Valproic Acid and Topiramate Induced Hyperammonemic Encephalopathy in a Patient With Normal Serum Carnitine

Abstract

A 17-year-old female developed hyperammonemic encephalopathy 2 weeks after valproic acid (VPA), 500 mg twice a day, was added to her regimen of topiramate (TPM), 200 mg twice a day. She presented to the emergency department (ED) with altered mental status, hypotension, bradycardia, and lethargy. Laboratory analysis showed mild non-anion gap hyperchloremic acidosis, serum VPA concentration of 86 mg/L, and urine drug screen result that was positive for marijuana. She was admitted to the pediatric intensive care unit for persistent symptoms, prolonged QTc, and medical history. Blood ammonia concentrations were obtained because of her persistent altered mental status, initially 94 µmol/L and a peak of 252 µmol/L. A serum carnitine profile was obtained at the time of hyperammonemia and was found to be normal (results were available postdischarge). VPA and TPM were discontinued on day 1 and day 2, respectively, as the patient's blood ammonia concentration remained elevated. On day 3, her mental status had returned to baseline, and blood ammonia concentrations trended downward; by day 4 her blood ammonia concentration was 23 µmol/L. VPA has been associated with numerous side effects including hyperammonemia and encephalopathy. Recently, drug interactions with TPM and VPA have been reported; however, serum carnitine concentrations have not been available. We discuss the possible mechanisms that VPA and TPM may affect serum ammonia and carnitine concentrations and the use of levocarnitine for patients or treating toxicity.INDEX TERMS: hyperammonemia, levocarnitine, serum carnitine, topiramate, valproic acid J Pediatr Pharmacol Ther 2013;18(2):128-136

Antiepileptic Drugs and Liver Disease

“…98 Concomitant use of AEDS, especially topiramate, can increase the risk of developing this complication. 99…”

Topiramate-induced hyperammonemic encephalopathy in a patient with mental retardation: A case report and review of the literature

“…Although the use of TPM can be associated with cognitive symptoms, this side effect appears to be due to a direct effect of the drug in the CNS and is not secondary to any metabolic abnormality. Hyperammonemia secondary to the combined use of TPM and other antiepileptic drugs, particularly VPA, has been reported but is probably not common, with only a few cases reported in the literature [1–8] .…”

“…As a group, antiepileptic drugs are a relatively common cause of encephalopathy, either by direct CNS effect, or, in some cases, by inducing hyperammonemia. This is a well-established complication of valproic acid and has now been reported to occur in patients previously treated with valproic acid to which TPM was added [1–8] . Topiramate is a broad-spectrum anticonvulsant that is also extensively used for migraine prophylaxis, as a mood stabilizer, and for alcohol dependency.…”

Encephalopathy Induced by Combination Therapy with Valproic Acid and Topiramate: Challenging the Utility of Serum Ammonia Measurement

“…Monotherapy with either valproic acid or topiramate or combination therapy with the 2 drugs has frequently been reported to cause encephalopathy. [2][3][4][5][7][8][9] In a recent retrospective chart analysis, the odds ratio for development of encephalopathy was 10 for patients receiving valproic acid -topiramate combination therapy relative to patients receiving valproic acid alone. 1 In the case reported here, the patient's improved neurologic status after withdrawal of valproic acid suggested that this drug had a role in the development of encephalopathy.…”

“…[1][2][3][4][5] Certain authors have proposed that this combination evokes a synergistic mechanism that produces hyperammonemia, which in turn results in encephalopathy. 2,6 Described here is a case of encephalopathy potentially induced by the combination of valproic acid and topiramate, in which serial serum ammonia measurements suggested that encephalopathy may occur before hyperammonemia.…”