Methotrexate-induced myelopathy

Last revised by Henry Knipe on 25 Nov 2022

Methotrexate-induced myelopathy is an uncommon toxic manifestation of intrathecal methotrexate administration that closely mimics subacute combined degeneration of the cord but with normal vitamin B12 and copper 1,2. It is far less common than methotrexate-related leukoencephalopathy.

Methotrexate-induced myelopathy is rare with only case reports and small series reported. As intrathecal methotrexate is most commonly administered for the treatment of hematologic malignancies, especially acute lymphocytic leukemia, the epidemiology of affected individuals largely matches that of the underlying diseases with most being children or young-to-middle-aged adults 1,2.

The clinical presentation of affected individuals relates to dorsal column impairment with bilateral paresthesia, lower-limb weakness and bowel and/or bladder dysfunction 2

CSF levels of myelin basic protein and homocysteine are often elevated 2

Although clinically and radiologically methotrexate-induced myelopathy is indistinguishable from subacute combined degeneration of the cord it is not believed to be due to abnormal vitamin B12 or copper metabolism 1. Rather, it has been postulated that methotrexate results in the disruption of normal methionine synthesis from homocysteine resulting in both the elevated levels of homocysteine detectable in CSF and the reduction of S-adenosylmethionine (synthesized from methionine) that is important in the maintenance of normal myelin sheaths 3. At present, however, it is unclear if this results in demyelination 3, or some form of axonal damage 2. Interpretation of postmortem samples has been complicated by concurrent radiation effects 2.

MRI demonstrates imaging features indistinguishable to subacute combined degeneration of the cord with bilateral long segment dorsal column high T2 signal 1-3

Unfortunately, treatment with vitamin B12 and folate supplementation does not appear effective 2

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