Reversible encephalopathy following 5‐fluorouracil‐based chemotherapy in patients with dihydropyrimidine dehyrogenase deficiency

Abstract

5-fluorouracil (5-FU) is one of the most frequently used chemotherapy agents for the treatment of a number of solid cancers. We report two patients with advanced gastric cancer who developed acute encephalopathy after receiving chemotherapy composed of 5-FU and oxaliplatin. One patient presented with altered consciousness and the other with generalized tonic clonic seizure. 5-FU-induced encephalopathy was suspected by clinical, radiological and electroencephalographic findings, and both patients had reduced expression of dihyropyrimidine dehydrogenase, the rate-limiting enzyme responsible for the catabolism of 5-FU. The neurological symptoms improved spontaneously, and did not recur in the following cycle of chemotherapy with the administration of a reduced dose of 5-FU. We suggest that the early recognition of this adverse event can reverse 5-FU-induced neurological symptoms and a dose reduction of the offending drug can prevent the recurrence of 5-FU induced encephalopathy.

Posterior reversible encephalopathy syndrome following chemotherapy with oxaliplatin and a fluoropyrimidine: A case report and literature review

“…The pathophysiology linking fluoropyrimidines and encephalopathy has not been well described but at least three pathogenic explanations have been suggested. The first theory proposes that a deficiency in dihydropyrimidine dehydrogenase (DPD), the initial and rate‐limiting enzyme in the catabolism of fluoropyrimidines, is associated with more severe and generalized forms of 5‐FU toxicity 27,28 . A deficiency in DPD results in the decreased metabolism of 5‐FU and the accumulation of toxic compounds.…”

“…Retrospective studies have suggested that up to 50% of 5‐FU toxicities maybe due to a DPD deficiency 29 . In one report, two patients developed an acute encephalopathy after receiving 5‐FU and oxaliplatin and on testing with quantitative real‐time polymerase chain reaction, both patients were shown to have reduced expression of DPD 28 . The second theory, proposed by Koenig and Patel, suggests that the neurotoxicity maybe due to the blockade of the Krebs cycle by fluoroacetate, a product of fluorouracil catabolism 30 .…”

“…Increasing numbers of antineoplastic therapies have been reported to be a cause of PRES, including several platinum‐based therapies such as cisplatin and carboplatin; however, only nine cases have been described following combination therapy with oxaliplatin and a fluoropyrimidine (Table 1). 28,38–48 Patients presented with seizure‐like activity (five of nine), confusion (four of nine), visual disturbance (three of nine) or headache (three of nine). Although hypertension and renal failure have been previously described as risk factors, six of the eight patients did not have pre‐existing medical conditions.…”

Delayed Posterior Reversible Leukoencephalopathy Syndrome Triggered by FLOT Chemotherapy

“…Platinum salts are a well-known trigger of AVP hypersecretion (6), and they have a direct toxic effect on endothelial cells (26,27). 5-Fluorouracil can cause a direct neurotoxic effect through the interruption of Krebs cycle or through thiamine deficiency (28,29); a neurotoxic effect is reported also in case of dihydropyrimidine dehydrogenase (DPD), the initial and ratelimiting enzyme in the catabolism of fluoropyrimidines (30,31).…”

Reversible Posterior Leukoencephalopathy Syndrome after Eribulin Mesylate Chemotherapy for Breast Cancer

“…Reversible Posterior Leukoencephalopathy syndrome (RPLS) has been first reported by Hinchey et al It is a rare neurologicoradiologic syndrome that is characterized by headache, altered alertness and behavior ranging from drowsiness to stupor, seizures and visual loss (1). Magnetic resonance imaging (MRI) reveals characteristic hyperintense lesions on T2-or FLAIR-weighted imaging and restricted diffusion with low ADC involving the posterior circulation areas (2)(3)(4). Recently, some cases have been reported in association with the increased use of cytotoxic and molecular target agents in cancer patients (5,6).…”