Elevation of homocysteine and excitatory amino acid neurotransmitters in the CSF of children who receive methotrexate for the treatment of cancer.
OBJECTIVE
Folate deficiency, either by diet or drug, increases plasma homocysteine (Hcy). Hcy damages cerebrovascular endothelium, and hyperhomocysteinemia is a risk factor for stroke. Hcy 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.


METHODS
In this retrospective analysis, we used high-performance liquid chromatography (HPLC) to measure Hcy, 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 more 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 micromol/L +/- 0.215 [mean +/- SEM], n = 23) than the control group (0.210 micromol/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 micromol/L +/- 32.0, n = 16) and CSA (28.4 micromol/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 Hcy, HCA, and CSA.


CONCLUSIONS
These data support our hypothesis that MTX-associated neurotoxicity may be mediated by Hcy and excitotoxic neurotransmitters.
Quinn
C T
CT
Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas 75235-9063, USA.
Griener
J C
JC
Bottiglieri
T
T
Hyland
K
K
Farrow
A
A
Kamen
B A
BA
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D002490:Central Nervous System / Q000187:drug effects; D002648:Child; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000031:analogs & derivatives / Q000134:cerebrospinal fluid; D018846:Excitatory Amino Acids / Q000134:cerebrospinal fluid*; D006710:Homocysteine / Q000031:analogs & derivatives / Q000134:cerebrospinal fluid*; D006801:Humans; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D009369:Neoplasms / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D018377:Neurotransmitter Agents; D012189:Retrospective Studies
D000964:Antimetabolites, Antineoplastic; D018846:Excitatory Amino Acids; D018377:Neurotransmitter Agents; D006710:Homocysteine; C007956:homocysteic acid; D003545:Cysteine; C013461:cysteine sulfinic acid; D008727:Methotrexate