CORRESPONDENCE Transient Encephalopathy Following High-Dose Methotrexate
Sir: Methotrexate can cause acute neurotoxicity characterized by confusion, disorientation, seizures, and focal neurologic deficits [1]. We read with interest the brief report by Peyriere et al. [2] of transient encephalopathy associated with high-dose methotrexate (HDMTX) in a child with leukemia. Our experience, and what has been commonly known of the condition, differs from their description. We would like to report an additional patient and comment on the management of similar cases.
A 14-year-old girl with acute lymphoblastic leukemia was to receive four 2-weekly courses of HDMTX 5 g/m 2 as 24-hr infusion followed by triple intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone at the end of each infusion. She had not been irradiated cranially. The first infusion was completed uneventfully. Nine days after the commencement of the second 5 g/m 2 infusion, the child presented with right hemiplegia and transient slurring of speech. The neurologic signs resolved completely over the next 48 hr. The third HDMTX infusion was then given at a dose of 2 g/m 2 . Nine days later, she presented again with choreiform movements involving her right upper and lower limbs. The symptoms resolved over 24 hr. The planned fourth HDMTX infusion was replaced by weekly oral treatment at 20 mg/m 2 /dose while the intrathecal medications were continued. No neurologic problems were reported thereafter. Her renal function remained normal throughout this period and only a mild elevation of alanine aminotransferase was observed. The serum methotrexate levels, measured at 48 hr after the commencement of HDMTX infusion, were 0.71, 0.33, and 0.11 mmol/L for the three courses of treatment, respectively. Magnetic resonance imaging showed a focal area of hyperintensity only over the left centrum semiovale on diffusion-weighted images following the first episode of encephalopathy. Following the second episode, the centrum semiovale of each cerebral hemisphere was symmetrically affected. In addition, there were small areas of hyperintense signals in both thalamic nuclei on the T2-weighted images. The patient was well and in first complete remission 11 months after diagnosis.
Our case thus differs from that reported by Peyriere et al.
[2] in two ways. (1) There was a delay in the onset of neurologic changes following HDMTX infusion; and (2) the pharmacokinetics of methotrexate did not appear to be related to the encephalopathy. These are similar to the observations in 8 among 259 patients with leukemia reported by Rubnitz et al.
[1]. In those patients, signs of neurologic deficits appeared 5-13 days after HDMTX, and methotrexate pharmacokinetic parameters in symptomatic patients were similar to matched controls. Thus, the case of encephalopathy described by Peyriere et al. appears to be directly related to an abnormally high serum methotrexate level, whereas the pathogenesis remains unknown for most other patients [1].