Vision recovery in human immunodeficiency virus-infected patients with optic neuropathy treated with highly active antiretroviral therapy: A case series

We describe three patients with bilateral, presumed human immunodeficiency virus (HIV)-induced optic neuropathy. The above diagnosis was made by exclusion of infectious agents and neoplasms by detailed clinical and laboratory investigations. All patients had decreased visual acuity, pale optic discs and constriction of visual fields. Improvement was documented in all three patients for visual acuity and in one patient for visual fields following treatment with highly active antiretroviral therapy (HAART). Optic neuropathy in HIV-positive patients does not necessarily carry a poor prognosis even when a treatable cause is not found. This article emphasizes the effectiveness of HAART in presumed HIV-induced optic neuropathy.

Optic nerve involvement in patients with human immunodeÞ ciency virus (HIV) infection can occur as a result of infections (cryptococcus, syphilis, tuberculosis, toxoplasmosis, herpes group of viruses), neoplasms (lymphoma), toxic eff ects of drugs (dideoxyinosine, ethambutol) or directly by the HIV virus. [1] The diagnosis of primary optic neuropathy probably due to HIV is thus by exclusion. We present three such cases.

Materials and Methods
Three patients with primary optic neuropathy probably due to HIV and a minimum follow-up of six months aft er starting highly active antiretroviral therapy (HAART) were included in this study. All the patients were on a combination of trimethoprim and sulphamethoxazole once daily for Pneumocystis carinii prophylaxis. Best-corrected visual acuity (BCVA), extraocular movements, pupillary, anterior segment, intraocular pressures and dilated fundus examinations were done in all patients. Visual Þ elds were assessed in eyes with good vision on Humphrey visual Þ eld analyzer (Zeiss, Germany).
The following investigations were done in all patients: Complete blood counts, serum electrolytes, blood sugar, blood and urine cultures for bacteria and fungi, ELISA for toxoplasmosis, herpes simplex (HSV)1 and 2, varicella zoster (VZV) and cytomegalovirus (CMV), venereal disease research laboratory test (VDRL) and treponema pallidum hemagglutination test (TPHA) for syphilis, chest X-ray and Mantoux test for tuberculosis. Cerebrospinal ß uid (CSF) was examined for glucose, cells, proteins, bacterial and fungal cultures, ELISA for toxoplasmosis and VDRL for syphilis. CSF smears for acid-fast bacilli (Ziehl Neelsen), Indian ink preparation and culture for Cryptococcus neoformans, latex agglutination test for Cryptococcus antigen were also done. Polymerase chain reaction (PCR) on the CSF for HSV, VZV and CMV were done in two cases. Magnetic resonance imaging (MRI) of the orbit and cranium were done to rule out any intracranial space-occupying lesions. In all three patients, the diagnosis of primary optic neuropathy, probably due to HIV, was by exclusion. Visually evoked potential (VEP) was done in one patient. Mitochondrial mutations associated with Leber's hereditary optic neuropathy were not tested for in our patients.

Case 1
A 30-year-old retrovirus positive male was referred for a bilateral slowly deteriorating vision over a six-month period. His CD4 and absolute lymphocyte counts at the time of referral were 120 cells ×10 6 /L and 2300 cells/mm 3 , respectively. At the time of presentation, he was on a combination of trimethoprim and sulphamethoxazole. BCVA was counting Þ ngers at 1 meter in both eyes. Old visual Þ elds two months prior to his referral showed constriction in both eyes. The optic discs were pale in both eyes [Figs. 1a and b]. There was no relative aff erent pupillary defect. VEP showed decreased amplitude and increased latency in both eyes. At seven months follow-up, following HAART, his BCVA has improved to 20/60 and 20/40 in the right and left eyes respectively. The CD4 count at this follow-up was 210 cells ×10 6 /L.

Case 2
A 13-year-old retrovirus positive girl was referred to us for a routine ophthalmic evaluation. At the time of examination, she was unaware of the poor vision in the left eye. Her BCVA was 20/30 and counting Þ ngers close to the face in the right eye and the left eye, respectively. Relative aff erent pupillary defect was noted in the left eye. CD4 counts were 287 cells ×10 6 /L. Mild optic disc pallor in the right eye and pale optic disc in the left eye was noted [Figs. 2a and b]. Visual Þ elds (HVF 30-2) in the right eye showed gross constriction [ Figures 3a and b]. Aft er starting HAART, her BCVA at 20 months follow-up is 20/20 in the right eye and counting Þ nger at 3 meters in the left eye. Serial visual Þ elds also showed improvement in the right eye [ Figures 4a and b]. The CD4 count at this follow-up was 662 cells ×10 6 /L.

Case 3
A 31-year-old retrovirus positive male complained of decrease in vision in both eyes. His BCVA in both eyes was hand movements close to face. CD4 count was 189 cells ×10 6 /L. Mild optic disc pallor was noted in both eyes. There was no relative aff erent pupillary defect. Visual Þ elds could not be done due to the poor vision. At six months follow-up aft er starting HAART, Indian Journal of Ophthalmology Vol. 57 No. 4 his BCVA is 20/200 in both eyes. The CD4 counts were not available at the last follow-up.

Discussion
Neuro-ophthalmological disturbances have been widely described in both asymptomatic and symptomatic HIV-positive subjects. [2,3] There is suffi cient evidence that optic nerves in HIV-infected patients can undergo chronic degeneration and consequent axonal loss. This could be due to infectious, inß ammatory and compressive causes. [2,4,5] The mechanism by which HIV induces primary optic neuropathy remains to be clariÞ ed. In a study by Sadun et al., [6] patchy axonal degeneration, oligodendrocyte, and myelin degeneration were noted in association with mononuclear cell inÞ ltration, suggesting that optic nerve degeneration may be mediated by HIV-infected macrophages. As the viral particles have never been detected in the optic nerve axons either by electron microscopy or in situ hybridization, the current hypothesis favors an immune-mediated mechanism possibly due to the indirect effect of cytokines released by the virus-infected macrophages, particularly TNF-α which plays a major role in HIV-induced neuronal apoptosis. [6,7] In our series, except the HIV infection, there was no other discernible cause of the optic neuropathy. The improvement seen (vision and in serial visual Þ elds) in our patients with HAART is suggestive that much of the optic nerve failure is due to a reversible dysfunction of the optic neurons rather than their death. HAART probably is eff ective in the initial phases when the axonal degeneration has still not set in. Our series could have been strengthened with electrophysiological studies like patt ern electro retinogram (ERG) in documenting evidence of any subclinical retinal dysfunction. [8] In conclusion, HIV may directly cause an optic neuropathy. Optic neuropathy in HIV-positive patients does not necessarily carry a poor prognosis even when a treatable cause is not found. This article emphasizes the eff ectiveness of HAART in presumed HIV-induced optic neuropathy.   Schwannoma is a benign tumor arising from Schwann cells of peripheral nerves. The tumor is normally solitary, smoothsurfaced, slow-growing and generally asymptomatic. It may develop at any age and there is no gender predilection. Head and neck are one of the most frequent localizations. [1] Ocular tissues are rarely aff ected, occasionally schwannoma arises in the orbit, and infrequently in the uveal tract, [2] conjunctiva, [1] or sclera. [3] To our knowledge, only eight cases of eyelid schwannoma have been published in the literature so far. [4][5][6][7][8][9] We report here two cases of eyelid schwannoma.

Case 1
A 47-year-old man was referred to us with a one-year history of a slowly enlarging, painless nodule on his right lower eyelid. Ocular examination was normal except for the presence of a Þ rm, non-tender nodule measuring 7 × 7 × 6 mm in the medial third of the right lower eyelid. There were no clinical Þ ndings indicative of neuroÞ bromatosis. The patient was operated under local anesthesia; tumor was completely removed via a horizontal eyelid crease incision. The postoperative course was uneventful and the patient was asymptomatic Þ ve years later.
Pathological studies showed an encapsulated spheric mass (6 mm in diameter) on macroscopic examination. Microscopic examination revealed a biphasic patt ern, with highly cellular areas of non-pigmented spindle cells, containing elongated nuclei arranged in fascicles, which were separated by homogenous acellular material (Antoni A patt ern). In other areas, the cells were more oval, and had rounded nuclei, clear cytoplasm and less basement membrane, and were loosely entwined within a clear myxoid matrix (Antoni B patt ern) [ Fig. 1]. No histopathologic features of malignancy were present. Immunochemistry for S-100 protein was strongly positive, but tumor cells did not react with HMB45. The Þ nal diagnosis was benign schwannoma Type A and B of the eyelid.

Case 2
A 20-year-old woman was referred to us for a chalazion of her left lower eyelid, which had been operated three times in four years. No tissues had been submitt ed for histopathological examination in earlier surgical procedures. Ocular examination was normal except for the presence of a Þ rm, non-tender painless nodule measuring 13 × 8 × 8 mm located in the middle of the left lower eyelid, independent of the lid margin [ Fig. 2]. There were no clinical Þ ndings indicative of neuroÞ bromatosis. The lesion was removed under local anesthesia by a full-thickness resection of the lid around the tumor.
On macroscopic examination the nodule was well-circumscribed, non-encapsulated, measuring 10 mm in diameter with yellow appearance on cut sections. Microscopic examination revealed fascicules and bundles of non-pigmented spindle cells with elongated bland nuclei, and abundant extracellular collagen with adipocytes and squamous cells displaying an Antoni A patt ern. There was no mitotic activity. Immunochemistry for S-100 protein was strongly positive, but tumor cells did not react with HMB45 [ Fig. 4]. Final diagnosis was benign schwannoma of the eyelid.

Discussion
Schwannoma (or neurilemmoma) is made up of proliferating Schwann cells of peripheral nerve sheaths. It is a neoplasm which occurs wherever schwann cells are present, that is in any myelinated peripheral nerve. In most cases, while schwannoma is sporadically manifested as a single benign neoplasm, the presence of multiple schwannomas in one patient is usually indicative of neuroÞ bromatosis 2 (NF-2) [Fig. 3]. However, the term schwannomatosis or neurilemmomatosis has been used to describe patients with multiple non-vestibular schwannomas with no other stigmatas of NF-2 or NF-1. [10]