Gems of Ophthalmology: Diseases of Uvea [1 ed.] 9789352702725, 9352702727

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Gems of Ophthalmology

DISEASES OF UVEA

Gems of Ophthalmology

DISEASES OF UVEA

Editors HV Nema MS Former Professor and Head Department of Ophthalmology Institute of Medical Sciences Banaras Hindu University Varanasi, Uttar Pradesh, India

Nitin Nema MS DNB Professor Department of Ophthalmology Sri Aurobindo Institute of Medical Sciences Indore, Madhya Pradesh, India

The Health Sciences Publisher New Delhi | London | Panama

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Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2018, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. Inquiries for bulk sales may be solicited at: [email protected] Gems of Ophthalmology—Diseases of Uvea First Edition: 2018 ISBN: 978-93-5270-272-5

Dedicated to Dr Jyotirmay Biswas for his continued work on Uveitis

Contributors Sharanya Abharam  DO DNB

Harsha Bhattacharjee  MS FICP

Fellow Department of Uveitis and Ocular Pathology Sankara Nethralaya Chennai, Tamil Nadu, India

Medical Director and Trustee Sri Sankaradeva Nethralaya Guwahati, Assam, India

Jyotirmay Biswas  Arshee Ahmed  DO DNB Associate Consultant Department of Uveitis and Ocular Pathology Sankara Nethralaya Chennai, Tamil Nadu, India

B Sowkath Ali MS Fellow Department of Uveitis and Ocular Pathology Sankara Nethralaya Chennai, Tamil Nadu, India

Radha Annamalai  DO DNB PhD Professor of Ophthalmology Sri Ramachandra University Chennai, Tamil Nadu, India

Eliza Anthony DNB Fellow Department of Uveitis and Ocular Pathology Sankara Nethralaya Chennai, Tamil Nadu, India

Kalpana Babu MS Consultant Vittala International Institute of Ophthalmology, Bengaluru Prabha Eye Clinic and Research Centre Bengaluru, Karnataka, India

Alay Banker MS Banker’s Retina Clinic and Retina Centre Ahmedabad, Gujarat, India

MS FMRF FNAMS FIC Path FAICO

Director Department of Uveitis and Ocular Pathology Sankara Nethralaya Chennai, Tamil Nadu, India

Suresh R Chandra MD Professor Department of Ophthalmology and Visual Sciences University of Wisconsin School of Medicine and Public Health Madison, Wisconsin, USA

Dipankar Das MS Senior Consultant Department of Ocular Pathology Uveitis and Neuro-Ophthalmology Services Sri Sankaradeva Nethralaya Guwahati, Assam, India

Ranju Kharel (Sitaula)  MD FAICO (Uvea) Assistant Professor BP Koirala Lions Centre for Ophthalmic Studies Institute of Medicine Tribhuvan University Kathmandu, Nepal

Manila Khatri MBBS Fellow Department of Ophthalmology CSM Medical University Lucknow, Uttar Pradesh, India

Deepa Banker MD

Reesha KR MS

Associate Professor of Pediatrics NHL Municipal Medical College and VS Hospital Ahmedabad, Gujarat, India

Fellow Department of Uveitis and Ocular Pathology Sankara Nethralaya Chennai, Tamil Nadu, India

viii  Gems of Ophthalmology—Diseases of Uvea

Padmamalini Mahendradas MS

Manotosh Ray  MD FRCS

Consultant Uveitis and Ocular Immunology Services Narayana Nethralaya Bengaluru, Karnataka, India

Senior Consultant National University Hospital, Singapore Assistant Professor Yong Loo Lin School of Medicine National University of Singapore Singapore

Parthopratim Dutta Majumder MS Consultant Department of Uveitis and Ocular Pathology Sankara Nethralaya Chennai, Tamil Nadu, India

Mark D Meyer MD Consultant Department of Ophthalmology and Visual Sciences University of Wisconsin School of Medicine and Public Health Madison, Wisconsin, USA

Saurabh Mistry MS Fellow Department of Uveitis and Ocular Pathology Sankara Nethralaya Chennai, Tamil Nadu, India

Prabhjot Kaur Multani  MBBS DNB Resident Sri Sankaradeva Nethralaya Guwahati, Assam, India

Krishnendu Nandi MS Consultant Vitreoretinal Service Sankara Nethralaya Chennai, Tamil Nadu, India

Ashwini Patil DNB Consultant MM Joshi Eye Institute Dharwad, Karnataka, India

Neha Peraka MS Vitreoretinal Fellow Narayana Nethralaya Bengaluru, Karnataka, India

Aniki Rothova  MD PhD Professor FC Donder’s Institute Department of Ophthalmology University Medical Center Utrecht and Department of Ophthalmology-immunology Netherland Ophthalmic Research Institute Amsterdam, Netherlands

Sudharshan S MS Consultant Department of Uveitis and Ocular Pathology Sankara Nethralaya Chennai, Tamil Nadu, India

Sandeep Saxena  MS FRCS Professor Retina Service Department of Ophthalmology CSM Medical University Lucknow, Uttar Pradesh, India

Yuen Yew Sen  MBBS MMed Associate Consultant National University Hospital Singapore

P Mahesh Shanmugam  DO FRCS PhD Head Department of Vitreoretinal and Ocular Oncology Services Sankara Eye Hospital Bengaluru, Karnataka, India

Hitesh R Sharma MS Department of Uveitis and Ocular Pathology Sankara Nethralaya Chennai, Tamil Nadu, India

Upender Wali MS A Ramana MS Fellow Department of Uveitis and Ocular Pathology Sankara Nethralaya Chennai, Tamil Nadu, India

Senior Specialist and Consultant Department of Ophthalmology College of Medicine and Health Sciences Sultan Qaboos University Muscat, Oman

Preface Uveitis causes visual impairment and blindness in a significant number of people. It is responsible for 10% blindness in the most productive working age group (occupational age group) in the Western hemisphere. Uveitic blindness can be prevented by early and accurate diagnosis of the disease and institution of timely treatment. Evidence-based diagnosis and proper treatment is necessary. The book, “Diseases of Uvea” comprehensively presents the clinical work-up, diagnosis and management strategies of uveitis for the benefit of readers. Anatomically, uveitis is classified into three types: anterior, intermediate and posterior; when inflammation involves the entire uveal tract, it is called panuveitis. Anterior uveitis is the most common type. Uveitis presents a challenge to clinicians as its etiology can only be established in less than 50% of patients and in the remaining 50% it remains presumptive or obscure. Broadly, the etiology of uveitis may be infective or noninfective. Infective uveitis can affect any part of uvea but when it involves the posterior pole of the eyeball, the results may be sight threatening and devastating. The noninfective uveitis is often associated with systemic disorders, such as juvenile idiopathic arthritis, ankylosing arthritis, sarcoidosis, Behçet disease, etc. Important bacterial, spirochetal, fungal, viral and parasitic affections of uvea have been described in the book. It also includes chapters on human immunodeficiency virus (HIV) and opportunistic infections in HIV. Recently, significant advancements have been reported in the field of diagnosis of uveitis. Besides serological tests, sophisticated imaging modalities help in establishing the diagnosis of uveitis. Biswas et al. have elaborated this point in the first chapter of the book. Polymerase chain reaction (PCR) test, a rapid and reliable molecular technique is currently used for the diagnosis of infectious as well as noninfectious uveitis. As per the guidelines, it is necessary to start the treatment of posterior uveitis with specific antibiotic and corticosteroids. When cases do not respond, immunosuppressive agents, like azathioprine ciclosporin, tacrolimus, mycophenolate mofetil and methotrexate, should be added to control the ocular inflammation. Immunosuppressive drugs are the main stay of treatment of noninfective uveitis. Parthpratim Majumder et al. in their chapter on Posterior uveitis have discussed the treatment of noninfectious uveitis. These drugs usually cause unpleasant side effects. However, their intravitreal use can minimize the side effects.

x  Gems of Ophthalmology—Diseases of Uvea

More recently, biological agents have been used for the treatment of uveitis. There is a growing opinion among ophthalmologists that early use of these drugs, in severe uveitis, can prevent sight loss more effectively than used as a last resort. The use of infliximab and adalimumab is reported to be effective in the treatment of refractive uveitis. The editors assure the readers that the major part of the work presented in this book comes from the Recent Advances in Ophthalmology series, edited by Dr HV Nema and Dr Nitin Nema. In each chapter, author/s have provided references to published work of their own group as well as relevant references from other experts for the benefit of those who want to read the topic in detail. The book is multi-authored, therefore, repetition could not be avoided. Readers can take the advantage of knowing the views of different authors. However, there is no ambiguity. The book is concise and information on uveal diseases is presented in an easily readable form. It is profusely illustrated. Postgraduate students, residents and general ophthalmologists will find it useful in their day-to-day clinical practice.

HV Nema MS Nitin Nema MS DNB

Acknowledgments We wish to record our grateful thanks to all authors for their spontaneity, cooperation and hard work. We are indebted to Dr Jyotirmay Biswas and his group (Dr Parthpratim Dutt Majumder and Dr S Sudarshan) for contributing a number of chapters on uveal diseases on a short notice. Besides contributing new chapters, they have also revised their old chapters. Credit goes to Mr Jitendar P Vij (Group Chairman), Jaypee Brothers Medical Publishers (P) Ltd who has agreed to start a new series—Gems of Ophthalmology. Diseases of Uvea is the second book of this series. Ms Charu Bali Siddhu and Ms Kritika Dua, Development Editors, deserve our appreciation for their continued interest in refining chapters and eliminating plagiarism.

Contents 1. Diagnostic Procedures in Uveitis

Jyotirmay Biswas, Reesha KR, Ranju Kharel (Sitaula)

1

2. Polymerase Chain Reaction in Intraocular Inflammation

23

3. Intraocular Tuberculosis

34

4. Ocular Sarcoidosis

50

5. Intermediate Uveitis: Clinical Features and Current Management

63

6. Presumed Ocular Histoplasmosis Syndrome

78

7. Ocular Syphilis

93

Jyotirmay Biswas, Krishnendu Nandi

Arshee Ahmed, B Sowkath Ali, Jyotirmay Biswas Eliza Anthony, Parthopratim Dutta Majumder, Jyotirmay Biswas

Radha Annamalai, Jyotirmay Biswas Suresh R Chandra, Mark D Meyer

Saurabh Mistry, Sudharshan Sridharan

8. Lyme Disease

105

9. Herpes Simplex and Varicella Zoster Related Uveitis

112

10. Recent Advances in the Diagnosis and Management of Ocular AIDS

127

11. HIV and Opportunistic Infections of Eye

152

12. Ocular Toxoplasmosis

178

13. Toxocariasis

190

14. Ocular Cysticercosis

199

15. Endophthalmitis

206

16. Ocular Involvement in Systemic Rheumatic Diseases

241

Kalpana Babu, Ashwini Patil Yuen Yew Sen, Manotosh Ray

Sudharshan S, Sharanya Abharam Alay Banker, Deepa Banker Aniki Rothova

Hitesh R Sharma, Parthopratim Dutta Majumder Hitesh R Sharma, Parthopratim Dutta Majumder Sandeep Saxena, Manila Khatri Parthopratim Dutta Majumder, A Ramana, Jyotirmay Biswas

xiv  Gems of Ophthalmology—Diseases of Uvea

17. Complications of Uveitis

263

18. White Dot Syndromes

287

19. Behçet’s Disease

312

20. Masquerade Syndrome

348

21. Recent Advances in Diagnosis and Management of Posterior Uveitis

361

22. Biologicals in the Treatment of Non-Infectious Uveitis

380

23. Advances in Intravitreal Therapeutics in Uveitis

399

24. Choroidal Melanoma

410

Neha Peraka, Padmamalini Mahendradas Jyotirmay Biswas, Radha Annamalai, Eliza Anthony Upender Wali

Dipankar Das, Harsha Bhattacharjee, Prabhjot Kaur Multani

Parthopratim Dutta Majumder, S Sudharshan, Jyotirmay Biswas Parthopratim Dutta Majumder, Jyotirmay Biswas Parthopratim Dutta Majumder, Jyotirmay Biswas P Mahesh Shanmugam

Index 429

CHAPTER

1 Diagnostic Procedures in Uveitis Jyotirmay Biswas, Reesha KR, Ranju Kharel (Sitaula)

INTRODUCTION Uveitis encompasses entities of varying duration, severity, location and above all a vast plethora of possible etiologies with quite similar and overlapping presentations. Examination of a patient with uveitis needs to be meticulous as the incidence of association with systemic diseases is high. Uveitis is often diagnosed based on clinical features alone (e.g., Fuchs’ heterochromic iridocyclitis, serpiginous choroiditis) with the help of ancillary tests (fundus fluorescein angiography, indocyanine green angiography, optical coherence tomography) or with the help of laboratory tests (sarcoid, tuberculous and syphilitic uveitis). The importance and role of biopsy are significant in masquerade syndromes, intraocular inflammation, infections, intraocular tumors and metastasis.1 Characteristic features displayed on one or more of the ocular imaging tools have made it possible to discern a number of specific uveitic entities. Sophisticated imaging modalities have also provided an insight into the pathogenesis of several uveitic entities. The diagnostic procedures used in uveitis can be broadly divided in two groups:

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DIAGNOSTIC IMAGING PROCEDURES Advances in the field of ocular imaging techniques have revolutionized the accurate diagnosis of the uveitic disorders and monitor its progression or regression in a better way. The following is the list of imaging procedures performed in uveitides: • Ultrasonography • Ultrasound biomicroscopy (UBM) • Fundus autofluorescence (FAF) • Fundus fluorescein angiography (FFA) • Indocyanine green angiography (ICGA) • Wide field angiography (WFA) • Optical coherence tomography (OCT)

Ultrasonography Ophthalmic ultrasonography is a noninvasive, safe, dynamic and simple imaging technique for the evaluation of posterior segment structures in eyes with or without media opacities. It is a useful adjunctive tool that has an important role for the differential diagnosis and follow-up of inflammatory and noninflammatory pathologies of the posterior segment. The sound wave transmitted from a probe into the eye travels in ocular media of different densities. In the normal eye, the vitreous is echolucent and the vitreoretinal interface produces a high spike. Inflammatory cellular infiltration of the vitreous cavity produces low reflective mobile echoes with diffuse distribution. Intravitreal hemorrhage produces higher reflective echoes. Posterior vitreous detachment is common in eyes with uveitis and appears as a mobile low reflective thin line, whereas retinal detachment has high reflective spike with no post-detachment movement. Focal retinochoroidal infiltrates or granulomas can also be imaged by ultrasonography in the form of localized thickening of the posterior layers and/or focal elevations toward the vitreous cavity. In cases of choroiditis, choroidal thickness is increased and appears as low to medium reflectivity. The posterior scleritis shows high reflective thickening of the posterior wall of the globe. Fluid accumulating in the Tenon’s space in posterior scleritis causes an echolucent zone posterior to the thickened wall continuous with the optic nerve giving rise to a characteristic T-sign image sign. Malignant or nonmalignant intraocular tumors mostly have ultrasonographic characteristics that differentiate these tumors from inflammatory lesions.

Ultrasound Biomicroscopy Ultrasound biomicroscopy (UBM) is a qualitative investigation to study the pathology of iris, ciliary body, pars plana and anterior portion of the posterior

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Diagnostic Procedures in Uveitis  3

Fig. 1.1:  Ultrasound biomicroscopy of a 48-year-old female of pars planitis showing 360° hypodense ciliary body with thin pars plana membrane at the ciliary process.

segment of eye. In UBM, a high frequency transducer (50–100 MHz) is incorporated into a B-scan ultrasound so that the resolution is better but penetration of ocular tissues is only up to the level of pars plana. UBM is considered useful in uveitis for the evaluation of thickness of pars plana region, detection of ciliochoroidal effusion, supraciliary effusion and foreign body at the angle. It can show pars planitis and pars plana membrane at the ciliary process (Fig. 1.1). It also detects exudates around the pars plana, vitreous base and peripheral retina. It is capable of identifying the presence of cells in the anterior and posterior chambers and anterior vitreous cavity in case of media opacity. It has proven to be the most useful technique in imaging morphologic abnormalities in eyes with hypotony.2

Fundus Autofluorescence Fundus autofluorescence (FAF) also is a noninvasive tool that allows in vivo imaging of retinal pigment epithelial (RPE) and outer retinal pathologies without the use of dye. This imaging is based on the autofluorescence phenomenon associated with lipofuscin granules in the RPE cells. Lipofuscin accumulation in the RPE cells is associated with photoreceptor outer segment turnover and renewal. In the normal eye, the FAF signal at the fovea is reduced because of the absorption by luteal pigment. The uses of FAF imaging in uveitis could be in inflammatory posterior uveitis like toxoplasmosis, serpiginous choroiditis, multifocal choroiditis with panuveitis, intraocular lymphoma, acute posterior multifocal placoid pigment epithelium (APMPPE),

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Fig. 1.2: Fundus autofluorescence angiography of a 54 years female with serpiginous choroiditis showing hyperfluorescence areas (blue arrow) suggesting active lesions along with hypofluorescence areas of inactivity (yellow arrow).

birdshot chorioretinopathy, serous retinal detachment, cystoid macular edema and secondary choroidal neovascular membrane.2 It can distinguish between active chorioretinal lesion and scar because an active lesion will appear hyperfluorescence while scar will appear hypofluorescence. Hence, in suspected case of reactivation of posterior fundus lesion, the hypofluorescence lesion will be surrounded by hyperfluorescence (Fig. 1.2).

Fundus Fluorescein Angiography An understanding of fundus fluorescein angiography (FFA) and the ability to interpret fluorescein angiograms are essential to accurately evaluate, diagnose and treat patients with retinal vascular and macular disease.3 In uveitis, fluorescein angiography is useful for the evaluation of optic disc inflammation, macular edema, occlusive and nonocclusive retinal vasculitis, neovascularization, RPE changes and exudative retinal detachment.2 Inflammation of the retinal capillaries can be detected by FFA even in its early stage. Hence, FFA is an essential imaging study in all uveitic entities where retinal vasculature is primarily involved, such as Behçet’s uveitis, Eales disease and intermediate uveitis. FFA can identify occlusive versus nonocclusive nature of retinal vasculitis. Abnormal patterns of FFA appear as either hypofluorescence or hyperfluorescence areas. Fluorescein angiography is essential to make this distinction and to guide treatment. Pattern of FFA in some uveitic diseases is shown in Table 1.1.

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Table 1.1:  Pattern of fundus fluorescein angiography (FFA) in some uveitic diseases. Disease

FFA (Early phase)

FFA (Late phase)

Acute multifocal posterior

Early hypofluorescent

Late hyperfluorescent

Pinpoint RPE leaks

Late pooling of dye in the

placoid pigment epitheliopathy Vogt-Koyanagi-Harada

subretinal space

disease/sympathetic ophthalmia Active toxoplasmic/

Early hypofluorescence

serpiginous choroiditis Posterior scleritis

Late fuzzy staining of active leading edge of lesion

Pinpoint RPE leaks

Late pooling of dye in the subretinal space

Multiple evanescent

Stippled early hyperfluores-

Hyperfluorescence persists

white dot syndrome

cence

in late phase

Cystoid macular edema

Progressive leakage and accu-

Petalloid pattern of parafo-

mulation of dye in the cystoid

veal hyperfluorescence

spaces surrounding fovea RPE: Retinal pigment epithelial.

Indocyanine Green Angiography Indocyanine green angiography (ICGA) is an invasive technique to analyze the inflammatory choroidal pathologies of choriocapillaris and the choroidal stroma. Choroidal impregnation by ICGA fluorescence is disturbed in chorioretinal inflammatory disorders causing areas of altered fluorescence, hence making it a very useful adjunctive tool in chorioretinal inflammatory diseases.4 Hypofluorescent spots appearing as dark dots have been described as an ICGA sign of active choroidal inflammation (Fig. 1.3) and they disappear after treatment. In ICGA type 1 pattern, choriocapillaris non-perfusion shows patchy/ geographic deposition in the early and intermediate phase persisting in the late frames whereas stromal choroiditis shows regular dots with an even distribution in the early phase.5 In type 2 pattern, choroidal vasculitis may be seen as early stromal vessel hyper fluorescence, but it is best appreciated as fuzziness of choroidal vessels in the intermediate phase ICGA. Numerous late phase pinpoints hyperfluorescence on ICGA is indicative of granulomatous disease. Hypofluorescent dots are best appreciated in the intermediate phase and tend to have a uniform size and distribution in Vogt-Koyanagi-Harada (VKH) disease, sympathetic ophthalmia (SO) and birdshot chorioretinopathy but may have random distribution in sarcoidosis and tuberculosis.2 In ocular toxoplasmosis, dark dots are typically seen only around the focus of retinochoroiditis. Pattern of ICGA in some uveitic diseases is summarized in Table 1.2. Thus ICGA may reveal essential diagnostic information, especially when funduscopy and FFA fail to explain visual loss in patients with inflammatory

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6  Gems of Ophthalmology—Diseases of Uvea

Fig 1.3: Case of acute posterior multifocal placoid pigment epitheliopathy with hypofluorescence areas in fundus fluorescence angiography (top) and indocyanine green angiography (bottom).

choroidal diseases, such as acute posterior multifocal placoid pigment epitheliopathy (Fig. 1.3), multiple evanescent white dot syndrome (MEWDS), multifocal choroiditis, early birdshot chorioretinopathy and acute idiopathic blind spot enlargement syndrome.2

Wide Field Angiography Wide field angiography (WFA) helps in visualizing significant retinal findings, which are likely to be missed by conventional 60° FFA. The newer WFA, also called as ultrawide field angiogram, discloses the true extent, nature

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Diagnostic Procedures in Uveitis  7

Table 1.2:  Pattern of Indocyanine green angiography (ICGA) in some uveitic diseases. Type of uveitis

ICGA findings

Serpiginous choroiditis

Hypofluorescent spots in early, intermediate and late phases

Multifocal choroiditis

Large hypofluorescent spots all over the retina with much number of spots as compared to FFA and late homogenous background fluorescence

Acute multifocal pos-

Well demarcated, irregularly sharp hypofluorescence in all

terior placoid pigment

phases

epitheliopathy Ampiginous choroiditis

Hypofluorescence in early and intermediate phases with heterogeneous background hyperfluorescence in late phases

Vogt-Koyanagi-Harada

Hypofluorescent spots scattered throughout the fundus

syndrome

becoming hyperfluorescence in the late stage of the study with confluent areas of hypofluorescence

Presumed tubercular

Extensive patchy hypofluorescence in the posterior pole with

choroiditis

ring of hyperfluorescence around hypofluorescence in late stages

Multiple evanescent

Hypofluorescent spots around the disc and posterior pole in inter-

white dot syndrome

mediate and late ICGA phases which was not apparent on FFA

FFA: Fundus fluorescein angiography.

and severity of retinal vasculitis that can thereby help to formulate the plan on laser photocoagulation and use of corticosteroid with or without immunosuppressant. It also allows a clear visualization of the areas of neovascularization and peripheral nonperfusion (Fig. 1.4) which thereby enhances the correct documentation of disease activity, progression and outcome of laser photocoagulation.6

Fig 1.4:  Montage right eye showing laser marks in the peripheral retina in a case of retinal vasculitis and the wide field fundus angiography showing laser scars with an active neovascular frond in superonasal quadrant.

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8  Gems of Ophthalmology—Diseases of Uvea

Optical Coherence Tomography Optical coherence tomography (OCT) imaging is identical to ultrasound, except that it uses light instead of sound to acquire high-resolution images of ocular structures as it relies on optical property rather than acoustic properties of ocular tissue and thereby helps in better understanding the pathologies and structural changes of the retinal disorders. The currently available spectral domain (SD)-OCT instruments allow improved visualization of four lines in the sensory retina, which represent the external limiting membrane (ELM), the photoreceptor inner and outer segment junction (IS/OS), the interdigitation of the photoreceptor outer segments (OS), the RPE, and the RPE-choriocapillaris complex.3 OCT is suitable for detecting and monitoring uveitic macular edema and provides important information about the fluid distribution in eyes with macular edema and the morphology of the vitreoretinal interface. The loss of the IS/OS junction on OCT in eyes with uveitic macular edema may be associated with poor visual acuity.2 Concurrent vitreoretinal traction in the form of an epiretinal membrane (ERM) appears as a hyperreflective line adhering to the retinal layer. ERM is found to be associated with macular thickness. OCT reveals characteristic findings in VKH disease and SO where there are areas of serous retinal detachment in the outer segment demarcated by the ELM and RPE line, hyperreflective bands indicating fibrinous septae within the serous detachment, disruption of the continuity of the RPE and IS/OS junction, and undulations and bumps on the RPE surface adjacent to the serous retinal detachment.2 OCT findings in APMPPE appear as mild hyperreflective area above the RPE in the photoreceptor layer in the early phase of the disease and nodular hyperreflective lesion on the plane of the RPE with mild underlying backscattering in the later phase.2 In serpiginous choroiditis, OCT shows increased reflectance of the choroid and deeper retinal layers, along with disruption of the photoreceptor IS/OS junction in both active and inactive lesions. The OCT can even be used to visualize the anterior chamber cells and angle structures in eyes with corneal haze. The recent advances have led to development of multimodal imaging where the FFA, ICGA, FAF and OCT can be done from a single device at one time (Figs. 1.5A to E).

INVASIVE PROCEDURES IN UVEITIS With advancing surgical techniques and instrumentations, the biopsy procedures (Table 1.3) have become safe to arrive at a correct diagnosis, thereby guiding appropriate treatment and also providing insights into the disease.

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Diagnostic Procedures in Uveitis  9

A

B

C

D

E

Figs. 1.5A to E:  Multimodality imaging of a 49-year-old female with ocular toxoplasmosis. (A) Color fundus photo showing retinochoroidal lesion at the macula with a satellite lesion. (B) Fundus autofluorescence angiogram showing hypofluorescence lesion with no activity. (C) Indocyanine green angiogram showing mid-phase hypofluorescence at the lesion site. (D) Fundus fluorescent angiogram showing retinochoroidal lesions with sharply demarcated margin, which is staining without leakage. (E) Optical coherence tomography shows normal foveal counter with retinochoroidal scar adjacent to the foveal zone. Table 1.3:  Various types of biopsy procedures used in uveitis. Biopsy procedures in uveitis

Chapter 01.indd 9

•

Anterior chamber paracentesis

•

Vitreous tap and diagnostic vitrectomy

•

Iris and ciliary body biopsy

•

Choroidal and retinochoroidal biopsy

•

Fine needle aspiration biopsy

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10  Gems of Ophthalmology—Diseases of Uvea

Fig. 1.6:  An 8-year-old girl with persistent hypopyon uveitis, not responding to topical and systemic steroid.

Anterior Chamber Paracentesis Anterior chamber (AC) paracentesis is a valuable procedure in the diagnosis of uveitis, particularly in diagnosing infective causes.7 There are various methods for performing AC paracentesis.8,9 We describe herein a simple and safe technique, which can be performed in an outpatient department (OPD) setting, taking adequate aseptic precautions. The indication for an anterior chamber paracentesis may be many, but some of the difficult situations are in patients with masquerade syndromes with persistent hypopyon (Fig. 1.6), and lens-induced uveitis (Fig. 1.7). When paracentesis is performed, the diagnosis can be confirmed on the cytopathologic evidence (Figs. 1.8 and 1.9).

Procedure After using local antibiotic drops and a local anesthetic, a tuberculin or 2 mL syringe with a 27–30-gauge needle is used. In the presence of fibrin or granulomatous uveitis, it is preferable to use a large bore of 25–26-gauge needles. The needle entry into the anterior chamber is oblique through the stroma via the lower limbus. This acts as a valvular self-sealing paracentesis wound on withdrawal of the needle. One should avoid touching the corneal endothelium and particularly the lens in phakic patients and should stay over the peripheral iris at all times. Obtain a 0.1–0.3 mL of aqueous, and on withdrawal external pressure is applied to the entrance with sterile cotton tipped applicator. A drop of antibiotic is instilled in the conjunctival sac and the eye is patched for half an hour after which the patient is re-examined to ensure anterior chamber reformation.

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Diagnostic Procedures in Uveitis  11

Fig. 1.7:  A 14-year-old girl with finger nail injury, on examination showed granulomatous uveitis with posterior synechiae, complicated cataract and ruptured anterior capsule of lens.

Fig. 1.8:  Aqueous aspirate of the patient in Figure 1.6 showing basophilic cohesive cells with hyperchromatic nuclei (H and E, × 400) suggestive of malignancy.

The procedure is quite safe. In case of infectious uveitis and endophthalmitis, a portion of the material should be sent to microbiology for direct smear and culture for bacteria, fungus and mycobacteria and polymerase chain reaction. Remaining fluid should undergo cytospin study to obtain better cell recovery for microscopic examination.

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Fig. 1.9:  Aqueous aspirate of the patient in Figure 1.7 showing macrophages with engulfed lens matter (H and E, × 400).

The authenticity of aqueous humor analysis has been reported following analysis of samples using smears, cultures, polymerase chain reaction (PCR) and real time PCR. Van der and Rothova et al.8 have reported the usefulness of AC tap in isolation of infection in posterior uveitis. Tran et al.10 had also supported the utility of PCR analysis of aqueous humor samples in necrotizing retinitis. Cytopathologic features of aqueous aspirate11 help in the diagnosis of lens-induced uveitis, masquerade syndrome, delayed endophthalmitis, parasitic uveitis, to name a few (Table 1.4). Complications that can occur following AC tap are rare; nevertheless, one needs to be aware of the possibility of wound leak, hyphema, iritis, lens touch and endophthalmitis.

Vitreous Tap and Diagnostic Vitrectomy Vitreous biopsy can be vitreous tap or diagnostic vitrectomy. Such vitreous biopsy is required in infective posterior uveitis, recalcitrant posterior Table 1.4:  Cytopathological findings in aqueous aspirate in uveitis. Diagnosis

Cytopathologic findings

Lens-induced uveitis

Macrophages engulfing lens particles, acute and chronic Inflammatory cells

Masquerade syndrome

Malignant cells, e.g., retinoblastoma cells and

(Retinoblastoma, leukemia)

leukemic cells

Parasitic uveitis

Eosinophils, polymorphs and sometimes the parasite

Postoperative endophthalmitis

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Bacteria or fungus and inflammatory cells

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Diagnostic Procedures in Uveitis  13

Fig. 1.10:  Montage fundus photo showing subretinal masses in a case of intraocular lymphoma.

uveitis, suspected large cell lymphoma, particularly in the elderly population. Material obtained from such procedures should be evaluated cytologically, and also subjected to PCR, detection of intraocular antibodies (by ELISA), flow cytometry and culture.12–14 Obtaining vitreous samples by tap is easier and can be done in the outpatient department,15 however, material obtained is small. A diagnostic vitrectomy when performed provides large amount of material (though diluted), but needs to be done always in an operation theater. A cytologic analysis of vitreous aspirate can be of conclusive evidence in phacoanaphylactic uveitis, endophthalmitis and in specific large cell lymphoma (Fig. 1.10). Cytological findings in vitreous biopsy in uveitic diseases are shown in Table 1.5. Table 1.5:  Showing cytological findings in vitreous biopsy. Diagnosis

Findings

Phacoanaphylactic uveitis

Lens fragments surrounded by polymorphs, epithiliod cells and giant cells

Large cell lymphoma

Large pleomorphic cells with prominent round or oval nuclei and scanty cytoplasm, micro nuclei are not present in such cells

Endophthalmitis

Acute and chronic inflammatory cells and causative organisms on appropriate stain

Uveitis

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Heterogenous lymphocytic infiltrate

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Technique of Vitreous Tap When performed in the outpatient department, the technique is similar to that of anterior chamber paracentesis. As the perforation of the sclera is more painful than performing a keratocentesis, subconjunctival injection of 0.1 mL of 2% lidocaine can be given at the site of scleral perforation and entry into the vitreous space, 3.5–4 mm posterior to the limbus in phakic and 3.0–3.5 mm posterior to the limbus in aphakic/pseudophakic patients. It should be better done in the operation theater under aseptic precautions. The vitreous sampling is done using 25–23-gauge needles. Most eyes with long-standing intraocular inflammation have liquefied vitreous or fluid pockets within the vitreous. In such a situation, fine bored 25-gauge needle can be used. When organization of vitreous is seen, 23-gauge needle is preferred. The needle is inserted in the vitreous cavity under direct visualization with slit-lamp. The empty syringe withdraws the vitreous, and manipulating the stopcock, a similar quantity of antibiotic is injected into the vitreous cavity. After the injection, the needle is slowly withdrawn from the eye. Complications with vitreous tap are vitreous hemorrhage, endophthalmitis, lens injury, retinal tears and secondary glaucoma.

Technique of Vitreous Sampling and Biopsy For analysis of the vitreous, it is essential to obtain undiluted vitreous specimen under sterile conditions intraoperatively. Newer techniques using vitrectomy with attachments and pneumovitrector have been described. Doft et al.16 obtained vitreous samples in eyes with endophthalmitis by directly connecting a syringe to the aspiration tube of the vitreous cutter. Others have used a collecting bottle with openings at both sides integrated into the aspiration system. Smiddy et al.17 obtained vitreous samples through a three-way stopcock through a manual aspiration. Scholda and co-workers18 have developed a new technique, in which a metal device is integrated into the aspiration system of the vitrectomy unit, which fits on standard laboratory plastic containers with integrated caps. Peyman has devised a full functional vitrectomy instrument (pneumovitrector) composed of an aspiration and cutting system combined with an infusion line for injecting air or gas into the vitreous cavity.19

Vitrectomy A more thorough standard three-port vitrectomy can be performed, especially when therapeutically indicated in cases of endophthalmitis. The undiluted vitreous can be sampled and aspirated via a side-port. All vitreous aspirated should be sent for examination because even the vitreous in the infusion line and vitrector can carry evidence of the pathology. Suction of vitreous in a patient with endophthalmitis is very tricky. The vitreous tends to

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put traction on the retina, leading to unanticipated tearing and splitting of the retina and ultimately retinal detachment. To minimize traction on the retina caused by vitreous condensation and fibrous tissue formations, it is best to aspirate vitreous in the operating room under sterile conditions and under the controlled suction and cutting with vitreous instrument. This is highly preferable to the unstable ‘sucking only’ of a large-bore needle aspiration at the pars plana. The cutting rate of the vitrectomy instrument should be turned up higher than 300 cuts per minute, which further serves to minimize tractional forces. Too much cutting of the vitreous, however, disturbs, disrupts, contorts and destroys the cellular elements of vitreous. The optimal degree of vitreous surgery should include aspiration with a minimum of cutting of cellular elements, but with enough rapid cutting so as not to prolong tractional forces. Such a vitreous sample diluted by the irrigating solution is then passed through a disposable membrane filter system. Adequate sterile technique must be maintained. The procedure for obtaining the vitreous includes a stop-cock assembly somewhere in the line before the machine receptacle is encountered by the sterile line. This varies with each machine used, but some forethought to the system allows for sterile maintenance of the fluid.

Handling and Testing of Aqueous and Vitreous Specimen The specimen should be handled in such a way as to allow the maximum number of tests to be performed based on the clinical diagnosis. To maximize the chance of detecting the offending agents, the aqueous humor and vitreous specimen obtained should be divided in two equal volumes. One half of the specimen is used for the following tests: Microbiology:  The samples should be immediately inoculated into blood agar, chocolate agar, brain–heart-infusion broth (BHIB), thioglycolate fluid (maintained at body temperature), Sabouraud’s agar, Brucella agar and BHIB with gentamicin (maintained at room temperature for fungal isolation). Polymerase chain reaction:  The PCR is a powerful method to amplify specific sequences of DNA from a large complex mixture of DNA. For example, one can design PCR primers to amplify a single locus from an entire genome. PCR done on these samples, particularly the vitreous sample, can be a significant indicator of the presence of the organism. A minimum volume of 0.05 mL should be reserved for this test especially when P. acnes, fungal endophthalmitis and uveitis of viral etiology are suspected. The other half of the original sample can be processed for the following tests. Nested polymerase chain reaction:  Nested PCR means that two pairs of PCR primers were used for a single locus. The logic behind this strategy is that if the wrong locus were amplified by mistake, the probability is very low that it would also be amplified a second time by a second pair of primers.

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Real time polymerase chain reaction:  In molecular biology, real-time polymerase chain reaction, also called quantitative real time polymerase chain reaction (Q-PCR/qPCR/qrt-PCR) or kinetic polymerase chain reaction (KPCR), is a laboratory technique, which is an evolution of PCR. In this technique, both evidence and quantification are done simultaneously and hence this investigation has the advantage of quantifying the load of the pathogen.

Cytology The entire sample can be spin down, the supernatant transpipetted and the pellet resuspended in formalin or glutaraldehyde. These pellets are passed through two or more millipore filters, and a number of specific staining methods including immunohistochemistry are carried out to identify the infiltrating cell types.20 The other technique includes cytocentrifuge by cytospin method (about 1000 revolutions for 5 min). Cytopathologic findings of vitreous aspirate are given in Table 1.5.

Antibodies The supernatant obtained after spinning down the cellular components within the aqueous humor should be subjected to ELISA. The local production of specific antibodies within the ocular fluids is an important indication for the possible etiology especially when toxocara or toxoplasma is suspected.21 In Europe, the estimation of the Goldmann Witmer coefficient is done as given below: Titer of antibody in aqueous concentration of serum globulin   × Titer of antibody in serum concentration of aqueous globulin   = Goldmann Witmer coefficient. Significance: • 0.5 to 2 = No intraocular antibody production. • 2 to 4 = Suggestive of intraocular antibody production. • 4 = Diagnostic of intraocular antibody production.

Flow Cytometric Analysis Flow cytometry (FCM) measures the physical and chemical properties of individual particle or cell moving in a single file in a fluid stream. The most clearly defined application of FCM is in diagnostic surgical pathology.1 It is an adjunct to histologic examination in the diagnosis of lymphoproliferative and leukemic processes. FCM is applied to the study of uveal melanomas, retinoblastomas and ocular lymphoid proliferations, especially masquerade

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syndrome. It is now also being used to provide valuable information regarding the ratio between the cytotoxic and helper T-cells, an indication for the immunologic events taking place during the course of the ocular disease. In a recent study, Davis et al.22 showed patient with intraocular lymphoma that the positive predictive value (PPV) of cytology was 100%, but the negative predictive value (NPV) was 60.9%. For infection, PPV for bacterial and fungal culture was 100% and NPV was 94.9%. CD 22 +ve B lymphocyte ≥ 20% of total cells on cytofluorographic analysis had a PPV of 88% for lymphoma.

Iris and Ciliary Body Biopsy Biopsy is usually performed in suspected tumors of iris and ciliary body. These lesions include glioneuromas, medulloepitheliomas, iridociliary cysts, leiomyomas, malignant melanomas and nematode granulomas.23 Indications of iris and ciliary body biopsy in uveitic conditions are: • Metastatic lesions to the iris and ciliary body masquerading as uveitis. • Ruptured iris cysts mimicking anterior uveitis. • Iris and ciliary body nodules secondary to granulomatous conditions like tuberculosis and sarcoidosis. Moorthy and co-workers reported three patients with coccidioidomycosis iridocyclitis diagnosed by biopsy of iris nodules.24

Choroidal and Retinochoroidal Biopsy Lesions within the choroid can be difficult to differentiate clinically, although technological advances in non-invasive imaging have helped to monitor the size and the growth. The ophthalmologist has to consider the option of perform­ing a choroidal or retinochoroidal biopsy. With advances in instrumentation and microsurgical techniques, endoretinal biopsy and chorioretinal biopsy can be performed easily and safely. Although the diagnosis of intraocular lymphoma can usually be made on the basis of diagnostic vitrectomy alone, sometimes it requires a more aggressive approach with choroidal biopsy, when pars plana vitrectomy and ex­tensive medical examination fails to confirm the diagnosis.

Transscleral Choroidal Biopsy After conjunctival recession and hemostasis, the area of sclera overlying the lesion is marked. A half-thickness scleral trapdoor hinged posteriorly is created. 7–0 preplaced vicryl sutures are placed to allow rapid closure. Diathermy is applied to the circumference of the biopsy site. An opening of smaller dimension is made into the suprachoroidal space within the floor of the lamellar scleral dissection. This opening is enlarged to expose the choroid which is excised using Vannas scissors taking care to avoid perforation of the retina. The scleral trap door is then sutured.25

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Internal Approach for Retinal, Subretinal or Chorioretinal Biopsy A vitreous biopsy is obtained at the beginning of the procedure before starting infusion.26 The biopsy site in case of detached retina is selected at the junction of involved and normal retina. Unimanual bipolar endocautery is used at the margin of the proposed biopsy site. A biopsy specimen of at least 2 × 2 mm is then cut with 20-gauge vertical cutting scissors. The specimen is left attached at one corner and an intraocular forceps is used to remove it from the eye. After reattaching the retina, endolaser is applied to the biopsy site and long-acting gas or silicone oil tamponade is used. In case of attached retina, combined retinal and choroidal biopsy is obtained. Intense endo-diode laser is first applied around the margin of the biopsy site. Two minutes later a 2 × 2 mm biopsy specimen is cut within the margins of the laser burns with vertically cutting intraocular scissors until sclera is visible.

Fine Needle Aspiration Biopsy Fine needle aspiration biopsy had been first described in as early as 1847, though the first report was published in 1930.1 FNAB offers a histopathologic correlation to the clinical diagnosis in the case of atypical presentation of intraocular tumors. It aids in effective planning and management, and enables histopathological diagnosis without sacrificing the eye or having to resort to open biopsy methods. FNAB has been recommended in following conditions: • Cases of suspected infectious subretinal lesions (abscess or tuberculoma) mimicking as choroidal tumors. Gregor and coworkers diagnosed a Nocardia asteroides subretinal abscess following a transvitreal FNAB.27 • Cases where diagnosis is difficult, distinction between benign and malignant lesion is not clear and all ancillary tests are inconclusive, and where therapeutic decisions will be made on the basis of cytological findings, like metastatic disease of the choroid but with no primary and cases where patient refuses recommended therapy until histopathological confirmation is obtained.

Technique of Fine Needle Aspiration Biopsy Approaches:  • Limbal route is used to approach anterior uveal lesions.28 For example, iris lesions, or in aphakic patients for posterior ciliary body lesions. • In the posterior segment lesions pars plana transvitreal approach is used.

Chapter 01.indd 18

In this approach, the needle is passed from the pars plana region (3.5 mm from the limbus) in the quadrant opposite to the lesion, through the vitreous gel. For some of the eyes with tumors located posteriorly, a vitrectomy needs to be performed before aspiration biopsy.

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Diagnostic Procedures in Uveitis  19

• Corneolimbal approach is used in patients with retinoblastoma, a highly friable tumor, as the chance of needle track dissemination is extremely high.

This approach through the zonules prevents dissemination of the tumor mass through the needle track. Through a corneolimbal approach the needle passes through multiple planes, thus wiping out the tumor cells as the needle is removed from the eye. • Subretinal fine needle aspiration biopsy can be done in cases of subretinal abscesses and tuberculomas, considering the site is approachable. Complications:  • The most common complication of FNAB is bleeding from the site of the needle track. • Orbital dissemination of tumor cells and distant metastatic spread caused by tumor implantation along the needle track have been reported which are rare now. • Iatrogenic retinal perforations are unavoidable by the indirect needle approach to the choroidal lesions and can theoretically cause a retinal detachment after FNAB.

Biopsy of Intraocular Lymphoma Steroids should be stopped before diagnostic procedures to increase the diagnostic yield in suspected lymphoma cases. Samples should be obtained from the densest part of the infiltrate.29 It is worthy to note that lymphoma cells undergo apoptosis 90–100μ from their blood supply. If a distinct subretinal mass is present, a direct subretinal biopsy is better than a vitreous tap. The cells of lymphoma are fragile (Fig. 1.11). Due to the associated presence of inflammatory cytokines, the cells may degenerate, and also the DNA degrades resulting in false negative results.30 Samples may be placed in cell culture media to improve viability of cells. Interleukin 10 (IL-10) levels have been found to be elevated in serum and vitreous of patients with non-Hodgkins lymphoma while interleukin 6 (IL-6) levels are elevated in the vitreous of patients with intraocular inflammation. Whitcup, et al. found in a study that IL-10 levels exceeded the IL-6 levels in all 5 of studied patients with primary central nervous system lymphoma involving the eye but in none of the 13 patients with uveitis.31

Biopsy in Vasculitis Biopsy of the temporal arteries is often performed for suspected inflammatory bowel disease (Crohn’s disease and ulcerative colitis) that can present with uveitis of both anterior nongranulomatous or posterior type. Frequent biopsies are taken to assess the activity of the disease and to assess changes

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Fig. 1.11:  Fine needle aspiration biopsy showing pleomorphic malignant cells in necrotic background (H and E, × 400).

that precede malignancy. The FNAB has a sensitivity and specificity rate of 84% and 98%, respectively.32

CONCLUSION In the future, newer association with infection, systemic disease and genetic patterns in uveitis will arise, and this needs to be explored further, focusing on the pathogenesis of the underlying ocular inflammation. However, while translating these research findings into clinical application, several points like cost effectiveness will have to be considered. The different immunological hypotheses of etiology of uveitis need to be verified and adopted or rejected, and management is done accordingly. Biopsy pathology in ocular inflammation has no doubt a well defined place in the investigation protocol, especially considering the rarity of certain types and the overlapping features that may coexist in the same patient. The most important consideration is that biopsy proven pathogenesis and etiology is reliable and treatment can be instituted based on the histopathological outcome.

REFERENCES   1. Biswas J, Annamalai R, Krishnaraj V. Biopsy Pathology in Uveitis. Middle East Afr J Ophthalmol. 2011;18(4):261-7.   2. Foster CS, Vitale AT. Diagnosis and Treatment of Uveitis. Philadelphia: WB Saunders Company; 2002. pp. 264-72, 315-32, 710-25, 31-812.  3. Ryan SJ. Retinal Imaging and Diagnostics. In: Sadda SR, ed. 1. 2013 ed.: Elsevier; 2013. pp. 28-81.

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Diagnostic Procedures in Uveitis  21

  4. Agrawal RV, Biswas J, Gunasekaran D. Indocyanine green angiography in posterior uveitis. Indian J Ophthalmol. 2013;61(4):148-59.  5. Gupta V, Gupta A. Ancillary investigations in uveitis. Indian J Ophthalmol. 2013;61(6):263-68.   6. Kaines A, Oliver S, Reddy S, et al. Ultrawide angle angiography for the detection and management of diabetic retinopathy. Int Ophthalmol Clin. 2009;49(2):539.   7. De Boer JH, Luyendijk L, Rothova A, et al. Analysis of ocular fluids for local antibody production in uveitis. Br J Ophthalmol. 1995;79(6):610-16.   8. Van der Lelij A, Rothova A. Diagnostic anterior chamber paracentesis in uveitis: a safe procedure? Br J Ophthalmol. 1997;81(11):976-9.   9. May DR, Noll FG. An improved approach to aqueous paracentesis. Ophthalmic Surg. 1988;19(11):821-2. 10. Tran TH, Rozenberg F, Cassoux N, et al. Polymerase chain reaction analysis of aqueous humour samples in necrotising retinitis. Br J Ophthalmol. 2003;87(1):79-83. 11. Biswas J. Pathology of uveitis. Afro-Asian J Ophthalmol. 1995;11:205-8. 12. Priem H, Verbraeken H, de Laey JJ. Diagnostic problems in chronic vitreous inflammation. Graefes Arch Clin Exp Ophthalmol. 1993;231(8):453-6. 13. Palexas GN, Green WR, Goldberg MF, et al. Diagnostic pars plana vitrectomy report of a 21-year retrospective study. Trans Am Ophthalmol Soc. 1995;93:281314. 14. Verbraeken H. Diagnostic vitrectomy and chronic uveitis. Graefes Arch Clin Exp Ophthalmol. 1996;234(1):S2-S7. 15. Liu K, Klintworth GK, Dodd LG. Cytologic findings in vitreous fluids. Acta cytol. 1999;43(2):201-6. 16. Doft BH, Donnelly K. A single sclerotomy vitreous biopsy technique in endophthalmitis. Arch Ophthalmol. 1991;109(4):465. 17. Smiddy WE, Michels RG, de Bustros S, et al. Histopathology of tissue removed during vitrectomy for impending idiopathic macular holes. Am J Ophthalmol. 1989;108(4):360-4. 18. Scholda CD, Egger SF, Lakits A, et al. A system for obtaining undiluted intraoperative vitreous biopsy samples. Arch Ophthalmol. 1996;114(10):1271-2. 19. Peyman GA. A pneumovitrector for the diagnostic biopsy of the vitreous. Ophthalmic Surg Lasers and Imaging Retina. 1996;27(3):246-7. 20. Ben Erza D. Diagnostic intraocular interventions. Ocular inflammation:  Basic and clinical concepts Martin Dunitz Ltd. 1999:83-9. 21. Joynson D, Payne R, Rawal B. Potential role of IgG avidity for diagnosing toxoplasmosis. J Clin Pathol. 1990;43(12):1032-3. 22. Davis JL. Diagnosis of intraocular lymphoma. Ocul Immunol Inflamm. 2004;12(1):7-16. 23. Johnston RL, Tufail A, Lightman S, et al. Retinal and choroidal biopsies are helpful in unclear uveitis of suspected infectious or malignant origin. Ophthalmology. 2004;111(3):522-8. 24. Moorthy RS, Rao NA, Sidikaro Y, et al. Coccidioidomycosis iridocyclitis. Ophthalmology. 1994;101(12):1923-8. 25. Foulds WS. The uses and limitations of intraocular biopsy. Eye. 1992;6(1): 11-27.

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26. Rutzen AR, Ortega-Larrocea G, Dugel PU, et al. Retinal and choroidal biopsy in intraocular inflammation: a clinicopathology study. Trans Am Ophthalmol Soc. 1994;92:431-55. 27. Gregor RJ, Chong CA, Augsburger JJ, et al. Endogenous nocardia asteroides subretinal abscess diagnosed by transvitreal fine-needle aspiration biopsy. Retina. 1989;9(2):118-21. 28. Shanmugam MP, Biswas J. Fine needle aspiration biopsy in the diagnosis of intraocular mass lesions. Indian J Ophthalmol. 1997;45(2):105-8. 29. Zaldivar RA, Martin DF, Holden JT, et al. Primary intraocular lymphoma: clinical, cytologic, and flow cytometric analysis. Ophthalmology.  2004; 111(9):1762-7. 30. Murray PI, Hoekzema R, van Haren M, et al. Aqueous humor interleukin-6 levels in uveitis. Invest Ophthalmol Vis Sci. 1990;31(5):917-20. 31. Whitcup SM, Stark-Vancs V, Wittes RE, et al. Association of interleukin 10 in the vitreous and cerebrospinal fluid and primary central nervous system lymphoma. Arch Ophthalmol. 1997;115(9):1157-60. 32. Midena E, Bonaldi L, Parrozzani R, et al. In vivo detection of monosomy 3 in eyes with medium-sized uveal melanoma using transscleral fine needle aspiration biopsy. Eur J Ophthalmol. 2006;16(3):422-5.

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CHAPTER

2 Polymerase Chain Reaction in Intraocular Inflammation Jyotirmay Biswas, Krishnendu Nandi

INTRODUCTION The polymerase chain reaction (PCR) is a powerful tool in molecular biology that allows the rapid production of analytic quantities of DNA from small amounts of starting material. Since the introduction of its modern form in 1988,1 PCR has revolutionized much of molecular biology and has greatly accelerated the development of molecular diagnostics. Kary B. Mullis from USA received a Nobel Prize in 1993 for inventing this technique. This powerful technique has numerous applications in diagnostic pathology, especially in the fields of microbiology and genetics. All practicing ophthalmologists should have a working knowledge of the uses of PCR. To diagnose uveitis, infectious endophthalmitis and protozoan eye diseases PCR has been used.2 This chapter discusses the use of PCR in the analysis of uveitis, and ways in which PCR is improving the knowledge of understanding of the mechanisms of uveitis.

BASIC TECHNIQUE The PCR is a technique involving enzymatic amplification of nucleic acid sequences in repeated cycles of denaturation, oligonucleotide annealing and DNA polymerase extension.3 It uses in vitro enzymatic synthesis to amplify specific DNA sequence within a few hours. The PCR consists of repetitive cycles of specific DNA synthesis, defined by short stretches of preselected DNA. With each cycle, there is a doubling of the final, desired DNA product such that million-fold amplification is possible.4

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24  Gems of Ophthalmology—Diseases of Uvea

The PCR is performed using two specific primers that flank the DNA region of interest. After enzymatic synthesis of the replicated strand is complete, the DNA is denatured into single strand. This allows the newly synthesized strand to serve as template for subsequent synthesis of new strand. Using an automated thermal heat block, 30–40 rounds of replication can be performed in just a few hours. Theoretically, the molar amount of PCR product doubles with each round of replication. Thirty-five cycles are typically used for diagnostic PCR. In order to perform PCR, we must have a source of DNA (DNA extracted from either an aqueous or vitreous specimen). It begins with the initial sample containing the target DNA and mixes in the appropriate primers, DNA polymerase, nucleotide triphosphates, and buffered salts. Following performance of PCR in the thermal cycler, the products may be detected in one of several ways. Generally, gel electrophoresis, with use of acrylamide or agarose, is employed to determine if a DNA fragment of expected size has been produced. Confirmation of the identity of the PCR product can be achieved by digesting the product with restriction endonuclease and observing the restriction digest pattern, a technique called fingerprinting. Ultimate identification of a DNA fragment can be achieved by sequencing the PCR product DNA. The PCR is an effective tool for amplifying DNA, however, for this to be adapted to measure RNA, the RNA sample first needs to be reverse transcribed to DNA via an enzyme known as a reverse transcriptase. This transcribed DNA is known as cDNA or complementary DNA

PCR Technique has various Variants Multiplex PCR is a variant of PCR in which two or more loci are simultaneously amplified. When faced with a clinical situation that suggests a differential diagnosis of subtypes of a particular virus, e.g., HHV 1–8, the multiplex PCR assay can provide a rapid and reliable diagnosis, even when only small sample amounts are available for examination. It acts as a good screening tool and enables rapid determination of the type of DNA sample present. Real-time PCR, also called quantitative real-time PCR (QRT-PCR) or kinetic PCR, is used to determine whether or not a specific sequence is present in the sample; and if it is present, the number of copies present in it. The procedure follows the general principle of PCR; however, in conventional PCR, the products of the reaction are assessed by gel electrophoresis at the end of the reaction, while in real-time PCR, the amplified DNA can be assessed while the test is still going on, as it accumulates in the reaction after each amplification cycle. Frequently, real-time PCR is combined with reverse transcription to quantify messenger RNA (mRNA) in cells or tissues. Nested PCR is a modification of PCR intended to reduce the contaminations in products due to the amplification of unexpected primer binding sites. Nested PCR involves two sets of primers, used in two successive runs of PCR, the second set intended to amplify a secondary target within the first run product.

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Polymerase Chain Reaction in Intraocular Inflammation  25

On nearly any ocular specimen or biopsy PCR can be performed. For diagnosis of uveitis, the obtained sample is usually an anterior chamber paracentesis or vitreous tap. Anterior chamber paracentesis of 50 microliters is usually sufficient for diagnostic purposes. For vitrectomy specimens, the initial preinfusion aspirate (100–500 microliters) is preferred. Specimens should be aseptically transferred to a sterile, capped tube (i.e., a 1.5-ml microfuge tube) and quick-frozen on dry ice or in liquid nitrogen. The sample should remain frozen until processed by the accepting laboratory; freeze–thaw cycles will release nucleases that will degrade all RNA and some DNA.5 The sensitivity for detection of foreign DNA is very high. Thus, PCR potentially is more sensitive than culture for detection of many organisms. By utilizing a secondary detection system in concert with the initial PCR reaction, perfect specificity can be assured. Although PCR would seem to have nearly ideal characteristics for a diagnostic test, the high sensitivity and specificity can cause significant pitfalls.

APPLICATION OF PCR PCR Diagnosis of Infectious Uveitis PCR has had a major impact on our ability to detect infectious agents. Since the first detection of Toxoplasma gondii DNA in ocular tissue with the use of PCR in 1990,5 PCR has been applied to the detection and diagnosis of various infective uveitis.6 The initial application of PCR diagnostics to ophthalmic disease was in the detection of viral uveitis. 7-10 Knox et al.10 performed PCR on aqueous or vitreous samples of 37 eyes of 38 patients, with “diagnostic dilemmas” in posterior uveitis. Of these cases, a definitive diagnosis of a viral infection could be made by PCR in 25 eyes. Of the PCR-negative cases, a number were ultimately diagnosed to be toxoplasmosis, and the remainder had natural histories inconsistent with viral retinitis. Thus, both positive and negative PCR results likely had diagnostic significance in this study. Probably the most common indication for performing diagnostic PCR for posterior uveitis is the presence of media opacity. Significant media opacity from cataract or dense vitritis can make otherwise straightforward diagnoses difficult. Mitchell et al. developed PCR primers with a sensitivity of 93% and specificity of 98% for the detection of Cytomegalovirus (CMV).11 Of the nine patients tested, four tested positive for CMV, and three for Varicella Zoster virus (VZV). The remaining two were subsequently judged to have toxoplasmosis. In all cases, the clinical course was consistent with the PCR-based diagnosis. The clinical diagnosis of atypical toxoplasmosis can also be problematic. Classical reactivation of toxoplasmosis can be diagnosed by clinical examination, but primary toxoplasmosis can resemble a number of other infectious acute retinitis.12,13 Initial studies of PCR diagnosis of Toxoplasma gondii were disappointing, showing sensitivities less than 50%.14,15 In 1993, Aouizerate

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26  Gems of Ophthalmology—Diseases of Uvea

et al. performed PCR on the aqueous of 59 eyes with suspected or confirmed infection with Toxoplasma gondii; the parasite was demonstrated in 20 cases (33.8%).14 However, recent advances in primer design, and utilizing highly repetitive pathogen DNA sequences, have greatly improved yields for PCR of T. gondii. Montoya et al.15 were able to detect Toxoplasma DNA in nearly 80% of patients with suspected ocular toxoplasmosis and positive serum IgG titers. Using a similar PCR assay, Bou et al.16 were able to detect T. gondii DNA in the peripheral blood of most patients with active ocular toxoplasmosis, raising the possibility that in the future, reactivation disease could be diagnosed via a blood test. Biswas et al. performed PCR on the aqueous in a case of suspected miliary tuberculosis of choroid, PCR has been found to be useful in cases of subretinal abscesses where final aspiration biopsy material showed Mycobacterium tuberculosis genome (Figs. 2.1 and 2.2).17 PCR is also helpful in detecting Leptospira related uveitis.18

PCR in Retinal Vasculitis Madhavan et al. reviewed their experience using PCR to tissue sections obtained from formalin-fixed and paraffin embedded tissues of epiretinal membrane (ERM) from 23 patients of Eales’ disease.19 Eleven out of 23 (47.8%) were positive for Mycobacterium tuberculosis genome, indicating association of this bacterium with Eales’ disease. Gupta et al. reported tubercular retinal vasculitis with varied fundus findings, and diagnosis was confirmed by doing PCR from the aqueous or vitreous humor.20

Fig. 2.1: A case of subretinal abscess.

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Polymerase Chain Reaction in Intraocular Inflammation  27

Fig. 2.2: Ethidium bromide stained 2% agarose gel with amplification products from a case of subretinal abscess suspected to be tuberculous. Lane 1: Reagent control of the first round, Lane 2: Reagent control of the second round, Lane 3: Aqueous humor - negative, Lane 4: Fine-needle aspiration biopsy specimen - positive, Lane 5: Blood - positive, Lane 6: Positive control M. tuberculosis (H37Rv), Lane 7: Phi × 174 DNA/Hinf I digest.

PCR Diagnosis of Noninfectious Uveitis PCR has also been implicated in studies of noninfectious uveitis. The most common application is human leukocyte antigen (HLA) typing. Saiki et  al. used PCR to enzymatically amplify a specific segment of beta-globin or HLA-DQ alpha gene in human genomic DNA.21 Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology is applied to HLA-DR, -DQ and –DW typing at the nucleotide level, eliminating the need for radioisotopes and allele specific oligonucleotide probes.22 Using this technique, Shino et al. reported complete association of the HLA-DRB104 and –DQB104 alleles with Vogt-Koyanagi-Harada (VKH) disease23 and it is more common for Asians. Polymerase chain reactionsequencing-based typing (PCR-SBT) is used for HLA-B51 alleles. Evaluation of intraocular cytokines and other inflammatory mediators and makers provides important information in noninfectious uveitis.24 Cytokines and inflammatory related transcripts are usually detected via reverse transcription-PCR (RT-PCR).24-26 The results from RT-PCR are complementary to data from Western blotting and/or immunohistochemistry.

PCR for Masquerade Syndrome The Masquerade syndrome consists of a group of disorders that occurs with intraocular inflammation (most commonly malignancy) and is often misdiagnosed as uveitis. PCR can be useful for diagnosing masquerade syndrome. Primary intraocular lymphoma is a subtype of central nervous system ­lymphoma

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28  Gems of Ophthalmology—Diseases of Uvea

involving the eye. It can often mimic chronic uveitis. Utilization of PCR has become a practical tool for the detection of IgH gene rearrangements and provides a helpful adjunct for the diagnosis of B-cell lymphoma in the eye.27

PCR for Endophthalmitis Although direct microscopy is the easiest and most rapid method to detect bacterial etiologies of endophthalmitis, its sensitivity is very low, with positive result varying from 4.2% to 46.5% for vitreous samples, which decreases further in aqueous fluid.28,29 More sensitive than microscopy, culture, is considered “the gold standard”. However, there have been no significant improvements in the yield of culture methods.30 Postoperative endophthalmitis is a vision-threatening complication of cataract surgery and presents even further diagnostic challenges. The organisms are frequently present in low numbers, and they can be difficult to culture. Yields from diagnostic vitreous biopsies in this condition are less than 50%. The endophthalmitis vitrectomy study reported culture yields of only 70%.31 Culture results are also slow to return, thus requiring patients be treated with broad-spectrum antibiotics for several days, even for relatively indolent bacteria. In cases where conventional techniques have low sensitivity, PCR, characterized by its high sensitivity and specificity, would be an ideal technique to detect bacterial pathogens in the eye. All bacteria share common, highly repetitive DNA sequences for their 16S ribosomal RNA. By designing primers to these conserved 16S sequences, PCR can be performed on biopsy material from eyes with suspected endophthalmitis, with the results available within 6–8 hours. Therese et al. demonstrated the utility of this approach for culture-negative endophthalmitis.29 They were able to determine a bacterial cause for endophthalmitis in 100% of culture-positive and 44% of culture-negative cases. Of the remaining culture-negative cases, one-third was found to be fungal. Lohmann et al.32 used 16S ribosomal primers as well as fungal PCR primers, along with culture and stain for 25 eyes with delayed-onset endophthalmitis. Aqueous culture and microscopy each had a 0% yield, but vitreous culture had a 24% yield in these patients. PCR of the aqueous yielded a diagnosis in 84% of the cases and PCR of a vitreous biopsy yielded a diagnosis in 92%. PCR, thus, has clear superiority to any other available diagnostic technique for diagnosis of endophthalmitis. Biswas et al. demonstrated Aspergillus fumigatus fungus by PCR-based RFLP (Restriction Fragment Length Polymorphism) technique from paraffin section of an eyeball of an 8-month-old child removed for endogenous endophthalmitis.33 Compared to the conventional technique, PCR for detection of fungal DNA was found to be a rapid and more sensitive method in the early diagnosis of postoperative fungal endophthalmitis.34,35 Semi-nested PCR is also helpful for rapid detection of panfungal genome directly from ocular specimens.36 PCRbased technology is a useful adjunct to conventional culture because when used with aqueous humor samples only, the association of both techniques

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Polymerase Chain Reaction in Intraocular Inflammation  29

allowed for a microbiological diagnosis in 71% of cases of postoperative acute and delayed-onset endophthalmitis.37 A universal bacterial PCR can be very helpful for the diagnosis of endogenous bacterial endophthalmitis at an early stage of the disease.38

APPLICATION OF REAL-TIME AND MULTIPLEX PCR IN UVEITIS Human Herpes Virus Little information exists on the prognostic or diagnostic significance of pathogen load in the diagnosis of infectious posterior uveitis. In their study, Dworkin L et al. concluded that, through the use of real-time PCR,39 one may be able to distinguish false positive from true-positive results by comparison of viral load. They suggested that, for cases of suspected VZV or herpes simplex virus (HSV) infection, viral titers of less than 10 pathogens per microliter may be false positive. Conversely, very high pathogen loads are more likely to be associated with active disease. Sugita et al. combined multiplex and real-time PCR to analyze the role of HHV in patients with uveitis and ocular lymphoma.40 In the study, they were able to rapidly screen for the detection of the virus genome of all eight types of human herpes viruses by using several different primer pairs. When positive results were noted, they used QRT-PCR to examine the viral load using different primer pairs. This allowed them to confirm their positive results through the use of two PCR combinations. They concluded that qualitative multiplex PCR might be a useful method for screening viral infections, and furthermore, QRT-PCR might make it possible to evaluate the clinical relevance of virus infections.

Epstein-Barr Virus In another similar study Yamamoto et al., studied the role of Epstein-Barr virus in uveitis by analyzing the aqueous and vitreous samples using both qualitative and real-time PCR.41 Though EBV was detected in the ocular fluids of many patients, only a small proportion of patients showed high viral loads using real-time PCR.

Cytomegalovirus Miyanaga M et al. have found that load of Cytomegalovirus (CMV) in the aqueous humor of patients with anterior iridocyclitis and endotheliitis is directly proportional to the documented endothelial cell loss. They assessed the CMV load using real-time PCR.42

Toxoplasmosis Ocular toxoplasmosis is a major cause of posterior uveitis worldwide. The diagnosis is based mainly on ophthalmological examination. Biological diagnosis

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30  Gems of Ophthalmology—Diseases of Uvea

is necessary in atypical cases, and this requires aqueous humor sampling by anterior chamber paracentesis. In a study by Talabani et al., they combined immunoblotting, real-time PCR and Goldmann-Witmer coefficient, to confirm Toxoplasma gondii as the causative agent in eyes with atypical retinochoroiditis.43 PCR analysis of aqueous humor samples detected taxoplasma DNA in 55% of patients. They found that, in contrast to the results of immunoblotting and the GWC, the results of PCR were not influenced by the interval between symptom onset and paracentesis. In addition, acute necrotizing retinal lesions were significantly larger in PCR-positive patients, with a mean of 3.5 optic disc diameters, than in PCR-negative patients, with a mean of 1.5 optic disc diameters.

Endophthalmitis There are certain limitations of conventional PCR in diagnosing cases of bacterial endophthalmitis. There are chances of cross-contamination and there are limitations on the interpretation of the real-time PCR melting curve. Goldscmidt et al. have described a new test called f-real-time PCR.44 The f-real-time PCR could detect Staphylococci, Streptococci, Haemophilus, Pseudomonas, Enterobacteria, Acinetobacter, Propionibacteriaceae and Corynebacteria in one run in 90 minutes while cultures require several hours to days.

CONCLUSION PCR is a powerful molecular technique for the evaluation of very small amounts of DNA and RNA. PCR can be a simple, rapid, sensitive and specific tool for the diagnosis of infection, autoimmunity and masquerade syndromes of the eye.

REFERENCES  1. Saiki RK, Gelfand DH, Stoffel S, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988;239(4839): 487-91.   2. Van Gelder RN. Application of polymerase chain reaction to diagnosis of ophthalmic disease. Surv Ophthalmol. 2001;46(3):248-58.   3. Erlich HA, Gelfand D, Sninsky JJ. Recent advances in the polymerase chain reaction. Science. 1991;252(5013):1643-51.   4. Remick DG, Kunkel SL, Holbrook EA, et al. Theory and application of polymerase chain reaction. Am J Clin Pathol. 1990;93(4 Suppl 1):S49-54.   5. Brezin AP, Egwuagu CE, Burnier M Jr, et al. Identification of Toxoplasma gondii in paraffin-embedded sections by the polymerase chain reaction. Am J Ophthalmol. 1990;110(6):599-604.   6. Mitchell SM, Fox JD, Tedder RS: Vitreous fluid sampling and viral genome detection for the diagnosis of viral retinitis in patients with AIDS. J Med Virol. 1994; 43(4):336-40.

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Polymerase Chain Reaction in Intraocular Inflammation  31

  7. Cunningham ET Jr, Short GA, Irvine AR, et al. Acquired immunodeficiency syndrome–associated herpes simplex virus retinitis. Clinical description and use of a polymerase chain reaction-based assay as a diagnostic tool. Arch Ophthalmol. 1996;114(7):834-40.   8. Abe T, Sato M, Tamai M. Correlation of varicella-zoster virus copies and final visual acuities of acute retinal necrosis syndrome. Graefes Arch Clin Exp Ophthalmol. 1998;236(10):747-52.   9. Abe T, Tsuchida K, Tamai M. A comparative study of the polymerase chain reaction and local antibody production in acute retinal necrosis syndrome and cytomegalovirus retinitis. Graefes Arch Clin Exp Ophthalmol. 1996;234(7): 419-24. 10. Knox CM, Chandler D, Short GA, et al. Polymerase chain reaction-based assays of vitreous samples for the diagnosis of viral retinitis. Use in diagnostic dilemmas. Ophthalmol. 1998;105:37-44. 11. Gerling J, Neumann-Haefelin D, Seuffert HM, et al. Diagnosis and management of the acute retinal necrosis syndrome. Ger J Ophthalmol. 1992;1(6):388-93. 12. Holland GN, Muccioli C, Silveira C, et al. Intraocular inflammatory reactions without focal necrotizing retinochoroiditis in patients with acquired systemic toxoplasmosis. Am J Ophthalmol. 1999;128(4):413-20. 13. Ronday MJ, Ongkosuwito JV, Rothova A, et al. Intraocular anti-Toxoplasma gondii IgA antibody production in patients with ocular toxoplasmosis. Am J Ophthalmol. 1999;127(3):294-300. 14. Aouizerate F, Cazenave J, Poirier L, et al. Detection of Toxoplasma gondii in aqueous humour by the polymerase chain reaction. Br J Ophthalmol. 1993;77(2):107-9. 15. Garweg J, Boehnke M, Koerner F. Restricted applicability of the polymerase chain reaction for the diagnosis of ocular toxoplasmosis. Ger J Ophthalmol. 1996;5:104-8. 16. Bou G, Figueroa MS, Marti-Belda P, et al. Value of PCR for detection of Toxoplasma gondii in aqueous humor and blood samples from immunocompetent patients with ocular toxoplasmosis. J Clin Microbiol. 1999;37(11): 3465-8. 17. Biswas J, Shome D. Choroidal tubercles in disseminated tuberculosis diagnosed by the polymerase chain reaction of aqueous humor. A case report and review of the literature. Ocul Immunol Inflamm. 2002;10(4):293-8. 18. Rathinam SR. Leptospirosis. Curr Opin Ophthalmol. 2002;13(6):381-6. 19. Madhavan HN, Therese KL, Gunisha P, et al. Polymerase chain reaction for detection of Mycobacterium tuberculosis in epiretinal membrane in Eales’ disease. Invest Ophthalmol Vis Sci. 2000;41(3):822-5. 20. Gupta A, Gupta V, Arora S, et al. PCR-positive tubercular retinal vasculitis: clinical characteristics and management. Retina. 2001;21:435-44. 21. Saiki RK, Bugawan TL, Horn GT, et al. Analysis of enzymatically amplified beta-globin and HLA-DQ alpha DNA with allele-specific oligonucleotide probes. Nature. 1986;324(6093):163-6. 22. Uryu N, Maeda M, Ota M, et al. A simple and rapid method for HLA-DRB and –DQB typing by digestion of PCR amplified DNA with allele specific restriction endonuclease. Tissue Antigens. 1990;35:20-31.

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32  Gems of Ophthalmology—Diseases of Uvea

23. Shindo Y, Ohno S, Yamamoto T et al. Complete association of the HLA-DRB1*04 and –DQB1*04 allele with Vogt-Koyanagi-Harada’s disease. Hum Immunol. 1994;39(3):169-76. 24. Murray PI, Clay CD, Mappin C, et al. Molecular analysis of resolving immune responses in uveitis. Clin Exp Immunol. 1999;117(3):455-61. 25. Li B, Yang P, Zhou H, et al. T-bet expression is upregulated in Behçet’s disease. Br J Ophthalmol. 2003;87(10):1264-7. 26. Siolverman MD, Zamora DO, Pan Y, et al. Constitutive and inflammatory mediator-regulated fractalkine expression in human ocular tissue and cultured cells. Invest Ophthalmol Vis Sci. 2003;44(4):1608-15. 27. Coupland SE, Bechrakis NE, Anatassiou G et al. Evaluation of vitrectomy specimens and choriorenital biopsies in the diagnosis of primary intraocular lymphoma in patients with masquerade syndrome. Graefes Arch Clin Exp Ophthalmol. 2003;241:860-87. 28. Barza M, Pavan PR, Doft BH, et al. Evaluation of microbiological diagnostic techniques in postoperative endophthalmitis in the endophthalmitis vitrectomy study. Arch Ophthalmol. 1997;115(9):1142-50. 29. Therese KL, Anand AR, Madhavan HN. Polymerase chain reaction in the diagnosis of bacterial endophthalmitis. Br J Ophthalmol. 1998;82(9):1078-82. 30. Anand AR, Madhavan HN, Therese KL. Use of polymerase chain reaction and DNA probe hybridization to determine the Gram reaction of the infecting bacterium in the intraocular fluids of the patients with endophthalmitis. J Infect. 2000;41:221-6. 31. Microbiologic factors and visual outcome in the endophthalmitis vitrectomy study. Am J Ophthalmol. 1996; 122(6):830-46. 32. Lohmann CP, Linde HJ, Reischl U. Improved detection of microorganisms by polymerase chain reaction in delayed endophthalmitis after cataract surgery. Ophthalmology. 2000;107(6):1047-51. 33. Biwas J, Bagyalakshmi R, Therese LK. Diagnosis of Aspergillus fumigatus endophthalmitis from formalin fixed paraffin-embedded tissue by polymerase chain reaction-based restriction fragment length polymorphism. Indian J Ophthalmol. 2008;56(1):65-6. 34. Tarai B, Gupta A, Ray P, et al. Polymerase chain reaction for early diagnosis of post-operative fungal endophthalmitis. Indian J Med Res. 2006;123(5): 671-8. 35. Anand A, Madhavan H, Neelam V, et al. Use of polymerase chain reaction in the diagnosis of fungal endophthalmitis. Ophthalmology. 2001;108(2): 326-30. 36. Bagyalakshmi R, Therese KL, Madhavan HN. Application of semi-nested polymerase chain reaction targeting internal transcribed spacer region for rapid detection of panfungal genome directly from ocular specimens. Indian J Ophthalmol. 2007;55(4):261-5. 37. Chiquet C, Lina G, Benito Y, Cornut PL, Etienne J, Romanet JP, Denis P, Vandenesch F. Polymerase chain reaction identification in aqueous humor of patients with postoperative endophthalmitis. J Cataract Refract Surg. 2007;33:635-41. 38. Kerkhoff FT, van der Zee A, Bergmans AM, Rothova A. Polymerase chain reaction detection of Neisseria meningitidis in the intraocular fluid of a patient with

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Polymerase Chain Reaction in Intraocular Inflammation  33

endogenous endophthalmitis but without associated meningitis. Ophthalmol. 2003;110:2134-6. 39. Dworkin LL, Gibler TM, Van Gelder RN. Real-time quantitative polymerase chain reaction diagnosis of infectious posterior uveitis. Arch Ophthalmol. 2002;120(11):1534-9. 40. Sugita S, Shimizu N, Watanabe K et al. Use of multiplex PCR and real-time PCR to detect human herpes virus genome in ocular fluids of patients with uveitis. Br J Ophthalmol. 2008;92(7):928-32. 41. Yamamoto S, Sugita S, Sugamoto et al. Quantitative PCR for the detection of genomic DNA of Epstein-Barr virus in ocular fluids of patients with uveitis. Jpn J Ophthalmol. 2008;52(6):463-7. 42. Miyanaga M, Sugita S, Shimizu N et al. A significant association of viral loads with corneal endothelial cell damage in cytomegalovirus anterior uveitis. Br J Ophthalmol. 2010;94:336-40. 43. Talabani H, Aseeraf M, Yera H et al. Contributions of immunoblotting, real-time PCR, and the Goldmann-Witmer coefficient to diagnosis of atypical toxoplasmic retinochoroiditis. J Clin Microbiol. 2009;47(7):2131-5. 44. Goldschmidt P, Degorge S, Benallaoua et al. New test for the diagnosis of bacterial endophthalmitis. Br J Ophthalmol. 2009;93(8):1089-95.

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CHAPTER

3 Intraocular Tuberculosis Arshee Ahmed, B. Sowkath Ali, Jyotirmay Biswas

INTRODUCTION Intraocular Tuberculosis (IOTB) is a form of extrapulmonary tuberculosis, which is caused by the bacillus Mycobacterium tuberculosis (M.TB). It is noteworthy that a single organism produces such varied clinical features in a single organ and also that it is rarely isolated from samples which make a definitive diagnosis of this disease elusive in most of the cases.

EPIDEMIOLOGY According to the WHO Global Tuberculosis Report 2015, out of the 9.6 million new tuberculous cases in 2014, 58% were in the south-east Asia region and western Pacific regions. India, Indonesia and China had the largest number of cases (23%, 10% and 10% of the global total, respectively). The WHO has now moved from STOP-TB Strategy (2006–2015) to END TB Strategy (2016–2035) and aims to attain a world free of TB. TB control program of India is on track as far as reduction in the disease burden is concerned. There was 50% reduction in the mortality rate by 2013 as compared to 1990 levels. Similarly, there was also a 55% reduction in TB prevalence rate as compared to 1990 levels.2

PATHOGENESIS Mycobacterium tuberculosis is an obligate, aerobic, nonmotile, nonsporebearing, slow-growing bacterium. Human beings are the only natural host for this organism. It spreads via inhalation of aerosolized droplets when infected patients cough or sneeze. It usually affects organs with high regional oxygen content like the apices of the lungs, kidneys, bones, meninges and the choroid. The choroid is known to have one of the highest blood flow rates in the human body.

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Intraocular Tuberculosis  35

IOTB has been postulated to have pathogenetic mechanisms similar to other forms of extrapulmonary TB. These include the following stages: • Bacterial dissemination M.TB is engulfed by alveolar macrophages and transported to hilar lymph nodes leading to priming of T cells. Macrophages/dendritic cells carrying M.TB or even free bacteria may disseminate to different parts of the eye. • Localization in ocular tissues Among various ocular tissues wherein the bacilli gets lodged, RPE is the most suited between different cell types to harbor M.TB. • Bacterial reactivation and initiation of inflammation M.TB can remain latent for long periods of time. The factors that can lead to its reactivation are not known.

Tuberculosis and Uveitis In patients with latent TB, antigenic mimicry between tubercular and retinal antigens could be a potential cause of uveitis. This hypothesis is supported by cytokine analysis of TB-associated uveitis that showed significantly increased interleukin-6 (IL-6) and other chemokines, but not IL-12, tumor necrosis factor-a (TNF-a) and interferon-g (IFN-g) that characterize active TB.3

CLINICAL FEATURES Ocular manifestations of tuberculosis are shown below (Fig. 3.1). • Anterior Uveitis:  Unilateral or bilateral  Usually granulomatous; can be nongranulomatous  Cornea—mutton fat keratic precipitates  AC—cells, flare, fibrinoid reaction

Fig. 3.1: Ocular manifestations of tuberculosis are shown in the schematic diagram.

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36  Gems of Ophthalmology—Diseases of Uvea

Fig. 3.2: A 21-year-old female patient with tubercular anterior uveitis showing mutton fat keratic precipitates, iris nodules, broad posterior synechiae and peripheral anterior synechiae.

•

•

Chapter 03.indd 36

   

Iris nodules (Fig. 3.2) angle nodules Posterior synechiae, peripheral anterior synechiae Complicated cataract Ciliary body granulomata Intermediate Uveitis:  Low grade, chronic uveitis  Vitritis  Snowball opacities  Snow banking  Peripheral vascular sheathing  Peripheral retinochoroidal granuloma Posterior uveitis:  Choroidal tubercles – Unilateral or bilateral – Tubercles measure between 0.5 and 3 mm in diameter – Overlying serous retinal detachment – Respond well to Alternative Treatment Technology (ATT) – Heal leaving behind pale atrophic areas with variable pigmentation  Tuberculoma – Large, solitary mass – Up to 14 mm in diameter (Figs. 3.3A and B) – Overlying hemorrhages, retinal folds, serous retinal detachment – Respond well to ATT and corticosteroids  Serpiginous-like choroiditis (SLC) – Important to differentiate it from serpiginous choroiditis

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Intraocular Tuberculosis  37

A

B

Figs. 3.3A and B: A patient who was a known case of spinal tuberculosis presented with blurred vision in the left eye. (A) Fundus photograph of the left eye showing tubercular granuloma involving the macula. (B) Magnetic resonance imaging (MRI) scan of the spine showing heterogenous, hyperintense signals from L1–L2 vertebrae with loss of intervening inter-vertebral disc morphology.

– Chronic inflammation of the retinal pigment epithelium, choriocapillaris – Immune-mediated hypersensitivity reaction in the presence of a few acid-fast bacteria in the choroid or retinal pigment epithelium – Seen in TB-endemic countries – Significant vitritis – Presence of multifocal lesions in posterior pole, juxtapapillary region—gray–white lesions with ill-defined edges, spread centrifugally with multiple recurrences – FFA shows early hypofluorescence and late hyperfluorescence – Responds well to combination of ATT and corticosteroids – Can show paradoxical worsening when treatment is initiated with ATT4  Subretinal abscess – Solitary, yellowish–white, circumscribed mass-like subretinal lesion – Often associated with overlying retinal hemorrhages – Vitritis – Can be diagnosed with the help of aqueous or vitreous samples subjected to polymerase chain reaction (PCR), microbial evaluation including smear, culture – Treatment must include ATT along with corticosteroids as this lesion responds very well to ATT5  Retinal vasculitis – Cause remains speculative; infective or hypersensitivity response to tubercular antigens – Predominantly venular involvement; occlusive vasculitis

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38  Gems of Ophthalmology—Diseases of Uvea

– – – – – –

Vitreous infiltrates (vitritis) Retinal hemorrhages (Figs. 3.4A and B) Neovascularization leading to recurrent vitreous hemorrhage Tractional retinal detachment Neuroretinitis Treatment with ATT, corticosteroids, and panretinal photocoagulation to the capillary nonperfusion areas as determined on FFA

A

B

Figs. 3.4A and B: Patient with tubercular retinal vasculitis, tested positive on Mantoux test and QuantiFERON-TB Gold test with positive findings on high-resolution computed tomography (HRCT)-Chest. (A) pre-treatment fundus photograph of the left eye showing disc edema, cotton wool spots, hemorrhages, internal limiting membrane (ILM) folds. (B) Post-treatment with ATT and corticosteroids, vasculitis resolved leaving behind sheathing of the infer-temporal arcade vessel.

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Intraocular Tuberculosis  39



Eales’ disease: an idiopathic vasculitis; affects healthy adults, mostly men, in third to fourth decade of life, characterized by periphlebitis, capillary nonperfusion, neovascularization, recurrent vitreous hemorrhage, and fibrovascular proliferation. Absence of intraocular inflammation and absence of healed or active choroiditis lesions are important differentiating features from TB vasculitis. Biswas et al.6 detected the M.TB genome by PCR detection in a significant number of vitreous fluid specimens with Eales’ disease, thus suggesting a possible association of M.TB in the pathogenesis of Eales’ disease.  Optic nerve involvement – Contiguous spread from choroid or hematogenous spread from the primary focus – Optic neuritis, ONH granuloma/tubercle, retrobulbar neuritis, neuroretinitis, optochiasmatic arachnoiditis  Endophthalmitis and Panophthalmitis – Patients with subretinal abscesses can develop endophthalmitis due to treatment with corticosteroids without ATT because of rapid multiplication of bacilli along with liquefaction necrosis – Scleral involvement can lead to panophthalmitis ending in globe perforation

Pathology Various ocular structures have been noted to be involved in specimens obtained from enucleated globe like sclera, cornea, conjunctiva, iris, ciliary body, vitreous adjacent to pars plana ciliaris, retina and choroid. The histopathology of ocular involvement characteristically reveals granulomatous inflammation with central caseous necrosis, and shows occasional acid-fast organisms. The granulomatous response consists of abundant epithelioid, histiocytes, occasional giant cells of Langerhans, and peripheral mononuclear cells, primarily made up of lymphocytes.3 The disease should be differentiated from syphilis, leprosy, sarcoidosis, tumors, etc. (Table 3.1). Table 3.1:  Differential diagnosis of tuberculosis. Infectious

Noninfectious

Neoplasia

Syphilis

Sarcoidosis

Retinoblastoma

Leprosy

Serpiginous choroiditis

Malignant melanoma

Toxoplasmosis

Sympathetic ophthalmia

lymphoma

Histoplasmosis

Vogt-Koyanagi-Harada disease

Metastatic tumor

Borreliosis

Acute posterior multifocal placoid

Brucellosis

pigment epitheliopathy

Herpetic retinochoroiditis Punctate inner choroidopathy Multifocal choroiditis and panuveitis

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40  Gems of Ophthalmology—Diseases of Uvea

Diagnostic Techniques (Table 3.2) • Immunologic  Tuberculin skin test (Mantoux test)  Interferon-g release assays (QuantiFERON-TB Gold or T-SPOT.TB) • Radiologic  Chest X-Ray  Chest computer-assisted tomography  Positron emission tomography (PET)/computer-assisted tomography (CT) • Bacteriologic  Smear  Culture • Molecular  Nucleic acid amplification tests • Histologic  Histopathology

Ancillary Investigations • Fundus Fluorescein Angiography (FFA): It is a very useful technique to study the various presentations of IOTB including TB-SLC, tubercles, tuberculomas, retinal vasculitis and inflammatory CNVMs. Active choroiditis lesions demonstrate hypofluorescence in early phases with hyperfluorescence in the late phases. SLC, shows an initial hypofluorescent active edge with late hyperfluorescence and diffuse staining of the active advancing edge. In cases of vasculitis, the presence of areas of capillary nonperfusion and neovascularization can be picked up on FFA determining the need and extent of panretinal photocoagulation. Inflammatory choroidal neovascular membrane (CNVM) can be diagnosed by the classical appearance of early lacy hyperfluorescence and intense leak with fuzziness of borders in late stages. • Indocyanine Green Angiography (ICGA): This angiography is useful in determining the extent of the choroidal lesion and the stage of disease and in evaluating treatment results. Herbort et al.8 suggested that hypofluorescent lesions seen in all phases of ICGA represent full-thickness choroidal granulomas or atrophic lesions. ICGA changes are reversible and, therefore, help in monitoring the disease. • Wide-field Imaging (WFI): It is especially useful in cases with vasculitis involving the peripheral vessels, usually veins in patients with Eales’ disease. Standard field FFA can miss the abnormalities in the peripheral retina. But with WFI, capillary nonperfusion areas in the periphery can be picked up earlier, preventing complications like neovascularization and bleeding.

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Chapter 03.indd 41

Radiologic

May be positive with BCG vaccination/exposure to

Higher cost. Not widely available. Possibly more sensitive to detect latent infection than TST but does not distinguish it from disease. May be negative or indeterminate in immunosuppressed states. Problems in collecting or transporting blood specimen may decrease the accuracy

Larger induration- more specific

More specific marker of Mycobacterium tuberculosis infection/previous exposure. Not influenced by Bacillus Calmette– Guérin (BCG) vaccination or exposure to atypical mycobacteria. Not as subject to biases and errors of placement and reading as

antigens

Interferon-g release test

after in vitro stimulation

of patients’ lymphocytes

with Mycobacterium

tuberculosis specific

antigens

Interferon-g release

assays (QFT-G,

T.SPOT.TB)

Chest X-ray

occupationaldisorders may lead to similar patterns.

is found (e.g., upper lobe infiltrates

and cavitation, Ghon’s focus, miliary Low sensitivity, especially for detection of lymphade-

either active or healed

infection

(Continued)

A normal result does not exclude ocular tuberculosis

nopathy.

Other infectious/granulomatous/lymphoproliferative/

Useful when a suggestive pattern

disease)

Not specific for tuberculosis.

Low cost and wide availability.

monary involvement,

administration and interpretation may lead to false results

extrapulmonary or military TB. Difficulties in test

May be negative in immunosuppressed states/children/

Look for evidence of pul-

the tuberculin skin test (TST)

Does not distinguish between latent and active TB

Wide availability

test for mycobacterial atypical mycobacteria.

Not specific

(Mantoux test)

Disadvantages

Low cost

Skin hypersensitivity

Immunologic Tuberculin skin test

Advantages

Principle

Type

Table 3.2:  Diagnostic modalities for intraocular tuberculosis.

Intraocular Tuberculosis  41

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Chapter 03.indd 42

Molecular

Bacteriologic

Type

Expensive and cumbersome needs long time for growth May not be widely available. Results may take up to 6–8 weeks in solid media Higher cost and limited availability. Variable sensitivity. Inferior sensitivity for non-respiratory specimens (not established for ocular samples). Does not allow ruling out tuberculous etiology. Detects only DNA (more prone to contamination and

of microorganism viability. Allows identification and drug sensitivity testing High specificity. Better sensitivity than microscopy. Fast results. Allows identification and investigation of genetic resistance patterns

M. tuberculosis after

seeding of clinical sam-

ples in culture media

Nucleic acid amplifi- Detects presence of

M. tuberculosis genomic

DNA in clinical samples

after amplification (e.g.,

various PCR techniques)

cation tests

(Continued)

microorganisms may not be viable or may be dormant)

identified through this method

Culture

Gold standard. Unequivocal proof

Other acid-fast organisms are also

Useful especially in specimens with

various clinical samples

Detects growth of

Low sensitivity (e.g., for sputum, detection threshold is > 5,000 bacilli/mL).

method. large bacillary load

Smear

(PET-CT) scan.

puted tomography

tomography–com-

Rapid and widely-available

A normal result does not exclude ocular tuberculosis

culomas.

(postinflammatory)

stained acid-fast bacilli in

Not specific for tuberculosis.

lymphadenopathy and for tuber-

either active or healed

chest

Identify the presence of

X-ray.

Modality of choice for detection of

pulmonary involvement,

raphy (CT) scan of

Positron emission

More sensitive than chest radiograph. Higher cost and greater radiation exposure than chest

Look for evidence of

Disadvantages

Advantages

Principle

Computed tomog-

Table 3.2  Continued

42  Gems of Ophthalmology—Diseases of Uvea

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Chapter 03.indd 43

Histopathology

LAMP

to use in small-scale hospitals, primary care facilities, and clinical laboratories in developing countries

complex, Mycobacterium

avium, and Mycobacte-

rium intracellulare 

lead to granulomatous inflammation. Low sensitivity for AFB detection

(especially with caseous

necrosis) support the

nostic

in this setting is diag-

diagnosis. Finding of AFB

Other microorganisms/noninfectious entities may also

lomatous inflammation

specimen.

affect PCR results, simple enough

bacterium tuberculosis

extent of tissue damage

conditions that usually adversely

detection of  Myco-

with evidence of granu-

robust to inhibitors and reaction

(LAMP) platform; for

Risks related to invasive procedure to obtain tissue

results visible to naked eye,

mal amplification

Allows the observation of the

sophisticated equipment,

loop-mediated isother-

Disadvantages

Stained tissue sections

Fast, easy operation without

Advantages

Based on the novel

Principle

Source: Adopted from Daniel V. Vasconcelos-Santos, Manfred Zierhut, Narsing A. Rao. Strengths and Weaknesses of Diagnostic Tools for Tuberculous Uveitis, Ocular Immunol Inflamm. 2009;17:5,351-5.7

QFT-G: QuantiFERON-TB Gold; AFB: Acid-fast bacilli.

Histologic

Type

Table 3.2  Continued

Intraocular Tuberculosis  43

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44  Gems of Ophthalmology—Diseases of Uvea

A

B

Figs. 3.5A and B: A 2-year-old male patient with positive QuantiFERON-TB Gold test presented with features of: (A) healed multifocal choroiditis. (B) Fundus autofluorescence showing complete absence of autofluorescence indicating healed lesions.

• Fundus Autofluorescence (FAF): It is a novel, noninvasive technique which can help in differentiating active from inactive choroiditis. Gupta  A  and Biswas J9 described the serial FAF pattern of serpiginous choroiditis and reported that in the initial phases the lesion appears hyperfluorescent. Sharpening of the hyper-autofluorescence borders indicated healing of the lesions. Completely healed lesions showed hypo or absence of fluorescence (Figs. 3.5A and B). • Optical Coherence Tomography (OCT): It helps in the assessment of macular complications like cystoid macular edema and inflammatory CNVM in these cases. Also, entities that may mimic tubercles like central serous chorioretinopathy (CSCR) and choroidal tumors can be excluded. Enhanced-depth imaging (EDI)-OCT of active TB-SLC lesions demonstrated infiltration of the choroid, elevation of the retinal pigment epithelium (RPE)-Bruch’s membrane complex and focal increase of choroidal thickness.10 These findings are not seen in noninfectious SLC and can help in differentiating between the two entities. • Ultrasonography (USG): It is a helpful tool in the diagnosis and follow-up of choroidal mass lesions like subretinal abscess, which characteristically show an anechoic space within the mass on A-scan. Tuberculomas can be differentiated from malignancies like retinoblastomas, malignant melanomas and metastatic tumors. • Ultrasound Biomicroscopy (UBM): It is a useful tool to study eyes with hypotony in patients with chronic uveitis and poor media clarity to assess the pars plana region. It can also pick up granulomas in this region. • Fine Needle Aspiration Cytology (FNAC): Samples can be taken for histopathology or for techniques like polymerase chain reaction (PCR) in cases, which present with diagnostic dilemmas.

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Intraocular Tuberculosis  45

Table 3.3:  The proposed classification of intraocular tuberculosis. Clinical diagnostic group

Case definition criteria

Confirmed IOTB

1. At least one clinical sign suggestive of IOTB

(Both 1 and 2)

2. Microbiological confirmation of M.TB from ocular fluids/

Probable IOTB

1. At least one clinical sign suggestive of IOTB (and other

tissues (1, 2 and 3 together)

etiologies excluded) 2. Evidence of chest X-Ray consistent with TB infection or clini­ cal evidence of extraocular TB or microbiological confirmation from sputum or EO sites 3. At least one of the following: a. Documented exposure to TB b. Immunological evidence TB infection

Possible IOTB (1, 2 and 3 together) OR (1 and 4)

1. At least one clinical sign suggestive of IOTB (and other etiologies excluded) 2. Chest X-Ray not consistent with TB infection and no clinical evidence of EO TB 3. At least one of the following: a. Documented exposure to TB b. Immunological evidence TB infection 4. Evidence of chest X-Ray consistent with TB infection or clinical evidence of EO TB but none of the characteristics given in 3

IOTB: Intraocular Tuberculosis; M.TB: Mycobacterium tuberculosis; EO: Eosinophilia.

Challenges in Diagnosis The diagnosis of IOTB remains a challenging issue because each of the tests available has its strengths and weaknesses as discussed above and because TB infection can present with features of any type of extraocular or intraocular inflammation. Gupta A et al.11 have proposed the classification of IOTB (Table 3.3) comprising of confirmed IOTB, probable IOTB and possible IOTB. These guidelines offer a greater degree of “certainty” of diagnosis as IOTB largely remains a presumptive diagnosis, as unequivocal evidence of infection is often not available. There are some signs which are consistent with IOTB; they are: Presence of cells in anterior chamber or vitreous along with: • Broad posterior synechiae • Retinal perivasculitis with or without discrete choroiditis/scar • Multifocal serpiginoid choroiditis • Choroidal granuloma • Optic disc granuloma • Optic neuropathy Approach for the diagnosis of tuberculous uveitis in immunocompetent individuals12 is shown in a Flowchart 3.1.

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46  Gems of Ophthalmology—Diseases of Uvea

Flowchart 3.1: Showing diagnosis of tuberculous uveitis in immunocompetent individuals.

(TST: Tuberculin skin test; IGRA: Interferon-gamma release assay; CT: Computer-assisted tomography; TB: Tuberculosis. *Anti-TB treatment for 8 weeks; presumed and definite TB require treatment for 6 months). Source: Adopted from Ang et al. Diagnosis of Ocular Tuberculosis. Ocular Immuno Inflamm. 2016;5:1-9.

MANAGEMENT Tuberculosis is a readily curable disease with highly effective treatment. The management of ocular TB includes medical management of the disease on the same lines as other forms of extrapulmonary TB and surgical management to treat complications developing due to chronic ocular disease.

Medical Management Anti-TB therapy has been known to eliminate latent TB and decreases a person’s lifetime risk of developing active TB by 90%.13 Majority of patients with uveitis secondary to presumed TB have underlying latent TB so treatment with timely ATT helps in reducing recurrences. In a study by Bansal et al.,14 the addition of ATT significantly improved the 5-year probability of no recurrence of inflammation in their cohort. Treatment is instituted in two distinct phases—the first intensive phase involves the use of four drugs—isoniazid, rifampicin, pyrazinamide and

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Intraocular Tuberculosis  47

ethambutol. After use for 2–3 months, only isoniazid and rifampicin are continued for another 6-9 months. The Center for Disease Control (CDC) recommends prolonged therapy for tuberculosis of any site that is slow to respond and thus, patients with intraocular TB may require prolonged therapy.15 Along with the initiation of ATT, low dose oral steroids are also commenced for a period of 4–6 weeks as they help in reducing the damage to ocular tissues, which can happen due to, delayed hypersensitivity. Essential first-line anti-TB drugs: • Isoniazid: It is a prodrug; activation of isoniazid produces oxygen-derived free radicals (superoxide, hydrogen peroxide, and peroxynitrite) and organic free radicals that inhibit the formation of mycolic acids of the bacterial cell wall, causing DNA damage and, subsequently, the death of the bacillus. It has a bactericidal effect on rapidly growing bacilli, but has a limited effect on slow-growing (generally intracellular) and intermittently growing (generally extracellular) bacilli. • Rifampicin: It inhibits the gene transcription of mycobacteria by blocking the DNA-dependent RNA polymerase, which prevents the bacillus from synthesizing messenger RNA and protein, causing cell death. It is a bactericidal drug that kills growing, metabolically active bacilli, as well as bacilli in the stationary phase, during which metabolism is reduced. • Pyrazinamide: It is a prodrug; enters the bacillus passively, is converted into pyrazinoic acid by pyrazinamidase, and reaches high concentrations in the bacterial cytoplasm due to an inefficient efflux system. Pyrazinoic acid decreases the intracellular pH to levels that cause the inactivation of enzymes-such as fatty acid synthase I, which plays a fundamental role in synthesizing fatty acids and, consequently, the impairment of mycolic acid biosynthesis. It is also bactericidal and is particularly potent in elimination of persistent bacilli in the sporadic multiplication phase which are responsible for bacteriological relapse. • Ethambutol: It interferes with the biosynthesis of arabinogalactan, the principal polysaccharide on the mycobacterial cell wall. It acts on intracellular and extracellular bacilli, principally on rapidly growing bacilli. Side effects of anti-TB drugs are well documented. Dose associated hepatotoxicity can be prevented by regular monitoring of liver-function tests. Other commonly seen side effects include cutaneous reactions, gastrointestinal intolerance, hematological reactions and renal failure. Side effects caused by these drugs are listed in Table 3.4. A baseline ophthalmic examination including visual acuity, visual fields and color vision should be documented for all patients before starting ethambutol. In case of any ocular side effect the drug should be stopped immediately. Vision improves spontaneously in many cases. Parenteral hydroxocobalamin can be considered for a 10–28 weeks period for those who do not improve spontaneously.

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48  Gems of Ophthalmology—Diseases of Uvea

Table 3.4:  Ocular side effects of anti-tubercular drugs. Drug

Side effect

Isoniazid

Optic neuritis, optic atrophy

Ethambutol

Optic neuritis, acquired red-green dyschromatopsia, central scotomas, disk edema, peripapillary splinter hemorrhages, optic atrophy retinal edema pigmentary changes at fovea (rare)

Rifabutin

Severe acute anterior uveitis (hypopyon uveitis), corneal endothelial deposits, inflammatory vitreous exudates and opacities

The emergence of MDR–TB (multidrug resistance) and XDR-TB (extremely drug resistant) entails the use of next generation drugs for extended periods. About 8–10 drugs have to be used for 18–24 months. Additional agents include ethionamide, kanamycin, cycloserine, rifabutin, fluoroquinolones, interferon-g and linezolid.

Surgical Management Complications may arise due to longstanding ocular disease leading to nonclearing vitreous hemorrhage, tractional retinal detachment, etc. Both the conditions need surgical intervention e.g., vitrectomy.

RESEARCH AND DEVELOPMENT2 • A diagnostic platform called the GeneXpert Omni is in development. It is meant for testing for TB and rifampicin-resistant TB using Xpert MTB/ RIF cartridges. It is supposed to be smaller, lighter and less expensive than current platforms. • A next generation cartridge called Xpert-Ultra is in development and intends to replace the Xpert MTB/RIF cartridge. It could potentially replace culture as the primary diagnostic tool for TB. • Eight new or repurposed anti-TB drugs are in advanced phases of clinical development. For the first time in six years, an anti-TB drug (TBA-354) is in Phase I trials. • Several new TB treatment resistant regimens are being tested for use in drug-susceptible and/or drug-TB in Phase II or Phase III trials. • Fifteen vaccine candidates are in clinical trials; emphasis has shifted from children to adolescents and adults.

REFERENCES   1. TB India 2015-RNTCP-Annual status report; p. 22.   2. WHO Global tuberculosis report 2015; p. 8.   3. Basu S, Wakefield D, Biswas J, et al. Pathogenesis and Pathology of Intraocular tuberculosis. Ocul Immunol Inflamm. 2015;23(4):353-7.

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Intraocular Tuberculosis  49

  4. Gupta V, Gupta A, Arora S, et al. Presumed tubercular serpiginous-like choroiditis: clinical presentation and management. Ophthalmol. 2003;110,1744-9.   5. Majumder PD, Biswas J, Bansal N, et al. Clinical profile of patients with tubercular subretinal abscess in a tertiary eye care center in southern India. Ocul Immunol Inflamm. 2016:1-5. [Epub ahead of print]   6. Biswas J, Sharma T, Gopal L, et al. Eales’ disease—an update. Surv Ophthalmol. 2002;47(3):197-214.   7. Daniel V. Vasconcelos-Santos, Manfred Zierhut, Narsing A. Rao. Strengths and weaknesses of diagnostic tools for tuberculous uveitis. Ocular Immunol Inflamm. 2009;17:5,351-5.   8. Herbort CP, LeHoang P, Guex-Crosier Y. Schematic interpretation of indocyanine green angiography in posterior uveitis using a standard angiographic protocol. Ophthalmol. 1998;105:432-440.   9. Gupta A, Biswas J. Fundus autofluorescence imaging to document evolution, progression and healing pattern of serpiginous choroiditis. Oman J Ophthalmol. 2014;7(2):100-1. 10. Rifkin LM, Munk MR, Baddar D, et al. A new OCT finding in tuberculous serpignous-like choroidopathy. Ocul Immunol Inflamm. 2015;23(1):53-8. 11. Gupta A, Sharma A, Bansal R, et al. Classification of Intraocular Tuberculosis. Ocul Immunol Inflamm. 2015;23(1):7-13. 12. Ang M, Vasconcelos DV, Sharma K, et al. Diagnosis of ocular tuberculosis. Ocular Immunol Inflamm. 2016:1-9. [Epub ahead of print] 13. Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep. 2000;49(RR-6):1-51. 14. Bansal R, Gupta A, Gupta V, et al. Role of anti-tubercular therapy in uveitis with latent/manifest tuberculosis. Am J Ophthalmol. 2008;146:772-9. 15. Centers for Disease Control: Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep. 2003;52:RR1.

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CHAPTER

4 Ocular Sarcoidosis Eliza Anthony, Parthopratim Dutta Majumder, Jyotirmay Biswas

INTRODUCTION Sarcoidosis is a multisystemic chronic granulomatous inflammatory disorder. It was first described by Jonathan Hutchinson in 1878. However, in 1909 ocular involvement was first described by Schumacher in a patient with nodular iritis.1

EPIDEMIOLOGY Prevalence of sarcoidosis varies among different countries and ethnic groups. It is found in African Americans and Caucasians of northeastern origin.2 Prevalence varies from as low as 3.7:100,000 in Japan to as high as 28.2:100,000 in Finland. The overall incidence of sarcoidosis is 6–10 per 100,000 with highest incidence occurring in 20–40 years age group.3 Although ocular sarcoidosis has bimodal pattern of incidence, first at 20–30 years of age and second at 50–60 years of age, but systemic sarcoidosis typically affects young adults.2,4 Ocular involvement is associated with predilection for female gender and African American race as compared to Caucasians.2

ETIOLOGY Sarcoidosis is caused by an exaggerated T cell immune response to multiple self- and non-self-antigens capable of generating a Th1-mediated response in a genetically susceptible individual and is not an immunodeficiency. No gene has been implicated yet in causation of sarcoidosis. HLADR17 and TNF polymorphism have been found to be very crucial in predicting disease severity and prognosis. In Lofgren’s syndrome high levels of TNF-a, associated with TNFA2 allele are described as a good prognostic marker. Butyrophilin-like

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Ocular Sarcoidosis  51

Table 4.1:  Agents implicated in the etiology of sarcoidosis.3 Serial number 1

Infectious agents

Scientific evidence in literature

Mycobacterium

Mycobacterial DNA and RNA is detected in sarcoid tissue

tuberculosis

but not isolated from culture from the sarcoid tissue. Although Mycobacterium tuberculosis catalases peroxidase (mKatG)-reactive, IFN-g-expressing T cells are found in patients with active sarcoidosis.

2 3

Propionibacterium Propionibacterium acnes rRNA and DNA has been demonacnes

strated in sarcoid tissue.

Epstein-Barr virus

Higher antibodies against EBV in sarcoid patients.

(EBV) 4

Herpes simplex

Higher antibodies against HSV in sarcoid patients.

virus (HSV) 5

Helicobacter pylori

Higher antibodies against H. pylori in sarcoid patients.

(H. pylori) 6 7

Association with

Sarcoidosis is known to occur following INF-g and antiviral

hepatitis C

therapy for Hepatitis C treatment.

INF-g

Sarcoidosis is known to occur following INF-g therapy for Hepatitis C treatment.

2 gene, located near HLA-DRB1 region has been described as a susceptibility gene.3 Agents implicated in the etiology of sarcoidosis are shown in Table 4.1. Histopathologically, sarcoidosis is characterized by a noncaseating granuloma with modified macrophages or epithelioid cells in the center surrounded by a rim of lymphocytes and fibroblasts.3 Inclusion bodies such as asteroids (contain lipoprotein; accumulation of cytoskeletal filaments; seen in 2–9%), Schaumann bodies (concentric, blue calcified laminated structures; accumulation of oxidized lipid within the lysozomes; seen in 48–88% of cases), Hamazaki-Wesenberg bodies (yellow, ovoid, periodic acidSchiff positive inclusion bodies that are giant lysosomes; seen in 11–68% of lymph nodes with sarcoidosis) and deposits of immunoglobulins can also be seen.5 Kveim-Siltzbach test is reported positive in almost all patients who have hilar lymphadenopathy, in absence of parenchymal involvement and erythema nodosum. Test is recorded as positive when a papule size ranging from a few millimeters to 1.5 cm is seen in a biopsy proven patient, 4–6 weeks after subcutaneous injection of a suspension derived from the spleen of a sarcoidosis patient.5 Immunohistochemical studies reveal the presence of CD4+T cells admixed with epithelioid cells in the center of the cellular infiltrate. In bronchoalveolar lavage (BAL) a high CD4/CD8 T-cell ratio is found in patients with sarcoidosis.3

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52  Gems of Ophthalmology—Diseases of Uvea

CLINICAL FEATURES Systemic Sarcoidosis Systemic sarcoidosis is frequently asymptomatic, incidentally detected on a routine chest radiography and can manifest as a severe disease. Patients may present with respiratory symptoms or constitutional symptoms like fever, malaise, weight loss and fatigue. Disease can have a self-limiting or a chronic course. It affects multiple organs including lungs (90–95%), lymph nodes (15–40%), skin (15–20%), eyes (12–20%), heart, liver, muscle and bones.2,3 Mortality rate is as high as 6% attributed mainly to respiratory, neurological and cardiovascular involvement.6

Pulmonary Sarcoidosis—Lung or Mediastinal Lymph Node Involvement Stages of pulmonary sarcoidosis are:3 Stage 1.  Bilateral hilar lymphadenopathy without parenchymal involvement Stage 2.  Bilateral hilar involvement with parenchymal involvement Stage 3. Pulmonary infiltrates including cystic changes without hilar lymphadenopathy Stage 4.  Pulmonary fibrosis Heerfordt’s syndrome (uveoparotid fever) comprises fever, uveitis, parotid swelling and facial palsy. Acute Lofgren’s syndrome consists of erythema nodosum, arthritis and hilar lymphadenopathy. Skin involvement occurs in 25% of patients including manifestations like erythema nodosum, lupus pernio (indurated violaceous plaque usually seen on face), subcutaneous granulomas and nodules, maculopapular lesions, hyper or hypopigmented plaques and necrotizing cutaneous vasculitis. There could be generalized lymphadenopathy or localized enlargement of lymph nodes in the thoracic area. In case of liver involvement elevated liver enzymes can be demonstrated.3 Although cardiac sarcoidosis is a very fatal form it is usually under diagnosed. It is seen in less than 5% of sarcoidosis patients. It can manifest as heart block with arrhythmias, congestive heart failure and pericardial abnormalities. Some studies have shown that peripheral chorioretinal atrophic lesions are associated with increased risk of cardiac disease that may require need for implantation of pacemaker.3,6 About 20% of patients have joint involvement in sarcoidosis. Approximately, 5–26% of sarcoidosis patients have neurological involvement comprising cranial nerve palsies, encephalopathy, hypothalamic and pituitary disorders. Neurological involvement could be secondary to direct sarcoid tissue infiltration or due to compressive effect of cerebral mass. In children less than 4 years of age, sarcoidosis manifests as a triad of rash, uveitis and arthritis. In older children, it can have multisystem involvement. Often sarcoidosis in children is misdiagnosed as juvenile chronic arthritis.3

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Ocular Sarcoidosis  53

Ocular Sarcoidosis Ocular involvement in sarcoidosis is observed in more than 25–60% of patients diagnosed with sarcoidosis. According to a few reports ocular involvement can be as high as 90%.7 Typical clinical presentation in case of ocular sarcoidosis is bilateral granulomatous uveitis. It is the presenting sign in 10–20% of patients and is the most common intraocular manifestations seen in almost 2/3rd of patients. The most common extraocular involvement is the lacrimal gland.2

Anterior Segment Involvement Sarcoidosis is usually bilateral and virtually involves almost all structures of the eyeball. The anterior segment involvements are summarized in Table 4.2. Table 4.2:  Anterior segment involvements in sarcoidosis. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Eyelid and conjunctival granulomas Lacrimal gland involvement Keratoconjunctivitis sicca Nongranulomatous anterior uveitis Mutton fat keratic precipitates (Fig. 4.1) Iris and pupillary nodules/iris mass Increase in intraocular pressure Tent-shaped peripheral anterior synechiae Nodules in trabecular meshwork Intermediate uveitis (16–38%)8,9

Fig. 4.1: Granulomatous anterior uveitis with mutton fat keratic precipitates on the corneal endothelium.

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54  Gems of Ophthalmology—Diseases of Uvea

Posterior Segment Involvement Posterior segment involvement is seen in 25% of ocular sarcoidosis cases and in 5% of the cases, it is the only manifestation. It is shown in Table 4.3. • Neurological manifestations include cranial nerve palsies, encephalopathy, chiasmal syndromes, motility disorders, disorders of the hypothalamus and pituitary gland. Table 4.3:  Involvement of posterior segment in sarcoidosis. 1. Snowballs or string of pearls vitreous opacities and vitritis (3–62%)10-12 2. Active or atrophic multifocal peripheral chorioretinal lesions11 (Fig. 4.2) and panuveitis I 9–13% cases9-13 3. Choroidal granuloma (Fig. 4.3) 4. Nodular and/or segmental periphlebitis with candle wax dripping (Fig. 4.4), and occlusive retinal vasculitis in 9–34%10-12 5. Retinal macroaneurysm 6. Hemorrhagic retinopathy with branch or central retinal venous occlusions 7. Acute posterior multifocal placoid pigment epitheliopathy and retinal pigment epithelial detachments 8. Optic nerve involvement is found in 7–34% patients.9,10 Optic disk nodules (Fig. 4.5)/granuloma/optociliary shunts/dilated collateral veins on the optic nerve head and optic atrophy may occur due to either direct sarcoid tissue infiltration or compression by a cerebral mass

Fig. 4.2:  Multifocal chorioretinal lesions.

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Ocular Sarcoidosis  55

Fig. 4.3:  Sarcoid nodule/granuloma.

Fig. 4.4:  Sarcoid vasculitis with candle wax dripping.

DIAGNOSIS Diagnostic criteria for ocular sarcoidosis as per International Workshop of Ocular Sarcoidosis, 20063 are listed in Table 4.4.

Ocular Complications •

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Ocular complications include cystoid macular edema (CME), cataract, glaucoma, retinal ischemia, optic disk edema, vascular occlusions, retinal and optic disk neovascularization, vitreous hemorrhage and retinal

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56  Gems of Ophthalmology—Diseases of Uvea

Fig. 4.5: Optic nerve head sarcoid granuloma. Table 4.4:  Criteria for the international diagnosis of sarcoidosis. 1

Biopsy supported diagnosis with compatible uveitis

Definitive ocular sarcoidosis

2

Biopsy not done, bilateral hilar lymphadenopathy

Presumed ocular sarcoidosis

with compatible uveitis 3

Biopsy not done; chest radiograph normal; 3 sugges- Probable ocular sarcoidosis tive signs out of 7* and 2 positive investigations

4

Biopsy negative; 4 suggestive ocular signs* and 2

Possible ocular sarcoidosis

positive investigations *Clinical signs of sarcoidosis3 1. Mutton fat keratic precipitates and/or iris nodules at pupillary margin or on stroma 2. Trabecular meshwork nodules and/or tent-shaped peripheral anterior synechiae 3. Snowballs/string of pearls in vitreous or vitreous opacities 4. Multifocal peripheral chorioretinal lesions (active or atrophic) 5. Nodular and/or segmental periphlebitis with or without candle wax exudates and/or macroaneurysms 6. Optic disk nodule/granuloma and/or solitary choroidal nodule 7. Bilateral inflammation (evident on clinical examination or on imaging)

detachment. Inflammatory neovascular membrane has also been reported in few studies. Band-shaped keratopathy is observed in chronic cases.2,3

Differential Diagnosis of Ocular Sarcoidosis2 • The differential diagnosis of sarcoidosis is listed in Table 4.5. • Among the list tuberculosis, syphilis, VKH, birdshot retinochoroidopathy and primary intraocular lymphoma can present with choroidal granulomas. • Granulomatous uveitis may be seen in VKH, tuberculosis, syphilis, toxoplasmosis, herpetic uveitis and multiple sclerosis.

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Table 4.5:  Differential diagnosis of sarcoidosis. Vogt-Koyanagi-Harada (VKH) syndrome

Sympathetic ophthalmia

Multifocal choroiditis

Primary intraocular lymphoma

Tuberculosis

Syphilis

Lyme disease

Birdshot retinochoroidopathy

Herpetic uveitis

Toxoplasmosis

Multiple sclerosis

Blau syndrome

Juvenile rheumatoid arthritis in children

Laboratory Investigations for Suspected Sarcoidosis • • • • •

Chapter 04.indd 57

Negative tuberculin test in a patient who has received Bacillus Calmette– Guérin (BCG) vaccination or who had a positive Mantoux test Elevated serum angiotensin-converting enzyme (ACE) and/or elevated serum lysozyme Chest X-ray—bilateral hilar lymphadenopathy Abnormal liver enzyme tests (any two of alkaline phosphatase, aspartate transaminase, alanine transaminase) High-resolution computed tomography (HRCT) chest in patients with normal chest radiograph  ACE is produced by the macrophages of the sarcoid granuloma. ACE levels are elevated in 60–90% of patients with active sarcoidosis.5 Although ACE levels can be normal in early stages of disease or when the epithelioid cell number is not large enough to cause an elevation as in ocular sarcoidosis. Normal ACE level in serum is approximately 52 units/liter, but serum ACE levels are age dependent. Serum ACE levels are higher in age group less than 21 years as compared to age group above 21 years. It is 84% sensitive and 95% specific, when ACE levels above 50 units/liter are considered.14 Elevated ACE levels in tears of patient with ocular sarcoidosis has also been described although it is not a specific test for sarcoidosis.14 Another study has reported one patient with normal serum ACE but elevated levels in aqueous humor.16.  Lysozyme is important in patients who are on ACE inhibitors. ACE and lysozyme can be elevated in uveitis caused by other disease also.5 It is secreted by epithelioid cells of the sarcoid granuloma. Other laboratory investigations include hypercalcemia, hypercalciuria, elevated erythrocyte sedimentation rate, C-reactive protein and elevated alkaline phosphatase. Hypercalcemia can be presented alone but it is always associated with hypercalciuria.17 Serum surfactant protein-D (SPD) is a new marker that was reported to be significantly elevated in sarcoidosis than in other uveitic etiologies.18

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58  Gems of Ophthalmology—Diseases of Uvea

Role of Ancillary Investigations in Diagnosis of Ocular Sarcoidosis Radiological examination: Nearly 50–89% of patients with systemic sarcoidosis present with bilateral hilar lymphadenopathy (Fig. 4.6). HRCT chest (Fig. 4.7) is more sensitive in detecting hilar lymphadenopathy than chest radiography19 and is also superior to transbronchial lung biopsy (TBLB) in diagnosis. Elderly age group, posterior synechiae and peripheral

Fig. 4.6:  High-resolution computed tomography (HRCT) chest showing bilateral hilar lymphadenopathy (arrow).

Fig. 4.7: Positron emission tomography computed tomography (PET CT) showing metabolically active multiple lymph nodes in the right paratracheal, subcarinal, bilateral hilar and paraaortic regions.

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multifocal chorioretinitis are significantly associated with HRCT findings indicative of sarcoidosis.20 However, the hilar lymphadenopathy can be present in ocular tuberculosis also. HRCT chest shows enlargement of right paratracheal lymph nodes, aortic plutonic window lymph nodes and mediastinal lymph nodes. However, lymph nodes are more discrete in sarcoidosis in contrast to conglomerate nature in ocular tuberculosis. Fissural nodule, subfissural nodule, micronodules with lymphangitic spread, which implies peribronchovascular, subpleural and interlobular septal distribution, are characteristically described in ocular sarcoidosis. Apical fibrosis is seen in tuberculosis. Few studies have described lymph node necrosis in case of which tuberculosis has to be ruled out especially in endemic areas. Alveolar densities and patchy ground glass opacities are reversible changes, while honeycombing, architectural distortion, bullae, and tractional bronchiectasis are irreversible changes seen in sarcoidosis. In cases where HRCT shows necrosis of lymph nodes it is important to rule out tuberculosis especially in endemic areas like India.21 Newer modalities like whole-body positron emission tomography (PET) scan, cardiac MRI can also provide additional useful information.21 PET scans are superior to gallium (Ga) scan. It helps in identifying the inflammation foci for diagnostic biopsy and to follow up disease activity in cases with extraocular sarcoidosis6 (Fig. 4.7). Ga citrate scanning is a nonspecific test in which uptake of radioactive isotope Ga-67 is assessed and graded in the lacrimal gland, salivary gland, thorax, spleen, liver and eyes, 48–72 hours after injection.3 Ga uptake of lacrimal and parotid gland is referred as panda pattern22 and the parahilar, infrahilar and right paratracheal lymph nodes uptake has been referred as lambda pattern.23 Pulmonary function test: Pulmonary function test (PFT) are more sensitive (70%) in cases with positive radiographic evidence and helps in initial diagnosis and follow up of patients with pulmonary involvement.5 Bronchoalveolar lavage and vitreous cytology: CD4/CD8 ratio greater than 3.5 in BAL and in vitreous infiltrating lymphocytes (vitreous cytology) have 94% and 100% specificity and 53% and 96.3% sensitivity, respectively, in predicting diagnosis of sarcoidosis3 but it is not pathognomic5. Transbronchial lung biopsy: TBLB also yields higher positive rates in presence of positive radiographic findings. When four biopsies are obtained at each bronchoscopy, the diagnostic yield increases to 90%.24 Tissue biopsy: Biopsy supported diagnosis is definitive diagnosis for ocular sarcoidosis. It can be obtained from conjunctiva, lacrimal gland or from skin tissue. Conjunctival biopsy gives positive yield in 14–40% cases. Lower lid is retracted and a 1 cm long and 3 mm wide conjunctival specimen is obtained from the stretched conjunctiva.5 Lacrimal gland biopsy is done in patients with clinically enlarged lacrimal gland and in cases with positive Ga uptake by the gland. Skin biopsy from the skin lesions like lupus pernio maculopapular

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rashes and subcutaneous nodules can also be taken to confirm the ocular diagnosis of sarcoidosis.5 Indocyanine green angiography and fluorescein angiography: Indocyanine green angiography helps to detect occult choroidal lesions.3 Fluorescein angiography shows retinal vascular leakage, early blocked fluorescence and late staining of choroidal granulomas, retinal pigment epithelium window defects and CME.2 Negative Mantoux test: It is due to cutaneous anergy25 that is the compartmentalization of immune response due to competitive depletion of the T-helper cells from the site of delayed type hypersensitivity reaction to the site of granuloma. Cutaneous anergy is seen with other skin antigens also.5

TREATMENT Corticosteroids Mainstay of therapy for systemic and ocular sarcoidosis is corticosteroids. Mild anterior uveitis is managed with topical steroids and cycloplegics. For resistant and severe cases, orbital disease, posterior uveitis and in neovascularization periocular and/or systemic steroids are used.5 Intravenous steroids are useful in very severe disease which has optic nerve or macular involvement. In cases of CME intravitreal steroids or sustained release steroid drug delivery devices like that of dexamethasone and flucinolone acetonide implants have been found useful.2

Immunosuppressive Immunomodulatory therapy may be used in cases that are unresponsive to corticosteroids. Methotrexate, mycophenolate mofetil, cyclosporine and azathioprine have been used successfully in treatment of sarcoidosis.2 Methotrexate is most frequently used. Low dose methotrexate (10–20 mg/week) is an effective as well as safe treatment.26 Biologicals—rituximab and infliximab have been reported to be successful in treating sarcoidosis.2 Intravitreal antiVEGFs are administered for the treatment of inflammatory neovascular membranes in sarcoidosis.2 Pan retinal photocoagulation to ischemic areas detected on fluorescein angiography, in cases of retinal neovascularization, shows good response.5 Secondary glaucoma unresponsive to medical management may need trabeculectomy and cryoablative therapy.11,27 Laser trabeculoplasty and conventional filtering procedures have not shown good results and, therefore, trabeculectomy with the use of antimetabolites or seton drainage devices might be necessary. Large sarcoid iris nodules may require sometimes surgical excision if they fail to respond to corticosteroids.5

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Prognosis of Ocular Sarcoidosis Early treatment offers a good prognosis. Poor visual prognosis is seen in chronic posterior uveitis or panuveitis, presentation at older age, delay in presentation and in cases with complications like glaucoma, cataract and CME.2

CONCLUSION Ocular sarcoidosis is a potentially blinding disease that demands early diagnosis and an aggressive management. It is seen in more than 25–60% of patients diagnosed with sarcoidosis. Ocular signs are variable and can involve any part of the eye and orbital structures, and thus it is very important to have a careful examination, strong suspicion, complete review of system and appropriate investigations help make the correct diagnosis.

REFERENCES  1. Schumacher G. Fall von beidersitiger iridocyclitis chronic bei bechschem multiplem benignem sarkoid. Munch Med Wochenschr. 1909;56:2664.  2. Garg SN. Sarcoidosis associated uveitis. In: Sen HN, Nussenblatt RB, Bodaghi B, et al., editors. Color Atlas and Synopsis of Clinical Ophthalmology (Wills Eye Institute) - Uveitis. Philadelphia: Lipincott Williams & Wilkins; 2012. pp. 65-71.  3. Babu K. Ocular Sarcoidosis. In: Biswas J, Majumder P, editors. Uveitis: An Update. New Delhi: Springer; 2016. pp. 133-41.  4. Rothova A. Ocular involvement in sarcoidosis. Br J Ophthalmol. 2000;84(1): 110-6.  5. Capella MJ, Foster CS. Sarcoidosis. In: Foster  CS, Vitale AT, editors. Diagnosis and Treatment of Uveitis. 2nd ed. New Delhi: Jaypee - Highlights; 2013. pp. 951-72.  6. Liu D, Birnbaum AD. Update on sarcoidosis. Curr Opin Ophthalmol. 2015;26(6):512-6.  7. Babu K, Kini R, Mehta R, et al. Clinical profile of ocular sarcoidosis in a South Indian patient population. Ocul Immunol Inflamm. 2010;18(5):362-9.  8. Obenauf CD, Shaw HE, Sydnor CF, et al. Sarcoidosis and its ophthalmic manifestations. Am J Ophthalmol. 1978;86(5):648-55.  9. Hunter DG, Foster CS. Ocular manifestation of sarcoidosis. In: Albert DM, Jackobiec FA, editors. Principles and Practice of Ophthalmology. Philadelphia: W.B. Saunders; 1994. pp. 443-50. 10. Jabs DA, John CJ. Ocular involvement in chronic sarcoidosis. Am J Ophthalmol. 1986;102(3):297-301. 11. Dana MR,  Merayo-Lloves J,  Schaumberg DA,  et al. Prognosticators for visual outcome in sarcoid uveitis. Ophthalmology. 1996;103(11):1846-53. 12. Rothova  A, Alberts C, Glasius E, et al. Risk factors  for  ocular  sarcoidosis. Doc Ophthalmol. 1989;72(3-4):287-96. 13. Crick  RP, Hoyle C, Smellie H. The  eyes  in  sarcoidosis. Br J Ophthalmol. 1961;45(7):461-81.

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14. Baarsma GS, La Hey E, Glasius E, et al. The predictive value of serum angiotensin converting enzyme and lysozyme levels in the diagnosis of ocular sarcoidosis. Am J Ophthalmol. 1987;104(3):211-7. 15. Immonen I, Friberg K, Sorsila R, et al. Concentration of angiotensin-converting enzyme in tears of patients with sarcoidosis. Acta Ophthalmol (Copenh). 1987;65(1):27-9. 16. Weinreb RN, Sandman R, Ryder MI, et al. Angiotensin-converting enzyme activity in human aqueous humor. Arch Ophthalmol. 1985;103(1):34-6. 17. Costabel U, Teschler H. Biochemical changes in sarcoidosis. Clin Chest Med. 1997;18(4):827-42. 18. Kitaichi N, Kitamura M, Namba K, et al. Elevation of surfactant protein D, a pulmonary disease biomarker, in the sera of uveitis patients with sarcoidosis. Jpn J Ophthalmol. 2010;54(1):81-4. 19. Chung YM, Lin YC, Liu YT, et al. Uveitis with biopsy-proven sarcoidosis in Chinese—a study of 60 patients in a uveitis clinic over a period of 20 years. J Chin Med Assoc. 2007;70(11):492-6. 20. Clement DS, Postma G, Rothova A, et al. Intraocular sarcoidosis: association of clinical characteristics of uveitis with positive chest high-resolution computed tomography findings. Br J Ophthalmol. 2010;94(2):219-22. 21. Babu K, Shukla SB, Philips M. High Resolution Chest Computerized Tomography in the Diagnosis of Ocular Sarcoidosis in a High TB Endemic Population. Ocul Immunol Inflmm. 2017;25(2):253-8. 22. Sulavik SB, Spencer RP, Weed DA, et al. Recognition of distinctive patterns of gallium-67 distribution in sarcoidosis. J Nucl Med. 1990;31(12):1909-14. 23. Sulavik SB, Spencer RP, Palestro CJ, et al. Specificity and sensitivity of distinctive chest radiographic and/or 67Ga images in the noninvasive diagnosis of sarcoidosis. Chest. 1993;103(2):403-9. 24. Gilman MJ, Wang KP. Transbronchial lung biopsy in sarcoidosis. An approach to determine the optimal number of biopsies. Am Rev Respir Dis. 1980;122(5): 721-4. 25. Boeck C. Nochmals zur Klinik und zur Stellung des “Benignen Miliarlupoids”. Arch dermatol Syph (Wien). 1916;121:707-41. 26. Dev S, McCallum RM, Jaffe GJ. Methotrexate treatment for sarcoid-associated panuveitis. Ophthalmology. 1999;106(1):111-8. 27. Akova YA, Foster CS. Cataract surgery in patients with sarcoidosis-associated uveitis. Ophthalmology. 1994;101(3):473-9.

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CHAPTER

5 Intermediate Uveitis: Clinical Features and Current Management Radha Annamalai, Jyotirmay Biswas

INTRODUCTION Intermediate uveitis (IU) is an inflammation that predominantly involves the anterior vitreous, peripheral retina and ciliary body (pars plana). The etiology of IU is believed to be associated with infections or systemic diseases and would vary depending on ethnicity and geographic locations. Pars planitis is defined as a subset of IU by the Standardization of Uveitis Nomenclature (SUN) Working Group in which there are snowballs in the vitreous and snowbank formation in the peripheral retina in the absence of systemic disease.1 Inflammation in the vitreous, pars plana and peripheral retina have been described using many names such as IU, pars planitis, chronic cyclitis, peripheral uveitis, vitritis, cylo chorioretinitis, chronic posterior cyclitis and peripheral uveoretinitis. A division of this entity into subtypes helps in management and identifying prognosis in these patients. The prevalence of IU is shown in Table 5.1. IU is prevalent in all age groups but is common between the third and fourth decades of life. Bilateral presentation is seen in 70–90% of patients in the western literature and in 37.6% in the south Indian patients.5 There is no gender predilection and 10–12% of pediatric uveitis is due to IU.6 Table 5.1:  Prevalence of intermediate uveitis.

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Western literature

14–22%2

Indian population

9.53

South India

25%4

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ETIOLOGY In terms of etiology, IU can be caused by infections such as tuberculosis (TB), Lyme disease, syphilis, cat-scratch fever, human T cell leukemia virus (HTLV-1) or due to autoimmune systemic diseases like multiple sclerosis (MS), sarcoidosis or intraocular lymphoma. Rarely, an IU-like picture can occur in toxocariasis, toxoplasmosis, Epstein-Barr virus and syphilis. Inflammation is mediated by T cells. During active disease, macrophages, epithelioid cells and multinucleated giant cells are seen.

Multiple Sclerosis It has been reported that 3–27% of patients with MS develop IU and 7.8–14.8% of patients with IU develop MS.7 A genetic association with human leukocyte antigens (HLA)-DR2 and HLA-DR15 is seen in both IU and MS in about 72% of patients.8 Multiple sclerosis needs to be considered in adults as it is rare in children and IU may be the first manifestation of the systemic disease. Typical neurological and MRI findings such as corpus callosum plaques establish the diagnosis.

Sarcoidosis About 25% of sarcoidosis patients develop IU and in 2–10% of the patients of IU sarcoidosis may be present.9 IU may be seen in Blau syndrome10 (familial juvenile systemic granulomatosis) which is considered a variant of childhood sarcoidosis. It is a chronic granulomatous anterior uveitis with large mutton fat keratic precipitates, broad-based posterior synechiae, iris nodules and may be associated with polyarthritis, hilar lymphadenopathy, lung infiltrates and skin nodules. Elevated serum angiotensin levels may not always be reliable as it is usually elevated in children compared to adults. Diagnosis is difficult and requires lysozyme levels, chest computed tomography or even a gallium scan and biopsy especially in young children.

Tuberculosis Vitritis in TB11 may present with a clinical picture similar to IU. Imaging, gamma interferon assay, tuberculin skin test may be needed to rule out TB as a cause of inflammation. Inflammatory bowel disease can be another etiology and requires endoscopy and biopsy for confirmation.

Lyme Disease12 It can present with vitreous inflammation and its presence can be confirmed by the positive history of exposure to ticks, chronic arthritis, and Lyme enzyme-linked immunosorbent assay and immunofluorescence assay.

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Primary Intraocular Lymphoma Primary intraocular lymphoma or primary central nervous system lymphoma (PCNSL) should be considered in persistent vitreous inflammation with or without subretinal infiltrates and has to be differentiated from IU. Retinal and vitreous infiltrates are the initial presentation of the disease in 10–20% of patients.13 It is more common in elderly age groups but can also occur in younger patients. Intraocular lymphoma is derived from B cell. Neurologic signs, cerebrospinal fluid analysis and magnetic resonance imaging (MRI) are required to detect it. In the case of primary intraocular lymphoma, cytological analysis of vitreous sample, immunohistochemistry, assay of interleukin  6, retinal biopsy and detection of gene rearrangement can make a definitive diagnosis. About two-thirds of intraocular lymphomas are manifestations of primary central nervous system lymphoma (PCNSL). IU has been reported in 10% of patients with syphilis.14

CLINICAL FEATURES OF INTERMEDIATE UVEITIS The common symptoms in IU are floaters or defective vision due to vitritis or macular edema. Anterior uveitis is present and can be more severe than the pars planitis. Vitritis is typical with vitreous floaters (Fig. 5.1) vitreous haze, which may range from traces to 4+ or vitreous exudates (Fig. 5.2). Snowball opacities in the vitreous are seen as yellow-white inflammatory aggregations of cells and debris in the peripheral, inferior or mid-vitreous. Exudates in the pars plana are not present in IU but their occasional presence indicates very severe inflammation. Periphlebitis, neovascularization and retinal detachment (RD) may be seen on fundus examination.

Fig. 5.1: Dense vitreous strands in intermediate uveitis.

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Fig. 5.2: Montage photograph of vitreous exudates.

Pars planitis is a subset of IU that occurs predominantly in children and adolescents and accounts for about 27% of all patients15 with pediatric uveitis. It is an idiopathic disease and its etiology remains unknown although an autoimmune process is proposed. Patients most frequently present with defective or blurred vision and floaters. Significant loss of vision indicates the development of complications such as cystoid macular edema (CME), and increase in floaters, which may suggest vitreous activity or vitreous hemorrhage. Pain, redness and photophobia are rare and their presence indicates associated iridocyclitis. Some pediatric patients may be asymptomatic or may develop strabismus or leukocoria. Anterior segment inflammation is rare and if present mild. Another indicator of the autoimmune nature of pars planitis is the detection of peripheral corneal endotheliopathy16 that is seen as peripheral corneal edema with small or mutton fat keratic precipitates arranged in a linear pattern between normal and edematous cornea. Vitreous findings are typical and diagnostic of IU. Examination shows the presence of vitreous cells, haze and snowball opacities. Retinal vasculitis and optic disc edema may be present on fundus examination. Snowballs opacities in the vitreous (Fig. 5.3) and snowbanks are typical and are present in up to 98% of patients.17 In severe disease, the opacities may extend through the entire periphery. The presence of snowbanking is diagnostic and would require further examination of the pars plana to look for neovascularization (Fig. 5.4). However, the snowbanks can be missed if indirect ophthalmoscopy with scleral depression is not done. Sheathing of retinal venules in the periphery and vasculitis can be present in 17–90% of the cases.18 Disc edema can occur in some patients but is not clinically detectable always and requires fluorescein angiography to confirm it. Following severe inflammation, new vessels can develop on the optic disc, on the snowbank or elsewhere and vitreous hemorrhage is particularly a risk in children.19

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Fig. 5.3: Snowball opacities.

Fig. 5.4: Snowbanking in the pars plana.

Complications A chronic or severe attack of IU can cause complications. Cataract, CME, optic disc edema, vitreous opacities, neovascularization and vitreous hemorrhage can develop and may be blinding although the disease itself is benign in the early stages. CME is the most frequent cause of visual loss. Less common complications include band-shaped keratopathy, secondary glaucoma, epiretinal membrane (ERM) (Fig. 5.5), vitreous condensations, cyclitic membranes and retinal detachment (RD).

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Fig. 5.5: Epiretinal membranes in resolved intermediate uveitis.

Cataracts have been reported as the most frequent complication of IU and is usually in the posterior subcapsular region.17 They can occur in 15–50% of eyes and their incidence increases based on severity, duration of IU or corticosteroid used for treatment.20 Both CME and ERM are features of chronicity in patients with irreversible macular changes.21 Macular edema is seen in 12–51%22 and ERMs in 34.6–36%.23 Optic disc swelling followed by optic atrophy is an uncommon feature. Glaucoma has an increased risk of visual loss and the incidence has been reported to be 11% at the end of 5 years.24 Active vitritis, long-duration of disease and use of steroid are associated with increased intraocular pressure. Periphlebitis can cause new vessels with resultant vitreous hemorrhage, RD or cyclitic membranes. Disc edema and optic neuritis can occur in the presence or absence of MS. Rhegmatogenous, tractional or exudative RD can develop. Exudative RD is believed to occur due to chronic inflammation which causes peripheral angiogenesis, intraretinal edema and cyst formation resulting in retinoschisis.25 Band keratopathy and peripheral corneal endotheliopathy are more common in childhood pars IU. Amblyopia can occur due to cataracts, band keratopathy or persistent macular edema and young children are at risk of permanent visual loss if not treated.26

Differential Diagnosis In pediatric age group, the most important differential diagnosis to be considered is sarcoidosis, familial juvenile systemic granulomatosis, Lyme disease and ocular toxocariasis. In adults, TB, multiple sclerosis, primary intraocular lymphoma, sarcoidosis and Fuchs’s uveitis syndrome should be kept in mind.

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Course The course of IU is varied but is chronic in the majority of patients which can lead to visual loss and complications in as many as 70% of patients.27 Since the incidence of anterior uveitis is less in IU and the disease has an insidious onset with a chronic asymptomatic course, it is diagnosed late in children. Therefore, they suffer from visual loss. Smith et al. reported that the natural course may be self-limiting in 10%, prolonged with exacerbations in 59% and may be a chronic smoldering disease in 31% of patients.28 The prognosis would depend on the severity of vitritis as macular edema develops in more severe vitreous inflammation. Prompt treatment improves the prognosis by preventing complications and improving vision. Children undergoing pars plana vitrectomy (PPV) have poor recovery of vision compared to adults and also are predisposed to developing more complications such as amblyopia and vitreous hemorrhage. Paroli et al. have suggested that the children of less than 10 years is associated with poorer vision.29 Other risk factors are male gender, longer duration of IU, anterior uveitis, severe vitritis and complications such as CME, cataract and RD. They are the common causes of severe visual loss in IU. Better prognosis is seen in age older than 5 years, female gender, better visual acuity at presentation and absence of corneal endotheliopathy.

INVESTIGATIONS IN INTERMEDIATE UVEITIS Laboratory workup, serological and ancillary tests help ruling out other causes of IU. They allow to assess progression and monitor response to treatment. Chest X-ray, purified protein derivative test and imaging are done in all patients because of the significant association between systemic disease and vitreous inflammation. A diagnosis of IU is made after ruling out any underlying disease and proving idiopathic status. Color fundus photography needs to be done during the initial visit and reviewed to document the signs of initial presentation and changes over time. Fundus fluorescein angiography (FFA) is required to detect the presence and extent of CME (Fig. 5.6) and to identify perivasculitis and neovascularization.30 Indocyanine green angiography (ICG) is performed to detect any associated choroidal inflammation or chorioretinitis. Optical coherence tomography (OCT) is a noninvasive tool for evaluation of the retina which is used to identify the pathology in each layer. It can detect CME during the acute stage and sequelae such as persistent macular edema (Fig. 5.7), ERM and macular hole in the chronic stage.31 Visualization of the fundus may be difficult due to cataract, vitritis, vitreous opacities or non-dilating pupil due to synechiae. In such situations, B scan ultrasonography32 is the investigation of choice as FFA and OCT may not provide adequate information. It uses a frequency of 8–10 MHz but better resolution can be obtained with higher frequencies such as 20 MHz and 50

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Fig. 5.6: Color photographs and Fundus fluorescein angiography (FFA) in intermediate uveitis showing cystoid macular edema (CME) in both eyes.

Fig. 5.7: Optical coherence tomography (OCT) showing cystoid spaces at macula and increased macular thickness in pars planitis.

MHz as cyclitic membranes and snowbanks can be detected even in a small pupil.33 Ultrasound biomicroscopy (UBM) demonstrates cyclitic membranes (Fig. 5.8), pars plana exudates and inflammatory aggregates in the vitreous.

MANAGEMENT Before starting treatment in patients with IU, the following should be considered: • First, the etiology has to be determined and the presence or absence of infection should be confirmed.

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Fig. 5.8: Ultrasound biomicroscopy (UBM) showing cyclitic membranes.

• Second, the extent of visual loss, the stage and severity of the inflammatory disease have to be determined. • Third, complications have to be looked for and, if any, have to be treated alongside. A systemic evaluation and complete blood count needs to be done to rule out infections and demyelinating diseases that can aggravate with immunosuppressive agents. No consensus has been reached about when to start treatment in the patients with good vision and minimal inflammatory activity. The guidelines for treatment given by Forrester et al. stated that a visual acuity of 20/40 (6/12) was to be considered as threshold for starting treatment while patients with better visual acuity should be kept under observation.34 However, this approach cannot always be practiced as inflammation can result in severe complications which can be avoided if treatment is started early. It may not be possible to recover vision even after treatment, if complications have set in. Now the criteria for management are changing and are based on the discretion of the uveitis specialist. Treatment would differ in IU if an infection is identified following laboratory tests. Specific anti-microbial agents would have to be initiated that may or may not be supported with steroid therapy. Response after treatment for infections such as TB, Lyme disease or toxocariasis is prompt and the rate of resolution of vitritis is high. Autoimmune disease such as MS or sarcoidosis would require steroids or immunosuppressive therapy. The most widely adopted method for treatment of IU is a stepladder approach. A four-step approach has been described by Kaplan in 1984.35 It consists of periocular corticosteroid injections followed by oral

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prednisolone, cryotherapy or laser photocoagulation, PPV and immunosuppressive treatment. The algorithm given by Kaplan was modified by Foster, who recommended a five-step approach by including systemic nonsteroidal anti-inflammatory drugs as the second step, if there was no response after three periocular corticosteroid injections. The third step was systemic steroids for 3 months followed by cryotherapy or laser photocoagulation and PPV or immunosuppressive treatment as steps four and five, respectively.

Corticosteroids Topical steroids play a role only if there is anterior uveitis and are ineffective for treatment of IU especially in phakic eyes. Periocular steroid injections are indicated in unilateral or asymmetrical involvement of IU with macular edema. Two or three injections of triamcinolone acetonide (40 mg) over a period of 2 months through either the supertemporal or the retroseptal route is the current practice.36 Complications of periocular injections are glaucoma, cataract, globe perforation and ptosis. Intravitreal triamcinolone acetonide injections are used in IU with significant macular edema. Intravitreal dexamethasone implant (Ozurdex) has been reported to improve vision that lasts for about 6 months in noninfectious intermediate and posterior uveitis.37 The safety of dexamethasone implants in children has also been proven and it is now considered an effective form of treatment in macular edema. The risk of complications such as cataract, glaucoma, endophthalmitis, retinal tear, RD and vitreous hemorrhage should be considered before therapy. For severe inflammation requiring high dose of corticosteroids, fluocinolone acetonide implants in the vitreous can be considered. Systemic administration of steroids is indicated in bilateral involvement or severe unilateral inflammation that has not responded to periocular injections. Oral prednisolone is given in the dose of 1–1.5 mg/kg/day and is tapered after activity resolves.

Immunosuppressives Immunosuppressives are indicated for long-term treatment to prevent the side effects of steroids or when steroids are contraindicated. The immunosuppressive drug used would depend on the age of the patient, severity of the disease and may be used in isolation or combination. All these agents require 1–2 months to be effective and hence corticosteroids have to be given as concomitant medication till their expected time of action. Methotrexate is the most commonly used immunosuppressive agent in children. It is a safe drug and is well tolerated in all age groups.38 Cyclosporine is also an effective drug for IU. Azathioprine has the advantage of low cost and fewer side effects. Other immunosuppressives such as chlo-

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rambucil and cyclophosphamide are avoided in children because they cause nephrotoxicity, hypertension, gingival hyperplasia and paresthesia. The dose of chlorambucil is 2.5–5 mg per kg per day and is indicated only in unresponsive cases.39 Anti-tumor necrosis factor-alpha (Anti-TNF-alpha) has been reported to be effective when there has been no response with conventional immunosuppressive agents. Infliximab and adalimumab are effective in pediatric non-infectious IU.40 Both the drugs have similar effect in terms of remission but adalimumab has been proven to be more efficient in preventing further attacks and maintaining remission. Biologics response-modifiers such as daclizumab, eternercept and interferon alpha are being increasingly used in refractory IU. A reduction of vitreous haze with interferon-beta has been reported. Interferon-alpha has also been proven to be equally potent in treating the macular edema.41 Tacrolimus in the dose of 0.1–0.2 mg per kg per day orally has the advantage of long-term efficacy in the treatment of uveitis.42 Treatment of macular edema with intravitreal bevacizumab is currently recommended when there has been no response with steroids.

Cryotherapy and Indirect Laser Photocoagulation Kaplan and Foster recommended cryotherapy before immunosuppressive treatment to induce regression of neovascularization of the vitreous base. Snowbanks in the peripheral retina can be treated with cryotherapy or indirect laser photocoagulation. The principle behind these procedures is to destroy the vascular component and reduce inflammatory mediators. Cryotherapy is applied in a double row to the pars plana and posterior to it to all areas of activity.43 It improves vision by decreasing vitritis and macular edema but complication such as RD may occur. It is not preferred now except when there is extensive neovascularization of the vitreous base and a history of vitreous hemorrhage. Photocoagulation can be applied as three to four rows. Laser photocoagulation is considered safer than cryotherapy and has fewer complications.44 It reduces inflammation by decreasing angiogenesis and release of factors that potentiate new vessel formation.

Pars Plana Vitrectomy Pars plana vitrectomy is indicated in patients who develop complications such as CME, vitreous condensation, vitreous hemorrhage, ERM, retinal traction and detachment, and have not responded to medical management.45,46 It decreases inflammation and improves visual outcome. The surgery reduces inflammatory mediators, corrects vitreoretinal traction, and provides vitreous sample for confirmation of diagnosis. In active IU, better results in terms of resolution and recovery of vision were obtained following PPV than with immunomodulatory therapy. However, in spite of

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PPV, vision may not improve due to macular edema or preexisting macular pathology.

Cataract Surgery Cataract surgery with implantation of intraocular lens is recommended in patients of cataract associated with IU, only after 3 months of control of inflammation. Ganesh et al. have reported that phacoemulsification with intraocular lens implantation was associated with better postoperative visual acuity in about 91% of patients.47 Adequate use of anti-inflammatory agents in the preoperative period and implantation of foldable hydrophobic acrylic intraocular lens can ensure good visual acuity.

CONCLUSION Obtaining a good history helps in the diagnosis of IU. The type and duration of symptoms, and number of recurrences may give a clue about the underlying disease. The diagnosis can be made following examinations based on clinical signs but laboratory and ancillary investigations are required to identify or exclude the associated disease. Determination of the etiology of the disease is important as the management and visual prognosis would vary depending on whether the disease is due to an infection or autoimmune process. Different modalities of treatment are thus discussed.

REFERENCES  1. 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.   2. Vadot E. Epidemiology of intermediate uveitis: a prospective study in Savoy. Dev Ophthalmol. 1992;23:33-4.  3. Rathinam SR, Namperumalsamy P. Global variation and pattern changes in epidemiology of uveitis. Indian J Ophthalmol. 2007;55(3):173-83.  4. Babu BM, Rathinam SR. Intermediate uveitis. Indian J Ophthalmol. 2010;58(1): 21-7.  5. Singh R, Gupta V, Gupta A. Pattern of uveitis in a referral eye clinic in north India. Indian J Ophthalmol. 2004;5(2):121-5.  6. Tugal-Tutkun I. Pediatric uveitis. J Ophthalmic Vis Res. 2011;6(4):259-69.  7. Porter R. Uveitis in association with multiple sclerosis. Br J Ophthalmol. 1972;56(6):478-81.  8. Breger BC, Leopold IH. The incidence of uveitis in multiple sclerosis. Am J Ophthalmol. 1966;62(3):540-5.  9. Zierhut M, Foster CS. Multiple sclerosis, sarcoidosis and other diseases in patients with pars planitis. Dev Ophthalmol. 1992;23:41-7.

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10. Manouvrier-Hanu S, Puech B, Piette F, et al. Blau syndrome of granulomatous arthritis, iritis, and skin rash: a new family and review of the literature. Am J Med Genet. 1998;76(3):217-21.  11. Sanghvi C, Bell C, Woodhead M, et al. Presumed tuberculosis uveitis: diagnosis, management, and outcome. Eye (Lond). 2011;25(4):475-80. 12. Breeveld J, Rothova A, Kuiper H. Intermediate uveitis and Lyme borreliosis. Br J Ophthalmol. 1992;76(3):181-2. 13. Davis JL. Diagnosis of intraocular lymphoma.  Ocul Immunol Inflamm. 2004;12(1):7-16.  14. Anshu A, Cheng CL, Chee SP. Syphilitic uveitis: an Asian perspective. Br J Ophthalmol. 2008;92(5):594-7. 15. Smith JA, Mackensen F, Sen HN, et al. Epidemiology and course of disease in childhood uveitis. Ophthalmology. 2009;116(8):1544-51. 16. García LA, Ortiz-Ponce G, Recillas-Gispert C. Peripheral corneal endotheliopathy and pars planitis. Ocul Immunol Inflamm. 1996;4(3):135-8. 17. Donaldson MJ, Pulido JS, Herman DC, et al. Pars planitis: a 20-year study of incidence, clinical features, and outcomes. Am J Ophthalmol. 2007;144(6):812-7. 18. Malinowski SM, Pulido JS, Folk JC. Long-term visual outcome and complications associated with pars planitis. Ophthalmology. 1993;100(6):818-24. 19. Lauer AK, Smith JR, Robertson JE, et al. Vitreous hemorrhage is a common complication of pediatric pars planitis. Ophthalmology. 2002;109(1):95-8. 20. Kaufman AH, Foster CS. Cataract extraction in patients with pars planitis. Ophthalmology. 1993;100(8):1210-7. 21. Nicholson BP, Zhou M, Rostamizadeh M, et al. Epidemiology of epiretinal membrane in a large cohort of patients with uveitis. Ophthalmology. 2014;121(12):2393-8. 22. Smith RE, Godfrey WA, Kimura SJ. Complications of chronic cyclitis. Am J Ophthalmol. 1976;82(2):277-82. 23. Deane JS, Rosenthal AR. Course and complications of intermediate uveitis. Acta Ophthalmol Scand. 1997;75(1):82-4. 24. Herbert HM, Viswanathan A, Jackson H, et al. Risk factors for elevated intraocular pressure in uveitis. J Glaucoma. 2004;13(2):96-9.  25. Pollack AL, McDonald HR, Johnson RN, et al. Peripheral retinoschisis and exudative retinal detachment in pars planitis. Retina. 2002;22(6):719-24. 26. Kalinina Ayuso V, ten Cate HA, van den Does P, et al. Young age as a risk factor for complicated course and visual outcome in intermediate uveitis in children. Br J Ophthalmol. 2011;95(5):646-51. 27. Romero R, Peralta J, Sendagorta E, et al. Pars planitis in children: epidemiologic, clinical, and therapeutic characteristics. J Paediatr Ophthalmol Strabismus. 2007;44(5):288-93. 28. Smith RE, Godfrey WA, Kimura SJ. Chronic cyclitis. I. Course and visual prognosis. Trans Am Acad Ophthalmol Otolaryngol. 1973;77(6):OP760-8. 29. Paroli MP, Spinucci G, Monte R, et al. Intermediate uveitis in a pediatric Italian population. Ocul Immunol Inflamm. 2011;19(5):321-6.

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30. Gupta A, Gupta V. Fundus photography. In: Gupta A, Gupta V, Herbort CP, et al., editors. Uveitis: Text and Imaging. New Delhi: Jaypee Brothers; 2009. pp. 50-60. 31. Pakzad-Vaezi K, Or C, Yeh S, et al. Optical coherence tomography in the diagnosis and management of uveitis. Can J Ophthalmol. 2014;49(1):18-29.  32. Greiner KH, Kilmartin DJ, Forrester JV, et al. Grading of pars planitis by ultrasound biomicroscopy–echographic and clinical study. Eur J Ultrasound. 2002;15(3):139-44. 33. Doro D, Manfrè A, Deligianni V, et al. Combined 50- and 20-MHz frequency ultrasound imaging in intermediate uveitis.  Am J Ophthalmol. 2006;141(5): 953-5. 34. Forrester JV, Okada AA, Ben Ezra D, et al. editors. Pars planitis. In: Posterior Segment İntraocular İnflammation: Guidelines. The Hague, Netherlands: Kugler Publications; 1998. pp. 93-7.  35. Kaplan HJ. Intermediate uveitis (pars planitis, chronic cyclitis)—A four step approach to treatment. In: Saari KM, editor. Uveitis Update. Amsterdam: Experta Medica; 1984. pp. 169-72. 36. Helm CJ, Holland GN. The effects of posterior subtenon injection of triamcinolone acetonide in patients with intermediate uveitis.  Am J Ophthalmol. 1995;120(1):55-64. 37. Lowder C, Belfort R Jr., Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis.  Arch Ophthalmol. 2011;129(5):545-53. 38. Malik AR, Pavesio C. The use of low dose methotrexate in children with chronic anterior and intermediate uveitis. Br J Ophthalmol. 2005;89(7):806-8. 39. Belfort R Jr, de Abreu MT, Petrilli AM, et al. Cytotoxic drugs in intermediate uveitis. Dev Ophthalmol. 1992;23:171- 6. 40. Tugal-Tutkun I, Ayranci O, Kasapcopur O, et al. Retrospective analysis of children with uveitis treated with infliximab. J AAPOS. 2008;12(6):611-3. 41. Deuter CM, Kötter I, Günaydin I, et al. Efficacy and tolerability of interferon alpha treatment in patients with chronic cystoid macular oedema due to non-infectious uveitis. Br J Ophthalmol. 2009;93(7):906-13.   42. Hogan AC, McAvoy CE, Dick AD, et al. Long-term efficacy and tolerance of tacrolimus for the treatment of uveitis. Ophthalmology. 2007;114(5): 1000-6. 43. Aaberg TM, Cesarz TJ, Flickinger RR Jr. Treatment of pars planitis. I. Cryotherapy. Surv Ophthalmol. 1977;22(2):120-5. 44. Ozdal PC, Berker N, Tugal-Tutkun I. Pars planitis: epidemiology, clinical characteristics, management and visual prognosis. J Ophthalmic Vis Res. 2015;10(4):469-80. 45. Stavrou P, Baltatzis S, Letko E, et al. Pars plana vitrectomy in patients with intermediate uveitis. Ocul Immunol Inflamm. 2001;9(3):141-51.

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46. Quinones K, Choi JY, Yilmaz T, et al. Pars plana vitrectomy versus immunomodulatory therapy for intermediate uveitis: a prospective, randomized pilot study. Ocul Immunol Inflamm. 2010;18(5):411-7. 47. Ganesh SK, Babu K, Biswas J. Phacoemulsification with intraocular lens implantation in cases of pars planitis. J Cataract Refract Surg. 2004;30(10): 2072-6.

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CHAPTER

6 Presumed Ocular Histoplasmosis Syndrome Suresh R Chandra, Mark D Meyer

INTRODUCTION Presumed ocular histoplasmosis syndrome (POHS) is a significant cause of permanent visual loss primarily in the United States. This entity is also referred to as ocular histoplasmosis or presumed ocular histoplasmosis, all of which describe the same clinical scenario. The clinical findings consistent with POHS include a clear vitreous, peripapillary atrophy (PPA) (Fig. 6.1), peripheral punched-out chorioretinal scars (Fig. 6.2) and disciform macular changes (Fig. 6.3). Although a clear etiology has not been elucidated, the

Fig. 6.1: Peripapillary atrophy.

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Fig. 6.2: Peripheral punched-out chorioretinal scars.

Fig. 6.3: Disciform macular changes.

organism Histoplasma capsulatum (H. capsulatum), generally has been the most accepted candidate responsible for the ocular sequelae. Woods and Wahlen1 first described the syndrome of ocular histoplasmosis in 1959 and described disciform macular disease and peripheral chorioretinal scars in patients with positive histoplasmin skin tests. Prior to these findings, Ried et al.2 in 1942 published reports of ocular disease in patients dying of disseminated histoplasmosis. Since these initial descriptions, numerous articles have followed generating a vast fund of knowledge regarding ocular

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histoplasmosis. This chapter will review the epidemiology, pathogenesis, clinical features, natural history, and treatment options of POHS.

EPIDEMIOLOGY A mild or subclinical infection with H. capsulatum is believed to be the inciting event prior to ocular manifestations. The organism, H. capsulatum, is a fungus in a yeast form. Typically, birds such as pigeons or chickens carry the fungus on their feathers. Additionally, bats are known for being infected with the fungus. These animals then shed the organism into the soil via their droppings. In the United States, H. capsulatum is endemic in a major geographical region involving the Ohio and Mississippi river valleys. States in this region include Illinois, Indiana, Missouri, Kentucky, Tennessee, and Mississippi. Ellis and Schlaegel3 demonstrated that 80% of the population in this region had positive skin test results. With regard to age, sex and race, most patients with POHS are usually in their thirties or forties. Most studies also agree that men and women are affected equally. Although typical fundus lesions seem to occur in equal frequency in whites and blacks, only a few cases of maculopathy have occurred in blacks. Gass and Wilkinson4 reported that within their practice, 100% of 130 patients with macular lesions consistent with POHS were white even though 50% of their clinic population was black or Hispanic.

PATHOGENESIS The fungus, H. capsulatum enters the body via the respiratory tract. Once inhaled, the infection is usually limited to mild respiratory symptoms. However, the organism also disseminates into the bloodstream, and in immunocompromised individuals, a life-threatening disease may ensue. POHS has been reported in patients who have the acquired immunodeficiency syndrome (AIDS).5 In immunocompetent hosts, it is postulated that the dissemination of H. capsulatum into the bloodstream allows for circulation within the choroid. Here it is believed that granulomas form similar to granuloma formation elsewhere in the body. It is believed that the body rapidly destroys the organism leaving small atrophic choroidal scars. Animal models have supported this and have demonstrated damage to Bruch’s membrane with secondary alterations of the retinal pigment epithelium (RPE).6,7 It has also been shown that around these minute scars resides a lymphocytic infiltration. Many thought that an exacerbation of the lymphocytic choroiditis perhaps via reinfection or a hypersensitivity reaction to H. capsulatum elsewhere in the body may be the precipitating event for enlarging chorioretinal scars.8,9 This may be the stimulation needed for choroidal neovascularization (CNV). Others believe that choroidal vascular decompensation may also be part of the choroidal neovascular membrane

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(CNVM) formation process.10 Finally, histocompatibility antigens have been studied to assess the concept of POHS as an immunologic process. Meredith11,12 found peripheral lesions had an association with human leukocyte antigens (HLA)-DRw2 and not HLA-B7. Alternatively, HLA-B7 was strongly associated in patients with macular lesions that Braley13 confirmed. Of his patients with macular lesions 78% were HLA-B7 positive compared to 20% of controls. Not only is it uncertain whether an allergic, vascular or immunologic event precipitates the findings seen in POHS, but also it is still unclear if H. capsulatum is solely responsible for the ocular manifestations. Much of this debate centers around Davidorf and Anderson’s work in 1970.14 They studied 353 school children who were exposed to H. capsulatum. Two years following exposure, all children who had become acutely ill had positive skin tests compared to 23.4% of those with negative skin tests. Interestingly, however, the incidence of fundus lesions was similar between the two groups. As one would expect, there are several arguments as to whether H. capsulatum is the cause for ocular disease. The factors supporting H. capsulatum as a cause include an improportionate number of diagnosis of POHS among patients living or having previously lived in an endemic region. Additionally, patients with disciform macular lesions have higher percentages of positive histoplasmin skin tests than those with negative tests. These arguments are made based upon several population-based studies. Asbury15 reported that 50% of 1417 institutionalized individuals in Ohio reacted positively to histoplasmin skin testing. Of the 1.6% with fundus histo spots, all had positive skin tests or radiographic evidence of histoplasmosis. Additionally, Smith and Ganley16-18 studied 842 individuals from Walkersville, Maryland and found that of the individuals with typical fundus lesions of POHS, 100% had positive skin tests. Alternatively, those who refute the causal link with H. capsulatum cite the following arguments. Some patients with the classic findings of POHS have never lived in an area known to harbor the organism. Reports from Great Britain exemplify this, as H. capsulatum has not been identified there, yet patients have been found demonstrating findings remarkably consistent with POHS. It is argued that perhaps a similar organism not yet identified may be responsible. This is exemplified by Braunstein et al.19 who found 15 patients in the United Kingdom with clinical findings of POHS but negative histoplasmin skin tests. Additionally, the majority of patients with positive skin tests never develop typical fundus findings. This is suggested by further analysis of Smith and Ganley’s work.16-18 Although all patients with fundus lesions tested positive to histoplasmin, only 4.4% of patients with positive skin tests had the typical fundus findings. Lastly, opponents also argue that H. capsulatum has never been isolated from an eye in patients with classic POHS. There have been scattered reports of finding the organism in the eye tissues, yet no organism has been found within classic chorioretinal scars or disciform lesions.

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CLINICAL FEATURES The clinical features of POHS include peripapillary chorioretinal atrophy, punched-out chorioretinal lesions, disciform macular lesions secondary to CNV and a clear vitreous. These findings may be unilateral, but most often are seen bilaterally. The peripapillary chorioretinal atrophy is usually contiguous with the optic disc. Many believe this occurs due to an underlying choroiditis, which damages the choriocapillaris, RPE, and Bruch’s membrane. Once this occurs the likelihood for peripapillary CNVMs increases. Gass and Wilkinson4 reported that 10% of CNVMs occurring in POHS are peripapillary in location. Punched-out chorioretinal scars, also termed histo spots, occur frequently in POHS. Most often these white appearing lesions with varying degrees of pigmentation occur mid-peripherally, but may be located within the macula. The lesions are discrete with sharp borders and usually range in size between one quarter and one disc diameter. Occasionally the histo spots may be arranged in a curvilinear row near the equator, which is termed, linear streaking20 (Fig. 6.4). The significance of linear streaking has not been elucidated and only occurs in a small subset of patients. Usually more than one histo spots are visualized on indirect ophthalmoscopy and frequently the lesions are seen bilaterally. Smith et al.21 found that 62% of patients with POHS had punched-out lesions in both eyes. New lesions may continue to form even after the initial diagnosis. According to a study by Schaegel,22 26% of histo spots developed while patients were followed over a 5-year period. Lewis and Schiffman23 reported that 19% of their patients with POHS acquired new histo spots. Many believe this supports the notion that POHS is an ongoing

Fig. 6.4: Linear streaking.

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disease process and patients need to be conscientiously followed for eventual risk of CNVM formation and subsequent vision loss. Disciform macular changes are the result of CNVM formation. A localized serous or hemorrhagic detachment may spontaneously resolve, but usually a discrete, gray, slightly elevated subretinal lesion will eventually develop representing CNV. Patients at this stage usually complain of visual loss, metamorphopsia, micropsia, or report a positive scotoma. At no point throughout this process is inflammation of the vitreous or anterior segment noted, which is contrary to multifocal choroiditis. Additionally, it is believed that the CNV occurs at the site of a previous chorioretinal scar. Once CNV occurs, varying degrees of pigmentation may be present, representing blood vessels growth within the subretinal space. The CNV in POHS according to Gass24 differs from CNV in macular degeneration. The differentiation arises from the growth pattern of invading choroidal vessels. The new vessel’s growth either invades Bruch’s membrane and proliferates under the RPE (type I) as seen in macular degeneration or perforates through the RPE and extends into the subretinal space (type II) as seen in POHS. This differentiation is important when considering treatment options, specifically the surgical removal. CNV is further classified according to location in relation to the foveal avascular zone (FAZ). The classifications include extrafoveal, juxtafoveal, and subfoveal. Extrafoveal lesions are located between 200 mm and 2500 mm from the center of the FAZ. Lewis25 reported that 69% of patients with extrafoveal CNVM had 20/40 or better vision at presentation. Juxtafoveal location is defined as having some part of the lesion 1–200 mm from the FAZ center. Lewis25 reported that 71% of this subset of patients had 20/200 or worse visual acuity at presentation. Lastly, subfoveal lesions are defined as having some part of the CNVM under the center of the FAZ. Fluorescein angiography plays an important role in patients with POHS and subsequent CNVM formation. Angiography is the method utilized to determine whether lesions are extrafoveal, juxtafoveal, or subfoveal. The neovascular membrane may be confined to the area noted clinically, but often extends beyond those borders. Typically, the CNVMs stain early often in a sea-fan formation and demonstrate late leakage (Fig. 6.5). Hypofluorescence will be seen if the CNVM has associated subretinal hemorrhage. This area of blockage is considered part of the entire lesion. This is crucial when considering treatment options, since subfoveal lesions are not considered for laser treatment. Other rare findings have been reported in association with POHS. Pulido et al.26 reported a case of suspected postcataract extraction histoplasmic endophthalmitis. Optic disc edema and blind spot enlargement has also been seen in a few patients.27 Lastly, a vitreous hemorrhage has been reported secondary to CNVM the formation with bleeding into the vitreous cavity.28 The typical appearance of POHS can be confused with other ocular diseases. When considering a differential diagnosis, the following diseases must be contemplated: coccidioides, multifocal choroiditis, panuveitis, birdshot choroidopathy, acute posterior

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Fig. 6.5: Fluorescein angiogram of patient in Figure 6.3 demonstrating late leakage associated with extrafoveal choroidal neovascular membrane (CNVM).

multifocal placoid pigment epitheliopathy (APMPPE), diffuse unilateral subacute neuroretinitis (DUSN), Behçet’s disease and toxoplasmosis.19,29

NATURAL HISTORY Once a diagnosis of POHS has been established, the resulting impact on vision is variable, ranging from asymptomatic histo spots to profound visual loss secondary to CNVM formation. Often, both eyes will demonstrate findings of POHS, especially if one eye has already developed a CNVM. Twenty-five to fifty-nine percent of patients with a disciform process in one eye will have histo spots in the fellow eye.23,30 If the histo spots in the fellow eye are located within the macula, the chances of CNVM formation in that eye are between 8% and 27% within 3 years.23,30-32 After CNV occurs, the single most important factor threatening the vision is proximity of the CNVM to the FAZ center. As stated earlier, patients with extrafoveal lesions generally have better initial and final visual outcomes. Other prognostic factors associated with better visual outcomes include lack of subretinal blood and small CNVM. If, however, the lesion is located under the center of the FAZ, not all patients do poorly. Approximately, 15% of patients with subfoveal lesions retain 20/40 vision or better without any treatment.33

TREATMENT Treatment approaches for POHS have been quite numerous since its recognition. Schlaegel34 discussed treatment options beginning with avoidance of stress, since emotional stress has been correlated with  inducing serous detachments in eyes with preexisting CNVMs. Additionally, Schlaegel et al.34-38

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discussed avoidance of aspirin and the Valsalva maneuver, histoplasmin desensitization, the use of amphotericin B, immunosuppressive agents, systemic and periocular steroids and photocoagulation. Most of these aforementioned attempts at treatment, in addition to antihistamine use, to attain better visual results over the natural course of POHS were unsuccessful. Specifically, in regard to desensitization, Schlaegel22 delivered histoplasmin subcutaneously in small doses and compared treated patients to controls and found no difference. Makley et al.39 further investigated amphotericin B use and likewise, found no treatment benefit. It is believed that amphotericin B provides no utility since the histo lesions likely represent sterile lesions with no inflammatory component. The benefits to steroid use are not as clear. Schlaegel38 initially reported that systemic steroids were beneficial for acute flare-ups and possibly for long-term protection against visual loss. This belief is controversial as many believe steroids have a limited role, if any, in the treatment of POHS. Gass40 believes steroid use should be limited to those patients with a recent history of visual loss and in patients with lesions too close to the FAZ center to use laser photocoagulation. If steroids are employed, most believe doses should start at 60–100 mg/day for several weeks followed by a slow taper. Additionally, the systemic side effects must be monitored closely if steroids are chosen as a treatment modality. Although systemic steroids have not previously been proven to be efficacious, intraocular steroid implants are currently being investigated. Patients with subfoveal CNVM not amenable to laser are receiving these implants with sustained release steroids for a more localized anti-inflammatory effect. The results of these studies are currently unavailable. The mainstay of treatment of POHS and subsequent CNVM formation is laser photocoagulation. Early studies believed that laser provided no treatment benefit. Maumenee et al.41 found that the majority of patients treated with xenon laser attained no improvement in visual outcomes. Work by Klein42 also demonstrated no difference between laser treatment and observation. Others, however, refuted the motion that laser was not beneficial. Sabates43 found that 48% of their patients retained visual acuity of at least 20/50 if the CNVMs were treated with intense laser burns. Gass44 found that 50% of patients retained 20/30 or better vision after treatment of extrafoveal CNVMs. Gitter et al.45 found 63% of their patients had 20/40 or better visual acuity following argon laser treatment. Cummings46 reported 20/40 or better visual acuity in 71% of patients following laser for extrafoveal lesions and in 68% of patients following treatment for juxtafoveal lesions at 5 years posttreatment. These results provided the necessary background to help formulate the macular photocoagulation study (MPS). The MPS was a multicenter randomized controlled clinical study which demonstrated that intense laser photocoagulation was beneficial in preventing severe visual loss from CNVMs in the subset of POHS patients. Specifically, three groups demonstrated benefit of laser treatment defined as preventing severe visual loss of six or more lines. Those groups

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included argon laser to extrafoveal CNVMs, krypton laser to juxtafoveal CNVMs and krypton laser to persistent or recurrent CNVMs.47-51 The MPS study defined extrafoveal lesions as angiographically located between 200 mm and 2500 mm from the center of the FAZ. In the treated eye, patients had evidence of additional histo spots and had a visual acuity of at least 20/100. Patients were treated with the argon blue-green laser with intense laser burns (currently the recommendation is to use green laser light). The laser burns were used to cover the entire CNVM and 100 mm beyond all borders. Intense laser burns were used, first outlining the CNVM and then heavy burns were applied to obtain a confluent whitening over the entire lesion

Fig. 6.6: Posttreatment status of extrafoveal CNVM with argon laser photocoagulation demonstrating intense burn.

Fig. 6.7: Laser scar with pigmentary changes eight months posttreatment.

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Figs. 6.8 and 6.9: Early and late phase fluorescein angiogram 4 months posttreatment demonstrating no recurrence of choroidal neovascular membrane (CNVM).

(Figs. 6.6 to 6.9). At 5 years, 9% of patients in the treated group lost six or more lines of vision and the median visual acuity was 20/40. In comparison, 44% of the non-treated group lost six or more lines of vision with a mean visual acuity of 20/80.52 Based upon this data, treatment of all extrafoveal CNVMs was recommended. Additionally, most juxtapapillary lesions were included in this subgroup of patients. As long as one and one-half clock hours of peripapillary nerve fiber layer could be spared when treating

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j­uxtapapillary CNVMs, these lesions should also be treated. The second group of patients noted to benefit from laser photocoagulation were those with juxtafoveal CNVMs. Lesions to be treated were defined as membranes angiographically located between 1 mm and 200 mm from the center of the FAZ. The hyperfluorescence of the CNVM could be located outside this zone if a portion of blood or blocked fluorescence was located 1–200 mm from the FAZ center. This allowed for large juxtapapillary lesions to be included in this subset of patients as well. The krypton red laser was used for several reasons including: less hemoglobin absorption, less xanthophyll absorption, and less inner retinal damage. Treatment of the non-foveal side covered the entire CNVM and extended to 100 mm beyond its border. On the foveal side, the entire lesion was treated if greater than 100 mm from the FAZ center. Longer duration burns were applied to avoid rupturing Bruch’s membrane, and burns were less white than with the argon protocol for extrafoveal lesions. At 5 years, patients in the treated group had an 8.5% chance of six or more lines of vision loss. In the non-treated control group, patients had a 27.9% chance of six or more lines of vision loss. These differences were statistically significant and treatment was, therefore, recommended for patients with juxtafoveal lesions. The MPS also showed that the chances of maintaining 20/40 vision or better was 60% if the CNVM was outside the FAZ compared to 15% if the CNVM was within the FAZ.48 The third group of patients that benefited from laser photocoagulation in the MPS study were those with persistent or recurrent membranes. A persistent CNVM is defined as displaying hyperfluorescence within 6 weeks after treatment. A recurrent CNVM displays leakage contiguous to or within the laser burn after 6 weeks of treatment. The persistence and recurrence rates differed within the extrafoveal and juxtafoveal treatment group. In the extrafoveal treated group, 26% had recurrent CNVMs at 5 years. Within the juxtafoveal treated group, 25% had persistent membranes and an additional 8% had recurrences at 2 years.53,54 The majority of these lesions were treatable membranes, and retreatment with the krypton red laser was proven beneficial. The MPS data also demonstrated that the percentage of persistent and recurrent CNVMs in POHS patients with extrafoveal and juxtafoveal lesions was smaller than for similar membranes due to age-related macular degeneration (AMD) and idiopathic causes. Studies have also been done to determine if laser photocoagulation for subfoveal neovascularization lesions would be beneficial. Fine et al.55 treated subfoveal lesions and found there was no benefit to treatment of new or recurrent subfoveal CNVMs. Laser photocoagulation through the center of the FAZ portends poor results and considering many patients have spontaneous membrane resolution and retain good vision, it was determined not to recommend laser for this subset of patients. As previously noted, CNVMs secondary to POHS are defined as type II membranes. Since these membranes extend above the RPE, many believe that surgical removal for subfoveal lesions may restore vision in some patients. Thomas56 found that 31% of his patients retained a visual acuity of 20/40 or better at nearly 1 year following

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surgical removal of subfoveal CNVMs. Currently, the Submacular Surgery Trial (SST) is investigating it further and should provide more definitive data regarding the outcomes of surgery versus observation. Most believe that surgery should be limited to subfoveal lesions since laser photocoagulation provides excellent results for juxtafoveal and extrafoveal membranes. Another recent development is the potential use of photodynamic therapy (PDT). Currently, PDT is becoming widely used for treatment of CNVMs in patients with AMD. PDT involves injection of an intravenous photosensitive drug that circulates within the CNVM. After infusion of the drug, non-thermal light is used to irradiate the CNVM at the peak absorption of the drug. The intent is to cause selective thrombosis and closure of CNV. Sickenberg57 has evaluated this technique in subfoveal CNVMs not related to AMD and found most patients gained at least one line of vision with no deterioration. Follow-up was short, however, ranging from 12 to 43 weeks and up to four separate treatments were given. Additional studies will confirm whether this technique will be beneficial for subfoveal lesions in patients with POHS.

CONCLUSION Presumed ocular histoplasmosis continues to be a common cause of visual loss. Patients characteristically demonstrate PPA, mid-peripheral chorioretinal spots, and disciform macular lesions. Individuals with these findings are at significant risk of eventual visual deterioration. Although many questions still remain in understanding the cause and pathogenesis of POHS, current treatment options offer significant benefit. In particular, laser photocoagulation to extrafoveal and juxtafoveal CNV is quite effective. With additional techniques currently being investigated, including surgical excision and PDT, subfoveal lesions may also be more effectively treated in the future.

REFERENCES  1. Wood AC, Wahlen HE. The probable role of benign histoplasmosis in the etiology of granulomatous uveitis. Trans Am Ophthalmol Soc. 1959;57:318-43.  2. Reid JD, Scherer JH, Herbut PA, et al. Systemic histoplasmosis diagnosed before death and produced experimentally in guinea pigs. J Lab Clin Med. 1942;27:419-34.   3. Ellis FD, Schlaegel TF Jr. The geographic localization of presumed histoplasmic choroiditis. Am J Ophthalmol. 1973;75(6):953-6.   4. Gass JD, Wilkinson CP. Fallow-up study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol. 1972;76(3):672-92.  5. Pasternak J, Bolivar R. Histoplasmosis in acquired immunodeficiency syndrome (AIDS): diagnosis by bone marrow examination. Arch Intern Med. 1983;143(10):2024.  6. Smith RE, Dunn S, Jester JV. Natural history of experimental histoplasmic choroiditis in the primate. I. Clinical features. Invest Ophthalmol Vis Sci. 1984;25(7):801-9.

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  7. Smith RE, Dunn S, Jester JV. Natural history of experimental histoplasmic choroiditis in the primate. II. Histopathologic features. Invest Ophthalmol Vis Sci. 1984;25(7):810-9.   8. Smith RE, Macy JI, Parrett C, et al. Variations in acute multifocal histoplasmic choroiditis in the primate. Invest Ophthalmol Vis Sci. 1978;17(10):1005-18.   9. Ganley JP. Epidemiologic characteristics of presumed ocular histoplasmosis. Acta Ophthalmo Suppl. 1973;119:1-63. 10. Aronson SB, Fish MB, Pollycove M, et al. Altered vascular permeability in ocular inflammatory disease. Arch Ophthalmol. 1971;85(4):455-66. 11. Meredith TA, Smith RE, Duquesnoy RJ. Association of HLA-DRw2 antigen with presumed ocular histoplasmosis. Am J Ophthalmol. 1980;89(1):70-6. 12. Meredith TA, Smith RE, Braley RE, et al. The prevalence of HLA-B7 in presumed ocular histoplasmosis in patients with peripheral atrophic scars. Am J Ophthalmol. 1978;86(3):325-8. 13. Braley RE, Meredith TA, Aaberg TM, et al. The prevalence of HLA-B7 in presumed ocular histoplasmosis. Am J Ophthalmol. 1978;85(6):859-61. 14. Davidorf FH, Anderson JD. Ocular lesions in the Earth Day histoplasmosis epidemic. Trans Am Acad Ophthalmol Otolaryngol. 1974;78:876-81. 15. Asbury T. The status of presumed ocular histoplasmosis: including a report of a survey. Trans Am Ophthalmol Soc. 1966;64:371-400. 16. Smith RE, Ganley JP. An epidemiologic study of presumed ocular histoplasmosis. Trans Am Acad Ophthalmol Otolaryngol. 1971;75(5): 994-1005. 17. Smith RE, Ganley JP. Presumed ocular histoplasmosis. I. Histoplasmin skin test sensitivity in cases identified during a community survey. Arch Ophthalmol. 1972;87(3):245-50. 18. Ganley JP, Smith RE, Knox DL, et al. Presumed ocular histoplasmosis. III. Epidemiologic characteristics of people with peripheral atrophic scars. Arch Ophthalmol. 1973;89(2):116-9. 19. Braunstein RA, Rosen DA, Bird AC. Ocular histoplasmosis syndrome in the United Kingdom. Br J Ophthalmol. 1974;58(11):893-8. 20. Fountain JA, Schlaegel TF Jr. Linear streaks of the equator in the presumed ocular histoplasmosis syndrome. Arch Ophthalmol. 1981;99(2):246-8. 21. Smith RE, Ganley JP, Knox DL. Presumed ocular histoplasmosis. II. Patterns of peripheral and peripapillary scarring in persons with nonmacular disease. Arch Ophthalmol. 1972;87:251-7. 22. Schlaegel TF Jr, Cofield DD, Clark G, et al. Photocoagulation and other therapy for histoplasmic choroiditis. Trans Am Acad Ophthalmol Otolaryngol. 1968;72(3):355-63. 23. Lewis ML, Schiffman JC. Long-term follow-up of the second eye in ocular histoplasmosis. Int Ophthalmol Clin. 1983;23(2):125-35. 24. Gass JD. Biomicroscopic and histopathologic considerations regarding the feasibility of surgical excision of subfoveal neovascular membranes. Trans Am Ophthalmol Soc. 1994;92:91-116. 25. Lewis ML, Van Newkirk MR, Gass JD. Follow-up study of presumed ocular histoplasmosis syndrome. Ophthalmology. 1980;87(5):390-9.

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26. Pulido JS, Folberg R, Carter KD, et al. Histoplasma capsulatum endophthalmitis after cataract extraction. Ophthalmology. 1990;97(2):217-20. 27. Beck RW, Sergott RC, Barr CC, et al. Optic disc edema in the presumed ocular histoplasmosis syndrome. Ophthalmology. 1984;91(2):183-5. 28. Kranias G. Vitreous hemorrhage secondary to presumed ocular histoplasmosis syndrome. Ann Ophthalmol. 1985;17(5):295-8, 302. 29. Gass JD. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. 3rd ed. ST Louis: CV Mosby; 1987. pp. 534-7. 30. Guttman FA. The natural course of active choroidal lesions in the presumed ocular histoplasmosis syndrome. Trans Am Ophthalmol Soc. 1979;77: 515-41. 31. Olk RJ, Burgess DB, McCormick PA. Subfoveal and juxtafoveal subretinal neovascularization in the presumed ocular histoplasmosis syndrome—Natural history. Ophthalmology. 1984;91:1592-602. 32. Gass JD. Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol. 1967;63(3):1-139. 33. Kleiner RC, Ratner CM, Enger C, et al. Subfoveal neovascularization in the ocular histoplasmosis syndrome: a natural history study. Retina. 1988;8:225-9. 34. Schlaegel TF. Ocular histoplasmosis. Grune and Stratton, Inc: New York; 1977. pp. 209-59. 35. Kaider RJ, Torsch T, O’Connor PR. Prognostic criteria in macular histoplasmic choroiditis. Int Ophthalmol Clin. 1975;15(3):41-9. 36. Giles CL, Falls HF. Further evaluation of amphotericin-B therapy in presumptive histoplasmosis chorioretinitis. Am J Ophthalmol. 1961;51:588-98. 37. Makley TA, Long JW, Sie T, et al. Presumed histoplasmic chorioretinitis with special emphasis on the present modes of therapy. Trans Am Acad Ophihal Otolar. 1965;69(3):443-57. 38. Schlaegel TF Jr. Corticosteroids in the treatment of ocular histoplasmosis. Int Ophthalmol Clin. 1983;23(2):111-23. 39. Makley TA Jr, Long JW, Suie T. Therapy of chorioretinitis presumed to be caused by histoplasmosis. Int Ophthalmol Clin. 1975;15(3):181-96. 40. Gass JD. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. 4th ed. ST Louis: CV Mosby; 1997. pp. 130-47. 41. Maumenee AE, Ryan SJ. Photocoagulation of disciform macular lesions in the ocular histoplasmosis syndrome. Am J Ophthalmol. 1973;75(1):13-6. 42. Klein ML, Fine SL, Patz A. Results of argon laser photocoagulation in presumed ocular histoplasmosis. Am J Ophthalmol. 1978;86(2):211-7. 43. Sabates FN, Lee KY, Ziemianski MC. A comparative study of argon and krypton laser. Photocoagulation in the treatment of presumed ocular histoplasmosis syndrome. Ophthalmology. 1982;89(7):729-34. 44. Gass JD. Photocoagulation of macular lesions. Trans Am Acad Ophthalmol Otolaryngol. 1971;75:580-2. 45. Gitter KA, Cohen G. Photocoagulation of active and inactive lesions of presumed ocular histoplasmosis. Am J Ophthalmol. 1975;79(3):428-36. 46. Cummings HL, Rehmar AJ, Wood WJ, et al. Long-term results of laser treatment in the ocular histoplasmosis syndrome. Arch Ophthalmol. 1995;113(4):465-8.

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47. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy. Three-year results from randomized clinical trials. Arch Ophthalmol. 1986;104(5):694-701. 48. Macular Photocoagulation Study Group. Laser photocoagulation for juxtafoveal choroidal neovascularization. Five-year results from randomized clinical trials. Arch Ophthalmol. 1994;112(4):500-9. 49. Argon laser photocoagulation for ocular histoplasmosis. Results of a randomized clinical trial. Arch Ophthalmol. 1983;101(9):1347-57. 50. Macular Photocoagulation Study Group. Krypton laser photocoagulation for neovascular lesions of ocular histoplasmosis. Results of a randomized clinical trial. Arch Ophthalmol. 1987;105(1):1499-507. 51. Burgess DB. Ocular histoplasmosis syndrome. Ophthalmology. 1986;93(7): 967-8. 52. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Arch Ophthalmol. 1991;109(8):1109-14. 53. Macular Photocoagulation Study Group. Persistent and recurrent neovascularization after krypton laser photocoagulation for neovascular lesions of ocular histoplasmosis. Arch Ophthalmol. 1989;107(3):344-52. 54. Macular Photocoagulation Study Group. Recurrent choroidal neovascularization after argon laser photocoagulation for neovascular maculopathy. Arch Ophthalmol. 1986;104(4):503-12. 55. Fine SL, Wood WJ, Isernhagen RD, et al. Laser treatment for subfoveal neovascular membranes in ocular histoplasmosis syndrome: results of a pilot randomized clinical trial. Arch Ophthalmol. 1993;111(1):19-20. 56. Thomas MA, Dickison JD, Melberg NS, et al. Visual results after surgical removal of subfoveal choroidal neovascular membranes. Ophthalmology. 1994;101(8):1384-96. 57. Sickenberg M, Schmidt-Erfurth U, Miller JW, et al. A preliminary study of photodynamic therapy using verteporfin for choroidal neovascularization in pathologic myopia, ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes. Arch Ophthalmol. 2000;118(3):327-36.

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CHAPTER

7 Ocular Syphilis Saurabh Mistry, Sudharshan Sridharan

INTRODUCTION Syphilis is an infectious disease caused by Treponema pallidum. Most common mode of spread is through sexual transmission.1–6 The prevalence of ocular syphilis has drastically decreased with the use of specific antibiotics. However, there has been a resurgence in recent times due to increased high-risk sexual behavior and associated HIV infection.7 The transmission can be transplacental or acquired postnatally by sexual contact. Acquired syphilis, if untreated, can be divided into four stages—primary, secondary, latent and tertiary.

Stages 1. Primary: Classical presentation—Single or multiple chancre (a firm, painless, non-itchy skin ulceration) 2. Secondary: Diffuse rash frequently involving the palms of the hands and soles of the feet, mouth or vagina 3. Latent: Can last years with few or no symptoms. 4. Tertiary: Rare and develops in untreated cases presenting with an obliterative endarteritis affecting multiple organ systems, including the brain, nerves, eyes, heart, blood vessels, liver, bones and joints.

OCULAR MANIFESTATIONS Ocular manifestations are varied and can occur at any stage of the disease and can affect all parts of the eye. Since it mimics a wide range of ocular disorders, it can be misdiagnosed and is called the “Great imitator”

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Table 7.1: Ocular findings in syphilis. Anatomic location

Ocular findings

Conjunctiva

Mucous patches, papillary conjunctivitis, granulomatous conjunctivitis

Sclera

Episcleritis and scleritis

Cornea

Stromal keratitis, marginal corneal infiltrates, keratic precipitates

Lens

Congenital cataract, uveitic cataract

Uveal tract

Iritis, iridocyclitis, iris nodules, multifocal choroiditis

Retina/RPE

Retinal vasculitis, RPE mottling, necrotizing retinitis, serous retinal detachment, CME, retinochoroiditis, tractional retinal detachment

Optic nerve

Optic atrophy, papilledema, inflammatory disc edema

Pupils

Argyll Robertson pupil

Cranial nerve and

Extraocular motility deficit

brainstem RPE: Retinal pigment epithelium; CME: Cystoid macular edema. Source: Aldave et al.5

(Table  7.1). The most common presentation among the disorders is syphilitic uveitis. Syphilitic uveitis can be vision threatening and can have dreaded ocular and systemic complications. Early diagnosis is crucial and can help save vision. The goal of this chapter is to review the recent trends in the epidemiology of syphilis, the clinical presentation, diagnosis and treatment of syphilitic uveitis, and also to provide guidance on management.

EPIDEMIOLOGY Syphilitic uveitis is still uncommon with reports ranging from 0.7 to 4.3% of the cases of uveitis.6–10 Recent increase in syphilitic uveitis has been noted to be coinciding with the resurgence of systemic syphilis all around the world.1,2,10 In early 2015, after ocular syphilis clusters were reported, Centers for Disease Control (CDC) issued a clinical advisory, notifying clinical providers and health departments of a potential increase in suspected ocular syphilis cases. They found that in 0.6% of syphilis cases, the patient had symptoms consistent with ocular syphilis.11 This resurgence in rates of syphilitic uveitis has been mainly due to high-risk sexual behavior among men who have sex with men (MSM), especially in those who are co-infected with the human immunodeficiency virus (HIV).12,13

CLINICAL PRESENTATION Ocular involvement in primary syphilis is uncommon. It is mainly limited to eye lid and conjunctival chancres due to direct inoculation from contaminated fingers or secretions.14 Although ophthalmic lesions may be observed both in

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secondary as well as in tertiary syphilis, there are a few differences. Chronic gummatous or granulomatous inflammation is typical of late stage disease, whereas more aggressive inflammation (example - iridocyclitis with vascularized nodules or roseolae and necrotizing retinitis) is seen in the early stage of the disease. Ocular inflammation seen in secondary syphilis is seen after the resolution of other systemic signs of secondary syphilis. Syphilitic uveitis can even present many years after the initial infection during the late latent stage of the disease. Patients with syphilitic uveitis may not have active signs and symptoms of systemic disease during initial presentation. Amaratunge et al. extensively reviewed 41 original reports on syphilitic uveitis in the English language literature published from 1984 to 2008.15 Among the 143 patients identified; 65% patients were HIV-positive and 35% were HIV-negative. Posterior uveitis was most commonly reported in 55.2%; followed by panuveitis in 25.2% cases; and anterior/intermediate uveitis was reported in only 19.6% cases.

Anterior Segment Involvement Anterior uveitis in secondary syphilis can present as an acute unilateral iridocyclitis. It can present as mild non-granulomatous to severe granulomatous disease. It is bilateral in about 50% of patients.14 Iris roseolae are vascular tufts in the middle-third of the iris surface, typically seen in secondary syphilis and are similar to infectious mucocutaneous lesions.16 The usual presentation in tertiary syphilis is chronic granulomatous inflammation with Koeppe and Busacca nodules. Gummas of the uveal tract can mimic iris tumors and even erode through the sclera. Patients presenting with gummas, responding poorly to topical steroids and with a history of skin rash, should be tested for a possibility of ocular syphilis.

Posterior Segment Involvement Treponemes can affect all layers of the eye unlike viruses or the mycobacterium which have a predilection for the retina or the choroid, respectively. The presentation is usually bilateral, often asymmetric and primarily affects the RPE and choriocapillaries, with or without vasculitis.17 Syphilitic posterior uveitis can present with variety of clinical manifestations including focal/ multifocal chorioretinitis, acute posterior placoid chorioretinitis, necrotizing retinitis, retinal vasculitis, intermediate uveitis and panuveitis (Fig. 7.1).18 Syphilitic chorioretinitis is the commonest and can present with significant vitritis.5,9,18,19 The typical presentation is a grayish-yellow colored lesion preferentially seen in the posterior pole and mid-periphery. They are initially small (one-half to one-disc diameter) but can coalesce to become large confluent lesions even with a serpiginous pattern. They can be associated with retinal vasculitis, disc edema, and/or serous retinal detachment.

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Fig. 7.1: Montage color fundus photograph showing retinitis with vasculitis in a patient with ocular syphilis.

Syphilitic uveitis can present with retinitis without choroiditis. Retinitis, usually affects the posterior pole and is characterized by focal areas of retinal edema, vasculitis, papillitis, and vitritis with minimal anterior segment inflammation.20 It can also present as necrotizing retinitis with patches of retinitis in the mid-peripheral retina that can become confluent and clinically indistinguishable from acute retinal necrosis (ARN), herpes simplex retinitis or cytomegalovirus retinitis. It is peripheral coalescing necrotizing retinitis in ARN while retinitis in ocular syphilis is located in the posterior pole. Syphilitic retinitis often has a uniquely diaphanous or ground-glass appearance in contrast to the opaque retinal whitening typically observed in patients with herpetic necrotizing retinitis or toxoplasmic retinochoroiditis.21 Another distinctive feature of syphilitic retinitis is the presence of superficial retinal precipitates overlying the areas of retinitis. These precipitates are small, creamy white and can migrate over inflamed retina during the evolution of the infection and its treatment.19 Acute syphilitic posterior placoid chorioretinitis (ASPPC)22 involving mainly the retinal pigment epithelium (RPE) was first described by Gass et al. in 1990. It can mimic acute posterior multifocal placoid pigment epitheliopathy (AMPPE) but can be differentiated clinically as ASPPC presents with one or more macular or juxtapapillary placoid yellowish or gray lesions with faded centers, at the level of the RPE, accompanied by vitritis. The placoid lesions in ASPPC are larger in size and often solitary which differentiates them from APMPPE. It is due to the result of an active inflammatory reaction at the level of the choriocapillaris–pigment epithelial–retinal photoreceptor complex. Fluorescein angiography of the lesion tends to show progressive hyperfluorescence, whereas ICGA may show either persistent

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hypofluorescence or late hyperfluorescence staining. Fluorescence in the area of the lesion may be variable with both techniques, producing a characteristic leopard-skin pattern.23 SD-OCT findings include loss of the normally distinct hyper-reflective bands associated with the photoreceptor-RPE complex, typically with nodular irregularity of the RPE and often with a localized serous retinal detachment and punctate choroidal hyper-reflectivity.24 All of these changes tend to normalize and vision is typically restored following appropriate treatment.25 Syphilitic retinal vasculitis involves all the vessels, viz., arteries, arterioles, capillaries and veins.26 The clinical spectrum can range from vascular staining evident only on FFA to increased vascular tortuosity, extensive perivascular exudation and fibrosis, and an obliteration of vessels from an occlusive vasculitis.26 Focal retinal vasculitis can even masquerade as a branch retinal vein occlusion.27 Syphilitic eye disease may also mimic intermediate uveitis with minimal anterior uveitis and significant vitritis. Associated signs such as macular edema, disc hyperemia and peripheral vasculitis may also be present. However, frank pars plana exudates are not usually seen in syphilitic vitritis. Optic neuropathy is frequently seen in patients with secondary syphilis.5 Patients can develop retrobulbar optic neuritis, papillitis with or without retinal vasculitis, perineuritis and neuroretinitis. Progressively visual loss secondary to optic atrophy can be seen as a manifestation of tertiary syphilis.5

Syphilis in Patients with HIV Co-infection Co-infection with HIV and syphilis is common due to shared risk factors related to sexual behavior.28 Syphilitic chancres like any genital ulceration increase the risk of acquiring and transmitting HIV29 and hence, HIV counselling and testing is warranted in all newly diagnosed syphilis patients. Ocular syphilis in HIV patients do not have a direct correlation with low CD4 counts.30 Usually CD4 counts are in low normal range.31 Posterior and panuveitis are more commonly seen in HIV-infected patients and can also be the initial manifestation.32 Central nervous system (CNS) involvement is more frequent in HIV-positive patients and is associated with CSF abnormalities (pleocytosis, elevated proteins) and neurological manifestations.31,33 However, it is difficult to attribute these alterations to HIV infection alone and/or neurosyphilis. Although these patients require high-dose intravenous penicillin based on the CSF findings, it is important to quantify CNS disease activity and to establish baseline CSF titers to monitor the efficacy of the therapy.34

DIAGNOSIS Diagnosis begins with ophthalmologic examination but requires serologic testing for confirmation.

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Direct Examination Direct microscopic identification of T. pallidum is possible using techniques such as dark field microscopy, silver staining and immunofluorescence staining.

Serodiagnosis Two general categories of serologic tests: 1. Nontreponemal tests, such as the Venereal Disease Research Laboratory (VDRL) and Rapid Plasma Reagin (RPR), and 2. Treponemal tests, such as the fluorescent treponemal antibody absorbed (FTA-ABS); T. pallidum particle agglutination (TP-PA); Enzyme immunoassays (EIAs) and Chemiluminescence immunoassays (CIAs). Nontreponemal tests are not very specific, but the titers decline as a result of treatment and are used as a tool to monitor response to the treatment. Nontreponemal tests may give false positive results in nonsyphilitic conditions such as viral infection, pregnancy or postimmunization. Moreover, they may be negative in as many as 30% of patients during the late latent or tertiary stages.5,14,35 After treatment, nontreponemal titers typically become negative while the more specific treponemal tests remain positive throughout life. The CDC currently recommends enzyme immunoassays (EIAs) and chemiluminescent immunoassays (CIAs) to detect antibodies to treponemal antigens as the best screening tests for syphilis followed by reflex testing of positive specimens with the nontreponemal test, RPR (Fig. 7.2). 36 The rationale for reverse-sequence testing is that there are significant numbers of patients with either very early syphilis (immunoglobulin M antibodies) or late syphilis (immunoglobulin G antibodies), such as those with neurosyphilis with ocular manifestations, who will be positive by treponemal-specific tests and negative by RPR (Fig. 7.2). Because sensitivity of the EIA or CIA tests is higher than RPR and specificity is lower, discordant results are expected. Specimen positive by EIA or CIA and negative on RPR are submitted for a confirmatory TP-PA test, and if that test is positive, a diagnosis of syphilis is considered confirmed. A negative EIA is considered definitive that syphilis is not present. Fluorescent treponemal antibody (FTA) is no longer recommended, as TP-PA has the best combination of sensitivity and specificity relative to the initial screening tests.28

CSF Evaluation Neurosyphilis is usually diagnosed if there are more than 20 white blood cells per microliter of CSF in a seropositive individual, or where CSF VDRL is positive.37 CDC guidelines for lumbar puncture at diagnosis of syphilis38 • Patients with neurologic, ophthalmic, or otologic signs or symptoms; • Evidence of active tertiary syphilic disease;

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Fig. 7.2: Centers for Disease Control recommended algorithm for reverse sequence serologic testing for syphilis. EIA: Enzyme immuno­ assay; CIA: Chemiluminescence immunoassay; RPR: Rapid plasma reagin; TP-PA: T. pallidum particle agglutination. Source: Centers for Disease Control webinar on reverse sequence testing.36

• Treatment failure [defined as a sustained fourfold increase in VDRL or RPR; or high (> 1:32) RPR titer that does not decline 2 titers over 6–12 months in early syphilis or 12–24 months in latent syphilis]. While a presumptive diagnosis of ocular syphilis can be made without it, a lumbar puncture wherever practically possible, can help confirm the diagnosis and monitor therapy. In instances of ocular syphilis and abnormal CSF test results, follow-up CSF examinations should be performed to assess treatment response.38

TREATMENT GUIDELINES38 Ocular syphilis with active clinical manifestations needs to be treated in the same manner as neurosyphilis, according to CDC guidelines.38 The drug of choice for ocular syphilis is penicillin administered parenterally. The recommended adult regimen is aqueous crystalline penicillin G 18–24 million units per day administered as 3–4 million units intravenously every 4 hours or by continuous infusion for 10–14 days. Alternatively, procaine

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Fig. 7.3: Posttreatment resolved lesions in the same patient (Fig. 7.1).

penicillin 2.4 million units intramuscularly once daily plus probenecid 500 mg orally four times a day, both for 10–14 days can also be used.38 An extended course of benzathine penicillin, 2.4 million units intramuscularly once per week for up to 3 weeks, can be considered to provide a longer duration of therapy. Subsequent four-fold decrease in titer by the same nontreponemal test is taken as evidence of a response to treatment (Fig. 7.3). Persons with HIV infection and primary or secondary syphilis should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy. All those patients who meet the criteria for treatment failure should be managed in the same manner as HIV-negative patients (i.e., a CSF examination and retreatment guided by CSF findings). If CSF examination is normal then treatment with benzathine penicillin G administered as 2.4 million units IM each at weekly intervals for 3 weeks is recommended. Jarisch–Herxheimer reaction is an acute febrile reaction accompanied by headache, myalgias, rigors or chills that occurs within 24 h of the initiation of treatment for ocular syphilis,.39 Typically, patients present with rapid loss of vision after the first adequate dose of penicillin. Use of systemic steroids before penicillin treatment of patients with neuro-ophthalmic manifestations of syphilis is recommended to avoid the Jarisch–Herxheimer reaction.40 Sexual partners of patients with ocular syphilis are at a risk of infection and hence should be notified. They should be provided treatment if sexual contact was made within 3 months plus the duration of symptoms for patients diagnosed with primary syphilis, 6 months plus duration of symptoms for those with secondary syphilis, and 1 year for patients with early latent syphilis.38

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Topical corticosteroids are effective in the management of interstitial keratitis and anterior uveitis.20 Oral and intravenous corticosteroids can be used to treat posterior uveitis, scleritis, and optic neuritis along with systemic penicillin.20 Tucker et al. comprehensively reviewed published series and case reports among HIV-infected individuals with ocular syphilis.41 Among the 101 patients identified; they found that ocular syphilis led to the HIV diagnosis in 52% of the cases. Importantly, they also found that 97% of patients improved following treatment with intravenous antibiotics supporting the notion that HIV infection per se does not lead to a poor outcome. Appropriate intravenous antibiotic therapy for ocular syphilis is associated with excellent outcomes in HIV-infected individuals.

Follow-Up The CDC recommends repeating a lumbar puncture if CSF pleocytosis was present initially (and recommends considering repeating an LP if the CSFVDRL or CSF protein evaluations were abnormal) every 6 months until the cell count had normalized. If the cell count did not decrease after 6 months, or CSF cell count or protein had not normalized after 6 months, retreatment should be considered.38 All patients with ocular syphilis should be evaluated regularly after treatment for their ophthalmic evaluation and also for follow-up titres of quantitative serologic nontreponemal tests. The patients should be followed by an ophthalmologist and infectious disease specialist posttreatment and they may need lifelong routine ophthalmologic care.

PROGNOSIS If syphilis is recognized early and treated with appropriate antibiotics, the majority of cases can result in a cure. If unrecognized, or treated inappropriately, in one-third of patients, the disease will progress to tertiary syphilis and can result in significant morbidity and mortality from cardiovascular and neurological complications.

CONCLUSION Syphilis is reemerging due to the current high-risk sexual habits and HIV co-infections. Syphilitic uveitis can be misdiagnosed as it can mimic many other ocular diseases. A high degree of suspicion for syphilis especially in atypical presentations, recurrent ocular inflammation with unknown etiology, in patients who fail to respond to or worsen on immunosuppressive therapy and more importantly in patients with HIV. All patients with ocular syphilis should undergo cerebrospinal fluid testing and HIV testing.

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Most patients with syphilitic uveitis are seen in the secondary stage, and hence timely diagnosis and appropriate treatment can prevent ocular and systemic morbidity and even mortality associated with the tertiary stage of the disease.

Key Points • Ocular Syphilis is termed the “Great imitator” as it mimics many ocular inflammatory pathologies. • Need to have a coordinated systemic evaluation and management in conjunction with an infectious disease. • Preretinal opacities or placoid chorioretinitis are typical features and can be diagnostic of ocular syphilis. • Enhanced imaging with OCT and ICG angiography can facilitate ophthalmological diagnosis. • Serologic diagnosis is imperative and has been revised to reserve sequence testing by the CDC. • Nontreponemal tests may be negative in patients with ocular syphilis and HIV infection. • Ocular syphilis can even be the initial manifestation and can lead to HIV diagnosis. • All patients with ocular syphilis should receive cerebrospinal fluid testing and HIV testing. • All ophthalmic manifestations of syphilis should be treated with a CDC-approved neurosyphilis regimen. • Appropriate intravenous antibiotic therapy for ocular syphilis is associated with excellent outcomes in HIV-infected individuals.

REFERENCES  1. Doris JP, Saha K, Jones NP, et al. Ocular syphilis: the new epidemic. Eye (Lond). 2006;20(6):703-5.   2. Chao JR, Khurana RN, Fawzi AA, et al. Syphilis: reemergence of an old adversary. Ophthalmology. 2006;113(11):2074-9.   3. Fonollosa A, Giralt J, Pelegrín L, et al. Ocular syphilis–back again: understanding recent increases in the incidence of ocular syphilitic disease. Ocul Immunol Inflamm. 2009;17(3):207-12.   4. Sethi S, Mewara A, Hallur V, et al. Rising trends of syphilis in a tertiary care center in North India. Indian J Sex Transm Dis. 2015;36(2):140-3.   5. Aldave AJ, King JA, Cunningham ET Jr. Ocular syphilis. Curr Opin Ophthalmol. 2001;12(6):433-41.   6. Rodriguez A, Calonge M, Pedroza-Seres M, et al. Referral patterns of uveitis in a tertiary eye care center. Arch Ophthalmol. 1996;114(5):593-9.   7. Das D, Bhattacharjee H, Bhattacharyya PK, et al. Pattern of uveitis in North East India: a tertiary eye care center study. Indian J Ophthalmol. 2009;57(2): 144-6.

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  8. Barile GR, Flynn TE. Syphilis exposure in patients with uveitis. Ophthalmology. 1997;104(10):1605-9.  9. Tamesis RR, Foster CS. Ocular syphilis. Ophthalmology. 1990;97(10): 1281-7. 10. Jones NP. The Manchester Uveitis Clinic: the first 3000 patients–epidemiology and casemix. Ocul Immunol Inflamm. 2015;23(2):118-26. 11. Available from: https://www.cdc.gov/mmwr/volumes/65/wr/mm6543a2.htm. 12. Mayer KH. Sexually transmitted diseases in men who have sex with men. Clin Infect Dis. 2011;53(Suppl 3):S79-83. 13. Buchacz K, Greenberg A, Onorato I, et al. Syphilis epidemics and human immunodeficiency virus (HIV) incidence among men who have sex with men in the United States: implications for HIV prevention. Sex Transm Dis. 2005;32(Suppl 10):S73-9. 14. Wilhelmus K, Lukehart S. Syphilis. In Ocular Infection and Immunity. Pepose  J, Holland G, Wilhelmus K, editors. St. Louis: Mosby; 1996. pp. 1437-66. 15. 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 patients. Clin Exp Ophthalmol. 2010;38(1):68-74. 16. Schwartz LK, O’Connor GR. Secondary syphilis with iris papules. Am J Ophthalmol. 1980;90(3):380-4. 17. Blodi FC, Hervouet F. Syphilitic chorioretinitis. A histologic study. Arch Ophthalmol. 1968;79(3):294-6. 18. Margo CE, Hamed LM. Ocular syphilis. Surv Ophthalmol. 1992;37(3):203-20. 19. Villanueva AV, Sahouri MJ, Ormerod LD, et al. Posterior uveitis in patients with positive serology for syphilis. Clin Infect Dis. 2000;30(3):479-85. 20. Kiss S, Damico FM, Young LH. Ocular manifestations and treatment of syphilis. Semin Ophthalmol. 2005;20(3):161-7. 21. Browning DJ. Posterior segment manifestations of active ocular syphilis, their response to a neurosyphilis regimen of penicillin therapy, and the influence of human immunodeficiency virus status on response. Ophthalmology. 2000;107(11):2015-23. 22. Gass JD, Braunstein RA, Chenoweth RG. Acute syphilitic posterior placoid chorioretinitis. Ophthalmology. 1990;97(10):1288-97. 23. Eandi CM, Neri P, Adelman RA, et al.; International Syphilis Study Group. Acute syphilitic posterior placoid chorioretinitis: report of a case series and comprehensive review of the literature. Retina. 2012;32(9):1915-41. 24. Pichi F, Ciardella AP, Cunningham ET Jr, et al. Spectral domain optical coherence tomography findings in patients with acute syphilitic posterior placoid chorioretinopathy. Retina. 2014;34(2):373-84. 25. Cunningham ET Jr, Eandi CM, Pichi F. Syphilitic Uveitis. Ocul Immunol Inflamm. 2014;22(1):2-3. 26. Yokoi M, Kase M. Retinal vasculitis due to secondary syphilis. Jpn J Ophthalmol. 2004;48(1):65-7. 27. Lobes LA Jr, Folk JC. Syphilitic phlebitis simulating branch vein occlusion. Ann Ophthalmol. 1981;13(7):825-7.

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28. Stevenson J, Heath M. Syphilis and HIV infection: an update. Dermatol Clin. 2006;24(4):497-507, vi. 29. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection. Sex Transm Infect. 1999;75(1):3-17. 30. Marra CM, Sahi SK, Tantalo L, et al. Enhanced molecular typing of Treponema pallidum: geographical distribution of strain types and association with neurosyphilis. J Infect Dis. 2010;202(9):1380-8. 31. Tran TH, Cassoux N, Bodaghi B, et al. Syphilitic uveitis in patients infected with human immunodeficiency virus. Graefes Arch Clin Exp Ophthalmol. 2005;243(9):863-9. 32. Chhablani JK, Biswas J, Sudharshan S. Panuveitis as a manifestation of ocular syphilis leading to HIV diagnosis. Oman J Ophthalmol. 2010;3(1):29-31. 33. Becerra LI, Ksiazek SM, Savino PJ, et al. Syphilitic uveitis in human immunodeficiency virus-infected and noninfected patients. Ophthalmology. 1989;96(12):1727-30. 34. Gordon SM, Eaton ME, George R, et al. The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection. N Engl J Med. 1994;331(22):1469-73. 35. Samson CM, Foster CS. Syphilis. In: Foster CS, Vitale AT, editors. Diagnosis and treatment of uveitis. Philadelphia: WB Saunders; 2001. pp. 237-44. 36. Available from: http://www.cdc.gov/std/syphilis/Syphilis-Webinar.htm. 37. Hart G. Syphilis tests in diagnostic and therapeutic decision making. Ann Intern Med. 1986;104(3):368-76. 38. Workowski KA, Bolan GA; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-03):1-137. 39. Fathilah J, Choo MM. The Jarisch-Herxheimer reaction in ocular syphilis. Med J Malaysia. 2003;58(3):437-9. 40. Danesh-Meyer H, Kubis KC, Sergott RC. Not so slowly progressive visual loss. Surv Ophthalmol. 1999;44(3):247-52. 41. Tucker JD, Li JZ, Robbins GK, et al. Ocular syphilis among HIV-infected patients: a systematic analysis of the literature. Sex Transm Infect. 2011;87(1):4-8.

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CHAPTER

8 Lyme Disease Kalpana Babu, Ashwini Patil

INTRODUCTION Lyme disease is an infectious, vector borne disease caused by a spirochete of the genus Borrelia and is transmitted by the Ixodes ticks (hard ticks).

HISTORY Lyme disease was first described in 1975 in a group of children living in Lyme, Connecticut in the United States of America who presented with inflammatory arthropathy that mimicked juvenile rheumatoid arthritis.1 A characteristic skin rash [erythema migrans (EM)], neurologic and cardiac abnormalities were associated with this illness.2 Steere labeled this illness as Lyme disease in 1977.1-3 Borrelia burgdorferi was identified as the causative agent by Burgdorfer and Barbour in 1982.4 There are three distinct species that cause the disease.

EPIDEMIOLOGY Lyme disease is endemic in forested areas of the Northern Hemisphere’s temperate regions—in particular North America, Europe and Asia. Isolated reports from Australia, Africa, Asia and South America have been reported in literature although these regions are not endemic for Lyme disease. Lyme disease is uncommon in India although there have been isolated reports from the Himalayan, North-Eastern and South India.5,6

TRANSMISSION AND IMMUNOPATHOGENESIS B. burgdorferi is injected into the skin by the bite of an infected Ixodes tick. The tick saliva downregulates the host immune response and promotes

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infection at the site of the bite. The spirochetes multiply and migrate outward within the dermis. The EM lesion in the skin is caused by the host inflammatory response to the bacteria. Failure of appearance of neutrophils in the EM lesion allows the spirochetes to survive and spread to the heart, musculoskeletal and nervous systems. If untreated, they may persist in the body for months or even years, despite the production of B. burgdorferi antibodies by the immune system. The borrelia’s outer surface protein (OspA) is highly antigenic and is downregulated. This could be to evade host defences.2 Later in the course of the disease, chronic inflammatory manifestations may occur in the absence of active infection. This is probably due to an autoimmune response as a result of molecular mimicry.

DEMOGRAPHICS Lyme disease can affect all ages. The incidence is highest in children