Leber's hereditary optic neuropathy in the setting of nucleoside analogue toxicity

Mitochondrial toxicity has become an increasingly recognized complication of antiretroviral therapy. We report a case of late-onset Leber's hereditary optic neuropathy (LHON), an inherited form of optic atrophy caused by a mutation of the mitochondrial genome, in a 57-year-old patient with HIV infection. We speculate on the role of antiretroviral therapy in producing disease expression at a late stage. A 57-year-old man was admitted to hospital in February 2000 with sudden painless loss of central vision in his right eye. HIV infection was diagnosed in 1986, and his course was complicated by cerebral toxoplasmosis, drug-induced peripheral neuropathy, and anaemia. Cytomegalovirus (CMV) retinitis, initially diagnosed in 1998, was controlled with valganciclovir. Zidovudine was commenced in 1991 and highly active antiretroviral therapy in 1996. Despite a persistent undetectable plasma viral load for the last 18 months of his life, his CD4 cell count remained below 100/μl. His total exposure to nucleoside analogues was 9 years. In August 1999 he developed neurological symptoms of ataxia, dizziness and left hand weakness, which resolved on cessation of efavirenz. Routine ophthalmology examination 7 days before his presentation in February 2000 revealed no evidence of active CMV retinitis or other abnormality. His visual acuity was 6/5 in the right eye and 6/12 in the left eye. One week later, after complaining of decreased vision in the right eye, he was noted to have optic nerve swelling of the right eye without evidence of active CMV retinitis, a marked reduction in visual acuity (6/60 in the right eye and 6/18 in the left eye), reduction of colour vision, a diffuse loss of sensitivity on visual field testing and a small centrocaecal defect in his right eye, consistent with optic neuritis. Despite numerous investigations, the aetiology of the optic neuritis was not determined. Both computed tomography scan and magnetic resonance imaging (MRI) of the brain demonstrated no evidence of an optic lesion, and lumbar puncture was non-diagnostic. He was treated with intravenous foscarnet and high-dose prednisolone for one month, with no improvement in vision. Two months later he developed identical signs and symptoms in his left eye. A further course of prednisolone was commenced with no effect, and over the next few months he suffered continued deterioration of vision. By September 2000, he had no remaining vision in either eye, and bilateral optic atrophy was present on examination. Despite good HIV control (undetectable viral load), the patient's condition deteriorated. Other neurological symptoms developed in addition to the loss of vision. Peripheral neuropathy had been present for some time, but in addition to this he developed rigidity, particularly of the upper limbs and whole-body tremor. An MRI was remarkable for increased signal in the optic tracts, putamen, cerebellum and medulla, which had developed since the previous MRI in February 2000. Repeat lumbar puncture was again non-diagnostic. The patient was bed bound and palliative care was instituted. He died 2 months later. A diagnosis of LHON was considered after the patient reported that his nephew had also been diagnosed with unilateral optic neuropathy. Genetic testing results became available after his death. The 14484 mutation of LHON was detected. LHON is an inherited form of bilateral optic atrophy, characterized by acute or subacute onset of painless central vision loss caused by degeneration of the retinal ganglion cells and optic nerve axons [1]. There may also be associated neurological abnormalities, including altered reflexes, ataxia and sensory neuropathies [2]. The usual age of onset is between 25 and 35 years, and it is more common in men than women. The primary aetiological event is a mutation of the mitochondrial genome, and one of three primary mutations occurring at base pairs 11778, 3460 or 14484, is present in over 90% of LHON families. A demonstration of one of the mutations is necessary, but not sufficient, for disease expression, and secondary aetiological factors are thought to be necessary for the development of disease [3]. Mitochondrial DNA is vulnerable to exogenously acquired mutations, which can be acquired from toxic agents such as alcohol, tobacco and drugs. Nucleoside reverse transcriptase inhibitors have been confirmed to cause mitochondrial toxicity both in vitro and in vivo[4]. Our patient had evidence of mitochondrial toxicity from his antiretroviral agents, demonstrated by peripheral neuropathy and anaemia, and he had an elevated serum lactate level. We hypothesize that the late onset of his LHON was related to mitochondrial damage caused by his antiretroviral therapy in addition to the primary mitochondrial 14484 mutation. This is the third case report of LHON in a patient with HIV, but the first with associated neurological abnormalities [2,5,6]. It is possible that the reduction in the amount of mtDNA and loss of function of the mitochondria in HIV-infected patients treated with nucleoside reverse transcriptase inhibitors could account for the expression of mtDNA genetic defects that would otherwise be overridden by normal neighbouring mtDNA strands and well-functioning neighbouring mitochondria. It is important to recognize this syndrome, as the potential for reversibility of loss of vision by removal of the nucleoside analogues needs to be tested. Jessica Z. Luzhanskya Anna B. Piercea Jennifer F. Hoya Anthony J. H. Hallab