Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer

Ann Oncol. 2008 Jan;19(1):178-84. doi: 10.1093/annonc/mdm466. Epub 2007 Oct 17.


Background: Little information is available about the diagnosis and management of acute methotrexate (MTX)-induced encephalopathy.

Methods: We reviewed clinical and magnetic resonance imaging (MRI) [including diffusion-weighted imaging (DWI)] characteristics of this complication in pediatric cancer patients treated from 2000 to 2006.

Results: Six of 754 (0.8%) patients with leukemia or lymphoma and 2 of 44 (4.5%) with bone sarcoma experienced acute encephalopathy within 2 weeks (median, 7.5 days) after receiving high-dose i.v. and/or intrathecal MTX. The signs and symptoms varied at presentation and during episodes: hemiparesis (eight patients, alternating from side to side in four), dysphasia (six), confusion/emotionality (six), headache (three), choreoathetosis (two), and seizure (two). All patients recovered after 1-7 days (median, 5.5 days). DWI revealed restricted diffusion in anatomic brain regions associated with the symptoms; changes on T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging were consistently less marked. After recovery, DWI findings were normal but T2 and/or FLAIR imaging usually showed residual abnormalities.

Conclusions: Acute MTX toxicity often manifests as fluctuating neurologic symptoms with alternating hemispheric involvement. Restricted diffusion on DWI is a reliable early sign of acute MTX encephalopathy and resolves as clinical status improves, despite the persistence of subtle abnormalities on MRI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Aminophylline / therapeutic use
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / adverse effects*
  • Antimetabolites, Antineoplastic / blood
  • Antimetabolites, Antineoplastic / therapeutic use
  • Bone Neoplasms / drug therapy
  • Brain / drug effects
  • Brain / pathology*
  • Child
  • Diffusion Magnetic Resonance Imaging
  • Female
  • Histiocytoma, Malignant Fibrous / drug therapy
  • Humans
  • Injections, Intravenous
  • Injections, Spinal
  • Leukemia / drug therapy
  • Male
  • Metabolic Clearance Rate
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects*
  • Methotrexate / blood
  • Methotrexate / therapeutic use
  • Neurotoxicity Syndromes / drug therapy
  • Neurotoxicity Syndromes / etiology*
  • Neurotoxicity Syndromes / pathology
  • Osteosarcoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Retrospective Studies


  • Antimetabolites, Antineoplastic
  • Aminophylline
  • Methotrexate