Case Presentation:

A 42 year old male presented with fatigue, dyspnea on exertion, and bleeding gums for two weeks. Initial labs showed a white cell count of 96.1k/uL with blasts, Hgb 6.6 g/dL, and a platelet count of 64 k/uL. Bone marrow (BM) biopsy showed acute lymphoblastic leukemia (ALL). A lumbar puncture (LP) showed a blast population in the CSF (<1 u/dL) consistent with CNS2 disease. Patient received induction chemotherapy following the adolescent/young adult protocol CALGB 10403. On day 29 of induction, he received an LP and was given intrathecal (IT) methotrexate (MTX) as a prophylactic measure against CNS leukemia. Repeat BM biopsy showed residual disease so he was given extended induction chemotherapy.

Patient underwent consolidation per protocol, but developed neutropenic fevers on day 20 and was admitted. On day 22, he received Vincristine and IT MTX. Two days later, he developed a fever of 103 F with stroke-like symptoms of altered mental status, left sided hemiplegia, and aphasia. He was intubated for airway protection and admitted to the ICU. Head CT showed a lucency in the splenium of the corpus collosum; MRI/MRA showed diffusion restriction of the right corona radiata centrum semiovale region and splenium of the corpus collosum which did not represent any one vascular distribution. Blood cultures, CSF cultures, CSF gram stain, and infectious serologies were negative. EEG showed nonspecific diffuse cerebral dysfunction with no epileptiform abnormalities. LP showed a total nucleated cell count of 6 per uL (44% segmented neutrophils, 44% lymphocytes, 12% macrophages), RBCs 13 per uL. CSF glucose and protein were 48 and 37 respectively. The patient’s neurological status spontaneously improved after ten days, and he was eventually stable for transfer out of the MICU. Cause of stroke-like symptoms was determined to be due to acute IT MTX induced leukoencephalopathy.


MTX-related leukoencephalopathy is a rare complication occurring in 3-10% of recipients, mostly seen in the pediatric population. Risk factors are young age high doses, and cranial irradiation. Chronic leukoencephalopathy (characterized by dementia, pseudobulbar palsy, and ataxia) is more common, whereas acute toxicity is rare, especially in the adult population. Acute toxicity can present with stroke-like symptoms of hemisensory and motor loss, dysarthria, and aphasia. A notable pattern found in reports is decreased apparent diffusion coefficient (ADC) values found in the periventricular white matter, especially in the centrum semiovale. The mechanism is unknown, but reassuringly, neurological resolution has been observed in most reported cases over the course of 10-14 days.


Acute MTX induced leukoencephalopathy is a rare complication in adult ALL patients receiving IT MTX and can be distinguished from stroke based on characteristic MRI ADC signal patterns and spontaneous resolution. It is imperative for physicians to be aware of this condition and to consider it in their differential diagnosis for patients receiving IT MTX.