Danielle A.J.E. Lambrechts

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.

The ketogenic diet as a treatment option in adults with chronic refractory epilepsy: Efficacy and tolerability in clinical practice

The ketogenic diet (KD) is a high-fat, low-protein, low-carbohydrate diet that is used as a treatment for patients with difficult-to-control epilepsy. The present study assesses the efficacy and tolerability of the KD as an add-on therapy in adults with chronic refractory epilepsy. 15 adults were treated with the classical diet or MCT diet. During a follow-up period of 1 year we assessed seizure frequency, seizure severity, tolerability, cognitive performance, mood and quality of life (QOL). We found a significant reduction in seizures among the patients who followed the diet at least 1 year (n=5). Of these 5 patients, 2 had a reduction between 50 and 90%. Analyzing the study months separately, we found a seizure reduction of ≥50% in 26.6% of the patients during at least 1 month of treatment. Common side-effects were gastrointestinal disorders, loss of weight and fatigue. There was a considerable, non-significant improvement found in mood and QOL scores. Improvements were independent of reduction in seizure frequency, indicating that the effects of the KD reach further than seizure control.

Research into the (Cost-) effectiveness of the ketogenic diet among children and adolescents with intractable epilepsy: design of a randomized controlled trial.

BackgroundEpilepsy is a neurological disorder, characterized by recurrent unprovoked seizures which have a high impact on the individual as well as on society as a whole. In addition to the economic burden, epilepsy imposes a substantial burden on the patients and their surroundings. Patients with uncontrolled epilepsy depend heavily on informal care and on health care professionals. About 30% of patients suffer from drug-resistant epilepsy. The ketogenic diet can be a treatment of last resort, especially for children. The beneficial effect of the ketogenic diet has been proven, but information is lacking about its cost-effectiveness. In the current study we will evaluate the (cost-) effectiveness of the ketogenic diet in children and adolescents with intractable epilepsy.Methods/DesignIn a RCT we will compare the ketogenic diet with usual care. Embedded in this RCT will be a trial-based and model-based economic evaluation, looking from a societal perspective at the cost-effectiveness and cost-utility of the ketogenic diet versus usual care. Fifty children and adolescents (aged 1-18) with intractable epilepsy will be screened for eligibility before randomization into the intervention or the usual care group. The primary outcome measure is the proportion of children with a 50% or more reduction in seizure frequency. Secondary outcomes include seizure severity, side effects/complaints, neurocognitive, socio-emotional functioning, and quality of life. Costs and productivity losses will be assessed continuously by a prospective diary and a retrospective questionnaire. Measurements will take place during consults at baseline, at 6 weeks and at 4 months after the baseline period, and 3, 6, 9 and 12 months follow-up after the 4 months consult.DiscussionThe proposed research project will be the first study to provide data about the cost-effectiveness of the ketogenic diet for children and adolescents with intractable epilepsy, in comparison with usual care. It is anticipated that positive results in (cost-) effectiveness of the proposed intervention will contribute to the improvement of treatment for epilepsy in children and adolescents and will lead to a smaller burden to society.Trial registrationThe study has been registered with the Netherlands Trial Registry (NTR2498).

A randomized controlled trial of the ketogenic diet in refractory childhood epilepsy

To evaluate the efficacy and tolerability of the ketogenic diet (KD) during the first 4 months of a randomized controlled trial (RCT) in refractory epilepsy patients aged 1–18 years.

Cognitive and behavioral impact of the ketogenic diet in children and adolescents with refractory epilepsy: A randomized controlled trial

PURPOSE The ketogenic diet (KD) is increasingly used for the treatment of refractory epilepsy in childhood because of the beneficial effect on seizure reduction. The aim of the current study was to objectively assess cognition and aspects of behavior during the first 4months of a randomized controlled study in children and adolescents. METHODS Participants from a tertiary epilepsy center were randomized to a KD group (intervention) or a care-as-usual (CAU) group (control). Follow-up assessments on cognition and behavior were performed approximately 4months after initiation of the KD with a combination of parent report questionnaires and individually administered psychological tests for the children. RESULTS A total of 50 patients were enrolled in this study, 28 patients from the KD group and 22 patients from the CAU group. The KD group showed lower levels of anxious and mood-disturbed behavior and was rated as more productive. Cognitive test results showed an improvement of activation in the KD group. CONCLUSIONS This study showed a positive impact of the KD on behavioral and cognitive functioning in children and adolescents with refractory epilepsy. More specifically, an activated mood and cognitive activation were observed in patients treated with the KD.

Cost-effectiveness of the ketogenic diet and vagus nerve stimulation for the treatment of children with intractable epilepsy

PURPOSE The objective of this study was to estimate the expected cost-utility and cost-effectiveness of the ketogenic diet (KD), vague nerve stimulation (VNS) and care as usual (CAU), using a decision analytic model with a 5-year time horizon. METHODS A Markov decision analytical model was constructed to estimate the incremental costs, quality-adjusted life years (QALYs) and successfully treated patient (i.e. 50% or more seizure reduction) of the treatment strategies KD, VNS and CAU, from a health care perspective. The base case considered children with intractable epilepsy (i.e. two or more antiepileptic drugs had failed) aged between 1 and 18 years. Data were derived from literature and expert meetings. Deterministic and probabilistic sensitivity analyses were performed. RESULTS Our results suggest that KD is more effective and less costly, and thus cost-effective compared with VNS, after 12 months. However, compared to CAU, neither KD nor VNS are cost-effective options, they are both more effective but also more expensive (€346,899 and €641,068 per QALY, respectively). At 5 years, VNS is cost-effective compared with KD and CAU (€11,378 and €68,489 per QALY, respectively) and has a 51% probability of being cost-effective at a ceiling ratio of €80,000 per QALY. CONCLUSIONS Our results suggest that on average the benefits of KD and VNS fail to outweigh the costs of the therapies. However, these treatment options should not be ignored in the treatment for intractable epilepsy in individual or specific groups of patients. There is a great need for high quality comparative studies with large patient samples which allow for subgroup analyses, long-term follow-up periods and outcome measures that measure effects beyond seizure frequency (e.g. quality of life). When this new evidence becomes available, reassessment of the cost-effectiveness of KD and VNS in children with intractable epilepsy should be carried out.