Clinical and electrophysiological characteristics of methotrexate encephalopathy in paediatric practice

Abstract

Methotrexate-induced subacute encephalopathy is one of the side effects of the aforementioned drug. The effect is characterized by certain neurological symptoms, presence of leukoencephalopathy on a magnetic resonance imaging (MRI) and slow-wave activity shown on an electroencephalogram (EEG). The aim of this work is to determine the clinical and electrophysiological characteristics of methotrexate-induced encephalopathy in paediatric patients with various types of cancer, as well as to compare the obtained data with researches and precedents presented in medical literature. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. A retrospective analysis of treatment results was performed on 31 patients aged 1.5-17 who had subacute methotrexate-induced encephalopathy. Most patients (n = 26) have been diagnosed with acute lymphoblastic leukemia (ALL). According to the theurapeutic protocols, the patients received intravenous, intrathecal and intraventricular methotrexate treatment. The severity of methotrexate-induced encephalopathy was determined according to the NCI-CTCAE scale (version 4.0). All the patients underwent the EEG study. MRI was performed on 26 patients. Methotrexate-induced encephalopathy developed after 2-12 (on average 5.3 ± 3.1) days after methotrexate administration. Encephalopathy of grade I occurred in 35.45% of cases, of grade II - in 19.6%, of grade III and IV - in 25.8 and 19.4% of cases. 5 patients had symptoms recurred after therapy continuation. The most frequent neurological symptoms were: pathological level of sleepiness (50.1%), impaired consciousness (32.3%), cognitive impairment (25.8%), epileptic seizures (19.6%) and ataxia (19.6%). Regression of neurological symptoms occurred in 26 patients after 1-10 (on average 3.3 ± 2.2) days, 5 patients had persistent neurological deficit. The EEG pattern was represented by diffuse theta-wave activity (39%), theta-delta activity (42%), delta activity (6.5%), beta activity (3.0%), a decrease of alpha rhythm amplitude (6.5%), where no changes occurred for only 1 patient. Pathologic changes were seen on MRI in 84.6% of cases. The interdependence between the EEG changes, the time of debut and resolution of encephalopathy has been established. However, there has been no connection found between the severity of encephalopathy, the EEG pattern, the way of methotrexate administration, the age of the patients, the clearance of methotrexate and previous neurological disoders. The data obtained on the clinical picture and the time frame of methotrexate-induced encephalopathy initiation were similar to foreign ones. In different cases of patients with methotrexate-induced encephalopathy, EEG is not always represented as diffuse slow-wave theta-activity. The patients are recommended to undergo initial EEG in order for the electrophysiological studies on methotrexate encephalopathy to be assessed correctly. Further studies of the risk factors of methotrexate-induced encephalopathy are required.