Elevation of homocysteine and excitatory amino acid neurotransmitters in the CSP of children who receive methotrexate for the treatment of cancer

Purpose: Folate deficiency, either by diet or drug, increases plasma homocysteine (Hcy). Hcy damages cerebrovascular endothelium, and hyperhomocysteinemia is a risk factor for stroke, Hey is metabolized to excitatory amino acid (EAA) neurotransmitters, such as homocysteic acid (HCA) and cysteine sulfinic acid (CSA), which may cause seizures and excitotoxic neuronal death. We postulated that excess Hcy and EAA neurotransmitters may partly mediate methotrexate (MTX)-associated neurotoxicity. Patients and Methods: In this retrospective analysis, we used high-performance liquid chromatography (HPLC) to measure Hey, HCA, and CSA in CSF from two groups of children: (1) a control group of patients with no MTX exposure, and (2) a treatment group of patients who had received MTX no mare than 7 days before a scheduled lumbar puncture. Results: The treatment group had a significantly (P = .0255) greater concentration of Hcy in CSF (0.814 mu mol/L +/-0.215 [mean +/- SEM], n = 23) than the control group (0.210 mu mol/L +/- 0.028, n = 34). HCA and CSA were not detected in CSF from control patients (n = 29); however, MTX caused marked accumulation of CSF HCA (119.1 mu mol/L +/- 32.0, n = 16) and CSA (28.4 mu mol/L +/- 7.7, n = 16) in the treatment group, patients with neurologic toxicity at the time of lumbar puncture had many of the highest concentrations of Hey, HCA, and CSA. Conclusion: These data support our hypothesis that MTX-associated neurotoxicity may be mediated by Hcy and excito-toxic neurotransmitters. (C) 1997 by American Society of Clinical Oncology.