5-FU induced leukoencephalopathy
General description
Fluorouracil (5-FU) is an antineoplastic drug classified as a fluoropyrimidine-based antimetabolite, widely used in the treatment of various cancers, including gastrointestinal cancers (such as gastric and colorectal cancer), head and neck cancers, cervical cancer, and more. In rare cases, 5-FU can cause leukoencephalopathy, commonly referred to as 5-FU encephalopathy, which may initially present with symptoms such as dizziness, unsteady gait, slurred speech, and memory impairment. If untreated, these symptoms can progress to more severe outcomes like confusion, agitation, sensorineural hearing loss, seizures, and even coma.
The risk of 5-FU-induced leukoencephalopathy is higher in patients who receive high doses or have a congenital deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme essential for 5-FU metabolism. This neurotoxicity can also be seen with 5-FU derivatives, including carmofur, tegafur, and capecitabine, all of which may lead to demyelination and white matter damage through disruption of the TCA cycle, as the 5-FU metabolite inhibits aconitase (aconitate hydratase), an enzyme critical in the TCA cycle.
Symptoms typically appear within a few days to weeks after starting 5-FU, though cases have been reported with symptoms emerging the day after initiation. The incidence of neurotoxicity with 5-FU is estimated to be around 5%, while the risk of leukoencephalopathy with carmofur, a 5-FU derivative, is approximately 0.026%. Because carmofur and tegafur accumulate more in the central nervous system with continuous dosing, they may pose a higher risk than 5-FU itself.
T2WI and FLAIR hyperintensity
In MRI examinations, early signs of 5-FU-induced leukoencephalopathy often include symmetrical high-signal intensities on T2-weighted and FLAIR images in the deep white matter of the cerebral hemispheres, particularly around the periventricular regions near the lateral ventricles. The subcortical U-fibers are typically spared. Additionally, high-signal areas and diffusion restriction may appear in regions such as the corticospinal tracts, splenium of the corpus callosum, and middle cerebellar peduncles. It is important to note that, even after discontinuing the drug, neurological symptoms and MRI findings may persist or progress for several weeks, requiring careful monitoring.