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Stichting Voor Ooglijders Prof. Dr. HJ De publicatie van dit proefschrift werd mede mogelijk gemaakt met fmanciele steun van: Stichting voor Ooglijders Prof. Dr. H.J. Flieringa Stichting Medical Workshop BV Kabi Pharmacia Bournonville-Pharma BV Ter herinnering aan mijn vader Omslag: Henry Cannon I Ebbo Clerlo: CLINICAL ASPECTS AND ETIOLOGY OF FUCHS' HETEROCHROMIC CYCLITIS (KLINISCHE ASPECTEN EN ETIOLOGIE VAN DE HETEROCHROME CYCLITIS VAN FUCHS) proefschrift Ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de Rector Magnificus Prof. dr. P.W.C. Akkermans M. Lit. en volgens besluit van het College van Dekanen. De openbare verdediding zal plaatsvinden op woensdag 3 November 1993 om 15.45 uur. door Ellen Carolien La Heij geboren te Arnstelveen PROMOTIE-COMMISSIE PROMOTORES' Prof. dr. P.T.V.M. de Jong Prof. dr. A. Kijlstra OVERIGE LEDEN, Prof. dr. F.T. Bosman Prof. dr. H.A. Drexhage CONTENTS Chapter 1 1.1 General Introduction ........................ 7 1. 2 Aim of the Thesis_ ................... __ ...... 8 Chapter 2 Fuchs' Heterochromic Cyclitis: Review of the Literature (submitted for publication) 2.1 Historical Background ........................ 9 2.2 Terminology and Classification ............... 9 2. 3 Epidemiology. .11 2. 4 Clinical Features ........................... 11. 2.5 Histopathology of the Iris ................. 22 2. 6 Etiologic Mechanisms ........................ 25 2.7 Therapy and Prognosis .................... ... 37 Chapter 3 Clin~c~l analysis of Fuchs' heterochromic cycl1t1s ........................................ 49 (Doc Ophthalmol. 1991;78:225-235). Chapter 4 Treatment and prognosis of secondary glaucoma in Fuchs' heterochromic cyclitis ............... .... 61 (Am J Ophthalmol. 1993, in press) Chapter 5 Quantitative analysis of iris translucency in Fuchs' heterochromic cyclitis ................. .. 83 (Invest Ophthalmol & Vis Sci. 1993;34, in press). Chapter 6 Fuchs' heterochromic cyclitis and retinal vascular abnormalities in progressive facial hemiatrophy ................................... 107 (Case-report, Eye 1993;7:426-428). Chapter 7 Fuchs' heterochromic cyclitis in congenital ocular toxoplasmosis ................................. 113 (Case-report, Br J Ophthalmol. 1991;6:372-373). Chapter 8 Contralateral active ocular toxoplasmosis in Fuchs' heterochromic cyclitis .............. .... 117 (Case report, Br J Ophthalmol. 1993;77:455-456). Chapter 9 Is Fuchs' heterochromic cyclitis associated with ocular toxoplasmosis? ................. ... 123 (The major part of this study was published in Arch Ophthalmol. 1992;110:806-811). Chapter 10 Does autoimmunity to S-antigen play a role in Fuchs' heterochromic cyclitis? ...................... 139 (Br J Ophthalmol. 1993;77:436-439). Chapter 11 High incidence of corneal epithelium antibodies in Fuchs' heterochromic cyclitis ................... 149 (Br J Ophthalmol. 1988;72:921-925). Chapter 12 Immune deposits in iris biopsies from patients with Fuchs' heterochromic cyclitis ............. ....... 155 (Am J Ophthalmol. 1992;113:75-80). Chapter 13 Further considerations on the etiology and pathogenesis of Fuchs' heterochromic cyclitis: current and previous studies .................... 165 Chapter 14 Summary ............................... ... 177 Samenvatting .................................... 181 Chapter 1 GENERAL INTRODUCTION Fuchs' heterochromic cyclitis is characterized by a chronic, low-grade non-granulomatous anterior uveitis with widely scattered small keratic precipitates, a variable degree of atrophy and depigmentation of the iris, and no synechiae. It is usually unilateral, although bilateral involvement has been reported in up to 10 % of cases. Fuchs' heterochromic cyclitis occurs in approximately 5 % of all patients with uveitis and is regarded as a distinct nosological entity. The typical age of onset is in the third or fourth decade, and there is an equal incidence among men and women. Because not all characteristic clinical signs are present at the same time, the diagnosis of Fuchs' heterochromic cyclitis is often difficult to make, especially in the earlier stages of the disease. No minimal clinical diagnostic criteria, pathognomonic for this eye disease, have been internationally accepted yet, and no laboratory tests are available to confirm the diagnosis of Fuchs' heterochromic cyclitis. Fuchs' heterochromic cyclitis may even be considered as the most commonly misdiagnosed form of uveitis. Cataract and glaucoma are two major complications in Fuchs' heterochromic cyclitis. A subcapsular cataract develops in almost all cases, whereas glaucoma occurs in approximately 20 % of the cases. Cataract extractions with or without intraocular lens implantation currently have excellent results. Glaucoma is considered to be the most serious complication, because the therapy of glaucoma (medical and surgical), as reported in the literature, has a poor outcome. The origin of Fuchs' heterochromic cyclitis is still unknown and many hypotheses for the etiology of this eye disease have been proposed since Ernst Fuchs presented his theory in 1906. In chronological order, these theories are the following: Sympathetic Theory, Hereditary Theory, Association with Toxoplasmosis, Vascular Theory and Immunologic Theory. Until now. no definite proof has been obtained to accept or to reject any of these theories. AIM OF THE THESIS The aim of this thesis was to study the clinical aspects and etiology of Fuchs' heterochromic cyclitis. An update of the literature on Fuchs' heterochromic cyclitis is presented in chapter 2. Clinical Aspects Based on an analysis of clinical findings in 51 patients, clinical diagnostic criteria for Fuchs' heterochromic cyclitis are proposed in chapter 3. In chapter 4, the severity and prognosis{ of secondary glaucoma are evaluated, based on a larger series of patients with Fuchs' heterochromic cyclitis who needed medical and surgical intervention for glaucoma. Iris Cha ter 1 translucency, an important clinical feature, is quantified in patients with Fuchs' heterochromic cyclitis by a modification of the direct compensation technique for the measurement of intraocular stray light in chapter 5. Etiology Different approaches have been used to study the various etiological theories on Fuchs' heterochromic cyclitis. One case report and a short review of the literature to support the sympathetic theory and the association between Fuchs' heterochromic cyclitis and the Parry Romberg syndrome are presented in chapter 6. Two cases with Fuchs' heterochromic cyclitis and a definite (congenital) ocular toxoplasmosis (chapter 7 and 8), and clinical and laboratory examinations for ocular toxoplasmosis in a larger series of patients with Fuchs' heterochromic cyclitis (chapter 9) are reported to elucidate the association between Fuchs' heterochromic cyclitis and toxoplasmosis-like chorioretinal lesions. The alternative hypothesis for the chorioretinal lesions in Fuchs' heterochromic cyclitis, namely that of autoimmunity directed against retinal antigens, was evaluated in chapter 10. Chapter 11 describes the detection of circulating autoantibodies against the anterior segment (uvea, cornea) of the eye in patients with Fuchs' heterochromic cyclitis. In chapter 12 the hypothesis of an immune complex vasculitis of the iris vessels was assessed with an immunofluorescence technique on peripheral iridectomies of patients with Fuchs' heterochromic cyclitis. Chapter 2 FUCHS' HETEROCHROMIC CYCLITIS: REVIEW OF THE LITERATURE Historical Background Fuchs' heterochromic cyclitis is a unique disease entity in many of its clinical aspects. In 1906, Ernst Fuchs (Fig. 1) presented a detailed description of 38 patients with heterochromic cyclitis, which he had closely examined in the preceding 10 to 15 years.' He combined the presentation of his clinical findings with histopathologic studies on post-mortem or post­ enucleation eyes from six of his patients. His clinical descriptions were very accurate and complete and little was left to add by later authors. Although his classical paper appeared in 1906, Fuchs was not the first author to observe this disease. He referred in his original manuscript to seven cases described by Weil in 1904. 2 Furthermore, Bistis3 had published a report of a similar symptom complex in 1898, although it is doubtful whether he recognized its inflammatory nature. 4 Still earlier, the coincidence of heterochromia and cataract was recognized by Lawrence in 1843, and a scientific report on this subject was published by Hutchinson in 1869 5 Tenninology and Classification Any inflammation of the uveal tract, which comprises the iris, ciliary body or choroid is called uveitis. 6 Usually, the inflammation is not confined to one of these intraocular structures. Adjacent tissues, including the retina, vitreous, and optic nerve are affected 6 7 simultaneously. · Therefore, these structures are also incorporated in the terminology of uveitis: inflammation of the iris and ciliary body is called iridocyclitis and inflammation of the retina 6 7 and choroid is called retinochoroiditis or chorioretinitis. · Because the etiology of uveitis remains frequently unknown, the International Uveitis Study Group (IUSG) has introduced a classification system based on the anatomical localization of the intraocular inflammation: anterior uveitis (iris and ciliary body), posterior uveitis (choroid, often including the retina), intermediate uveitis (peripheral retina and pars plana of ciliary body), or panuveitis (generalized 8 9 inflammation of the whole uvea). • For Fuchs' heterochromic
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