Abstract Introduction Acute encephalopathy in critically ill patients requires a broad differential diagnosis, including metabolic, infectious, autoimmune, toxic, and iatrogenic causes. Polypharmacy and supplement use can make evaluation complex particulary when overlapping mechanisms contribute to altered mental status. Our case describes a rare sequential presentation of serotonin syndrome, likely triggered by supratherapeutic ondansetron and supplement interaction, followed by suspected adalimumab-induced autoimmune encephalitis. The case emphasizes the importance of detailed medication and supplements review in the intensive care setting. Case Presentation A 21-year-old man with ankylosing spondylitis treated with adalimumab for one year presented unresponsive after several days of nausea, vomiting, and headache. The day before presentation, he received ketorolac and ondansetron at an urgent care clinic. On arrival, he was febrile (38.9 °C) with leukocytosis (24.9 × 109/L), hyponatremia (Na 113 mmol/L), and creatine kinase 18,000 U/L. Neuroimaging was unremarkable. He was intubated and treated empirically for meningitis. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis (WBC 121 cells/µL, protein 117 mg/dL) with normal glucose. EEG showed no epileptiform activity. On hospital day two, inducible clonus and hyperreflexia raised concern for serotonin syndrome. Collateral history revealed excessive ondansetron ingestion and daily use of creatine and Ashwagandha. Cyproheptadine therapy was initiated, leading to rapid improvement. Re-exposure to ondansetron reproduced the symptoms, confirming serotonin toxicity. Despite resolution, persistent headache and nausea prompted further evaluation. Autoimmune testing demonstrated positive anti-histone antibodies. Adalimumab was discontinued, and high-dose intravenous methylprednisolone (250 mg q6h for 3 days) resulted in complete recovery. Discussion This case demonstrates two uncommon, medication-related causes of encephalopathy occurring sequentially in the same patient. Serotonin syndrome can occur with agents outside the typical antidepressant category, including ondansetron, and may be potentiated by supplements that influence serotonin metabolism and receptor activity. In addition, TNF-α inhibitors such as adalimumab have been associated with autoimmune complications, including lupus-like reactions and antibody-mediated encephalitis. The positive anti-histone antibody and response to corticosteroids support an autoimmune mechanism in this case. Recognition of these overlapping toxic and immune processes requires careful clinical correlation and a high index of suspicion. Conclusion This case highlights the diagnostic complexity of dual drug-induced encephalopathies in critical care. A detailed medication and supplement history is essential when evaluating acute encephalopathy. Early identification and targeted therapy can lead to complete recovery and prevent recurrence in patients with overlapping toxic and autoimmune mechanisms. This abstract is funded by: None
Abdullah et al. (Fri,) studied this question.