the herpes virus group and is a common causative agent of infectious mononucleosis syndrome in adult population. • A number of ocular inflammatory conditions such as conjunctivitis, dry eye, keratitis, uveitis, choroiditis, retinitis, papillitis, and ophthalmoplegia have been reported with Epstein Barr Virus. • While there are specific serological tests to identify Epstein Barr Virus infection, treatment is supportive and therapeutic response to antiviral agents is limited.

Suggested Reading Matoba AY. Ocular disease associated with Epstein-Barr virus infection. Surv Ophthalmol. 1990;35(2):145–50. Schmoll C, McAtamney S, Madill S. Identification of Epstein-Barr Virus in a case of aggressive retinochoroiditis. Eye. 2013;27 (7):893–4. Touge C, Agawa H, Sairenji T, Inoue Y. High incidence of elevated antibody titers to Epstein-Barr virus in patients with uveitis. Arch Virol. 2006;151(5):895–903.

Chikungunya and the Eye Padmamalini Mahendradas

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 Case 1: Non-granulomatous Anterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 Case 2: Unilateral Chikungunya Retinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 Case 3: Bilateral Multifocal Retinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367

Introduction Chikungunya fever is a debilitating viral infection caused by a single-stranded RNA virus of the genus Alphavirus following bite by a mosquito vector. Systemic features include sudden onset of fever with chills, headache, and skin rash. Ocular features can be present at the time of fever or can manifest after many weeks or months with conjunctivitis, episcleritis, keratitis, anterior uveitis, retinitis, choroiditis, neuroretinitis, panuveitis, optic neuritis, central retinal artery occlusion, exudative retinal detachment, lagophthalmos, cranial nerve palsies, and secondary glaucoma. Anterior uveitis and retinitis are the most common ocular manifestations of chikungunya.

Case 1: Non-granulomatous Anterior Uveitis A 45-year-old female presented with complaints of discomfort and photophobia 6 weeks following the resolution of chikungunya fever. Visual acuity was 6/6, N6 in both eyes. Anterior segment examination revealed pigmented keratic precipitates in the inferior cornea right eye (A) and pigmented

and stellate keratic precipitates in the left eye (B), with 1+ cells and 2+ flare in the anterior chamber of both eyes. Intraocular pressure was 22 mm of Hg in the right eye and 24 mm of Hg in the left eye. Chikungunya infection was confirmed by the presence of IgM antibodies in the serum. The patient was treated with topical prednisolone acetate 1% eye drops and homatropine 2% eye drops with timolol maleate 0.5% eye drops to both eyes (Fig. 1).

Case 2: Unilateral Chikungunya Retinitis A 46-year-old female presented with decreased vision in the left eye since three days with h/o fever and with rashes since 4 weeks. On examination the right eye was normal. The left eye visual acuity was 6/24p, N36. Intraocular pressure was normal. Anterior segment examination was normal. Fundus examination revealed (A) confluent area of retinal whitening suggestive of retinitis. Fundus fluorescein angiography reveals (B) early hypofluorescence in the posterior pole and (C) late hyperfluorescence in the posterior pole. (D) Spectral domain optical coherence tomography (SD-OCT) revealed

P. Mahendradas (*) Uveitis and Ocular Immunology, Narayana Nethralaya Eye Hospital, Bangalore, Karnataka, India e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_59

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Fig. 1 Slit lamp biomicroscopic photographs of chikungunya anterior uveitis showing the presence of pigmented keratic precipitates in the right eye (a) with pigmented and stellate keratic precipitates in the left eye (b) (Courtesy: Fig. 1 from Mahendradas et al. 2013)

increased reflectivity in the nerve fiber layer zone corresponding to the areas of retinitis with after shadowing and fluid-filled spaces in the outer retina with serous retinal detachment. Chikungunya IgM antibody was positive from the serum. (E) Color fundus photograph shows resolving retinitis lesion 2 weeks after initiation of systemic steroid therapy. (F) SD-OCT shows decreased area of hyperreflectivity in the inner retina with resolving retinal detachment. (G) Color fundus photograph after 4 months shows complete resolution of retinitis. (H) SD-OCT shows resolution of retinitis with thinning of the inner retinal layers. At final follow-up, visual acuity in the left eye was 6/9, N6 (Fig. 2).

Case 3: Bilateral Multifocal Retinitis A 45-year-old female, 4 weeks post chikungunya fever, presented with decreased vision in both eyes. On examination visual acuity at presentation was 6/60 in the right eye, and left eye was counting finger at 1 m. Intraocular pressure was normal. 3A–F: (A and B) Fundus examination of both eyes shows confluent areas of retinal whitening especially along the arcades, few superficial hemorrhages, and macular edema. (C and D) Corresponding red-free photographs of both eyes show similar features as Fig. 3a and b. (E) Fundus fluorescein angiogram (FFA) right eye shows areas of capillary non-perfusion corresponding to the areas of retinal whitening seen on Fig. 3a with vascular leakage in the posterior pole. (F) Fundus fluorescein angiogram left eye shows hyperfluorescence with capillary non-perfusion in the macular area. (G) Late-phase FFA right eye shows hyperfluorescence due to the vascular leakage in the posterior pole.

(H) Late-phase FFA left eye shows leakage from the optic disc with widespread vasculitis and staining of retinal infiltrates. Color fundus photographs of both eyes, 6 months later, show pigment epithelial changes in both eyes with temporal disc pallor in the left eye (I & J). Final best-corrected visual acuity was 6/9, N6 in the right eye and counting finger at 1 m, 30 mm induration at 48 h) and she had a positive QuantiFERON Gold TB ® test.

In view of the significant inflammation, macular edema, and optic disc leakage, she was initiated on 1 mg/kg oral corticosteroids (60 mg/day oral prednisone) along with antitubercular therapy (consisting of isoniazid, ethambutol,

Pars Planitis (Idiopathic Intermediate Uveitis of the Pars Planitis Type)

rifampicin, and pyrazinamide). Due to persistent inflammation and intolerance to oral corticosteroids, oral azathioprine was added 1 month after antitubercular therapy as a steroidsparing agent. 3 months after therapy, her BCVA was recorded as 20/30 OU. Her inflammation has significantly subsided and she is on revised therapy with antitubercular agents along with 2 mg/kg/day oral azathioprine.

Case 2: Macular Edema in a Patient with Pars Planitis A 43-year-old Asian Indian male patient presented with diminution of vision in the right eye for the past 3 months. His BCVA was 20/80 in OD. Clinical examination using slit-lamp biomicroscopy revealed presence of 1+ vitreous cells along with a hazy media. Fundus examination showed a dull foveal reflex (Fig. 3). FA revealed the presence of disc hyperfluorescence along with perifoveal leakage suggestive of CME (Fig. 3). Optical coherence tomography (OCT) of OD revealed presence of intraretinal cystoid spaces confirming the presence of CME. The patient was thoroughly investigated for the etiology of the uveitis. However, all the tests were negative. A

Fig. 3 Fundus photograph (a) of patient #2 (Case 2) with unilateral pars planitis involving the right eye (OD) shows media haze due to vitritis and a dull foveal reflex due to underlying macular edema. Fluorescein angiography (b) shows presence of perifoveal leakage suggestive of

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diagnosis of PP was considered. The patient had only unilateral involvement with macular edema and was counseled to receive an injection of intravitreal dexamethasone implant (Ozurdex ®). One month after the injection, the patient had marked resolution in the macular leakage on FA (Fig. 4) and resolution of the intraretinal cystoid spaces on OCT. His BCVA improved from 20/80 to 20/25 in OD. Key Points • While PP has a variable natural course and prognosis, most cases show progressive worsening of inflammation and tissue damage in the absence of therapy. It is therefore imperative to strategically initiate a system of escalating anti-inflammatory therapy with/without immunosuppressive agents based upon the clinical findings and disease response. • Depending upon the severity of vitreous inflammation, some patients may develop blinding sequelae and complications such as tractional RD and optic disc edema. • In general, the disease prognosis is worse in patients diagnosed at a younger age. Given the severe and debilitating nature of PP, patients should be thoroughly evaluated for other causes of IU such as multiple sclerosis, and prompt management with corticosteroids, immunosuppressive

macular edema and disc hyperfluorescence. Optical coherence tomography of OD (c) shows presence of multiple cystoid spaces in OD along indicating cystoid macular edema

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Fig. 4 Fundus photograph (a) and fluorescein angiography (b) of the same patient (patient #2, Fig. 3) after treatment with intravitreal injection of dexamethasone implant (Ozurdex ®) recorded after 1 month shows resolution of vitritis and perifoveal leakage on fluorescein angiography.

The disc is also normal without hyperfluorescence seen in Fig. 3. Optical coherence tomography of OD (c) shows resolution of cystoid macular edema in OD seen in Fig. 3

agents, or biological agents should be initiated when indicated. • Multimodal imaging is employed in the management of these patients to understand and determine the exact extent of tissue damage in eyes with pars planitis.

Henderly DE, Genstler AJ, Smith RE, Rao NA. Changing patterns of uveitis. Am J Ophthalmol. 1987;103(2):131–6. 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(3):509–16. Malinowski SM, Pulido JS, Folk JC. Long-term visual outcome and complications associated with pars planitis. Ophthalmology. 1993;100(6):818–24. Nikkhah H, Ramezani A, Ahmadieh H, et al. Childhood pars planitis; clinical features and outcomes. J Ophthalmic Vis Res. 2011;6(4):249–54. Prieto JF, Dios E, Gutierrez JM, Mayo A, Calonge M, Herreras JM. Pars planitis: epidemiology, treatment, and association with multiple sclerosis. Ocul Immunol Inflamm. 2001;9(2):93–102. Raja SC, Jabs DA, Dunn JP, et al. Pars planitis: clinical features and class II HLA associations. Ophthalmology. 1999;106(3):594–9. Romero R, Peralta J, Sendagorta E, Abelairas J. Pars planitis in children: epidemiologic, clinical, and therapeutic characteristics. J Pediatr Ophthalmol Strabismus. 2007;44(5):288–93.

Suggested Reading de-Boer J, Berendschot TT, van-der-Does P, Rothova A. Long-term follow-up of intermediate uveitis in children. Am J Ophthalmol. 2006;141(4):616–21. Donaldson MJ, Pulido JS, Herman DC, Diehl N, Hodge D. Pars planitis: a 20-year study of incidence, clinical features, and outcomes. Am J Ophthalmol. 2007;144(6):812–7. Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study. Ophthalmology. 2004;111(3):491–500.

Posterior Scleritis Aniruddha Agarwal, Kanika Aggarwal, Muhammad Amir, Ramanuj Samanta, Rupesh Agrawal, and Vishali Gupta

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479 Case 1: Multimodal Imaging in a Patient with Posterior Scleritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480 Case 2: Posterior Scleritis Associated with Anterior Chamber Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . 480 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482

Introduction Posterior scleritis is relatively uncommon and often misdiagnosed clinical entity due to its variable presentation and protean clinical features. Various conditions such as orbital pseudotumor, chronic central serous chorioretinopathy, VogtKoyanagi-Harada disease, and even white dot syndromes may mimic posterior scleritis leading to a diagnostic challenge. This condition often presents in middle age, but there are a number of series published in literature that describe pediatric posterior scleritis. Common ocular symptoms include sudden loss of vision, redness, and pain. There may be associated proptosis or swelling due to extraocular involvement. Pain is the hallmark

A. Agarwal (*) · K. Aggarwal (*) · R. Samanta (*) · V. Gupta (*) Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India e-mail: [email protected]; [email protected]; ramanuj. [email protected]; [email protected]; [email protected] M. Amir (*) National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore e-mail: [email protected] R. Agrawal (*) National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore

clinical feature of posterior scleritis, differentiating it from other entities. Ophthalmic features of posterior scleritis include exudative retinal detachment, choroidal folds, optic neuritis, subretinal mass, macular and/or disk edema, and retinal striae. Nodular posterior scleritis may present as a sclerochoroidal mass with high internal reflectivity on ultrasound, mimicking a tumor-like growth. Ultrasound B-scan is a useful technique in the diagnosis of posterior scleritis. It can also rule out other pathologies such as intraocular mass lesions. A characteristic finding on ultrasound is the “T-sign” which consists of squaring off of the optic nerve along with surrounding fluid in the Tenon’s space. Nodules can also be localized in cases of nodular scleritis. While fluorescein angiography does not have any diagnostic finding, it can be used to rule out other entities such as central serous chorioretinopathy. Rarely, computerized tomography (CT-scan) or magnetic resonance imaging (MRI) may help in the diagnosis by detecting scleral thickening. Management of posterior scleritis includes antiinflammatory agents and systemic corticosteroids. Majority of the cases respond well to systemic administration of corticosteroids, and thus, posterior scleritis has an overall favorable prognosis. However, a few cases may require systemic immunosuppressive therapy such as cyclosporine or cyclophosphamide. While most cases show complete resolution of choroidal folds and subretinal fluid, sometimes the choroidal folds may persist even after adequate immunosuppressive regimen.

Department of Medical Retina, Moorfields Eye Hospital NHS Foundation Trust, London, UK e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_74

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Case 1: Multimodal Imaging in a Patient with Posterior Scleritis

Case 2: Posterior Scleritis Associated with Anterior Chamber Inflammation

A 45-year-old female presented to the ophthalmology clinic with complaints of sudden decrease in vision in the left eye for the past 10 days. There was mild redness, pain, and swelling associated with the decrease in vision. There was no history of previous ocular complaints. Review of systems was negative. Ocular examination revealed a best-corrected visual acuity (BCVA) of 20/20 in the right eye (OD) and 20/80 in the left eye (OS). Intraocular pressures were normal in both eyes. Anterior segment examination did not reveal any signs of inflammation. Dilated fundus examination showed presence of 1+ vitreous cells, choroidal folds along with subretinal fluid, wrinkling of the internal limiting membrane, and inferior exudative retinal detachment (Fig. 1). Diagnosis of Vogt-Koyanagi-Harada (VKH) disease was considered, and the patient underwent fluorescein angiography (FA). FA did not reveal pinpoint hyperfluorescence suggestive of VKH disease. Enhanced-depth imaging optical coherence tomography showed presence of choroidal thickening, choroidal folds, and subretinal fluid (Fig. 2). B-scan ultrasonography showed presence of choroidal thickening and few vitreous echoes suggestive of vitritis. “T-sign” was positive on ultrasound B-scan (Fig. 3). Thus, the diagnosis was revised to posterior scleritis, and the patient was advised 3 days of intravenous methylprednisolone (1 g/day) followed by oral prednisone (1 mg/kg). At one week follow-up visit, the choroidal folds, subretinal fluid, and vitritis resolved in the left eye, and the BCVA was recorded as 20/25 (Fig. 2).

A 58-year-old Indian female presented with a 4-day history of left eye pain and redness. She had a history of cataract extraction performed 3 weeks ago in that eye. On ocular examination, there were 3+ cells, 1+ flare in the anterior chamber associated with tortuous retinal vessels, and choroidal folds. There was no evidence of optic disk swelling or retinitis/vasculitis (Fig. 4). B-scan ultrasonography performed demonstrated a positive “Tsign” (Fig. 5). She was started on oral prednisolone (1 mg/kg). On review 1 and 3 days later, her symptoms improved with reduced anterior chamber cells and choroidal folds.

Key Points • Posterior scleritis is an uncommon inflammation of the ocular coats that is often misdiagnosed as other entities such as orbital pseudotumor, central serous chorioretinopathy, or retrobulbar mass, among others. • The manifestations of this condition are protean. Common findings on ophthalmoscopy include choroidal folds, exudative retinal detachment, and “T-sign” on B-scan ultrasonography. • While the diagnosis is often challenging, the condition usually responds well to systemic therapy with corticosteroids. Rarely, systemic immunosuppressive agents may be needed for adequate control of inflammation.

Fig. 1 Ultrawide field fundus photography of the left eye (a) shows presence of tortuous retinal vessels and choroidal folds. These folds are better observed on fundus autofluorescence imaging (b)

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Fig. 2 Enhanced-depth imaging optical coherence tomography (EDIOCT) of the left eye at the time of presentation (a), 2 days (b) and 1 week (c). At presentation, the OCT shows presence of subretinal fluid

and choroidal folds (a). Following intravenous methylprednisolone therapy, there is resolution of fluid and choroidal folds (b and c)

Fig. 3 Ultrasound B-scan of the left eye shows presence of a positive “T-sign” and sub-Tenon’s fluid (black arrowheads)

Fig. 4 Color fundus photography of the left eye shows tortuous retinal vessels and choroidal folds

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Fig. 5 Ultrasound B-scan of the left eye shows presence of sub-Tenon’s fluid (black arrowheads) (a) and a positive “T-sign” (b)

Suggested Reading Agrawal R, Lavric A, Restori M, Pavesio C, Sagoo MS. Nodular posterior scleritis: clinico-sonographic characteristics and proposed diagnostic criteria. Retina. 2016;36:392–401. Gonzalez-Gonzalez LA, Molina-Prat N, Doctor P, Tauber J, Foster CS, de la Sainz M. Clinical features and presentation of posterior scleritis: a report of 31 cases. Ocul Immunol Inflamm. 2014;22:203–7. González-López JJ, Lavric A, Dutta Majumder P, Bansal N, Biswas J, Pavesio C, Agrawal R. Bilateral posterior scleritis: analysis of

18 cases from a large cohort of posterior scleritis. Ocul Immunol Inflamm. 2016;24:16–23. Lavric A, Gonzalez-Lopez JJ, Majumder PD, Bansal N, Biswas J, Pavesio C, Agrawal R. Posterior scleritis: analysis of epidemiology, clinical factors, and risk of recurrence in a cohort of 114 patients. Ocul Immunol Inflamm. 2016;24:6–15. Uchihori H, Nakai K, Ikuno Y, Gomi F, Hashida N, Jo Y, Nishida K. Choroidal observations in posterior scleritis using highpenetration optical coherence tomography. Int Ophthalmol. 2014;34:937–43.

Sarcoid Uveitis John Gonzales

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 Case 1: Granulomatous Anterior and Intermediate Uveitis Progressing to Panuveitis . . . . . . . . . . . . . . . 484 Case 2: Sarcoid Posterior Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484 Case 3: A Patient of Sarcoidosis with Systemic Involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489

Introduction Sarcoidosis remains an enigma. While we understand its hallmark feature is that of granulomatous inflammation on histopathology, but there are systemic immune dysfunctions that complicate the picture. Sarcoid continues to fascinate physicians because its precise cause(s) remains to be elucidated. However, a genetic predisposition in the setting of the appropriate environmental milieu may play a role in the generation of sarcoidosis. While sarcoidosis most frequently affects the lungs, this disease that can have protean manifestations may involve numerous other organs. Ocular involvement can be seen in up to 50% of cases of sarcoidosis and may be the initial presentation of the disease. While it is true that sarcoidosis is characterized by noncaseating granulomas obtained from an involved organ, clinical and laboratory features and radiographic imaging are often combined to support a diagnosis of sarcoidosis. For example, berylliosis is also associated with the formation of noncaseating granulomas. Tuberculosis and syphilis should be excluded as a possibility as these can masquerade as ocular sarcoidosis. Thus, a thorough review of a patient’s past medical history, review of systems, and

social history play important roles in the evaluation of ocular sarcoidosis. There are some clinical features and evaluative tests that are particularly helpful in suggesting a diagnosis of sarcoidosis. To that end, the International Workshop on Ocular Sarcoidosis (IWOS) curated these findings to help clinicians identify patients that should be especially considered of having sarcoidosis and to help make a more robust case for pursuing certain ancillary tests in order to identify extraocular involvement, which may have therapeutic implications. Intraocular sarcoidosis most frequently presents as a bilateral anterior granulomatous uveitis and may exhibit granulomatous keratic precipitates (KPs), including medium-sized granulomatous as well as the larger, mutton-fat KPs. The iris may show nodules including Busacca and Koeppe nodules. The angle should be inspected via gonioscopy to identify Berlin nodules as well as tent-shaped PAS (resembling the tall peaks that characterize circus tents), the latter not entirely pathognomonic for sarcoidosis, but a very suggestive feature. Posterior synechiae may be present due to uncontrolled inflammation. Intermediate uveitis may be another presentation in sarcoidosis characterized by vitritis, snowballs (or string of pearls), and snowbanks. Posterior uveitis manifests as optic nerve head nodules, choroidal nodules, vasculitis (in particular, nodular or segmental

J. Gonzales (*) F.I. Proctor Foundation, University of California San Francisco, San Francisco, CA, USA e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_62

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periphlebitis sometimes appearing as candle wax drippings), and macroaneurysms. Diagnostic evaluations that should be performed should include chest X-ray and/or high-resolution CT chest, specific and nonspecific treponemal serologic tests, tuberculosis skin test or interferon gamma release assay (IGRA), AST, ALT, GGT, angiotensin-converting enzyme (ACE), and lysozyme. Syphilis and tuberculosis should be ruled out as they can masquerade as uveitis that is compatible with sarcoidosis. Liver function tests, if elevated, may suggest hepatic involvement, and ACE and lysozyme, if elevated, may further suggest sarcoidosis. Chest X-ray can evaluate for bilateral hilar lymphadenopathy, while high-resolution CT chest may show interstitial fibrosis or better demonstrate pulmonary nodules or lymphadenopathy. The treatment of sarcoidosis frequently requires oral corticosteroids, especially when there is intermediate, posterior, or panuveitis. However, even chronic anterior uveitis that is robust or requires prolonged use of frequent corticosteroid drops may require oral corticosteroids. Patients should be advanced to corticosteroid-sparing systemic immunomodulatory therapy when uveitis is chronic or patients are intolerant of or unresponsive to corticosteroids. Antimetabolites (including methotrexate, mycophenolate mofetil, or azathioprine) or T-cell/calcineurin inhibitors (such as cyclosporine and tacrolimus) can be used, though no prospective randomized trials exist comparing the use of various types of IMT for ocular sarcoidosis. If intraocular inflammation fails antimetabolites or T-cell inhibitors, then biologics, such as infliximab or adalimumab, may be utilized. It is important to rule out tuberculosis prior to starting these antitumor necrosis factor (anti-TNF) biologics. Systemic IMT should be managed by an internist, pulmonologist, rheumatologist, and/or a uveitis specialist who is familiar with the use of these medications and monitoring serologic laboratories.

J. Gonzales

Case 1: Granulomatous Anterior and Intermediate Uveitis Progressing to Panuveitis A 29-year-old Caucasian woman presented with the gradual onset of floaters. She was noted to have visual acuity of 20/25 in both eyes, no afferent pupillary defect, and intraocular pressures of 15 mm Hg in both eyes. Slit lamp examination revealed 3+ anterior chamber cells and 1+ flare in both eyes. There were small- to medium-sized keratic precipitates (KPs) involving the corneal endothelium. Dilated funduscopic examination revealed ½+ vitreous haze in both eyes with snowballs noted mainly inferiorly in both eyes (Fig. 1). Past medical history was notable for skin nodules that were biopsied and revealed noncaseating granulomas that were consistent for sarcoidosis. A chest X-ray was negative for bilateral hilar lymphadenopathy and pulmonary nodules. The patient was started on oral prednisone, from which she was tapered off over 3 weeks. She subsequently was noted to develop choroidal nodular lesions in the posterior pole of both eyes (Figs. 2 and 3). She was restarted on both systemic prednisone and methotrexate 25 mg orally each week. The prednisone was tapered over several months as the methotrexate became increasingly therapeutic. She exhibited control of her uveitis with methotrexate as steroid-sparing therapy.

Case 2: Sarcoid Posterior Uveitis A 42-year-old Caucasian man presented with an abrupt onset of floaters and blurry vision in the left week of 2-week duration. Visual acuity was 20/40 in both eyes, there was no afferent pupillary defect, and intraocular pressures were 16 mm Hg in both eyes. Slit lamp examination of the right eye was unremarkable but in the left eye were fine keratic

Fig. 1 There are snowballs in the vitreous seen in both eyes (Photographs courtesy Ying Qian, MD)

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Fig. 2 Choroidal nodules noted just inferonasal to the disc in both eyes (Photographs courtesy Ying Qian, MD)

Fig. 3 Fluorescein angiography reveals choroidal lesions that stain in late frames of the angiogram. There are lesions within the temporal arcades in the left eye not appreciated well on fundus photography. Additionally, the left eye exhibits mild staining of the disc (Photos courtesy Ying Qian, MD)

Fig. 4 A periphlebitis characterizes the posterior segment findings in this example of sarcoid panuveitis

precipitates (KPs), 1+ anterior chamber cell, no flare, and 2+ anterior vitreous cells. Dilated funduscopic examination of the right eye was unremarkable, while the left eye exhibited ½+ vitreous haze, sharp disc, and flat macula. There was a

periphlebitis characterized by sheathing and perivenular and intraretinal hemorrhages (Figs. 4 and 5). Diagnostic testing includes purified protein derivative (PPD) skin test, rapid plasma regain (RPR), and fluorescent

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Fig. 5 (a) Fluorescein angiography shows an occlusive vasculitis (involving the venule of the superior arcade) and some patchy areas of blockage due to intraretinal hemorrhages as patchy areas of nonperfusion. (b) Wedge of nonperfusion seen on FA. (c) OCT of the macula shows that there is no cystoid macular edema, but inflammatory cells and clumps can be see well (in the vitreous, along the posterior hyaloid face, and posterior to the hyaloid face)

treponemal antibody (FTA-ABS), which were negative or nonreactive. Chest X-ray revealed hilar lymphadenopathy and a high-resolution computed tomographic (HRCT) scan of the chest (2.5 m axial images obtained at 10 mm intervals) further revealed hilar and mediastinal adenopathy without interstitial abnormalities. The patient was referred to pulmonary medicine and a mediastinoscopy with biopsy was performed. Histopathologic inspection of the biopsied lung tissue revealed interstitial fibrosis and noncaseating granulomas characterized by multinucleated giant cells. Additionally, accompanying special stains of mucicarmine, Gomori methenamine silver (GMS), periodic acid-Schiff (PAS), and acidfast bacilli (AFB) failed to reveal fungal or mycobacterial organisms. The patient was subsequently commenced on oral prednisone at 1 mg/kg/day in addition to oral methotrexate 25 mg weekly with resolution of the periphlebitis (Fig. 6), vitritis, and anterior chamber cell. Panretinal photocoagulation (PRP) was applied to the areas of peripheral nonperfusion (Fig. 7). The patient’s vision ultimately improved to 20/25 in each eye.

Case 3: A Patient of Sarcoidosis with Systemic Involvement A 36-year-old African man presented with the insidious development of floaters, light sensitivity, and intermitted ocular redness of the right eye over a 7-month period. His past

Fig. 6 After therapy with systemic prednisone and methotrexate is commenced, there is marked improvement in the vasculitis

medical history was significant for hypothyroidism treated with levothyroxine. Review of systems disclosed a 16-pound weight loss over the past 10 months, recurrent fevers and night sweats, and a persistent and productive cough. His visual acuity at presentation was 20/30 in the right eye and 20/25 in the left. Slit lamp examination revealed medium-sized granulomatous KPs in Arlt’s triangle in both

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Fig. 7 Neovascularization of the disc and periphery due to secondary nonperfusion occurred requiring PRP

Fig. 9 Numerous light tannish colored Busacca’s nodules pepper the iris diffusely Fig. 8 Granulomatous KPs are present mainly within Arlt’s triangle

eyes and 3+ anterior chamber cell and 1+ flare in both eyes (Fig. 8). Koeppe’s nodules at the pupillary border were noted in both eyes (Fig. 9). There was ½+ vitreous haze in both eyes upon dilated funduscopic examination, and there was vascular sheathing in a candlewax dripping pattern involving the venules of the superior and inferior temporal arcades (Fig. 10). Given that he came from a continent endemic for tuberculosis, this entity was at the top of the differential. A PPD skin test was placed and a CXR was performed. The PPD was negative, but the CXR showed bilateral hilar lymphadenopathy. Additionally, RPR and FTA-ABS were nonreactive, but angiotensin-converting enzyme (ACE) was elevated at 90 U/L. The patient was subsequently referred to pulmonary medicine for evaluation of sarcoidosis. However, there was a higher suspicion on their part for “hot tub lung” secondary to

mycobacterium avium intracellulare (MAC). Testing for human immunodeficiency virus (HIV), however, proved to be negative, so further investigation via high-resolution computed tomography (HRCT) chest was performed. The HRCT revealed numerous small nodules in a peribronchovascular distribution in the upper lobes in addition to bihilar and mediastinal lymphadenopathy (Fig. 11). Mediastinoscopy was performed and the biopsied lung tissue revealed numerous noncaseating granulomas with a random distribution. The granulomas were associated with a lymphocytic inflammation and were frequently present as discrete nodules (Fig. 12). Stains for acid-fast organisms and fungi were negative. The patient also had echocardiography performed as heart arrhythmias can be seen in sarcoidosis. Indeed, the EKG was mildly abnormal with normal sinus rhythm but nonspecific T wave abnormalities in the anterior leads.

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Fig. 10 Segmental periphlebitis along both the superior and inferior temporal arcades in a “candle wax dripping” appearance

Fig. 11 HRCT chest. Innumerable clusters of perilymphatic nodules along the pleura, peribronchovascular regions, and interlobular septa in an upper lobe predominance in conjunction with bilateral hilar and paratracheal lymphadenopathy compatible with sarcoidosis

The patient was commenced on oral prednisone at 1 mg/kg/day dosing, and this was reduced over time. His intraocular inflammation became inactive, and he was eventually tapered off of oral prednisone with close monitoring to evaluate for recurrences that would warrant advancement to systemic immunomodulatory therapy. Key Points • The gold standard for the diagnosis of sarcoidosis is histopathology with the identification of noncaseating granulomas. However, in extrapulmonary cases, particularly the eye, biopsy is not always possible.

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Fig. 12 Pulmonary biopsy tissue. Hematoxylin and eosin (H&E) stain showing noncaseating granuloma centrally

• Histopathology should also involve the use of special stains, including GMS and AFB to evaluate for other possible etiologies of granulomatous inflammation. • Chest X-ray and/or high-resolution CT chest (HRCT) should be performed in patients suspected of having sarcoidosis as the radiographic features may be consistent with sarcoidosis. Coupled with ruling out other causes of bilateral hilar lymphadenopathy, pulmonary nodules, and interstitial fibrosis, pulmonary specialists may monitor patients or, if definitive diagnosis will have implications for treatment, suggest a biopsy of lung tissue. • Ocular sarcoidosis exhibits particularly suggestive features including granulomatous (medium-sized and mutton-fat) KPs, iris and angle nodules, vitreous snowballs and string of pearls, periphlebitis, and choroidal, and optic nerve nodules. • A thorough review of systems and past medical, sexual, and social history will aid in determining the diagnostic testing that should be performed. However, given that tuberculosis and syphilis may masquerade as sarcoid uveitis, tuberculosis testing (TB skin testing or serologic testing with an IGRA) and syphilis evaluation (both nonspecific and specific treponemal tests) should routinely be performed. • Treatment of ocular sarcoidosis often requires the use of oral prednisone at 1 mg/kg/day dosing. However, given the chronic nature of the intermediate, posterior, or panuveitis presentations of the disease, systemic corticosteroid-sparing immunomodulatory therapy is necessary to manage inflammation. • ICGA can be useful to reveal choroidal sarcoid involvement not seen on fundus photographs or on FFA.

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Suggested Reading Birnbaum AD, Oh FS, Chakrabarti A, Tessler DA Goldstein HH. Clinical features and diagnostic evaluation of biopsy-proven ocular sarcoidosis. Arch Ophthalmol. 2011;129(4):409–13. Herbort CP, Rao NA, Mochizuki M. International criteria for the diagnosis of ocular sarcoidosis: results of the first International

489 Workshop on Ocular Sarcoidosis (IWOS). Ocul Immunol Inflamm. 2009;17:160–9. Jones N, Mochizuki M. Sarcoidosis: epidemiology and clinical features. Ocul Immunol Inflamm. 2010;18(2):72–9. Papadia M, Herbort CP, Mochizuki M. Diagnosis of ocular sarcoidosis. Ocul Immunol Inflamm. 2010;18(6):432–41.

Sarcoid Vasculitis Hiroshi Takase

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 Case 1: Occlusive Retinal Vasculitis in a Patient with Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 Case 2: An Elderly Woman with Sarcoid Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 Case 3: Retinal Macroaneurysms in Sarcoid Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496

Introduction Sarcoidosis is a multisystem chronic inflammatory disorder of unknown etiology. Characteristic disorder of sarcoidosis is the formation of inflammatory granulomas in systemic organs such as the eye, lung, skin, heart, and the liver. The typical form of intraocular inflammation by sarcoidosis is granulomatous uveitis that is described well by the “International diagnostic criteria of ocular sarcoidosis” (IWOS criteria). In IWOS criteria, vasculitis is listed as one of the clinical signs suggestive of ocular sarcoidosis, described as “nodular and/or segmental periphlebitis ( candle wax drippings) and/or macroaneurysm in an inflamed eye.” This section describes the features of vasculitis seen in patients with sarcoidosis by showing three representative cases.

diffuse vitreous opacity, and nodular periphlebitis with candle wax drippings (Figs. 1 and 2) were observed by slit-lump examination and indirect fundoscopy. Optic hyperemia was also observed in the right fundus. Fluorescence angiography (FA) revealed the presence of severer vasculitis than expected by the color fundus photos (Figs. 3 and 4). A chest X-ray revealed the presence of bilateral hilar lymphadenopathy (BHL), and noncaseating epithelioid granulomas were detected by skin biopsy of her facial nodules. Because of the typical ocular symptoms and the biopsy results, she was diagnosed as biopsy-proven sarcoidosis. Her ocular symptoms as well as facial nerve palsy responded well to 0.5 mg/kg of oral prednisolone, and the vasculitis disappeared 3 months later (Fig. 5). However, nonperfusion area and retinal neovascularization developed in the peripheral retina of the right eye (Fig. 6), therefore focal laser photocoagulation was performed.

Case 1: Occlusive Retinal Vasculitis in a Patient with Sarcoidosis A 32-year-old woman was referred to our clinic due to bilateral foggy vision and facial nerve palsy. Mutton fat keratic precipitates, tent-shaped peripheral anterior synechia, H. Takase (*) Department of Ophthalmology and Visual Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_85

Case 2: An Elderly Woman with Sarcoid Vasculitis A 72-year-old woman visited our clinic due to decreased visual acuity and floaters bilaterally. Ocular hypertension, angle nodules, and peripheral anterior synechia were

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Fig. 1 Right eye of a 32-year-old woman with biopsy-proven sarcoidosis. White nodular exudates, so-called candle wax drippings, are seen along with the retinal veins (Arrows). White retinal exudates and optic hyperemia are also seen

Fig. 3 Fluorescein angiography image of the right eye of a 32-yearold woman with biopsy-proven sarcoidosis. Nodular hyperfluorescent spots corresponding to the candle wax drippings as seen in the color fundus image are seen along with the retinal vein (Arrows). Hyperfluorescence of the optic disc and retinal capillaries are also seen

Fig. 2 Left eye of a 32-year-old woman with biopsy-proven sarcoidosis. A “candle wax dripping” is seen along with the retinal veins (Arrow). The appearance of the fundus is hazy because of diffuse vitreous opacity

Fig. 4 Fluorescein angiography image of the left eye of a 32-yearold woman with biopsy-proven sarcoidosis. Nodular hyperfluorescent spots are seen along with the retinal vein, and the number is more than the candle wax drippings seen in the color fundus photo (Arrows). Hyperfluorescence of the retinal capillaries are also seen

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Fig. 5 Color fundus photos and fluorescein angiography images of a 32-year-old woman with biopsy-proven sarcoidosis after oral corticosteroid treatment. Candle wax drippings and nodular hyperfluorescent spots totally disappeared after oral corticosteroid treatment

observed bilaterally by slit-lump examination. Although apparent vasculitis was not seen by indirect fundoscopy (Fig. 7), FA revealed the segmental hyperfluorescence of retinal veins in both eyes (Fig. 8). Systemic investigations revealed negative tuberculin skin test, BHL by chest X-ray, and positive biopsy result by transbronchial lung biopsy. Combination of 0.5 mg/kg of oral prednisolone and subtenon injection of triamcinolone acetonide ameliorated the intraocular inflammation.

Case 3: Retinal Macroaneurysms in Sarcoid Vasculitis An 81-year-old woman was referred to our clinic due to bilateral posterior uveitis. Fundus was hazy due to diffuse vitreous opacity in both eyes, but a macroaneurysms was observed in the right fundus (Fig. 9). FA revealed the presence of hyperfluorescent spots surrounded with hypofluorescent area corresponding to the macroaneurysms and the blockage by retinal hemorrhage, respectively.

Fig. 6 Fluorescein angiography image of the right eye of a 32-yearold woman with biopsy-proven sarcoidosis after oral corticosteroid treatment. In the temporal peripheral retina, hypofluorescent area corresponding to nonperfusion area and hyperfluorescent spots corresponding to retinal neovascularization are seen

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Fig. 7 Color fundus photos of a 72-year-old woman with biopsyproven sarcoidosis. White retinal exudate is seen in the nasalsuperior area of the fovea, and diffuse vitreous are seen bilaterally, but no apparent retinal vasculitis is observed

Fig. 8 Fluorescein angiography images of a 72-year-old woman with biopsy-proven sarcoidosis. Nodular hyperfluorescent spots are seen along with the retinal vein, suggesting the presence of phlebitis

Periphlebitis was also observed by FA (Fig. 10). Systemic investigations revealed negative tuberculin skin test and positive biopsy result by skin biopsy of her facial nodules. Subtenon injection of triamcinolone acetonide ameliorated the intraocular inflammation. Key Points • Retinal vasculitis is one of the major ocular involvements of sarcoidosis as described in IWOS criteria. The major form of vasculitis in this disease is phlebitis. Arteritis is less common in sarcoidosis. • Sarcoid vasculitis is usually described as “nodular/segmental periphlebitis” or “candle wax drippings,” and

about 40% of patients with ocular sarcoidosis exhibit retinal vasculitis. • Sarcoid vasculitis can be observed by an indirect fundoscopy as a white sheath of the peripheral retinal vein. However, in many cases, sarcoid vasculitis is not visible by indirect fundoscopy or color fundus images but detected only when FA is performed. Therefore, FA should be performed as much as possible not to miss this important clinical sign of sarcoidosis. • Macroaneurisms seen with posterior intraocular inflammation are also an important sign of sarcoidosis. • Sarcoid vasculitis usually responds well to systemic administration or topical injection of corticosteroids, but

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Fig. 9 Color fundus photos of the right eye of an 81-year-old woman with biopsy-proven sarcoidosis. Color fundus photo of the posterior pole shows macroaneurysms surrounded with retinal hemorrhage along with the superior temporal retinal artery (White arrows).

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“Candle wax drippings” are observed along with the superior vein (Black arrows). Sclerosed white retinal arteries are seen, in particular, in the nasal retina (Arrow heads).

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Fig. 10 Fluorescein angiography images of the right eye of an 81-year-old woman with biopsy-proven sarcoidosis. FA shows hyperfluorescent spots surrounded with hypofluorescent area corresponding

to the macroaneurism and the blockage by retinal hemorrhage (Arrows). Periphlebitis was also observed by FA. Retinal arteries do not show dye leakage

if vasculitis is limited in the peripheral retina, aggressive therapy is usually unnecessary. • Retinal nonperfusion area and retinal neovascularization occurs in some cases, and focal retinal photocoagulation should be performed after sufficient anti-inflammatory treatment is done.

criteria for the diagnosis of ocular sarcoidosis: results of the first International Workshop on Ocular Sarcoidosis (IWOS). Ocul Immunol Inflamm. 2009;17:160–9. Rothova A. Ocular involvement in sarcoidosis. Br J Ophthalmol. 2000;84:110–6. Takase H, Mochizuki M. The role of imaging in the diagnosis and management of ocular sarcoidosis. Int Ophthalmol Clin. 2012;52:113–20. Talat L, Lightman S, Tomkins-Netzer O. Ischemic retinal vasculitis and its management. J Ophthalmol. 2014;2014:197675.

Suggested Reading Abu El-Asrar AM, Herbort CP, Tabbara KF. Differential diagnosis of retinal vasculitis. Middle East Afr J Ophthalmol. 2009;16:202–18. Herbort CP, Rao NA, Mochizuki M. Members of Scientific Committee of First International Workshop on Ocular Sarcoidosis. International

Acute Retinal Pigment Epithelitis Alessandro Invernizzi

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497 Case: ARPE in a Young Boy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498

Introduction Acute retinal pigment epithelitis (ARPE) is a rare, transient macular disorder that usually occurs in healthy young adults. ARPE pathogenesis remains unknown, although its first description by Krill was made more than 40 years ago. Even though bilateral cases have been reported the disease is unilateral in most of cases and resolves within few weeks with a good visual prognosis and no need for treatment. According to the largest series of cases in the literature, patients usually complain of blurred vision and/or a central scotoma with acute onset. In about 1/6 of cases flu-like prodromal symptoms are referred. Traditionally, the diagnosis is based on the funduscopic detection of fine pigment stippling in the macular area, surrounded by hypopigmented halos (Fig. 1). By definition, no other signs of intraocular inflammation including anterior chamber alterations or vitritis are associated with ARPE. Fluorescein angiography (FA) findings which are represented by a window defect related to the RPE hypopigmentation may be subtle in the acute phases of the disease and become clear only in the later stages. Indocyanine green angiography (ICGA) doesn’t show remarkable signs during very early phases of the exam

A. Invernizzi (*) Uveitis and Ocular Infectious Diseases Service - Eye Clinic, Department of Biomedical and Clinical Science, Luigi Sacco Hospital, University of Milan, Milan, Italy e-mail: [email protected] © Springer Nature India Private Limited 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_67

since choroidal vascularization seams preserved. During the early/mid phase of the angiogram, a patchy macular hyperfluorescence can be noted. However, it is during the late phases of the exam that ARPE’s most characteristic sign on ICGA, represented by a hyperfluorescent halo with a cockade like appearance of the macular area, can be observed. In the last few years, many reports have focused on spectral domain optical coherence tomography (SD-OCT) appearance of ARPE. According to the majority of them, the primary site of damage occurring during the disease and visualized on OCT scans as abnormal reflectivity or structural disruption can be located at the “RPE inner layer”. This structure may represent the interdigitation of the apical processes of the RPE with the cone outer segments; thus, it has now been renamed as interdigitation zone by the IN-OCT consensus. During the acute stages of the disease, SD-OCT can demonstrate alterations extending from this level trough the overlaying retinal layers up to the outer nuclear layer. As the disease self-resolves, a progressive restoration on the outer retinal layers can be demonstrated by consecutive OCT-based follow-ups. Being ARPE a disease of unknown origin, the diagnosis is based on suggestive clinical findings and on the exclusion of other conditions causing a compatible clinical picture. The differential diagnosis includes: multiple evanescent white dot syndrome, acute posterior multifocal placoid pigment epitheliopathy, acute macular neuroretinopathy, punctate inner choroidopathy/multifocal choroiditis, and laser-induced retinopathy. However, considering ARPE lesions are mainly limited to the foveal region and each of the other conditions listed 497

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Fig. 1 Fundus pictures of a patient affected by ARPE at baseline examination. No signs of inflammation are present (a). The only detectable alteration consists in a hypopigmented yellowish area in the macular region better appreciable in the enlarged view (b)

above shows distinctive signs on the different imaging techniques, a multimodal imaging approach should help the clinicians in reaching a proper diagnosis and avoid useless treatment.

Case: ARPE in a Young Boy (Courtesy of Anita Agarwal, MD, Professor of Ophthalmology, Retina, Vitreous and Uveitis Vanderbilt University School of Medicine, Vanderbilt Eye Institute Nashville, TN 37232 – US) A 17-year-old boy presented with decreased vision 2 weeks after a viral flu-like illness. He complained of a central visual blur in the left eye and no symptoms in the right. At first visit, his best correct visual acuity (BCVA) was 20/20 in his right eye and 20/30 in his left eye. Anterior segment as well as intraocular pressure was within normal limits. Posterior segment of the right eye didn’t show significant alterations. On the contrary, funduscopic examination of the left eye (Fig. 1) revealed pigmentary yellow changes in the foveal area. No other remarkable alterations were detectable. Baseline SD-OCT (Fig. 2a) encompassing the fovea in the left eye revealed a disruption of the outer retinal layers extending from the interdigitation zone to the outer nuclear layer and corresponding to the funduscopic changes. These characteristic alterations in absence of any other inflammatory signs were interpreted as ARPE. Considering

the self-healing nature of the disease, no treatment was suggested, and a weekly follow-up was planned for the first 30 days. At 1-month visit, BCVA was improved to 20/25, and SD-OCT revealed a partial restoration of the external retinal structures (Fig. 2b). As a consequence of the assessed clinical improvement, the time between follow-up visits was extended, and a monthly check was scheduled. At last follow-up, about 4 months after the disease presentation, BCVA was back to 20/20 and SD-OCT demonstrated a complete restoration of foveal photoreceptors and the ellipsoid and interdigitation zone (Fig. 2c). Key Points • ARPE is mostly a unilateral self-limiting condition of unknown cause, with acute onset and excellent outcome. • Typical symptoms are represented by decreased vision with central blurring. • Funduscopic examination along with SD-OCT is fundamental for a proper diagnosis and follow-up of the disease.

Suggested Reading Baillif S, Wolff B, Paoli V, Gastaud P, Mauget-Faÿsse M. Retinal fluorescein and indocyanine green angiography and spectral-domain optical coherence tomography findings in acute retinal pigment epitheliitis. Retina. 2011;31(6):1156–63. Chittum ME, Kalina RE. Acute retinal pigment epitheliitis. Ophthalmology. 1987;94:1114–9. Cho HJ, Han SY, Cho SW, Lee DW, Lee TG, Kim CG, Kim JW. Acute retinal pigment epitheliitis: spectral-domain optical coherence

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Fig. 2 Spectral domain optical coherence tomography of a patient affected by ARPE at presentation (a), 1 month (b) and 4 months follow-up (c). At baseline (a) a disruption of the outer retinal layers extending from the interdigitation zone up to the outer nuclear layer is clearly visible in the foveal area. At 1 month (b) outer limiting membrane appears normal, and a partial restoration of the ellipsoid and interdigitation zone is visible. At 4 months (c) the retinal anatomy is completely restored

tomography findings in 18 cases. Invest Ophthalmol Vis Sci. 2014;55(5):3314–9. Deutman AF. Acute retinal pigment epitheliitis. Am J Ophthalmol. 1974;78:571–8. Friedman MW. Bilateral recurrent acute retinal pigment epitheliitis. Am J Ophthalmol. 1975;79:567–70. Krill AE, Deutman AF. Acute retinal pigment epithelitis. Am J Ophthalmol. 1972;74:193–205.

Luttrull JK. Acute retinal pigment epitheliitis. Am J Ophthalmol. 1997;123:127–9. Staurenghi G, Sadda S, Chakravarthy U, Spaide RF, International Nomenclature for Optical Coherence Tomography (IN•OCT) Panel. Proposed lexicon for anatomic landmarks in normal posterior segment spectral-domain optical coherence tomography: the IN•OCT consensus. Ophthalmology. 2014;121(8):1572–8.

Autoimmune Retinopathy Karen R. Armbrust, Maggie M. Wei, Brett G. Jeffrey, and H. Nida Sen

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501 Case 1: Photopsias, Normal Fundus Appearance, Visual Field Loss, and Diminished Cone ERG Responses in AIR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501 Case 2: Progressive Visual Field Loss and ERG Abnormalities in AIR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502 Case 3: AIR with Asymmetric Symptoms and Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503 Case 4: AIR Diagnosis Is Established by Positive Serum Anti-retinal Antibodies . . . . . . . . . . . . . . . . . . . . . 504 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508

Introduction Non-paraneoplastic autoimmune retinopathy (AIR) is characterized by vision loss, visual field defects, and electroretinography (ERG) changes in the setting of positive serum anti-retinal antibodies. AIR may cause severe visual disturbance, even in the setting of a normal or nearly normal fundus examination. Vision loss is typically painless, progressive, and bilateral, though it may be asymmetric. Central or peripheral vision may be affected. Patients also may present with dyschromatopsia, photopsias, photoaversion, and/or nyctalopia, depending on whether rods, cones, or both are affected. Positive serum anti-retinal antibody testing is required, though not sufficient, for the diagnosis, but interpretation of these tests is complicated by a lack of laboratory standardization and the presence of anti-retinal antibodies in

K. R. Armbrust (*) · M. M. Wei · H. N. Sen Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA e-mail: [email protected]; [email protected]; [email protected] B. G. Jeffrey Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA Retina Consultants of Austin, Austin, TX, USA e-mail: [email protected]

unaffected individuals as well as in those with other ocular or systemic autoimmune diseases. It is critical for all patients with suspected AIR to undergo evaluation for underlying malignancy, given the phenotypic overlap between non-paraneoplastic AIR, cancer-associated retinopathy (CAR), and melanoma-associated retinopathy (MAR). There is no proven treatment for AIR, but most uveitis specialists offer at least a trial of immunosuppressive therapy.

Case 1: Photopsias, Normal Fundus Appearance, Visual Field Loss, and Diminished Cone ERG Responses in AIR A 63-year-old female with history of mild ulcerative colitis presented with 10 months of constant photopsias OU. Bestcorrected visual acuity was 20/16 OD and 20/16 OS. Dilated fundus examination and fundus autofluorescence (FAF) imaging showed no abnormality OU (Figs. 1 and 2). Macular optical coherence tomography (OCT) showed disruption of the ellipsoid zone sparing the fovea OU (Fig. 3). Goldmann visual field (GVF) testing showed constriction of central isopters OU and an arcuate scotoma OD (Fig. 4). Color vision testing with Ishihara plates and Farnsworth D-15 panel was normal OU. Fluorescein angiography

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2020 V. Gupta et al. (eds.), The Uveitis Atlas, https://doi.org/10.1007/978-81-322-2410-5_104

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Fig. 1 Color fundus montage images show normal, healthyappearing retinas, vasculature, and optic nerves OU

Fig. 2 FAF images were unremarkable OU

Fig. 3 Spectralis time domain OCT shows parafoveal ellipsoid zone loss with fovea sparing OD (panel a) and OS (panel b)

(FA) was normal without evidence of optic disc or vascular leakage OU. Full field ERG showed reduced cone responses OD > OS (Table 1, Fig. 5). An age-appropriate malignancy evaluation with the patient’s primary care provider was unremarkable. Anti-retinal antibody testing performed at the Oregon Health & Science University was positive for anti-retinal antibodies against the 46-kDa enolase protein. Serum anti-retinal antibody immunohistochemical testing at the National Institutes of Health showed immunoreactivity in the photoreceptor layer. The

patient’s visual field deficits and ERG changes have remained stable on immunosuppressive therapy for the past 3 years.

Case 2: Progressive Visual Field Loss and ERG Abnormalities in AIR A 41-year-old female presented with a 4-year history of floaters, photopsias, nyctalopia, and visual field constriction OS. One year after symptom onset, the patient noted

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Fig. 4 GVF testing shows an arcuate scotoma OD and constricted central isopters OU. Testing stimuli: I1e (brown), I2e (purple), I3e (green), I4e (red), and V4e (blue) Table 1 Full field ERG shows decreased cone response amplitudes OD > OS and borderline flicker response amplitudes OD compared to a normal subject. Rod responses are within the normal range OU, although the

DA Rod LA Cone LA Flicker

OD 183 53 63

Amplitude (uV) OS 233 63 87

amplitude is decreased OD compared to OS. DA Rod = dark adapted with 0.01 cd-s/m2 light intensity; LA Cone = light adapted with 3 cd-s/m2 light intensity; LA Flicker = light adapted with 30 Hz stimulus frequency

Normal >167 >101 >66

photoaversion OS. Her best-corrected visual acuity at presentation was 20/20 OD and 20/32 OS. Color vision testing with Ishihara plates was normal OU. Dilated fundus examination, FAF imaging, and macular OCT showed no abnormality OU. GVF testing performed 8 months prior to presentation at the National Eye Institute was normal OD and showed mild constriction OS (Fig. 6). Full field ERG showed an undetectable rod response and diminished cone response OS; ERG responses OD were within normal limits (Table 2, Fig. 7). Serum anti-retinal antibody immunohistochemical testing was positive for immunoreactivity in the photoreceptor layer. An age-appropriate malignancy evaluation was unremarkable. Two years after presentation, the patient developed photopsias OD and, in contrast to case 1, showed disease progression. Repeat testing showed additional visual field loss OU (Fig. 8) and new reductions and delays in both rod and cone ERG responses OD (Table 3, Fig. 9). The electronegative ERG suggests the possibility of MAR, but no evidence of melanoma was found in the malignancy evaluation.

OD 86.5 32.5 30.0

Implicit time (ms) OS 84.5 32.5 30.5

Normal 66

Fig. 7 ERG responses in a normal subject (thin solid line), the patient’s right eye (thick solid line), and the patient’s left eye (thick dashed line).

OD 88.0 29.5 29.5

Implicit time (ms) OS 0 35.0 35.0

Normal 66

Fig. 9 ERG responses in a normal subject (thin solid line), the patient’s right eye (thick solid line), and the patient’s left eye (thick dashed line)

Fig. 10 Fundus photographs are unremarkable except for mild C:D asymmetry

Fig. 11 Montages of FAF images show no abnormality

time was prolonged OU. DA Rod = dark adapted with 0.01 cd-s/m2 light intensity; LA Cone = light adapted with 3 cd-s/m2 light intensity; LA Flicker = light adapted with 30 Hz stimulus frequency

OD 118.5 35.5 37.5

Implicit time (ms) OS 111.5 35.0 32.5

Normal 66

visual changes, and no evidence of malignancy after a thorough work-up. • An evaluation for occult malignancy should be performed in all patients with suspected AIR.

OD 78 36 32

Implicit time (ms) OS 77 29 27

Normal 272 507 514 527

LA 3 >45 177 161 174

LA 30 Hz >27 137 115 150

OS DA 0.01 >72 196 294 342

DA 3 (b-wave) >272 361 493 422

LA 3 >45 121 175 143

LA 30 Hz >27 81 138 138

OD DA 0.01 28 122

DA 3 (b-wave) 46 9

LA 30 Hz >28 5

DA 3 (b-wave)