CNS nontumor
Toxic and metabolic disorders
Methotrexate toxicity

Author: Kymberly A. Gyure, M.D. (see Authors page)

Revised: 18 August 2017, last major update January 2015

Copyright: (c) 2002-2017, PathologyOutlines.com, Inc.

PubMed Search: Methotrexate toxicity [title]

Cite this page: Gyure, K.A. Methotrexate toxicity. PathologyOutlines.com website. http://pathologyoutlines.com/topic/cnsmethotrexate.html. Accessed November 18th, 2017.
Definition / general
  • Chemotherapeutic agents, either alone or combined with radiation therapy, may lead to cognitive decline with an associated leukoencephalopathy
  • Most common offending agent is methotrexate, particularly when it is administered intrathecally
Terminology
  • Term disseminated necrotizing leukoencephalopathy (DNL) has been applied to the progressive and fatal form of neurologic disease induced by combined intrathecal methotrexate administration and radiation (Cancer 1975;35:291)
Epidemiology
  • Methotrexate is used predominantly to treat leukemia and lymphoma, including primary CNS lymphoma
  • Patients treated for childhood leukemia are at particular risk for developing methotrexate related leukoencephalopathy
Sites
  • Predominantly white matter
Pathophysiology
  • Methotrexate is a folic acid antagonist which inhibits DNA synthesis
  • It also indirectly inhibits the synthesis of methionine, which is necessary for the formation and maintenance of myelin, leading to vacuolar degeneration of white matter (Acta Neuropathol 1989;78:291)
  • Most individuals with severe neurologic complications secondary to methotrexate also have a history of radiation therapy and a synergistic effect of methotrexate and radiation is considered to be likely to lead to serious damage to white matter
Clinical features
  • Cognitive decline, decrease in IQ
Radiology description
  • Cerebral atrophy, decreased density of white matter on CT scans, diffuse periventricular hyperintensities on T2 weighted MR images and calcifications in the basal ganglia
Radiology images

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Toxic leukoencephal-opathy

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Neurotoxicity

Case reports
Treatment
  • There is currently no effective treatment for methotrexate related leukoencephalopathy
Gross description
  • Discrete, gray brown foci of friable white matter with associated edema
Microscopic (histologic) description
  • Vacuolation or necrosis, axonal swellings (spheroids), macrophage infiltrates, gliosis
Microscopic (histologic) images

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Contributed by Dr. Kymberly Gyure

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Methotrexate hepatotoxicity, liver