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Show Journal of Neuro- Ophthalmology 21( 2): 92- 94, 2001. © 2001 Lippincott Williams & Wilkins, Inc., Philadelphia Optic Neuropathy in a Patient With AIDS Judith E. A. Warner, MD, and Kristen M. Ries, MD We present a patient with acquired immunodeficiency syndrome ( AIDS) with bilateral sequential optic neuropathies attributed to the 14484 mutation of Leber hereditary optic neuropathy ( LHON). We discuss the potential interaction of the mitochondrial mutation with antiretroviral therapy and review the literature. Key Words: Leber- AIDS- Optic neuropathy. The differential diagnosis of visual loss in a patient with AIDS is broad, spanning from cornea to cortex and encompassing all visual structures between. The medications used in the management of the disorder, both primarily for suppression of the human immunodeficiency virus ( HIV) and secondarily for the management of opportunistic infections, are increasingly effective but have significant toxicities. We present the case of a man with AIDS with bilateral sequential optic neuropathies of an unusual cause. CASE REPORT A 36- year- old truck driver had been human immunodeficiency virus ( HIV) positive since 1991. He declined antiretroviral therapy and further care ( Table 1). In November 1998, he was admitted for progressive lower extremity weakness, back pain, and urinary retention. Acute cytomegalovirus ( CMV) myelopathy was diagnosed by magnetic resonance imaging ( MRI) and a positive CMV polymerase chain reaction ( CMV- PCR) in the cerebrospinal fluid. Results from ophthalmic examination for CMV retinopathy were normal. His viral load had increased, and his CD4 cell count diminished. In follow- up 1 month later, he was recovering well, able to walk with a cane, and was taking intravenous ganciclovir, trimethoprim/ sulfamethoxazole ( TMP/ SMX) Manuscript received January 10, 2001; accepted April 24, 2001. Supported in part by a grant from Research to Prevent Blindness, Inc., New York, New York, to the Department of Ophthalmology and Visual Sciences, University of Utah. From the Department of Ophthalmology and Visual Sciences ( JEAW), Department of Neurology ( JEAW), and Department of Internal Medicine and Division of Infectious Diseases ( KMR), University of Utah Health Sciences Center, Salt Lake City, Utah. Address correspondence and reprint requests to Judith E. A. Warner, MD, Department of Ophthalmology and Visual Sciences, John Moran Eye Center, 50 North Medical Drive, Salt Lake City, UT 84132. double strength, fluconazole, nelfinavir, combined zidovudine/ lamivudine, and efavirenz. In January 1999, without any other symptoms, he failed his driver's license exam because of new visual loss OS. He recalled that it had been blurry for a few weeks. He saw his provider in mid- February, when he was found to be anemic with hematocrit of 16.9%. Zidovudine/ lamivudine was discontinued; he received three units of packed red blood cells; and stavudine and lamivudine were started. In March 1999, he was referred for neuro- ophthalmic evaluation because of new visual loss OD. The left eye had not changed since January. He described his vision as being dim or dark, with color loss. There had been no pain with either eye's involvement. On examination, he was a gaunt ill- appearing man in no distress. His best- corrected visual acuity was 20/ 200 OD and 20/ 400 OS. He saw 2/ 13 Ishihara pseudoisoch-romatic color plates OD and none OS. His pupils were normal, with the exception of a left relative afferent pupillary defect. Visual fields were constricted, with central and nasal defects. External exam was normal, as was slit lamp biomicroscopy. The optic nerves were pallid and atrophic bilaterally, with more pallor OS than OD. There was no evidence of past or present retinopathy. He had smoked one to two packs of cigarettes per day for the past 10 years. He denied recreational drug use or alcohol abuse. His past medical history was notable only for the previously mentioned events, an appendectomy at age 21, and bacterial gastritis at age 24. There was no family history of blindness, although his father was reported to have poor night vision. His antiretroviral medications were stavudine, lamivudine, nelfinavir, and efavirenz, and he remained on intravenous ganciclovir, TMP/ SMX, and fluconazole. An extensive evaluation was undertaken for a compressive or infectious cause of his visual loss, including lumbar puncture. No clear cause was discovered. There was no improvement after a brief course of prednisone. Pulmonary nodules were biopsied and were found to result from Mycobacterium avium intracellulars Two months later, he developed seizures, left hemiparesis, and depressed mental status and was found to have CMV meningoencephalitis. His anti- HIV therapy was unchanged. New CMV retinitis was discovered. His optic nerves were chalky white. Lactate was elevated at 4.5 mmol/ L ( normal: 0.5- 2.2 mmol/ L). He was able to 92 OPTIC NEUROPATHY IN A PATIENT WITH AIDS 93 Date 1996 November 1998 December 1998 February 1999 TABLE 1. Medications, CD4 count, and viral load during course HAART medications 0 0 Zidovudine, lamivudine, nelfinavir, efavirenz Stavudine, lamivudine, nelfinavir, efavirenz CD4+/ CD3+ ( 398- 1535 #/ uL) 330 61 275 136 '. of patients' % CD4+/ CD3- ( 33- 57%) 25 7 19 24 illness 4- ( HIV1 Viral load RNA copies/ mL) 45,000 910 370 HAART, highly active antiretroviral therapy. leave the hospital after a protracted course but died shortly thereafter. An autopsy was not performed. Several weeks after his death, a report of genetic testing revealed a T to C transition at the mitochondrial position 14484, compatible with the diagnosis of Leber hereditary optic neuropathy ( LHON). DISCUSSION The visual loss suffered by our patient was typical for LHON, with painless severe bilateral sequential optic neuropathies occurring without remission. LHON is a maternally inherited optic neuropathy affecting primarily men in the late teens through mid- 20s. It is associated with a variety of mitochondrial mutations, although not all people harboring the mutation will experience visual loss. Environmental factors that stress the body's mitochondrial respiratory capacity may initiate phenotypic expression of the disease ( 1). We propose that his visual loss was caused by LHON precipitated by antiretroviral therapy. Our patient had been HIV positive for many years, and his viral count at the time of the visual loss was relatively improved from months earlier, making it unlikely that his visual loss was a direct result of HIV infection. Although he had previously had CMV myelopathy, he was thought to be in remission, on treatment, at the time of the visual loss. He subsequently developed CMV retinopathy, but this was not present until 3 months after the onset of his optic neuropathies. CMV has been associated with optic neuritis, but typically the patients have not only papillitis but also CMV retinitis ( 2). No other infectious causes of optic neuropathy were discovered. Medication- related toxic neuropathies typically cause simultaneous involvement. Ganciclovir is not believed to be toxic to optic nerves or the central nervous system. TMP/ SMX has not been reported to cause optic neuropathy. This patient was not found to be vitamin deficient and did not have compressive lesions or elevated intracranial pressure. Our patient's visual loss occurred shortly after initiation of highly active antiretroviral therapy ( HAART). The temporal association between the onset of his visual loss and the initiation of HAART suggests causation. Luke's letter to the editor ( 3) reports an HIV- positive man harboring the 11778 Leber mutation with visual loss on long- term zidovudine ( AZT), a nucleoside analogue reverse transcriptase inhibitor ( NRTI). The visual loss occurred 6 months after the addition of indinavir ( protease inhibitor) and nevirapine ( non- NRTI). This report links the occurrence of visual loss to chronic use of zidovudine. There are also several reports of a remitting optic neuropathy thought to be the direct result of HIV infection ( 4- 6). In most of these cases, the patients were not on NRTI therapy. The exception is one of the cases presented by Newman and Lessell ( 6). This man was diagnosed with AIDS and placed on zidovudine 5 months before visual loss. The Leber mutation was not reported in this case, and the patient had substantial recovery of his vision- temporally associated with the initiation of prednisone- arguing against LHON as the cause. There have been numerous reports of the NRTI zidovudine causing mitochondrial toxicity. One study demonstrated that 17% of 41 patients treated chronically with zidovudine therapy had clinical evidence of mitochondrial myopathy ( 7). Zidovudine is thought to cause mitochondrial toxicity in two ways. The first way is via competitive and noncompetitive inhibition of mitochondrial DNA polymerase gamma, causing mutation and depletion of mitochondrial DNA ( mtDNA) and the enzymes it encodes. The second way, a result of the first, is impaired oxidative phosphorylation ( 8). Wang et al. ( 9) described depletion of normal mtDNA, and relative and absolute increase in deleted mtDNA in Kearns- Sayre syndrome fibroblasts cultured in therapeutic levels of zidovudine. Stavudine, or d4T, has been implicated in NRTI- associated lactic acidosis clinically ( 10) and was shown to be a more potent in vitro inhibitor of mtDNA polymerase gamma than zidovudine ( 11). Clinically, it can cause a peripheral axonal neuropathy ( 12). Lamivudine ( another NRTI) is not thought to be toxic to mitochondria ( 13), although it has not been studied for additive effect on mitochondrial toxicity when used in combination with zidovudine, a common application. Our patient's initial visual loss occurred several months after starting the combination drug zido-vudine/ lamivudine. The second eye became involved within weeks after switching to stavudine and lamivudine. All of these medications are NRTIs shown to stress oxidative phosphorylation. Evaluation of visual loss in patients with AIDS is complex, requiring careful investigation of infectious causes. We cannot completely exclude the possibility that our patient's optic neuropathies were caused by CMV or another infection. His CMV was thought to be in remission and other causative infections were not discovered. LHON and HIV are disorders that tend to affect younger men, so they may occur together without requiring a link. We also cannot exclude the possibility that the association of the NRTI use with the visual loss was coincidental rather than causative. The precipitation of J Neuro- Ophthalmol, Vol. 21, No. 2, 2001 94 J. E. A. WARNER AND K. M. RIES the visual loss of LHON by oxidative stress is controversial, and attempts to demonstrate the association have proven ambiguous. A recent large study failed to show an association between LHON onset and use of tobacco or alcohol ( 14). We suggest that our patient lost vision because of the combination of the LHON mutation and HAART therapy with several medications known to have mitochondrial toxicity. One possibility to explain the onset of visual loss is oxidative stress induced by mitochondrial toxicity in a patient with poor reserves caused by mutated mitochondria. Another less likely explanation is an increasing proportion of mutated mitochondrial DNA compared with wild- type DNA, resulting in a threshold effect optic neuropathy. There is no current established management for LHON, but we would suggest that potent combinations of NRTIs be used with caution in patients with family histories suggestive of LHON. For patients on NRTIs experiencing monocular optic neuropathy without a clear cause, cessation of high- intensity therapy may be indicated until LHON is excluded. REFERENCES 1. Newman NJ. Hereditary optic neuropathies. In: Miller NR, Newman NJ, eds. Clinical Neuro- Ophthalmology. 5th ed. Baltimore: Williams & Wilkins, 1998: 753. 2. Mansor AM, Li HK. Cytomegalovirus optic neuritis: characteristics, therapy and survival. Ophthalmologic!! 1995; 209: 260- 6. 3. Luke C, Comely OA, Fricke J, et al. Late onset of Leber's hereditary optic neuropathy in HIV infection [ letter]. Br J Ophthalmol 1999; 83: 204- 5. 4. Goldsmith P, Jones RE, Ozuzu GE, et al. Optic neuropathy as the presenting feature of HIV infection: recovery of vision with highly active antiretroviral therapy [ letter]. Br J Ophthalmol 2000; 84: 551- 3. 5. Burton BJ, Leff AP, Plant GT. Steroid- responsive HIV optic neuropathy. J Neuroophthalmol 1998; 18: 25- 9. 6. Newman NJ, Lessell S. Bilateral optic neuropathies with remission in two HIV- positive men. J Clin Neuroophthalmol 1992; 12: 1- 5. 7. Peters BS, Winter J, Landon DN, et al. Mitochondrial myopathy associated with chronic Zidovudine therapy in AIDS. Q J Med 1993; 86: 5- 15. 8. Brinkman K, Kukuda TN. Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long- term antiretroviral therapy? Curr Opin Infect Dis 2000; 13: 5- 11. 9. Wang H, Lemire BD, Cass CE, et al. Zidovudine and dideoxy-nucleosides deplete wild- type mitochondrial DNA levels and increase deleted mitochondrial DNA levels in cultured Kearns- Sayre syndrome fibroblasts. Biochim Biophys Acta 1996; 1316: 51- 9. 10. Boxwell DE, Styrt BA. Lactic acidosis ( LA) in patients receiving nucleoside reverse transcriptase inhibitors ( NRTIs). Abstracts 39th Annu Intersci Conference Antimicrob Agents Chemother. San Francisco: 1999: 496. 11. Martin JL, Brown CE, Matthews- Davis N, et al. Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994; 38: 2743- 9. 12. Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995; 1: 417- 22. 13. Honkoop P, DeMan RA, Scholte HR, et al. Effect of lamivudine on morphology and function of mitochondria in patients with chronic hepatitis B. Hepatology 1997; 26: 211- 5. 14. Kerrison JB, Miller NR, Hsu F- C, et al. A case- control study of tobacco and alcohol consumption in Leber hereditary optic neuropathy. Am J Ophthalmol 2000; 130: 803- 12. / Neuro- Ophthalmol, Vol. 21, No. 2, 2001 |
