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Arch Ophthalmol. 2002;120:88-90.

Acute retinal necrosis (ARN) is a viral retinitis occurring predominantly in immunocompetent persons. Clinical diagnosis is based on the presence of 1 or more peripheral foci of retinal necrosis that show rapid circumferential progression and often result in early retinal detachment. Characteristically, the active phase is associated with anterior chamber inflammation and vitritis. We report a series of cases in which recurrent anterior uveitis (AU) occurred in the absence of recurrence of posterior segment inflammatory activity or retinitis, after the initial episode of healed ARN. No patient was infected with human immunodeficiency virus. All patients responded to treatment with topical corticosteroids and mydriatics, without recourse to further antiviral treatment; they did not commonly experience a subsequent attack of ARN. To our knowledge, this is the first report of isolated recurrent AU following healed ARN.

Acute retinal necrosis is a fulminant viral retinitis first described in 1971 by Urayama et al¹ in Japan, where it was initially known as Kirisawa uveitis. The American Uveitis Society's diagnostic criteria for ARN include the following: 1 or more foci of retinal necrosis with discrete borders commonly in the peripheral retina that show rapid circumferential progression, dense vitritis, AU, and occlusive vasculitis.² Other features that may be associated but are not required for the diagnosis include optic neuritis or papillitis with subsequent optic atrophy, early retinal detachment, and scleritis.² The usual causative organism is varicella-zoster virus, but herpes simplex virus (HSV) types 1 and 2 and cytomegalovirus have been implicated.³ The diagnosis may be confirmed by the detection of viral DNA by polymerase chain reaction of a vitreous biopsy specimen or by the identification of intraocular antibody.

Acute retinal necrosis may occasionally follow a mild self-limiting course, but in general requires aggressive treatment with high-dosage intravenous acyclovir or famciclovir, which may reduce the incidence of the development of bilateral disease.⁴ High-dosage oral prednisolone may be required, particularly if optic disc swelling is present. To reduce the risk of retinal detachment, prophylactic laser demarcation may be performed around necrotic foci. Despite such treatment, the prognosis for maintaining vision is generally poor. Visual loss results from early retinal detachment, papillitis with secondary optic atrophy, or extensive necrosis involving the macula.

Recurrence of ARN is documented, and second-eye involvement may occur several years later.⁵ However, the recurrence of AU in the absence of active ARN, vitritis, or retinitis has not been reported, to our knowledge.

Report of Cases
A retrospective case-note analysis of patients seen by the Moorfields Eye Hospital's uveitis service, London, England, was undertaken. Between 1992 and 1998, 19 patients with classic appearance of ARN were identified. Ten were women and 9 were men, with a mean age of 44 years (range, 18-79 years). No patients were infected with human immunodeficiency virus. The causative organism was determined in 5 patients by polymerase chain reaction of a vitreous biopsy specimen. Of these, 1 was due to HSV-1; 2, to HSV-2; and 2, to varicella-zoster virus. Four patients had bilateral disease.

Nine patients developed retinal detachment (2 bilateral), and all but 1 underwent retinal reattachment surgery. Six patients had optic disc swelling; 5 of these went on to develop a retinal detachment.

All were treated with a standard regimen of 7 days of intravenous acyclovir (10 mg/kg of body weight 3 times a day) followed by either 800 mg of oral acyclovir 5 times daily or 1 g of oral valcyclovir 3 times daily for 6 to 12 weeks, in conjunction with oral prednisolone at a starting dose of 40 to 80 mg. Patients with severe intraocular inflammation received cyclosporine in addition to corticosteroids. In all cases, the initial inflammatory process resolved within 3 to 6 months of treatment.

Of the 19 patients, 7 developed AU in the absence of vitritis or new foci of retinitis after complete resolution of the initial inflammation. Two patients had a history of herpetic recurrent AU before the development of ARN, but the AU had been dormant for several years. Patient 5 had a history of uveitis as a child between age 5 and 14 years and an isolated episode during pregnancy at age 22. She had not had symptomatic AU for 33 years before the development of ARN. Patient 6 had had recurrent AU following dendritic ulceration between age 1 and 30 years. He had not had symptomatic AU for 13 years before the episode of ARN. Another patient had recurrent AU after ARN associated with recurrent severe scleritis.

One patient developed a second episode of ARN in the same eye after the initial episode had healed and following a subsequent episode of the isolated AU. However, this second episode of ARN occurred 4 months after complete resolution of isolated AU. This was followed by another attack of isolated AU 3 months after the second episode of ARN had completely resolved, lasting 1 month. Five months later, she had another episode of isolated AU in the absence of vitritis or retinitis, but this was accompanied by cystoid macula edema. Following an orbital floor injection of methylprednisolone acetate, the AU and deficiency resolved within 4 months. The cystoid macula edema recurred 1 month later, but with further treatment resolved completely within another 6 months.

The AU seen after resolution of ARN was generally consistent with that seen initially, with similar or less severe inflammation. Five of the 7 patients had nongranulomatous AU in the initial attack and in all episodes of recurrent AU. Two patients with granulomatous AU in the initial attack went on to have nongranulomatous recurrent AU. Only 1 patient had 3+ cells and flare during the initial episode of ARN. The isolated AU that followed was much less severe (1+ cells and 1+ flare). Three patients had 2+ cells and flare during the initial ARN, 1 subsequently developing AU with 2+ cells and 2+ flare but the other 2 having a milder (1+ cells and flare) AU after resolution. The remaining 3 patients had mild (1+ cells and flare) AU associated with the initial ARN and similarly mild (1+ cells and flare) subsequent isolated AU. One patient had fine keratoprecipitate at the time of the ARN but not in subsequent attacks of AU, and another patient developed fine keratoprecipitate with the subsequent AU. With the recurrent AU, one patient developed mild posterior synechiae, but another developed extensive posterior synechiae followed by iris bombé and required laser peripheral iridectomy. The 2 patients with prior herpetic anterior segment involvement had segmental iris atrophy.

All responded to treatment with topical corticosteroids and mydriatics without additional antiviral treatment, and the AU did not herald a further attack of ARN. Only 1 patient with AU after healed ARN had previously had a polymerase chain reaction done on a vitreous biopsy specimen; this yielded HSV-1 DNA. This was a patient with preceding herpetic anterior chamber involvement (patient 6). The characteristics of the ARN are summarized for each patient in Table 1. An outline of the subsequent clinical course and episodes of AU is given in Table 2.

View this table: [in this window] [in a new window] Table 1. Characteristics of Acute Retinal Necrosis (ARN) in Patients Who Subsequently Developed Isolated Anterior Uveitis (AU) After Healed ARN*

View this table: [in this window] [in a new window] Table 2. Characteristics of Anterior Uveitis Occurring After Healed Acute Retinal Necrosis (ARN)

In this study, the occurrence of AU following healed ARN was not related to the severity of the initial episode of ARN. In a multiple logistic regression analysis, severity factors, including duration of ARN, presence or absence of bilateral disease, relapse of ARN, optic disc swelling, and retinal detachment, were studied. The occurrence of AU following healed ARN did not show a statistically significant association with any of these factors, but a larger sample size would be required to evaluate this conclusively.

Comment
In this retrospective clinical study, we found that healed ARN may be followed by recurrent AU in the absence of posterior segment inflammation or a recurrence of ARN. This phenomenon could be either a direct effect of the virus itself, persistent or reactivated, or a secondary immunological effect. In this study, 7 of 19 patients with ARN developed recurrent AU. Only 1 of the 7 developed a second episode of ARN. This observation does not favor a hypothesis of recurrent low-grade herpetic infection or a latent herpetic infection resulting in an intermittent inflammatory response analogous to the recurrence of the common cold sore. Furthermore, in 1 patient, the anterior chamber was tapped at the time of an episode of subsequent AU, and HSV DNA was not detected by polymerase chain reaction. This patient did not have a history of herpetic disease or AU before ARN. Similarly, this would not support recurrent low-grade persistent herpetic infection as a likely cause, but clearly a negative result in 1 case does not conclusively negate the low-grade infection hypothesis in the other patients.

We therefore hypothesize that isolated AU following healed ARN could be a secondary immune event. Similar to the sensitization to retinal S antigen following panretinal photocoagulation, the destruction of retinal tissue may release antigen that may incite the production of antibodies against ocular tissue. Molecular mimicry between T cells specific for the virus could be implicated, cross-reacting with ocular tissue, the molecular structure of which may be native, altered, or rendered manifest by the initial tissue damage. As this phenomenon does not occur in all patients with ARN, there may be a genetic predisposition to the development of recurrent AU following healed ARN.

Two of the 7 patients in this series with recurrent AU had had anterior segment herpetic disease that predated the ARN. As a history of ocular herpetic disease or cold sores is rare in patients with ARN, it is possible that previous herpetic anterior segment involvement, even several years earlier, could predispose patients with ARN to the development of recurrent AU after resolution of the ARN.

Recurrent AU may follow healed ARN without evidence of recurrent herpetic involvement. It is possible that the destructive retinitis results in an autoimmune response, and recurrent anterior chamber immune-mediated inflammation can occur.

AUTHOR INFORMATION

Marie Comer, MRCP, FRCOphth; Stephanie Young, FRACO, FRACS; Susan Lightman, PhD, FRCP, FRCOphth
London, England

Corresponding author: Susan Lightman, PhD, FRCP, FRCOphth, Department of Clinical Ophthalmology, Institute of Ophthalmology, Moorfields Eye Hospital, City Road, London EC1V 2PD, England (e-mail: s.lightman{at}ucl.ac.uk).

REFERENCES
1. Urayama A, Yamada N, Sasaki T, et al. Unilateral acute uveitis with retinal periarteritis and detachment. Jpn J Clin Ophthalmol. 1971;25:607-619. 2. Holland G and the Executive Committee of the American Uveitis Society. Standard diagnostic criteria for the diagnosis of the acute retinal necrosis syndrome. Am J Ophthalmol. 1994;117:663-667. WEB OF SCIENCE | PUBMED 3. Rugger-Brandle E, Roux L, Leuenberger PM, et al. Bilateral ARN: identification of the presumed infectious agent. Ophthalmology. 1984;91:1648-1658. WEB OF SCIENCE | PUBMED 4. Palay DA, Sternberg P Jr, Davis J, et al. Decrease in the risk of bilateral acute retinal necrosis by acyclovir therapy. Am J Ophthalmol. 1991;112:250-255. PUBMED 5. Schlingemann RO, Bruinenberg M, Wertheim-van Dillen P, Feron E. Twenty years' delay of fellow eye involvement in herpes simplex virus type 2–associated bilateral acute retinal necrosis syndrome. Am J Ophthalmol. 1996;122:891-892. PUBMED

SECTION EDITOR: W. RICHARD GREEN, MD

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