Neuropsychiatric complications associated with 5 fluorouracil chemotherapy: a narrative review

Neuropsychiatric toxicity related to 5-fluorouracil (5-FU) chemotherapy is an uncommon but clinically significant adverse effect that is frequently underrecognized. This narrative review summarizes the clinical spectrum, proposed mechanisms, diagnostic features, management strategies, and outcomes of 5-FU–associated neuropsychiatric complications. A literature search of PubMed/MEDLINE and EMBASE identified English-language case reports and case series published between 1960 and 2023 describing neuropsychiatric manifestations temporally related to 5-FU or its prodrugs. Symptoms typically emerged within 2–4 days following administration of 5‑FU, primarily manifesting as acute encephalopathy or changes in mental status including toxic leukoencephalopathy, manic or psychotic symptoms, seizures, and cerebellar dysfunction. Hyperammonemia was the most consistent biochemical abnormality, and brain MRI frequently demonstrated reversible bilateral white-matter changes, often involving the corpus callosum. Management centred on immediate cessation of 5-FU and supportive care, including hydration, ammonia-lowering therapy, and thiamine supplementation, with most patients achieving favorable neurological recovery. Early recognition and prompt intervention are critical to optimal outcomes. However, the absence of standardized diagnostic criteria, limited prospective data, and uncertainty regarding safe rechallenge strategies underscore the need for pharmacogenetically informed approaches and larger multicentre observational studies.