Efficacy and cognitive side effects of tiagabine and topiramate in patients with epilepsy
Introduction
Topiramate (TPM) and tiagabine (TGB) have been shown to be two novel antiepileptic drugs (AEDs) effective as adjunctive medication (for an overview on TPM, see Waugh and Goa [1]; for TGB, see Deckers et al. [2]). Whereas TGB inhibits the reuptake of GABA, thereby enhancing the level of GABA in the synaptic cleft and lengthening the inhibitory effect of this neurotransmitter [3], TPM has multiple mechanisms of action: The drug inhibits voltage- and receptor-gated calcium channels, modulates voltage-dependent chloride channels, and blocks excitatory neurotransmission. TPM also enhances GABA-mediated inhibition. Recent research suggests a neuroprotective function of both TPM and TGB in an animal model [4]. Efficacy and tolerability of the new AEDs, including TPM and TGB, in the treatment of refractory epilepsy have recently been described in a comprehensive overview [5]. TPM is highly effective as adjunctive therapy and monotherapy in patients with partial seizures, as well as in patients with generalized tonic–clonic seizures, with a responder rate ranging from 27 to 50.6% depending on dosage of medication. TGB, in contrast, is licensed only for adjunctive treatment in patients with partial seizures. The responder rate ranges from 20 to 36%. Greater efficacy of TPM is also indicated by the “number of patients needed to treat” until one patient experiences a seizure reduction of at least 50% (3 TPM vs 6 TGB) [6].
In clinical practice the efficacy of a given AED must always be weighed against possible negative side effects. In this respect, TGB appears to be preferable to TPM in that no [7] or only minor [8], [9], [10], [11] cognitive side effects in patients with partial seizures have been reported. Therefore, TGB has been especially recommended for patients for whom it is particularly important that the antiepileptic treatment does not cause any deterioration in cognitive performance [12]. TPM, in contrast, has been shown to frequently lead to cognitive impairment, particularly in language (fluency), working memory, and psychomotor speed [13], [14], [15], [16], [17]. Different study or control groups [13], [18] (sample bias), titration speed [13], [19], retest intervals, and different neuropsychological measures may account for different findings (for an overview, see Aldenkamp et al. [20] and Ortinski and Meador [21]). It has, for example, been shown that gradual titration and small initial doses are helpful in limiting the occurrence of adverse events [22], [23], [24]. TPM-induced cognitive impairment appears to be reversible after discontinuation of the drug [14], [25], [26]. Some studies suggest that cognitive impairment is especially bad during titration and that improvement can be observed after reaching the maintenance phase [19]. However, Huppertz et al. [14] report on cognitive deficits as not being transient during titration. In addition, cognitive impairment has been reported to occur independently of TPM blood serum levels [27]. As for individual risk factors, no group has yet been found to be at particular risk, nor have predicting factors been discerned [28]. The aim of the present study is therefore to compare two novel AEDs (TPM and TGB), which differ with respect to their impact on seizures and cognition. TPM and TGB were given as add-on therapy in patients with refractory epilepsy in a randomized, open trial, taking a broad selection of neuropsychological measures and mood variables as outcome variables. Task selection considered the aforementioned critical cognitive domains to give a comprehensive perspective on the specificity (or pattern) of cognitive side effects of the selected AED.
As for the cognitive side effects of TPM, it has to be pointed out that up to now no randomized study with thorough and standardized neuropsychological testing has been reported [20].
Section snippets
Study design
In an open prospective study, patients with intractable epilepsy, aged 18 to 65, were randomly assigned to one of two parallel study groups. All participants had reported at least three epileptic seizures (complex partial and/or generalized tonic–clonic) in the month prior to the study. Study medication was administered as add-on treatment in addition to either one, two, or three other AEDs, which varied among subjects.
Exclusion criteria were: nonepileptic seizures, primarily generalized
Patients
Forty-one adult patients aged 18 to 65 with at least three complex partial or secondary generalized seizures a month were included in the study. Thirty patients underwent the neuropsychological testing at T2 and were included in the comparison T1–T2a. All three neuropsychological examinations were administered to by 21 patients, who were included in the comparison T2b–T3. There was no statistical difference between treatment groups in the number of patients. Furthermore, these groups were
Discussion
This study demonstrates the comparable efficacy and tolerability of the two novel AEDs TGB and TPM as add-on therapy in patients with refractory epilepsy: 8.1% of all patients for whom seizure frequency was ascertainable became seizure free; 29.7% of the patients reported a seizure reduction of at least 50% (intention-to-treat analysis); 70.7% of all patients tolerated the study medication irrespective of the study group (intention-to-treat analysis). The overall dropout rate was 48.8%, 19.5%
Acknowledgments
We thank the patients who agreed to undergo multiple neuropsychological tests for this study. Patients were not paid for participation. The assessment of neuropsychological data was financially supported by Sanofi-Synthelabo (now Cephalon) through Study. ML 818100.
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