Eales Disease Associated with Serpiginous Choroiditis

CA. Conglomerate tubercle: myth or reality? Tamil Nadu Ophthalmic Assoc J. Comment. Although tuberculous infection and/or hy- 1998;38:23-24. 6. Umadevi K, Madhavi R. Observations on the morphology and life-cycle of persensitivity has been associated with both Eales dis- Procerovum varium (Onji & Nishio, 1916) (Trematoda: Heterophyidae). Syst ease and serpiginous choroiditis, the evidence remains Parasitol. 2000;46(3):215-225. inconclusive.1 M tuberculosis has been detected by polymerase chain reaction from vitreous biopsies in patients with Eales disease, but the same biopsies were negative for mycobacterial cultures.3 In patients with systemic tu- Eales Disease Associated berculosis, the development of Eales disease is uncom- With Serpiginous Choroiditis mon.4 A positive QuantiFERON result was detected in 11 of 21 patients with serpiginous-like choroiditis.5 Cho- ales disease is an idiopathic, usually bilateral, roidal tuberculous lesions mimicking serpiginous cho- inflammatory, retinal vascular occlusive disor- roiditis have been described and named tubercular ser- E der.1 Serpiginous choroiditis is an idiopathic, piginous-like choroiditis.2 Previous authors6 believe that usually bilateral, recurrent acute progressive inflam- tubercular serpiginous-like choroiditis may be distin- mation of the inner choroid and retinal pigment guishable from classic serpiginous choroiditis by the pres- epithelium.2 To our knowledge, we describe the ence of vitritis and smaller, multifocal lesions in the fun- first case of Eales disease followed by serpiginous cho- dus of patients from tuberculosis endemic regions. roiditis. To our knowledge, the coexistence of Eales disease and serpiginous choroiditis has been reported only once Report of a Case. A 49-year-old immunocompetent white before, in a 35-year-old Pakistani man with bilateral man had gradual vision loss in his left eye. Visual acuity ampiginous chorioretinitis followed by unilateral Eales was 20/20 OD and 20/100 OS. Anterior segment exami- disease.7 Mantoux skin test results were positive with no nation of the left eye demonstrated small, white, central active tuberculosis infection. Although an association be- keratic precipitates but no cells or flare. Fundus exami- tween serpiginous choroiditis and retinal periphlebitis nation revealed left temporal retinal vascular occlusive and/or vein occlusions was previously reported, testing disease, arteriolar and venous sheathing, and peripheral for tuberculosis in these cases was either not performed retinal ischemia with neovascularization (Figure, A). The or had negative results.8 Furthermore, in our patient, the right eye was normal. Complete blood cell count, throm- area of Eales disease was distinct from the peripapillary bophilia screen, antinuclear antibody, syphilis serology, serpiginous choroiditis. and QuantiFERON results were normal. An anterior Our patient does not fit into either category of ser- chamber paracentesis was negative for herpes simplex vi- piginous disease previously described.6 Unlike patients rus, varicella-zoster virus, and cytomegalovirus by poly- with tubercular serpiginous-like choroiditis, he had a soli- merase chain reaction. Chest radiograph and tuberculin tary, peripapillary lesion and negative results on exten- skin testing results were normal. Eales disease was di- sive investigation for tuberculosis; unlike patients with agnosed, scatter laser photocoagulation was applied to classic serpiginous choroiditis, he exhibited bilateral in- areas of ischemic retina, and systemic corticosteroids (60 traocular inflammation with vitritis in the right eye and mg/d) and mycophenolate mofetil (1.5 g/d) were keratic precipitates in both eyes. Because it is improb- prescribed. able that these 2 rare conditions would coexist, it is pos- After 9 months, slowly progressive lobular peripap- sible that Eales disease and serpiginous choroiditis rep- illary choroiditis (Figure, B), peripheral temporal reti- resent manifestations of the same underlying inflammatory nal vascular occlusive disease with vitritis, and keratic disease. precipitates developed in the right eye (Figure, C). Vi- sual acuity remained 20/20. On fluorescein angiogra- Adrian T. Fung, MBBS, MMed, FRANZCO phy, the area of peripapillary choroiditis revealed hyper- Massimo Nicolò, MD fluorescent transmission defect and periphlebitis. Retinal Susanne Yzer, MD, PhD neovascularization was detected at the edge of the cap- Carlo Enrico Traverso, MD illary closure temporally. Bilateral Eales disease and right Lawrence A. Yannuzzi, MD serpiginous choroiditis were diagnosed and the ischemic areas were photocoagulated. Author Affiliations: Vitreous-Retina-Macula Consul- During the following 7 years, the capillary closure and tants of New York and LuEsther T. Mertz Retinal Re- retinal neovascularization progressed bilaterally, with de- search Center, Manhattan Eye, Ear, and Throat Insti- velopment of cataract, rubeotic glaucoma, cystoid macu- tute (Drs Fung, Yzer, and Yannuzzi) and Department of lar edema, and progressive serpiginous choroiditis with Ophthalmology, Columbia University (Drs Yzer and Yan- vitritis in the right eye (Figure, D-F). For this reason, bi- nuzzi), New York; and Fondazione per la Macula Onlus lateral intravitreal bevacizumab and triamcinolone ace- (Dr Nicolò) and Department of Neuroscience, Ophthal- tonide injections and right intravitreal dexamethasone mology, and Genetics, University of Genova (Drs Ni- implants (Ozurdex), peribulbar triamcinolone injec- colò and Traverso), Genova, Italy. tions, phacoemulsification with intraocular lens implan- Correspondence: Dr Massimo Nicolò, Clinica Oculis- tation, and pars plana vitrectomy were performed. Poly- tica, Di.N.O.G.Mi, Università di Genova, Viale Bene- merase chain reaction results from the vitreous for detto XV, n.5 16132 Genova, Italy (massimo.nicolo Mycobacterium tuberculosis, herpes simplex virus, and vari- @unige.it). cella-zoster virus were negative. Conflict of Interest Disclosures: None reported.

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C D

E F

Figure. Bilateral Eales disease and right serpiginous choroiditis. The patient had left temporal retinal vascular occlusion and neovascularization (A), followed 9 months later by right peripapillary serpiginous choroiditis (B) and peripheral retinal vascular occlusion and neovascularization (C). Peripheral scatter argon laser photocoagulation was applied judiciously to ischemic retina in both eyes to minimize any proinflammatory effects. The area of peripapillary serpiginous choroiditis slowly expanded during the following 7 years, visible on color photographs (D), fluorescein angiography (E), and fundus autofluorescence imaging (F).

Funding/Support: This work was supported by The 2. Gupta V, Gupta A, Arora S, Bambery P, Dogra MR, Agarwal A. Presumed tubercular serpiginouslike choroiditis: clinical presentations and management. Macula Foundation, Inc and Stichting Wetenschap- Ophthalmology. 2003;110(9):1744-1749. pelijk Onderzoek Oogziekenhuis Rotterdam, Rotter- 3. Madhavan HN, Therese KL, Gunisha P, Jayanthi U, Biswas J. Polymerase chain damse Blindenbelangen, Stichting Blindenhulp, Gelderse reaction for detection of Mycobacterium tuberculosis in epiretinal membrane in Eales’ disease. Invest Ophthalmol Vis Sci. 2000;41(3):822-825. Blinden Stichting, Landelijke Stichting voor Blinden. 4. Biswas J, Badrinath SS. Ocular morbidity in patients with active systemic tuberculosis. Int Ophthalmol. 1995-1996;19(5):293-298. 1. Biswas J, Sharma T, Gopal L, Madhavan HN, Sulochana KN, Ramakrishnan 5. Mackensen F, Becker MD, Wiehler U, Max R, Dalpke A, Zimmermann S. S. Eales disease: an update. Surv Ophthalmol. 2002;47(3):197-214. QuantiFERON TB-Gold: a new test strengthening long-suspected tubercu-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 lous involvement in serpiginous-like choroiditis. Am J Ophthalmol. 2008; volved relatives) were counseled and consented accord- 146(5):761-766. 6. Vasconcelos-Santos DV, Rao PK, Davies JB, Sohn EH, Rao NA. Clinical fea- ing to the Declaration of Helsinki, and the study was ap- tures of tuberculous serpiginouslike choroiditis in contrast to classic serpigi- proved by the local ethics committee. Full ophthalmic nous choroiditis. Arch Ophthalmol. 2010;128(7):853-858. 7. Wong R, Graham E, Scoppettuolo E, Moin M, Stanford MR. Case report: ampigi- history, examination, and electrophysiology were per- nous chorioretinopathy associated with Eales disease in a patient with pre- formed. The patients’ DNA was extracted, and direct sumed tuberculosis. Retin Cases Brief Rep. 2011;5:249-250. (dideoxy/Sanger) sequencing of all ABCA4 exons and a 8. Friberg TR. Serpiginous choroiditis with branch vein occlusion and bilateral periphlebitis: case report. Arch Ophthalmol. 1988;106(5):585-586. 25–base pair flanking sequence was performed using standard protocols. The pathogenicity of all sequence variants was determined using standard software (Alamut Detection Rate of Pathogenic Mutations version 1.5; Interactive Biosoftware). Multiplex ligation- in ABCA4 Using Direct Sequencing: Clinical dependent probe amplification analysis (P151 and P152 and Research Implications kits; MRC-Holland) was used to identify copy number variants. We determined phase and segregation when possible. A confident molecular diagnosis was defined as the e set out to determine the mutation detection rate in 50 subjects referred with pos- presence of 2 or more pathogenic mutations. sible Stargardt disease (STGD) using direct W Results. Of 50 patients, 34 had a phenotype compatible sequencing of the ABCA4 gene (GenBank NM_000350). Pathogenic mutations in ABCA4 have been found to cause with STGD. Of these 34 patients, 27 (79%) had at least Stargardt disease (STGD)/fundus flavimaculatus as well 2 pathogenic mutations; 7 of the 34 patients had a single as some cases of cone-rod dystrophy, autosomal reces- mutation identified, 2 of the 34 had premature termina- sive retinitis pigmentosa, and bull’s-eye maculopathy.1,2 tion codons (stop codon and frameshift), and 5 of the Mutation detection rates reported in patients are highly 34 had known missense mutations. The identification of variable, depending on multiple factors including the phe- a single mutation supports the clinical diagnosis but is notype and mutation detection method used.3-5 Because not conclusive; however, the carrier rate is estimated to next-generation sequencing is likely to be introduced into be 1 in 35 to 1 in 50 patients, so we would not expect as clinical diagnostics, we revisited direct (Sanger) sequenc- many as one-fifth of our patients to be carriers by chance ing, currently the gold standard for mutation detection, alone. Among the 50 patients, 11 were diagnosed as hav- in a large group of patients with STGD to determine the ing STGD by other centers in the past but on current clini- number of patients receiving a confident molecular di- cal review were reclassified as shown in the Table, re- agnosis using a sequencing approach. flecting both progression of the disorder and the presence of phenocopies or misdiagnoses. In 5 of the 11 patients, Methods. Fifty patients with STGD or other possible the identification of 2 pathogenic mutations confirmed ABCA4 retinopathies were recruited. All patients (and in- the historical diagnosis and all had chorioretinal atro-

Table. Results From Direct Sequencing of the ABCA4 Gene in 50 Patients

Change 1 Change 2 Grade, Age at Macula Subject Amino Amino Onset, Flecks/ Additional No. Nucleotide Acid Nucleotide Acid Phase Segregation y Phenotype Cones/Rodsa Variants Conclusion 11AϾG M1V 2588GϾC G863A In trans Unaffected 30 STGD mϩ/0/0 R2030Q 3 PVs parents carriers 2 161GϾA C54Y 2588GϾC G863A In trans Affected 12 STGD m/0/0 0 2 PVs sibling with same mutations 3 161GϾA C54Y 5882GϾA G1961E NK NK 18 STGD m/0/0 0 2 PVs 4 634CϾT R212C 4457CϾT P1486L In trans Unaffected 17 STGD m/0/0 0 2 PVs parents carriers 5 2588GϾC G863A 4469GϾA C1490Y NK NK 48 STGD mϩ/0/1 0 2 PVs 6 2971GϾC G991R 4254-2AϾG Splice NK NK 21 STGD m/0/0 0 2 PVs 7 2971GϾC G991R 3602TϾG L1201R NK NK 18 STGD mϩϩ/NP/NP V643M Ͼ2 PVs (likely), G885E (likely), G1441D (unlikely), V2244V (highly likely) 8 3322CϾT R1108C 768GϾT V256V NK NK 13 STGD mϩϩ/1/1 0 2 PVs 9 3322CϾT R1108C 6079CϾT L2027F NK NK 26 STGD mϩ/0/0 0 2 PVs 10 3386GϾT R1129L 4469GϾA C1490Y In trans Unaffected 15 STGD mϩ/0/0 R152Q 2 PVs parents (unlikely) carriers

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