J.A.R.J. Hulsman

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

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 200mg/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 25mg/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.

The impact of side effects on long-term retention in three new antiepileptic drugs

OBJECTIVE To determine long-term retention, percentage of patients withdrawing because of adverse events, percentage of patients achieving seizure freedom, safety profile of the new anti-epileptic drugs lamotrigine, levetiracetam and topiramate. METHODS All patients treated with lamotrigine, levetiracetam or topiramate in the Epilepsy Centre were identified. Each drug was analyzed from introduction of the drug in the Netherlands up to a final assessment point 2 years later. RESULTS Data from 1066 patients were included: 336 for lamotrigine, 301 for levetiracetam, 429 for topiramate. Two-year retention rates were 69.2% (lamotrigine), 45.8% (levetiracetam), 38.3% (topiramate); (LTG vs. LEV at p<0.001; LTG vs. TPM at p<0.001; LEV vs. TPM at p=0.005). Seizure freedom rates were lowest for lamotrigine and highest for levetiracetam. Adverse events played a role in drug discontinuation in 154/429 patients (35.9%) on topiramate, 52/336 patients (15.5%) on lamotrigine (p<0.001), 68/301 patients (22.5%) on levetiracetam (p<0.001). Mood and general CNS-effects are common in patients on lamotrigine and levetiracetam, and neurocognitive side effects are most prevalent in patients on topiramate. A positive effect on cognition is frequently noted in patients on lamotrigine. CONCLUSION A drug that is only modestly efficacious but has a favourable safety profile may look better than a drug that is more efficacious but produces clinically meaningful adverse events. Therefore, a drugs retention rate is mainly determined by its side effect profile. As a consequence, retention rate was highest for lamotrigine and lowest for topiramate. Intermediate retention rates were seen with levetiracetam use.

Long-term effects of levetiracetam and topiramate in clinical practice: A head-to-head comparison.

OBJECTIVE Two of the most commonly prescribed new antiepileptic drugs as add-on therapy for patients with chronic refractory epilepsies are topiramate and levetiracetam. In regulatory trials, both drugs were characterized as very promising new antiepileptic drugs. However, results from these highly controlled short-term clinical trials cannot simply be extrapolated to everyday clinical practice, also because head-to-head comparisons are lacking. Therefore, results from long-term open label observational studies that compare two or more new AEDs are crucial to determine the long-term performance of competing new antiepileptic drugs in clinical practice. METHOD We analyzed all patients referred to a tertiary epilepsy centre who had been treated with topiramate from the introduction of the drug in spring 1993 up to a final assessment point mid-2002 and all patients who had been treated with LEV in the same centre from the introduction of the drug in early 2001 up to a final assessment point end-2003 using a medical information system. RESULTS Three hundred and one patients were included for levetiracetam and 429 patients for TPM. Retention rate after 1 year was 65.6% for LEV-treated patients and 51.7% for TPM-treated patients (p=0.0015). Similarly, retention rates for LEV were higher at the 24-month mark: 45.8% of LEV-treated patients and 38.3% of TPM-treated patients were still continuing treatment (p=0.0046). Adverse events led to drug discontinuation in 21.9% of TPM-treated patients compared to 6.0% of LEV-treated patients (p<0.001). The number of patients discontinuing treatment because of lack of efficacy was similar for both groups. Seizure freedom rates varied between 11.6 and 20.0% for TPM and between 11.1 and 14.3% for LEV per 6-months interval. Several important AED specific adverse events leading to drug discontinuation were identified, including neurocognitive side effects from TPM and mood disorders from LEV. CONCLUSION The retention rate for LEV is significantly higher than for TPM. LEV had a more favourable side effect profile than TPM with comparable efficacy. Patients on TPM discontinued treatment mainly because of neurocognitive side effects. In the treatment with LEV, the effects on mood must not be underestimated.

Blood beta-hydroxybutyrate correlates better with seizure reduction due to ketogenic diet than do ketones in the urine

PURPOSE To investigate whether it is better to use blood beta-hydroxybutyrate (BHB) or urinary ketones to monitor ketogenic diet (KD). METHOD In 33 patients on KD we measured ketosis in two different ways. At the 3-monthly visits to the clinic we measured BHB in capillary blood obtained by finger-prick and the level of ketones in the urine using a urine dipstick. If the patient was able to collect urine, the urinary ketones were also measured every day at home. We compared the degree of ketosis with seizure reduction. RESULTS BHB measured during the 3-monthly visits correlated with seizure reduction at 3 and 6 months (p=0.037 and 0.019, respectively). Urinary ketones measured at the same time did not correlate at any visit. The averaged values of the daily measured ketones in the urine did not correlate either. CONCLUSIONS BHB correlates better with seizure reduction than do ketones in urine. It is, therefore, better to use BHB to monitor KD even if BHB is measured less frequently than urinary ketones.

The Effect of Antiepileptic Drugs on Cognition: Patient Perceived Cognitive Problems of Topiramate versus Levetiracetam in Clinical Practice

Summary:  Introduction: Neurocognitive complaints may interfere with long‐term antiepileptic drug (AED) treatment and are an important issue in clinical practice. Most data about drug‐induced cognitive problems are derived from highly controlled short‐term clinical trials. We analyzed such cognitive complaints for the two most commonly used AEDs in a clinical setting using patient perceived problems as primary outcome measure.

Pharmacokinetics and cognitive effects of carbamazepine formulations with different dissolution rates.

Objective: In this study our aim was to assess pharmacokinetic effects and adverse cognitive effects of switches between generic and branded formulations of carbamazepine (CBZ). Method: Twelve patients were included in a randomized open-label, observer-blind, cross-over design with a double-baseline period, comparing three different formulations of carbamazepine in monotherapy – the innovatory branded form Tegretol and two generic forms, CBZ Pharmachemie and CBZ Pharbita. Cognitive assessment was carried out at baseline and 3 days after a cross-over. Results: Area under the curve and a number of pharmacokinetic properties (serum concentration day curves, change in serum concentration (delta scores), peak/trough concentrations and peak time) did not differ among the three CBZ formulations. Therefore, the basic assumption for this study, i.e. to test pharmacokinetic-related differences in cognitive profile, was not met. In line with these findings, none of the cognitive variables showed statistically significant differences with respect to the cognitive profile during the day. Conclusion: Switches between the investigated generic CBZ formulations and the branded product did not result in any difference in cognitive profiles. These results are not necessarily valid, though, for other generic forms of CBZ, for other types of antiepileptic drugs or for CBZ treatment in higher doses or in polytherapy.

Loreclezole monotherapy in patients with partial seizures

Monotherapy is preferable in the treatment of epilepsy; a new antiepileptic drug has to be checked on its efficacy in monotherapy. In this study patients who had successfully been treated with loreclezole in previous studies were gradually withdrawn from their antiepileptic comedication. Nine patients participated in the study. Reduction of comedication was well tolerated in all, no serious side effects occurred. In 6 patients seizure frequency remained unchanged, i.e., within 50% limits. Two patients experienced a clear increase in seizure frequency. In 2 patients reintroduction of a second antiepileptic drug was mandatory. One patient experienced a further reduction in seizure frequency when monotherapy was reached. This observation indicates efficacy of loreclezole, also in monotherapy.