New drug treatments for epilepsy.
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Anticonvulsants↗
Biomedical subjects
A G Marson
Publications and source records attributed to A G Marson.
Carbamazepine versus valproate monotherapy for epilepsy.
BACKGROUND: Carbamazepine and valproate are drugs of first choice for epilepsy. Despite the lack of hard evidence from individual randomized controlled trials, there is strong clinical belief that valproate is the drug of choice for generalized epilepsies and carbamazepine for partial epilepsies. OBJECTIVES: To overview the best evidence comparing carbamazepine and valproate monotherapy SEARCH STRATEGY: Our search strategy included: (a) MEDLINE 1966-99, (b) The Cochrane Library 1999 issue 4, (c) The trial register of the Cochrane Epilepsy Group (d) the pharmaceutical industry. SELECTION CRITERIA: Randomized controlled trials comparing carbamazepine and valproate monotherapy for epilepsy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcome measures were time to withdrawal of allocated treatment, time to 12 month remission, and time to first seizure post randomization. Data were analysed using the stratified Logrank test with results expressed as hazard ratios (HR) (95% CI), where HR>1 indicates an event is more likely on valproate. A test for an interaction between treatment and epilepsy type (partial versus generalized) was also undertaken. MAIN RESULTS: Results Data were available for 1265 patients from five trials, representing 85% of the patients recruited into the eight trials that met our inclusion criteria. The main overall results (HR 95% CI) were: Time to treatment withdrawal 0.97 (0.79-1.18), 12 month remission 0.87 (0.74-1.02), first seizure 1.09 (0.96-1.25) suggesting no overall difference for these outcomes. The test for an interaction between treatment and epilepsy type was non significant for time to treatment withdrawal and 12 month remission, but significant for time to first seizure. The age distribution of adults classified as having a generalized epilepsy indicate that significant numbers of patients may have had their epilepsy misclassified. REVIEWER'S CONCLUSIONS: We have found some evidence to support the policy of using carbamazepine as the first treatment of choice in partial epilepsies, but no evidence to support the choice of valproate in generalized epilepsies, but confidence intervals are too wide to confirm equivalence. Misclassification of patients may have confounded our results, and has important implications for the design and conduct of future trials.
Adult↗
Gabapentin for drug-resistant partial epilepsy.
BACKGROUND: The majority of epileptic patients have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding a new antiepileptic drug, gabapentin, when used as an add-on treatment for drug-resistant partial epilepsy OBJECTIVES: To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for patients with drug-resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trial register, the Cochrane Controlled Trials Register of The Cochrane Library Issue 4, 1998. In addition, we contacted Parke Davis (manufacturers of gabapentin) and experts in the field to seek any ongoing studies or unpublished studies. SELECTION CRITERIA: Randomized placebo controlled double blind add-on trials of gabapentin in patients with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted the relevant data. The following outcomes were assessed: (a) 50% or greater reduction in seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. Primary analyses were intention to treat. Sensitivity best and worst case analyses were also undertaken. Summary odds ratios were estimated for each outcome. Dose response was evaluated in regression models, and Number Needed to Treat (NNTs) were calculated for individual doses. MAIN RESULTS: Four trials were included representing 750 randomized patients. EFFICACY: Overall odds ratio (OR) (95% Confidence Interval (CI)) for 50% or greater reduction in seizure frequency compared to placebo 2.22 (1.49 - 3.32). Dose regression analysis shows increasing efficacy with increasing dose, with 28.5% (21.5 - 36.7) of patients responding to 1800mg of gabapentin compared to placebo, NNT 6.7 (3.0 - 10.5). Global effectiveness: treatment withdrawal OR (95% CI) compared to placebo 1.40 (0.76 - 2.55); Side effects: OR (99% CI) compared to placebo. dizziness 2.26 (1.28 - 3.99); fatigue 2.29 (1.11 - 4.74); somnolence 2.04 (1.21 - 3.45) were significanty associated with gabapentin. REVIEWER'S CONCLUSIONS: Gabapentin has efficacy as an add-on treatment in patients with drug-resistant partial epilepsy. However, trials reviewed were of relatively short duration, and provide no evidence for the long term efficacy of gabapentin. Results cannot be extrapolated to monotherapy or patients with other epilepsy types.
Acetates↗
Zonisamide for drug-resistant partial epilepsy.
BACKGROUND: The majority of epileptic patients have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding a new antiepileptic drug, zonisamide, when used as an add-on treatment for drug-resistant partial epilepsy. OBJECTIVES: To evaluate the efficacy and tolerability of zonisamide when used as an add-on treatment for patients with drug -resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trial register, the Cochrane Controlled Trials Register (Cochrane Library Issue 4, 1999). In addition, we contacted Dianippon and Elan Pharma (makers and licensees of zonisamide) and experts in the field to seek any ongoing studies or unpublished studies. SELECTION CRITERIA: Randomized placebo controlled add-on trials of zonisamide in patients with drug-resistant 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) adverse events. Primary analyses were intention to treat. Sensitivity best and worst case analyses were also undertaken. Summary odds ratios (ORs) were estimated for each outcome. MAIN RESULTS: Three trials were included with 499 patients randomized. EFFICACY: Overall odds ratio (OR, 95% CI) for 50% reduction in seizure frequency compared to placebo was 2.07 (1.36,3.15) for a 400mg/day dose of zonisamide. When the full treatment period of 12 weeks was considered for all three trials including varied rates of titration to 400mg/day the OR compared to placebo was 2.72 (1.74,4. 25). There was insufficient evidence to support a dose response relationship between dose and responder rate. Tolerability: Treatment withdrawal OR compared to placebo was 1.74 (1.03,2.95). Adverse events: ataxia 3.94 (1.23,12.57), somnolence 2.11 (1.11, 3. 98), agitation 3.52 (1.26,9.68), agitation and irritability 2.43(1. 04,5.66) and anorexia 2.98(1.38,6.42) were significantly associated with zonisamide. REVIEWER'S CONCLUSIONS: Zonisamide has efficacy as an add-on treatment in patients with drug-resistant partial epilepsy. Minimum effective and maximum tolerated doses cannot be identified. The trials reviewed were of 12 week duration and results cannot be used to conform longer periods of effectiveness in seizure control. The results cannot be extrapolated to monotherapy or to patients with other seizure types or epilepsy syndromes.
Anticonvulsants↗
Topiramate for drug-resistant partial epilepsy.
BACKGROUND: The majority of epileptic patients have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarize the current evidence regarding a new antiepileptic drug, topiramate, when used as an add-on treatment for drug-resistant partial epilepsy. OBJECTIVES: To evaluate the efficacy and tolerability of topiramate when used as an add-on treatment in patients with drug resistant partial epilepsy. SEARCH STRATEGY: (a) The Cochrane Library (1999 Issue 1); (b) The controlled trial register of the Cochrane Epilepsy Group; (c) Johnson and Johnson, makers of topiramate; (d) Experts in the field. SELECTION CRITERIA: Randomized placebo controlled add-on trials of topiramate in patients with drug resistant epilepsy. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted the relevant data. The following outcomes were assessed: (a) 50% or greater reduction in seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. Primary analyses were intention to treat. Summary odds ratios (OR) were estimated for each outcome. Dose response was evaluated in regression models. MAIN RESULTS: Six trials were included representing 743 randomized patients. EFFICACY: Overall OR (95% CIs) for 50% or greater reduction in seizure frequency compared to placebo 4.06 (2.86-5.78). Dose regression analysis shows increasing efficacy with increasing dose, but found no advantage for doses over 400 mg per day. Global effectiveness: treatment withdrawal OR (95% CIs) compared to placebo 2.57 (1.65-4.00). Side effects: OR (99% CIs)compared to placebo, dizziness 1.99 (1.20-3.29); fatigue 2.52 (1. 47-4.32); nausea 2.84 (1.36-5.93); somnolence 2.89 (1.72-4.85) and 'thinking abnormally' 3.71 (2.02-6.80) were significantly associated with topiramate. REVIEWER'S CONCLUSIONS: Topiramate has efficacy as an add-on treatment in patients with drug resistant partial epilepsy. However, trials reviewed were of relatively short duration, and provide no evidence for the long term efficacy of topiramate. Results cannot be extrapolated to monotherapy or patients with other epilepsy types.
Anticonvulsants↗
Lamotrigine add-on for drug-resistant partial epilepsy.
BACKGROUND: Epilepsy is a common neurological disorder, affecting almost 0.5 to 1% of the population. Nearly 30% of patients with epilepsy are refractory to currently available drugs. Lamotrigine is one of the newer antiepileptic drugs and is the topic of this review. OBJECTIVES: To examine the effects of lamotrigine on seizures, side effects, cognition and quality of life, when used as an add-on treatment for patients with drug-resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trials register, the Cochrane Controlled Trials Register (Cochrane Library Issue 1, 2000), MEDLINE (January 1966 to December 1999) and reference lists of articles. We also contacted the manufacturers of lamotrigine (Glaxo-Wellcome). SELECTION CRITERIA: Randomized placebo controlled trials, of patients with drug-resistant partial epilepsy of any age, in which an adequate method of concealment of randomization was used. The studies may be double, single or unblinded. For crossover studies, the first treatment period was treated as a parallel trial. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the trials for inclusion and extracted data. Primary analyses were by intention to treat. Outcomes included 50% or greater reduction in seizure frequency, treatment withdrawal (any reason), side effects, effects on cognition, and quality of life. MAIN RESULTS: We found three parallel add-on studies and eight cross-over studies, which included 1243 patients (199 children and 1044 adults). The overall Peto's Odds Ratio (OR) and 95% confidence intervals (CIs) across all studies for 50% or greater reduction in seizure frequency was 2.71 (1.87, 3.91) indicating that lamotrigine is significantly more effective than placebo in reducing seizure frequency. The overall OR (95%CI) for treatment withdrawal (for any reason) is 1.12 (0.78, 1. 61). The 99% CIs for ataxia, dizziness, nausea, and diplopia do not include unity, indicating that they are significantly associated with lamotrigine. The limited data available preclude any conclusions about effects on cognition and quality of life, though there may be minor benefits in affect balance (happiness) and mastery. REVIEWER'S CONCLUSIONS: Lamotrigine add-on therapy is effective in reducing the seizure frequency, in patients with drug-resistant partial epilepsy. Further trials are needed to assess the long term effects of lamotrigine, and to compare it with other add-on drugs.
Anticonvulsants↗
Individual patient data meta-analysis of randomized anti-epileptic drug monotherapy trials.
Meta-analysis may be based on either aggregate data or individual patient data (IPD). Three reasons why IPD are desirable for the meta-analysis of anti-epileptic drug (AED) monotherapy trials are: (1) to undertake a more complete analysis of time-to-event outcomes; (2) to investigate the interaction between AED and type of epilepsy; and (3) to undertake re-analysis of the trial to obtain results for all relevant outcomes. We demonstrate that IPD meta-analysis is possible in AED research. Problems arose from missing data at four levels: (1) unknown trials; (2) known trials but no IPD supplied; (3) known trials but missing outcome data for some individuals within trials; and (4) known trials but missing covariate data for some individuals within trials. Empirical evidence of the reliability of meta-analyses based on aggregate rather than individual patient data is still lacking. Examples of other benefits such projects may bring include improvements to the design of a new trial in the area, in terms of the sample size considerations, the definition of outcomes and data collection.
Anticonvulsants↗
Quality-of-life and behavioral outcome measures in randomized controlled trials of antiepileptic drugs: a systematic review of methodology and reporting standards.
PURPOSE: To review the methodology and use of quality-of-life and behavioral measures used in randomized controlled trials (RCTs) of antiepileptic drugs in patients with epilepsy. METHODS: Trial reports were found by searching a previously developed comprehensive database of epilepsy RCTs and searching through journals by hand. Inclusion and exclusion criteria were applied, and methodological and quality-of-life and behavioral measure data were extracted. RESULTS: There were 52 different measures used in 46 trials, with the Profile of Mood States, the Minnesota Multiphasic Personality Inventory, and the Washington Psychosocial Seizure Inventory being applied the most frequently. Overall, evidence of the reliability, validity, and sensitivity of measures used in populations of people with epilepsy was sparse. There was also little information on the clinical interpretation of the results. CONCLUSION: Our results highlight a consistent failure to apply quality-of-life and behavioral measures in RCTs in a systematic way. We found repeated evidence of researchers' failure to review the use of previous measures and selection of measures without evidence of their appropriateness for use in a population with epilepsy. We recommend the use of quality-of-life and behavioral measures in RCTs with proven psychometric properties in a population with epilepsy.
Adult↗
Report of a pragmatic trial comparing clobazam and "standard" treatment in childhood epilepsy.
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Anti-Anxiety Agents↗
Studies of drugs in epilepsy cited by author are not evidence based.
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Anticonvulsants↗
Neuropsychological outcomes in randomized controlled trials of antiepileptic drugs: a systematic review of methodology and reporting standards.
PURPOSE: To systematically review the methodology and use of neuropsychological tests in randomized controlled trials (RCTs) of antiepileptic drugs (AEDs) in patients with epilepsy. METHODS: Trial reports were found by searching Medline 1966-1996 and searching through journals by hand. Inclusion and exclusion criteria were applied, and methodological and neuropsychological test data was extracted by using a proforma. RESULTS: 43 reports met our inclusion criteria, representing 40 RCTs. as three RCTs had generated two reports. Twenty-two were actively controlled, and 18 were placebo-controlled studies. Reporting of basic methods such as randomization method was poor. There has been no uniform approach to the use of neuropsychological tests, and a total of 87 has been used. The Stroop Colour Word Test and the Finger Tapping Test were most commonly used, at 13 times each, but were not used or reported in a uniform manner. CONCLUSIONS: Poor reporting of methods and the use of a plethora of neuropsychological tests create great difficulties for anyone wishing to make sense of currently available data. If we are better to understand the neuropsychological effects of AEDs, a more rational approach is needed, for which recommendations are made.
Adult↗
The new antiepileptic drugs: a systematic review of their efficacy and tolerability.
PURPOSE: Gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS) are all in use as "add-on" treatment for patients with refractory epilepsy. There have been no comparative randomized controlled trials allowing an evidence-based choice between these drugs. We report a series of meta-analyses of randomized placebo-controlled add-on trials in which these drugs have been tested in patients with partial epilepsy. This work provides an estimate of each drug's efficacy and tolerability compared with placebo. These estimates are compared across drugs to give broad estimates of comparative efficacy and tolerability. METHODS: Trial reports were found by searching Medline, by searching through journals by hand, and by contacting the pharmaceutical industry. The outcomes chosen were the proportion of patients who (a) have a > or = 50% reduction in seizure frequency (50% responders); (b) withdrew from the study (any reason); or (c) reported the following side effects: ataxia, dizziness, fatigue, nausea, or somnolence. Overall odds ratio (OR) with 95% confidence intervals (CIs; 50% responders) or 99% CIs; side effects) were calculated. RESULTS: Twenty-nine trials were included, representing 4,091 randomized patients. The ORs for 50% response (95% CI) were GBP, 2.29 (1.53-3.43); LTG, 2.32 (1.47-3.68); TGB, 3.03 (2.01-4.58); TPM, 4.07 (2.87-5.78); VGB, 3.67 (2.44-5.51); and ZNS, 2.7 (1.36-4.47). ORs for discontinuation were GBP, 1.36 (0.75-2.49); LTG, 1.19 (0.79-1.79); TGB, 1.81 (1.21-2.70); TPM, 2.56 (1.64-4.00); VGB, 2.58 (126-5.27); and ZNS, 4.23 (1.71-10.49). CONCLUSIONS: We have clear evidence that each of these drugs is better than placebo at preventing seizures. When results are compared across drugs, the confidence intervals overlap, and we have no conclusive evidence of differences in efficacy or tolerability. Despite this, the agent that appears most effective may be twice as effective as the agent that appears least effective, and the agent that appears most likely to cause discontinuation may be 4 times more likely to do so than the treatment that appears least likely to do so. Comparative randomized studies are needed further to evaluate these drugs.
Acetates↗
New antiepileptic drugs: a systematic review of their efficacy and tolerability.
OBJECTIVES: To evaluate the efficacy and tolerability of the newly developed antiepileptic drugs gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide in patients with refractory partial epilepsy. DESIGN: Systematic review of published and unpublished randomised controlled trials of add-on treatment with new antiepileptic drugs. SUBJECTS: 20 published and eight unpublished trials representing 3883 patients with refractory partial epilepsy. MAIN OUTCOME MEASURES: Proportion of patients who (a) showed 50% or greater reduction in frequency of seizures (50% responders) and (b) withdrew from each study for any reason. RESULTS: Odds ratios (95% confidence intervals) relative to placebo for 50% responders were 2.29 (1.53 to 3.43) for gabapentin, 2.32 (1.47 to 3.68) for lamotrigine, 3.03 (2.01 to 4.58) for tiagabine, 4.22 (2.80 to 6.35) for topiramate, 3.68 (2.45 to 5.51) for vigabatrin, and 2.47 (1.36 to 4.47) for zonisamide. Odds ratios for withdrawal were 1.36 (0.75 to 2.49) for gabapentin, 1.19 (0.79 to 1.79) for lamotrigine, 1.81 (1.21 to 2.70) for tiagabine, 2.42 (1.43 to 4.11) for topiramate, 2.58 (1.26 to 5.27) for vigabatrin, and 5.70 (1.76 to 18.49) for zonisamide. Comparing results for each drug showed that all of the 95% confidence intervals overlapped, indicating that they were not significantly different in terms of efficacy and tolerability. CONCLUSIONS: All six drugs were significantly better than placebo at reducing frequency of seizures. These results do not allow an evidence based choice between these drugs as we have no conclusive indication of differences in efficacy or tolerability.
Acetates↗
Comparing antiepileptic drugs.
The physician's choice of antiepileptic drug for a particular patient should be based on firm evidence. The current body of evidence generated from randomized, controlled monotherapy trials is discussed. Attention is focused on four recently published randomized trials in which monotherapy with one drug is compared with monotherapy with another. The limitations of our current knowledge are discussed and some suggestions for future research are made.
Anticonvulsants↗
How easy are randomized controlled trials in epilepsy to find on Medline? The sensitivity and precision of two Medline searches.
Recognition of the need for more scientifically acceptable review strategies is increasing. Systematic reviews have rarely been performed on randomized controlled trials (RCTs) in the field of epilepsy. We have 355 published RCTs on a database, which will be used as a data source from systematic reviews. We wished to test the sensitivity and precision of two Medline search strategies, and to identify reasons why RCTs were missed. Both a basic and a comprehensive search strategy were used to search Medline from 1966 to 1993. Three journals (Epilepsia, Epilepsy Research, Acta Neurological Scandinavica) were searched by hand. The sensitivity and precision of these Medline search strategies in these three journals was calculated. We investigated articles missed by our comprehensive search to ascertain why they had been missed. Of the 308 RCTs on the database published between 1966 and 1993, 275 were found by our comprehensive Medline search, whereas 103 were found by our basic search. The overall precision of our comprehensive and basic searches was 35 and 72%, respectively. The overall sensitivity of our comprehensive and basic searches was 86 and 66%, respectively. Our comprehensive search failed to find 16 RCTs published in the three journals searched by hand. Articles were missed because they were inadequately indexed on Medline and/or did not contain adequate methodological information in their titles or abstracts. To find all relevant trials, a search strategy must be as sensitive as possible, but this sensitivity inevitably involves loss of precision. The National Library of Medicine is addressing indexing problems with Medline, but the quality of reports also must be improved to enhance retrieval.
Abstracting and Indexing↗