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BACKGROUND: This is an updated version of the original Cochrane review published in Issue 1, 2006 of the Cochrane Database of Systematic Reviews. Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment up to 70% of individuals with active epilepsy have the potential to become seizure‐free and to go into long‐term remission shortly after starting drug therapy with a single antiepileptic drug (AED) in monotherapy. The correct choice of first‐line antiepileptic therapy for individuals with newly diagnosed seizures is of great importance. It is important that the choice of AEDs for an individual is made using the highest quality evidence regarding the potential benefits and harms of the various treatments. It is also important that the effectiveness and tolerability of AEDs appropriate to given seizure types are compared to one another. Carbamazepine or lamotrigine are first‐line recommended treatments for new onset partial seizures and as a first‐ or second‐line treatment for generalised tonic‐clonic seizures. Performing a synthesis of the evidence from existing trials will increase the precision of the results for outcomes relating to efficacy and tolerability and may assist in informing a choice between the two drugs. OBJECTIVES: To review the time to withdrawal, remission and first seizure with lamotrigine compared to carbamazepine when used as monotherapy in people with partial onset seizures (simple or complex partial and secondarily generalised) or generalised onset tonic‐clonic seizures (with or without other generalised seizure types). SEARCH METHODS: The first searches for this review were run in 1997. For the most recent update we searched the Cochrane Epilepsy Group Specialized Register (17 October 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 17 October 2016) and MEDLINE (Ovid, 1946 to 17 October 2016). We imposed no language restrictions. We also contacted pharmaceutical companies and trial investigators. SELECTION CRITERIA: Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic‐clonic seizures comparing monotherapy with either carbamazepine or lamotrigine. DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was time to withdrawal of allocated treatment and our secondary outcomes were time to first seizure post‐randomisation, time to six‐month, 12‐month and 24‐month remission, and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial‐specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI. MAIN RESULTS: We included 13 studies in this review. Individual participant data were available for 2572 participants out of 3394 eligible individuals from nine out of 13 trials: 78% of the potential data. For remission outcomes, a HR < 1 indicated an advantage for carbamazepine and for first seizure and withdrawal outcomes a HR < 1 indicated an advantage for lamotrigine. The main overall results (pooled HR adjusted for seizure type) were: time to withdrawal of allocated treatment (HR 0.72, 95% CI 0.63 to 0.82), time to first seizure (HR 1.22, 95% CI 1.09 to 1.37) and time to six‐month remission (HR 0.84, 95% CI 0.74 to 0.94), showing a significant advantage for lamotrigine compared to carbamazepine for withdrawal but a significant advantage for carbamazepine compared to lamotrigine for first seizure and six‐month remission. We found no difference between the drugs for time to 12‐month remission (HR 0.91, 95% CI 0.77 to 1.07) or time to 24‐month remission (HR 1.00, 95% CI 0.80 to 1.25), however only two trials followed up participants for more than one year so the evidence is limited. The results of this review are applicable mainly to individuals with partial onset seizures; 88% of included individuals experienced seizures of this type at baseline. Up to 50% of the limited number of individuals classified as experiencing generalised onset seizures at baseline may have had their seizure type misclassified, therefore we recommend caution when interpreting the results of this review for individuals with generalised onset seizures. The most commonly reported adverse events for both of the drugs across all of the included trials were dizziness, fatigue, gastrointestinal disturbances, headache and skin problems. The rate of adverse events was similar across the two drugs. The methodological quality of the included trials was generally good, however there is some evidence that the design choice of masked or open‐label treatment may have influenced the withdrawal rates of the trials. Hence, we judged the quality of the evidence for the primary outcome of treatment withdrawal to be moderate for individuals with partial onset seizures and low for individuals with generalised onset seizures. For efficacy outcomes (first seizure, remission), we judged the quality of evidence to be high for individuals with partial onset seizures and moderate for individuals with generalised onset seizures. AUTHORS' CONCLUSIONS: Lamotrigine was significantly less likely to be withdrawn than carbamazepine but the results for time to first seizure suggested that carbamazepine may be superior in terms of seizure control. A choice between these first‐line treatments must be made with careful consideration. We recommend that future trials should be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow‐up, choice of outcomes and analysis, and presentation of results.

Objective Idiopathic generalized epilepsies (IGEs) account for approximately 30% of all patients with epilepsy. Both the IGEs and type 1 diabetes mellitus (T1D) represent serious worldwide problems, because of related medical and social management costs. Clinical experience suggested the two conditions were seen in individuals more frequently than might be expected by chance. Methods We compared the population prevalence of T1D in 15- to 30-year-olds to a cohort of 518 15- to 30-year-olds with IGE. Results We found a highly significant excess of T1D in our IGE cohort, with an odds ratio of 4.4 (95% confidence interval, 2.1–9.2). Interpretation Our results suggest that the prevalence of T1D is increased by a factor of four in young adults with IGE. To our knowledge, this is the first published association between the two conditions and expands the diseases known to be associated with T1D. Ann Neurol 2006;59:204–206

Combining the results of individual studies using meta-analysis may be undertaken using either aggregate data (AD) or individual patient data (IPD). In any meta-analysis it is important to consider statistical heterogeneity between studies. Potential sources of heterogeneity can be explored using regression models with either AD or IPD. An overview of approaches and empirical assessment of how the results and conclusions differ from these analyses is undertaken using a meta-analysis of five randomized controlled trials comparing two antiepileptic drugs with time-to-event outcomes. Alternative meta-regression models using AD are compared to stratified Cox regression models using IPD. Age as a potential cause of heterogeneity is detected by both AD and IPD regression models. Time from first ever seizure to randomization is only identified by some AD models. A more thorough explanation of heterogeneity is obtained from the model using IPD but further empirical evidence comparing IPD and AD results are needed.

Decreased arterial carbon dioxide tension (PaCO2) results in decreased cerebral blood flow, which is associated with diminished cerebral electrical activity. In such a situation, cerebral fractional oxygen extraction (CFOE) would be expected to increase to preserve cerebral oxygen delivery. This study aimed to determine whether changes in blood gases in infants less than 30 wk' gestation were associated with changes in background electroencephalograms (EEG) and CFOE. Thirty-two very low birth weight infants were studied daily for the first three days after birth. Digital EEG recordings were performed for 75 min each day. CFOE, mean blood pressure and arterial blood gases were measured midway through each recording. EEG was analysed by (a) spectral analysis and (b) manual calculation of interburst interval. Blood pressure, pH and PaCO2 did not have any effect on the EEG. On day one, only PaCO2 showed a relationship with the relative power of the delta frequency band (0.5-3.5 Hz) and the interburst interval. The relative power of the delta band remained within normal limits when PaCO2 was between 24 and 55 mmHg on day one. There was a negative association between PaCO2 and CFOE. The associations between PaCO2 and EEG measurements were strongest on day one, weaker on day two, and absent on day three. The slowing of EEG and increased CFOE at lower levels of PaCO2 are likely to be due to decreased cerebral oxygen delivery induced by hypocarbia. When PaCO2 was higher, there was suppression of the EEG.

Summary Background The relative risks and benefits of starting or withholding antiepileptic drug treatment in patients with few or infrequent seizures are unclear. We sought to compare policies of immediate versus deferred treatment in such patients and to assess the effects of these policies on short-term recurrence and long-term outcomes. Methods We undertook an unmasked, multicentre, randomised study of immediate and deferred antiepileptic drug treatment in 1847 patients with single seizures and early epilepsy. Outcomes comprised time to first, second, and fifth seizures; time to 2-year remission; no seizures between years 1 and 3 and between years 3 and 5 after randomisation; and quality of life. Analysis was by intention to treat. Findings 404 patients invited to join the trial did not consent to randomisation; 722 were subsequently assigned immediate treatment with antiepileptic drugs and 721 were assigned deferred treatment. Immediate treatment increased time to first seizure (hazard ratio 1·4 [95% CI 1·2 to 1·7]), second seizure (1·3 [1·1 to 1·6]), and first tonic-clonic seizure (1·5 [1·2 to 1·8]). It also reduced the time to achieve 2-year remission of seizures (p=0·023). At 5-years follow-up, 76% of patients in the immediate treatment group and 77% of those in the deferred treatment group were seizure free between 3 and 5 years after randomisation (difference −0·2% [95% CI −5·8% to 5·5%]). The two policies did not differ with respect to quality of life outcomes or serious complications. Interpretation Immediate antiepileptic drug treatment reduces the occurrence of seizures in the next 1–2 years, but does not affect long-term remission in individuals with single or infrequent seizures.

Continuous EEG monitoring has not been used widely in neonatal intensive care, especially in the care of extremely premature infants, probably in part because of a lack of a reliable quantitative method. The purpose of this study was to quantify the EEG of the very premature infants just after birth by using spectral analysis and to describe the characteristics of the spectral signal when infants were clinically stable. Digital EEG recordings were performed on 53 infants who were < or =30 wk gestation for 75 min each day during the first 4 d after birth. Artefact was rejected manually after visual inspection of trace. The EEG was analyzed by manual measurement of interburst interval and automatically by spectral analysis using Fast Fourier Transformation. Spectral analysis generated the normal ranges of the relative power of the delta (0.5-3.5 Hz), theta (4-7.5 Hz), alpha (8-12.5 Hz), and beta (13-30 Hz) frequency bands, spectral edge frequency, and symmetry. The median (range) relative power of the delta band increased significantly from 68% (62-76%) on day 1 to 81% (72-89%) on day 4 (p=0.001). The interburst intervals became progressively shorter between days 1 [14s (10-25)] and 3 [8s (6-12)]; there were no significant differences between days 3 and 4. The relative power of the delta band seemed to be the most useful and repeatable spectral measurement for continuous long-term monitoring. However, automatic artefact rejection software needs to be developed before continuous quantitative EEG monitoring can be used in the neonatal intensive care environment.

The choice of antiepileptic drugs (AEDs) is rapidly increasing. This review looks at the evidence that guides the decision of which AED to start as monotherapy and aims to aid the choice of treatment if monotherapy fails. Unfortunately, the evidence supporting the prescribing of new drugs is sparse, because most randomised controlled trials answer questions focused on regulatory requirements rather than on clinical use. Ultimately, the choice of one AED will be determined by an individual risk-benefit assessment in which the most effective drug for an individual patient is chosen, and one that would have the lowest risk of significant harm. It is the risk of chronic toxic effects and issues of teratogenicity for women that may affect the choice of drug therapy to the greatest degree. In the future there is a need to improve the quality of clinical data on efficacy and harmful effects of AEDs.

Background This is an updated version of the original Cochrane review published in The Cochrane Library 2001, Issue 4. Worldwide, particularly in the developing world, phenytoin and phenobarbitone are commonly used antiepileptic drugs, 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 best evidence comparing phenobarbitone and phenytoin when used as monotherapy in participants with partial onset seizures or generalised tonic-clonic seizures with or without other generalised seizure types. Search methods We searched the Cochrane Epilepsy Group trials register (31 May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL Issue 5 of 12, The Cochrane Library 2012) and MEDLINE (1946 to May week 4, 2012). We hand-searched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. Selection criteria Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of phenobarbitone monotherapy with phenytoin monotherapy. Data collection and analysis This was an individual participant data (IPD) review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. Cox proportional hazards regression models were used to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) with the generic inverse variance method used to obtain the overall pooled estimate of HRs and 95% CIs. Main results Data have been obtained for four of eight studies meeting the inclusion criteria, amounting to 599 individuals, or approximately 63% of the potential data. The main overall results (pooled HR, 95% CI) were (a) time to treatment withdrawal 1.62 (1.23 to 2.14); (b) time to 12-month remission 0.90 (0.69 to 1.18) (c) time to six-month remission 0.92 (0.73 to 1.16) and (d) time to first seizure 0.85 (0.68 to 1.05). These results indicate a statistically significant clinical advantage for phenytoin in terms of treatment withdrawal. However, this result may have been confounded by several factors including substantial statistical heterogeneity between studies and lack of blinding in two studies. Authors' conclusions The results of this review show that 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 adverse effects. Several factors may have confounded the results of this review.

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.

In a meta-analysis of randomized controlled trials with time-to-event outcomes, an aggregate data approach may be required for some or all included studies. Variation in the reporting of survival analyses in journals suggests that no single method for extracting the log(hazard ratio) estimate will suffice. Methods are described which improve upon a previously proposed method for estimating the log(HR) from survival curves. These methods extend to life-tables. In the situation where the treatment effect varies over time and the trials in the meta-analysis have different lengths of follow-up, heterogeneity may be evident. In order to assess whether the hazard ratio changes with time, several tests are proposed and compared. A cohort study comparing life expectancy of males and females with cerebral palsy and a systematic review of five trials comparing two anti-epileptic drugs, carbamazepine and sodium valproate, are used for illustration.

We examine the common clinical belief that there is an interaction between epilepsy type and the two standard anti-epileptic drugs, valproate and carbamazepine, using data from several randomized clinical trials. Epilepsy type is not always easy to define, and three possible reclassifications are investigated to see whether misclassification of epilepsy type within the trials has potentially masked such an interaction. Regression modelling is employed to investigate whether heterogeneity between trial results can be explained by patient factors. Our work suggests that uncertainty in epilepsy type classification should be recognized in future studies. We also generate the hypothesis that the interaction of drug effect with age may reflect the perceived interaction with epilepsy type. We suggest that in any context where misclassification is likely, it is worth considering the use of an explicit 'unclassified' group, and investigating whether additional covariates can answer the substantive question.

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.

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 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.

INTRODUCTION: Epilepsy is known to impair quality of life (QoL) but the impact of epilepsy on QoL in meningioma population is not certain. The aim of this cross-sectional postal study was to investigate the effects of benign meningioma and epilepsy on QoL. METHOD: Three patient groups were recruited: (1) meningioma without epilepsy; (2) meningioma with epilepsy; and (3) epilepsy without meningioma. Three QoL questionnaires were used: (a) Sf-36; (b) Fact-Br; and (c) the Liverpool Adverse Events Profile (LAEP). Mean scores of each scale were compared between meningioma patients with and without epilepsy, and between epilepsy patients with and without meningioma. Regression models identified factors that correlated with poor QoL. RESULTS: There were 229 participants (mean age 59.9 ± 12.2 years); 109 meningioma, 56 meningioma and epilepsy, and 64 epilepsy without meningioma. QoL was impaired in the meningioma with epilepsy group compared to the meningioma without epilepsy group in all questionnaires; but only the Fact-Br was significantly impaired (t-test; p = 0.012). Antiepileptic drugs (AEDs) significantly impaired QoL in the regression analyses, while seizures were less influential. QoL was impaired in the epilepsy without meningioma group compared to the meningioma and epilepsy group, but this difference was not significant (t-test; p = 0.44). Increased seizure frequency and AEDs (particularly Levetiracetam) significantly impaired QoL in the regression analyses. CONCLUSION: In meningioma, epilepsy has a minor impact on QoL; but AEDs significantly impair QoL and this has potential implications for seizure management. Meningioma patients with epilepsy have comparable QoL to epilepsy patients without meningioma.

Background High mobility group box 1 (HMGB1) is a chromatin binding protein that is passively released by necrotic cells and actively secreted in response to inflammatory stimuli in a hyperacetylated form. HMGB1 is upregulated in the brain after injury and can regulate localised inflammatory reactions resulting in seizures. Antiepileptic drugs prevent seizures but have no disease modifying effect or influence on natural history. Immunomodulatory antiepileptic drugs have huge potential, but can have serious adverse effects. Patient stratification is required to maximise the benefit to risk ratio. We investigated serum and brain concentrations of HMGB1 in rodent models of seizures and epilepsy and in people with refractory epilepsy. Methods We used three experimental models in this study. Adult male C57BL/6J mice received repeated intraperitoneal injections of kainic acid (KA) until the onset of convulsive status epilepticus; status epilepticus was terminated after 2 h with diazepam, with brain and blood samples obtained at 3, 6, 24, and 72 h and 7 and 14 days thereafter. Tonic seizures were induced in adult male CF1 mice by maximal electroshock (MES) delivered via corneal electrodes, with brain and blood samples obtained at 1, 4, 8, 16, and 24 h after seizure induction. Finally, serial samples were obtained at baseline, 1, 4, 8, and 12 h after an observed seizure from people with drug refractory epilepsy undergoing videoelectroencephalograph telemetry. Total HMGB1 expression was measured by western blot and immunohistochemistry in brain and by ELISA in serum. Expression of individual HMGB1 isoforms was determined by liquid-chromatography tandem mass-spectrometry (LC-MS/MS). Findings HMGB1 expression was significantly raised in hippocampus and cortex (p vs 3 h 16·5 [1·5], p vs 4 h 19·7 [11·3], p vs 4 h 15·2 [7·0], p vs 0·7 [0·3], p vs 1·25 [0·71], p Interpretation These findings suggest that blood and brain HMGB1 concentrations are increased as a result of seizures in both animal models and patients with epilepsy. Increases in HMGB1 might occur as a consequence of seizures. Patients with refractory epilepsy have higher baseline HMGB1, which might predispose them to recurrent seizure activity. The association between HMGB1 and seizures requires further exploration. Funding UK Medical Research Council, ICON, GlaxoSmithKline, AstraZeneca, the Medical Evaluation Unit.

Background Carbamazepine (CBZ) is an effective antiepileptic drug. However, it can cause cutaneous adverse reactions in up to 10% of patients. These reactions include life-threatening conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. It has been hypothesised that CBZ is metabolised to reactive metabolites that form haptens with cellular proteins, which are then presented by specific HLA alleles, HLA-B*1502 and HLA-A*3101, activating the immune system and triggering hypersensitivity in susceptible individuals. CBZ 10, 11-epoxide (CBZ-E) is a major circulating metabolite of CBZ and retains therapeutic activity. It is also sufficiently electrophilic to react with glutathione and proteins in vitro. However, the structures of the protein adducts were unknown. Our aim was to determine the structure of these CBZ-E protein adducts using high sensitivity proteomics tools. Methods Initially, synthetic CBZ-E was incubated with human glutathione S-transferase pi (hGSTP) or human serum albumin (HSA). Both proteins form adducts with various reactive chemicals. Subsequently, to determine whether metabolically generated CBZ-E could also form protein adducts, CBZ was incubated with human supersomes (CYP3A4, CYP2E1, CYP2B6) and hGSTP. Tryptic peptide analysis by advanced liquid chromatography-tandem mass spectrometry was used to characterise CBZ-E adduct formation. Findings An adduct was identified at cys-47 of hGSTP, and adducts were identified at his146 and his338 of HSA after incubation with CBZ-E. After incubation of CBZ with human supersomes and hGSTP the dihydrohydroxy thioether adduct at cys47 of hGSTP was again identified, indicating that metabolic activation of CBZ to CBZ-E in vivo might also yield stable protein adducts. Interpretation We have shown for the first time, to our knowledge, that CBZ-E, an abundant CBZ metabolite in man, can form covalent adducts with hGSTP and HSA in vitro. These adducts and similar adducts of other proteins could be responsible for triggering hypersensitivity reactions. Further work will focus on confirming the presence of HSA-CBZ-E adducts in patients and determining the immunogenicity of these adducts in vitro. Funding UK Medical Research Council, ICON, GlaxoSmithKline, AstraZeneca, the Medical Evaluation Unit.

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.

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.

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.

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.

Summary: 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.

This article comes from Clinical Evidence (2000;3:573-576), a new resource for clinicians produced by the BMJ Publishing Group. Clinical Evidence is an extensively peer-reviewed publication that summarizes the best available evidence on the effects of common clinical interventions gleaned from thorough searches and appraisal of the world literature. It became available in the United States late last year. Please see advertisement for more information or, alternatively, visit the web site at www.evidence.org. QUESTIONS: What are the effects of medical treatment of Bell's palsy in adults and children? How effective is steroid therapy? How effective is antiviral therapy?

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 methods We searched the Cochrane Epilepsy Group's Specialized Register (27 July 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2007), and MEDLINE (1966 to July 2007). No language restrictions were imposed. We also contacted pharmaceutical companies and researchers in the field. 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) with 95% confidence intervals (CIs), 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 participants from five trials, representing 85% of the participants recruited into the eight trials that met our inclusion criteria. The main overall results (HR) were: time to treatment withdrawal 0.97 (95% CI 0.79 to 1.18); 12 month remission 0.87 (95% CI 0.74 to 1.02); first seizure 1.09 (95% CI 0.96 to 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 individuals may have had their epilepsy misclassified. Authors' 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 people with epilepsy may have confounded our results, and has important implications for the design and conduct of future trials.

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.

Summary : 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 350% 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.

Editor—Two letters commenting on our systematic review of trials of new antiepileptic drugs1 deserve a response. We agree with A J A Elferink and B J Van Zwieten-Boot that the number needed to treat is a useful statistic, but we believe that they are wrong to suggest that we should have presented it rather than odds ratios.2 We had in fact undertaken a risk difference analysis (1/number needed to treat) and found much greater heterogeneity with …

Hypersensitivity reactions account for 2–6% of all hospital admissions. Severe hypersensitivity reactions such as hypersensitivity syndrome (HSS), acute generalised exanthematous pustulosis (AGEP), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are associated with significant mortality and long–term morbidity including scarring and blindness. These hypersensitivity reactions are comparatively common with antiepileptic drug (AED) therapy. The incidence of HSS is approximately 1 in 500 AED exposures whilst SJS/TEN is estimated to occur in 1 in 5000 exposures to carbamazepine (CBZ). More recently, research has demonstrated that susceptibility to certain AED–induced hypersensitivity reactions are strongly associated with genetic risk factors. For example, carriage of HLA–B*1502 was associated with 100–fold greater risk of developing SJS/TEN with CBZ in Asians whilst carriage of HLA–A*3101 in Europeans, Japanese and Koreans was associated with 10–fold greater risk of developing all hypersensitivity reactions to CBZ. The BNSU for severe hypersensitivity to AEDs was setup to raise awareness of AED–induced severe hypersensitivity reactions amongst neurologists and increase recruitment of these patients to the molecular genetics of adverse drug reaction study at the University of Liverpool. The aim of the molecular genetics of hypersensitivity study is to validate previously reported genetic associations and identify new genetic associations in drug hypersensitivity. This will allow development of genetic tests that can inform drug choice enabling clinicians to optimise efficacy and minimise the side–effects to AED treatment in future. Potential patients identified by the BNSU for hypersensitivity to AEDs will be consented and asked to provide a sample of venous blood or saliva for extraction and storage of DNA. Clinical details about the hypersensitivity reaction will then be completed by the neurology team caring for the patient. The BNSU for severe hypersensitivity to AEDs started in August 2011. Since then 14 neurologists have used the system and 16 cases have been reported. Case descriptions were provided for 12 of these cases. Lamotrigine was the most frequently reported AED and associated with six cases of hypersensitivity. This was followed by carbamazepine which was the culprit drug in five cases of hypersensitivity and phenytoin responsible for one hypersensitivity reaction. SJS/TEN was suspected or diagnosed in seven patients. Four patients had a suspected diagnosis of HSS and an unknown reaction was recorded in one patient. Following analysis of these case descriptions ten patients were suitable for recruitment to the molecular genetics of adverse drug reaction study. One of these patients has been recruited and their DNA stored whilst the other nine patients are awaiting R&D approval at their NHS Trusts. The BNSU for hypersensitivity to AEDs has been successful over the first 18 months and identified ten patients who have suffered with severe hypersensitivity to AED therapy. National recruitment schemes such as the BNSU are important because they enable clinicians and researchers to recruit large numbers of patients for rare conditions such as severe hypersensitivity reactions to AEDs. Without these coordinated national schemes genetic association studies would not have sample sizes large enough to provide adequate power to detect significant genetic associations.

Summary: 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 for 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 Neurologica 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.

Aim To determine if adverse event (AE) outcomes from RCTs of AEDs across non-epilepsy indications (neuropathy & migraine) can be meta-analysed with data from epilepsy trials Method We searched for RCTs meeting inclusion criteria. AEDs included were topiramate, gabapentin, valproate, oxcarbazepine, lacosamide and others. Extracted data were analysed using RevMan 5.0. AEs analysed were; dizziness, ataxia, headache, fatigue, nausea, somnolence, AE withdrawals and any AE. Effect size summary statistics were calculated using the Mantel-Haenszel method. Statistical heterogeneity was assessed using a random effects model generating an I2 statistic. Results Hundred and six RCTs met inclusion criteria. When dizziness was analysed, test between indications showed no heterogeneity (I2=0%) for gabapentin, topiramate, lacosamide and lamotrigine. However, heterogeneity was significant (I2=59%) for oxcarbazepine. When fatigue was the AE outcome, there was no heterogeneity (I2=0%) when we analysed data for gabapentin, lamotrigine, lacosamide, oxcarbazepine and topiramate. When somnolence was the AE outcome, heterogeneity was insignificant for oxcarbazepine (I2=8%), lacosamide (I2=0%) and topiramate (I2=0%), but significant for gabapentin (I2=56%) and lamotrigine (I2=60%). In instances where there was significant heterogeneity, the size of relative risk was greater in the non-epilepsy indications Conclusion AEs of AEDs from non-epilepsy trials could be used in meta-analysis due to low statistical heterogeneity for some interventions and outcomes. Nevertheless this was not the case in all AEDs or outcomes. Effect sizes were larger in the non-epilepsy indications overall.

The biological processes underlying the development of pharmacoresistance in epilepsy are poorly understood, but multiple interconnected genes and pathways are likely to be involved. At least 12 microarray studies on brain tissue from epilepsy surgery have been performed in order to investigate the causes of epilepsy pharmacoresistance, but they have failed to make a significant impact because (1) doubts have been raised about their reproducibility, (2) only a small number of the gene expression changes found in each microarray study have been independently validated, and (3) the results of different studies have not been integrated to give a coherent picture of the genetic changes involved in epilepsy pharmacoresistance. To overcome these limitations, we (1) assessed the reproducibility of the included microarray studies: we calculated the size of the overlap between lists of differentially regulated genes from pairs of microarray studies and determined if this is greater than would be expected by chance alone, (2) used an inter-study cross-validation technique to simultaneously verify the expression changes of large numbers of genes, (3) used the combined results of the different microarray studies to perform an integrative analysis based on enriched Gene Ontology terms, networks and pathways. Using these techniques, we have respectively (1) demonstrated that there are statistically significant overlaps between the gene expression changes in different publications, (2) simultaneously verified the differential expression of 233 genes, (3) identified the biological processes, networks and genes likely to be most important in the development of pharmacoresistant epilepsy.

Objectives Decisions regarding choice and dose of anti-epileptic drug (AED) are driven by considering the potential benefits of reducing seizure frequency against the potential harms of alternative AEDs. Such decisions should be made using the best available evidence, which often requires a quantitative synthesis of data from multiple randomised controlled trials (RCT). However, the systematic review and meta-analysis of harms data is hindered by problems such as inadequate reporting, heterogeneity of harms definitions, and selective reporting bias. Here we will evaluate the quality of reporting of harms data in epilepsy trials, and assess the potential added value of incorporating harms data beyond the clinical indication of epilepsy.

Background The choice of antiepileptic drug for an individual should be based upon the highest quality evidence regarding potential benefits and harms of the available treatments. Systematic reviews and meta-analysis of randomised controlled trials should be a major source of evidence supporting this decision making process. We summarise all available individual patient data evidence from randomised controlled trials that compared at least two out of eight antiepileptic drugs given as monotherapy. Methods Multiple treatment comparisons from epilepsy monotherapy trials were synthesized in a single stratified Cox regression model adjusted for treatment by epilepsy type interactions and making use of direct and indirect evidence. Primary outcomes were time to treatment failure and time to 12 month remission from seizures. A secondary outcome was time to first seizure. Results Individual patient data for 6418 patients from 20 randomised trials comparing eight antiepileptic drugs were synthesized. For partial onset seizures (4628 (72%) patients), lamotrigine, carbamazepine and oxcarbazepine provide the best combination of seizure control and treatment failure. Lamotrigine is clinically superior to all other drugs for treatment failure but estimates suggest a disadvantage compared to carbamazepine for time to 12 month remission [Hazard Ratio (95% Confidence Interval) = 0.87(0.73 to 1.04)] and time to first seizure [1.29(1.13 to 1.48)]. Phenobarbitone may delay time to first seizure [0.77(0.61 to 0.96)] but at the expense of increased treatment failure [1.60(1.22 to 2.10)]. For generalized onset tonic clonic seizures (1790 (28%) patients) estimates suggest valproate or phenytoin may provide the best combination of seizure control and treatment failure but some uncertainty remains about the relative effectiveness of other drugs. Conclusion For patients with partial onset seizures, results favour carbamazepine, oxcarbazepine and lamotrigine. For generalized onset tonic clonic seizures, results favour valproate and phenytoin.

EDITOR—We were surprised to read Brodie's letter claiming the existence of “hard empirical evidence” to support a mechanistic approach in the management of epilepsy.1 He refers to an unpublished study in which patients with partial seizures resistant to monotherapy with carbamazepine (a sodium channel blocker) were randomised to take additional valproate or vigabatrin (drugs with GABA-ergic mechanisms).2 In those patients who responded to dual therapy, withdrawal of carbamazepine was attempted, with a view to achieving monotherapy with either …

Summary Background The MRC Multicentre trial for Early Epilepsy and Single Seizures (MESS) showed a reduced risk of further seizures in patients, for whom treatment with antiepileptic drugs was uncertain, who were randomly assigned immediate treatment compared with delayed treatment. However, there was no evidence of long-term remission rates. This study was undertaken to assess the role of patient characteristics and treatment in the prediction of seizure recurrence. This will enable decision-making on the basis of the perceived risk of treatment compared with the benefit of reducing the risk of further seizures in the initial years after diagnosis. Methods A prognostic model was developed based on individual patient data from MESS to enable identification of patients at low, medium, or high risk of seizure recurrence. A split-sample approach was used in which the model was developed on a subsample of the full data and validated on the remainder of the sample. Distinction of the prognostic groups and predictive accuracy of the model were assessed. Findings Number of seizures of all types at presentation, presence of a neurological disorder, and an abnormal electroencephalogram (EEG) were significant factors in indicating future seizures. Individuals with two or three seizures, a neurological disorder, or an abnormal EEG were identified as the medium-risk group, those with two of these features or more than three seizures as the high-risk group, and those with a single seizure only as the low-risk group. Interpretation The model shows that there is little benefit to immediate treatment in patients at low risk of seizure recurrence, but potentially worthwhile benefits are seen in those at medium and high risk.

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. Key messages At present there is insufficient evidence to guide a choice between these new treatments We systematically reviewed randomised placebo controlled studies of supplementary gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide Each drug was significantly better than placebo at preventing seizures, but none was significantly different from the others in terms of efficacy or tolerability, though the confidence intervals were wide Randomised trials comparing active treatments are needed to further evaluate these drugs

BACKGROUND: This is an update of the Cochrane Review first published in 2010; it includes one additional study. Primary generalised tonic‐clonic seizures are a type of generalised seizure. Other types of seizures include: absence, myoclonic, and atonic seizures. Effective control of tonic‐clonic seizures reduces the risk of injury and death, and improves quality of life. While most people achieve seizure control with one antiepileptic drug, around 30% do not, and require a combination of antiepileptic drugs. OBJECTIVES: To assess the effectiveness and tolerability of add‐on lamotrigine for drug‐resistant primary generalised tonic‐clonic seizures. SEARCH METHODS: For the latest update, we searched these databases on 19 March 2019: Cochrane Register of Studies (CRS) Web, MEDLINE Ovid, and the WHO International Clinical Trials Registry Platform (ICTRP). The CRS includes records from the Cochrane Epilepsy Group Specialized Register, CENTRAL, Embase, and ClinicalTrials.gov. We imposed no language restrictions. We also contacted GlaxoSmithKline, manufacturers of lamotrigine. SELECTION CRITERIA: Randomised controlled parallel or cross‐over trials of add‐on lamotrigine for people of any age with drug‐resistant primary generalised tonic‐clonic seizures. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology; two review authors independently assessed trials for inclusion, evaluated risk of bias, extracted relevant data, and GRADE‐assessed evidence. We investigated these outcomes: (1) 50% or greater reduction in primary generalised tonic‐clonic seizure frequency; (2) seizure freedom; (3) treatment withdrawal; (4) adverse effects; (5) cognitive effects; and (6) quality of life. We used an intention‐to‐treat (ITT) population for all analyses, and presented results as risk ratios (RRs) with 95% confidence intervals (CIs); for adverse effects, we used 99% CIs to compensate for multiple hypothesis testing. MAIN RESULTS: We included three studies (total 300 participants): two parallel‐group studies and one cross‐over study. We assessed varied risks of bias across studies; most limitations arose from the poor reporting of methodological details. We meta‐analysed data extracted from the two parallel‐group studies, and conducted a narrative synthesis for data from the cross‐over study. Both parallel‐group studies (270 participants) reported all dichotomous outcomes. Participants taking lamotrigine were almost twice as likely to attain a 50% or greater reduction in primary generalised tonic‐clonic seizure frequency than those taking a placebo (RR 1.88, 95% CI 1.43 to 2.45; low‐certainty evidence). The results between groups were inconclusive for the likelihood of seizure freedom (RR 1.55, 95% CI 0.89 to 2.72; very low‐certainty evidence); treatment withdrawal (RR 1.20, 95% CI 0.72 to 1.99; very low‐certainty evidence); and individual adverse effects: ataxia (RR 3.05, 99% CI 0.05 to 199.36); dizziness (RR 0.91, 99% CI 0.29 to 2.86; very low‐certainty evidence); fatigue (RR 1.02, 99% CI 0.13 to 8.14; very low‐certainty evidence); nausea (RR 1.60, 99% CI 0.48 to 5.32; very low‐certainty evidence); and somnolence (RR 3.73, 99% CI 0.36 to 38.90; low‐certainty evidence). The cross‐over trial (26 participants) reported that 7/14 participants with generalised tonic‐clonic seizures experienced a 50% or greater reduction in seizure frequency with add‐on lamotrigine compared to placebo. The authors reported four treatment withdrawals, but did not specify during which treatment allocation they occurred. Rash (seven lamotrigine participants; zero placebo participants) and fatigue (five lamotrigine participants; zero placebo participants) were the most frequently reported adverse effects. None of the included studies measured cognition. One parallel‐group study (N = 153) evaluated quality of life. They reported inconclusive results for the overall quality of life score between groups (P = 0.74). AUTHORS' CONCLUSIONS: This review provides insufficient information to inform clinical practice. Low‐certainty evidence suggests that lamotrigine reduces the rate of generalised tonic‐clonic seizures by 50% or more. Very low‐certainty evidence found inconclusive results between groups for all other outcomes. Therefore, we are uncertain to very uncertain that the results reported are accurate, and suggest that the true effect could be grossly different. More trials, recruiting larger populations, over longer periods, are necessary to determine lamotrigine's clinical use.

Background Retention time (time to treatment failure) is a commonly used outcome in antiepileptic drug (AED) studies. Methods Two datasets are used to demonstrate the issues in a competing risks analysis of AEDs. First, data collection and follow-up considerations are discussed with reference to information from 15 monotherapy trials. Recommendations for improved data collection and cumulative incidence analysis are then illustrated using the SANAD trial dataset. The results are compared to the more common approach using standard survival analysis methods. Results A non-significant difference in overall treatment failure time between gabapentin and topiramate (logrank test statistic = 0.01, 1 degree of freedom, p-value = 0.91) masked highly significant differences in opposite directions with gabapentin resulting in fewer withdrawals due to side effects (Gray's test statistic = 11.60, 1 degree of freedom, p = 0.0007) but more due to poor seizure control (Gray's test statistic = 14.47, 1 degree of freedom, p-value = 0.0001). The significant difference in overall treatment failure time between lamotrigine and carbamazepine (logrank test statistic = 5.6, 1 degree of freedom, p-value = 0.018) was due entirely to a significant benefit of lamotrigine in terms of side effects (Gray's test statistic = 10.27, 1 degree of freedom, p = 0.001). Conclusion Treatment failure time can be measured reliably but care is needed to collect sufficient information on reasons for drug withdrawal to allow a competing risks analysis. Important differences between the profiles of AEDs may be missed unless appropriate statistical methods are used to fully investigate treatment failure time. Cumulative incidence analysis allows comparison of the probability of failure between two AEDs and is likely to be a more powerful approach than logrank analysis for most comparisons of standard and new anti-epileptic drugs.

Background For patients who continue to have seizures despite ongoing treatment, surgical resection of the epileptic focus may be considered, and can result in seizure-freedom. Currently, non-invasive tests provide information to inform the scope and positioning of invasive electroencephalography (EEG) electrodes. However, these technologies could replace intracranial EEG in at least some patients if their ability to accurately locate a seizure focus could be established. In order to inform clinical practice, studies need to investigate the clinical value of a test, and the impact of the results of that test on the decision-making process and subsequently on clinical outcomes. Objectives The aims of this systematic review were to determine the diagnostic accuracy of non-invasive technologies, how these technologies impact on the decision-making process, associations with surgical outcome, and the gaps in the current evidence base. In addition, a decision-analytical model was designed to consider the potential use of existing data to determine the cost-effectiveness of options for presurgical work-up. Data sources Eighteen electronic databases were searched without language restrictions [including MEDLINE, EMBASE, BIOSIS Previews, PASCAL, ClinicalTrials.gov, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Register of Diagnostic Studies] from 2003 to July 2010. A prior, wider-ranging HTA review in this area conducted by the Centre for Reviews and Dissemination was used as the source for studies prior to 2003. Reference lists of included studies and relevant reviews were also searched, and a citation search of key papers undertaken. Review methods Systematic reviews of the diagnostic accuracy, clinical utility and cost-effectiveness of non-invasive technologies used to define the seizure focus in patients with refractory epilepsy being considered for surgery were undertaken according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Thirteen diagnostic accuracy studies, seven outcome prediction studies and one study reporting the impact of test results on the decision-making process ('decision study') were included. The decision study was used to aid the development of a decision-analytical model to illustrate how data from appropriately designed clinical studies can be utilised. Results Data from the diagnostic accuracy studies could not determine the contribution of the tests to the decision-making process. The number of index tests that could not be classified as correctly, non- or wrongly localising as indicated by a surgical outcome was high, up to 53%. The decision study reported fluorodeoxyglucose positron emission tomography influencing the decision for or against surgery in 78 of the 110 patients. The constructed decision-analytical model provided provisional cost-effectiveness results from the included diagnostic strategies. It demonstrated the feasibility of extending such analysis to all diagnostic strategies if suitable data were to become available. Limitations There were a number of limitations of the available evidence, and overall, the quality of the available evidence was poor; only one study met the inclusion criteria that evaluated the use an index test on the decision-making process. Most of the available data was from the diagnostic accuracy studies; those currently available did not provide information on either the diagnostic accuracy or clinical utility of the tests being evaluated. Further limitations were the generally small study sizes, patient selection bias and the substantial clinical heterogeneity across the studies. Conclusions The current evidence base is abundant but not adequately informative; there is no acceptable reference standard, reporting of clinical outcomes tends to be only following surgery, and decision level and clinical effectiveness studies are lacking. The additional value of diagnostic technologies for the localisation of epileptic foci is related to the impact on treatment decisions and the value of the treatments themselves; this needs to be considered fully in informing cost-effectiveness. Appropriately designed studies are needed to determine the added value of diagnostic regimens. Ultimately, how research informs the actual decision problem(s) faced by clinicians and the NHS needs to be considered; decision modelling is central to this issue. Funding The National Institute for Health Research Health Technology Assessment programme.

OBJECTIVE To review the effectiveness and/or accuracy, cost-effectiveness, and predictive value of neuroimaging of the cerebral cortex to visualise the seizure focus in people with refractory epilepsy being considered for surgery. DATA SOURCES Electronic databases, Internet searches, hand searching and consultation with experts. METHODS A systematic review was undertaken according to published guidelines. Results of diagnostic accuracy studies were analysed according to the imaging test evaluated. For each study the proportion of patients who were correctly localised, not localised, partially localised or incorrectly localised by the index test was calculated. Due to the heterogeneity present between studies, statistical pooling was not performed. Instead, a narrative synthesis of results is presented. For studies using multivariate analysis to look at the association of neuroimaging findings and outcome following surgery, all factors considered in the analyses were presented. Studies were grouped according to the neuroimaging technique investigated and the findings discussed with reference to possible sources of heterogeneity between studies. RESULTS No randomised controlled trials (RCTs) were identified, with the majority of studies evaluating the diagnostic accuracy of various imaging techniques in the localisation of epileptic seizure foci. There was significant heterogeneity (p

Background Prognostic indices, derived from prognostic models, can be used to stratify patients in clinical trials. This includes stratifying eligible patients for randomisation, stratifying randomisation, or identifying subgroups for the trial analysis. However, before an index can be used for these purposes, it needs to be validated externally in independent data. We demonstrate methods of external validation, including methods for handling a covariate missing from the validation dataset, via a prognostic model for risk of seizure recurrence following a first ever seizure.