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Valproate is the most effective treatment for idiopathic generalized epilepsy. Current guidance precludes its use in females of childbearing potential, unless other treatments are ineffective or not tolerated, because of high teratogenicity. This risk was recently extended to males. New guidance will limit use both in males and females aged <55 years, resulting in withdrawal of valproate from males already taking it, as occurs for females. Whether there are risks of personal harm (including injury or death) associated with valproate withdrawal has not yet been quantified for males or females 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 males and females. We performed a retrospective cohort study of internationally derived electronic health data within the TriNetX Global Collaborative Network. Included were males and females aged 16-54 years with ≥1 epilepsy disease or symptom code between 1 December 2017 and 1 December 2018, and ≥2 valproate prescriptions over the preceding 2 years (1 January 2015-30 November 2017). Five-year propensity-matched risks of mortality and a range of morbidity outcomes were compared between those remaining ON versus withdrawn from valproate during the 1 December 2017-1 December 2018 recruitment period, regardless of whether switched to another antiseizure medication.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). In total, 8991 males and 5243 females taking valproate were recruited. Twenty-eight per cent of males and 36% of females were subsequently withdrawn from valproate.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), males: 1.181 (CI 1.083-1.288), females: 1.242 (CI 1.125-1.371)], hospital admission [HRs overall: 1.160 (CI 1.081-1.246), males: 1.132 (CI 1.027-1.249), females: 1.147 (CI 1.033-1.274)], falls [HRs overall: 1.179 (CI 1.041-1.336), males: 1.298 (CI 1.090-1.546)], injuries [HRs overall: 1.095 (CI 1.021-1.174), males: 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), females: 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Valproate is the most effective treatment for idiopathic generalised epilepsy. Currently, its use is restricted in women of childbearing potential owing to high teratogenicity. Recent evidence extended this risk to men's offspring, prompting recommendations to restrict use in everybody aged <55 years. This study will evaluate mortality and morbidity risks associated with valproate withdrawal by emulating a hypothetical randomised-controlled trial (called a "target trial") using retrospective observational data. The data will be drawn from ~250m mainly US patients in the TriNetX repository and ~60m UK patients in Clinical Practice Research Datalink (CPRD). These will be scanned for individuals aged 16-54 years with epilepsy and on valproate who either continued, switched to lamotrigine or levetiracetam, or discontinued valproate between 2014-2024, creating four groups. Randomisation to these groups will be emulated by baseline confounder adjustment using g-methods. Mortality and morbidity outcomes will be assessed and compared between groups over 1-10 years, employing time-to-first-event and recurrent events analyses. A causal prediction model will be developed from these data to aid in predicting the safest alternative antiseizure medications. Together, these findings will optimise informed decision-making about valproate withdrawal and alternative treatment selection, providing immediate and vital information for patients, clinicians and regulators., Competing Interests: A.G.M. declares i) a UCB Pharma grant paid to University of Liverpool for the National Audit of Seizure Management in Hospitals (NASH) study, which is unrelated to the submitted work; ii) an Angelini grant to be paid to University of Liverpool as co-applicant for A multi-method PRoject to maximise efficient and equitable pathways tO suPport from a rEgional epiLepsy centre (PROPEL), which is unrelated to the submitted work; iii) Honoraria paid to University of Liverpool for lectures unrelated to the submitted work given at educational events sponsored by Sanofi, Eiasi, and GSK; iii) Support from Angelini for attendance unrelated to the submitted work at the 2024 International League Against Epilepsy (ILAE) congress. G.K.M declares an Angelini grant to be paid to University of Liverpool as co-applicant on the PROPEL study, which is unrelated to the submitted work; ii) Honoraria to be paid to University of Liverpool for delivering a lecture at an educational event sponsored by Angelini which was unrelated to the submitted work. The remaining authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All authors confirm there are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2024 Mbizvo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The critical success index (CSI) is an established metric used in meteorology to verify the accuracy of weather forecasts. It is defined as the ratio of hits to the sum of hits, false alarms, and misses. Translationally, CSI has gained popularity as a unitary outcome measure in various clinical situations where large numbers of true negatives may influence the interpretation of other, more traditional, outcome measures, such as specificity (Spec) and negative predictive value (NPV), or when unified interpretation of positive predictive value (PPV) and sensitivity (Sens) is needed. The derivation of CSI from measures including PPV has prompted questions as to whether and how CSI values may vary with disease prevalence (P), just as PPV estimates are dependent on P, and hence whether CSI values are generalizable between studies with differing prevalences. As no detailed study of the relation of CSI to prevalence has been undertaken hitherto, the dataset of a previously published test accuracy study of a cognitive screening instrument was interrogated to address this question. Three different methods were used to examine the change in CSI across a range of prevalences, using both the Bayes formula and equations directly relating CSI to Sens, PPV, P, and the test threshold (Q). These approaches showed that, as expected, CSI does vary with prevalence, but the dependence differs according to the method of calculation that is adopted. Bayesian rescaling of both Sens and PPV generates a concave curve, suggesting that CSI will be maximal at a particular prevalence, which may vary according to the particular dataset.

Background: Methods to undertake diagnostic accuracy studies of administrative epilepsy data are challenged by lack of a way to reliably rank case-ascertainment algorithms in order of their accuracy. This is because it is difficult to know how to prioritise positive predictive value (PPV) and sensitivity (Sens). Large numbers of true negative (TN) instances frequently found in epilepsy studies make it difficult to discriminate algorithm accuracy on the basis of negative predictive value (NPV) and specificity (Spec) as these become inflated (usually >90%). This study demonstrates the complementary value of using weather forecasting or machine learning metrics critical success index (CSI) or F measure, respectively, as unitary metrics combining PPV and sensitivity. We reanalyse data published in a diagnostic accuracy study of administrative epilepsy mortality data in Scotland., Method: CSI was calculated as 1/[(1/PPV) + (1/Sens) - 1]. F measure was calculated as 2.PPV.Sens/(PPV + Sens). CSI and F values range from 0 to 1, interpreted as 0 = inaccurate prediction and 1 = perfect accuracy. The published algorithms were reanalysed using these and their accuracy re-ranked according to CSI in order to allow comparison to the original rankings., Results: CSI scores were conservative (range 0.02-0.826), always less than or equal to the lower of the corresponding PPV (range 39-100%) and sensitivity (range 2-93%). F values were less conservative (range 0.039-0.905), sometimes higher than either PPV or sensitivity, but were always higher than CSI. Low CSI and F values occurred when there was a large difference between PPV and sensitivity, e.g. CSI was 0.02 and F was 0.039 in an instance when PPV was 100% and sensitivity was 2%. Algorithms with both high PPV and sensitivity performed best in terms of CSI and F measure, e.g. CSI was 0.826 and F was 0.905 in an instance when PPV was 90% and sensitivity was 91%., Conclusion: CSI or F measure can combine PPV and sensitivity values into a convenient single metric that is easier to interpret and rank in terms of diagnostic accuracy than trying to rank diagnostic accuracy according to the two measures themselves. CSI or F prioritise instances where both PPV and sensitivity are high over instances where there are large differences between PPV and sensitivity (even if one of these is very high), allowing diagnostic accuracy thresholds based on combined PPV and sensitivity to be determined. Therefore, CSI or F measures may be helpful complementary metrics to report alongside PPV and sensitivity in diagnostic accuracy studies of administrative epilepsy data., Competing Interests: Declarations of interest None of the authors have any conflict of interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: GKM is supported by an NIHR Clinical Lectureship (CL-2022-07-002). IB is supported by an NIHR Senior Investigator Award (NIHR205131). IB is on the Data Safety Monitoring Board and Advisory Board for Liverpool City Region Civic Data Cooperative. We declare no other competing interests.

The risks of cardiovascular events (CVEs) in people with epilepsy (PWE) are not well understood. To establish the short- and long-term burden of CVEs in PWE. Electronic health records from a global federated health research network (TriNetX) were used to establish a cohort of PWE. Primary outcomes were: (1) the proportion of people experiencing a composite outcome of cardiac arrest, acute heart failure (HF), acute coronary syndrome (ACS), atrial fibrillation (AF), severe ventricular arrhythmia or all-cause death within 30 days of a seizure; and (2) the 5-year risk for a composite outcome of ischemic heart diseases, stroke, hospitalization, or all-cause death in the PWE experiencing early CVEs. Cox-regression analyses with propensity score matching was used to produce hazard ratios (HRs) and 95% confidence intervals (CI). In 271,172 PWE (mean age 50 ± 20 years; 52% females), the 30-day risk of CVEs following seizure was: 8.7% for the composite outcome, 0.9% for cardiac arrest, 0.8% for HF, 1.2% for ACS, 4.1% for AF, 0.7% for severe ventricular arrhythmias, and 1.6% for all-cause death. For the 15,120 PWE experiencing CVEs within 30 days of seizure, the 5-year adjusted risks for all composite outcomes measured were significantly increased (overall HR: 2.44, 95% CI 2.37-2.51), ischemic heart diseases HR 3.23 (95% CI 3.10-3.36), stroke HR 1.56 (95% CI 1.48-1.64), hospitalization HR 2.03 (95% CI 1.97-2.10), and all-cause death HR 2.75 (95% CI 2.61-2.89). The large proportions of PWE with active disease that experience CVEs and the poor long-term outcome associated suggest the existence of an "epilepsy-heart syndrome.", Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gregory Y.H. Lip is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim and Daiichi-Sankyo. No fees are received personally. All other authors report no disclosures., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To examine whether epilepsy-related deaths increased during the COVID-19 pandemic and if the proportion with COVID-19 listed as the underlying cause is different between people experiencing epilepsy-related deaths and those experiencing deaths unrelated to epilepsy., Methods: This was a Scotland-wide, population-based, cross-sectional study of routinely-collected mortality data pertaining to March-August of 2020 (COVID-19 pandemic peak) compared to the corresponding periods in 2015-2019. ICD-10-coded causes of death of deceased people of any age were obtained from a national mortality registry of death certificates in order to identify those experiencing epilepsy-related deaths (coded G40-41), deaths with COVID-19 listed as a cause (coded U07.1-07.2), and deaths unrelated to epilepsy (death without G40-41 coded). The number of epilepsy-related deaths in 2020 were compared to the mean observed through 2015-2019 on an autoregressive integrated moving average (ARIMA) model (overall, men, women). Proportionate mortality and odds ratios (OR) for deaths with COVID-19 listed as the underlying cause were determined for the epilepsy-related deaths compared to deaths unrelated to epilepsy, reporting 95% confidence intervals (CIs)., Results: A mean number of 164 epilepsy-related deaths occurred through March-August of 2015-2019 (of which a mean of 71 were in women and 93 in men). There were subsequently 189 epilepsy-related deaths during the pandemic March-August 2020 (89 women, 100 men). This was 25 more epilepsy-related deaths (18 women, 7 men) compared to the mean through 2015-2019. The increase in women was beyond the mean year-to-year variation seen in 2015-2019. Proportionate mortality with COVID-19 listed as the underlying cause was similar between people experiencing epilepsy-related deaths (21/189, 11.1%, CI 7.0-16.5%) and deaths unrelated to epilepsy (3,879/27,428, 14.1%, CI 13.7-14.6%), OR 0.76 (CI 0.48-1.20). Ten of 18 excess epilepsy-related deaths in women had COVID-19 listed as an additional cause., Conclusions: There is little evidence to suggest there have been any major increases in epilepsy-related deaths in Scotland during the COVID-19 pandemic. COVID-19 is a common underlying cause of both epilepsy-related and unrelated deaths., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

Competing Interests: Declaration of interests We declare no competing interests.

This study aimed to develop a risk prediction model for epilepsy-related death in adults. In this age- and sex-matched case-control study, we compared adults (aged ≥16 years) who had epilepsy-related death between 2009 and 2016 to living adults with epilepsy in Scotland. Cases were identified from validated administrative national datasets linked to mortality records. ICD-10 cause-of-death coding was used to define epilepsy-related death. Controls were recruited from a research database and epilepsy clinics. Clinical data from medical records were abstracted and used to undertake univariable and multivariable conditional logistic regression to develop a risk prediction model consisting of four variables chosen a priori. A weighted sum of the factors present was taken to create a risk index-the Scottish Epilepsy Deaths Study Score. Odds ratios were estimated with 95% confidence intervals (CIs). Here, 224 deceased cases (mean age 48 years, 114 male) and 224 matched living controls were compared. In univariable analysis, predictors of epilepsy-related death were recent epilepsy-related accident and emergency attendance (odds ratio 5.1, 95% CI 3.2-8.3), living in deprived areas (odds ratio 2.5, 95% CI 1.6-4.0), developmental epilepsy (odds ratio 3.1, 95% CI 1.7-5.7), raised Charlson Comorbidity Index score (odds ratio 2.5, 95% CI 1.2-5.2), alcohol abuse (odds ratio 4.4, 95% CI 2.2-9.2), absent recent neurology review (odds ratio 3.8, 95% CI 2.4-6.1) and generalized epilepsy (odds ratio 1.9, 95% CI 1.2-3.0). Scottish Epilepsy Deaths Study Score model variables were derived from the first four listed before, with Charlson Comorbidity Index ≥2 given 1 point, living in the two most deprived areas given 2 points, having an inherited or congenital aetiology or risk factor for developing epilepsy given 2 points and recent epilepsy-related accident and emergency attendance given 3 points. Compared to having a Scottish Epilepsy Deaths Study Score of 0, those with a Scottish Epilepsy Deaths Study Score of 1 remained low risk, with odds ratio 1.6 (95% CI 0.5-4.8). Those with a Scottish Epilepsy Deaths Study Score of 2-3 had moderate risk, with odds ratio 2.8 (95% CI 1.3-6.2). Those with a Scottish Epilepsy Deaths Study Score of 4-5 and 6-8 were high risk, with odds ratio 14.4 (95% CI 5.9-35.2) and 24.0 (95% CI 8.1-71.2), respectively. The Scottish Epilepsy Deaths Study Score may be a helpful tool for identifying adults at high risk of epilepsy-related death and requires external validation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The Critical Success Index (CSI) and Gilbert Skill score (GS) are verification measures that are commonly used to check the accuracy of weather forecasting. In this article, we propose that they can also be used to simplify the joint interpretation of positive predictive value (PPV) and sensitivity estimates across diagnostic accuracy studies of epilepsy data. This is because CSI and GS each provide a single measure that takes the weather forecasting equivalent of PPV and sensitivity into account. We have re-analysed data from our recent systematic review of diagnostic accuracy studies of administrative epilepsy data using CSI and GS. We summarise the results and benefits of this approach., (© 2023 International League Against Epilepsy.)

Background: Attention Deficit Hyperactivity Disorder (ADHD) can co-occur in up to 40% of people with epilepsy. There is debate about the efficacy and tolerability of stimulant and non-stimulant drugs used to treat people with ADHD and co-occurring epilepsy., Objectives: To assess the effect of stimulant and non-stimulant drugs on children and adults with ADHD and co-occurring epilepsy in terms of seizure frequency and drug withdrawal rates (primary objectives), as well as seizure severity, ADHD symptoms, cognitive state, general behaviour, quality of life, and adverse effects profile (secondary objectives)., Search Methods: We searched the following databases on 12 October 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 9 October 2020), CINAHL Plus (EBSCOhost, 1937 onwards). There were no language restrictions. 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 Specialised Registers of Cochrane Review Groups including Epilepsy.  SELECTION CRITERIA: We included randomised controlled trials of stimulant and non-stimulant drugs for people of any age, gender or ethnicity with ADHD and co-occurring epilepsy., Data Collection and Analysis: We selected articles and extracted data according to predefined criteria. We conducted primary analysis on an intention-to-treat basis. We presented outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), except for individual adverse effects where we quoted 99% CIs. We conducted best- and worst-case sensitivity analyses to deal with missing data. We carried out a risk of bias assessment for each included study using the Cochrane risk of bias tool and assessed the overall certainty of evidence using the GRADE approach., Main Results: We identified two studies that matched our inclusion criteria: a USA study compared different doses of the stimulant drug osmotic-release oral system methylphenidate (OROS-MPH) with a placebo in 33 children (mean age 10.5 ± 3.0 years), and an Iranian study compared the non-stimulant drug omega-3 taken in conjunction with risperidone and usual anti-seizure medication (ASM) with risperidone and ASM only in 61 children (mean age 9.24 ± 0.15 years). All children were diagnosed with epilepsy and ADHD according to International League Against Epilepsy and Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria, respectively. We assessed both studies to be at low risk of detection and reporting biases, but assessments varied from low to high risk of bias for all other domains. OROS-MPH No participant taking OROS-MPH experienced significant worsening of epilepsy, defined as: 1. a doubling of the highest 14-day or highest two-day seizure rate observed during the 12 months before the trial; 2. a generalised tonic-clonic seizure if none had been experienced in the previous two years; or 3. a clinically meaningful intensification in seizure duration or severity (33 participants, 1 study; low-certainty evidence). However, higher doses of OROS-MPH predicted an increased daily risk of a seizure (P < 0.001; 33 participants, 1 study; low-certainty evidence). OROS-MPH had a larger proportion of participants receiving 'much improved' or 'very much improved' scores for ADHD symptoms on the Clinical Global Impressions for ADHD-Improvement tool (33 participants, 1 study; low-certainty evidence). OROS-MPH also had a larger proportion of people withdrawing from treatment (RR 2.80; 95% CI 1.14 to 6.89; 33 participants, 1 study; moderate-certainty evidence). Omega-3 Omega-3 with risperidone and ASM were associated with a reduction in mean seizure frequency by 6.6 seizures per month (95% CI 4.24 to 8.96; 56 participants, 1 study; low-certainty evidence) and an increase in the proportion of people achieving 50% or greater reduction in monthly seizure frequency (RR 2.79, 95% CI 0.84 to 9.24; 56 participants, 1 study; low-certainty evidence) compared to people on risperidone and ASM alone. Omega-3 with risperidone and ASM also had a smaller proportion of people withdrawing from treatment (RR 0.65, 95% CI 0.12 to 3.59; 61 participants, 1 study; low-certainty evidence) but a larger proportion of people experiencing adverse drug events (RR 1.40, 95% CI 0.44 to 4.42; 56 participants, 1 study; low-certainty evidence) compared to people on risperidone and ASM alone., Authors' Conclusions: In children with a dual-diagnosis of epilepsy and ADHD, there is some evidence that use of the stimulant drug OROS-MPH is not associated with significant worsening of epilepsy, but higher doses of it may be associated with increased daily risk of seizures; the evidence is of low-certainty. OROS-MPH is also associated with improvement in ADHD symptoms. However, this treatment was also associated with a large proportion of treatment withdrawal compared to placebo. In relation to the non-stimulant drug omega-3, there is some evidence for reduction in seizure frequency in children who are also on risperidone and ASM, compared to children who are on risperidone and ASM alone. Evidence is inconclusive whether omega-3 increases or decreases the risk of adverse drug events. We identified only two studies - one each for OROS-MPH and omega-3 - with low to high risk of bias. We assessed the overall certainty of evidence for the outcomes of both OROS-MPH and omega-3 as low to moderate. More studies are needed. Future studies should include: 1. adult participants; 2. a wider variety of stimulant and non-stimulant drugs, such as amphetamines and atomoxetine, respectively; and 3. additional important outcomes, such as seizure-related hospitalisations and quality of life. Clusters of studies which assess the same drug - and those that build upon the evidence base presented in this review on OROS-MPH and omega-3 - are needed to allow for meta-analysis of outcomes., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: This study was undertaken to investigate the trends and mechanisms of epilepsy-related deaths in Scotland, highlighting the proportion that were potentially avoidable., Methods: This was a retrospective observational data-linkage study of administrative data from 2009-2016. We linked nationwide data encompassing mortality records, hospital admissions, outpatient attendance, antiepileptic drug (AED) prescriptions, and regional primary care attendances. Adults (aged ≥16 years) suffering epilepsy-related death were identified for study using International Classification of Diseases, 10th Revision coding combined with AED prescriptions. We reported epilepsy-related mortality rate (MR), age-specific mortality ratios, multiple cause-of-death frequencies, and the proportion of potentially avoidable deaths (identified as those with an underlying cause listed as avoidable by the Office for National Statistics)., Results: A total of 1921 epilepsy-related deaths were identified across Scotland; 1185 (62%) decedents were hospitalized for seizures in the years leading up to death, yet only 518 (27%) were seen in a neurology clinic during the same period. MR remained unchanged over time, ranging from 5.9 to 8.7 per 100 000 Scottish population (95% confidence interval [CI] = -.05 to .66 per 100 000 for annual change in MR). Mortality ratios were significantly increased in young adults aged 16-54 years (2.3, 95% CI = 1.8-2.8), peaking at age 16-24 years (5.3, 95% CI = 1.8-8.8). Sudden unexpected death in epilepsy (SUDEP) constituted 30% of the 553 young adult epilepsy-related deaths, with several other non-SUDEP fatal mechanisms identified including aspiration pneumonia, cardiac arrest, AED or narcotic poisoning, drowning, and alcohol dependence. Seventy-six percent of young adult epilepsy-related deaths were potentially avoidable., Significance: Epilepsy-related deaths are a major public health problem in Scotland, given that they are not reducing, people are dying young, and many deaths are potentially avoidable. SUDEP is only one of several important mechanisms by which epilepsy-related deaths are occurring in young adults. Services may need to be re-evaluated to improve specialist referral following seizure-related hospital admissions., (© 2021 International League Against Epilepsy.)

Aim: To examine whether receiver operating characteristic plots and area under the curve (AUC) values may be potentially misleading when assessing cognitive screening instruments as binary predictors rather than as categorical or continuous scales. Materials & methods: AUC was calculated using different methods (rank-sum, diagnostic odds ratio) using data from test accuracy studies of two binary classifiers of cognitive status (applause sign, attended with sign), a screener producing categorical data (Codex), and a continuous scale screening test (Mini-Addenbrooke's Cognitive Examination). Results: For all screeners, AUC calculated using diagnostic odds ratio method was greater than using rank-sum method. When Codex and Mini-Addenbrooke's Cognitive Examination were analyzed as binary (single fixed threshold) tests, AUC using rank-sum method was lower than when screeners were analyzed as categorical or continuous scales, respectively. Conclusion: If cognitive screeners producing categorical or continuous measures are dichotomized, calculated AUC may be an underestimate, thus affecting screening test accuracy.

Epileptic seizures have been described as one feature of prion diseases, but are an unusual clinical presentation. The aim of this narrative Review was to summarize current knowledge of epileptic seizures in the various forms of prion diseases, from a clinical perspective. Examination of the published literature identified no systematic studies; the evidence base is largely anecdotal, consisting mainly of case studies and small case series. Hence, uncertainty prevails as to seizure frequency, semiology, treatment, and pathogenesis in prion diseases. Seizures probably occur in around 10% of sporadic cases but less frequently in iatrogenic and familial forms, with the possible exception of the E200K mutation. The literature suggests a predominance of focal motor and nonconvulsive status epilepticus. Electroencephalographic accompaniments include periodic lateralized or generalized periodic epileptiform discharges (PLEDs, GPEDs), sometimes predating the more typical periodic sharp wave complexes. There are no convincing accounts of successful antiepileptic drug therapy. The underlying mechanisms of epileptogenesis in prion diseases may include loss of cellular prion protein function (PrP c ) and aggregation of abnormally folded prion protein (PrP Sc ). The need for systematic studies and clinical trials to expand the evidence base surrounding epilepsy and prion diseases is evident., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: We investigate the case-ascertainment accuracy for potentially active epilepsy of four administrative healthcare datasets used to identify deceased adults in Scotland., Methods: In this diagnostic accuracy study, unique patient identifiers were used to link administrative healthcare data for adults (aged 16 years and over) who died in Scotland between 01/01/09-01/01/16. Cases were ascertained from linking mortality records, hospital admissions, antiepileptic drug (AED) prescriptions, and primary care attendances. We assessed ICD-10 codes G40 (epilepsy), G41 (status epilepticus), and R56.8 (seizures) listed as causes of death and as hospital admission reasons, various AEDs, and F25 primary care epilepsy Read codes. These epilepsy indicators were searched through 01/01/09-01/01/16, suggesting active epilepsy during a maximal period of seven years before death. They were compared to epilepsy diagnoses made from medical records reviewed by a senior epileptologist, with a second senior epileptologist independently reviewing the medical records in a 10 % sample to check for specialist interrater agreement in epilepsy diagnoses. We validated how accurately epilepsy was identified by each dataset alone and when combined, calculating positive predictive value (PPV) and sensitivity (with 95 % confidence intervals (CIs))., Results: 159,032 deceased potential epilepsy cases were captured across the four datasets. Medical records reviewed in a random sample of 936 confirmed that epilepsy was present in 614 and absent in 322. Specialist interrater diagnostic agreement was substantial (100 medical records reviewed in duplicate, kappa = 0.72, CI 0.58-0.86). G40-41 cause of death codes had a PPV of 86 % (CI 84-89 %) and sensitivity of 73 % (CI 69-76 %). Adding R56.8 lowered PPV to 69 % (CI 65-72 %) and raised sensitivity to 87 % (CI 84-90 %). The optimal algorithm combining two datasets consisted of F25 Read codes paired with AEDs (PPV 86 % (CI 80-92 %), sensitivity 93 % (CI 88-97 %)). Also effective was pairing G40-41 and/or R56.8 cause of death codes with AEDs (PPV 91 % (CI 89-94 %), sensitivity 81 % (CI 77-84 %)). Whilst algorithms combining three datasets raised PPV to as high as 93-95 %, the associated sensitivities were low (71 % at most)., Conclusions: Routinely-collected Scottish data can accurately identify epilepsy in deceased adults. It may be necessary to combine the diagnostic coding used with AEDs to ensure optimal case-ascertainment. The results help inform the design of future Scottish epilepsy mortality studies recruiting from administrative data sources., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To determine the association of epilepsy with incident dementia by conducting a nationwide, retrospective data-linkage, cohort study to examine whether the association varies according to dementia subtypes and to investigate whether risk factors modify the association., Methods: We used linked health data from hospitalization, mortality records, and primary care consultations to follow up 563,151 Welsh residents from their 60th birthday to estimate dementia rate and associated risk factors. Dementia, epilepsy, and covariates (medication, smoking, comorbid conditions) were classified with the use of previously validated code lists. We studied rate of dementia and dementia subtypes in people with epilepsy (PWE) and without epilepsy using (stratified) Kaplan-Meier plots and flexible parametric survival models., Results: PWE had a 2.5 (95% confidence interval [CI] 2.3-2.6) times higher hazard of incident dementia, a 1.6 (95% CI 1.4-1.8) times higher hazard of incident Alzheimer disease (AD), and a 3.1 (95% CI 2.8-3.4) times higher hazard of incident Vascular dementia (VaD). A history of stroke modified the increased incidence in PWE. PWE who were first diagnosed at ≤25 years of age had a dementia rate similar to that of those diagnosed later in life. PWE who had ever been prescribed sodium valproate compared to those who had not were at higher risk of dementia (hazard ratio [HR] 1.6, 99% CI 1.4-1.9) and VaD (HR 1.7, 99% CI 1.4-2.1) but not AD (HR 1.2, 99% CI 0.9-1.5)., Conclusion: PWE compared to those without epilepsy have an increased dementia risk., (© 2020 American Academy of Neurology.)

Our objective was to undertake a systematic review ascertaining the accuracy of using administrative healthcare data to identify epilepsy cases. We searched MEDLINE and Embase from 01/01/1975 to 03/07/2018 for studies evaluating the diagnostic accuracy of routinely collected healthcare data in identifying epilepsy cases. Any disease coding system in use since the International Classification of Diseases, Ninth Revision (ICD-9) was permissible. Two authors independently screened studies, extracted data, and quality-assessed studies. We assessed positive predictive value (PPV), sensitivity, negative predictive value (NPV), and specificity. The primary analysis was a narrative synthesis of review findings. Thirty studies were included, published between 1989 and 2018. Risks of bias were low, high, and unclear in 4, 14, and 12 studies, respectively. Coding systems included ICD-9, ICD-10, and Read Codes, with or without antiepileptic drugs (AEDs). PPVs included ranges of 5.2%-100% (Canada), 32.7%-96.0% (USA), 47.0%-100% (UK), and 37.0%-88.0% (Norway). Sensitivities included ranges of 22.2%-99.7% (Canada), 12.2%-97.3% (USA), and 79.0%-94.0% (UK). Nineteen studies contained at least one algorithm with a PPV >80%. Sixteen studies contained at least one algorithm with a sensitivity >80%. PPV was highest in algorithms consisting of disease codes (ICD-10 G40-41, ICD-9 345) in combination with one or more AEDs. The addition of symptom codes to this (ICD-10 R56; ICD-9 780.3, 780.39) lowered PPV. Sensitivity was highest in algorithms consisting of symptom codes with one or more AEDs. Although using AEDs alone achieved high sensitivities, the associated PPVs were low. Most NPVs and specificities were >90%. We conclude that it is reasonable to use administrative data to identify people with epilepsy (PWE) in epidemiological research. Studies prioritizing high PPVs should focus on combining disease codes with AEDs. Studies prioritizing high sensitivities should focus on combining symptom codes with AEDs. We caution against the use of AEDs alone to identify PWE., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Drug resistance is common in focal epilepsy. In this update, we summarised the current evidence regarding add-on levetiracetam in treating drug-resistant focal epilepsy. The original review was published in 2001 and last updated in 2012., Objectives: To evaluate the effectiveness of levetiracetam when used as an add-on treatment for people with drug-resistant focal epilepsy., Search Methods: We searched the Cochrane Register of Studies (CRS Web, which includes the Cochrane Epilepsy Group Specialized Register and CENTRAL), MEDLINE Ovid, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) to November 2018. We 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 certainty of the evidence. Outcomes investigated included 50% or greater reduction in focal seizure frequency (response), treatment withdrawal, adverse effects (including a specific analysis of changes in behaviour), cognitive effects, and quality of life (QoL). Primary analysis was intention-to-treat. We performed meta-analysis for all outcomes using a Mantel-Haenszel approach and calculated risk ratios (RR), with 95% confidence intervals (CI) for all estimates apart from adverse effects (99% CIs). We assessed heterogeneity using a Chi² test and the I² statistic., Main Results: This update included 14 trials (2455 participants), predominantly possessing low risks of bias. Participants were adults in 12 trials (2159 participants) and children in the remaining two (296 participants). The doses of levetiracetam tested were 500 mg/day to 4000 mg/day in adults, and 60 mg/kg/day in children. Treatment ranged from 12 to 24 weeks. When individual doses were examined, levetiracetam at either 500 mg/day or 4000 mg/day did not perform better than placebo for the 50% or greater reduction in seizure frequency outcome (500 mg: RR 1.60, 95% CI 0.71 to 3.62; P = 0.26; 4000 mg: RR 1.64, 95% CI 0.59 to 4.57; P = 0.34). Levetiracetam was significantly better than placebo at all other individual doses (1000 mg to 3000 mg). RR was significantly in favour of levetiracetam compared to placebo when results were pooled across all doses (RR 2.37, 95% CI 2.02 to 2.78; 14 studies, 2455 participants; moderate-certainty evidence). Dose-response analysis demonstrated that the odds of achieving response (50% or greater reduction in seizure frequency) were increased by nearly 40% (odds ratio (OR) 1.39, 95% CI 1.23 to 1.58) for each 1000 mg increase in dose of levetiracetam. There were important levels of heterogeneity across multiple comparisons. Participants were not significantly more likely to experience treatment withdrawal with levetiracetam than with placebo (pooled RR 1.11, 95% CI 0.89 to 1.40; 13 studies, 2428 participants; high-certainty evidence). Somnolence was the most common adverse effect, affecting 13% of participants, and it was significantly associated with levetiracetam compared to placebo (pooled RR 1.62, 99% CI 1.19 to 2.20; 13 studies, 2423 participants; moderate-certainty evidence). 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). Levetiracetam had a positive effect on some aspects of cognition and QoL in adults and worsened certain aspects of child behaviour., Authors' Conclusions: Overall, this review update finds that in both adults and children with drug-resistant focal epilepsy, levetiracetam added on to usual care is more effective than placebo at reducing seizure frequency, it is unlikely to be stopped by patients, and it has minimal adverse effects outside of potential worsening behaviour in children. These findings are unchanged from the previous review update in 2012. This review update contributes two key additional findings: 1. a 500 mg daily dose of levetiracetam is no more effective than placebo at reducing seizures; and 2. the odds of response (50% reduction in seizure frequency) are increased by nearly 40% for each 1000 mg increase in dose of levetiracetam. It seems reasonable to continue the use of levetiracetam in both adults and children with drug-resistant focal epilepsy., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: This systematic review of epilepsy mortality systematic reviews evaluates comparative risks, causes, and risk factors for all-cause mortality in people with epilepsy (PWE) to specifically establish the burden of epilepsy-related deaths., Methods: MEDLINE and Embase were searched from conception to 26/12/2018 for systematic reviews evaluating all-cause mortality in PWE of any age. Independent study selection, data extraction and quality assessment were performed. Deaths were separated into epilepsy-related and unrelated using a recently published classification system. Outcomes included standardized mortality ratio (SMR) and mortality rate (MR) in a primary analysis of comparative risks, causes, and risk factors for all-cause and epilepsy-related mortality. A narrative synthesis of review findings was used to present results, including from a secondary analysis of individual epilepsy-related death risk factors., Results: Six moderate or high-quality systematic reviews were included in the primary analysis, evaluating 103 observational studies. All-cause mortality remained similarly high between 1950 and present (median SMR range 2.2-3.4). Africa had the highest SMR (median 5.4, range 2.6-7.2). SMRs were also higher for children <18 years (median 7.5, range 3.1-22.4) than adults (median 2.6, range 1.3-8.7), and for epilepsy-related (median 3.8, range 0.0-82.4,) than unrelated causes (median 1.7, range 0.7-17.6). Structural brain disease conferred the greatest risk for all-cause mortality (SMR range 24.0-41.5). Common epilepsy-related causes included alcohol, drowning, pneumonia, and suicide. In secondary analysis of nine additional systematic reviews, epilepsy-related death risk factors were reported for sudden unexpected death in epilepsy (SUDEP), drowning and suicide., Conclusions: Premature all-cause mortality remains a major problem in PWE globally, particularly in children and young adults, with most being epilepsy-related and potentially preventable. SUDEP is only one of several other common and important epilepsy-related causes of death., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: We describe a patient copresenting with epilepsia partialis continua, tuberculosis, and hemophagocytic lymphohistiocytosis. To our knowledge, this is the first documented case of this triad., Case Presentation: A 54-year-old black South African woman presented to a hospital in Scotland with an acute history of right-sided facial twitching, breathlessness, and several months of episodic night sweats. Clinical examination revealed pyrexia and continuous, stereotyped, right-sided facial contractions. These worsened with speech and continued through sleep. A clinical diagnosis of epilepsia partialis continua was made, and we provide a video of her seizures. Computed tomographic imaging of the chest and serous fluid analyses were consistent with a diagnosis of disseminated Mycobacterium tuberculosis. An additional diagnosis of hemophagocytic lymphohistiocytosis was made following the identification of pancytopenia and hyperferritinemia in peripheral blood, with hemophagocytosis evident in bone marrow investigation. We provide images of her hematopathology. The patient was extremely unwell and was hospitalized for 6 months, including two admissions to the intensive care unit for ventilatory support. She was treated successfully with high doses of antiepileptic drugs (benzodiazepines, levetiracetam, and phenytoin) and 12 months of oral antituberculosis therapy, and she underwent chemotherapy with 8 weeks of etoposide and dexamethasone for hemophagocytic lymphohistiocytosis, followed by 12 months of cyclosporine and prednisolone., Conclusions: This combination of pathologies is unusual, and this case report helps educate clinicians on how such a patient may present and be managed. A lack of evidence surrounding the coexpression of this triad may represent absolute rarity, underdiagnosis, or incomplete case ascertainment due to early death caused by untreated tuberculosis or hemophagocytic lymphohistiocytosis. Further research is needed.

We report two cases of adults presenting with transient loss of consciousness (TLoC) followed by a rapid recovery. Careful history taking revealed a stereotyped prodrome of déjà vu, raising the possibility of these events being focal seizures rather than syncope. The patients were commenced on antiepileptic drugs (AEDs) at the same time as having cardiac monitoring organised. This confirmed asystole during the seizure symptoms, resulting in TLoC. It was assumed that the cardiac arrhythmia explained the entire picture, a permanent pacemaker (PPM) was inserted, and the AEDs were withdrawn in one patient and not commenced in the other. However, they both subsequently presented with worsening seizures, including generalised tonic-clonic seizures, despite a functioning pacemaker. The seizures improved on restarting AEDs. The cases illustrate the diagnostic and management difficulties of patients presenting with ictal asystole, a condition that requires input from various medical specialities. There is no strong evidence base for the management of ictal asystole, but we favour a combined approach of AEDs and PPM insertion., Competing Interests: No conflict of interests declared

Introduction: In an increasingly digital age for healthcare around the world, administrative data have become rich and accessible tools for potentially identifying and monitoring population trends in diseases including epilepsy. However, it remains unclear (1) how accurate administrative data are at identifying epilepsy within a population and (2) the optimal algorithms needed for administrative data to correctly identify people with epilepsy within a population. To address this knowledge gap, we will conduct a novel systematic review of all identified studies validating administrative healthcare data in epilepsy identification. We provide here a protocol that will outline the methods and analyses planned for the systematic review., Methods and Analysis: The systematic review described in this protocol will be conducted to follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE and Embase will be searched for studies validating administrative data in epilepsy published from 1975 to current (01 June 2018). Included studies will validate the International Classification of Disease (ICD), Ninth Revision (ICD-9) onwards (ie, ICD-9 code 345 and ICD-10 codes G40-G41) as well as other non-ICD disease classification systems used, such as Read Codes in the UK. The primary outcome will be providing pooled estimates of accuracy for identifying epilepsy within the administrative databases validated using sensitivity, specificity, positive and negative predictive values, and area under the receiver operating characteristic curves. Heterogeneity will be assessed using the I 2 statistic and descriptive analyses used where this is present. The secondary outcome will be the optimal administrative data algorithms for correctly identifying epilepsy. These will be identified using multivariable logistic regression models. 95% confidence intervals will be quoted throughout. We will make an assessment of risk of bias, quality of evidence, and completeness of reporting for included studies., Ethics and Dissemination: Ethical approval is not required as primary data will not be collected. Results will be disseminated in peer-reviewed journals, conference presentations and in press releases., Prospero Registration: CRD42017081212., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Relapsing polychondritis (RPC) is a rare, immune-mediated condition affecting approximately 3.5 per million population per year. Neurological involvement in RPC is still rarer and is presumed to be the result of a vasculitic process, although this is seldom confirmed in the literature. We present two cases of RPC complicated by cognitive dysfunction with contrasting clinical trajectories. Our findings suggest that there are two clinical phenotypes of cognitive dysfunction in RPC. The first is a fulminant, multisystem presentation with sub-acute cognitive decline mimicking central nervous system vasculitis, and we provide histopathological evidence of this process occurring. The other is an insidious cognitive decline without associated constitutional or systemic symptoms.

Unlabelled: The typical placebo response (ie, the nonspecific effects in the placebo group including benign natural course, regression to the mean, expectation/conditioning effects, and others) in randomized trials in complex regional pain syndrome (CRPS) is unknown. We recently observed a surprising near-absence of placebo response in a randomized controlled trial we conducted on patients with long-standing (≥6 months) CRPS. To investigate the idea that there may be an absence of placebo response in long-standing CRPS further, we conducted a systematic review and meta-analysis of placebo responses in randomized controlled trials conducted in patients with CRPS of ≥6 months. We systematically identified suitable randomized controlled trials published between 1966 and September 2013. We calculated the mean difference and standard error of the mean difference for placebo responses and synthesized individual effect sizes at 4 specified time periods of interest (15-30 minutes, 1 week, 3-4 weeks, and 6 weeks or more) via meta-analysis using the method of inverse-variance. Heterogeneity was assessed according to the I(2) statistic. For primary analysis, we pooled trial-specific effect sizes over the 4 time points. We analyzed data from 340 participants from 18 trials out of a possible 361 participants from 20 trials (94% of participants analyzed). Significant heterogeneity was present between trials; therefore, we interpreted trends from visual inspection of individual trials and pooled estimates. Placebo response was significant at the earliest time period (15-30 minutes). There was no significant evidence of placebo response at any of the other time periods. These results inform the design of future trials, and they caution against the "therapeutic" use of placebo in long-standing CRPS., Perspective: In this meta-analysis of placebo responses in randomized controlled trials in long-standing CRPS, published during 1966 to 2013, we found no evidence for placebo analgesia, except at very early time points. Results inform the design of future placebo analgesia research in long-standing CRPS., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

The adverse effects profile of levetiracetam in epilepsy is still being fully described. We recently published a Cochrane Review evaluating the effectiveness of levetiracetam, added on to usual care, in treating drug-resistant focal epilepsy. The five most common adverse effects were reported and analysed with no scope for reporting any less common adverse effects than those. Here, we report and analyse the remaining adverse effects (including the five most common). These were (in decreasing order of frequency) somnolence; headache; asthenia; accidental injury; dizziness; infection; pharyngitis; pain; rhinitis; abdominal pain; flu syndrome; vomiting; diarrhoea; convulsion; nausea; increased cough; anorexia; upper respiratory tract infection; hostility; personality disorder; urinary tract infection; nervousness; depression; aggression; back pain; agitation; emotional liability; psychomotor hyperactivity; pyrexia; rash; ECG abnormalities; decreased appetite; nasal congestion; irritability; abnormal behaviour; epistaxis; insomnia; altered mood; anxiety; bloody urine; diplopia; dissociation; memory impairment; pruritis; increased appetite; acne; and stomach discomfort. Only somnolence and infection were significantly associated with levetiracetam. When adverse effects pertaining to infection were combined, these affected 19.7% and 15.1% of participants on levetiracetam and placebo (relative risk 1.16, CI 0.89-1.50, Chi(2) heterogeneity p = 0.13). Somnolence and infection further retained significance in adults while no single adverse effect was significant in children. This review updates the adverse effects profile data on levetiracetam use by empirically reporting its common and uncommon adverse effects and analysing their relative importance statistically using data from a group of trials that possess low Risk of Bias and high Quality of Evidence GRADE scores.

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.