Developing an alternative care pathway for emergency ambulance responses for adults with epilepsy: A Discrete Choice Experiment to understand which configuration service users prefer. Part of the COLLABORATE project.

INTRODUCTION: To identify service users' preferences for an alternative care pathway for adults with epilepsy presenting to the ambulance service. METHODS: Extensive formative work (qualitative, survey and knowledge exchange) informed the design of a stated preference discrete choice experiment (DCE). This hypothetical survey was hosted online and consisted of 12 binary choices of alternative care pathways described in terms of: the paramedic's access to medical records/ 'care plan', what happens next (described in terms of conveyance), time, availability of epilepsy specialists today, general practitioner (GP) notification and future contact with epilepsy specialists. DCE scenarios were described as: (i) typical seizure at home. (ii) typical seizure in public, (iii) atypical seizure. Respondents were recruited by a regional English ambulance service and by national public adverts. Participants were randomised to complete 2 of the 3 DCEs. RESULTS: People with epilepsy (PWE; n = 427) and friends/family (n = 167) who completed the survey were representative of the target population. PWE preferred paramedics to have access to medical records, non-conveyance, to avoid lengthy episodes of care, availability of epilepsy specialists today, GP notification, and contact with epilepsy specialists within 2-3 weeks. Significant others (close family members or friends) preferred PWE experiencing an atypical seizure to be conveyed to an Urgent Treatment Centre and preferred shorter times. Optimal configuration of services from service users' perspective far out ranked current practice (rank 230/288 possible configurations). DISCUSSION: Preferences differ to current practice but have minimal variation by seizure type or stakeholder. Further work on feasibility of these pathways in England, and potentially beyond, is required.

Service users' preferences and feasibility - which alternative care pathway for adult ambulance users achieves the optimal balance? Workshops for the COLLABORATE project.

INTRODUCTION: Adults presenting to the ambulance service for diagnosed epilepsy are often transported to emergency departments (EDs) despite no clinical need. An alternative care pathway (CP) could allow paramedics to divert them from ED and instigate ambulatory care improvements. To identify the most promising CP configuration for subsequent testing, the COLLABORATE project surveyed people with epilepsy and family/friends who had recently used the English ambulance service to elicit preferences for 288 CP configurations for different seizures. This allowed CPs to be ranked according to alignment with service users' preferences. However, as well as being acceptable to users, a CP must be feasible. We thus engaged with paramedics, epilepsy specialists and commissioners to identify the optimal configuration. METHODS: Three Knowledge Exchange workshops completed. Participants considered COLLABORATE's evidence on service users' preferences for the different configurations. Nominal group techniques elicited views on the feasibility of users' preferences according to APEASE criteria. Workshop groups specified the configuration/s considered optimum. Qualitative data was analysed thematically. Utility to users of the specified CP configurations estimated using the COLLABORATE preference survey data. RESULTS: Twenty-seven participants found service users' preferences broadly feasible and outlined delivery recommendations. They identified enough commonality in preferences for different seizures to propose a single CP. Its configuration comprised: 1) patients staying where they were; 2) paramedics having access to medical records; 3) care episodes lasting <6 h; 4) paramedics receiving specialist advice on the day; 5) patient's GP being notified; and 6) a follow-up appointment being arranged with an epilepsy specialist. Preference data indicated higher utility for this configuration compared to current care. DISCUSSION: Stakeholders are of the view that the CP configuration favoured by service users could be NHS feasible. It should be developed and evaluated.

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.

The outcomes measured and reported in observational studies of incidental and untreated intracranial meningioma: A systematic review.

Background: The clinical management of patients with incidental intracranial meningioma varies markedly and is often based on clinician choice and observational data. Heterogeneous outcome measurement has likely hampered knowledge progress by preventing comparative analysis of similar cohorts of patients. This systematic review aimed to summarize the outcomes measured and reported in observational studies. Methods: A systematic literature search was performed to identify published full texts describing active monitoring of adult cohorts with incidental and untreated intracranial meningioma (PubMed, EMBASE, MEDLINE, and CINAHL via EBSCO, completed January 24, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were de-duplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the "Core Outcome Measures in Effectiveness Trials" (COMET) initiative. Results: Thirty-three published articles and 1 ongoing study were included describing 32 unique studies: study designs were retrospective n = 27 and prospective n = 5. In total, 268 verbatim outcomes were reported, of which 77 were defined. Following de-duplication, 178 unique verbatim outcomes remained and were grouped into 53 standardized outcome terms. These were classified using the COMET taxonomy into 9 outcome domains and 3 core areas. Conclusions: Outcome measurement across observational studies of incidental and untreated intracranial meningioma is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set for use in future observational studies.

The outcomes measured and reported in intracranial meningioma clinical trials: A systematic review.

Background: Meningioma clinical trials have assessed interventions including surgery, radiotherapy, and pharmacotherapy. However, agreement does not exist on what, how, and when outcomes of interest should be measured. To do so would allow comparative analysis of similar trials. This systematic review aimed to summarize the outcomes measured and reported in meningioma clinical trials. Methods: Systematic literature and trial registry searches were performed to identify published and ongoing intracranial meningioma clinical trials (PubMed, Embase, Medline, CINAHL via EBSCO, and Web of Science, completed January 22, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were deduplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the "Core Outcome Measures in Effectiveness Trials" (COMET) initiative. Results: Thirty published articles and 18 ongoing studies were included, describing 47 unique clinical trials: Phase 2 n = 33, phase 3 n = 14. Common interventions included: Surgery n = 13, radiotherapy n = 8, and pharmacotherapy n = 20. In total, 659 verbatim outcomes were reported, of which 84 were defined. Following de-duplication, 415 unique verbatim outcomes remained and were grouped into 115 standardized outcome terms. These were classified using the COMET taxonomy into 29 outcome domains and 5 core areas. Conclusions: Outcome measurement across meningioma clinical trials is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a core outcome set for use in future meningioma clinical trials.

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.

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.

Identification and Assessment of Outcome Measurement Instruments in Cauda Equina Syndrome: A Systematic Review.

STUDY DESIGN: This was a systematic review of surgically managed Cauda Equina Syndrome (CES) Outcome Measurement Instruments (OMI). OBJECTIVE: A core outcome set (COS) defines agreed outcomes which should be reported as a minimum in any research study for a specific condition. This study identified OMIs used in the wider CES literature and compare these to the established CESCOS. METHODS: To identify measurement methods and instruments in the CES surgical outcome evidence base, a systematic review was performed. Medline, Embase and CINAHL plus databases were queried. In addition, a secondary search for validation studies of measurement instruments in CES was undertaken. Identified studies from this search were subject to the COSMIN risk of bias assessment. RESULTS: In total, 112 studies were identified investigating surgical outcomes for CES. The majority (80%, n = 90) of these OMI studies were retrospective in nature and only 55% (n = 62) utilised a measurement method or instrument. The remaining 50 studies used study specific definitions for surgical outcomes defined within their methods. Of the 59 measurement instruments identified, 60% (n = 38 instruments) were patient reported outcome measures. Only one validated instrument was identified, which was a patient reported outcome measure. The validated instrument was not used in any study identified in the initial search (to identify measurement instruments). CONCLUSIONS: This review highlights the wide heterogeneity of measurement instruments used in surgically managed CES research. Subsequently, there is need for consensus agreement on which instrument or instruments should be used to measure each core outcome for CES surgical outcomes.

'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.

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.

Variation in seizure risk increases from antiseizure medication withdrawal among patients with well-controlled epilepsy: A pooled analysis.

OBJECTIVE: Guidelines suggest considering antiseizure medication (ASM) discontinuation in seizure-free patients with epilepsy. Past work has poorly explored how discontinuation effects vary between patients. We evaluated (1) what factors modify the influence of discontinuation on seizure risk; and (2) the range of seizure risk increase due to discontinuation across low- versus high-risk patients. METHODS: We pooled three datasets including seizure-free patients who did and did not discontinue ASMs. We conducted time-to-first-seizure analyses. First, we evaluated what individual patient factors modified the relative effect of ASM discontinuation on seizure risk via interaction terms. Then, we assessed the distribution of 2-year risk increase as predicted by our adjusted logistic regressions. RESULTS: We included 1626 patients, of whom 678 (42%) planned to discontinue all ASMs. The mean predicted 2-year seizure risk was 43% [95% confidence interval (CI) 39%-46%] for discontinuation versus 21% (95% CI 19%-24%) for continuation. The mean 2-year absolute seizure risk increase was 21% (95% CI 18%-26%). No individual interaction term was significant after correcting for multiple comparisons. The median [interquartile range (IQR)] risk increase across patients was 19% (IQR 14%-24%; range 7%-37%). Results were unchanged when restricting analyses to only the two RCTs. SIGNIFICANCE: No single patient factor significantly modified the influence of discontinuation on seizure risk, although we captured how absolute risk increases change for patients that are at low versus high risk. Patients should likely continue ASMs if even a 7% 2-year increase in the chance of any more seizures would be too much and should likely discontinue ASMs if even a 37% risk increase would be too little. In between these extremes, individualized risk calculation and a careful understanding of patient preferences are critical. Future work will further develop a two-armed individualized seizure risk calculator and contextualize seizure risk thresholds below which to consider discontinuation. PLAIN LANGUAGE SUMMARY: Understanding how much antiseizure medications (ASMs) decrease seizure risk is an important part of determining which patients with epilepsy should be treated, especially for patients who have not had a seizure in a while. We found that there was a wide range in the amount that ASM discontinuation increases seizure risk-between 7% and 37%. We found that no single patient factor modified that amount. Understanding what a patient's seizure risk might be if they discontinued versus continued ASM treatment is critical to making informed decisions about whether the benefit of treatment outweighs the downsides.

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.

Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin.

Background: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug. Methods: Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants. Results: The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing. Conclusion: We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.

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.

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.

National audit of pathways in epileptic seizure referrals (NAPIER): A national, multicentre audit of first seizure clinics throughout the UK and Ireland.

BACKGROUND: Current guidelines set clinical standards for the management of suspected first seizures and epilepsy. We aimed to assess if these standards are being met across first seizure clinics nationally, to describe variations in care and identify opportunities for service delivery improvement. METHODS: Multicentre audit assessing the care of adults (≥16 years) referred to first seizure clinics from 31st December 2019 going backwards (30 consecutive patients per centre). Patients with pre-existing diagnosis of epilepsy were excluded. Anonymised referral, clinic, and follow-up data are reported with descriptive statistics. RESULTS: Data provided for 727 patients from 25 hospitals in the UK and Ireland (median age 41 years [IQR 26-59], 52% males). Median time to review was 48 days (IQR 26-86), with 13.8% (IQR 3.3%-24.0%) of patients assessed within 2 weeks. Seizure recurrence was seen in 12.7% (IQR 6.6%-17.4%) of patients awaiting first appointment. Documentation for witness accounts and driving advice was evident in 85.0% (IQR 74.0%-100%) and 79.7% (IQR 71.2%-96.4%) of first seizure/epilepsy patients, respectively. At first appointment, discussion of sudden unexpected death in epilepsy was documented in 30.1% (IQR 0%-42.5%) of patients diagnosed with epilepsy. In epilepsy patients, median time to MRI neuroimaging was 37 days [IQR 22-56] and EEG was 30 days [IQR 19-47]. 30.4% ([IQR 0%-59.5%]) of epilepsy patients were referred to epilepsy nurse specialists. CONCLUSIONS: There is variability nationally in the documented care of patients referred to first seizure clinics. Many patients are facing delays to assessment with epilepsy specialists with likely subsequent impact on further management.

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.

Epilepsy-Heart Syndrome: Incidence and Clinical Outcomes of Cardiac Complications in patients with Epilepsy.

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."