The use of valproic acid (VPA) (also known as Depakote, Depakene, and others) frequently results in elevated plasma ammonia. In some people, hyperammonemia may be clinically significant, resulting in hyperammonemic encephalopathy, which may be severe. Valproic acid-induced hyperammonemic encephalopathy may occur in people with normal liver function, despite normal doses and serum levels of VPA. We describe 2 cases of valproic acid-induced hyperammonemic encephalopathy in patients with supratherapeutic VPA levels, although the condition has been described in people with normal VPA lev- Valproic acid (VPA) is effective in the treatment of seizure disorders, bipolar disorder, migraine headache prophylaxis, neuropathic pain, restless legs syndrome, dementia-related agitation, and social anxiety disorder, among other conditions. VPA has numerous drug interactions and toxicities; severe toxicities include hepatic damage, pancreatitis, teratogenicity, thrombocytopenia, and hyperammonemia. Here we depict 2 case reports of VPAinduced hyperammonemic encephalopathy (VHE), both occurring in patietns with no history of underlying liver disease. In one instance, the patient was able to function, but with significant cognitive limitations. In the second case, the patient was comatose. Both of the patients we describe also had supratherapeutic VPA levels, but VHE is a welldocumented potential complication of the use of VPA in the medical literature, and it may occur in people with normal VPA levels.1 Because of the wide spectrum of symptoms associated with VHE, physicians should consider hyperammonemia in the differential diagnosis of any patient taking VPA who shows changes in behavior, cognition, or orientation. Case ReportsCase 1 A 51-year-old woman was transferred from a psychiatric hospital to an emergency department to evaluate the recent deterioration in her mental status. She had been admitted to the psychiatric hospital for an exacerbation of posttraumatic stress disorder and was placed on extended-release VPA at 1,000 mg nightly. After 7 days of treatment she was no longer responsive to verbal stimuli. Her medical history was significant for migraine headaches, posttraumatic stress disorder, and major depression. Her medications included topiramate (for migraine prophylaxis), quetiapine, and VPA. In the emergency department, she was nonresponsive to verbal or painful stimuli; her vital signs were normal. Her pupils were equal at 5 mm and her ammonia level was 232 mol/L (N ϭ 10 to 47); her VPA level was 145 g/mL (N ϭ 50 to 100); and aspartate aminotransferase and alanine aminotransferase were normal at 17 IU/L and 19 IU/L, respectively. The remainder of laboratory tests, including all liver tests, were normal. For the first 24 hours, the patient remained nonresponsive; her This article was externally peer reviewed.

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