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Annals of Oncology Advance Access originally published online on October 17, 2007
Annals of Oncology 2008 19(1):178-184; doi:10.1093/annonc/mdm466
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© 2007 European Society for Medical Oncology. For Permissions, please email: journals.permissions@oxfordjournals.org

pediatric malignancies

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.

Key words: 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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