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PROGRESSIVE OUTER RETINAL NECROSIS CAUSED BY VARICELLA-ZOSTER VIRUS IN CHILDREN WITH ACQUIRED IMMUNODEFICIENCY SYNDROME

2003; Lippincott Williams & Wilkins; Volume: 22; Issue: 4 Linguagem: Inglês

10.1097/01.inf.0000059962.59114.3a

1532-0987

Kenneth Purdy, John R. Heckenlively, Joseph A. Church, Margaret Keller,

Retinal and Optic Conditions

We report three HIV-infected children with bilateral progressive outer retinal necrosis caused by varicella-zoster virus. All three lost vision in both eyes. Aggressive treatment strategies with combination intravenous antiviral therapy in addition to intravitreal antiviral therapy and appropriate surgical management may prevent blindness. Rapid recognition of this distinct clinical syndrome is essential to improve visual outcome. Ocular manifestations of AIDS are rare and generally occur in persons with severely impaired cell-mediated immunity. Cytomegalovirus (CMV) retinitis is the most common ocular complication in all age groups. During the past decade an unusual retinopathy caused by varicella-zoster virus (VZV) or, much less commonly, to herpes simplex viruses (HSV), has been reported in adults with AIDS. 1–8 This syndrome, progressive outer retinal necrosis, has also been observed in persons with low numbers of functioning T lymphocytes because of hematologic malignancy, autoimmune disease and chronic immunosuppressive medications. 9–13 Although progressive outer retinal necrosis has been described in an adolescent boy with acute myelogenous leukemia and graft-vs.-host disease after hematopoietic stem cell transplantation, 9 no series of progressive outer retinal necrosis cases has been reported among children with HIV disease. We present three children with AIDS who developed this devastating opportunistic infection. Case 1. A 7-year-old Colombian girl was hospitalized in December 1999 because of deterioration of her vision. Her past medical history was significant for Williams syndrome and secondary supravalvular aortic insufficiency. She underwent corrective cardiac surgery at age 2 years in Colombia, at which time she received blood transfusions. Seven months before admission she developed varicella that resolved during 2 weeks. Five months before hospitalization she complained of difficulty seeing with the left eye. Three weeks before admission she began to lose vision in the right eye and to stumble frequently. Her parents brought her to the United States for medical care. She was seen at another institution where she was initially thought to have AIDS and CMV retinitis. Obliterative vasculitis was noted, and granulomatous retinal disease was also considered. At Harbor-UCLA Medical Center 3 days later, intravenous ganciclovir therapy was started. An ophthalmologic evaluation revealed that light perception was absent in the left eye and diminished in the right eye despite a right visual acuity of 20/200. The right retina had an exudative detachment that spared the macula. Obliterative chorioretinitis, vascular tortuosity and patchy areas of pale white retina were present. No anterior chamber or vitreous body inflammatory cells were observed. The left retina was detached. Intravenous acyclovir was added to ganciclovir on the third hospital day when the diagnosis of retinal necrosis caused by VZV or HSV was considered. By the fourth hospital day the right retina had detached further. Progressive outer retinal necrosis was suspected. Ganciclovir was discontinued, and intravenous foscarnet was added to the intravenous acyclovir. She was transferred to another hospital for specialized vitreous surgery, where she underwent a partial right retinectomy, pars plana vitrectomy with silicone oil, laser photocoagulation of the superior retinal quadrants to prevent further detachment and placement of a right intravitreous ganciclovir implant. An HIV enzyme-linked immunosorbent assay was positive, the CD4+ T cell count was 52 cells/mm3 and the plasma HIV-1 RNA viral load was 205 000 copies/ml. Plasma CMV DNA PCR and CMV-specific IgM and IgG antibodies were negative. HSV antibodies were negative, but the VZV IgG was elevated. Highly active antiretroviral therapy (HAART) was administered, and intravenous acyclovir and foscarnet were continued for 6 weeks. Daily maintenance foscarnet was continued for 1 year. Intravenous antiviral medications were stopped and oral acyclovir started after the CD4 count had exceeded 200 cells/mm3 for several months, and the patient had developed lymphocyte proliferation to VZV antigen. Currently the patient perceives light from the left eye and remains blind in the right eye. She has not had symptomatic VZV reactivation for more than 3 years. Her most recent plasma HIV RNA viral load was <50 copies/ml. Case 2. A 13-year-old girl with perinatally acquired HIV was hospitalized in October 2000 because of a 3-day history of rapidly deteriorating left visual acuity. Two months before admission HAART had been discontinued because of poor compliance. She continued to take prophylactic trimethoprim-sulfamethoxazole and azithromycin. She had no history of varicella or zoster. On the day of admission, the patient went to an optometrist because of rapidly dimming vision. Retinal examination revealed multiple retinal opacifications in the left eye with poor light perception and acuity, but no abnormal findings in the right eye, which had 20/20 acuity. She had not experienced tearing, scleral redness, eye pain, rash, vomiting or other symptoms. She was referred to Children's Hospital Los Angeles for further management. The initial ophthalmologic evaluation revealed peripheral detachment of the left retina with minimal light perception and acuity limited to hand movements. The right visual acuity was 20/70, and the optic disc was mildly edematous, but no retinopathy was observed. Neither uveitis nor vitreitis was noted. Oral candidiasis was observed, but there were no other significant findings. The admission CD4 count was 65 cells/mm3, and the plasma HIV RNA viral load was 116 000 copies/ml. She was diagnosed with CMV retinitis, and ganciclovir was administered. The following day a retinal detachment was noted in the periphery of the right eye. By the fourth hospital day, the right retinal opacifications extended to become confluent, the right visual acuity worsened to 20/100 and she could not perceive light from the left eye. High dose intravenous foscarnet was added, and HAART was reinitiated. An intravitreal ganciclovir implant was placed in the right eye on Hospital Day 5. The retinopathy ceased to advance after the third postoperative day. The right aqueous humor was positive for VZV by PCR amplification of specific viral DNA sequences. Ganciclovir was discontinued, and acyclovir was added to the foscarnet. Despite several months of therapy with foscarnet and acyclovir and the gradual reconstitution of her cellular immunity, she remained functionally blind in both eyes. Subsequently her viral load decreased to <50 copies RNA/ml and she remains adherent to her HAART regimen. She has not had symptomatic VZV reactivation. Case 3. A 15-year-old girl with transfusion-associated AIDS was hospitalized at Children's Hospital Los Angeles in September 1996 because of rapidly decreasing vision in the left eye. She developed progressive varicella at age 11 years and responded to therapy with acyclovir and foscarnet. During the next 4 years, she developed multiple episodes of zoster and received intravenous acyclovir and foscarnet treatment during each episode. At age 13 years a central venous catheter was placed to provide daily intravenous acyclovir prophylaxis. She continued to have recurrences of zoster. Culture of the zoster lesions revealed a strain of VZV possessing a thymidine kinase mutation that confers high level resistance to acyclovir. Acyclovir was discontinued, and ganciclovir and foscarnet were infused daily through the central venous catheter. On the day of admission, she developed new zoster lesions and rapidly dimming vision in her left eye. She denied blurring, tearing, eye pain, visual changes in the right eye, fever and other symptoms. On admission acuity was 20/25 in the left eye and 20/20 in the right. At initial ophthalmologic evaluation the left retina had multiple punctate outer retinal opacities and two small retinal tears. There was no involvement of the left macula or optic nerve head. No uveitis, vitreitis or other eye findings were observed. The CD4 count at the time of admission was 7 cells/mm3, and the HIV RNA viral load was 330 000 copies/ml. HAART and foscarnet were administered, but the left retinal lesions became confluent within 2 days. Similar lesions appeared in the right retina and progressed similarly. During the next 16 months, vision in both eyes deteriorated to bare light perception. She developed chronic neutropenia and died with invasive pulmonary aspergillosis at 16 years of age. Discussion. Reported ocular manifestations of VZV in AIDS patients include zoster ophthalmicus, acute retinal necrosis (ARN), retrobulbar optic neuritis, stromal keratitis, chronic infectious pseudodendritic keratitis, uveitis and progressive outer retinal necrosis. 3, 14, 15 Progressive outer retinal necrosis was first identified during the late 1980s in adults with AIDS and was first reported in the literature in 1990. 2 To date nearly all reported cases have been adult AIDS patients. Progressive outer retinal necrosis may involve any part of the retina at presentation (including the macula), induces little or no anterior chamber or vitreal inflammation, rarely causes pain or scleritis, is rarely associated with occlusive vasculopathy and progresses rapidly, leading to detachment of one or both retinas. 1–5 Patients often complain of dimming of vision or constriction of visual fields. 1 In contrast ARN, a retinopathy caused by the same herpesviruses (most commonly HSV), affects both immunocompetent and immunocompromised persons, including children 16, 17; is associated with a necrotizing vasoocclusive retinitis, arteritis and vitreitis; initially tends to involve only the peripheral retina; and is less frequently bilateral at presentation. Retinal detachment is also common with ARN. In contrast to progressive outer retinal necrosis lesions, CMV retinopathy lesions generally have irregular, dry, granular borders and tend not to be as multifocal, although several CMV lesions may coexist in one eye. 1 In the largest published series of AIDS patients with progressive outer retinal necrosis (38 individuals ages 6 to 58 years; median age, 37 years), 22 of 33 patients (67%) capable of providing a medical history reported antecedent zoster. Nine of these 22 (41%) had herpes zoster ophthalmicus. 4 Among 15 patients in whom the date of onset of zoster was documented, zoster preceded progressive outer retinal necrosis by a median of 2 months (range, 2 months to 2 years). The median CD4 count at presentation was 21/mm3 (range, 0 to 130/mm3). The most common initial symptom of progressive outer retinal necrosis was unilaterally decreased central vision. Eye lesions were characterized by multifocal opacification of the deep retinal layers at onset and rapid progression to blindness. Retinal and vitreous biopsies were performed on 11 eyes of patients undergoing surgery for retinal detachment. One eye was positive for VZV by culture and direct fluorescent antibody staining; two others were positive by PCR amplification of VZV-specific DNA from the aqueous humor. HSV-1 and HSV-2 were not detected by culture, direct fluorescent antibody staining or PCR. Intravenous acyclovir, ≥10 mg/kg every 8 h, was administered to 22 patients (58%) for a median of 14 days. Of these patients 8 patients experienced progression, 9 patients experienced slowing of disease and 4 patients experienced quiescence. Although unilateral involvement occurred in 28 (74%) patients at presentation, 6 (16%) developed bilateral retinal involvement within 1 month after presentation and 27 (71%) had bilateral eye disease at the last follow-up visit (median time after presentation, 12 weeks). Retinal detachments occurred in 43 of 61 evaluated eyes (70%), including 13 of 14 that received prophylactic laser photocoagulation, suggesting that laser treatment is seldom effective in preventing detachments in necrotizing retina. Second eye involvement occurred in 10 of 15 patients with initial unilateral eye involvement who received oral acyclovir secondary prophylaxis (800 mg orally 5 times per day). Most patients experienced complete visual loss. Despite the dismal outcome of these early cases, recent case reports suggest that combination antiviral therapy directed toward causative viruses, surgery or both may limit the progression of progressive outer retinal necrosis and improve long term acuity. Acyclovir plus foscarnet, ganciclovir plus foscarnet, intravitreal ganciclovir combined with intravenous acyclovir or foscarnet, and intravitreal ganciclovir combined with foscarnet and prophylactic laser photocoagulation may halt disease progression and preserve vision. 18–21 More recently a patient with progressive outer retinal necrosis was successfully treated with three doses of intravitreal foscarnet, intravenous acyclovir and an intravitreal ganciclovir implant. 22 Intravenous cidofovir has also been used successfully to treat recurrent progressive outer retinal necrosis in an adult AIDS patient who received oral famciclovir prophylaxis after disseminated VZV infection. 23 The use of prophylactic laser photocoagulation to prevent retinal detachment in this situation is controversial and has been associated with an increased frequency of retinal detachment. 4 Low numbers of patients, differences in treatment duration and doses, differences in underlying immunosuppression and other factors hinder interpretation of data from these case reports, but combination antiviral therapy and the use of intravitreal ganciclovir may be more effective than systemic monotherapy.