Calcium antagonists as an add-on therapy for drug-resistant epilepsy.

BACKGROUND: As up to 30% of patients with epilepsy do not have their seizures controlled with current treatments, there have been continuous attempts to find new antiepileptic drugs based on increasing knowledge of cellular and molecular biology involved in the genesis of epilepsy and seizures. Calcium has been established to play a major role in seizure occurrence, thus, calcium antagonists that can alter the effects of calcium on brain cells have been investigated for effect on epileptic seizures. OBJECTIVES: To evaluate the effects of calcium antagonists on seizures, side effects, quality of life and cognition, when used as an add-on therapy for patients with drug-resistant epilepsy. SEARCH STRATEGY: We searched MEDLINE from 1966 to 2000 and the Cochrane Epilepsy Group trials register, the Cochrane Controlled Trials Register (The Cochrane Library Issue 1, 2001). SELECTION CRITERIA: Randomized placebo-controlled add-on trials of any calcium antagonists in patients with drug-resistant epilepsy. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted data. Outcomes were: (a) 50% or greater reduction in seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. For crossover trials, the first treatment period was treated as a parallel trial. Analyses were by intention to treat. Due to problems acquiring the data needed from crossover trials, overall results from these trials were summarised in tables. MAIN RESULTS: Eleven trials were included. One parallel and seven crossover trials of flunarizine, two crossover trials of nimodipine and one crossover trial of nifedipine. For flunarizine, the odds ratio (OR) (95% Confidence Intervals (CIs)I) for a 50% or greater reduction in seizure frequency for the parallel trial was 1.64 (0.55, 4.94) indicating a non-significant advantage for flunarizine. We were unable to acquire data for this outcome from the seven crossover trials. The overall OR (95% CI) for treatment withdrawal for flunarizine was 5.83 (2.06, 16.45) indicating patients were significantly more likely to have flunarizine withdrawn than placebo. No side effects were statistically associated with flunarizine. For nifedipine we were unable to acquire the data we required from the two crossover trials for our specified outcomes. For the outcomes reported in the trials, nifedipine had no significant effect in seizures frequency. For nimodipine, we only had data from the first treatment period from one of the two crossover trials (17 subjects). The ORs (95% CIs) for a 50% or greater reduction in seizure frequency was 11.34 (1.00, 128.03) and for treatment withdrawal was 2.46 (0.22, 27.75). REVIEWER'S CONCLUSIONS: Flunarizine may have a weak effect on seizure frequency, but had a significant withdrawal rate probably due to side effects, and should not be recommended for use as an add-on treatment. Similarly, there is no convincing evidence to support the use of nifedipine or nimodipine as add-on treatments for epilepsy.

Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review.

OBJECTIVE: To undertake a systematic review and meta-analysis of placebo controlled add-on trials of levetiracetam, oxcarbazepine, remacemide and zonisamide for patients with drug resistant localization related epilepsy. METHODS: We searched Medline, The Cochrane Library and contacted the relevant pharmaceutical companies. Outcomes were 50% or greater reduction in seizure frequency and treatment withdrawal for any reason. Data were synthesised in a meta-analysis. The effect of dose was explored in regression models for levetiracetam and remacemide. RESULTS: We found four trials (1023 patients) of levetiracetam, two (961) of oxcarbazepine, two (388) of remacemide and three (499) of zonisamide. Ignoring dose, the relative risks (95% CI) for a 50% response were 3.78 (2.62-5.44), 2.51 (1.88-3.33), 1.59 (0.91-2.97) and 2.46 (1.61-3.79), respectively. There was evidence for increasing effect with increasing dose for levetiracetam, oxcarbazepine and remacemide. The relative risks for treatment withdrawal were 1.21 (0.88-1.66), 1.72 (1.35-2.18), 1.90 (1.00-3.60) and 1.64 (1.02-2.62), respectively. CONCLUSIONS: These data suggest a useful effect for levetiracetam, oxcarbazepine and zonisamide. Levetiracetam has the more favourable 'responder-withdrawal ratio' followed by zonisamide and oxcarbazepine.

Cognitive status in the community dwelling Thai elderly.

OBJECTIVE: To survey the prevalence of cognitive impairment in the elderly and to estimate the prevalence of dementia in the community dwelling Thai population. To assess the psychometric property of Thai Mental State Examination (TMSE). MATERIAL AND METHOD: We conducted a countrywide survey of 3,177 Thai elderly who were 60 years old and over from 1995 to 1997. Medical history and ability to carry out daily activities were taken by trained medical personnel. Thai Mental State Examination (TMSE) was used for cognitive study. Every elderly person involved in this study was examined by either an internist or a neurologist. Blood was taken for haematological and biochemical analysis. SPSS 6.0 was the main statistical analysis of the data. RESULTS: Three thousand one hundred and seventy seven elderly people were enrolled in this study, thirty eight point eight per cent were male and sixty one point two per cent were female. There was correlation between age, education and TMSE (r=-0.345, r=0.473, p<0.001). We found no correlation between TMSE, mean arterial blood pressure (BP), systolic BP, diastolic BP, haematocrit, cholesterol, triglyceride, blood sugar and syphilitic serology. Multiple cut off points of TMSE was proposed to utilise the twenty fifth percentile in each five yearly age interval. Those who were under the 25th percentile of TMSE and had impaired daily activities were diagnosed as dementia. The prevalence of dementia was 9.88 percentiles in our study. CONCLUSION: Dementia is a common problem in the Thai elderly. As treatment has become available for several etiologies of dementia, early detection and assessment of dementia with a cognitive screening test are essential. Public education to distinguish between dementia and old age needs to be emphasised.

Levetiracetam add-on for drug-resistant localization related (partial) epilepsy.

BACKGROUND: The majority of patients with epilepsy have a good prognosis and their seizures are well controlled by a single antiepileptic drug. However, up to 30% develop refractory seizures, particularly those with partial seizures. In this review, we summarise the current evidence regarding a new antiepileptic drug, levetiracetam, when used as an add-on treatment for drug-resistant localization related (partial) epilepsy. OBJECTIVES: To evaluate the effects of levetiracetam on seizures, side effects, quality of life and cognition, when used as an add-on treatment for patients with a drug-resistant localization related (partial) epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trials register, the Cochrane Controlled Trials Register (Cochrane Library Issue 2, 2000). In addition, we contacted UCB SA (makers of levetiracetam) and experts in the field to seek any ongoing studies or unpublished studies. SELECTION CRITERIA: Randomized placebo controlled add-on trials of levetiracetam in patients with a drug-resistant localization related (partial) epilepsy. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted relevant data. The following outcomes were assessed: (a) 50% or greater reduction in total seizure frequency; (b) treatment withdrawal (any reason); (c) side effects; (d) cognitive effects; (e) quality of life. Primary analyses were intention to treat. Sensitivity best and worst case analyses were also undertaken. Summary odds ratios (ORs) were estimated for each outcome. Dose response was evaluated in regression models. MAIN RESULTS: Four trials (1023 patients) were included. All four trials had data for treatment withdrawal and side effect outcomes. Three trials (904 patients) had data for 50% or greater reduction in seizure frequency. Three trials (595 patients) had data for quality of life and cognitive outcomes. The overall Odds Ratio (OR) (95% Confidence Interval (CI)) for 50% or greater reduction in total seizure frequency outcome was 3.81 (2.78,5.22). Dose regression analysis shows clear evidence that levetiracetam reduces seizure frequency with an increase in efficacy with increasing dose of levetiracetam. Approximately 15% of patients taking 1000 mg and 20-30% of patients taking 3000 mg levetiracetam per day have a 50% or greater reduction in seizure frequency. Patients were not significantly more likely to have levetiracetam withdrawn, OR (95% CI) 1.25 (0.87,1.80). The following side effects were significantly associated with levetiracetam: dizziness 2.36 (1.21, 4.61) and infection 1.82 (1.05, 3.14) whereas accidental injury was significantly associated with placebo 0.55 (0.32, 0.93). Quality of life and cognitive effect outcomes suggest that levetiracetam has a positive effect on cognition and some aspects of quality of life. REVIEWER'S CONCLUSIONS: Levetiracetam reduces seizure frequency when used as an add-on treatment for patients with a drug-resistant localization related (partial) epilepsy, and seems well tolerated. Minimum effective and maximum tolerated doses have not been identified. The trials reviewed were of 16-24 weeks duration and results cannot be used to confirm longer term effects. Our results cannot be extrapolated to monotherapy or to patients with other seizure types or epilepsy syndromes. Great care should also be taken with any attempt to apply these results to children.