High-dose Methotrexate (HDMTX)-Induced Generalised Tonic-clonic Seizures in a Relapsed B-ALL Patient: Challenges in Management and Continuation of HDMTX

Abstract

Background: Acute Lymphoblastic Leukaemia (ALL) is the most common childhood cancer. Methotrexate (MTX) is an important drug used in the treatment of ALL patients to eliminate clinically evident CNS disease at diagnosis as well as to prevent CNS relapse for both CNS-involved and non-involved groups at diagnosis. MTX is also responsible for neurotoxicity in some cases. Management of MTX-induced neurotoxicity and further continuation of MTX in such cases is a very challenging issue for physicians. Aim: Here, a case was described that developed MTX-induced neurotoxicity, the use of levetiracetam, and the successful continuation of all the remaining HDMTX and ITMTX without any further neurotoxic events. Case: A six-year-old boy was diagnosed with B-ALL, treated with the MRC-11 protocol, and faced an event of generalised tonic-clonic seizures while receiving high-dose methotrexate (HDMTX), then rescued with intravenous diazepam. Following this, the MRC-11 protocol continued to use intrathecal (IT) and oral methotrexate (MTX), but HDMTX was taken out of the other treatments. After completing MRC-11 maintenance five years later at the age of fourteen, the patient experienced a relapse of B-ALL, with no involvement in the CNS or both testicles. We treated this relapsed case using the BFM 2002 protocol. Once again, the patient experienced generalised tonic-clonic seizures while receiving folic acid rescue following the completion of Day+8 HDMTX and IT MTX in the consolidation phase. The seizures subsided immediately, within three minutes of their onset, with the assistance of intravenous diazepam. Clinically, there was no focal sign of any neurological deficit and no abnormal enhancement in the brain's MRI. We kept the patient on regular oral levetiracetam. No further seizures were observed. The patient then received the remaining days (Day+22, Day+36, and Day+50) of HDMTX and ITMTX, as well as the intensification and maintenance phases, according to protocol, without any seizures. Anti-convulsant oral levetiracetam was continued for three (3) months more after the completion of the maintenance phase (total of two years and three months since starting); within this period, no seizure was reported, and then oral levetiracetam was discontinued. Conclusion: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. In addition to this, levetiracetam can be an alternative drug for the long-term management and prevention of HDMTX-related neurotoxicity.