LEUKOENCEPHALOPATHY FOLLOWING HIGH-DOSE-IV METHOTREXATE CHEMOTHERAPY WITH LEUCOVORIN RESCUE

Abstract

Seven patients with bone or soft tissue sarcomas but without metastatic CNS disease developed a chronic leukoencephalopathy after high-dose (8000-15,000 mg/m2) i.v. methotrexate (MTX) chemotherapy with leucovorin (LV) rescue. Approximately 12 MTX-LV treatment were administered over a 3-7 mo. period. No patient had cranial irradiation. The syndrome usually began several months after the initiation of chemotherapy with subtle personality changes followed by a progressive dementia, focal seizures, pseudobulbar palsy, spastic quadriparesis and stupor. Computerized tomographic scans revealed diffuse white matter hypodensity in 5 patients and atropic changes in 5 patients. Serum MTX concentrations were elevated in 4 of 6 patients prior to several MTX-LV treatments; apparently MTX persisted in tissues for a long time. Abnormally high levels of MTX were detected in the CSF of all 4 patients several days after an MTX-LV treatment at a time when their encephalopathy was most severe. Pathologic brain material was obtained from 3 patients and revealed a spectrum of abnormalities. The syndrome observed in these patients clinically resembles the one described in children with acute lymphatic leukemia who received cranial irradiation and large cumulative amounts of low-dose (12-20 mg/m2) systemic MTX without LV.