Elsevier

Epilepsy & Behavior

Volume 5, Issue 3, June 2004, Pages 380-387
Epilepsy & Behavior

Topiramate in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center

https://doi.org/10.1016/j.yebeh.2004.03.002Get rights and content

Abstract

For the treatment of patients with chronic refractory epilepsies, information about the long-term efficacy and safety profile of any new antiepileptic drug is crucial. Topiramate has been proven to be effective in patients with refractory chronic partial epilepsies in short-term controlled clinical trials, but the long-term retention, long-term efficacy, and long-term side-effect profile have not been sufficiently investigated. We analyzed all patients who had been treated with topiramate in the Epilepsy Centre Kempenhaeghe from the introduction of the drug in the spring of 1993 up to a final assessment point in mid-2002. In total, 470 patients were identified. The data show that the clinical dose achieved was about 200 mg/day, reached after approximately 6 months of treatment. Further dose escalation in the survivors was slow, with a mean dose of about 300 mg/day after 24 months of treatment. Mean titration dose is 25 mg/week, but titration strategy is mostly individual and responds to patient complaints. With respect to seizure frequency, 10–15% of the patients were seizure-free at the 6-month evaluation; 4 patients achieved a 2-year remission. Retention rate was 53% after 1 year, 45% after 2 years, 38% after 3 years, and 30% after 4 years. At 4 years, almost 70% of the patients had discontinued topiramate. The main reason was adverse events, which accounted for about 65% of the discontinuations. Behavioral side effects were dominant, with mental slowing (27.6%), dysphasia (16.0%), and mood problems (agitation: 11.9%) being the most frequently reported side effects. In about 10% of the patients side effects led to discontinuation despite the obvious favorable effects on seizure frequency. Comparisons between the patients who discontinued topiramate treatment and those who continued topiramate showed that discontinuation was associated with comedication (vigabatrin and lamotrigine). Our conclusion is that TPM is associated with a high incidence of side effects in clinical practice, affecting long-term retention. Meaningful prognostic factors that may help us in clinical decision making, i.e., to prevent the side effects or to help us identify those at risk, have not been found.

Introduction

For the 20–30% of patients with pharmacoresistant epilepsies, the recent introduction of new antiepileptic drugs (AEDs) is an important and welcome development [1]. One of these new AEDs is topiramate (TPM), a sulfamated monosaccharide, which has multiple mechanisms of action [2]. TPM has been proven to be effective in patients with refractory chronic partial epilepsies in short-term controlled clinical trials [3]. For patients with refractory epilepsy, however, the value of a drug in clinical practice cannot be derived simply from the outcomes of such controlled trials. For example, a mere 11% of the patients discontinued treatment in most of the controlled clinical trials, whereas this rate seems to be much higher in clinical practice [4]. The main reason is the relatively short duration of clinical trials—12 weeks on average for most trials designed for registration purposes. Patients with refractory epilepsy will, however, as a rule, need long-term treatment. Therefore more information is needed about the long-term profile of a new drug in clinical practice. Several studies have shown retention rate to be the best indicator of the long-term clinical usefulness of a particular drug [5]. Retention rate is considered to be a composite of drug efficacy and drug safety and expresses the willingness of patients to continue drug treatment. It is therefore clinically the most relevant parameter of an antiepileptic drug. The 1-year retention rate for TPM is reported to be 55% [6], comparable to the 1-year retention rates for lamotrigine (LMT, 60%), vigabatrin (VGB, 58%), and gabapentin (GBP, 45%) [7]. In a follow-up study, the 2-year retention rate for TPM was 42%, and the 3-year rate, 30% [5]. Previous studies have clearly shown that treatment with TPM is associated with all kinds of side effects. CNS-related side effects are the most frequently reported side effects and have the most serious impact on daily life [4], especially with respect to neurocognitive effects [8]. Most of the side effect reports come from clinical trials and thus represent the adverse effects of the drugs in the short term and in relatively controlled circumstances. It is not clear whether the tolerability problems are long-term, although some evidence indicates that habituation for TPM occurs at a later stage than for most AEDs [9]. We were particularly interested in which factors influence long-term retention. TPM was first introduced as an experimental drug in The Netherlands in 1993 and became licensed in 1999. As yet, however, the long-term profile of the drug in refractory patients is not available for clinical decision making. For our specific patient group (i.e., patients with refractory epilepsies in a tertiary epilepsy referral and care center) such data become increasingly more important as more drugs and nonpharmacological options become available. We therefore performed a systematic audit of TPM use in the “real life” setting of our center, analyzing all patients who had received or who are still using TPM.

Section snippets

Methods

The study was approved by the ethics committee. All patients who had been treated with TPM in the Epilepsy Centre Kempenhaeghe from the introduction of the drug in spring 1993 up to a final assessment point mid-2002 were identified by means of our automated medical information system (MIS) and subsequently analyzed. Of the 470 patients who were identified, 37 (7.9%) were already exposed to TPM on referral to our center. These patients were also included in the analysis, but were not used in

Results

Table 1 lists the main characteristics of the patients. Four hundred seventy patients were identified. Thirty-seven patients (7.9%) had already received TPM before referral to our center. The mean age of the study group was 34.9 (SD 8.6); patients were equally distributed with respect to gender. Patients had epilepsy for a mean of 20.7 years (SD 13.6). Localization related epilepsy was the most frequent type of epilepsy, while partial-onset seizures were the most frequent seizure type. CT and

Discussion

The clinical experience with topiramate has been reported in a few studies [i.e., [6], [8]]. The added value of this study is the large number of patients included (n=470), the long period of evaluation (almost 10 years, from first patient in 1993 up to our assessment in 2002), and the unselected group (i.e., all patients who received TPM treatment in our center). Our study produced results that may be used in clinical practice:

First, the clinical dose achieved in our patient group was about 200

Acknowledgements

We thank Gloria Roberts for revising the English text.

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