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CLINICAL SCIENCE: CONCISE COMMUNICATION

Aseptic meningitis and optic neuritis preceding varicella-zoster progressive outer retinal necrosis in a patient with AIDS

Franco-Paredes, Carlos; Bellehemeur, Thomasa; Merchant, Alia; Sanghi, Pramoda; DiazGranados, Carlos; Rimland, David

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Abstract

Introduction

Varicella-Zoster Virus infection (VZV) can occur at any stage of HIV infection. Dermatomal herpes zoster is often the first manifestation of AIDS. Moreover, due to VZV neurotrophism, a wide spectrum of neurological complications of herpes zoster infection has been described in HIV-infected individuals. These manifestations include granulomatous angiitis of the central nervous system, ascending polyradiculopathy, myelitis, encephalitis, peripheral motor neuropathies and retinal necrosis syndrome [1].

In addition, VZV has been shown to cause necrotizing retinitis and this has been proven by corioretinal biopsy cultures, immunohistochemistry and by VZV PCR of aqueous humor [2–5].

Optic neuritis in HIV-infected patients has been commonly associated to neurosyphilis [6], cryptococcal meningitis [7], toxoplamosis [8] and, the HIV- associated optic neuritis [9]. Recently, VZV has also been recognized as an important cause of optic neuritis in this group of patients. The diagnosis of VZV optic neuritis is usually made by a well-defined temporal association between dermatomal or disseminated herpes zoster infection and visual loss. Cases of VZV optic neuropathy have been difficult to diagnose because of the scarcity of pathologic specimens available in these cases [9]. Culberstson et al. did not find evidence of direct viral invasion of the optic nerve in three enucleated eyes from immunocompetent patients with acute retinal necrosis associated with VZV [10].

Shayegani et al. in 1996 [11] described the first case of a unique presentation of VZV disease in a patient with AIDS in which bilateral VZV optic neuritis preceded typical VZV retinitis. Friedlander subsequently reported three more patients [9] with VZV-related optic neuropathy, one of whom had a similar presentation of retrobulbar optic neuropathy followed by retinitis. Lee et al. described two more cases of this entity [12] and Meenken et al. [13] described one more case with the same clinical presentation.

Herein we report the case of an HIV-infected individual who presented with VZV meningitis and retrobulbar optic neuritis preceding the onset of progressive outer retinal necrosis, in which this latter complication was precipitated by the use of intravenous steroids. We also review the literature of seven additional reported cases of retrobulbar optic neuritis preceding VZV retinitis.

Case report

A 34-year old Caucasian male with AIDS presented to the hospital with 1-week history of headaches, nausea and vomiting, fever up to 39 °C and neck stiffness. He also reported blurred vision on the left eye for the same amount of time. His past medical history was significant for HIV/AIDS diagnosed in 1993: his CD4 cell count was 66 × 106/l and his viral load was 110 203 RNA copies/ml 7 months before admission. He had received multiple antiretroviral regimens, the last combination consisting of zidovudine, lamivudine, and efavirenz were discontinued 12 months prior to admission due to elevation of liver enzyme levels. Toxoplasma IgG and Rapid plasma reagin test had been negative on multiple occasions. He also had a diagnosis of chronic hepatitis C, manifested as moderately elevated liver enzyme levels, a negative first- and second-generation HCV antibody test but positive qualitative HCV RNA by PCR. Trimethoprim–sulfamethoxazole was the only medication he was reportedly receiving. His physical examination at the time of admission revealed a temperature of 38.8 °C, and a pulse of 80 b.p.m. He was jaundiced and had neck stiffness. Eye examination revealed a normal retina. His abdominal examination was remarkable for a liver palpable 2 cm below the costal margin. Laboratory evaluation showed a whole blood count of 870/l, hematocrit of 29.3% and platelets of 26 × 103/l. He had a sodium level of 128 mEq/l and a creatinine of 0.7 mg/dl. Liver tests were significant for aspartate aminotransferase of 361 IU/l, alanine aminotransferase of 190 IU/l, alkaline phosphatase of 275 IU/l and total bilirrubin of 10.3 mg/dl. Analysis of cerebrospinal fluid (CSF) showed a whole blood count of 110 × 103 cells/l, red blood cells of 225 × 103 cells/l and a differential of 100% lymphocytes. The patient's CSF glucose level was 111 mg/dl and the protein level was 280 mg/dl. CSF Gram stain and culture were negative. Cryptococcal antigen in serum and CSF were both negative. Serum rapid plasma reagin and fluorescent treponemal antibody, and CSF venereal disease reference laboratory tests were also negative. CSF Herpes Simplex Virus (HSV) PCR and CSF Cytomegalovirus (CMV) PCR were also negative. The presence of VZV was confirmed by a positive cerebrospinal fluid VZV DNA PCR.

Despite negative serologic tests for syphilis, the presence of lymphocytic meningitis and, retrobulbar optic neuritis prompted empirical therapy for neurosyphilis with intravenous penicillin. Direct ophthalmologic examination showed a normal retina on admission but the ophthalmology service thought that his exam was consistent with retrobulbar optic neuritis. A magnetic resonance imaging of the head and orbits was unrevealing.

The patient's headaches improved by day 5, but vision in his left eye became progressively worse to only light perception. On day 11 the ophthalmology service recommended intravenous steroids for the treatment of possible HIV optic neuropathy. Two days after the administration of steroids, his visual loss became more severe and at this point his retinal exam showed signs of progressive outer retinal necrosis. Intravenous foscarnet was started together with intraocular ganciclovir. One day after antiviral therapy was initiated the patient developed a vesicular rash compatible with either varicella or disseminated zoster. Despite antiviral treatment he had minimal recovery of his vision loss 3 months after treatment.

Discussion

The natural history of herpes zoster in HIV-seropositive individuals resembles that seen in immunocompetent individuals, although a few important differences have been noted. HIV-seropositive patients may have a higher risk of zoster involving cranial dermatomes [14] and a higher risk of multidermatomal zoster [15]. HIV-infected individuals also have a higher risk of recurrent episodes of HZ [16,17].

The increased frequency of the VZV central nervous system complications is associated with herpes zoster involving cranial dermatomes, but it can occur with other dermatomal areas, disseminated zoster or without cutaneous manifestations [1,18].

In HIV-infected individuals, VZV retintitis may occur in one of two clinical syndromes [19]. The first is acute retinal necrosis, which also may be seen in immunologically normal hosts. Acute retinal necrosis can occur at any stage of HIV infection and is characterized by prominent anterior chamber reaction, marked vitritis, occlusive retinal and choroidal vasculitis, and a full-thickness retinal necrosis. Typically, the lesions begin peripherally and extend circumferentially. Retinal detachment occurs in two-thirds of patients [19–22]. Affected patients may have a history of cutaneous herpes zoster occurring either simultaneously with the retinitis or preceding it [19–22].

The second clinical syndrome occurs in patients with low CD4 cell counts, typically < 50 × 106/l and is termed progressive outer retinal necrosis. This variant is characterized by multifocal retinal opacification that progresses rapidly and is associated with little or no ocular inflammation. Approximately two-thirds of patients will develop bilateral disease and pathology often begins in the posterior pole. Intravenous foscarnet and intraocular ganciclovir are most commonly prescribed for therapy; other reports suggest that the combination of both acyclovir and foscarnet along with intraocular therapy is associated with a better outcome. Visual outcome is extremely poor, with most reported cases to date resulting in long-term decreased visual loss. In addition, involvement of the other eye, even with antiviral therapy, is > 70%, and retinal detachment is frequent [19,23].

In the wide spectrum of neurological complications of dermatomal zoster infection in HIV-infected individuals, optic neuritis has been described in some patients concomitantly or preceding the development of VZV retinitis [9,12,13,23] (Table 1). As some cases of VZV retinitis developed after VZV encephalitis, it is tempting to speculate that the invasion of the retina in this subset of patients could arise from the optic nerve [24]. Some of these cases also have reported the occurrence of aseptic meningitis preceding the onset of retinal necrosis. In our patient the temporal association of VZV meningitis and optic neuritis with subsequent development of progressive outer retinal necrosis suggest a common pathogenic mechanism. The preceding use of steroids before the onset of progressive outer retinal necrosis was reported in three of the seven patients reported in the literature [9,11,12], therefore it is possible that steroid use in our patient contributed to the onset of retinitis.

T1-11
Table 1:
Characterisitics of eigth patients with Varicella-Zoster Virus (VZV) retrobulbar optic neuritis preceding retinitis in patients with AIDS.

A history of dermatomal herpes zoster was reported in only five out of eight patients (62.5%). One had Ramsay Hunt syndrome, one had simultaneous trigeminal ophthalmic branch zoster, and three patients had thoracic herpes zoster. Only the report by Lee et al. mentioned the association of lymphocytic meningitis in two patients preceding the occurrence of retinitis, similar to our patient. Most reports suggest that the combination of intravenous ganciclovir with or without acyclovir and intraocular therapy is the treatment of choice for this entity. Unfortunately four out of the eight reported patients (50%) developed permanent visual loss with retinal detachment. Our patient had minimal improvement in his visual acuity despite intravenous foscarnet and intraocular ganciclovir therapy.

In summary, in patients with HIV/AIDS who developed acute visual loss, VZV optic neuritis should be considered in the differential diagnosis, particularly in those patients with a history of recent cutaneous herpes zoster. In addition, optic neuritis in these patients may be the harbinger of fulminant VZV retinal necrosis, which may be delayed or aborted in some cases with early combination antiviral therapy. This case also points out the possible role of steroids as a contributor to the onset of progressive outer retinal necrosis in patients with VZV CNS involvement and the importance of early diagnosis and aggressive combination therapy via systemic and intravitreous routes in order to preserve vision.

Acknowledgments

Sponsorship: Supported in part by a NIH/AIDS International Training and Research Program of Emory University (D43 TW01042-01) (to C.F.-P.)

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Keywords:

Varicella-Zoster Virus; retinitis; progressive outer retinal necrosis; optic neuritis

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