Abstracts

Rationale: In the 1970s and 80s, standard treatment for childhood acute lymphocytic leukemia included both intrathecal methotrexate and whole-brain irradiation. During acute treatment, seizures were not uncommon. The development of intractable epilepsy years after treatment, however, has not been described in the literature.Methods: We reviewed the records of five patients who were treated for acute lymphocytic leukemia as children who later developed intractable epilepsy. Charts were reviewed to determine the age at diagnosis and treatment of leukemia, type of leukemia, intravenous and intrathecal chemotherapeutic agents received, dose of cranial irradiation received, age at seizure onset, results of electroencephalogram (EEG), brain CT or MRI, seizure type(s) and frequency, anti-epileptic medications used, neuropsychological testing results, other medical and developmental history, and current level of functioning.Results: All of the patients were diagnosed with leukemia before age 7; none of the patients had central nervous system disease. They were treated with both whole-brain irradiation and intrathecal chemotherapy; all received intrathecal methotrexate, and two patients received intrathecal cytosine arabinoside as well. All of the patients developed epilepsy one to twelve years after leukemia treatment ceased. The patients have many different seizure types, and have been tried on multiple antiepileptic drugs. In four out of the five patients, EEGs showed temporal epileptiform discharges. Three patients had areas of high T2 signal in the white matter on brain MRI. All five patients have moderate to severe cognitive impairment.Conclusions: Successful treatment for childhood leukemia may be followed by signs of cerebral injury including intractable epilepsy. We propose that neurotoxicity resulting from exposure to intrathecal methotrexate and cranial irradiation may have contributed to the intractable epilepsy seen in our five patients. Methotrexate causes neurotoxicity by several mechanisms, including homocysteine-induced vascular endothelial injury and buildup of sulfur-containing amino acids. Cranial irradiation damages neurons in the hippocampus, where neurogenesis continues throughout life. The damage caused by these anti-leukemic treatments likely played a role in the development of intractable epilepsy in our patients.