A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure.

Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial epilepsy syndrome characterized by distinctive phenotypic heterogeneity within families. The SCN1B c.363C>G (p.Cys121Trp) variant has been identified in independent, multi-generational families with GEFS+. Although the variant is present in population databases (at very low frequency), there is strong clinical, genetic, and functional evidence to support pathogenicity. Recurrent variants may be due to a founder event in which the variant has been inherited from a common ancestor. Here, we report evidence of a single founder event giving rise to the SCN1B c.363C>G variant in 14 independent families with epilepsy. A common haplotype was observed in all families, and the age of the most recent common ancestor was estimated to be approximately 800 years ago. Analysis of UK Biobank whole-exome-sequencing data identified 74 individuals with the same variant. All individuals carried haplotypes matching the epilepsy-affected families, suggesting all instances of the variant derive from a single mutational event. This unusual finding of a variant causing an autosomal dominant, early-onset disease in an outbred population that has persisted over many generations can be attributed to the relatively mild phenotype in most carriers and incomplete penetrance. Founder events are well established in autosomal recessive and late-onset disorders but are rarely observed in early-onset, autosomal dominant diseases. These findings suggest variants present in the population at low frequencies should be considered potentially pathogenic in mild phenotypes with incomplete penetrance and may be more important contributors to the genetic landscape than previously thought.

Morbidity and mortality risks associated with valproate withdrawal in young men and women with epilepsy.

Valproate is the most effective treatment for idiopathic generalised epilepsy. Current guidance precludes its use in women of childbearing potential, unless other treatments are ineffective or not tolerated, because of high teratogenicity. This risk was recently extended to men. New guidance will limit use both in men and women aged <55 years, resulting in withdrawal of valproate from men already taking it, as occurs for women. Whether there are risks of personal harm (including injury or death) associated with valproate withdrawal has not yet been quantified for men or women on valproate, meaning clinicians cannot reliably counsel either sex when discussing valproate withdrawal with them, despite that this concern may be at the forefront of patients' and clinicians' minds. We assessed whether there are any morbidity or mortality risks associated with valproate withdrawal in young men and women. We performed a retrospective cohort study of internationally derived electronic health data within the TriNetX Global Collaborative Network. Included were men and women aged 16-54 years with ≥1 epilepsy disease or symptom code between 01/12/2017-01/12/2018 and ≥2 valproate prescriptions over the preceding two years (01/01/2015-30/11/2017). 5-year propensity-matched risks of mortality and a range of morbidity outcomes were compared between those remaining on vs. withdrawn from valproate during the 01/12/2017-01/12/2018 recruitment period, regardless of whether switched to another antiseizure medication. Survival analysis was undertaken using Cox-proportional hazard models, generating hazard ratios (HRs) with 95% confidence intervals (CIs). 8,991 men and 5,243 women taking valproate were recruited. 28% of men and 36% of women were subsequently withdrawn from valproate. Valproate withdrawal was associated with significantly increased risks of emergency department attendance (HRs overall: 1.236 (CI 1.159-1.319), men: 1.181 (CI 1.083-1.288), women: 1.242 (CI 1.125-1.371)), hospital admission (HRs overall: 1.160 (CI 1.081-1.246), men: 1.132 (CI 1.027-1.249), women: 1.147 (CI 1.033-1.274)), falls (HRs overall: 1.179 (CI 1.041-1.336), men: 1.298 (CI 1.090-1.546)), injuries (HRs overall: 1.095 (CI 1.021-1.174), men: 1.129 (CI 1.029-1.239)), burns (HRs overall: 1.592 (CI 1.084-2.337)), and new-onset depression (HRs overall 1.323 (CI 1.119-1.565), women: 1.359 (CI 1.074-1.720)). The risk of these outcomes occurring was 1-7% higher in those withdrawn from valproate than in those remaining on valproate. Overall, valproate withdrawal was not associated with increased mortality. These results may help patients and clinicians have a more informed discussion about personal safety when considering valproate withdrawal.

Association of antiseizure medications and adverse cardiovascular events: A global health federated network analysis.

OBJECTIVE: A diagnosis of epilepsy has been associated with adverse cardiovascular events (CEs), but the extent to which antiseizure medications (ASMs) may contribute to this is not well understood. The aim of this study was to compare the risk of adverse CEs associated with ASM in patients with epilepsy (PWE). METHODS: A retrospective case-control cohort study was conducted using TriNetX, a global health federated network of anonymized patient records. Patients older than 18 years, with a diagnosis of epilepsy (International Classification of Diseases, 10th Revision code G40) and a medication code of carbamazepine, lamotrigine, or valproate were compared. Patients with cardiovascular disease prior to the diagnosis of epilepsy were excluded. Cohorts were 1:1 propensity score matched (PSM) according to age, sex, ethnicity, hypertension, heart failure, atherosclerotic heart disease, atrial and cardiac arrythmias, diabetes, disorders of lipoprotein metabolism, obesity, schizophrenia and bipolar disorder, medications, and epilepsy classification. The primary outcome was a composite of adverse CEs (ischemic stroke, acute ischemic heart disease, and heart failure) at 10 years. Cox regression analyses were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) following 1:1 PSM. RESULTS: Of 374 950 PWE included; three cohorts were established after PSM: (1) carbamazepine compared to lamotrigine, n = 4722, mean age 37.4 years; (2) valproate compared to lamotrigine, n = 5478, mean age 33.9 years; and (3) valproate compared to carbamazepine, n = 4544, mean age 37.0 years. Carbamazepine and valproate use were associated with significantly higher risk of composite cardiovascular outcome compared to lamotrigine (HR = 1.390, 95% CI = 1.160-1.665 and HR = 1.264, 95% CI = 1.050-1.521, respectively). Valproate was associated with a 10-year higher risk of all-cause death than carbamazepine (HR = 1.226, 95% CI = 1.017-1.478), but risk of other events was not significantly different. SIGNIFICANCE: Carbamazepine and valproate were associated with increased CE risks compared to lamotrigine. Cardiovascular risk factor monitoring and careful follow-up should be considered for these patients.

Clinical prediction models for treatment outcomes in newly diagnosed epilepsy: A systematic review.

Up to 35% of individuals diagnosed with epilepsy continue to have seizures despite treatment, commonly referred to as drug-resistant epilepsy. Uncontrolled seizures can directly, or indirectly, negatively impact an individual's quality of life. To inform clinical management and life decisions, it is important to be able to predict the likelihood of seizure control. Those likely to achieve seizure control will be able to return sooner to their usual work and leisure activities and require less follow-up, whereas those with a poor prognosis will need more frequent clinical attendance and earlier consideration of epilepsy surgery. This is a systematic review aimed at identifying demographic, clinical, physiological (e.g., electroencephalographic), and imaging (e.g., magnetic resonance imaging) factors that may be predictive of treatment outcomes in patients with newly diagnosed epilepsy (NDE). MEDLINE and Embase were searched for prediction models of treatment outcomes in patients with NDE. Study characteristics were extracted and subjected to assessment of risk of bias (and applicability concerns) using the PROBAST (Prediction Model Risk of Bias Assessment Tool) tool. Baseline variables associated with treatment outcomes are reported as prognostic factors. After screening, 48 models were identified in 32 studies, which generally scored low for concerns of applicability, but universally scored high for susceptibility to bias. Outcomes reported fit broadly into four categories: drug resistance, short-term treatment response, seizure remission, and mortality. Prognostic factors were also heterogenous, but the predictors that were commonly significantly associated with outcomes were those related to seizure characteristics/types, epilepsy history, and age at onset. Antiseizure medication response was often included as a baseline variable, potentially obscuring other factor relationships at baseline. Currently, outcome prediction models for NDE demonstrate a high risk of bias. Model development could be improved with a stronger adherence to recommended TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis) practices. Furthermore, we outline actionable changes to common practices that are intended to improve the overall quality of prediction model development in NDE.

Epilepsy and the risk of adverse cardiovascular events: A nationwide cohort study.

BACKGROUND AND PURPOSE: Epilepsy is associated with higher morbidity and mortality compared to people without epilepsy. We performed a retrospective cross-sectional and longitudinal cohort study to evaluate cardiovascular comorbidity and incident vascular events in people with epilepsy (PWE). METHODS: Data were extracted from the French Hospital National Database. PWE (n = 682,349) who were hospitalized between January 2014 and December 2022 were matched on age, sex, and year of hospitalization with 682,349 patients without epilepsy. Follow-up was conducted from the date of first hospitalization with epilepsy until the date of each outcome or date of last news in the absence of the outcome. Primary outcome was the incidence of all-cause death, cardiovascular death, myocardial infarction, hospitalization for heart failure, ischaemic stroke (IS), new onset atrial fibrillation, sustained ventricular tachycardia or fibrillation (VT/VF), and cardiac arrest. RESULTS: A diagnosis of epilepsy was associated with higher numbers of cardiovascular risk factors and adverse cardiovascular events compared to controls. People with epilepsy had a higher incidence of all-cause death (incidence rate ratio [IRR] = 2.69, 95% confidence interval [CI] = 2.67-2.72), cardiovascular death (IRR = 2.16, 95% CI = 2.11-2.20), heart failure (IRR = 1.26, 95% CI = 1.25-1.28), IS (IRR = 2.08, 95% CI = 2.04-2.13), VT/VF (IRR = 1.10, 95% CI = 1.04-1.16), and cardiac arrest (IRR = 2.12, 95% CI = 2.04-2.20). When accounting for all-cause death as a competing risk, subdistribution hazard ratios for ischaemic stroke of 1.59 (95% CI = 1.55-1.63) and for cardiac arrest of 1.73 (95% CI = 1.58-1.89) demonstrated higher risk in PWE. CONCLUSIONS: The prevalence and incident rates of cardiovascular outcomes were significantly higher in PWE. Targeting cardiovascular health could help reduce excess morbidity and mortality in PWE.

'Knowledge exchange' workshops to optimise development of a risk prediction tool to assist conveyance decisions for suspected seizures - Part of the Risk of ADverse Outcomes after a Suspected Seizure (RADOSS) project.

PURPOSE: Suspected seizures present challenges for ambulance services, with paramedics reporting uncertainty over whether or not to convey individuals to emergency departments. The Risk of ADverse Outcomes after a Suspected Seizure (RADOSS) project aims to address this by developing a risk assessment tool utilizing structured patient care record and dispatch data. It proposes a tool that would provide estimates of an individual's likelihood of death and/or recontact with emergency care within 3 days if conveyed compared to not conveyed, and the likelihood of an 'avoidable attendance' occurring if conveyed. Knowledge Exchange workshops engaged stakeholders to resolve key design uncertainties before model derivation. METHOD: Six workshops involved 26 service users and their significant others (epilepsy or nonepileptic attack disorder), and 25 urgent and emergency care clinicians from different English ambulance regions. Utilizing Nominal Group Techniques, participants shared views of the proposed tool, benefits and concerns, suggested predictors, critiqued outcome measures, and expressed functionality preferences. Data were analysed using Hamilton's Rapid Analysis. RESULTS: Stakeholders supported tool development, proposing 10 structured variables for predictive testing. Emphasis was placed on the tool supporting, not dictating, care decisions. Participants highlighted some reasons why RADOSS might struggle to derive a predictive model based on structured data alone and suggested some non-structured variables for future testing. Feedback on prediction timeframes for service recontact was received, along with advice on amending the 'avoidable attendance' definition to prevent the tool's predictions being undermined by potential overuse of certain investigations in hospital. CONCLUSION: Collaborative stakeholder engagement provided crucial insights that can guide RADOSS to develop a user-aligned, optimized tool.

Midbrain structure volume, estimated myelin and functional connectivity in idiopathic generalised epilepsy.

BACKGROUND: Structural and functional neuroimaging studies often overlook lower basal ganglia structures located in and adjacent to the midbrain due to poor contrast on clinically acquired T1-weighted scans. Here, we acquired T1-weighted, T2-weighted, and resting-state fMRI scans to investigate differences in volume, estimated myelin content and functional connectivity of the substantia nigra (SN), subthalamic nuclei (SubTN) and red nuclei (RN) of the midbrain in IGE. METHODS: Thirty-three patients with IGE (23 refractory, 10 non-refractory) and 39 age and sex-matched healthy controls underwent MR imaging. Midbrain structures were automatically segmented from T2-weighted images and structural volumes were calculated. The estimated myelin content for each structure was determined using a T1-weighted/T2-weighted ratio method. Resting-state functional connectivity analysis of midbrain structures (seed-based) was performed using the CONN toolbox. RESULTS: An increased volume of the right RN was found in IGE and structural volumes of the right SubTN differed between patients with non-refractory and refractory IGE. However, no volume findings survived corrections for multiple comparisons. No myelin alterations of midbrain structures were found for any subject groups. We found functional connectivity alterations including significantly decreased connectivity between the left SN and the thalamus and significantly increased connectivity between the right SubTN and the superior frontal gyrus in IGE. CONCLUSIONS: We report volumetric and functional connectivity alterations of the midbrain in patients with IGE. We postulate that potential increases in structural volumes are due to increased iron deposition that impacts T2-weighted contrast. These findings are consistent with previous studies demonstrating pathophysiological abnormalities of the lower basal ganglia in animal models of generalised epilepsy.

Lamotrigine add-on therapy for drug-resistant focal epilepsy.

BACKGROUND: This is an updated version of a Cochrane Review last updated in 2020. Epilepsy is a common neurological disorder, affecting 0.5% to 1% of the population. In nearly 30% of cases, epilepsy is resistant to currently available drugs. Pharmacological treatment remains the first choice to control epilepsy. Lamotrigine is a second-generation antiseizure medication. When used as an add-on (in combination with other antiseizure medications), lamotrigine can reduce seizures, but with some adverse effects. OBJECTIVES: To evaluate the benefits and harms of add-on lamotrigine, compared with add-on placebo or no add-on treatment in people with drug-resistant focal epilepsy. SEARCH METHODS: For this update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) on 3 October 2022 with no language restrictions. CRS Web includes randomised and quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups, including Epilepsy. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that investigated add-on lamotrigine versus add-on placebo or no add-on treatment in people of any age with drug-resistant focal epilepsy. We used data from the first period of eligible cross-over trials. DATA COLLECTION AND ANALYSIS: For this update, two review authors independently selected trials and extracted data. Our primary outcome was 50% or greater reduction in seizure frequency. Our secondary outcomes were treatment withdrawal, adverse effects, cognitive effects, and quality of life. Primary analyses were by intention-to-treat. We performed sensitivity best- and worse-case analyses to account for missing outcome data. We calculated pooled risk ratios (RRs) with 95% confidence intervals (95% Cls) for dichotomous outcomes. MAIN RESULTS: We identified no new studies for this update, so the results and conclusions of the review are unchanged. We included five parallel-group studies in adults or children, eight cross-over studies in adults or children, and one parallel study with a responder-enriched design in infants. In total, these 14 studies enroled 1806 eligible participants (38 infants, 199 children, 1569 adults). Baseline phases ranged from four to 12 weeks and treatment phases ranged from eight to 36 weeks. We rated 11 studies (1243 participants) at low overall risk of bias and three (697 participants) at unclear overall risk of bias due to lack of information on study design. Four studies (563 participants) reported effective blinding. Lamotrigine compared with placebo probably increases the likelihood of achieving 50% or greater reduction in seizure frequency (RR 1.80, 95% CI 1.45 to 2.23; 12 trials, 1322 participants (adults and children); moderate-certainty evidence). There is probably little or no difference in risk of treatment withdrawal for any reason among people treated with lamotrigine versus people treated with placebo (RR 1.11, 95% CI 0.91 to 1.37; 14 trials; 1806 participants; moderate-certainty evidence). Lamotrigine compared with placebo is probably associated with a greater risk of ataxia (RR 3.34, 99% Cl 2.01 to 5.55; 12 trials; 1525 participants; moderate-certainty evidence), dizziness (RR 1.76, 99% Cl 1.28 to 2.43; 13 trials; 1768 participants; moderate-certainty evidence), nausea (RR 1.81, 99% CI 1.22 to 2.68; 12 studies, 1486 participants; moderate-certainty evidence), and diplopia (RR 3.79, 99% Cl 2.15 to 6.68; 3 trials, 944 participants; moderate-certainty evidence). There is probably little or no difference in the risk of fatigue between lamotrigine and placebo (RR 0.82, 99% CI 0.55 to 1.22; 12 studies, 1552 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Lamotrigine as an add-on treatment for drug-resistant focal seizures is probably effective for reducing seizure frequency. Certain adverse effects (ataxia, dizziness, diplopia, and nausea) are probably more likely to occur with lamotrigine compared with placebo. There is probably little or no difference in the number of people who withdraw from treatment with lamotrigine versus placebo. The trials were of relatively short duration and provided no long-term evidence. In addition, some trials had few participants. Further trials are needed to assess the long-term effects of lamotrigine and to compare lamotrigine with other add-on drugs.

Immunomodulatory interventions for focal epilepsy.

BACKGROUND: This is an updated version of an original Cochrane Review published in 2013 (Walker 2013). Epilepsy is a common neurological disorder affecting 0.5% to 1% of the population. Pharmacological treatment remains the first choice to control epilepsy. However, up to 30% of people do not respond to drug treatment, and therefore do not achieve seizure remission. 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 assess the efficacy and tolerability of immunomodulatory interventions on seizures, adverse effect profile, cognition, and quality of life, compared to placebo controls, when used as additional therapy for focal epilepsy in children and adults. SEARCH METHODS: For the latest update, we searched the following databases on 11 November 2021: Cochrane Register of Studies (CRS Web) and Medline (Ovid) 1946 to 10 November 2021. CRS Web includes randomised or quasi-randomised, controlled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. We placed no language restrictions. We reviewed the bibliographies of retrieved studies to search for additional reports of relevant studies. SELECTION CRITERIA: Randomised placebo-controlled trials of add-on immunomodulatory drug interventions, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded. Eligible participants were children (aged over 2 years) and adults with focal epilepsy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. We assessed the following outcomes. 1. 50% or greater reduction in seizure frequency. 2. Seizure freedom. 3. Treatment withdrawal for any reason. 4. Quality of life. 5. ADVERSE EFFECTS: We used an intention-to-treat (ITT) population for all primary analyses, and we presented results as risk ratios (RRs) with 95% confidence intervals (95% Cl). MAIN RESULTS: We included three randomised, double-blind, placebo-controlled trials on a total of 172 participants. All trials included children and adults over two years of age with focal epilepsy. Treatment phases lasted six weeks and follow-up from six weeks to six months. One of the three included trials described an adequate method of concealment of randomisation, whilst the other two trials were rated as having an unclear risk of bias due to lack of reported information around study design. Effective blinding of studies was reported in all three trials. All analyses were by ITT. One trial was sponsored by the manufacturer of an immunomodulatory agent and therefore was at high risk of funding bias. Immunomodulatory interventions were significantly more effective than placebo in reducing seizure frequency (risk ratio (RR) 2.30, 95% confidence interval (CI) 1.15 to 4.60; 3 studies, 172 participants; moderate-certainty evidence). For treatment withdrawal, there was insufficient evidence to conclude that people were more likely to discontinue immunomodulatory intervention than placebo (RR 1.04, 95% CI 0.28 to 3.80; 3 studies, 172 participants; low-certainty evidence). The RR for adverse effects was 1.16 (95% CI 0.84 to 1.59; 1 study, 66 participants; low-certainty evidence). Certain adverse effects such as dizziness, headache, fatigue, and gastrointestinal disorders were more often associated with immunomodulatory interventions. There were little to no data on cognitive effects and quality of life. No important heterogeneity between studies was found for any of the outcomes. We judged the overall certainty of evidence (using the GRADE approach) as low to moderate due to potential attrition bias resulting from missing outcome data and imprecise results with wide confidence intervals. AUTHORS' CONCLUSIONS: Immunomodulatory interventions as add-on treatment for children and adults with focal epilepsy appear to be effective in reducing seizure frequency. It is not possible to draw any conclusions about the tolerability of these agents in children and adults with epilepsy. Further randomised controlled trials are needed.

Prognosis of adults and children following a first unprovoked seizure.

BACKGROUND: Epilepsy is clinically defined as two or more unprovoked epileptic seizures more than 24 hours apart. Given that, a diagnosis of epilepsy can be associated with significant morbidity and mortality, it is imperative that clinicians (and people with seizures and their relatives) have access to accurate and reliable prognostic estimates, to guide clinical practice on the risks of developing further unprovoked seizures (and by definition, a diagnosis of epilepsy) following single unprovoked epileptic seizure. OBJECTIVES: 1. To provide an accurate estimate of the proportion of individuals going on to have further unprovoked seizures at subsequent time points following a single unprovoked epileptic seizure (or cluster of epileptic seizures within a 24-hour period, or a first episode of status epilepticus), of any seizure type (overall prognosis). 2. To evaluate the mortality rate following a first unprovoked epileptic seizure. SEARCH METHODS: We searched the following databases on 19 September 2019 and again on 30 March 2021, with no language restrictions. The Cochrane Register of Studies (CRS Web), MEDLINE Ovid (1946 to March 29, 2021), SCOPUS (1823 onwards), ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). CRS Web includes randomized or quasi-randomized, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. In MEDLINE (Ovid) the coverage end date always lags a few days behind the search date. SELECTION CRITERIA: We included studies, both retrospective and prospective, of all age groups (except those in the neonatal period (< 1 month of age)), of people with a single unprovoked seizure, followed up for a minimum of six months, with no upper limit of follow-up, with the study end point being seizure recurrence, death, or loss to follow-up. To be included, studies must have included at least 30 participants. We excluded studies that involved people with seizures that occur as a result of an acute precipitant or provoking factor, or in close temporal proximity to an acute neurological insult, since these are not considered epileptic in aetiology (acute symptomatic seizures). We also excluded people with situational seizures, such as febrile convulsions. DATA COLLECTION AND ANALYSIS: Two review authors conducted the initial screening of titles and abstracts identified through the electronic searches, and removed non-relevant articles. We obtained the full-text articles of all remaining potentially relevant studies, or those whose relevance could not be determined from the abstract alone and two authors independently assessed for eligibility. All disagreements were resolved through discussion with no need to defer to a third review author. We extracted data from included studies using a data extraction form based on the checklist for critical appraisal and data extraction for systematicreviews of prediction modelling studies (CHARMS). Two review authors then appraised the included studies, using a standardised approach based on the quality in prognostic studies (QUIPS) tool, which was adapted for overall prognosis (seizure recurrence). We conducted a meta-analysis using Review Manager 2014, with a random-effects generic inverse variance meta-analysis model, which accounted for any between-study heterogeneity in the prognostic effect. We then summarised the meta-analysis by the pooled estimate (the average prognostic factor effect), its 95% confidence interval (CI), the estimates of I² and Tau² (heterogeneity), and a 95% prediction interval for the prognostic effect in a single population at three various time points, 6 months, 12 months and 24 months. Subgroup analysis was performed according to the ages of the cohorts included; studies involving all ages, studies that recruited adult only and those that were purely paediatric. MAIN RESULTS: Fifty-eight studies (involving 54 cohorts), with a total of 12,160 participants (median 147, range 31 to 1443), met the inclusion criteria for the review. Of the 58 studies, 26 studies were paediatric studies, 16 were adult and the remaining 16 studies were a combination of paediatric and adult populations. Most included studies had a cohort study design with two case-control studies and one nested case-control study. Thirty-two studies (29 cohorts) reported a prospective longitudinal design whilst 15 studies had a retrospective design whilst the remaining studies were randomised controlled trials. Nine of the studies included presented mortality data following a first unprovoked seizure. For a mortality study to be included, a proportional mortality ratio (PMR) or a standardised mortality ratio (SMR) had to be given at a specific time point following a first unprovoked seizure. To be included in the meta-analysis a study had to present clear seizure recurrence data at 6 months, 12 months or 24 months. Forty-six studies were included in the meta-analysis, of which 23 were paediatric, 13 were adult, and 10 were a combination of paediatric and adult populations. A meta-analysis was performed at three time points; six months, one year and two years for all ages combined, paediatric and adult studies, respectively. We found an estimated overall seizure recurrence of all included studies at six months of 27% (95% CI 24% to 31%), 36% (95% CI 33% to 40%) at one year and 43% (95% CI 37% to 44%) at two years, with slightly lower estimates for adult subgroup analysis and slightly higher estimates for paediatric subgroup analysis. It was not possible to provide a summary estimate of the risk of seizure recurrence beyond these time points as most of the included studies were of short follow-up and too few studies presented recurrence rates at a single time point beyond two years. The evidence presented was found to be of moderate certainty. AUTHORS' CONCLUSIONS: Despite the limitations of the data (moderate-certainty of evidence), mainly relating to clinical and methodological heterogeneity we have provided summary estimates for the likely risk of seizure recurrence at six months, one year and two years for both children and adults. This provides information that is likely to be useful for the clinician counselling patients (or their parents) on the probable risk of further seizures in the short-term whilst acknowledging the paucity of long-term recurrence data, particularly beyond 10 years.

Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.

BACKGROUND: Prenatal exposure to certain anti-seizure medications (ASMs) is associated with an increased risk of major congenital malformations (MCM). The majority of women with epilepsy continue taking ASMs throughout pregnancy and, therefore, information on the potential risks associated with ASM treatment is required. OBJECTIVES: To assess the effects of prenatal exposure to ASMs on the prevalence of MCM in the child. SEARCH METHODS: For the latest update of this review, we searched the following databases on 17 February 2022: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to February 16, 2022), SCOPUS (1823 onwards), and ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP). No language restrictions were imposed. SELECTION CRITERIA: We included prospective cohort controlled studies, cohort studies set within pregnancy registries, randomised controlled trials and epidemiological studies using routine health record data. Participants were women with epilepsy taking ASMs; the two control groups were women without epilepsy and untreated women with epilepsy. DATA COLLECTION AND ANALYSIS: Five authors independently selected studies for inclusion. Eight authors completed data extraction and/or risk of bias assessments. The primary outcome was the presence of an MCM. Secondary outcomes included specific types of MCM. Where meta-analysis was not possible, we reviewed included studies narratively. MAIN RESULTS: From 12,296 abstracts, we reviewed 283 full-text publications which identified 49 studies with 128 publications between them. Data from ASM-exposed pregnancies were more numerous for prospective cohort studies (n = 17,963), than data currently available for epidemiological health record studies (n = 7913). The MCM risk for children of women without epilepsy was 2.1% (95% CI 1.5 to 3.0) in cohort studies and 3.3% (95% CI 1.5 to 7.1) in health record studies. The known risk associated with sodium valproate exposure was clear across comparisons with a pooled prevalence of 9.8% (95% CI 8.1 to 11.9) from cohort data and 9.7% (95% CI 7.1 to 13.4) from routine health record studies. This was elevated across almost all comparisons to other monotherapy ASMs, with the absolute risk differences ranging from 5% to 9%. Multiple studies found that the MCM risk is dose-dependent. Children exposed to carbamazepine had an increased MCM prevalence in both cohort studies (4.7%, 95% CI 3.7 to 5.9) and routine health record studies (4.0%, 95% CI 2.9 to 5.4) which was significantly higher than that for the children born to women without epilepsy for both cohort (RR 2.30, 95% CI 1.47 to 3.59) and routine health record studies (RR 1.14, 95% CI 0.80 to 1.64); with similar significant results in comparison to the children of women with untreated epilepsy for both cohort studies (RR 1.44, 95% CI 1.05 to 1.96) and routine health record studies (RR 1.42, 95% CI 1.10 to 1.83). For phenobarbital exposure, the prevalence was 6.3% (95% CI 4.8 to 8.3) and 8.8% (95% CI 0.0 to 9277.0) from cohort and routine health record data, respectively. This increased risk was significant in comparison to the children of women without epilepsy (RR 3.22, 95% CI 1.84 to 5.65) and those born to women with untreated epilepsy (RR 1.64, 95% CI 0.94 to 2.83) in cohort studies; data from routine health record studies was limited. For phenytoin exposure, the prevalence of MCM was elevated for cohort study data (5.4%, 95% CI 3.6 to 8.1) and routine health record data (6.8%, 95% CI 0.1 to 701.2). The prevalence of MCM was higher for phenytoin-exposed children in comparison to children of women without epilepsy (RR 3.81, 95% CI 1.91 to 7.57) and the children of women with untreated epilepsy (RR 2.01. 95% CI 1.29 to 3.12); there were no data from routine health record studies. Pooled data from cohort studies indicated a significantly increased MCM risk for children exposed to lamotrigine in comparison to children born to women without epilepsy (RR 1.99, 95% CI 1.16 to 3.39); with a risk difference (RD) indicating a 1% increased risk of MCM (RD 0.01. 95% CI 0.00 to 0.03). This was not replicated in the comparison to the children of women with untreated epilepsy (RR 1.04, 95% CI 0.66 to 1.63), which contained the largest group of lamotrigine-exposed children (> 2700). Further, a non-significant difference was also found both in comparison to the children of women without epilepsy (RR 1.19, 95% CI 0.86 to 1.64) and children born to women with untreated epilepsy (RR 1.00, 95% CI 0.79 to 1.28) from routine data studies. For levetiracetam exposure, pooled data provided similar risk ratios to women without epilepsy in cohort (RR 2.20, 95% CI 0.98 to 4.93) and routine health record studies (RR 0.67, 95% CI 0.17 to 2.66). This was supported by the pooled results from both cohort (RR 0.71, 95% CI 0.39 to 1.28) and routine health record studies (RR 0.82, 95% CI 0.39 to 1.71) when comparisons were made to the offspring of women with untreated epilepsy. For topiramate, the prevalence of MCM was 3.9% (95% CI 2.3 to 6.5) from cohort study data and 4.1% (0.0 to 27,050.1) from routine health record studies. Risk ratios were significantly higher for children exposed to topiramate in comparison to the children of women without epilepsy in cohort studies (RR 4.07, 95% CI 1.64 to 10.14) but not in a smaller comparison to the children of women with untreated epilepsy (RR 1.37, 95% CI 0.57 to 3.27); few data are currently available from routine health record studies. Exposure in utero to topiramate was also associated with significantly higher RRs in comparison to other ASMs for oro-facial clefts. Data for all other ASMs were extremely limited. Given the observational designs, all studies were at high risk of certain biases, but the biases observed across primary data collection studies and secondary use of routine health records were different and were, in part, complementary. Biases were balanced across the ASMs investigated, and it is unlikely that the differential results observed across the ASMs are solely explained by these biases. AUTHORS' CONCLUSIONS: Exposure in the womb to certain ASMs was associated with an increased risk of certain MCMs which, for many, is dose-dependent.

ANTECEDENTES: La exposición prenatal a determinados fármacos anticonvulsivos (FAC) se asocia con un mayor riesgo de malformaciones congénitas graves (MCG). La mayoría de las mujeres con epilepsia continúan tomando FAC durante todo el embarazo y, por lo tanto, se requiere información sobre los riesgos potenciales asociados con el tratamiento con FAC. OBJETIVOS: Evaluar los efectos de la exposición prenatal a los FAC sobre la prevalencia de MCG en el niño. MÉTODOS DE BÚSQUEDA: Para la última actualización de esta revisión se hicieron búsquedas el 17 de febrero de 2022 en las siguientes bases de datos: Registro Cochrane de Estudios (Cochrane Register of Studies [CRS Web]), MEDLINE (Ovid, 1946 hasta el 16 de febrero de 2022), SCOPUS (1823 en adelante) y ClinicalTrials.gov , Plataforma de registros internacionales de ensayos clínicos (ICTRP). No se impusieron restricciones de idioma. CRITERIOS DE SELECCIÓN: Se incluyeron estudios prospectivos controlados de cohortes, estudios de cohortes establecidos dentro de registros de embarazos, ensayos controlados aleatorizados y estudios epidemiológicos que utilizaron datos rutinarios de los historiales médicos. Las participantes fueron mujeres con epilepsia que tomaban FAC; los dos grupos de control fueron mujeres sin epilepsia y mujeres con epilepsia que no recibían tratamiento. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Cinco autores seleccionaron de forma independiente los estudios para inclusión. Ocho autores completaron la extracción de los datos y las evaluaciones del riesgo de sesgo. El desenlace principal fue la presencia de una MCG. Los desenlaces secundarios incluyeron tipos específicos de MCG. Cuando no fue posible realizar un metanálisis, los estudios incluidos se examinaron de forma narrativa. RESULTADOS PRINCIPALES: De 12 296 resúmenes, se revisaron 283 publicaciones a texto completo que identificaron 49 estudios con 128 publicaciones entre ellos. Los datos de los embarazos expuestos a FAC fueron más numerosos en el caso de los estudios prospectivos de cohortes (n = 17 963), que los datos actualmente disponibles de estudios de registros sanitarios epidemiológicos (n = 7913). El riesgo de MCG en los hijos de mujeres sin epilepsia fue del 2,1% (IC del 95%: 1,5 a 3,0) en los estudios de cohortes y del 3,3% (IC del 95%: 1,5 a 7,1) en los estudios de registros sanitarios. El riesgo conocido asociado con la exposición al valproato de sodio fue evidente en todas las comparaciones, con una prevalencia agrupada del 9,8% (IC del 95%: 8,1 a 11,9) a partir de los datos de los estudios de cohortes y del 9,7% (IC del 95%: 7,1 a 13,4) a partir de los estudios con datos rutinarios de los historiales médicos. Este fue elevado en casi todas las comparaciones con otros FAC como monoterapia, con diferencias absolutas de riesgo que variaron entre el 5% y el 9%. Múltiples estudios han constatado que el riesgo de MCG depende de la dosis. Los niños expuestos a la carbamazepina tuvieron una mayor prevalencia de MCG tanto en los estudios de cohortes (4,7%; IC del 95%: 3,7 a 5,9) como en los estudios con datos rutinarios de los historiales médicos (4,0%; IC del 95%: 2,9 a 5,4), que fue significativamente superior a la de los niños nacidos de mujeres sin epilepsia tanto en los estudios de cohortes (RR 2,30; IC del 95%: 1,47 a 3,59) como en los estudios de historias clínicas habituales (RR 1,14; IC del 95%: 0,80 a 1,64), con resultados significativos similares en comparación con los hijos de mujeres con epilepsia que no reciben tratamiento tanto en los estudios de cohortes (RR 1,44; IC del 95%: 1,05 a 1,96) como en los estudios con datos rutinarios de los historiales médicos (RR 1,42; IC del 95%: 1,10 a 1,83). Para la exposición al fenobarbital, la prevalencia fue del 6,3% (IC del 95%: 4,8 a 8,3) y del 8,8% IC del 95%: 0,0 a 9277,0) a partir de los datos de estudios de cohortes y los datos de estudios con datos rutinarios de los historiales médicos, respectivamente. Este aumento del riesgo fue significativo en comparación con los hijos de mujeres sin epilepsia (RR 3,22; IC del 95%: 1,84 a 5,65) y los nacidos de mujeres con epilepsia que no reciben tratamiento (RR 1,64; IC del 95%: 0,94 a 2,83) en estudios de cohortes; los datos procedentes de estudios con datos rutinarios de los historiales médicos fueron limitados. En cuanto a la exposición a la fenitoína, la prevalencia de MCG fue elevada en los datos de los estudios de cohortes (5,4%; IC del 95%: 3,6 a 8,1) y en los datos rutinarios de los historiales médicos (6,8%; IC del 95%: 0,1 a 701,2). La prevalencia de MCG fue mayor en los niños expuestos a la fenitoína en comparación con los hijos de mujeres sin epilepsia (RR 3,81; IC del 95%: 1,91 a 7,57) y los hijos de mujeres con epilepsia que no reciben tratamiento (RR 2,01; IC del 95%: 1,29 a 3,12); no hubo datos procedentes de estudios con datos rutinarios de los historiales médicos. Los datos agrupados de los estudios de cohortes indicaron un riesgo significativamente mayor de MCG en los niños expuestos a lamotrigina en comparación con los niños nacidos de mujeres sin epilepsia (RR 1,99; IC del 95%: 1,16 a 3,39); con una diferencia de riesgos (DR) que indica un riesgo 1% mayor de MCG (DR 0,01. IC del 95%: 0,00 a 0,03). Esto no se repitió en la comparación con los hijos de las mujeres con epilepsia que no reciben tratamiento (RR 1,04; IC del 95%: 0,66 a 1,63), que contenía el mayor grupo de niños expuestos a la lamotrigina (> 2700). Además, también se encontró una diferencia no significativa tanto en comparación con los hijos de mujeres sin epilepsia (RR 1,19; IC del 95%: 0,86 a 1,64) como con los hijos de mujeres con epilepsia que no reciben tratamiento (RR 1,00; IC del 95%: 0,79 a 1,28) a partir de los estudios con datos rutinarios. Para la exposición al levetiracetam, los datos agrupados proporcionaron razones de riesgos similares a las de las mujeres sin epilepsia en los estudios de cohortes (RR 2,20; IC del 95%: 0,98 a 4,93) y en los estudios con datos rutinarios de los historiales médicos (RR 0,67; IC del 95%: 0,17 a 2,66). Los resultados agrupados de los estudios de cohortes (RR: 0,71; IC del 95%: 0,39 a 1,28) y de los estudios con datos rutinarios de los historiales médicos (RR: 0,82; IC del 95%: 0,39 a 1,71) respaldan esta afirmación cuando se comparan con los hijos de las mujeres con epilepsia que no reciben tratamiento. En el caso del topiramato, la prevalencia de MCG fue del 3,9% (IC del 95%: 2,3 a 6,5) a partir de los datos de los estudios de cohortes y del 4,1% (0,0 a 27.050,1) a partir de los estudios con datos rutinarios de los historiales médicos. Las razones de riesgos fueron significativamente más altas para los niños expuestos al topiramato en comparación con los hijos de mujeres sin epilepsia en estudios de cohortes (RR 4,07; IC del 95%: 1,64 a 10,14), pero no en una comparación más pequeña con los hijos de mujeres con epilepsia que no reciben tratamiento (RR 1,37; IC del 95%: 0,57 a 3,27); actualmente se dispone de pocos datos a partir de estudios con datos rutinarios de los historiales médicos. La exposición en el útero al topiramato también se asoció con RR significativamente mayores en comparación con otros FAC para las hendiduras orofaciales. Los datos de todos las demás FAC fueron extremadamente limitados. Debido a los diseños observacionales, todos los estudios presentaron un alto riesgo de ciertos sesgos, pero los sesgos observados en los estudios de obtención de datos primarios y el uso secundario de historiales médicos rutinarios fueron diferentes y, en parte, complementarios. Los sesgos estaban equilibrados entre los FAC investigados, y es poco probable que los resultados diferenciales observados entre los FAC se expliquen únicamente por estos sesgos. CONCLUSIONES DE LOS AUTORES: La exposición en el útero a ciertos FAC se asoció con un mayor riesgo de ciertos MCG que, para muchos, depende de la dosis.

Raring to go? A cross-sectional survey of student paramedics on how well they perceive their UK pre-registration course to be preparing them to manage suspected seizures.

BACKGROUND: Paramedics convey a high proportion of seizure patients with no clinical need to emergency departments (EDs). In a landmark study, only 27% of UK paramedics reported being "Very…"/ "Extremely confident" making seizure conveyance decisions. Improved pre-registration education on seizures for paramedics is proposed. Clarity is needed on its potential given recent changes to how UK paramedics train (namely, degree, rather than brief vocational course). This study sought to describe UK student paramedics' perceived readiness to manage seizures and educational needs; compare this to what they report for other presentations; and, explore subgroup differences. METHODS: Six hundred thirty-eight students, in year 2 or beyond of their pre-registration programme completed a cross-sectional survey. They rated perceived confidence, knowledge, ability to care for, and educational needs for seizures, breathing problems and, headache. Primary measure was conveyance decision confidence. RESULTS: For seizures, 45.3% (95% CI 41.4-49.2) said they were "Very…"/"Extremely confident" to make conveyance decisions. This was similar to breathing problems, but higher than for headache (25.9%, 95% CI 22.6-29.5). Two hundred and thirty-nine participants (37.9%, 95% CI 34.1-41.8) said more seizure education was required - lower than for headache, but higher than for breathing problems. Subgroup differences included students on university-based programmes reporting more confidence for conveyance decisions than those completing degree level apprenticeships. CONCLUSIONS: Student paramedics report relatively high perceived readiness for managing seizures. Magnitude of benefit from enhancements to pre-registration education may be more limited than anticipated. Additional factors need attention if a sizeable reduction to unnecessary conveyances for seizures is to happen.

Outpatient neurology diagnostic coding: a proposed scheme for standardised implementation.

Clinical coding uses a classification system to assign standard codes to clinical terms and so facilitates good clinical practice through audit, service design and research. However, despite clinical coding being mandatory for inpatient activity, this is often not so for outpatient services, where most neurological care is delivered. Recent reports by the UK National Neurosciences Advisory Group and NHS England's 'Getting It Right First Time' initiative recommend implementing outpatient coding. The UK currently has no standardised system for outpatient neurology diagnostic coding. However, most new attendances at general neurology clinics appear to be classifiable with a limited number of diagnostic terms. We present the rationale for diagnostic coding and its benefits, and the need for clinical engagement to develop a system that is pragmatic, quick and easy to use. We outline a scheme developed in the UK that could be used elsewhere.

High b-value diffusion tractography: Abnormal axonal network organization associated with medication-refractory epilepsy.

Diffusion magnetic resonance imaging (dMRI) tractography has played a critical role in characterizing patterns of aberrant brain network reorganization among patients with epilepsy. However, the accuracy of dMRI tractography is hampered by the complex biophysical properties of white matter tissue. High b-value diffusion imaging overcomes this limitation by better isolating axonal pathways. In this study, we introduce tractography derived from fiber ball imaging (FBI), a high b-value approach which excludes non-axonal signals, to identify atypical neuronal networks in patients with epilepsy. Specifically, we compared network properties obtained from multiple diffusion tractography approaches (diffusion tensor imaging, diffusion kurtosis imaging, FBI) in order to assess the pathophysiological relevance of network rearrangement in medication-responsive vs. medication-refractory adults with focal epilepsy. We show that drug-resistant epilepsy is associated with increased global network segregation detected by FBI-based tractography. We propose exploring FBI as a clinically feasible alternative to quantify topological changes that could be used to track disease progression and inform on clinical outcomes.

The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial.

BACKGROUND: Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy. METHODS: This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). FINDINGS: 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95-1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83-1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08-1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319-1·458) compared with 1·222 (1·110-1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs. INTERPRETATION: These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. FUNDING: National Institute for Health Research Health Technology Assessment programme.

The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial.

BACKGROUND: Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy. METHODS: We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5-12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). FINDINGS: 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0-94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96-1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of -0·040 (95% central range -0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years. INTERPRETATION: Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

A systems medicine strategy to predict the efficacy of drugs for monogenic epilepsies.

OBJECTIVE: Monogenic epilepsies are rare but often severe. Because of their rarity, they are neglected by traditional drug developers. Hence, many lack effective treatments. Treatments for a disease can be discovered more quickly and economically by computationally predicting drugs that can be repurposed for it. We aimed to create a computational method to predict the efficacy of drugs for monogenic epilepsies, and to use the method to predict drugs for Dravet syndrome, as (1) it is the archetypal monogenic catastrophic epilepsy; (2) few antiseizure medications are efficacious in Dravet syndrome; and (3) predicting the effect of drugs on Dravet syndrome is challenging, because Dravet syndrome is typically caused by an SCN1A mutation, but some antiseizure medications that are efficacious in Dravet syndrome do not affect SCN1A, and some antiseizure medications that affect SCN1A aggravate seizures in Dravet syndrome. METHODS: We have devised a computational method to predict drugs that could be repurposed for a monogenic epilepsy, based on a combined measure of drugs' effects upon (1) the function of the disease's causal gene and other genes predicted to influence its phenotype, (2) the transcriptomic dysregulation induced by the casual gene mutation, and (3) clinical phenotypes. RESULTS: Our method correctly predicts drugs that are more effective, less effective, ineffective, and aggravating for seizures in people with Dravet syndrome. Our method correctly predicts the positive "hits" from large-scale screening of compounds in an animal model of Dravet syndrome. We predict the relative efficacy of 1462 drugs. At least 38 drugs are ranked higher than one or more of the antiseizure drugs currently used for Dravet syndrome and have existing evidence of antiseizure efficacy in animal models. SIGNIFICANCE: Our predictions are a novel resource for identifying new treatments for seizures in Dravet syndrome, and our method can be adapted for other monogenic epilepsies.

Worth the paper they are printed on? Findings from an independent evaluation of the understandability of patient information leaflets for antiseizure medications.

OBJECTIVE: The Patient Information Leaflet (PIL) is an authoritative document that all people with epilepsy in the EU receive when prescribed antiseizure medication (ASM). We undertook the first independent, comprehensive assessment to determine how understandable they are. Regulators state that when patients are asked comprehension questions about them, ≥80% should answer correctly. Also, recommended is that PILs have a maximum reading requirement of US grade 8. METHODS: Study 1: We obtained 140 current ASM PILs written in English. "Readability" was assessed using four tests, with and without adjustment for influence of familiar, polysyllabic words. A total of 179 online materials on epilepsy were also assessed. Study 2: Two PILs from Study 1 were randomly selected (Pregabalin Focus; Inovelon) and shown to 35 people from the UK epilepsy population. Their comprehension was assessed. Study 3: To understand whether the student population provides an accessible alternative population for future examination of ASM PILs, Study 3 was completed, using the same methods as Study 2, except that participants were 262 UK university students. RESULTS: Study 1: No PIL had a reading level of grade 8. Median was grade 11. Adjusting for context, the PILs were still at grade 10.5. PILs for branded ASMs were most readable. PILs were no more readable than (unregulated) online materials. Study 2: Users struggled to comprehend the PILs' key messages. The eight questions asked about pregabalin were typically answered correctly by 54%. For Inovelon, it was 62%. Study 3: Most student participants comprehended the PILs' key messages. The questions about Inovelon were answered correctly by 90%; for pregabalin it was 86%. SIGNIFICANCE: This is the first independent and comprehensive examination of ASM PILs. It found that PILs being used fail to meet recommendations and regulatory requirements and risk not being understandable to a substantial proportion of users. In finding that people from the epilepsy population differ markedly in comprehension of PILs compared to students, this study highlights the importance of completing user testing with the target population.

High-mobility group box 1 as a predictive biomarker for drug-resistant epilepsy: A proof-of-concept study.

Currently no sensitive and specific biomarkers exist to predict drug-resistant epilepsy. We determined whether blood levels of high-mobility group box 1 (HMGB1), a mediator of neuroinflammation implicated in drug-resistant epilepsies, identifies patients with drug-resistant seizures. Patients with drug-resistant epilepsy express significantly higher levels of blood HMGB1 than those with drug-responsive, well-controlled seizures and healthy controls. No correlation existed between blood HMGB1 levels and total pretreatment seizure count or days since last seizure at new epilepsy diagnosis, indicating that blood HMGB1 does not solely reflect ongoing seizures. HMGB1 distinguishes with high specificity and selectivity drug-resistant versus drug-responsive patients. This protein therefore has potential clinical utility to act as a biomarker for predicting response to therapy, which should be addressed in prospective clinical studies.

Statins as antiepileptogenic drugs: Analyzing the evidence and identifying the most promising statin.

Many brain insults and injuries are "epileptogenic": they increase the risk of developing epilepsy. It is desirable to identify treatments that are "antiepileptogenic": treatments that prevent the development of epilepsy, if administered after the occurrence of an epileptogenic insult. Current antiepileptic drugs are not antiepileptogenic, but evidence of antiepileptogenic efficacy is accumulating for a growing number of other compounds. From among these candidate compounds, statins are deserving of particular attention because statins are reported to be antiepileptogenic in more published studies and in a wider range of brain insults than any other individual or class of compounds. Although many studies report the antiepileptogenic effect of statins, it is unclear how many studies provide evidence that statins exhibit the following two essential features of a clinically viable antiepileptogenic drug: the drug must exert an antiepileptogenic effect even if it is initiated after the epileptogenic brain insult has already occurred, and the antiepileptogenic effect must endure even after the drug has been discontinued. In the current work, we interrogate published preclinical and clinical studies, to determine if statins fulfill these essential requirements. There are eight different statins in clinical use. To enable the clinical use of one of these statins for antiepileptogenesis, its antiepileptogenic effect will have to be established through future time- and resource-intensive clinical trials. Therefore, it is desirable to review the published literature to determine which of the statins emerges as the most promising candidate for antiepileptogenic therapy. Hence, in the current work, we also collate and analyze published data-clinical and pre-clinical, direct and indirect-that help to answer the question: Which statin is the most promising candidate to take forward into an antiepileptogenesis clinical trial?