Valproate-induced hyperammonemic encephalopathy (VHE), predisposing causes, clinical, laboratory, and EEG findings, and therapy are reviewed from the Hospital del Mar, Barcelona, Spain. Urea cycle enzyme deficiency, especially ornithine transcarbamylase (OTC), is an inherited cause of hyperammonemia and a risk factor for developing VHE in patients taking VPA. Screening tests are recommended in patients with a known family history of OTC deficiency, and in patients who develop unexplained episodes of confusion, lethargy, and vomiting, and/or increased frequency of seizures, while on VPA therapy. Blood ammonia level, renal and liver function, and urinary orotic acid excretion should be tested. Blood VPA levels are within therapeutic ranges in most cases of VHE, and the dose of VPA and the height of the ammonia level are not related to VHE severity. Organic acidemias should be suspected when hyperammonemia is associated with acidosis, ketosis, and low bicarbonate level. Topiramate and phenobarbital favor hyperammonemia, because of inhibition of cerebral glutamine synthetase; topiramate also inhibits carbonic anhydrase, leading to hyperammonemia by affecting the urea cycle. Polytherapy, including topiramate, phenobarbital, phenytoin and carbamazepine, should be avoided with VPA. Hyperammonemia leads to an increase in cerebral glutamine, which produces astrocyte swelling and cerebral edema. The EEG shows continuous generalized slowing, a predominance of theta and delta activity, occasional bursts of frontal rhythmic delta, and triphasic waves. Prompt diagnosis and treatment with supplements of carnitine can lead to a favorable response. [1]

COMMENT. In contrast to the above report and others, Beghi E et al [2] found a significant correlation between serum ammonia level and VPA dosage. A review of 132 fatal cases of valproate hepatotoxicity worldwide found that 65% were developmentally delayed, 75% were taking additional AEDs, and 65% were below 2 years of age [3]. In a report of 29 valproate case fatalities in the US between 1986 and 1996, risk factors also included young age (1:600 risk <2 years), and coincident metabolic disorders (Alpers’ disease) [4]. Metabolic testing is recommended in young children (<2 years) with developmental abnormalities before prescribing VPA.

A review of the role of valproate therapy in the treatment of pediatric epilepsy emphasizes its superior efficacy and minimizes its toxicity [5]. Given the number of fatalities reported in the past two decades, the potential adverse effects of valproate deserve at least equal attention and caution. The risks of valproate in the prophylaxis of febrile seizures, for example, outweigh the benefits [6], and in pediatric epilepsy, careful monitoring is mandatory. The FDA-approved indications for valproate are complex partial seizures + other seizure types and simple and complex absence seizures (as monotherapy or adjunctive therapy); mania in adults; and migraine prophylaxis in adults. [7]