Methotrexate encephalopathy. A neuropathologic study

The present report is a neuropathologic study of three patients who died from a severe form of necrotizing encephalopathy following intrathecal methotrexate therapy and craniospinal irradiation for acute lymphoblastic leukemia. During the early phase the lesion presented as multifocal coalescing areas of coagulation necrosis in the deep white matter. In the diseased areas the myelin was lost and the axons were severely swollen and fragmented. During the late stage the white matter was reduced to a thin gliotic calcified layer. The pathogenesis of this lesion is unclear, but the preferential involvement of the white matter with sparing of the cortical gray matter and basal ganglia makes it unlikely that direct chemical injury is the cause. The distribution of the lesion suggests a vascular disturbance due to endothelial injury caused by interaction of the methotrexate with tissue infiltrated by leukemic cells and altered by irradiation.