Unusual cause of hyperammonemia in two cases with short-term and long-term valproate therapy successfully treated by single dose carglumic acid.

Valproic acid (VPA) is an antiepileptic drug which is used in the treatment of various seizure disorders including tonic-clonic, myoclonic, absence, partial seizures and psychiatric disorders. VPA is usually well tolerated, but severe adverse effects may occur. Hyperammonaemic encephalopathy (HE) is a rare and potentially fatal complication of VPA treatment. The mechanism by which valproate induces hyperammonemia remains incompletely understood but is likely to relate to the urea cycle. Herein we present two cases with valproate-induced hyperammonemia at therapeutic valproate levels without signs of liver failure and were successfully treated by a single dose of carglumic acid.

Introduction

Valproic acid (VPA) is an antiepileptic drug which is used in the treatment of various seizure disorders including tonic-clonic, myoclonic, absence, and partial seizures and psychiatric disorders. Although usually well-tolerated, VPA is known to be associated with idiosyncratic side effects.[1] Valproate-induced hyperammonemia without evidence of hepatotoxicity is an important idiosyncratic side effect and 16-52% of patients receiving VPA treatment may have mild elevations in ammonia.[2] Hyperammonemia can occur in patients receiving usual VPA dosages for short- and long-term treatment and can be successfully treated by single dose of carglumic acid. The mechanism by which valproate induces hyperammonemia remains incompletely understood, but is likely to relate to the urea cycle.[3] We present two cases with valproate-induced hyperammonemia at therapeutic valproate levels without signs of liver failure and were successfully treated by a single dose of carglumic acid.

Case Report

Case 1

A 15-year-old male with a 1-month history of epilepsy, headache, and hemiparesis was admitted to the pediatric intensive care unit with altered mental status. The child was managed conservatively along with intravenous antibiotics and was started on intravenous valproate at a dosage of 33 mg/kg and levetiracetam 44 mg/kg was added for breakthrough seizures. He was intubated because of impaired consciousness with increasing confusion and lethargy and increased seizure frequency. The alteration of consciousness was subsequent to the administration of valproate and not due to a progression of the disease. A metabolic encephalopathy was suspected. Laboratory investigations revealed hyperammonemia 283 μg/dl 6 days after initiating valproic acid (VPA) and no signs of hepatotoxicity. There was no family history of any genetic-metabolic disorder. The valproate was ceased and a single dose of carglumic acid 100 mg/kg per day was administered through a nasogastric tube, followed by a rapid improvement in the patient's mental state and a return of the ammonia level to the normal range (50 μg/dl). Blood ammonia remained normal thereafter.

Case 2

A 17-months-old male has a history of mental and motor retardation, microcephaly, and epilepsy. He was admitted to the intensive care unit with seizure and respiratory depression. Supportive care in the form of mechanical ventilation, hydration, and antibiotics were administered. His medications included valproate (50 mg/kg/day po) and phenobarbital (5 mg/kg/day) for the last 1 year. An electroencephalography revealed hypsarrhythmia. Magnetic resonance imaging showed schizencephaly. He was consulted to department of pediatric metabolism due to diagnostic confusion with nonketotic hyperglycinemia. His metabolic tests were normal including tandem mass spectrometry and urine organic acid analysis. His serum ammonia level was 189 μg/dl. His liver function test results including aspartate aminotransferase and alanine aminotransferase were within normal limits. After discontinuation of VPA and initiation of carglumic acid 100 mg/kg by nasogastric route, his serum ammonia concentration decreased to 69 μg/dl within 12 h. His neurologic status improved within a day.

Discussion

Hyperammonemia is most commonly caused by liver disease or inborn errors of metabolism. Less common causes include medications like 5-fluorouracil, salicylate, asparaginase, acetazolamide, diuretics, and VPA.[456]

Valproate is partly metabolized in the liver by oxidation which produces active metabolites. Significant contribution to hyperammonemia caused by valproate probably results from the reduction of hepatic levels of N-acetylglutamate, a positive allosteric modulator of carbamoyl phosphate synthetase-1 which catalyzes the first step in urea biosynthesis. VPA interferes with this process through direct inhibition of carbamoylphosphate synthetase and indirectly by depleting carnitine.[3] Valproate binds to carnitine preventing transportation and beta oxidation of long chain fatty acids, which in turn leads to increased oxidation of amino acids resulting in elevated serum ammonia level.

The management of valproate related hyperammonemia is generally supportive, with discontinuation of therapy, supplementation with N-carbamylglutamate, L-carnitine, and frequent monitoring. N-carbamylglutamate is a structural analog of N-acetylglutamate, licensed as an orphan drug for the treatment of hyperammonemia due to N-acetylglutamate synthetase (NAGS) deficiency. Carnitine supplementation tends to normalize elevated plasma ammonia concentrations by binding to VPA and relieving the inhibition of urea synthesis.[78]

Comedications with other antiepileptic drugs including phenytoin, phenobarbital, and topiramate increase the risk of valproate related hyperammonemia. Concomitant use of valproate with phenobarbital predisposed to hyperammonemia in the second case we presented. Combination therapy with valproate and levatiracetam can increase vulnerability to hyperammonemia at the initiation of treatment or at high doses and intravenous usage of both drugs. Avoidance of polypharmacy can prevent drug interactions potentially leading to the development of valproate-induced hyperammonemia.[910] According to previous literature, valproate-induced hyperammonemia has been reported to occur almost equally in both genders. Valproate-induced hyperammonemia was noted in two patients with the same gender in this report. There does not seem to be any relationship between the development of valproate-induced hyperammonemia and serum valproate levels.[11]

Valproate-induced hyperammonemia can be acute or subacute with progression of lethargy to coma and death. Valproate-induced hyperammonemia typically occurs in the presence of normal liver functions.[12] In case of a patient presenting with encephalopathy, regardless of the duration of therapy, the diagnosis of valproate-induced hyperammonemia should be suspected in any patient on valproate therapy, ammonia levels should be checked, and valproate should be discontinued. Rapid diagnosis and management will help in reducing valproate-induced hyperammonemia-related potentially life-threatening complications.[13]

Valproate-induced hyperammonemia can occur in patients receiving usual VPA dosages for short- or long-term treatment, but data on the use of carglumic acid in these patients are limited. In conclusion, this experience suggests that carglumic acid could be considered for the treatment of valproate-induced hyperammonemia. The patients reported here showed a dramatic fall in plasma ammonia concentrations with a single dose of carglumic acid (100 mg/kg). Of course, trials with more patients are needed in order to demonstrate its usefulness.