Leukoencephalopathy with transient splenial lesions related to 5‐fluorouracil or capecitabine

Abstract

Background 5‐Fluorouracil (5‐FU) and its oral prodrug capecitabine have been rarely but consistently associated with acute central nervous system toxicity, including transient leukoencephalopathies involving the splenium of the corpus callosum. Methods We performed a retrospective search in the French Pharmacovigilance database (FPDB) (January 1985−July 2020) for adult patients affected by solid cancers who developed acute toxic leukoencephalopathies with splenial lesions following treatment with 5‐FU or capecitabine. A comprehensive review of the literature helped to circumstantiate our findings. Results Our research in the FPDB identified six patients who, within 3 days from their first cycle of 5‐FU or capecitabine, developed acute neurological symptoms, including gait ataxia (n = 4), dysarthria (n = 3), dysmetria (n = 2), headache (n = 2), and confusion (n = 2). Brain magnetic resonance imaging (MRI) showed T2/FLAIR (fluid‐attenuated inversion recovery) hyperintensities in the corpus callosum, with diffusion restriction and no contrast enhancement, generally accompanied by additional alterations in the bilateral supratentorial white matter (n = 5). All patients discontinued the agent supposedly responsible for the toxicity and experienced full recovery after a median of 8.5 days from symptom onset. Control MRI showed a progressive normalization of acute MRI abnormalities. Literature review identified 26 cases with similar clinical and paraclinical characteristics. A single patient from the literature resumed 5‐FU at a lower dose, with no recurrent toxicity. Conclusions 5‐FU and capecitabine might be responsible for acute leukoencephalopathies with transient splenial lesions that are generally reversible upon drug discontinuation. Resuming the agent responsible for toxicity might be feasible in selected cases, after having excluded dihydropyrimidine dehydrogenase deficiency, if expected benefits outweigh the risks.

5-Fluorouracil-induced acute leukoencephalopathy: Case report and literature review

“…These signs are suggestive of toxic leukoencephalopathy, as they reflect histological changes in the affected tissue, notably intramyelin and oligodendroglial edema (T2 and FLAIR hyperintensity), accumulation of vacuoles in myelin (DWI hyperintensity), and gadolinium enhancement could be explained by the blood-brain barrier (BBB) disruption due to the release of proinflammatory cytokines deleterious to the tight junctions of the BBB [ 2 , 10 , 11 ]. Perrain et al, in their series of 6 patients, reported no cases of gadolinium enhancement, which confirms the rarity of this sign and the atypical nature of our case [6] . DWI abnormalities are potentially reversible and can completely disappear [1] .…”

“…Several clinical signs of 5-FU neurotoxicity have been described, such as headache, dysarthria, cerebellar syndrome, oculomotor disorders, confusion, cognitive disorders, Parkinson's syndrome, seizure, and coma [5] , [6] , [7] . Diagnosis of TL is based on a number of arguments, including the onset of symptoms after taking 5-FU, and the exclusion of other etiologies that may explain the neurological signs [8] .…”

Stroke‐like presentation of acute toxic leukoencephalopathy due to capecitabine treatment with extensive intramyelinic edema

“…Upon capecitabine discontinuiation, all patients experienced full clinical-radiological recovery after a median of 8.5 days from symptom onset. 14 Obadia et al reported a 45-year-old woman treated by capecitabine for breast cancer with metastatic bone lesions, who presented with nausea, headaches, muscle cramps, dysarthria, and swallowing disorder. MRI showed bilateral and symmetric high signal intensities of deep white matter, corpus callosum, and corticospinal tracts with regression upon discontinuation.…”

“…Brain MRI showed T2/FLAIR hyperintensities in the corpus callosum, with diffusion restriction and no contrast enhancement. Upon capecitabine discontinuiation, all patients experienced full clinical‐radiological recovery after a median of 8.5 days from symptom onset 14 …”

“…Resuming capecitabine might be feasible in some cases if expected benefits outweigh the risks. Perrain et al for example, suggested resuming capecitabine in selected cases after excluding DYPD deficiency 14 . Bougea et al also reported a 50‐year‐old woman who presented an isolated episode of dysarthria and ataxia under capecitabine, bevacizumab, and oxaliplatin treatment due to reversible multifocal leukoencephalopathy, which did not recur after readministration of chemotherapy 3 .…”