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Acute Methotrexate Toxicity

  • Background: Acute lymphocytic leukemia (ALL) is a common malignancy often treated with intrathecal injections of methotrexate (MTX). MTX inhibits cell replication by blocking the enzyme dihydrofolate reductase, disrupting the conversion of folic acid to tetrahydrofolic acid. MTX is associated with acute neurotoxicity.
  • Acute MTX neurotoxicity often presents clinically with acute onset stroke-like symptoms between 6 and 11 days after MTX therapy. Diffusion abnormalities are the first detectable abnormality on MRI. Not all areas of reduced diffusion go on to develop T2 abnormality on FLAIR; the process is reversible. Not all patients who have an episode of acute MTX neurotoxicity will develop a reaction on subsequent treatment injections.
  • Key Diagnostic Features: Reduced diffusion in the white matter sparing the cortex, with or without associated T2 abnormality on FLAIR. No enhancement upon intravenous injection of gadolinium contrast. Usually involves the centrum semiovale, and is often bilateral. DWI abnormalities are sometimes reversible; may resolve without ever demonstrating T2 abnormality.
  • DDx: venous infarction; PML; lymphoma; ADEM
  • Rx: Discontinue MTX. Promising early experimental results with dextrometorphan.

Suggested Reading

Fisher MJ, Khademian ZP, Simon EM, et al. Diffusion-Weighted MR Imaging of Early Methotrexate-Related Neurotoxicity in Children. AJNR Am J Neuroradiol 2005;26:1686-9.

Rollins N, Winick N, Bash R, et al. Acute Methotrexate Neurotoxicity: Findings on Diffusion-Weighted Imaging and Correlation with Clinical Outcome. AJNR Am J Neuroradiol 2004;25:1688-95.

Sandoval C, Kustcher M, Jayabose S, et al. Neurotoxicity of Intrathecal Methotrexate: MR Imaging Findings. AJNR Am J Neuroradiol 2003;24:1887-90.

December 10, 2012
A 34-year-old man with acute onset of aphasia and left hemiparesis. History of CNS B-cell acute lymphocytic leukemia. One day after intrathecal methotrexate injection. Prior injection was 8 days earlier. No history of radiation therapy.
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