Neurotoxicity is an adverse effect of methotrexate (MTX) in the treatment of pediatric cancers. The majority of patients tolerate subsequent doses without recurrence of symptoms. Patients whom experience irreversible neurologic symptoms are poorly described, with existing literature suggestive of a relationship to radiation therapy.

Up to 15 percent of patients receiving MTX will develop neurotoxicity symptoms, with a variable presentation that can include altered mental status, seizures, and stroke-like episodes. Neurotoxicity symptoms typically occur 3-11 days from the last dose of MTX and last minutes to days, and typically resolve within two weeks. It is rare to have recurrence of neurotoxicity symptoms when re-challenged with MTX but severe recurrences have been described. Despite preventative measures, some patients develop severe MTX-related neurotoxicity that is unrecoverable. While few adult studies discuss severe and fatal MTX-related leukoencephalopathy without radiation, these cases are rare and not previously described in the pediatric literature.

A retrospective review was conducted for two patients undergoing treatment for ALL whom developed severe neurologic compromise with imaging consistent with MTX leukoencephalopathy.

Both patients were adolescent Hispanic females undergoing treatment for HR B-ALL. MRI demonstrated transient diffuse high signal intensity changes in the WM on T2/FLAIR imaging. It is also notable that transient restriction diffusion is a feature found along multiple vascular territories involving the deep cerebral WM.