Methotrexate-induced neurotoxicity: Diagnostic challenges and the role of neurophysiological testing

Methotrexate (MTX) is widely used in the treatment of acute lymphocytic leukemia (ALL) and other oncohematological conditions. Although subacute MTX-related neurotoxicity is relatively rare, it can present with dramatic, fluctuating neurological deficits that mimic other serious conditions. Diagnosis may be complicated by the frequent presence of asymptomatic white matter abnormalities on MRI, commonly attributed to chronic MTX toxicity. We report an 18-year-old ALL patient who developed severe, fluctuating neurological symptoms 11 days after the third intrathecal administration of MTX. MRI showed bilateral, symmetric diffusion-restrictive white matter lesions. Absent cortical motor evoked potentials (MEPs) with preserved responses to spinal stimulation indicated corticospinal tract involvement localized to the brain, supporting a diagnosis of MTX-induced neurotoxicity. Treatment with high-dose dextromethorphan led to rapid and complete recovery. This case underscores the value of early neurophysiological testing-particularly MEPs-in identifying corticospinal tract involvement and differentiating symptomatic neurotoxicity from chronic, asymptomatic MRI findings. Prompt recognition can accelerate diagnosis, guide treatment, and prevent unnecessary interventions.