@article{fd9ee7d32698426284bbb13baf44c14d,
title = "SEIZURES IN CHILDHOOD LYMPHOBLASTIC LEUKAEMIA PATIENTS",
abstract = "Features of seizures in children with acute lymphoblastic leukaemia were examined in relation to the type of treatment received for central nervous system prophylaxis. Of the 1289 patients in the study, 132(10%) had experienced one or more seizures. In 96 the seizures had not been associated with any recognisable aetiology and, with 3 exceptions, had been generalised or focal motor in type. Status epilepticus had occurred in one-third of the group with seizures. Initial seizure rates among patients in continuous complete remission were significantly related to the method of central nervous system prophylaxis. Those who had received intrathecal methotrexate repeatedly with or without moderate doses of methotrexate intravenously or prior prophylactic cranial irradiation had a 20-fold higher seizure risk during remission induction, and a 37-fold higher risk during the 6th to 12th month of therapy, than did those who had received irradiation and only five intrathecal injections of methotrexate early in the course of treatment. Other clinical factors associated with an increased frequency of seizures were escalation of intravenous methotrexate dosage following cranial irradiation and treatment of meningeal leukaemia with intrathecal methotrexate. Parenterally administered methotrexate thus seems to increase susceptibility to seizure development in childhood leukaemia patients.",
author = "Ochs, {Judith J.} and Pui, {Ching Hong} and Clara Mason and Bowman, {W. Paul} and Minnie Abromowitch and Simone, {Joseph V.}",
note = "Funding Information: Most seizures had occurred a week after intrathecal administration of MTX both in patients in continuous complete remission and in those with meningeal leukaemia, making it unlikely that the seizures were a direct toxic effect of the drug. Current theories of seizure induction include defects in the y-aminobutyric acid (GABA) inhibitory system.19 Because MTX interferes with dihydrofolate reductase and the reduction oftetrahydrobiopterin,2O it may limit the brain{\textquoteright}s supply of GABA and thus increase susceptibility to seizures. Cranial irradiation perhaps breaks down the blood-brain barrier and so permits greater penetration of MTX into brain parenchyma.21,22 A prolonged rise in brain MTX levels has been shown in patients with meningeal leukaemia,23 and this may partly explain the high frequency of seizures in patients with this complication. For children with seizures who require intrathecal therapy for meningeal leukaemia, our policy now is to continue giving IT MTX if seizures do not recur, are not temporally associated with intrathecal administration of MTX, or are not unusually severe. Otherwise, we substitute intrathecal cytarabine with or without hydrocortisone. If a child with meningeal leukaemia is given drugs intrathecally, prophylactic use of anticonvulsants may be advisable. Also because of its neurotoxicity and lack of significant therapeutic efficacy after prophylactic cranial irradiation,24 we now exclude IT MTX from maintenance regimens for patients in continuous complete remission who have had cranial irradiation. The development of a seizure disorder after therapy for leukaemia warrants careful and extended follow- up, since 2 of 5 such patients were eventually found to have biopsy-confirmed intracranial neoplasms, despite having had normal CT brain scans at the time of seizure onset. The long-term clinical significance of seizures in leukaemia patients is not known. With newer approaches to CNS prophylaxis that rely on more intensive or prolonged intrathecal therapy, the frequency, temporal pattern, and severity of seizures may change. Unfortunately, existing methods for assessing the CNS do not enable us to predict which patients with newly diagnosed ALL will have a seizure. However, since children with MTX-associated seizures are probably also prone to other forms of neurotoxicity, they should undergo regular assessments of the CNS, including neuropsychological examinations. We thank Dr R. A. Price for his encouragement, Mr John Gilbert for editorial help, Michael Hancock for biostatistical assistance, and Ms Peggy Vandiveer for typing the manuscript. This work was supported by Cancer Center Support Grant CA 21765 and Leukaemia Program Project Grant CA 20180 from the National Cancer Institute, US Public Health Service, and by the American Lebanese Syrian Associated Charities (ALSAC). Correspondence should be addressed to J. 0., St Jude Children{\textquoteright}s Research Hospital, 332 North Lauderdale, PO Box 318, Memphis, Tennessee 38101, USA.",
year = "1984",
month = dec,
day = "29",
doi = "10.1016/S0140-6736(84)91621-0",
language = "English",
volume = "324",
pages = "1422--1424",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Ltd",
number = "8417-8418",
}