Uncommon Extrapyramidal Reaction to Ondansetron

We describe the case of a 77-year-old man, who was admitted for the initiation of chemotherapy for stage IV small cell lung cancer without cerebral metastases. On the first day post-admission, the patient developed altered mental status and right-sided weakness after premedication with ondansetron and dexamethasone. Symptoms resolved spontaneously within 90 minutes. An ischemic event was suspected despite unremarkable brain imaging. Prophylactic anticoagulation and statins were initiated. Five days later, a second episode of altered mental status, anisocoria, facial paresis, and severe dysarthria occurred following ondansetron administration. Bloodwork revealed significant hyponatremia (116 mEq/L), suggesting Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), despite this suspicion, there was no further investigation to confirm this diagnosis due to rapid symptom reversal after biperiden administration, implicating an adverse reaction to ondansetron. Ondansetron and metoclopramide were discontinued, hyponatremia was corrected, and no further episodes occurred during the hospital stay. This case highlights the necessity of awareness for adverse reactions of ondansetron that can mimic cerebrovascular events and the need for a thorough revision of medication in complex cases.