Neurotoxicity due to CNS therapy for leukemia

CNS symptoms ranging from mild to lethal have occurred following CNS radiotherapy and intrathecal chemotherapy. Cranial radiotherapy often produces signs of mild encephalopathy, with predominance of somnolence. In rare cases, it appears that CNS radiotherapy may be followed by progressive encephalopathy. Intrathecal methotrexate frequently causes symptoms of meningeal irritation. Occasionally cases of weakness and paralysis, and rare instances of severe encephalopathy, may occur. However, in leukemic children treated with intensive chemotherapy and CNS radiotherapy who develop neurological complications, it is often difficult to determine which of many possible factors may be causing the CNS symptoms. The pathogenesis of the various forms of methotrexate neurotoxicity is poorly understood. The best-established cause for these symptoms is high concentrations of methotrexate in the CSF or porlonged exposure of the brain to low CSF concentrations of methotrexate. These elevated concentrations of the drug may in turn be due to impaired elimination of the drug from the cerebrospinal fluid (usually due to overt CNS leukemia) or to increased dosage in relation to cerebrospinal fluid volume (due to adolescent age). Leukoencephalopathy is occasionally found at autopsy in children given intensive therapy with CNS radiotherapy and intrathecal methotrexate, together with intensive systemic chemotherapy. It was proposed that alteration of the blood-brain barrier by cranial radiotherapy allows systemically administered anti-leukemic drugs to enter the brain and to cause necrotic changes in the CNS white matter. Leukoencephalopathy also occurs following intraventricular administration of methotrexate. CNS-toxicity due to intrathecal cytosine arabinoside is clinically similar to the symptoms seen following intrathecal methotrexate.