Acute Retinal Necrosis Syndrome in a Child

We recently cared for an 11-year-old child with acute retinal necrosis syndrome, an ophthalmologic condition characterized by the triad of anterior uveitis, occlusive retinal vasculitis and progressive peripheral retinal necrosis. Acute retinal necrosis syndrome occurs primarily in nonimmunocompromised adults as a result of reactivated herpes simplex or varicella-zoster virus infection. Antiviral and antiinflammatory therapy appears to reduce the incidence of vision-threatening retinal necrosis and involvement of the contralateral eye. Acute retinal necrosis syndrome (ARN) is an ophthalmologic condition characterized by a triad of clinical findings including moderate to severe anterior uveitis and vitritis, severe occlusive vasculitis of the arteries of the retina and progressive peripheral retinal necrosis. 1–4 The usual age of patients with ARN is 20 to 60 years; children have only rarely been reported to have ARN. 5, 6 In addition although ARN is well-described in the ophthalmologic literature, there are very few descriptions reported in the pediatric or internal medicine literature. We recently cared for a child with ARN and describe his case along with a brief review of the current literature 1–29 to familiarize pediatricians with this uncommon but serious illness. Case report. An 11-year-old boy complained of right eye pain on movement and blurred vision for 6 days before admission. He noted progressive decrease in visual acuity and color distinction. Three days before admission the eye became red, irritated, swollen and more painful, but without associated photophobia or excessive tearing. The boy denied joint pain or swelling, fever, rash or trauma to the eye. His past medical history was significant only for chickenpox at age 3 years. On admission the child had visual acuity of 20/30 in the left eye and 20/100 in the right eye. Right anterior uveitis was also detected, along with “mutton-fat granulomatous” keratitic precipitates on the inferior cornea and 4+ cells and 3+ flare in the anterior chamber. In addition there was hemorrhagic necrosis of the right retina involving the inferior and superior nasal quadrants in the far periphery, vasculitis of the superior temporal vascular arcade and a pale, swollen optic nerve. Cerebrospinal fluid (CSF) obtained by lumbar puncture showed lymphocytic pleocytosis (24 white blood cells/μl, differential count of 94% lymphocytes and 6% monocytes). The CSF protein and glucose values were normal (59 and 20 mg/dl, respectively), and bacterial, viral and fungal cultures were sterile. Cranial magnetic resonance imaging scan showed borderline abnormally high T2 weighted signal intensity of the right optic nerve. After ARN syndrome was diagnosed, treatment was begun with antiinflammatory, antiviral and anticoagulant medication (methylprednisolone 1 g/day iv in two divided doses for 3 days, prednisone 1% ophthalmic drops every 2 h, acyclovir 1500 mg/m 2 /day iv in three divided doses for 10 days and aspirin 325 mg every day). The child’s symptoms and ocular findings improved rapidly with treatment. Serial ophthalmologic examinations showed decreasing cells and keratitic precipitates in the anterior chamber and minimal temporal extension of the hemorrhagic necrosis. Visual acuity improved to 20/50, and eye movement became painless. The left eye remained unaffected throughout the hospital course. Subsequent laboratory findings included negative blood PCR amplification and IgG antibody tests for cytomegalovirus and negative serum antibody titers for Leptospira, Toxocara, Histoplasma, Toxoplasma, Bartonella, syphilis and Lyme disease. Serum IgG antibodies to herpes simplex (HSV) and varicella-zoster (VZV) viruses were present; PCR assays on the CSF for both viruses were negative. The child was discharged to receive oral acyclovir (800 mg every 6 h) for 3 months. He developed a right retinal detachment ∼6 weeks after hospitalization and underwent laser therapy demarcation of the retina. After 30 months of follow-up, the left eye had remained disease-free, and his right eye visual acuity was stable at 20/100. Discussion. History of ARN. The acute retinal necrosis syndrome was first described in the Japanese medical literature by Urayama et al. 7 in 1971, who used the term Kirisawa’s uveitis for 6 patients who had panuveitis, retinal arteritis progressing to peripheral retinal necrosis and retinal detachment. Within a decade six cases of similar findings but occurring in both eyes simultaneously were described in the US 8 and in the United Kingdom. 9 An entity related to ARN termed progressive outer retinal necrosis or rapidly progressive herpetic retinal necrosis occurs in HIV-infected patients. 2, 3, 10–12 However, ARN itself most often occurs in immunocompetent hosts. Clinical findings. Scattered case reports of children with ARN have been published, 6, 17–19 but the majority of patients (>80%) have had disease onset at >20 years old, with a mean age of onset of ARN of ∼40 years. 5, 23, 24, 27 Patients with typical ARN often have a prodrome of low grade fever, headaches and neck stiffness. 2–4, 13, 14 Conjunctival injection with a ciliary flush is seen in association with moderately painful eye movements. Visual acuity may be diminished, with complaints of hazy vision and floaters. Ophthalmoscopic examination of the anterior chamber reveals mild to moderate cellular reaction with fine or large “mutton-fat granulomatous” keratitic precipitates. Uveitis and later vitritis can be severe enough to obstruct examination of the posterior pole. The anterior uveitis progresses to panuveitis within several days to 1 to 2 weeks, with retinal necrosis beginning as small patches of retinal whitening termed “thumbprinting.” In two-thirds of cases within 5 days the necrosis coalesces and progresses to involve a 360-degree area. 2 In most cases the necrosis remains peripheral, sparing the macula (and thus central vision). Vasoocclusive retinal and choroid vasculitis is associated with the retinal necrosis. Optic nerve atrophy or inflammation is characteristic of ARN, but its presence is not required to satisfy diagnostic criteria. 1 Other than reports of lymphocytic CSF pleocytosis, routine laboratory findings are nonspecific. 2–4, 13, 14 The most serious complication of ARN syndrome is not the initial uveitis or the vasculitis, but rather the development of full thickness necrotic retinal holes that appear during the recovery phase of the illness. These retinal holes, along with increasing vitreal fibrous traction on the retina, lead to rhegmatogenous retinal detachment that has been reported to occur in 25 to 75% of cases, at a mean time of 65 days after onset. 2, 3, 13, 15 The contralateral eye is affected in ∼33% of cases (range, 20 to 70%), usually within the first 4 to 6 weeks of the onset of disease in the original eye. 2, 3 Scattered case reports have noted disease onset in the contralateral eye up to 20 to 30 years later. 16, 17 Etiology. ARN appears to be a reactivated herpes virus infection, occurring years after the primary infection (either chickenpox or herpes simplex mucocutaneous disease). 2–5, 18, 27 Rarely ARN occurs as a primary viral necrotizing retinitis, most commonly associated with chickenpox. 2, 4, 19 In 1982 Culbertson et al. 20 first described eosinophilic intranuclear inclusions consistent with herpesvirus infection in the retinal pigment epithelium and vascular endothelium by electron microscopy from an enucleated eye of a patient with ARN. Subsequently histopathologic, immunocytochemical and light and electron microscopic findings indicative of herpesvirus infection were detected in the enucleated eyes from another patient with ARN. 21 A number of other investigators have since demonstrated the intraocular presence of HSV-1, HSV-2, or VZV in patients with ARN by various means, including intraocular antibody synthesis, in situ antigen detection and viral culture of vitreal and retinal tissue, in situ hybridization of viral DNA and PCR amplification of viral DNA sequences from eye tissue. 2–5, 18, 22, 27 Recently intraocular T lymphocytes of patients with HSV-1-associated ARN were shown to be reactive to HSV-1 tegument proteins. 28, 29 VZV and HSV-1 appear to occur predominantly in patients >25 years of age, whereas HSV-2 is found in those <25 years of age. 5, 27 Treatment. Because it appears that VZV, HSV-1 and HSV-2 are the etiologic agents of ARN, most ophthalmologists recommend initial treatment with parenteral acyclovir. However, no prospective, randomized, double blind, placebo-controlled trial data exist to confirm the efficacy, length of treatment or dose of acyclovir required. The current recommendation (based on the two studies discussed below) is to give 1500 mg/m 2 /day iv in three divided doses for 10 days as early in the disease course as possible, followed by oral acyclovir (800 mg five times a day for an adult) for 3 months. 2, 3, 14, 23–25 Use of this sequential intravenous/oral regimen by Blumenkranz et al. 23 in an open trial of 12 patients with clinically diagnosed ARN resulted in regression of retinal lesions in a mean of 3.9 days after starting therapy, with complete regression of active disease noted at 32.5 days. No significant progression of retinal lesions was detected after 48 h of iv therapy, and no contralateral eye was affected after a mean follow-up of 14.5 months. The authors concluded that recovery was more rapid in treated patients than that of untreated historical patients. 23 In a retrospective survey of 54 patients with unilateral ARN, Palay et al. 24 demonstrated a 2-fold decrease of disease onset in the contralateral eye from 75% to 35% in those given sequential intravenous and oral acyclovir. However, in neither study did the use of acyclovir affect the amount of vitritis or the frequency of retinal detachment. 2, 23 It would be useful to study acyclovir therapy in a prospective, randomized controlled trial, but the severity and low incidence of the disease, combined with the need for long term follow-up, may prohibit performance of such a study. Antithrombotic therapy (e.g. heparin or aspirin) has been suggested as an adjunctive treatment for the ophthalmic vasculitis of ARN, because platelet hyperaggregation has been reported. 2, 3, 26 Systemic glucocorticosteroids also have been reported to decrease vitritis and severe intraocular inflammation, but firm data are not available to prove their efficacy against retinal necrosis and detachment. 2, 24 Surgical therapy of ARN may include prophylactic laser photocoagulation to prevent rhegmatogenous retinal detachment, but data proving efficacy are limited. 2, 24 Once detachment occurs, scleral buckling, vitrectomy with laser photocoagulation or vitreal gas or oil tamponade may be useful. 2, 10, 24 Prognosis. The long term visual prognosis of ARN varies widely. Several reports have indicated that ∼33% of patients are left with 20/200 vision or worse. 13, 23 Even with successful retinal reattachment, only five of nine eyes in one series had visual acuity of 20/200 or better, with the other four eyes having at best a visual acuity of 20/400. 15 On occasion, if the retina remains attached visual acuity of 20/50 or better has been reported. 13 Unlike other types of uveitis, chronic inflammation or episodic bouts do not occur with ARN. 14