A 4-year-old female patient was diagnosed with relapsing acute lymphocytic leukemia (ALL). She was admitted to the pediatric intensive care unit (PICU) due to septic shock with respiratory failure. During her recovery, after extubation and weaning of sedation, she developed altered mental status, with a Glasgow Coma Scale (GCS) of 12/15, and focal jerks. Her neurological examination was significant for aphasia. She also had features of dysautonomia, with unstable body temperature, labile blood pressure, and profuse sweating, which were noted to be aggravated by urinary retention or constipation.

CT of the brain showed that the patient had generalized cerebral atrophy. MRI showed patchy to confluent T2/ fluid-attenuated inversion recovery (FLAIR) hyperintense signal and restricted diffusion in bilateral centrum semiovale and corpus callosum ( Fig. 74.1 ).

Methotrexate-induced leukoencephalopathy. Brain MRI, (A and B) axial DWI show bilateral asymmetric restricted diffusion in the corona radiata extending into periatrial white matter without mass effect ( arrows ). There is also involvement of splenium of corpus callosum ( arrowhead ). DWI , Diffusion-weighted imaging. (Case courtesy Mai-Lan Ho, MD.)

Electroencephalography (EEG) was recorded during a semiconscious state and was abnormal, with diffuse slow background and nonreactivity to painful stimulation. The findings were suggestive of generalized cerebral dysfunction with nonspecific etiology. EEG after thiamine demonstrated excessive intermittent slow waves over the bilateral frontotemporal region with right emphasis and independent right temporal slow waves in awake and sleep states. There were also three episodes of electroclinical seizures (eye staring, frequent eye blinking, and left-hand movement) with bilateral frontotemporal slow waves spreading to frontocentral regions and more prominent over the right temporal region. A lumbar puncture (LP) was performed and showed normal cell counts, differential, Gram stain and cultures were negative, and protein, glucose, lactate, and amino acids were normal. SLC19A3 gene testing was negative.

The patient was covered with levetiracetam, following which there were no definite further seizures. She was also treated with aminophylline, thiamine, folinic acid, and pyridoxine, and biotin, with improvement in GCS.

Toxic leukoencephalopathy can be caused by exposure to neurotoxic organic solvents, heavy metals, and drugs. The differential includes CNS infection (either meningitis or encephalitis), inflammatory, vasculitis, vascular, and neoplastic disorders. Methotrexate (MTX)-induced CNS neurotoxicity usually presents days after high-dose intrathecal chemotherapy and may mimic an acute ischemic stroke. Clinical features include subacute encephalopathy with fluctuating course, often followed by improvement of symptoms. Treatment varies, but leucovorin rescue with aminophylline is typically well tolerated to bypass MTX inhibition of dihydrofolate reductase (DHFR), essential for the synthesis of purines and pyrimidines in DNA and RNA.