Valproate-induced hyperammonemic encephalopathy: a case report

Abstract

Background: Hyperammonemic encephalopathy is a rare and serious adverse reaction to valproate. Although there is documentation of this reaction in previous reports, very little is still known about the exact mechanism of action. In addition, there are no established guidelines of the next steps needed when a patient does develop this reaction. Therefore, this case report highlights what is known as well as the areas of research still needed. Case presentation: Our patient was a 57-year-old Caucasian woman with a medical history of bipolar I disorder, opioid use disorder, benzodiazepine use disorder, and Crohn's disease who was admitted to our behavioral health unit for suicidal ideation. She had been experiencing multiple panic attacks for 2.5 weeks along with poor sleep, increased energy, excessive spending, and feelings of helplessness. The patient was diagnosed with bipolar I disorder, manic episode without psychotic features, and benzodiazepine use disorder. She was started on valproic acid, citalopram, propranolol, and quetiapine. By day 6 of her hospitalization, the patient had altered mental status, varying levels of consciousness, confusion, and ataxic gait. Her ammonia levels were found to be elevated. All of her medications were discontinued, and lactulose was initiated. She returned to her baseline mentation within 48 hours and was discharged with lithium and quetiapine. The treatment team concluded that this patient had valproate-induced hyperammonemic encephalopathy, a rare but reversible reaction to valproate. Conclusion: Fortunately, rapid identification of this rare condition led to a favorable outcome in our patient. This case report illustrates the course of treatment in a patient who experienced this reaction and reviews current knowledge as well as areas of needed research in regard to valproate-induced hyperammonemic encephalopathy.

A Case of Valproic-Acid Induced Hyperammonemic Encephalopathy

“…Furthermore, VPA metabolism occurs in the liver via glucuronic acid conjugation and mitochondrial beta-and cytosolic omega-oxidation. VPA requires carnitine for entry into mitochondria; chronic use, high doses, or overdose can cause carnitine deficiency leading to VPA-induced toxicity [1]. Moreover, the metabolites of VPA, such as propionate and 4-en-VPA, are involved in the pathogenesis of VPA-induced hyperammonemia.…”

“…VP-CoA has also been implicated to directly inhibit the activity of NAGS, resulting in VPA-induced hyperammonemia [2,10]. Prior literature suggests that genetic defects in two essential urea cycle enzymes, CPS-I and ornithine transcarbamylase (OTC), could contribute to VPA-induced hyperammonemia [1,10]. This explains why VPA-induced hyperammonemia occurs only in a subset of patients [10].…”

“…Another plausible mechanism is drug-drug interactions. Drugs such as phenytoin, carbamazepine, and phenobarbital can affect the function of CPS-1 [1]. Topiramate, an anticonvulsant, is known to inhibit both the urea cycle and glutamine synthetase activity.…”

“…Valproic acid (VPA) is an antiepileptic medication that is frequently used in the treatment of epilepsy, migraines, and psychiatric disorders, including bipolar disorder and schizophrenia [1]. Although usually well-tolerated, VPA has been associated with a wide range of side effects ranging from nausea and vomiting to major adverse drug reactions such as pancreatitis and hepatotoxicity [2,3].…”

Hyperammonemia in patients receiving valproic acid in the hospital setting: A retrospective review

“…Hyperammonemia is a known side effect of VPA and has been documented in several case reports. [1][2][3][4][5][6][7][8][9][10][11][12] VPA-induced hyperammonemia is thought to be due to disruption of the urea cycle and resultant decrease in ammonia metabolism or by decreasing glutamate metabolism. 13,14 While many patients with hyperammonemia remain asymptomatic, hyperammonemia can lead to somno-lence, vomiting, ataxia, increased frequency of seizures, mental status changes, and coma.…”