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Treatment of AIDS-associated myelopathy with L-methionine

A placebo-controlled study

From the Albert Einstein College of Medicine and Beth Israel Medical Center (Drs. Di Rocco, Werner, and Tagliati, M. Liu and A. Scarano) and Departments of Community Medicine and Statistics (Dr. Godbold) and Neurology (Dr. Simpson), Mount Sinai School of Medicine, New York, NY, and Institute of Metabolic Diseases (Dr. Bottiglieri), Baylor University Medical Center, Dallas, TX.

Address correspondence and reprint requests to Dr. A. Di Rocco, Department of Neurology, Albert Einstein College of Medicine-Beth Israel Medical Center, PACC, 10 Union Square East, 2R, New York, NY 10003; e-mail: adirocco{at}aecom.yu.edu

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.

Received December 31, 2003. Accepted in final form June 3, 2004.

Drs. Di Rocco and Werner ceded their orphan designation rights for L-methionine for the treatment of AIDS-associated myelopathy to Gonopia Biomedical GBH (Saarbrucken, Germany) in return for equities in the company.