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Annals of Oncology Advance Access published online on October 17, 2007
Annals of Oncology, doi:10.1093/annonc/mdm466
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© 2007 European Society for Medical Oncology

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

H. Inaba1,2, R. B. Khan3,4, F. H. Laningham3,5, K. R. Crews6,7, C.-H. Pui1,2 and N. C. Daw1,2,*

1 Department of Oncology
3 Department of Radiological Sciences
6 Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN
2 Department of Pediatrics
4 Department of Neurology
5 Department of Radiology; College of Medicine
7 College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA

* Correspondence to: Dr N. C. Daw, Department of Oncology, MS 260, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794, USA. Tel: +1-901-495-2573; Fax: +1-901-521-9005; E-mail: najat.daw{at}stjude.org

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.

encephalopathy, leukemia, magnetic resonance imaging, methotrexate, neurotoxicity, osteosarcoma

Received for publication June 20, 2007. Revision received August 27, 2007. Accepted for publication August 29, 2007.


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