General description

Methotrexate leukoencephalopathy is a toxic condition resulting from methotrexate (MTX), a folate antagonist used in the treatment of leukemia, central nervous system lymphoma, osteosarcoma, and rheumatoid arthritis. MTX inhibits dihydrofolate reductase, disrupting folate metabolism and causing significant DNA synthesis impairment. It can also interfere with the conversion of homocysteine to methionine and S-adenosylmethionine (SAM), further impairing DNA synthesis and repair, myelin formation, and causing vascular endothelial damage.

Although MTX does not easily cross the blood-brain barrier, high-dose intravenous therapy or intrathecal and intraventricular administration can increase the risk of leukoencephalopathy. Patients who undergo concurrent radiation therapy may also have a higher risk due to blood-brain barrier disruption. Risk factors include high-dose MTX, intrathecal administration, younger age, and radiation therapy.

MTX leukoencephalopathy can present in various forms:

Acute MTX leukoencephalopathy typically arises 3–14 days after MTX administration, presenting with stroke-like symptoms such as hemiparesis, unilateral sensory loss, aphasia, dysarthria, and dysphagia. While many cases are transient and improve upon discontinuing MTX, some may require further intervention.

Chronic MTX leukoencephalopathy progresses slowly, sometimes leading to lasting neurological symptoms, cognitive decline, and functional impairment, potentially resembling dementia.

Disseminated necrotizing leukoencephalopathy (DNL) is a rare but severe complication that can arise during MTX therapy, particularly with high-dose, intrathecal administration or in combination with radiation therapy. This condition is marked by rapid neurological deterioration and poor prognosis, often resulting in death within several months to a year. When combined with radiation therapy, DNL may also lead to heterotopic calcification in areas such as the basal ganglia or the cortico-medullary junction, a condition known as mineralizing microangiopathy. While these calcifications are a notable finding, their direct clinical impact remains uncertain.

Radiographic features

Acute MTX leukoencephalopathy

In the acute phase, T2WI and FLAIR show no abnormalities, while DWI and ADC reveal ovoid or circular areas of diffusion restriction in the centrum semiovale, typically sparing the subcortical U-fibers.

Chronic MTX leukoencephalopathy

T2WI and FLAIR sequences typically reveal patchy areas of hyperintensity in the deep white matter, especially in the frontal and parietal lobes, without diffusion restriction. This makes it challenging to distinguish chronic MTX leukoencephalopathy from age-related or chronic ischemic changes based on a single imaging study.

Disseminated necrotizing leukoencephalopathy (DNL)

DNL typically presents with scattered necrotic lesions in the deep white matter, which may appear on MRI with nodular or ring-like enhancement. In cases of long-term survivors, these lesions often later calcify, and calcifications may be seen on CT.