Effects of chemotherapy on the central nervous system. A study of parenteral methotrexate in long-term survivors of leukemia and lymphoma in childhood.

Twenty-three children surviving more than 5 years from the diagnosis of leukemia, lymphoma, or malignant histiocytosis were evaluated for clinical evidence of central nervous system disease. Severe impairment, consisting of seizures, paraplegia, and dementia was present in 4, all of whom received methotrexate (MTX) and other agents for 2 to 7 years. Brain biopsies in 3 of these children showed white-matter gliosis and no evidence of viral or other infections or leukemic infiltrates. Of the remaining children 10/19 were found to have mild clinical or EEG abnormalities. All had received i.v. MTX with other drugs for 2-6 years; 5 did not receive cranial irradiation. Common to all impaired patients was the administration of intravenous methotrexate in relatively high doses over a prolonged period of time. Impairment in nervous system function may present as a spectrum of deficiencies, with the most severe resulting in death, or as in the 4 patients described here, profound dementia and dependence. Less dramatic changes in functioning, may, however, result from various combinations of chemotherapy and radiation therapy. Methods of assessing their etiology and impact on survivors need now to be devised.