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Treatment of AIDS-associated myelopathy with l-methionine

Background: The histopathology of AIDS-associated myelopathy (AM) closely resembles that of myelopathies due to cobalamin or folate deficiency, with white matter vacuolization in the spinal cord. The pathogenesis of AM appears unrelated to direct HIV infection of the spinal cord. There is abnormal trans-methylation metabolism in AM, with decreased availability of the methyl group donor S-adenosyl-methionine (SAM). The authors hypothesized that treatment with l-methionine, the direct metabolic precursor of SAM, might improve AM. Objective: To determine the safety and efficacy of l-methionine treatment in AM. Methods: Fifty-six patients with clinical diagnosis of AM were randomized to a Phase II, double-blind, placebo-controlled study comparing the effect of l-methionine 6 g/day in two divided doses with that of placebo. Study duration was 12 weeks. All patients had somatosensory evoked potentials with prolonged central conduction time (CCT) at entry. Change in CCT was the primary endpoint of the study. Frequency of adverse events (AEs) was used to assess safety. Secondary endpoints were strength, spasticity, and urinary function. Biochemical measurements included serum methionine and homocysteine and CSF SAM. Results: There were no significant differences in AEs between the two groups. Serum homocysteine increased in l-methionine-treated patients from 7.2 (±5.2 SD) to 12.6 (±6.15 SD) μmol/L. The mean CCT at baseline was 25.9 milliseconds (±7.3 SD) for the treatment group and 24.1 milliseconds (±7.0 SD) for the placebo group. At completion, it was 3.0 milliseconds (±6.1 SD) for the treatment group and 23.6 milliseconds (±5.5 SD) for the placebo group (p = 0.17). In a subset of 15 patients with CSF studies, SAM levels increased in the l-methionine but not in the placebo group (p = 0.07). There was no significant effect of treatment on strength, spasticity, or urinary function. Conclusions: l-Methionine was safe and well tolerated although in some patients induced an increase of serum homocysteine. There was a nonsignificant improvement in CCT in treated patients but no benefit in any of the clinical measures.