Neurotoxicity and Elevated Cerebrospinal-Fluid Methotrexate Concentration in Meningeal Leukemia

Abstract

Cerebrospinal-fluid methotrexate concentration was measured in 25 patients receiving intrathecal therapy for prophylaxis or treatment of meningeal leukemia. In 20 patients with no manifestations of neurotoxicity, the mean antifolate value in the cerebrospinal fluid was 1.7 X 10^–7 M two days after administration of 12 to 15 mg per square meter of intrathecal methotrexate, and declined thereafter with a half-life of 12 to 18 hours. Five patients with severe neurotoxicity had cerebrospinal-fluid methotrexate concentrations averaging 13.8 times higher than the mean, and these concentrations were consistently higher than the range of antifolate values in the asymptomatic patients. One patient with values 20 to 100 times greater than the mean in asymptomatic patients sustained a fatal myelopathy, and in another, with an apparent antifolate half-life of 48 hours, irreversible neurologic sequelae developed. These observations suggest that the neurotoxicity associated with intrathecal methotrexate may be secondary to prolonged exposure to excessive drug concentrations in the central nervous system. (N Engl J Med 289:770–773, 1973)