Abstracts

It has been suggested that topiramate (TPM) enhances the risk of valproate(VPA)-associated hyperammonemic encephalopathy (HE). We report findings on four cases of HE on concomitant therapy with VPA and TPM.
We reviewed the medical records of patients on concomitant treatment with VPA and TPM seen at the Indiana University Epilepsy Program between 9/00 and 3/03 looking for cases of HE. All patients were examined at the time of the HE. Phone contacts were also made with patients or local physicians as needed to obtain more detailed information.
Four patients with refractory partial epilepsy, aged 18-60 years (3 males, 1 female), were found to have HE on the combination of VPA and TPM. Two of the cases were able to tolerate VPA therapy well for years and developed HE within 3 weeks of starting TPM. One case was on chronic treatment with TPM and developed HE 3 weeks after initiating VPA. One case was able to tolerate the combination of VPA and TPM for 4 years but developed HE 2 weeks after the dose of VPA was increased from 1000 to 2000 mg/d. Three patients were taking a third antiepileptic drug (phenobarbital, oxcarbazepine, carbamazepine). All patients presented with somnolence, confusion, dysarthria and worsening of seizure control. Also noted were gait ataxia (2 cases), asterixis (1 case). The mean ammonia concentration in venous blood was 112.25 [mu]mol/L (normal: 15-35 [mu]mol/L) with a range of 63-147[mu]mol/L. Liver function and routine hematological tests were normal in all cases. Serum concentrations of VPA and TPM were within the therapeutic range in 3 cases, in 1 patient a random VPA level was187 [mu]g/ml. In 3 patients the HE resolved rapidly with normalization of the ammonia concentrations after the discontinuation of VPA. One patient improved after a reduction in the dose of VPA and was maintained on the combination of VPA and TPM. This patient has continued to show slightly elevated ammonia levels and intermittent signs and symptoms of mild HE for the past 12 months.
Our cases support the possibility that TPM enhances the risk of VPA-associated HE. The fact that four cases were found within a relatively short period of time suggests that this is not an uncommon problem. The clinical manifestations of HE could be misinterpreted as a direct toxic effect of the medication, especially TPM, so it is important that physicians are aware of this complication for its prompt detection. It appears that HE develops shortly after the combination of drugs is started (2-3 weeks) so monitoring for this problem early on is important. Routine ammonia levels for monitoring purposes are probably not necessary but should be obtained in patients developing excessive somnolence or confusion. Discontinuation of VPA usually results in a rapid resolution of the encephalopathy.