Neurotoxicity Due to Central Nervous System Therapy for Childhood Leukemia

Therapy for occult or overt meningeal leukemia produces subclinical or clinical neurotoxicity in a variable proportion of children with acute lymphoblastic leukemia (ALL). The type, frequency, and permanence of these central nervous system (CNS) changes depend primarily on the therapy itself, although the contribution of additional factors, such as young age, may be substantial. Neurotoxicity in patients who have received 2,400 cGy cranial irradiation plus 5 concurrent doses of intrathecal methotrexate as CNS prophylaxis has been characterized more fully than the CNS changes accompanying other forms of therapy. Cross-sectional studies using cranial computed tomography scans to evaluate structural changes in the brain have shown ventricular dilatation in 15%, white matter hypodensity in 3.5%, and calcifications in 8%. The principal neuroendocrine effect is decreased growth velocity during therapy and adolescence, with significant decreases in final height in approximately one-third of children. Secondary cerebral gliomas with a poor prognosis are being reported with increasing regularity, but the true risk of this complication is still unknown. Use of parenteral methotrexate as the sole method of CNS prophylaxis is associated with transient focal white matter hypodensity. Neuroendocrine and neuropsychologic sequelae associated with this therapy are minimal; however, much of the available information is based on patients treated with regimens that had unacceptably high CNS relapse rates or whose length of follow-up was brief. With more aggressive, and hence more effective, prophylaxis with intrathecal methotrexate, spinal cord myelopathy may become a significant new area of neurotoxicity. Clinically significant CNS toxicity develops in the majority of patients who receive treatment for meningeal relapse. The leukemia itself is a prime contributing factor to this neurotoxicity. In patients who are subsequently cured of leukemia, acute neurotoxicity consists mainly of seizures; the most significant sequelae appearing after the cessation of therapy consists of significant drops in full scale IQ.