Biomedical subjects
Publications and source records attributed to A G Marson.
In the Multi-Centre Study of Early Epilepsy and Single Seizures (MESS), patients were randomly allocated to immediate or delayed antiepileptic drug treatment. For time to first seizure recurrence, MESS provides strong evidence of an effect for carbamazepine as monotherapy but mixed evidence of an effect for valproate.
OBJECTIVE: To compare the effects of carbamazepine and lamotrigine monotherapy for people with partial onset seizures or generalized onset tonic-clonic seizures. METHODS: A systematic review and meta-analysis using data on individual patients from randomized trials comparing lamotrigine with carbamazepine monotherapy. The review draws on the search strategy developed for the Cochrane Epilepsy Group, which searches MEDLINE and the Cochrane Controlled Trials register, and hand searches relevant journals. The outcomes considered were time to antiepileptic drug withdrawal, which would usually be for either inadequate seizure control or unacceptable adverse effects, time to first seizure, and 6-month remission. RESULTS: Five randomized trials were identified containing data for 1,384 participants. Time to treatment withdrawal significantly improved with lamotrigine compared to carbamazepine (hazard ratio 0.55, 95% CI 0.35 to 0.84, random effects), while time to first seizure (hazard ratio 1.14, 95% CI 0.92 to 1.43, fixed effects) and seizure freedom at 6 months (relative risk 0.92, 95% CI 0.81 to 1.04, fixed effects) favor carbamazepine although the results are not significant. CONCLUSIONS: Lamotrigine is significantly less likely to be withdrawn than carbamazepine, but results for time to first seizure suggest a nonsignificant trend that carbamazepine may be superior in terms of seizure control. Trials were of too short a duration to measure clinically important efficacy outcomes such as time to 12-month remission. Current industry-sponsored trials fail to adequately inform clinical practice and further more clinically relevant trials are needed in which longer-term outcomes are assessed before the place of lamotrigine in the treatment of epilepsy is defined.
BACKGROUND: Worldwide, phenytoin is a commonly used antiepileptic drug. Oxcarbazepine is one of the newer antiepileptic drugs and has similar chemical properties to its parent compound carbamazepine. For the new drugs such as oxcarbazepine, it is important to know how they compare with standard treatments. OBJECTIVES: To review the best evidence comparing oxcarbazepine and phenytoin when used as monotherapy in patients with epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group's Specialized Register (December 2005), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005), and MEDLINE (1966 to November 2005). No language restrictions were imposed. We checked the reference lists of retrieved studies for additional reports of relevant studies. We also contacted pharmaceutical companies to try and identify any unpublished studies. SELECTION CRITERIA: Randomized controlled trials in children or adults with epilepsy. Trials must have included a comparison of oxcarbazepine monotherapy with phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Outcomes were (a) time on allocated treatment; (b) time to achieve 6, 12 and 24-month remission; (c) time to first seizure post randomization; (d) quality of life measures if available. Clinical heterogeneity was assessed by reviewing differences across trials in characteristics of randomized patients, dosing protocols and trial design. Data were analysed on an intention to treat basis. Stratified logrank tests were used to obtain study-specific and overall estimates of hazard ratios (with 95% confidence intervals), where a HR > 1 indicates that an event is more likely on phenytoin. MAIN RESULTS: Individual patient data were available for 480 patients from two trials, representing 100% of the patients recruited into the two trials that met our inclusion criteria. By convention, for the outcomes time to withdrawal of allocated treatment and time to first seizure a hazards ratio (HR) > 1 indicates a clinical advantage for oxcarbazepine and for time to 6 and 12-month remission a HR > 1 indicates a clinical advantage for phenytoin. The main overall results (HR, 95% confidence interval (CI)) were: (i) time to withdrawal of allocated treatment 1.64 (1.09 to 2.47), (ii) time to 6-month remission 0.89 (0.66 to 1.22), (iii) time to 12-month remission 0.92 (0.62 to 1.37), (iv) time to first seizure 1.07 (0.83 to 1.39). The overall results indicate that oxcarbazepine is significantly better than phenytoin for time to treatment withdrawal, but suggest no overall difference between oxcarbazepine and phenytoin for other outcomes. Results stratified by seizure type indicate no significant advantage for either drug for patients with generalized onset seizures, but a potentially important advantage in time to withdrawal for oxcarbazepine for patients with partial onset seizures: HR 1.92 (95% CI 1.17 to 3.16). The age distribution of adults classified as having generalized epilepsy suggests a significant number of patients may have had their epilepsy misclassified. AUTHORS' CONCLUSIONS: For patients with partial onset seizures oxcarbazepine is significantly less likely to be withdrawn, but current data do not allow a statement as to whether oxcarbazepine is equivalent, superior or inferior to phenytoin in terms of seizure control. Guidelines recommend carbamazepine as a first line treatment for patients with partial onset seizures and more evidence is needed regarding the comparative effects of oxcarbazepine and carbamazepine to further inform policy. For patients with generalized onset tonic-clonic seizures, valproate is considered the first line standard treatment and the results of this review do not inform current treatment policy. Misclassification of patients' epilepsy type may have confounded the results of this review.
BACKGROUND: The choice of an antiepileptic drug (AED) for any individual should take into account reliable information about seizure control, adverse effects and cost. Carbamazepine is the usual drug of choice for people with newly-diagnosed partial onset seizures. Lamotrigine is a relatively new AED which is licensed in many countries for use as an initial monotherapy. OBJECTIVES: To review the best evidence comparing carbamazepine and lamotrigine when used as monotherapy in people with partial onset seizures, or generalized onset tonic-clonic seizures with or without other generalized seizure types. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group's Specialized Register (July 2005), the Cochrane Central Register of Controlled Trials (CENTRAL) (TheCochraneLibrary Issue 2, 2005), and MEDLINE (1966 to August 2005). No language restrictions were imposed. We also contacted pharmaceutical companies and trial investigators. SELECTION CRITERIA: Randomized controlled trials, blinded or unblinded, in which children or adults with partial onset seizures or generalized onset tonic-clonic seizures were randomized to monotherapy with either carbamazepine or lamotrigine. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcomes were (1) time to treatment withdrawal, (2) time to first seizure post randomization, and (3) seizure freedom at six months. Time to event data were analysed using a stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI); binary data were expressed as relative risks (RR) and 95% confidence intervals (95% CI). A HR or a RR greater than 1 indicated an event was more likely on lamotrigine than carbamazepine. MAIN RESULTS: Individual patient data were available for 1384 participants (100% of total randomized) from the five trials that met our inclusion criteria. The main results (HR (95% CI)) were (1) time to treatment withdrawal 0.55 (0.35 to 0.84) (random-effects), (2) time to first seizure post randomization 1.14 (95% CI 0.92 to 1.43), and (3) seizure freedom at six months RR 0.92 (95% CI 0.81 to 1.04). The review suggested that time to treatment withdrawal was significantly improved with lamotrigine compared to carbamazepine, while time to first seizure and seizure freedom at six months favoured carbamazepine although the results were not statistically significant. AUTHORS' CONCLUSIONS: Lamotrigine was significantly less likely to be withdrawn than carbamazepine but results for time to first seizure suggested that carbamazepine may be superior in terms of seizure control. Trials were of too short a duration to measure important seizure outcomes such as time to 12 month remission. Further trials are needed in which longer-term outcome is assessed as well as measures such as psychosocial outcome and quality of life.
BACKGROUND: The majority of people with epilepsy 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 zonisamide, when used as an add-on treatment for drug-resistant partial epilepsy. OBJECTIVES: To evaluate the effects of zonisamide when used as an add-on treatment for people with drug-resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group Specialized Register (August 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005). In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing/unpublished studies. SELECTION CRITERIA: Randomized placebo controlled add-on trials of zonisamide in people with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Outcomes were: (1) 50% or greater reduction in total seizure frequency; (2) treatment withdrawal; (3) adverse events. Primary analyses were intention-to-treat. Summary relative risks (RRs) were estimated for each outcome. MAIN RESULTS: Four trials (850 participants) were included. The overall RR with 95% confidence intervals (CIs) for 50% reduction in seizure frequency compared to placebo for 300 to 500 mg/day of zonisamide was 2.44 (95% CI 1.81 to 3.30). The RR for any dose zonisamide (100 to 500 mg per day) was 2.35 (1.74 to 3.17). Two trials provide evidence of a dose response relationship for this outcome. The RR for treatment withdrawal for 300 to 500 mg/day zonisamide compared to placebo was 1.64 (1.20 to 2.26), and for 100 to 500 mg per day was 1.47 (1.07 to 2.02). The CIs of the following adverse effects indicate that they are significantly associated with zonisamide: ataxia 4.50 (99% CI 1.05 to 19.22); dizziness 1.77 (99% CI 1.00 to 3.12); somnolence 1.96 (99% CI 1.12 to 3.44); agitation 2.37 (99% CI 1.00 to 5.64); and anorexia 3.00 (99% CI 1.31 to 6.88). AUTHORS' CONCLUSIONS: Zonisamide has efficacy as an add-on treatment in people 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 confirm longer periods of effectiveness in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.
BACKGROUND: Absence seizures are brief epileptic seizures which present in childhood and adolescence. They are characterised by sudden loss of awareness and an electroencephalogram (EEG) typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of anticonvulsant for a child with typical absence seizures. OBJECTIVES: To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures, when compared with placebo or each other. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group's Specialised Register (March 2005), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to March 2005) and EMBASE (1988 to March 2005). No language restrictions were imposed. In addition, we contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively. SELECTION CRITERIA: Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with absence seizures: ethosuximide; sodium valproate; lamotrigine or placebo. DATA COLLECTION AND ANALYSIS: Outcome measures were: (1) proportion of individuals seizure free at 1, 3, 6, 12 and 18 months post randomisation; (2) people with a 50% or greater reduction in seizure frequency; (3) normalisation of EEG and/or negative hyperventilation test and (4) adverse effects. Data were independently extracted by two review authors. Results are presented as relative risks (RR) with 95% confidence intervals (95% CI). MAIN RESULTS: Five small trials were found, four of them were of poor methodological quality. One trial (29 participants) compared lamotrigine with placebo using a response conditional design. Individuals taking lamotrigine were significantly more likely to be seizure free than participants taking placebo during this short trial. Another trial compared lamotrigine with sodium valproate, the study lacked power to detect the difference in efficacy. Three studies compared ethosuximide, but because of diverse study designs and populations studied, we decided not to pool results in a meta-analysis. None of these studies found a difference between valproate and ethosuximide with respect to seizure control, but confidence intervals were wide and the existence of important differences could not be excluded. AUTHORS' CONCLUSIONS: Although ethosuximide, lamotrigine and valproate are commonly used to treat people with absence seizures we have insufficient evidence to inform clinical practice, and the few trials included in this review were of poor methodological quality and did not have sufficient number of participants. More trials of better quality are needed.
BACKGROUND: In developing countries, phenobarbitone is commonly used but its use in Europe and the USA has decreased due to concerns over adverse effects. Carbamazepine is recommended as the drug of choice for partial onset seizures, and there is concern that it may worsen some generalized onset seizure types. We report a review using individual patient data in which carbamazepine and phenobarbitone are compared. OBJECTIVES: To review the effects of carbamazepine compared to phenobarbitone monotherapy for people with partial onset seizures or generalized onset tonic-clonic seizures. SEARCH STRATEGY: The Cochrane Controlled trials register (Cochrane Library Issue 2, 2002); MEDLINE; EMBASE; handsearching; contacting experts and original trial investigators; contacting manufacturers of carbamazepine. SELECTION CRITERIA: Randomized or quasi-randomized, blinded or unblinded controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. DATA COLLECTION AND ANALYSIS: Outcome measures were (i) time to withdrawal of allocated treatment, (ii) time to 12 month remission, and (iii) time to first seizure. Data were analysed using a stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (CIs), where a HR>1 indicates an event is more likely on phenobarbitone. A test for interaction between treatment and seizure type (partial versus generalized onset) was also undertaken. MAIN RESULTS: Data are available for 684 participants from four trials, representing 59% of the participants recruited into the nine trials that met our inclusion criteria. The main overall results (HR 95% CI) adjusted for seizure type were, (i) time to withdrawal 1.63(1.23 to 2.15), (ii) time to 12 month remission 0.87(0.65 to 1.17), (iii) time to first seizure 0.85(0.68 to 1.05). The review suggests that time to withdrawal is significantly improved with carbamazepine compared to phenobarbitone. No overall difference between drugs is identified for the outcomes 'time to 12 month remission' and 'time to first seizure'. Statistical heterogeneity was not encountered. An interaction between treatment and seizure type, confirmed statistically, was identified for time to first seizure, where phenobarbitone was favoured for partial onset seizures and carbamazepine for generalized onset tonic-clonic seizures. REVIEWER'S CONCLUSIONS: We found no overall difference between carbamazepine and phenobarbitone for time to 12 month remission or time to first seizure, however, subgroup analyses for time to first seizure suggest an advantage with phenobarbitone for partial onset seizures and a clinical advantage with carbamazepine for generalized onset tonic-clonic seizures. Phenobarbitone is significantly more likely to be withdrawn, indicating that it is less well tolerated than carbamazepine.
BACKGROUND: Absence seizures are brief epileptic seizures which present in childhood and adolescence. They are characterised by sudden loss of awareness and an electroencephalogram (EEG) typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of anticonvulsant for a child with typical absence seizures. OBJECTIVES: To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures, when compared with placebo or each other. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trials register, the Cochrane Central Register of Controlled Trials (The Cochrane Library issue 1, 2003), MEDLINE (January 1966 to March 2003) and EMBASE (1988 to March 2003). We also contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively. SELECTION CRITERIA: Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with absence seizures: ethosuximide; sodium valproate; lamotrigine or placebo. DATA COLLECTION AND ANALYSIS: Outcome measures were: (i) proportion of individuals seizure free at 1, 6 and 18 months post randomisation; (ii) people with a 50% or greater reduction in seizure frequency; (iii) normalisation of EEG and/or negative hyperventilation test and (iv) adverse effects. Data were independently extracted by two reviewers. Results are presented as relative risks (RR) with 95% confidence intervals (95% CI). MAIN RESULTS: Four small trials were found, which were of poor methodological quality. One trial (29 participants) compared lamotrigine with placebo using a response conditional design. Individuals taking lamotrigine were significantly more likely to be seizure free than participants taking placebo during this short trial. Three studies compared ethosuximide, but because of diverse study designs and populations studied, we decided not to pool results in a meta-analysis. None of these studies found a difference between valproate and ethosuximide with respect to seizure control, but confidence intervals were wide and the existence of important differences could not be excluded. REVIEWER'S CONCLUSIONS: Although ethosuximide, lamotrigine and valproate are commonly used to treat people with absence seizures we have insufficient evidence to inform clinical practice, and the few trials included in this review were of poor methodological quality. More trials of better quality are needed.
BACKGROUND: Epilepsy is a common neurological condition, affecting 0.5 to 1% of the population. Nearly 30 per cent of people with epilepsy have seizures that are refractory to currently available drugs. In response to this problem, potential new drugs are being developed. Remacemide is one of these. OBJECTIVES: To evaluate the effects of add-on treatment with remacemide upon seizures, adverse effects, cognition and quality of life for people with drug-resistant localization related epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trials register (4 July 2002), the Cochrane Controlled Trials Register (The Cochrane Library Issue 2, 2002) and MEDLINE (28 May 2002). In addition, we contacted AstraZeneca (makers of remacemide) and colleagues in the field to see if they were aware of any trials that we had missed. SELECTION CRITERIA: Randomized placebo controlled add-on trials of people of any age with localization related seizures, in which an adequate method of concealment of randomization was used. The studies could be blinded or unblinded and be of parallel or crossover design. They had to have a minimum treatment period of eight weeks. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted data. Any disagreements were resolved by discussion. Outcomes investigated included 50 per cent or greater reduction in seizure frequency, treatment withdrawal, adverse effects, effects on cognition and quality of life. The primary analyses were by intention-to-treat. Dose response was evaluated in regression models. MAIN RESULTS: Two parallel group trials were included representing 514 individuals. Daily doses of 300, 600, 800 and 1200mg of remacemide were tested. The overall relative risk (RR) for remacemide versus placebo with 95% confidence intervals(CI) for a 50 per cent or greater reduction in seizure frequency was 1.59(95% CI 0.91 to 2.79). Due to differences in response rates among trials, regression models were unable to provide reliable estimates of responses to individual doses. Regression models did however suggest a significant effect for 800-1200mg remacemide per day. Remacemide was more likely to be withdrawn than placebo, the RR for treatment withdrawal was 1.90(95% CI 1.00 to 3.60). The RR for dizziness indicates that it is significantly associated with remacemide 3.08(99% CI 1.37 to 6.95). Effects on cognition and quality of life were not reported. REVIEWER'S CONCLUSIONS: Given the modest effect on seizure frequency and significant withdrawal rate it is unlikely that remacemide will be further developed as an antiepileptic drug.
BACKGROUND: Epilepsy is a common neurological condition, affecting almost 0.5 to 1 per cent of the population. Nearly 30 per cent of people with epilepsy are resistant to currently available drugs. Tiagabine is one of the newer antiepileptic drugs and its effects as an adjunct (add-on) to standard drugs is assessed in this review. OBJECTIVES: To evaluate the effects of add-on treatment with tiagabine upon seizures, side effects, cognition and quality of life for people with drug-resistant localization related seizures. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trials register (28 March 2002), the Cochrane Controlled Trials Register (Cochrane Library Issue 1, 2002), MEDLINE (1966 to November 2001). In addition, we contacted Sanofi~Synthelabo (makers of tiagabine) and experts in the field to seek any unpublished or ongoing studies. SELECTION CRITERIA: Randomized placebo controlled add-on trials of people of any age with localization related seizures, in which an adequate method of concealment of randomization was used. The studies could be double, single or unblinded and be of parallel or crossover design. They had to have a minimum treatment period of eight weeks. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted data. Any disagreements were resolved by discussion. Outcomes investigated included 50 per cent or greater reduction in seizure frequency; treatment withdrawal; side effects; effects on cognition and quality of life. The primary analyses were by intention-to-treat. Worst case and best case analyses were also calculated for seizure outcomes. Dose response was evaluated in regression models. MAIN RESULTS: Three parallel group and two crossover group trials were included. The overall relative risk (RR) for a 50 per cent or greater reduction in seizure frequency (tiagabine versus placebo) was 3.16(95% confidence interval 1.97 to 5.07). Due to differences in response rates among trials, regression models were unable to provide reliable estimates of responses to individual doses. The RR for treatment withdrawal was 1.81(95% confidence interval 1.25 to 2.62). The 99% confidence interval for the following side effects: dizziness; fatigue; nervousness and tremor did not include unity, indicating that they are significantly associated with tiagabine. For cognitive and quality of life outcomes the limited data available suggested that there were no significant effects on cognition and mood and adjustment. REVIEWER'S CONCLUSIONS: Tiagabine reduces seizures frequency but is associated with some side effects when used as an add-on for people with drug-resistant localization related seizures.
BACKGROUND: Worldwide, carbamazepine and phenytoin are commonly used antiepileptic drugs. This review summarizes evidence from randomized controlled trials in which these two drugs have been compared. OBJECTIVES: To review the best evidence comparing carbamazepine and phenytoin when used as monotherapy in subjects with partial onset seizures, or generalized onset tonic-clonic seizures with or without other generalized seizure types. SEARCH STRATEGY: We searched: (a) the trial register of the Cochrane Epilepsy Group; (b) The Cochrane Controlled Trials Register (Cochrane Library Issue 4, 2001); (c) MEDLINE 1966-2001. In addition we hand searched relevant journals and contacted the pharmaceutical industry and researchers in the field to seek any ongoing or unpublished studies. SELECTION CRITERIA: Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of carbamazepine monotherapy with phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcomes were time to (a) withdrawal of allocated treatment, (b) 12 month remission, (c) six month remission, and (d) first seizure post randomization. Data were analysed using a stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR>1 indicates an event is more likely on phenytoin. MAIN RESULTS: Individual patient data are available for 551 participants from three trials, representing 63% of the participants recruited into the nine trials that met our inclusion criteria. By convention, for the outcomes time to six and 12 month remission HR>1 indicates a clinical advantage for phenytoin, whilst for time to withdrawal and first seizure HR>1 indicates a clinical advantage for carbamazepine. Results (HR (95% CI)) were: (i) time to withdrawal of allocated treatment 0.97(0.74 to 1.28), (ii) time to 12 month remission 1.00(0.78 to 1.29), (iii) time to six month remission 1.10(0.87 to 1.39), (iv) time to first seizure 0.91(0.74 to 1.12). The results suggest no overall difference between carbamazepine and phenytoin for these outcomes. REVIEWER'S CONCLUSIONS: We have not found evidence that a significant difference exists between carbamazepine and phenytoin for the outcomes examined in this review. Confidence intervals are wide and the possibility of important differences existing has not been excluded.
BACKGROUND: Cerebral malaria is a common complication of Plasmodium falciparum infection, and kills over a million people every year. People with cerebral malaria become unconscious, and often have protracted convulsions. It is unclear whether giving anticonvulsant drugs routinely to people with cerebral malaria will improve the outcome of treatment and prevent death. OBJECTIVES: To evaluate the effect of routine anticonvulsant drugs in people with cerebral malaria. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group specialized trials register (November 2001), The Cochrane Controlled Trials Register (Issue 4, 2001), MEDLINE (1966 to November 2001), EMBASE (1988 to October 2001), LILACS (2001, 40a Edition CD-ROM), Science Citation Index (November 2001), African Index Medicus (1999), reference lists of articles, and research organizations. We also contacted the authors for addtional information. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials of people with cerebral malaria. The trials compared anticonvulsant drugs started on admission to hospital with no anticonvulsant drug or placebo. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data from those trials eligible for inclusion. We assessed the methodological quality of the included trials by considering allocation sequence, concealment of allocation, blinding, and inclusion of all randomized participants. We used Review Manager (version 4.1) for the meta-analysis and also explored possible sources of heterogeneity. MAIN RESULTS: Three trials with a total of 573 participants met the inclusion criteria. These trials all compared phenobarbitone with placebo or no treatment. In the two trials with adequate allocation concealment, death was more common in the anticonvulsant group (Relative Risk 2.0; 95% confidence interval 1.20 to 3.33; fixed effect model). In all three trials, phenobarbitone compared with placebo or no treatment was associated with fewer convulsions (Relative Risk 0.30; 95% confidence interval 0.19 to 0.45; fixed effect model). REVIEWER'S CONCLUSIONS: Routine phenobarbitone in cerebral malaria is associated with fewer convulsions but possibly more deaths. Further trials with adequate design, more participants, and different doses of anticonvulsant drugs are needed.
BACKGROUND: Phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset (simple partial, complex partial and secondary generalized tonic-clonic seizures) seizures whilst valproate is more effective in generalized onset seizures (generalized tonic-clonic seizures, absence, myoclonus) although there is no evidence from randomized controlled trials to support this belief. The use of individual patient data meta-analysis enabled us to examine time to event outcomes which are important in epilepsy monotherapy trials, and also to examine treatment-covariate interactions. OBJECTIVES: To review the best evidence comparing phenytoin and valproate when used as monotherapy in subjects with partial onset seizures, or generalized onset tonic-clonic seizures with or without other generalized seizure types. SEARCH STRATEGY: Our search strategy included: (i) the Cochrane Epilepsy Group trial register, (ii) MEDLINE 1966-2000, (iii) hand-searching relevant journals, (iv) the pharmaceutical industry, and (v) researchers in the field. SELECTION CRITERIA: Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of phenytoin monotherapy with valproate monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcomes were time to (i) withdrawal of allocated treatment, (ii) 12 month remission, (iii) six month remission, and (iv) first seizure post randomization. Data were analysed using stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR>1 indicates an event is more likely on phenytoin. A test for interaction between treatment and seizure type (partial onset versus generalized onset) was also undertaken for each outcome. MAIN RESULTS: Data were available for 669 subjects from five trials, representing 60% of the subjects recruited into the eleven trials that met our inclusion criteria. One important limitation of these data is that in four of the five trials, for patients classified as having generalized onset seizures, tonic-clonic seizures were the only seizure types recorded at follow up, despite the fact that some patients will have been experiencing other generalized seizure types such as absence or myoclonus. Their results for the generalized seizures therefore relate only to generalized onset tonic-clonic seizures. The main overall results were as follows (HR(95% CI), HR>1 indicates a clinical advantage for phenytoin for both remission outcomes and a clinical advantage for valproate for the outcomes time to withdrawal and time to first seizure) (i) time to withdrawal of allocated treatment 1.10(0.79-1.54), (ii) time to 12 month remission 1.04(0.78-1.38), (iii) time to six month remission 0.89(0.71-1.11), and (iv) time to first seizure 0.92(0.74-1.14). The results suggest no overall difference between drugs for these outcomes. The test for an interaction between treatment and seizure type (generalized versus partial onset) was non significant for all outcomes. REVIEWER'S CONCLUSIONS: We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. As generalized seizures such as absence and myoclonus were counted in only one trial, results do not address the treatment of these seizure types. We found no unequivocal evidence to overthrow or support the policy of using valproate in generalized onset tonic-clonic seizures and phenytoin in partial onset seizures.
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.
BACKGROUND: Worldwide, phenytoin and phenobarbitone are commonly used antiepileptic drugs. They are more likely to be used in the developing world than the developed world, primarily because they are inexpensive. The aim of this review is to summarise data from existing trials comparing phenytoin and phenobarbitone. OBJECTIVES: To review the effects of phenobarbitone compared to phenytoin when used as monotherapy in patients with partial onset seizures or generalized tonic-clonic seizures with or without other generalized seizure types. SEARCH STRATEGY: Our search strategy has included: a) MEDLINE 1966 to 1998, b) the controlled trials register of the Cochrane Library, c) hand-searching relevant journals, d) the pharmaceutical industry, e) researchers in the field. SELECTION CRITERIA: Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of phenobarbitone monotherapy with phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcomes were time to a) withdrawal of allocated treatment, b) 12 month remission, and c) first seizure post randomization. Data were analysed using a stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR>1 indicates an event is more likely to occur earlier on phenobarbitone than phenytoin. MAIN RESULTS: To date, data have been obtained for four of ten studies meeting the inclusion criteria, amounting to 599 patients, or approximately 65% of the potential data. The main overall results (HR, 95% CI) were: a) time to treatment withdrawal 1.62 (1.22 to 2.14), b) time to 12 month remission 0.93 (0.70 to 1.23), c) time to first seizure 0.84 (0.68 to 1.05). These results indicate a statistically significant clinical advantage for phenytoin in terms of treatment withdrawal and a non-significant advantage in terms of 12 month remission. Results for time to first seizure suggest a non-significant clinical advantage for phenobarbitone. REVIEWER'S CONCLUSIONS: The results of this review favour phenytoin over phenobarbitone, as phenobarbitone was significantly more likely to be withdrawn than phenytoin. Given that no significant differences for seizure outcomes were found, the higher withdrawal rate with phenobarbitone may be due to side effects.
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.
This paper provides an overview of the types of neuropsychological and behavioural measures used in randomised controlled trials (RCTS) of antiepileptic drugs (AEDs) in patients with epilepsy. The results of previous systematic reviews are reported in respect of the methods used in clinical trials to assess cognitive and behavioural effects of AED treatment. There were 46 trials incorporating behavioural measures and 40 trials incorporating neuropsychological measures. The evidence supporting the choice of test, and their reliability, validity, and sensitivity to change was minimal. It is concluded that poor reporting of methods and a plethora of both neuropsychological and behavioural measures make it difficult to provide any meaningful comments about the effects of AED treatment. A much more standardised approach to assessing these effects is necessary.
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.