Valproate-Associated Hyperammonemic Encephalopathy Despite Nontoxic Serum Levels and Preserved Liver Function: A Case Report

Abstract

Abstract

Valproate-associated hyperammonemic encephalopathy (VHE) is a potentially serious adverse effect that may occur despite nontoxic serum valproate concentrations and preserved liver function. We report a 49-year-old man with intellectual disability and long-standing drug-resistant epilepsy treated with valproate, phenytoin, phenobarbital, cenobamate, levetiracetam, and several psychotropic medications. He was admitted with severe and persistent impairment of consciousness. Initial kidney and liver function were preserved, and brain computed tomography showed no acute abnormalities. Electroencephalography demonstrated diffuse and bilateral frontotemporal slowing without electrographic seizure activity. Serum ammonia was 88.1 µmol/L and subsequently increased to 126.5 µmol/L, while valproate concentrations remained therapeutic or subtherapeutic. Phenytoin was initially supratherapeutic, but correction of its concentration did not produce meaningful neurological improvement. An extended metabolic, nutritional, autoimmune, infectious, toxicologic, and hepatic evaluation revealed no alternative cause. VHE was suspected, and valproate was gradually withdrawn without levocarnitine. This was followed by sustained neurological recovery and a decrease in serum ammonia to 43.1 µmol/L. This case emphasizes the importance of measuring serum ammonia in patients receiving valproate who develop otherwise unexplained altered mental status, particularly in the setting of intellectual disability and extensive antiseizure polytherapy.