Massive myelinolytic leukoencephalopathy in a patient medicated with low-dose oral methotrexate for rheumatoid arthritis: an autopsy report

Acta Neuropathol. 2007 Oct;114(4):425-30. doi: 10.1007/s00401-007-0214-9. Epub 2007 Mar 15.


The authors describe a 68-year-old female who developed a rapidly progressing leukoencephalopathy involving the cerebrum and brain stem. The disease appeared during low-dose oral methotrexate (MTX) therapy for rheumatoid arthritis. An extensive clinical investigation discounted other possible causes of white matter lesions. Autopsy identified an uninterrupted severe demyelinating, partially liquefactive necrosis-like lesion in the white matter accompanied by astrogliosis and occasional swollen axons therein. The lesion was generally symmetrical, and distributed throughout the whole cerebral white matter except for the bilateral temporal lobes and the rostral part of the frontal lobes. The internal capsules and cerebral peduncles were spongy, and the central and lateral parts of the pons, especially the transverse cerebellopontine tracts, were affected similarly. It was of note that the lesion was accompanied by neither vascular diseases nor lymphocyte infiltration. Thus, the pathological findings were similar to those of a severe form of central and extrapontine myelinolysis, and clearly different from ordinary MTX leukoencephalopathy reported in patients receiving intrathecal or intravenous MTX therapy, known as "disseminated necrotizing leukoencephalopathy". Another possibility is that synergistic effects of several white-matter-damaging disorders may have contributed to the hitherto unknown lesion. To our knowledge, this is the first autopsy record that describes an oral MTX-associated neurological disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology
  • Adenocarcinoma / surgery
  • Administration, Oral
  • Aged
  • Anti-Inflammatory Agents / therapeutic use
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Antirheumatic Agents / administration & dosage
  • Antirheumatic Agents / adverse effects*
  • Arthritis, Rheumatoid / drug therapy*
  • Brain Diseases / chemically induced*
  • Brain Diseases / pathology*
  • Demyelinating Diseases / chemically induced
  • Demyelinating Diseases / pathology
  • Female
  • Humans
  • Lung Neoplasms / pathology
  • Lung Neoplasms / surgery
  • Magnetic Resonance Imaging
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects*
  • Phenylpropionates / therapeutic use
  • Prednisolone / therapeutic use


  • Anti-Inflammatory Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antirheumatic Agents
  • Phenylpropionates
  • loxoprofen
  • Prednisolone
  • Methotrexate