Topiramate: efficacy and tolerability in children according to epilepsy syndromes

Abstract

To evaluate the efficacy and tolerability of topiramate (TPM) as add-on therapy in children less than 12 years of age with refractory epilepsy, according to epilepsy syndromes, we conducted an open, prospective, pragmatic and multicenter study in France. Efficacy was assessed, especially according to epilepsy syndromes, as well as tolerability. We included 207 children (41 of whom were less than 4 years of age). TPM was effective (responders with >50% decrease in seizure frequency) in 50% of 128 patients with partial epilepsy, and in 44% of 79 patients with generalized epilepsy. In case of generalized epilepsy, responders more frequently had generalized symptomatic epilepsy, severe myoclonic epilepsy and myoclono-astatic epilepsy, whereas response rate was mild in both infantile spasms and Lennox–Gastaut syndrome (LGS). Improvement was well maintained in all patients during the treatment period (median 5.6 months). Seizure frequency/severity increased (worsening) in 13% of patients with partial epilepsy and 17% with generalized epilepsy (particularly in those with infantile spasms), and resulted in withdrawal of TPM for 8%. The most frequently reported adverse events were moderate neurobehavioral and gastrointestinal disorders. Adverse events led to withdrawal of TPM from 13.5% of patients. Children less than 4 years of age had particularly good tolerability. Results confirm that TPM is effective and well tolerated in children under 12 years of age in a broad range of epilepsy syndromes, including refractory partial epilepsy, and symptomatic and myoclonic generalized epilepsy. Use of TPM should be considered in children under 4 years of age, and slow and progressive titration is important.

Introduction

Topiramate (TPM) is an antiepileptic drug (AED) which appears to have a broad range of antiseizure activity in adults. Placebo-controlled clinical trials have shown that TPM is also effective when used as adjunct in children with refractory partial-onset seizures, Lennox–Gastaut syndrome (LGS) and generalized tonic-clonic seizures. TPM is approved for these epilepsy syndromes in children over 4 years of age. This AED significantly reduced seizure frequency in children with partial-onset epilepsy after 16 weeks of double-blind adjunctive treatment; the frequency of secondary generalized seizures was also markedly reduced (Elterman et al., 1999, Ritter et al., 2000). TPM was also found to be useful as adjunctive therapy in the management of LGS, and significantly reduced the mean frequency of drop attacks compared with placebo (Sachdeo et al., 1999). Furthermore, there was a significant reduction in seizure rates following treatment with TPM in a mixed adult/pediatric population with primary generalized tonic-clonic seizures (Biton et al., 1999).

In other epilepsy syndromes, there are no available controlled data to date and open data remain relatively scarce. Open studies suggested efficacy of TPM in West (Glauser et al., 1998, Glauser et al., 2000a) and Dravet syndromes (severe myoclonic epilepsy in infancy) (Nieto-Barrera et al., 2000, Coppola et al., 2002b). Other studies reported efficacy of TPM in small populations of absence seizures and combined seizure types (Ormrod and McClellan, 2001, Cross, 2002). Although most of these epilepsy syndromes occur early in life, very few patients were treated under 4 years of age. Eleven of them were included in the pilot trial concerning West syndrome (Glauser et al., 1998).

With respect to tolerability, adverse events associated with adjunctive TPM therapy in children have been predominantly neurobehavioral, and generally mild to moderate in severity (Ormrod and McClellan, 2001). Loss of appetite resulting in weight loss has been a problem in some individuals. However, overall withdrawal rates were low in controlled trials.

In order to complete the data in refractory childhood epilepsy, we conducted an open, multicenter, prospective, pragmatic study to assess the efficacy and tolerability of TPM as add-on therapy in children aged less than 12 years. Efficacy regarding epilepsy syndromes, and the efficacy and safety of TPM in infants and children under 4 years of age were of particular interest.