Rare but Critical: Isolated Zonisamide-Induced Hyperammonemic Encephalopathy

Introduction: Zonisamide is a sulfonamide anticonvulsant approved for the treatment of partial-onset seizures. While its known adverse effects include metabolic acidosis, nephrolithiasis, and cognitive disturbances, hyperammonemia is a rare complication when zonisamide is used with other anti-epileptic therapies. We report a case of hyperammonemic encephalopathy induced by zonisamide alone in a patient without known underlying hepatic or renal disease. Case Description: A 62-year-old male with a history of hypertension, hyperlipidemia, blindness, and seizure disorder managed with zonisamide presented with altered mental status. The patient's last known well state was earlier that week, but the exact timeline was unclear. He had no known history of liver or kidney disease on admission. Upon presentation, the patient was intubated for airway protection. Laboratory findings showed leukocytosis, acute kidney injury, severely elevated ammonia (525 μmol/L), and lactic acidosis, with normal liver function tests. He was admitted to the intensive care unit for continuous renal replacement therapy (CRRT) and management of septic shock. His hospital course was complicated by bacterial pneumonia, new-onset atrial fibrillation, and recurrent seizures. On imaging, no definitive liver disease was noted. Extensive workup for toxin ingestion and other causes of encephalopathy was unremarkable. Given the elevated ammonia level and absence of hepatic dysfunction, zonisamide-induced hyperammonemic encephalopathy was considered the most probable diagnosis despite therapeutic serum zonisamide levels. With CRRT and discontinuation of zonisamide, patient's ammonia levels, renal function, and mental status improved, and the patient was discharged. Discussion: Hyperammonemia is a rare but serious adverse effect of zonisamide. The proposed mechanism involves the inhibition of carbonic anhydrase, resulting in metabolic acidosis and elevated ammonia levels. One previous case report has documented hyperammonemic encephalopathy associated with zonisamide use in a patient concurrently taking valproate. This case highlights the need to consider zonisamide as a potential cause of hyperammonemic encephalopathy, even in the absence of hepatic dysfunction, concurrent antiepileptic use, or supratherapeutic drug levels. Prompt discontinuation of zonisamide and treatment of complications can lead to resolution of symptoms.