Transient encephalopathy following high-dose methotrexate treatment in childhood acute lymphoblastic leukemia

Abstract

The purpose of this study was to determine the incidence of and pharmacokinetic parameters associated with the development of transient encephalopathy following the administration of high-dose methotrexate and intrathecal chemotherapy in children with acute lymphoblastic leukemia (ALL). Two hundred and fifty-nine children with newly diagnosed ALL treated on one of two consecutive trials were analyzed. Presenting features in patients who developed transient encephalopathy were compared with those of patients who did not experience this event. For each patient who developed transient encephalopathy, methotrexate pharmacokinetic parameters were compared with those of matched controls. The cumulative incidence of acute encephalopathy was 3% (SE 1%) at 1 year and was associated with age greater than or equal to 10 years at diagnosis. Pharmacokinetic data did not differ between patients who developed transient encephalopathy and those who did not. The majority of patients had no long-term sequelae and were able to receive further courses of methotrexate without modification. Transient focal neurologic deficits occur in about 3% of children with ALL following the administration of intravenous and intrathecal methotrexate. These events cannot be predicted by pharmacokinetic parameters of methotrexate disposition. However, these events are generally benign, suggesting that patients who experience acute encephalopathy should continue to receive this important chemotherapeutic agent.

Methotrexate Induced Acute Encephalopathy-Occurrence on Re-challenge and Response to Aminophylline

“…Encephalopathy can occur with intrathecal as well as intravenous methotrexate [1,4,6]. The exact pathogenesis is unclear-making it difficult to predict its occurrence in a given patient.…”

“…MTX, age [ 10 years etc. have been implicated [1,8]. Prior episodes probably constitute a risk, although safety of rechallenge has also been described [4][5][6].…”

“…Mostly manifesting as a mild and transient neurological dysfunction, rarely it can be severe and lifethreatening [4,5]. Similarly, majority of the patients tolerate re-challenge but it can recur with a variable reported incidence ranging from 10 to 56 % [1,2,4,6]. Here we describe a patient who developed rapidly progressing life threatening encephalopathy upon re-challenging HDMTx which responded to Aminophylline.…”

“…There were no neurological deficits and the cerebrospinal fluid (CSF) was acellular. He was treated with the BFM-95 lymphoblastic leukemia protocol [1] and achieved remission by 28th day of induction. The consolidation phase (involving four courses of fortnightly HDMtx 5 g/m 2 over 24 h with leucovorin rescue, 6-mercaptopurine and intrathecal methotrexate) was started 2 months after initiating therapy.…”

“…Methotrexate induced encephalopathy occurs in 0.8-15 % of patients treated with high dose methotrexate (HDMtx) [1][2][3][4][5]. Mostly manifesting as a mild and transient neurological dysfunction, rarely it can be severe and lifethreatening [4,5].…”