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Show " 19Y2 Raven Press, Ltd, New York Bilateral Optic Neuropathies with Remission in Two HIV- Positive Men Nancy J. Newman, M. D. and Simmons Lessell, M. D. Two patients seropositive for the human immunodeficiency virus ( HIV) developed bilateral optic neuropathies. Evaluations failed to identify an infectious or neoplastic etiology. Both patients improved. one in temporal relatil1n to treatment with azidothymidine ( AZT). the other during oral steroid therapy. Optic neuropathY in HIV- positive patients does not necessarily carry a poor prognosis even when a treatable cause is not found. A role for primarv HIV infection in the pathogenesis remains speculative. Key Words: AIDs- HlV- Optic neuropathy. From the Departments of Ophthalmologv and Neurologv. Emory University School of Medicine ( N. j. N.). Atlanta, Georgia. and the Department of Ophthalmology. Harvard MedlCal School and the Massachusetts Eye and Ear Infirmary ( S L.). Boston. Massachusetts. U. S. A Address correspondence and reprint requests to Dr. Nancy j, Newman. Neuro- OphthaImology Unit. Emory Eve Center, 1327 Clifton Road. N. E. Atlanta. GA 30322. U. SA This study was supported in part by a departmental grant from Research to Prevent Blindness. Inc ( Dr. Newman). Optic nerve disease in patients infected with the human immunodeficiency virus ( HIV) may occur secondary to opportunistic infections or neoplasms ( 1- 15). We report on two HIV- positive men with bilateral retrobulbar optic neuropathies that subsequently improved and in whom no specific infectious or neoplastic etiology other than the HIV virus was implicated. CASE STUDIES Case 1 A 39- year- old homosexual man was referred because of bilateral visual loss, His medical history was notable for a psychiatric disorder characterized by auditory hallucinations for which he received thiothixene hydrochloride and nortriptyline hydrochloride. Eighteen months before presentation he was discovered to be HIV- positive. He smoked one pack of cigarettes per day. There was no personal or family history of ophthalmic or neurologic disease. Ten days before referral. he awoke with bilaterally blurred vision and slight retrobulbar pain aggravated by eye movement. His vision gradually failed, and he was evaluated at a local hospital. Acuity was then best correctible to 20/ 30 bilaterally. and ophthalmoscopic examination was normal. General physical examination, complete blood count, urinalysis, serological test for syphilis, and head computerized tomographic ( CT) scan were normal. Cerebrospinal tluid ( CSF) analysis revealed 17 white blood cells/ mm3 and 120 mg of protein/ lOO cc. Within 1 week, vision deteriorated to 20/ 400 00 and finger counting OS. On neuroophthalmic examination, his acuity was 5/ 200 00 and hand motions perception OS; and he was unable to identify colors with either eye, Goldmann perimetry revealed only an island of residual visual field to the V4e stimulus below N. ,. NEWMAN AND S. LESSELL fixation 00. A leit relative afferent pupil defect was evident. The rest of his eye, general physical, and neurological examinations revealed no abnormalities. His hematocrit was 34.5, and the total WBC was 4,900 with a normal differential. Cerebrospinal tluid contained 24 white blood cells and six red blood cells/ mm~. The white cells were plasmacytoid with surface markers characteristic of a reactive pleocytosis. The protein content was 115 mg' 7(. Cryptococcal antigen was negative, and cultures for bacteria, mycobacteria, and fungi grew no organisms. Blood and CSF VORL and FTA- Abs tests were negative. Serum vitamin 812 level was normal. No abnormalities were seen on a magnetic resonance image ( MRI) scan of the head with gadolinium injection, but both optic nerves appeared thickened on a CT scan. Mitochondrial analysis of his blood failed to reveal the 11,778 point mutation associated with Leber's hereditary optic neuropathy. He received oral prednisone 60 mglday for 1 week followed by rapid tapering without noticeable benefit. Similarly, 2 weeks of intravenous penicillin did not appear to help. Azidothymidine ( AZT) was begun 4 weeks after the onset of symptoms at a dose of 100 mg x 5/ day. Within 10 days, he noticed some improvement in his vision, and acuity was measured as 3/ 200 00 and 21100 as. Slight optic disc pallor was apparent for the first time. Eight weeks after the onset of symptoms, visual acuity was 5/ 70 00 and 5/ 40 as. Four months after the onset of symptoms, his vision had improved to 13/ 200 00 and 20170 as. Visual fields showed bilateral relative central scotomas, and ophthalmoscopy revealed pronounced optic atrophy. Eight months after onset, visual acuity stabilized at 20170 00 and 20/ 40 as. Case 2 A 27- year- old homosexual man was referred because of bilateral visual loss. Five months earlier, he complained of generalized fatigue followed by left leg weakness and numbness. He was discovered to be HIV- positive, and an HIV- associated myelopathy was diagnosed. An MRI of the cervical spinal cord was normal. CSF analysis revealed a protein of 68 mg%, glucose of 48 mg' 7c and 29- 50 white cells ( 97- 99% lymphocytes). Cryptococcal antigen and cultures for bacterial, mycobacterial, and fungal organisms were negative. CSF and serum VORL and FTA- Abs were nonreactive, but CSF and serum antibodies to HIV and cytomegalovirus ( CMV) were present. He was begun on AZT. The patient did not use cigarettes, alcohol, or recreational drugs. There was no personal or family history of ophthalmologic or neurologic disease. Four months before referral, the patient's vision 00 suddenly decreased, and there was eye pain aggravated by eye movement. No funduscopic abnormalities were noted; acute retrobulbar optic neuritis was diagnosed. The vision remained poor, but stable, in the right eye. An MRI of the brain was normal except for one small bright lesion without mass effect adjacent to one of the lateral ventricles. Approximately 3 months later, the patient noted blurring of vision as, also with accompanying mild discomfort on eye movement. Repeat CSF analysis revealed a protein of 81 mg%, glucose of 47 mg( 7c, and 15 white cells. IgG was elevated, and the VORL, cryptococcal antigen, and cultures were negative. The patient's vision progressively deteriorated over the next month, and intravenous gancyciovir was begun as empirical therapy for CMV. The patient was referred for neuroophthalmic examination 4 months after the onset of visual loss 00, 1 month after onset of symptoms in as. Visual acuity was hand motions perception superonasally 00 and 20/ 200 as. Colors were grossly identified as. Goldmann visual fields demonstrated a temporal island of vision to the V4e stimulus 00 and an inferior defect with central involvement as. There was a right relative afferent pupil defect. Slit lamp biomicroscopy was normal. Ophthalmoscopic examination revealed temporal pallor of the right disc and possibly early pallor of the left disc. The patient was continued on AZT and intravenous gancyclovir and also received a 2- week course of intravenous penicillin. Vision continued to slowly deteriorate as. One month after referral, 60 mg oral prednisone was started. Although the patient had noted some improvement in the vision 00 before the initiation of steroids, he reported definite improvement in vision 00 3 days after the prednisone was begun. This improvement continued, plateaued with an attempt to taper the steroids, and resumed when the prednisone dose was increased. An examination 3 weeks after the prednisone was begun showed acuities of 10/ 200 00 and 41200 OS. Goldmann visual fields demonstrated a relative central scotoma 00 and a dense central scotoma to the V4e stimulus OS. There was now a left relative afferent pupil defect, and both optic discs were pale. Over the next month, vision gradually improved to 20/ 30 OD and 20/ 40 OS. Steroids and gancyclovir were discontinued, and AZT was maintained. There was no change in his vision over the next 4 months. HIV OPTIC NEUROPATHIES 3 DISCUSSION HIV- associated optic nerve disease may occur secondary to compressive, infiltrative, infectious, inflammatory, or vascular etiologies ( 1- 16). Although neoplasms occur with great frequency in HIV- positive patients, compressive and infiltrative lesions of the optic nerve are relatively rare ( 1722). Lymphoma is found infrequently in the orbit; but intracranial lymphoma, toxoplasmosis, or eosinophilic granuloma can cause anterior visual pathway dysfunction ( 19- 21,23). Opportunistic infections underlie the majority of optic neuropathies associated with HIV. Syphilitic infection can result in unilateral or bilateral retrobulbar optic neuropathies, papillitis, or optic perineuritis ( 1,2,4- 6). Standard clinical or laboratory evidence of treponemal infection may be absent or altered by concurrent HIV infection ( 24- 26). This phenomenon has prompted many authorities to recommend, on an empirical basis, penicillin trials at neurosyphilis doses in patients with optic neuropathies of unclear origin ( 1,24,27). Similarly, the natural history and response to treatment of syphilitic optic neuropathy may be altered by HIV infection ( 1,24,26). Cryptococcal meningitis can result in optic neuropathies, presumably on the basis of perineuritic adhesive arachnoiditis ( 7). Although the cytomegalovirus has been isolated in optic nerve tissue ( 9) and implicated in profound visual loss most consistent with optic neuropathy ( 8), concurrent CMV retinitis or papillitis is the rule ( 8,9). Toxoplasma gondii, although a common cause of intracranial infiltrative disease in patients with AIDS, rarely involves ocular structures ( 10,20). As is the case with CMV, when toxoplasma optic nerve infiltration occurs, simultaneous retinochoroiditis is prominent. Herpes zoster has been implicated in at least three cases of optic neuropathy with papillitis, only one responsive to acyclovir ( 1,11,12). Hepatitis B may similarly result in papillitis ( 13). Although progressive multifocal leukoencephalopathy ( PML) is a common cause of cerebral white matter lesions in AIDS patients, involvement of the prechiasmal visual pathways by the JC papova virus has yet to be described. Primary HIV infection has been postulated as the underlying mechanism in one case of presumed anterior ischemic optic neuropathy ( 16) and in a case of optic neuritis that did improve ( 14), but it is likely that the latter case represented reactivation of neurosyphilis with papillitis. In our patients, neuro- imaging excluded compressive etiologies. The absence of disc edema and associated retinochoroiditis made infectious causes such as CMV and toxoplasma unlikely. The isolated involvement of the optic nerves and the eventual recovery of vision argued against PML, although there is at least one report of spontaneous improvement in AIDS patients with biopsyproven PML ( 28). Cryptococcal meningitis may rarely be antigen negative ( 29). However, the lack of other systemic and neurologic symptoms and signs, and the recovery of vision without specific antifungal treatment in our patients made this an unlikely diagnosis. Syphilis must be considered in any retrobulbar optic neuropathy, especially in patients infected with the AIDS virus. Our patients had both cerebrospinal fluid pleocytosis and elevated protein, nonspecific findings that are not inconsistent with neurosyphilis. There were no other neurologic or systemic findings suggestive of treponemal infection, and repeated serum and CSF analysis failed to provide laboratory confirmation of this diagnosis. It must be emphasized that HIV- positive patients may have nonreactive serum and CSF VDRLs ( 24- 26). Both of our patients received treatment for neuro- syphilis with intravenous penicillin ( an empirically based decision). In neither patient was recovery coincident with antibiotic treatment. HIV has been directly implicated in the pathogenesis of neurologic and ophthalmologic disease ( 30- 36). This neurotropic virus is capable of establishing latency in the nervous system early in its course ( 30,33,36,37). HIV has been isolated, and immunocytochemical and in situ hybridization studies have demonstrated the presence of viral antigens and nucleic acids in neural and ocular tissues from patients with AIDS ( 33,35,36,38- 40). Cerebrallesions are found predominantly in the subcortical white matter ( 31). Proposed mechanisms of HIV- mediated disease include direct viral infection, HIV- mediated vasculitis, postviral- mediated immune attack on neural components, or autoimmune destruction of neural or vascular structures secondary to abnormal immunoregulation caused by the primary HIV infection ( 41). Primary HIV infection has been implicated in the pathogenesis of the AIDS dementia complex, vacuolar myelopathy, peripheral neuropathies, and cranial neuropathies ( 30,31,41- 43). These manifestations may coincide with HIV seroconversion, may be the only clinical indication of chronic HIV infection, or may be part of the full clinical picture of AIDS ( 30,41). Isolated facial paralysis, for example, is frequently associated with HIV seroconversion and usually improves spontaneously ( 42,43). An acute demyelinating polyradiculopathy similar to Guillain- Barre and a more JClin Neuro- ophthalmol. Vol. 12. No. L 1992 4 N. f. NEWMAN AND S. LESSELL chronic demyelinating polyneuropathy have been linked to primary HIV infection ( 41,42). They may be responsive to steroids, plasmaphoresis, or AZT ( 41,42,44). Of course, it is possible that our patients' bilateral optic neuropathies were entirely unrelated to HIV infection. Patients in this age group may suffer idiopathic acute or subacute optic neuropathies, occasionally bilateral. The typical course is that of progressive loss of central vision over days with eye pain, and spontaneous improvement after weeks or a few months, not the prolonged progression and recovery demonstrated by our patients. However, series of patients with idiopathic bilateral optic neuropathies and prolonged progressive deterioration, some of whom also eventually recovered their vision, have been described ( 45,46). Multiple sclerosis- like illnesses have been reported in HIV- positive patients, and in several cases, an etiologic association was postulated ( 47,48). Three of the patients described by Berger et al. ( 47) had HIV seropositivity demonstrated within 3 months of the onset of their neurologic disease, and all three had optic neuritis as part of their clinical picture. Improvement in vision was the rule in all cases, in two without medical treatment, in one after steroid therapy. Our second patient had a myelopathy followed by sequential bilateral optic neuropathies and a single small white matter lesion on MRI. His optic neuropathies were atypical for optic neuritis, but clinically, his findings are not inconsistent with the diagnosis of multiple sclerosis. Although the patient was on several medications, his symptomatic recovery was most closely related temporally to steroid therapy. In contrast, our first patient had no other neurologic symptoms or signs, a normal MRI, and no improvement in vision related to a prednisone trial. His visual recovery was most temporally related to treatment with AZT. 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