AMINOPHYLLINE FOR METHOTREXATE-INDUCED NEUROTOXICITY

Methotrexate, a mainstay treatment for children with acute lymphoblast ic leukaemia, can cause neurotoxicity, with paralysis, seizures, somno lence, anorexia, and headaches. The pathophysiology of this reaction i s unknown. It has been suggested that the anti-inflammatory effect of methotrexate in patients with arthritis is due to adenosine release br ought on by inhibition of purine synthesis. Since adenosine is a centr al nervous system depressant, we wondered whether adenosine release in the central nervous system could account for some of the neurotoxicit y due to methotrexate, and whether that toxicity could be lessened by displacement of adenosine from its receptor by aminophylline. 6 patien ts (age 3-16 years) who had methotrexate-induced neurotoxicity unrespo nsive to standard treatment received 2.5 mg/kg aminophylline. In addit ion, the concentration of adenosine in the cerebrospinal fluid (CSF) f rom 11 children completing a 24-h systemic methotrexate protocol was c ompared with that in 8 newly diagnosed patients and 12 who had not rec eived any treatment for at least a week. 4 of 6 patients with toxic si gns and symptoms attributed to methotrexate and unrelieved by steroids , epidural blood patch, promethazine, 5-hydroytryptamine antagonists, paracetamol, and narcotics, had complete resolution of neurotoxicity a fter or during a l-h infusion of aminophylline; 2 others had a pronoun ced improvement but persistent nausea. CSF adenosine concentrations of patients receiving methotrexate, even when there was very slight or n o toxicity, were greatly increased compared with control subjects (mea n values of 217 and 51 nmol/L, median 175 and 52 nmol/L). Subacute met hotrexate neurotoxicity may be mediated by adenosine and relieved by a minophylline.