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BACKGROUND: The majority of people with epilepsy have a good prognosis and their seizures are well controlled by a single antiepileptic drug, but up to 30% develop drug-resistant epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding the 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 people with drug-resistant partial epilepsy. SEARCH METHODS: This is an updated version of the original Cochrane review published in The Cochrane Library 2009, Issue 4. We searched the Cochrane Epilepsy Group's Specialised Register (14 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 4, The Cochrane Library) (April 2013) and MEDLINE (1946 to 14 May 2013). We imposed no language restrictions. SELECTION CRITERIA: Randomised, placebo-controlled, double-blind, add-on trials of gabapentin in people with drug-resistant partial epilepsy. Trials using an active drug control group or which compared doses of gabapentin were also included in the review. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: (a) seizure frequency and seizure freedom; (b) treatment withdrawal (any reason); (c) adverse effects. Primary analyses were intention-to-treat. We also undertook sensitivity best and worst-case analyses. We estimated summary risk ratios for each outcome and evaluated dose-response in regression models. MAIN RESULTS: Eleven trials were included representing 2125 randomised participants. We combined data from six trials in meta-analyses of 1206 randomised participants. The overall risk ratio (RR) for 50% or greater reduction in seizure frequency compared to placebo was 1.89 (95% confidence interval (CI) 1.40 to 2.55). Dose regression analysis (for trials in adults) shows increasing efficacy with increasing dose, with 25.3% (19.3 to 32.3) of people responding to 1800 mg of gabapentin compared to 9.7% on placebo, a 15.5% increase in response rate (8.5 to 22.5). The RR for treatment withdrawal compared to placebo was 1.05 (95% CI 0.74 to 1.49). Adverse effects were significantly associated with gabapentin compared to placebo. Risk ratios were as follows: ataxia 2.01 (99% CI 0.98 to 4.11), dizziness 2.43 (99% CI 1.44 to 4.12), fatigue 1.95 (99% CI 0.99 to 3.82) and somnolence 1.93 (99% CI 1.22 to 3.06). No significant differences were found for the adverse effects of headache (RR 0.79, 99% CI 0.46 to 1.35) or nausea (RR 0.95, 99% CI 0.52 to 1.73). Overall the studies together are rated as low/unclear risk of bias due to information on each risk of bias domain not being available. AUTHORS' CONCLUSIONS: Gabapentin has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a three-month period. The results cannot be extrapolated to monotherapy or to people with other epilepsy types.

Background Epilepsy is a common neurological disorder made particularly disabling in the 30% of patients who do not achieve freedom from seizures despite multiple trials of antiepileptic drugs (AEDs). Experimental and clinical evidence supports a role for inflammatory pathway activation in the pathogenesis of epilepsy which, if effectively targeted by immunomodulatory interventions, highlights a potentially novel therapeutic strategy. Objectives To evaluate the efficacy and tolerability of immunomodulatory interventions as additional therapy in focal epilepsy syndromes in adults. Search methods We searched the Cochrane Epilepsy Group Specialised Register (2 August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 7), MEDLINE (Ovid, 1946 to July week 3, 2012), the World Health Organization's International Clinical Trials Registry (2 August 2012), ClinicalTrials.gov (2 August 2012) and the Current Controlled Trials International Standard Randomised Controlled Trial Number Register (2 August 2012). There were no language restrictions. We reviewed the bibliographies of retrieved studies to search for additional reports of relevant studies. Selection criteria Randomised controlled trials of add-on immunomodulatory drug interventions for the treatment of focal epilepsy in adults (aged over 16 years). Data collection and analysis Three review authors independently assessed trial quality and extracted data. The primary outcomes were 50% or greater reduction in seizure frequency and seizure freedom; the secondary outcomes included serious and commonly occurring adverse effects, allergy, withdrawal and quality of life assessment. Main results We identified one study involving both children and adults (n=61) that assessed the effect of intravenous immunoglobulin (IVIG) as add-on therapy for the treatment of epilepsy. The authors found no significant difference between IVIG and placebo for the primary outcomes of seizure freedom or 50% or greater reduction in seizure frequency. The study reported a statistically significant effect for global blind assessment (rating scale involving multiple seizure-related parameters) in favour of IVIG. Secondary outcomes including adverse effects and allergies were not demonstrated. Authors' conclusions It is not possible to draw any conclusions about the role of immunomodulatory interventions in reducing seizure frequency or the safety of these agents in adults with epilepsy. Further randomised controlled trials are needed.

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 methods We searched the Cochrane Epilepsy Group's Specialized Register (4 April 2008), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2008), and MEDLINE (1950 to March week 4, 2008). No language restrictions were imposed. We checked the reference lists of included 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.

The incidence of seizures following supratentorial craniotomy for non-traumatic pathology has been estimated to be 15% to 20%; however, the risk of experiencing a seizure may vary from 3% to 92% over a five-year period. Postoperative seizures can precipitate the development of epilepsy; seizures are most likely to occur within the first month of cranial surgery. The use of antiepileptic drugs (AEDs) administered pre- or postoperatively to prevent seizures following cranial surgery has been investigated in a number of randomised controlled trials.To determine the efficacy and safety of AEDs when used prophylactically in people undergoing craniotomy and to examine which AEDs are most effective.We searched the Cochrane Epilepsy Group's Specialized Register (September 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 9, 2012), and MEDLINE (1946 to September 2012). No language restrictions were imposed.Randomised controlled trials of people with no history of epilepsy who were undergoing craniotomy for either therapeutic or diagnostic reasons were included. Trials with adequate randomisation methods and concealment were included; these could either be blinded or unblinded parallel trials. No minimum treatment period was stipulated, trials using active drugs or placebo as a control group were included.Two review authors (JP and JG) independently selected trials for inclusion and carried out data extraction and risk of bias assessments. Any disagreements were resolved through discussion. Outcomes investigated included the number of patients experiencing seizures (early - occurring within first week following craniotomy and late - occurring after first week following craniotomy), the number of deaths and the number of people experiencing disability and adverse effects. Due to the heterogeneous nature of the trials, data from the trials were not combined in a meta-analysis; the findings of the review are presented in narrative format.Six RCTs (N = 1398) were eligible for inclusion within the review with publication dates ranging between 1983 and 1999. Two trials compared a single AED (phenytoin) with a placebo. One three-arm trial compared two AEDs (carbamazepine, phenytoin) with no treatment. A second three-arm trial compared phenytoin, phenobarbital and no treatment. Two other trials were head-to-head trials of AEDs (phenytoin vs. valproate and zonisamide vs. phenobarbital). Of the four trials comparing AEDs with controls only one trial reported a significant difference between AED treatment and controls for early seizure occurrence. All other comparisons were non-significant. Of the head-to-head trials, none reported statistically significant differences between treatments for either early or late seizures. One head-to-head trial showed an increase in the number of deaths following one AED treatment compared to another AED treatment. Incidences of adverse effects of treatment were poorly reported, no significant differences between treatment groups were found due to the limited number of reported occurrences.There is little evidence to suggest that AED treatment administered prophylactically is effective or not effective in preventing post-craniotomy seizures. The current evidence base is limited due to the differing methodologies employed in the trials and inconsistencies in reporting of outcomes. Further evidence from good-quality, contemporary trials is required in order to assess the effectiveness of prophylactic AED treatment compared to control groups or other AEDs in preventing post-craniotomy seizures properly.

Background Epilepsy is a common neurological condition which affects between 0.5% and 1% of the population. Approximately 30% of people with epilepsy do not respond to treatment with currently available drugs, and the majority of these people have partial epilepsy. Vigabatrin is an antiepileptic drug licensed for use in the treatment of refractory epilepsy. No major side effects associated with the use of vigabatrin were detected by initial randomised controlled trials of the drug. However, longer term observational studies have subsequently identified that its use is associated with asymptomatic visual field constriction. Objectives The objective of this review is to synthesise evidence from short-term, randomised, placebo-controlled trials of vigabatrin. We summarise the effects of vigabatrin on seizures and short-term side effects when used as an add-on treatment for people with drug-resistant partial epilepsy. A review of longer term observational studies and estimates of proportions of patients developing visual field constrictions is currently being undertaken and results will be cited here in due course. Search strategy We searched the Cochrane Epilepsy Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (T h e Cochrane Library Issue 1, 2008), MEDLINE (1950-March 2008), and reference lists of articles. We also contacted the manufacturers of vigabatrin (Hoechst Marion Roussel). Selection criteria We included randomised, double-blind, placebo-controlled, fully published trials of vigabatrin, in people with drug-resistant partial epilepsy. Data collection and analysis Two review authors assessed trials for inclusion and extracted data. Primary analysis was by intention-to-treat (ITT). Outcomes evaluated included 50% or greater reduction in seizure frequency, treatment withdrawal and side effects observable in the short term. Results are presented on the relative risk (RR) scale with 95 or 99% confidence intervals (CI). Main results Eleven suitable trials, testing doses between 1000 mg and 6000 mg, were identified and included in the analysis. There were 982 observations on 747 patients in the primary ITT analysis of treatment efficacy. Patients treated with vigabatrin were significantly more likely to obtain a 50% or greater reduction in seizure frequency compared with those treated with placebo (RR 2.58 (95% CI 1.87 to 3.57)). Those treated with vigabatrin were also significantly more likely to have treatment withdrawn (RR 2.49 (95% CI 1.05 to 5.88)), and more likely to experience a number of side effects, significantly so for fatigue or drowsiness. There was some evidence of small study effect bias, with smaller studies tending to report greater estimates of RR than larger studies. It is possible that the actual relative risk of obtaining 50% reduction in seizure frequency may therefore be less than that obtained by a meta-analysis of fully published studies. Authors' conclusions This review of randomised controlled trials shows that vigabatrin can reduce seizure frequency in people with drug-resistant partial epilepsy. Short-term follow up of patients shows some side effects are associated with its use. Further analysis of longer term observational studies is required to evaluate how likely patients are to develop visual field defects, and whether such side effects are associated with dose and duration of drug use.

The physician's choice of antiepileptic drug for a particular patient should be based on firm evidence. The current body of evidence generated from randomized, controlled monotherapy trials is discussed. Attention is focused on four recently published randomized trials in which monotherapy with one drug is compared with monotherapy with another. The limitations of our current knowledge are discussed and some suggestions for future research are made.

Background Epilepsy is an important neurological condition and drug resistance in epilepsy is particularly common in individuals with focal seizures. In this review, we summarise the current evidence regarding a new antiepileptic drug, levetiracetam, when used as add-on treatment for controlling drug-resistant focal epilepsy. This is an update to a Cochrane Review that was originally published in 2001. Objectives To evaluate the effectiveness of levetiracetam, added on to usual care, in treating drug-resistant focal epilepsy. Search methods We searched the Cochrane Epilepsy Group's Specialized Register (August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 7, 2012), and MEDLINE (1946 to August week 1, 2012). We also contacted the manufacturers of levetiracetam and researchers in the field to seek any ongoing or unpublished trials. Selection criteria Randomised, placebo-controlled trials of add-on levetiracetam treatment in people with drug-resistant focal epilepsy. Data collection and analysis Two review authors independently selected trials for inclusion, assessed trials for bias, extracted data, and evaluated the overall quality of evidence. Outcomes investigated included 50% or greater reduction in focal seizure frequency (response); less than 50% reduction in focal seizure frequency (non-response); treatment withdrawal; adverse effects (including a specific analysis of changes in behaviour); cognitive effects and quality of life (QoL). Risk ratios (RR) with 95% confidence intervals (CIs) were used as measures of effect (99% CIs for adverse effects). Primary analyses were Intention-to-Treat (ITT). Dose response and inter-trial heterogeneity were evaluated in regression models. Main results Eleven trials (1861 participants) were included. They predominantly possessed low risks of bias. Participants were adults in nine trials (1565 participants) and children in the remaining two trials (296 participants). The dose of levetiracetam tested was 1000 to 4000 mg/day in adults, and 60 mg/kg/day in children. Treatment ranged from 12 to 24 weeks. For the 50% or greater reduction in focal seizure frequency outcome, the RR was significantly in favour of levetiracetam at all doses. The naive estimates, ignoring dose, showed children (52% responded) as better responders than adults (39% responded) on levetiracetam. 25% of children and 16% of adults responded to placebo. The Number Needed to Treat for an additional beneficial outcome for children and adults was four (95% CI three to seven) and five (95% CI four to six), respectively. The significant levels of statistical heterogeneity between trials on adults precluded valid provision of an overall RR (ignoring dose). Results for the two trials that tested levetiracetam 2000 mg on adults were sufficiently similar to be combined to give an RR for 50% or greater reduction in focal seizure frequency of 4.91 (95% CI 2.75 to 8.77), with an RR of 0.68 (95% CI 0.60 to 0.77) for non-response. At this dose, 37% and 8% of adults were responders in the levetiracetam and placebo groups, respectively. Regression analysis demonstrated that much of the heterogeneity between adult trials was likely to be explained by different doses of levetiracetam tested and different years of trial publication. There was no evidence of statistical heterogeneity between trials on children. For these trials, the RR for 50% or greater reduction in focal seizure frequency was 1.91 (95% CI 1.38 to 2.63), with an RR of 0.68 (95% CI 0.56 to 0.81) for non-response. 27% of children responded. Participants were not significantly more likely to have levetiracetam withdrawn (RR 0.98; 95% CI 0.73 to 1.32 and RR 0.80; 95% CI 0.43 to 1.46 for adults and children, respectively). For adults, somnolence (RR 1.51; 99% CI 1.06 to 2.17) and infection (RR 1.76; 99% CI 1.03 to 3.02) were significantly associated with levetiracetam. Accidental injury was significantly associated with placebo (RR 0.60; 99% CI 0.39 to 0.92). No individual adverse effect was significantly associated with levetiracetam in children. Changes in behaviour were negligible in adults (1% affected; RR 1.79; 99% CI 0.59 to 5.41) but significant in children (23% affected; RR 1.90; 99% CI 1.16 to 3.11). Cognitive effect and QoL outcomes suggested that levetiracetam had a positive effect on cognition and some aspects of QoL in adults. In children, levetiracetam did not appear to alter cognitive function but there was evidence of worsening in certain aspects of child behaviour. The overall quality of evidence used was high. Authors' conclusions This update adds seven more trials to the original review, which contained four trials. At every dose analysed, levetiracetam significantly reduced focal seizure frequency relative to placebo. This indicates that levetiracetam can significantly reduce focal seizure frequency when it is used as an add-on treatment for both adults and children with drug-resistant focal epilepsy. As there was evidence of significant levels of statistical heterogeneity within this positive effect it is difficult to be precise about the relative magnitude of the effect. At a dose of 2000 mg, levetiracetam may be expected to be 3.9 times more effective than placebo; with 30% of adults being responders at this dose. At a dose of 60 mg/kg/day, levetiracetam may be expected to be 0.9 times more effective than placebo; with 25% of children being responders at this dose. When dose was ignored, children were better responders than adults by around 4% to 13%. The results grossly suggest that one child or adult may respond to levetiracetam for every four or five children or adults, respectively, that have received levetiracetam rather than placebo. The drug seems to be well tolerated in both adults and children although non-specific changes in behaviour may be experienced in as high as 20% of children. This aspect of the adverse-effect profile of levetiracetam was analysed crudely and requires further investigation and validation. It seems reasonable to continue the use of levetiracetam in both adults and children with drug-resistant focal epilepsy. The results cannot be used to confirm longer-term or monotherapy effects of levetiracetam or its effects on generalised seizures. The conclusions are largely unchanged from those in the original review. The most significant contribution of this update is the addition of paediatric data into the analysis.

Background: Patients who present with only simple or complex partial seizures have a poorly documented prognosis. Treatment may be advocated to prevent future secondary generalised seizures, reduce the frequency of further simple or complex partial seizures or a combination of both. Methods: A full statistical analysis on 1334 patients was carried out. The outcomes measured were post-randomisation times to first seizure of any type and first tonic–clonic seizure. Methodology was adopted that accounted for individuals' underlying pre-randomisation seizure counts and allowed for the possibility that there may be a proportion of the sample that will not experience post-randomisation seizure recurrence. Results: 103 subjects randomised to the MESS (Multicentre Study of Early Epilepsy and Single Seizures) study had only partial seizures at randomisation. Only 17 of these had a tonic–clonic seizure during follow-up. The presence of an abnormal EEG at randomisation influenced this risk: an estimated 23% of those with EEG abnormality were at risk of tonic–clonic seizures during follow-up compared with 16% of those with a normal EEG. The group did, however, continue to have partial seizures during follow-up, and modelling showed that the impact of treatment on these seizures was significantly less than the effects of treatment on the frequency of tonic–clonic seizures in those patients with such pre-randomisation seizures. Conclusion: Patients presenting with a history of only partial seizures are at low risk of subsequent tonic–clonic seizures in the period of time to which therapeutic decisions are relevant. The effects of the antiepileptic drugs used in the MESS study are greater for tonic–clonic seizures than they are for partial seizures.

To assess the reporting of adverse events (AEs) in randomised controlled trials (RCTs) of antiepileptic drugs (AEDs) using the CONSORT statement for harms 2004, and to determine if reporting has changed since introduction of this standard.One hundred and fifty two RCTs were included from a search of papers published between 1999 and 2008 inclusive. We identified 23 criteria in the CONSORT statements. The mean number of criteria met per trial was 11.3 (95%CI 10.6-12.0). Commercially funded studies met 12.6 and non-commercially funded met 9.4 (p0.001). Trials recruiting adults met 12.5 and trials recruiting children met 9.3 (p0.001). Trials published before 2004 met 11.6 and trials published after 2004 met 11.1 (p=0.53). Commercially funded trials met the majority of criteria more than non-commercially sponsored trials, particularly for definition of AEs (RR 3.15, CI 1.67-5.95) and the use of a validated dictionary of terms (RR 3.46, CI 1.41-8.44). Definitions for AEs (RR 2.32, CI 1.07-5.02) and details of analyses (RR 2.05, CI 1.01-4.15) were reported in adult trials more often than trials in children.Reporting of AEs in RCTs of AEDs is poor and has not improved since the publication of the CONSORT guidelines on the reporting of harms. Commercially funded trials were better reported than non-commercially funded trials and trials recruiting adults were better reported than trials recruiting children. These findings have serious implications as poor reporting precludes bias being detected and hinders adequate risk benefit analyses. Journal editors, authors and reviewers should be encouraged to follow current guidance.

Objective Carbonic anhydrase (CA) inhibitors topiramate and zonisamide can induce metabolic acidosis in some patients. Our aims were to assess the prevalence and severity of this acidosis and to determine its predictors. Methods For 70 patients established on treatment with topiramate (n=55) or zonisamide (n=14) or both (n= 1 ), we measured electrolytes, and genotyped single nucleotide polymorphisms (SNPs) in the main renal CA isoenzymes (II, IV and XII). Results Twenty-six percent of patients had a metabolic acidosis (serum bicarbonate

Objective: Adverse effects (AEs) are a major concern when starting antiepileptic drug (AED) treatment. This study quantified the extent to which AE reporting in people with new-onset seizures started on AEDs is attributable to the medication per se, and investigated variables contributing to AE reporting. Methods: We pooled data from 2 large prospective studies, the Multicenter Study of Early Epilepsy and Single Seizures and the Northern Manhattan Study of incident unprovoked seizures, and compared adverse event profile (AEP) total and factor scores between adult cases prescribed AEDs for new-onset seizures and untreated controls, adjusting for several demographic and clinical variables. Differences in AEP scores were also tested across different AED monotherapies and controls, and between cases and controls grouped by number of seizures. Results: A total of 212 cases and 206 controls were identified. Most cases (94.2%) were taking low AED doses. AEP scores did not differ significantly between the 2 groups. Depression, female gender, symptomatic etiology, younger seizure onset age, ≥2 seizures, and history of febrile seizures were associated with higher AEP scores. There were no significant differences in AEP scores across different monotherapies and controls. AEP scores increased in both cases and controls with increasing number of seizures, the increment being more pronounced in cases. Conclusions: When AED treatment is started at low doses following new-onset seizures, AE reporting does not differ from untreated individuals. Targeting specific factors affecting AE reporting could lead to improved tolerability of epilepsy treatment.

Objective To determine for how long after a first unprovoked seizure a driver must be seizure-free before the risk of recurrence in the next 12 months falls below 20%, enabling them to regain their driving licence. Design Randomised controlled trial: Multicentre study of early Epilepsy and Single Seizures (MESS). Setting UK hospital outpatient clinics from 1 January 1993 to 31 December 2000. Participants People entered MESS if they had had one or more unprovoked seizures and both the participant and the clinician were uncertain about the need to start antiepileptic drug treatment. The subset of people used for this analysis comprised participants aged at least 16 years with a single unprovoked seizure. Main outcome measure Risk of seizure recurrence in the 12 months after a seizure-free period of 6, 12, 18, or 24 months from the date of the first (index) seizure. Regression modelling was used to investigate how antiepileptic treatment and several clinical factors influence the risk of seizure recurrence. Results At six months after the index seizure the risk of recurrence in the next 12 months for those who start antiepileptic drugs was significantly below 20% (unadjusted risk 14%, 95% confidence interval 10% to 18%). For patients who did not start treatment the risk estimate was less than 20% but the upper limit of the confidence interval was greater than 20% (18%, 13% to 23%). Multivariable analyses identified subgroups with a significantly greater than 20% risk of seizure recurrence in the 12 months after a six month seizure-free period, such as those with a remote symptomatic seizure with abnormal electroencephalogram results. Conclusion After a single unprovoked seizure this reanalysis of MESS provides estimates of seizure recurrence risks that will inform policy and guidance about regaining an ordinary driving licence. Further guidance is needed as to how such data should be utilised; in particular, whether a population approach should be taken with a focus on the unadjusted results or whether attempts should be made to individualise risk. Guidance is also required as to whether the focus should be on risk estimates only or on the confidence interval as well. If the focus is on the estimate only our unadjusted estimates suggest that treated and untreated patients are eligible to drive after being seizure-free for six months. If the focus is also on confidence intervals, direction is needed as to whether a conservative or liberal approach should be taken. Trial registration Current Controlled Trials [ISRCTN98767960][1]. [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN98767960

Vigabatrin is an efficacious antiepileptic drug licensed as add-on therapy in refractory epilepsy and used in infantile spasms. Eight years after licensing, there emerged a strong and possibly causative association with bilateral visual field loss. We report a systematic review ascertaining the magnitude of risk of vigabatrin associated visual field loss (VAVFL) and any clinical predictors of risk.Electronic searches, including MEDLINE (1966-2009), EMBASE (1974-2009), and CINAHL (1982-2009), were conducted. Reports, published in full, of observational studies investigating the prevalence of visual field loss in patients with partial epilepsy treated with vigabatrin were included. Outcomes were the proportion with visual field loss, and the relative risk of VAVFL compared to similar nonexposed patients with epilepsy.Thirty-two studies were identified, which included 1,678 patients exposed to vigabatrin and 406 controls. Of the 1,678 exposed patients, 738 (44%) had visual field loss compared to just 30 (7%) among the 406 controls. The random-effects estimate for the proportion of adults with visual field loss was 52% [95% confidence interval (CI) 46-59]. The estimate for children was lower at 34% (95% CI 25-42). The relative risk for field loss in vigabatrin-exposed patients was 4.0 (95% CI 2.9-5.5). Larger mean cumulative dose of vigabatrin and increasing age were associated with a higher proportion of patients with visual field loss.Vigabatrin should be reserved for patients with epilepsy for whom there is no other alternative or for patients who have determined the benefit of ongoing treatment to outweigh the risk of VAVFL.

We present a model for meta-regression in the presence of missing information on some of the study level covariates, obtaining inferences using Bayesian methods. In practice, when confronted with missing covariate data in a meta-regression, it is common to carry out a complete case or available case analysis. We propose to use the full observed data, modelling the joint density as a factorization of a meta-regression model and a conditional factorization of the density for the covariates. With the inclusion of several covariates, inter-relations between these covariates are modelled. Under this joint likelihood-based approach, it is shown that the lesser assumption of the covariates being Missing At Random is imposed, instead of the more usual Missing Completely At Random (MCAR) assumption. The model is easily programmable in WinBUGS, and we examine, through the analysis of two real data sets, sensitivity and robustness of results to the MCAR assumption. Copyright (C) 2010 John Wiley & Sons, Ltd.

Topiramate is licensed for the treatment of epilepsy and for migraine prophylaxis, but is also used off-licence for a wide range of indications. With the increasing use of topiramate, reports have emerged that topiramate can cause metabolic acidosis in some patients. It does this by impairing both the normal reabsorption of filtered HCO(3)(-) by the proximal renal tubule and the excretion of H(+) by the distal renal tubule. This combination of defects is termed mixed renal tubular acidosis (RTA). The mechanism involves the inhibition of the enzyme carbonic anhydrase, which is consistent with the fact that genetic deficiency of carbonic anhydrase is associated with mixed RTA. Topiramate-induced RTA can make patients acutely ill, and chronically, can lead to nephrolithiasis, osteoporosis and, in children, growth retardation. There is no proven method for predicting or preventing the effect of topiramate on acid-base balance, but patients with a history of renal calculi or known RTA should not receive topiramate. The utility of regular monitoring of HCO(3)(-) levels has not been proven and is not routine practice currently. For patients with persistent RTA, topiramate should usually be discontinued as alternative agents are available.

PURPOSE: To compare the cognitive profile of newly diagnosed untreated epilepsy patients with healthy volunteers using a comprehensive neuropsychological test battery. METHODS: A total of 155 untreated patients with newly diagnosed epilepsy, and no known brain pathology, were assessed before the start of treatment with antiepileptic medication. Their scores across the neuropsychological measures were compared with 87 healthy volunteers from the general population equated for age and sex. RESULTS: After adjusting for age, sex, and education, patients with epilepsy performed significantly worse than healthy volunteers on 6 of 14 cognitive measures, particularly in the domains of memory and psychomotor speed. Cognitive performance was not related to the number of seizures, type of epilepsy, or mood. When an impairment index was calculated, 53.5% patients had a least one abnormal score [>2 standard deviations (SD) below the control mean] on the test battery compared with 20.7% of healthy volunteers. DISCUSSION: Newly diagnosed untreated patients with epilepsy are cognitively compromised before the start of antiepileptic drug medication. The domains most affected are memory and psychomotor speed. More than one-half of the patients had at least one abnormal test score across the test battery. There were no differences in epilepsy-related or mood variables between those who demonstrated dysfunction and those that did not.

Background Epilepsy has a pervasive impact on the lives of people with intellectual disability and their carers. The delivery of high-quality care is impacted on by the complexity and diversity of epilepsy in this population. This article presents the results of a consensus clinical guideline process. Results A Delphi process identified a list of priority areas for the development of evidence-based guidelines. All guidelines were graded and consensus on scoring was achieved across the guideline group. Conclusion There is a dearth of high-quality evidence from well-constructed studies on which to base guidance. However, the development of internationally derived consensus guidelines may further support the management of epilepsy in adults with an intellectual disability.

About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission.We conducted a systematic review and aimed to answer the following clinical questions: What are the benefits and risks of starting anti-epileptic drug treatment following a single seizure? What are the effects of monotherapy in newly diagnosed partial epilepsy, and in newly diagnosed generalised epilepsy (tonic clonic type)? What are the effects of additional treatments in people with drug-resistant partial epilepsy? Which people in remission from seizures are at risk of relapse on withdrawal of drug treatment? What are the effects of behavioural and psychological treatments for people with epilepsy? What are the effects of surgery in people with drug-resistant temporal lobe epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).We found 59 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.In this systematic review we present information relating to the effectiveness and safety of the following interventions: addition of second-line drugs (gabapentin, levetiracetam, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin, or zonisamide), amygdalohippocampectomy, anti-epileptic drug withdrawal for people in remission, anti-epileptic drugs after a single seizure, biofeedback, carbamazepine, cognitive behavioural therapy (CBT), educational programmes, family counselling, hemispherectomy, lesionectomy, phenobarbital, phenytoin, relaxation therapy (alone or plus behavioural modification therapy), sodium valproate, temporal lobectomy, topiramate, vagus nerve stimulation as adjunctive therapy for partial seizures, and yoga.

Publisher Summary This chapter focuses primarily on data from epidemiological studies and randomized controlled trials that have addressed prognosis and outcome for patients with single seizures and early epilepsy. For patients with a single seizure or early epilepsy, when compared to deferred treatment, immediate treatment with one of the current firstline antiepileptic drugs reduces the risk of seizure recurrence, but has no impact on the longer-term seizure outcome in epilepsy. Consensus holds that antiepileptic drug treatment should be initiated for the majority of patients who have had two or more seizures, as the risk of recurrence is high, although the aim of treatment is to control seizures rather than influence the natural history of epilepsy. For patients with a single seizure, the recurrence risk is generally low, and there is a trade-off between preventing seizures and adverse effects of antiepileptic drugs such that neither policy is associated with overall quality-of-life gains. Patients can be identified at a low, medium, and high risk of seizure recurrence to aid patients and clinicians in discussions regarding the pros and cons of starting antiepileptic drug treatment following a single seizure.

Where possible, the decision as to when to start antiepileptic drug treatment should be informed by the results of randomized controlled trials. For patients presenting with their first seizure, randomized controlled trials have demonstrated that compared to no or delayed treatment, antiepileptic drugs reduce the risk of a second seizure, but do not alter longer term seizure outcomes. A prognostic model has been developed to identify patients at low, medium and high risk of recurrence, to further inform treatment decisions. For patients presenting with two or more seizures, consensus holds that treatment should be initiated if the seizures were of significant symptomatology such that the patient would wish treatment, and they occurred over a period of less than 6-12 months. However, randomized controlled trials recruiting an unselected population of patients following two or more seizures have not been undertaken and the magnitude of any treatment effect is therefore unknown. This consensus is based upon data from observational studies that show a high rate of a 3rd or 4th seizures even with antiepileptic drug treatment. Recurrence risks for patients with two or more seizures of minor symptomatology (e.g., simple partial seizures) or seizures separated by long time periods of time have been investigated in a randomized control trial. They may wish to start antiepileptic drug treatment if they are in a medium or high recurrence risk group as defined by a prognostic model.

Up to 70% of people who are treated with a single anticonvulsant will enter remission within a short time of being diagnosed with epilepsy.1 Optimal first choice treatments have been identified in some comparative randomised controlled trials and guidelines from the National Institute for Health and Clinical Excellence.2 3 Lamotrigine or carbamazepine are usually the preferred initial treatment of seizures with localised onset in the brain, whereas valproate is preferred for generalised epilepsy syndromes.4 5 However, despite optimal doses of a first line anticonvulsant, many patients with localised onset seizures (10-15/100 000 each year worldwide) do not enter remission and continue to have seizures of varying severity and frequency, which are associated with considerable psychosocial distress.6 7 The evidence base to support management of these patients is minimal,2 and it is uncertain which of the following available options is optimal

The majority of people with epilepsy have a good prognosis and their seizures are controlled by a single antiepileptic drug. However, up to 20% of patients from population-based studies and up to 30% from clinical series (not population-based) develop drug-resistant epilepsy, especially those with partial onset 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.To evaluate the efficacy and safety of topiramate when used as an add-on treatment for drug-resistant partial epilepsy.We searched the Cochrane Epilepsy Group Specialized Register (10 May 2007); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2007). No language restrictions were imposed. We also contacted the manufacturers of topiramate and researchers in the field to see any ongoing or published studies.Randomized placebo controlled add-on trials of topiramate recruiting people with drug-resistant partial epilepsy.Two review authors 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 relative risks (RR) with 95% confidence intervals (95% CI) are presented. Dose response was evaluated in regression models.Ten trials were included representing 1312 randomized participants. Baseline phases ranged from 4-12 weeks and double-blind phases from 11-19 weeks. The RR for a 50% or greater reduction in seizure frequency compared to placebo was 2.85 (95% CI 2.27 to 3.59). Dose regression analysis shows increasing effect with increasing dose, but found no advantage for doses over 300 or 400 mg per day. The RR for treatment withdrawal compared to placebo was 2.26 (95% CI 1.55 to 3.31). The RR for the following side effects indicate that they are significantly associated with topiramate: ataxia 1.95 (99% CI 1.04 to 3.65); dizziness 1.55 (99% CI 1.08 to 2.22); fatigue 2.19 (99% CI 1.43 to 3.35); nausea 2.35 (99% CI 1.28 to 4.29); somnolence 2.18 (99% CI 1.47 to 3.21) and 'thinking abnormally' 5.77 (99% CI 2.50 to 13.35).Topiramate has efficacy as an add-on treatment for 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 treating other epilepsy types.

Background Epilepsy effects approximately 1% of the population, with up to 30% of patients continuing to have seizures despite antiepileptic drug treatment. Objectives To assess the efficacy and tolerability of clobazam when used as an add-on therapy for patients with refractory partial onset or generalised onset seizures. Search methods We searched the following databases: (a) The Cochrane Epilepsy Group Specialised Register (February 2011); (b) The Cochrane Central Register of Controlled Trials (CENTRAL Issue 1, The Cochrane Library 2011); (c) MEDLINE (1948 to January 2011); (d) Database of Abstracts of Reviews of Effectiveness (DARE Issue 1, The Cochrane Library 2011); (e) BIOSIS Previews (February 2011). Selection criteria Randomised trials of add-on clobazam, with adequate methods of allocation concealment, recruiting patients with drug refractory partial or generalised onset seizures, with a minimum treatment period of eight weeks. Data collection and analysis Two review authors independently selected trials for inclusion and extracted relevant data. The following outcomes were assessed: 50% or greater reduction in seizures; seizure freedom; treatment withdrawal and adverse effects. Main results Four cross-over studies, representing 196 participants, were included. However, due to significant methodological heterogeneity and differences in outcome measures it was not possible to summarise data in a meta-analysis. Only two of the studies reported a 50% or greater seizure reduction compared to placebo; 57.7% and 52.4%. Side effects were only described in two of the studies, reportedly present in 36% and 85% of patients. Authors' conclusions Clobazam as an add-on treatment may reduce seizure frequency and may be most effective in partial onset seizures. However, it is not clear who will best benefit and over what time-frame. A large scale, randomised controlled trial conducted over a greater period of time, incorporating subgroups with differing seizure types, is required to inform clinical practice.

Summary Purpose Observational studies may provide important information on the long-term effects of treatments for epilepsy, but systematic reviews of observational studies may be more prone to heterogeneity and biases. These issues were investigated in a systematic review of non-randomised add-on anti-epileptic drug studies. Methods Searches of MEDLINE (1966–2006), EMBASE (1974–2006), CINAHL (1982–2006), the Cochrane database of systematic reviews, the Cochrane Controlled Trials register, the DARE database and hand-searching congress proceedings were conducted. Randomised controlled trials, follow-on randomised controlled trials and prospective and retrospective cohort studies of gabapentin, topiramate, or levetiracetam as add-on therapy in adults (>12 years old) were identified. Outcomes were 50% responders and proportion seizure free. Results Thirty-eight non-randomised gabapentin studies, 82 topiramate and 84 levetiracetam studies were identified. There was marked heterogeneity of effect estimates from observational studies which prohibited the pooling of estimates in random effects models. Median effect estimates were larger and more varied for observational studies than randomised placebo-controlled trials (RCTs). For example, the median value (10 th and 90 th percentile) for 50% responders for gabapentin was 36% (15 and 71%) compared to 23% (19 and 38%) for gabapentin RCTs. Patient and study covariates in meta-regression models could not explain the vast heterogeneity. Publication bias was evident and a sensitivity analysis, allowing for the effects of publication bias, showed that effect estimates could increase by up to 6% for seizure freedom rates. Discussion Reports of observational anti-epileptic studies give limited information on patient selection and characteristics. Systematic reviews of observational studies are prone to significant heterogeneity and bias which cannot adequately be explained by reported study characteristics. Reporting standards for observational studies of anti-epileptic drugs could be improved by following guidelines for reporting non-randomised studies of interventions.

BACKGROUND: Approximately 30% of patients with epilepsy remain refractory to drug treatment and continue to experience seizures whilst taking one or more antiepileptic drugs (AEDs). Several non‐pharmacological interventions that may be used in conjunction with or as an alternative to AEDs are available for refractory patients. In view of the fact that seizures in people with intellectual disabilities are often complex and refractory to pharmacological interventions, it is evident that good quality randomised controlled trials (RCTs) are needed to assess the efficacy of alternatives or adjuncts to pharmacological interventions. This is an updated version of the original Cochrane review (Beavis 2007) published in The Cochrane Library (2007, Issue 4). OBJECTIVES: To assess data derived from randomised controlled trials of non‐pharmacological interventions for people with epilepsy and intellectual disabilities. Non‐pharmacological interventions include, but are not limited to, the following. • Surgical procedures. • Specialised diets, for example, the ketogenic diet, or vitamin and folic acid supplementation. • Psychological interventions for patients or for patients and carers/parents, for example, cognitive‐behavioural therapy (CBT), electroencephalographic (EEG) biofeedback and educational intervention. • Yoga. • Acupuncture. • Relaxation therapy (e.g. music therapy). SEARCH METHODS: For the latest update of this review, we searched the Cochrane Epilepsy Group Specialised Register (19 August 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) via CRSO (19 August 2014), MEDLINE (Ovid, 1946 to 19 August 2014) and PsycINFO (EBSCOhost, 1887 to 19 August 2014). SELECTION CRITERIA: Randomised controlled trials of non‐pharmacological interventions for people with epilepsy and intellectual disabilities. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria and extracted study data. MAIN RESULTS: One study is included in this review. When two surgical procedures were compared, results indicated that corpus callosotomy with anterior temporal lobectomy was more effective than anterior temporal lobectomy alone in improving quality of life and performance on IQ tests among people with epilepsy and intellectual disabilities. No evidence was found to support superior benefit in seizure control for either intervention. This is the only study of its kind and was rated as having an overall unclear risk of bias. The previous update (December 2010) identified one RCT in progress. The study authors have confirmed that they are aiming to publish by the end of 2015; therefore this study (Bjurulf 2008) has not been included in the current review. AUTHORS' CONCLUSIONS: This review highlights the need for well‐designed randomised controlled trials conducted to assess the effects of non‐pharmacological interventions on seizure and behavioural outcomes in people with intellectual disabilities and epilepsy.

Summary Purpose Open-label extension studies, or follow-on randomised controlled trials (FORCTs) are widely believed to be prone to patient selection biases which may inflate effect estimates. This study investigates the reporting and analysis of efficacy outcomes in FORCTs and critically evaluates the associated underlying assumptions. We propose an alternative method of analysis, in line with that recommended in the analysis of RCTs, the intention to treat (ITT) approach, in which it is assumed that all patients who discontinue treatment are non-responders. Methods A systematic review of FORCTs and randomised controlled trials (RCT) of topiramate, levetiracetam and gabapentin as adjuvant therapy in refractory adult epilepsy was conducted. Sample sizes and numbers of responders, along with reported outcomes were extracted. To evaluate the feasibility of the assumptions underlying the various methods of analysis, the most common causes of discontinuation were evaluated. For each FORCT, we compared the reported outcome to the proposed ITT analysis. Results The 10 FORCT reports identified all excluded from the analysis patients who dropped out of the RCT. Adverse events or inefficacy were the main reasons for treatment discontinuation. Analysis based on the ITT method, led to smaller effect estimates than those reported. For example, a FORCT of levetiracetam reported a responder rate of 43%, which reduced to 28% under an ITT analysis, comparable to an ITT analysis outcome of 26% for the parent RCT. Conclusions FORCTs can provide important information about long-term efficacy and tolerability of newer therapies. However, current reporting methods are likely to be misleading as outcomes are reported for the subset of patients continuing with treatment at the end of the FORCT. Since the majority of patients who discontinue treatment do so for reasons associated with inefficacy, an analysis based on the ITT approach more closely reflects the outcomes of the patients.

OBJECTIVES To compare clinicians' choice of one of the standard epilepsy drug treatments (carbamazepine or valproate) versus appropriate comparator new drugs. DESIGN A clinical trial comprising two arms, one comparing new drugs in carbamazepine and the other with valproate. SETTING A multicentre study recruiting patients with epilepsy from hospital outpatient clinics. PARTICIPANTS Patients with an adequately documented history of two or more clinically definite unprovoked epileptic seizures within the last year for whom treatment with a single antiepileptic drug represented the best therapeutic option. INTERVENTIONS Arm A was carbamazepine (CBZ) versus gabapentin (GBP) versus lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM). Arm B valproate (VPS) versus LTG versus TPM. MAIN OUTCOME MEASURES Time to treatment failure (withdrawal of the randomised drug for reasons of unacceptable adverse events or inadequate seizure control or a combination of the two) and time to achieve a 12-month remission of seizures. Time from randomisation to first seizure, 24-month remission of seizures, incidence of clinically important adverse events, quality of life (QoL) outcomes and health economic outcomes were also considered. RESULTS Arm A recruited 1721 patients (88% with symptomatic or cryptogenic partial epilepsy and 10% with unclassified epilepsy). Arm B recruited 716 patients (63% with idiopathic generalised epilepsy and 25% with unclassified epilepsy). In Arm A LTG had the lowest incidence of treatment failure and was statistically superior to all drugs for this outcome with the exception of OXC. Some 12% and 8% fewer patients experienced treatment failure on LTG than CBZ, the standard drug, at 1 and 2 years after randomisation, respectively. The superiority of LTG over CBZ was due to its better tolerability but there is satisfactory evidence indicating that LTG is not clinically inferior to CBZ for measures of its efficacy. No consistent differences in QoL outcomes were found between treatment groups. Health economic analysis supported LTG being preferred to CBZ for both cost per seizure avoided and cost per quality-adjusted life-year gained. In Arm B for time to treatment failure, VPS, the standard drug, was preferred to both TPM and LTG, as it was the drug least likely to be associated with treatment failure for inadequate seizure control and was the preferred drug for time to achieving a 12-month remission. QoL assessments did not show any between-treatment differences. The health economic assessment supported the conclusion that VPS should remain the drug of first choice for idiopathic generalised or unclassified epilepsy, although there is a suggestion that TPM is a cost-effective alternative to VPS. CONCLUSIONS The evidence suggests that LTG may be a clinical and cost-effective alternative to the existing standard drug treatment, CBZ, for patients diagnosed as having partial seizures. For patients with idiopathic generalised epilepsy or difficult to classify epilepsy, VPS remains the clinically most effective drug, although TPM may be a cost-effective alternative for some patients. Three new antiepileptic drugs have recently been licensed in the UK for the treatment of epilepsy (levetiracetam, zonisamide and pregabalin), therefore these drugs should be compared in a similarly designed trial.

BACKGROUND: The prevalence of epilepsy among people with intellectual disabilities is much higher than in the general population. Seizures in this population are often complex and refractory to treatment and antiepileptic medication may have a profound effect upon behaviour (Kerr 1997). This is an updated version of a Cochrane Review first published in Issue 3, 2007. OBJECTIVES: To assess the data available from randomised controlled trials (RCTs) of the efficacy of antiepileptic drug (AED) interventions in people with epilepsy and intellectual disabilities. SEARCH METHODS: For the latest update of this review, we searched the Cochrane Epilepsy Group Specialised Register (2 September 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO) (2 September 2014), MEDLINE (Ovid, 1946 to 3 September 2014) and PsycINFO (EBSCOhost, 1887 to 3 September 2014). SELECTION CRITERIA: Randomised and quasi‐randomised controlled trials (RCTs) of pharmacological interventions for people with epilepsy and a learning disability. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We assessed epilepsy/seizure, behavioural and cognitive outcomes, as well as quality of life and adverse effects. MAIN RESULTS: We included 14 RCTs (1116 participants) in the present review. Data were heterogenous and a descriptive analysis is presented. In the majority of cases where antiepileptic drugs (AEDs) were trialled in this population, we found moderate reductions in seizure frequency in that there was a significantly higher rate of responders (reduction of 50% or more) in the treatment group compared with the placebo group, with some studies reporting a higher incidence of seizure freedom in the treatment group. In general, AEDs that are proven to be effective in the general epilepsy population are also effective for refractory epilepsy in people with intellectual disability. It is not possible to comment on the relative efficacy of medications, making clinical decisions difficult. In trial settings patients continued on treatment in the majority of cases. Placebo groups often experienced fewer adverse events. Where adverse events were experienced they appeared similar to those in the general population. The methods by which adverse events were recorded and reported appeared to be inconsistent, resulting in very large variation between studies. This is problematic as clinically relevant interpretation of these findings is limited. The quality of evidence provided in the present review is low to moderate. Additionally the majority of studies lacked or used non‐reliable measures of behavioural exacerbation. However, where measured, little obvious impact on behaviour was seen in terms of behaviour disorder. AUTHORS' CONCLUSIONS: This review broadly supports the use of AEDs to reduce seizure frequency in people with refractory epilepsy and intellectual disability. The evidence suggests that adverse events are similar to those in the general population and that behavioural adverse events leading to discontinuation are rare; however, other adverse effects are under‐researched.

Summary: Introduction: Time to first seizure is a common outcome in antiepileptic drug (AED) studies. Previous studies have typically failed to find statistically significant differences between carbamazepine (CBZ) and valproate (VPS). We re-analyzed a meta-analysis comparing CBZ and VPS monotherapy with new powerful statistical methods that incorporate baseline seizure rate information. Methods: Individual patient data were available on 1,265 patients from a meta-analysis of five trials. The outcome measure was time to first seizure after randomization, adjusted for background variables and baseline seizure rate. Results: We found strong evidence of an interaction between treatment and epilepsy type, and between treatment and age. For generalized onset seizures, VPS was statistically significantly better than CBZ: VPS delayed the first seizure after treatment 58%, 52%, 44%, and 36% longer than CBZ for individuals aged 10, 20, 30, or 40, respectively. For partial onset seizures in individuals older than 30, CBZ was significantly better then VPS; CBZ delayed the time to first seizure by 9%, 25%, 44%, and 66% longer than VPS for individuals aged 20, 30, 40, or 50, respectively. Conclusion: The results show clear age-varying differences between the effectiveness of CBZ and VPS for generalized onset and partial onset seizures, which have not been identified in previous studies using standard statistical methods. In future trials of AED monotherapy or add-on where time to first or Nth seizure is an outcome, methodology that can incorporate baseline seizure rate information would allow more powerful comparisons between treatments or between treatment and placebo.

Objective: To compare the impact of policies of immediate vs deferred treatment in patients with few or infrequent seizures on quality of life (QoL) outcomes. Methods: We conducted a multicenter, randomized, unblinded study of immediate and deferred treatment. QoL data were collected by mail, using validated measures, for participants living in the UK and without major learning disability. Baseline questionnaires were returned by 441 adult patients; 333 returned 2-year follow-up questionnaires. This analysis is based on 331 patients (162 randomized to immediate, 169 to deferred treatment) returning both baseline and 2-year questionnaires. Results: There were no significant differences at 2 years in QoL outcomes by treatment group. Patients randomized to deferred treatment were no more likely to report impairments in general health, cognitive function, psychological well-being, or social function. The one area of functioning affected was driving, where those randomized to deferred treatment were disadvantaged. There were clear QoL impacts both of taking antiepileptic drugs and, to an even greater extent, of continuing seizures. Conclusions: In treatment uncertain patients, there is a clear trade-off between adverse effects of seizures and adverse effects of taking antiepileptic drugs, i.e., neither policy examined in our study was associated with overall quality of life gains or losses longer term.

Summary Background Carbamazepine is widely accepted as a drug of first choice for patients with partial onset seizures. Several newer drugs possess efficacy against these seizure types but previous randomised controlled trials have failed to inform a choice between these drugs. We aimed to assess efficacy with regards to longer-term outcomes, quality of life, and health economic outcomes. Methods SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm A recruited 1721 patients for whom carbamazepine was deemed to be standard treatment, and they were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, and time to 12-months remission, and assessment was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. Findings For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0·78 [95% CI 0·63–0·97]), gabapentin (0·65 [0·52–0·80]), and topiramate (0·64 [0·52–0·79]), and had a non-significant advantage compared with oxcarbazepine (1·15 [0·86–1·54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0·75 [0·63–0·90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0·91 [0·77–1·09]), topiramate (0·86 [0·72–1·03]), and oxcarbazepine (0·92 [0·73–1·18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (−8 to 7) and 5 (−3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine. Interpretation Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures.

Summary Background Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. Methods SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. Findings For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1·57 [95% CI 1·19–2·08]), but there was no significant difference between valproate and lamotrigine (1·25 [0·94–1·68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1·55 [1·07–2·24] and topiramate (1·89 [1·32–2·70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0·76 [0·62–0·94]), and for the subgroup with an idiopathic generalised epilepsy 0·68 (0·53–0·89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. Interpretation Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

IntroductionIt is unknown why over one-third of patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS) continue to experience seizures despite temporal lobe surgery. We investigated the relationship between hippocampal internal architecture (HIA) on preoperative MRI, and postoperative seizure outcome in patients with refractory mTLE and HS.MethodsHIA was assessed on preoperative T2-STIR MR images using a published scoring system1 for 79 patients undergoing evaluation at University Hospital Bonn, Germany. Patients underwent amygdalohippocampectomy and received postoperative outcome assessment using the International League Against Epilepsy (ILAE) classification. Hippocampal volumes were obtained using 3D T1-weighted images. Quantitative histopathological assessment was performed on resected hippocampal specimens.ResultsNo significant differences in ipsilateral or contralateral HIA ratings, or HIA score asymmetry, were found between patients rendered seizure free (ILAE I) compared to those continuing to experience postoperative seizures (ILAE II-VI). HIA significantly correlated with neuronal density in CA3 and CA4 in the pathologic hippocampus, and hippocampal volumes bilaterally. There was no significant correlation between HIA and clinical variables.ConclusionAlthough valuable in determining seizure laterality, HIA does not predict postoperative outcome.AcknowledgementsThis work was supported by a UK MRC grant awarded to SSK (Grant Number: MR/K023152/1). References:1Ver Hoef 2013