Pharmacokinetics and biochemical effects of a fatal intrathecal methotrexate overdose.

A nine-year-old boy with non-Hodgkin's lymphoma inadvertantly received 54 times the standard dose of intrathecal methotrexate (650 mg vs 12 mg). He sustained an immediate and subsequently fatal necrotizing leukoencephalopathy despite an early cerebrospinal fluid (CSF) exchange, intravenous leucovorin and dexamethasone, and supportive care. Following the CSF exchange which removed 78% of the administered dose of methotrexate, the CSF and serum methotrexate levels were 50-100-fold higher than seen following standard therapy. A slightly prolonged CSF methotrexate half-life suggested a decreased rate of clearance of methotrexate from the CSF, either due to saturation or destruction of the transport mechanisms. CSF levels of myelin basic protein and serum levels of lactic dehydrogenase, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, and uric acid were all markedly increased, suggesting both white and grey matter necrosis.