Development of an International Standard Set of Outcomes and Measurement Methods for Routine Practice for Infants, Children, and Adolescents with Epilepsy: The International Consortium for Health Outcomes Measurement Consensus Recommendations.

At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. The International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group of experts in epilepsy, people with epilepsy, and their representatives to develop minimum sets of standardized outcomes and outcome measurement methods for clinical practice. Using modified Delphi consensus methods with consecutive rounds of online voting over 12 months, a core set of outcomes and corresponding measurement tool packages to capture the outcomes were identified for infants, children, and adolescents with epilepsy. Consensus methods identified 20 core outcomes. In addition to the outcomes identified for the ICHOM Epilepsy adult standard set, behavioral, motor, and cognitive/language development outcomes were voted as essential for all infants and children with epilepsy. The proposed set of outcomes and measurement methods will facilitate the implementation of the use of patient-centered outcomes in daily practice.

Development of an International Standard Set of Outcomes and Measurement Methods for Routine Practice for Adults with Epilepsy: The International Consortium for Health Outcomes Measurement Consensus Recommendations.

At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. Therefore, the International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group of experts in epilepsy, people with epilepsy and their representatives to develop minimum sets of standardized outcomes and outcomes measurement methods for clinical practice that support patient-clinician decision-making and quality improvement. Consensus methods identified 20 core outcomes. Measurement tools were recommended based on their evidence of strong clinical measurement properties, feasibility, and cross-cultural applicability. The essential outcomes included many non-seizure outcomes: anxiety, depression, suicidality, memory and attention, sleep quality, functional status, and the social impact of epilepsy. The proposed set will facilitate the implementation of the use of patient-centered outcomes in daily practice, ensuring holistic care. They also encourage harmonization of outcome measurement, and if widely implemented should reduce the heterogeneity of outcome measurement, accelerate comparative research, and facilitate quality improvement efforts.

National plans and awareness campaigns as priorities for achieving global brain health.

Neurological conditions are the leading cause of death and disability combined. This public health crisis has become a global priority with the introduction of WHO's Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders 2022-2031 (IGAP). 18 months after this plan was adopted, global neurology stakeholders, including representatives of the OneNeurology Partnership (a consortium uniting global neurology organisations), take stock and advocate for urgent acceleration of IGAP implementation. Drawing on lessons from relevant global health contexts, this Health Policy identifies two priority IGAP targets to expedite national delivery of the entire 10-year plan: namely, to update national policies and plans, and to create awareness campaigns and advocacy programmes for neurological conditions and brain health. To ensure rapid attainment of the identified priority targets, six strategic drivers are proposed: universal community awareness, integrated neurology approaches, intersectoral governance, regionally coordinated IGAP domestication, lived experience-informed policy making, and neurological mainstreaming (advocating to embed brain health into broader policy agendas). Contextualised with globally emerging IGAP-directed efforts and key considerations for intersectoral policy design, this novel framework provides actionable recommendations for policy makers and IGAP implementation partners. Timely, synergistic pursuit of the six drivers might aid WHO member states in cultivating public awareness and policy structures required for successful intersectoral roll-out of IGAP by 2031, paving the way towards brain health for all.

Estimating the active and lifetime prevalence and incidence of epilepsy in Asian Countries: A systematic review and meta-analysis.

OBJECTIVE: In the current era of the World Health Organization's Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders 2022-2031 (IGAP), precise and updated estimates of epilepsy burden are vital in formulating policies to improve the care of persons with epilepsy, especially in Asian countries with significant treatment gap. Hence, we aimed to consolidate the available data and quantify epilepsy prevalence and incidence estimates in Asian countries. METHODS: We systematically searched PubMed, Embase, Ovid, and Scopus databases from inception until March 2023 for studies reporting epilepsy prevalence and incidence in Asian countries. We applied random effects meta-analysis to generate the pooled prevalence and incidence using the Meta package in R. Additionally, we performed a subgroup meta-analysis to explore the potential sources of heterogeneity. A meta-regression analysis was conducted to examine the trend of epilepsy over time. RESULTS: A total of 99 studies with 100,654,124 participants were included in the meta-analysis. The pooled prevalence was 5.6 per 1000 (95 % confidence interval (CI) 4.4-6.8) for active epilepsy and 6.7 per 1000 (95 % CI 5.7-7.9) for lifetime epilepsy. The pooled incidence rate of epilepsy was 52.5 per 100,000 person-years (95 % CI 42.7-79.4). The subgroup analysis revealed a higher prevalence of active epilepsy (6.7/1000) and lifetime epilepsy (8.6/1000) in West Asia than in other regions. The funnel plot and Egger's test (p-value =<0.0001) revealed publication bias for active epilepsy. CONCLUSION: Our findings highlight a high prevalence of active and lifetime epilepsy in West Asia and emphasize the necessity of implementing and formulating specific strategies to tackle the epilepsy burden in this region. Furthermore, high-quality epidemiological studies incorporating economic burdens and comorbidities associated with epilepsy in Asia are still needed.

Protocol for the development of an international Core Outcome Set for treatment trials in adults with epilepsy: the EPilepsy outcome Set for Effectiveness Trials Project (EPSET).

BACKGROUND: A Core Outcome Set (COS) is a standardised list of outcomes that should be reported as a minimum in all clinical trials. In epilepsy, the choice of outcomes varies widely among existing studies, particularly in clinical trials. This diminishes opportunities for informed decision-making, contributes to research waste and is a barrier to integrating findings in systematic reviews and meta-analyses. Furthermore, the outcomes currently being measured may not reflect what is important to people with epilepsy. Therefore, we aim to develop a COS specific to clinical effectiveness research for adults with epilepsy using Delphi consensus methodology. METHODS: The EPSET Study will comprise of three phases and follow the core methodological principles as outlined by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. Phase 1 will include two focused literature reviews to identify candidate outcomes from the qualitative literature and current outcome measurement practice in phase III and phase IV clinical trials. Phase 2 aims to achieve international consensus to define which outcomes should be measured as a minimum in future trials, using a Delphi process including an online consensus meeting involving key stakeholders. Phase 3 will involve dissemination of the ratified COS to facilitate uptake in future trials and the planning of further research to identify the most appropriate measurement instruments to use to capture the COS in research practice. DISCUSSION: Harmonising outcome measurement across future clinical trials should ensure that the outcomes measured are relevant to patients and health services, and allow for more meaningful results to be obtained. CORE OUTCOME SET REGISTRATION: COMET Initiative as study 118 .

Core Competencies in Clinical Neuropsychology as a Training Model in Europe.

The multitude of training models and curricula for the specialty of clinical neuropsychology around the world has led to organized activities to develop a framework of core competencies to ensure sufficient expertise among entry-level professionals in the field. The Standing Committee on Clinical Neuropsychology of the European Federation of Psychologists' Associations is currently working toward developing a specialty certification in clinical neuropsychology to establish a cross-national standard against which to measure levels of equivalency and uniformity in competence and service provision among professionals in the field. Through structured interviews with experts from 28 European countries, we explored potential areas of core competency. Specifically, questions pertained to the perceived importance of a series of foundational, functional, and other competencies, as well as current training standards and practices, and optimal standards. Our findings revealed considerable agreement (about three quarters and above) on academic and clinical training, despite varied actual training requirements currently, with fewer respondents relegating importance to training in teaching, supervision, and research (a little over half), and even fewer to skills related to management, administration, and advocacy (fewer than half). European expert clinical neuropsychologists were in agreement with previous studies (including those conducted in the United States, Australia, and other countries) regarding the importance of sound theoretical and clinical training but management, administrative, and advocacy skills were not central to their perspective of a competent specialist in clinical neuropsychology. Establishing a specialty certificate in clinical neuropsychology based on core competencies may enable mobility of clinical neuropsychologists across Europe, and, perhaps, provide an impetus for countries with limited criteria to reconsider their training requirements and harmonize their standards with others.

Uses and abuses of the neuropsychological assessment in the presurgical evaluation of epilepsy surgery candidates.

Recent guidelines from the International League Against Epilepsy (ILAE) delineating the role of the neuropsychologist in the assessment of epilepsy surgery patients stress the collaborative contribution neuropsychologists should make to seizure characterization, lateralization and localization in the pre-surgical setting. The role they should play in the comprehensive counselling of surgical candidates, including exploration of the patient's expectations of surgical treatment is also mandated. In this paper we present two contrasting case studies which illustrate the importance of these roles and the impact they can have on patient outcomes. In Case A we describe the patient journey of a 69-year-old women with left hippocampal sclerosis and concordant neurophysiology and seizure semiology. We present the series of discussions and decisions which led her to reject the surgical option following a detailed exploration of her motivations for surgery and the likely cognitive consequences of the procedure. In Case B we describe the series of errors and omissions which led to the failure of a clinical team to correctly interpret and integrate neuropsychological findings into the larger clinical picture of a 19-year-old woman with a seven year history of seizures. These errors ultimately culminated in the patient undergoing a right temporal lobe resection to treat psychogenic nonepileptic seizures (PNES). The extent of integration of the data from the clinical neuropsychological assessment in the full presurgical evaluation was critical in determining the outcomes in both of these cases. Surgery did not solve Case B's problems and left her with the lifelong cognitive vulnerabilities that are associated with unilateral temporal lobe resection. In contrast, Case A was a good surgical candidate, but comprehensive integration of the neuropsychological findings into the larger clinical picture established that surgery was not the best solution to the problem she wished to solve.

Lamotrigine versus levetiracetam or zonisamide for focal epilepsy and valproate versus levetiracetam for generalised and unclassified epilepsy: two SANAD II non-inferiority RCTs.

BACKGROUND: Levetiracetam (Keppra®, UCB Pharma Ltd, Slough, UK) and zonisamide (Zonegran®, Eisai Co. Ltd, Tokyo, Japan) are licensed as monotherapy for focal epilepsy, and levetiracetam is increasingly used as a first-line treatment for generalised epilepsy, particularly for women of childbearing age. However, there is uncertainty as to whether or not they should be recommended as first-line treatments owing to a lack of evidence of clinical effectiveness and cost-effectiveness. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of lamotrigine (Lamictal®, GlaxoSmithKline plc, Brentford, UK) (standard treatment) with levetiracetam and zonisamide (new treatments) for focal epilepsy, and to compare valproate (Epilim®, Sanofi SA, Paris, France) (standard treatment) with levetiracetam (new treatment) for generalised and unclassified epilepsy. DESIGN: Two pragmatic randomised unblinded non-inferiority trials run in parallel. SETTING: Outpatient services in NHS hospitals throughout the UK. PARTICIPANTS: Those aged ≥ 5 years with two or more spontaneous seizures that require anti-seizure medication. INTERVENTIONS: Participants with focal epilepsy were randomised to receive lamotrigine, levetiracetam or zonisamide. Participants with generalised or unclassifiable epilepsy were randomised to receive valproate or levetiracetam. The randomisation method was minimisation using a web-based program. MAIN OUTCOME MEASURES: The primary outcome was time to 12-month remission from seizures. For this outcome, and all other time-to-event outcomes, we report hazard ratios for the standard treatment compared with the new treatment. For the focal epilepsy trial, the non-inferiority limit (lamotrigine vs. new treatments) was 1.329. For the generalised and unclassified epilepsy trial, the non-inferiority limit (valproate vs. new treatments) was 1.314. Secondary outcomes included time to treatment failure, time to first seizure, time to 24-month remission, adverse reactions, quality of life and cost-effectiveness. RESULTS: Focal epilepsy. A total of 990 participants were recruited, of whom 330 were randomised to receive lamotrigine, 332 were randomised to receive levetiracetam and 328 were randomised to receive zonisamide. Levetiracetam did not meet the criteria for non-inferiority (hazard ratio 1.329) in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio vs. lamotrigine 1.18, 97.5% confidence interval 0.95 to 1.47), but zonisamide did meet the criteria (hazard ratio vs. lamotrigine 1.03, 97.5% confidence interval 0.83 to 1.28). In the per-protocol analysis, lamotrigine was superior to both levetiracetam (hazard ratio 1.32, 95% confidence interval 1.05 to 1.66) and zonisamide (hazard ratio 1.37, 95% confidence interval 1.08 to 1.73). For time to treatment failure, lamotrigine was superior to levetiracetam (hazard ratio 0.60, 95% confidence interval 0.46 to 0.77) and zonisamide (hazard ratio 0.46, 95% confidence interval 0.36 to 0.60). Adverse reactions were reported by 33% of participants starting lamotrigine, 44% starting levetiracetam and 45% starting zonisamide. In the economic analysis, both levetiracetam and zonisamide were more costly and less effective than lamotrigine and were therefore dominated. Generalised and unclassifiable epilepsy. Of 520 patients recruited, 260 were randomised to receive valproate and 260 were randomised to receive to levetiracetam. A total of 397 patients had generalised epilepsy and 123 had unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio 1.19, 95% confidence interval 0.96 to 1.47; non-inferiority margin 1.314). In the per-protocol analysis of time to 12-month remission, valproate was superior to levetiracetam (hazard ratio 1.68, 95% confidence interval 1.30 to 2.15). Valproate was superior to levetiracetam for time to treatment failure (hazard ratio 0.65, 95% confidence interval 0.50 to 0.83). Adverse reactions were reported by 37.4% of participants receiving valproate and 41.5% of those receiving levetiracetam. Levetiracetam was both more costly (incremental cost of £104, 95% central range -£587 to £1234) and less effective (incremental quality-adjusted life-year of -0.035, 95% central range -0.137 to 0.032) than valproate, and was therefore dominated. At a cost-effectiveness threshold of £20,000 per quality-adjusted life-year, levetiracetam was associated with a probability of 0.17 of being cost-effective. LIMITATIONS: The SANAD II trial was unblinded, which could have biased results by influencing decisions about dosing, treatment failure and the attribution of adverse reactions. FUTURE WORK: SANAD II data could now be included in an individual participant meta-analysis of similar trials, and future similar trials are required to assess the clinical effectiveness and cost-effectiveness of other new treatments, including lacosamide and perampanel. CONCLUSIONS: Focal epilepsy - The SANAD II findings do not support the use of levetiracetam or zonisamide as first-line treatments in focal epilepsy. Generalised and unclassifiable epilepsy - The SANAD II findings do not support the use of levetiracetam as a first-line treatment for newly diagnosed generalised epilepsy. For women of childbearing potential, these results inform discussions about the benefit (lower teratogenicity) and harm (worse seizure outcomes and higher treatment failure rate) of levetiracetam compared with valproate. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30294119 and EudraCT 2012-001884-64. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 75. See the NIHR Journals Library website for further project information.

BACKGROUND AND METHODS: The SANAD II trial was a clinical trial designed to identify the most clinically effective and cost-effective treatment for adults and children aged > 5 years with newly diagnosed epilepsy. There are two main epilepsy types: focal and generalised. In focal epilepsy, seizures start at a single place in the brain (a focus), whereas in generalised epilepsy seizures start in both sides of the brain at the same time. Anti-seizure medications are the main treatment. For people with newly diagnosed epilepsy, the first anti-seizure medication should control the seizures as quickly as possible while avoiding side effects. The first-choice treatments are lamotrigine (Lamictal®, GlaxoSmithKline plc, Brentford, UK) for focal epilepsy and valproate (Epilim®, Sanofi SA, Paris, France) for generalised epilepsy (however, the latter should be avoided in women who could become pregnant). A number of newer anti-seizure medications have been approved for NHS use, but it is unclear whether or not they should be used as first-line treatments. The SANAD II trial focused on the new medicines levetiracetam (Keppra®, UCB Pharma Ltd, Slough, UK) and zonisamide (Zonegran®, Eisai Co. Ltd, Tokyo, Japan). We recruited 1510 people aged ≥ 5 years with newly diagnosed epilepsy: 990 with focal epilepsy and 520 with generalised or unclassified epilepsy. FINDINGS: FOCAL EPILEPSY: People starting treatment with levetiracetam or zonisamide were significantly less likely to have a 12-month remission from seizures than people starting treatment with lamotrigine, unless they were changed to another anti-seizure medication. Side effects that were thought to be caused by anti-seizure medications were reported by 33% of participants starting lamotrigine, 44% of those starting levetiracetam and 45% of those starting zonisamide. The cost-effectiveness analyses showed that neither levetiracetam nor zonisamide is value for money for the NHS when compared with lamotrigine. The SANAD II findings do not support the use of levetiracetam or zonisamide as first-line treatments in focal epilepsy. FINDINGS: GENERALISED AND UNCLASSIFIABLE EPILEPSY: People starting treatment with levetiracetam were significantly less likely to have a 12-month remission from seizures than people starting valproate, unless they were changed to another anti-seizure medication. Side effects that were thought to be caused by anti-seizure medications were reported by 37% of participants starting valproate and 42% of participants starting levetiracetam. The cost-effectiveness analyses showed that levetiracetam is not good value for money for the NHS when compared with valproate. The SANAD II findings do not support the use of levetiracetam as a first-line treatment for newly diagnosed generalised epilepsy. Importantly, our results will inform treatment decisions for women, who may choose a less effective treatment that is safer in pregnancy.

European Clinical Neuropsychology: Role in Healthcare and Access to Neuropsychological Services.

This study analyzed aspects of the work of clinical neuropsychologists across Europe. There are no published comparisons between European countries regarding the nature of clinical neuropsychologists' work. Forty-one national psychological and neuropsychological societies were approached, of which 31 (76%) responded. Data from seven countries with less than 10 neuropsychologists were excluded. A license is required to practice clinical neuropsychology in 50% of the countries. Clinical neuropsychologists work independently in 62.5%. Diagnostic/assessment work is the most frequently reported activity (54%). Most neuropsychologists work in public hospitals, followed by health centers. Adult neuropsychology was the most frequent area of activity. Services in public institutions are covered by public entities (45.8%), or by a combination of patient funds and public entities (29.2%) and only 4.2% by the patient; whereas services in private institutions are covered by the patient (26.1%) and the combination of patient, public entities (21.7%) or patient and private entities (17.4%). The data suggest that the number of neuropsychologists working across European countries is considerably low in comparison to other medical professionals. The results of the survey identified similar aspects of neuropsychologists' work, despite variations in terms of reimbursement and mechanisms, reflecting economic and healthcare differences. Estimates on the number of clinical neuropsychologists suggest insufficient access to neuropsychological services.

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

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

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

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

Clinical Neuropsychology as a Specialist Profession in European Health Care: Developing a Benchmark for Training Standards and Competencies Using the Europsy Model?

The prevalence and negative impact of brain disorders are increasing. Clinical Neuropsychology is a specialty dedicated to understanding brain-behavior relationships, applying such knowledge to the assessment of cognitive, affective, and behavioral functioning associated with brain disorders, and designing and implementing effective treatments. The need for services goes beyond neurological diseases and has increased in areas of neurodevelopmental and psychiatric conditions, among others. In Europe, a great deal of variability exists in the education and training of Clinical Neuropsychologists. Training models include master's programs, continuing education courses, doctoral programs, and/or post-doctoral specialization depending on the country, with no common framework of requirements, although patients' needs demand equal competencies across Europe. In the past 5 years, the Standing Committee on Clinical Neuropsychology of the European Federation of Psychologists' Association has conducted a series of surveys and interviews with experts in the field representing 30 European countries. The information, along with information from the existing literature, is used in presenting an overview of current and relevant topics related to policy and guidelines in the training and competencies in Clinical Neuropsychology. An option for the way forward is the EuroPsy Specialist Certificate, which is currently offered in Work and Organizational Psychology, and in psychotherapy. It builds upon the basic certificate and complements national standards without overriding them. General principles can be found that can set the basis for a common, solid, and comprehensive specialty education/training, sharpening the Neuropsychologists' competencies across Europe. The requirements in Clinical Neuropsychology should be comparable to those for the existing specialty areas in the EuroPsy model. Despite the perceived challenges, developing a specialist certificate appears a step forward for the development of Clinical Neuropsychology. Recommendations are proposed toward a shared framework of competencies by the means of a common level of education/training for the professionals in Europe. Benchmarking training standards and competencies across Europe has the potential of providing protection against unqualified and ethically questionable practice, creating transparency, raising the general European standard, and promoting mobility of both Clinical Neuropsychologists and patients in Europe, for the benefit of the professional field and the population.

Study protocol for a pragmatic randomised controlled trial comparing the effectiveness and cost-effectiveness of levetiracetam and zonisamide versus standard treatments for epilepsy: a comparison of standard and new antiepileptic drugs (SANAD-II).

INTRODUCTION: Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Over the past 20 years, a number of new drugs have been approved for National Health Service (NHS) use on the basis of information from short-term trials that demonstrate efficacy. These trials do not provide information about the longer term outcomes, which inform treatment policy. This trial will assess the long-term clinical and cost-effectiveness of the newer treatment levetiracetam and zonisamide. METHODS AND ANALYSIS: This is a phase IV, multicentre, open-label, randomised, controlled clinical trial comparing new and standard treatments for patients with newly diagnosed epilepsy. Arm A of the trial randomised 990 patients with focal epilepsy to standard AED lamotrigine or new AED levetiracetam or zonisamide. Arm B randomised 520 patients with generalised epilepsy to standard AED sodium valproate or new AED levetiracetam. Patients are recruited from UK NHS outpatient epilepsy, general neurology and paediatric clinics. Included patients are aged 5 years or older with two or more spontaneous seizures requiring AED monotherapy, who are not previously treated with AEDs. Patients are followed up for a minimum of 2 years. The primary outcome is time to 12-month remission from seizures. Secondary outcomes include time to treatment failure (including due to inadequate seizure control or unacceptable adverse reactions); time to first seizure; time to 24-month remission; adverse reactions and quality of life. All primary analyses will be on an intention to treat basis. Separate analyses will be undertaken for each arm. Health economic analysis will be conducted from the perspective of the NHS to assess the cost-effectiveness of each AED. ETHICS AND DISSEMINATION: This trial has been approved by the North West-Liverpool East REC (Ref. 12/NW/0361). The trial team will disseminate the results through scientific meetings, peer-reviewed publications and patient and public involvement. TRIAL REGISTRATION NUMBERS: EudraCT 2012-001884-64; ISRCTN30294119.

Effects of periconceptional folate on cognition in children of women with epilepsy: NEAD study.

OBJECTIVE: Emerging evidence suggests potential positive neuropsychological effects of periconceptional folate in both healthy children and children exposed in utero to antiseizure medications (ASMs). In this report, we test the hypothesis that periconceptional folate improves neurodevelopment in children of women with epilepsy by re-examining data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study. METHODS: The NEAD study was an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes in 311 children of 305 women with epilepsy treated with ASM monotherapy. Missing data points were imputed with Markov chain Monte Carlo methods. Multivariate analyses adjusted for multiple factors (e.g., maternal IQ, ASM type, standardized ASM dose, and gestational birth age) were performed to assess the effects of periconceptional folate on cognitive outcomes (i.e., Full Scale Intelligence Quotient [FSIQ], Verbal and Nonverbal indexes, and Expressive and Receptive Language indexes at 3 and 6 years of age, and executive function and memory function at 6 years of age). RESULTS: Periconceptional folate was associated with higher FSIQ at both 3 and 6 years of age. Significant effects for other measures included Nonverbal Index, Expressive Language Index, and Developmental Neuropsychological Assessment Executive Function at 6 years of age, and Verbal Index and Receptive Language Index at 3 years of age. Nonsignificant effects included Verbal Index, Receptive Index, Behavior Rating Inventory of Executive Function-Parent Questionnaire Executive Function, and General Memory Index at 6 years of age, and Nonverbal Index and Expressive Index at 3 years of age. CONCLUSIONS: Use of periconceptional folate in pregnant women with epilepsy taking ASMs is associated with better cognitive development. CLINICALTRIALSGOV IDENTIFIER: NCT00021866.

Investigating imaging network markers of cognitive dysfunction and pharmacoresistance in newly diagnosed epilepsy: a protocol for an observational cohort study in the UK.

INTRODUCTION: Epilepsy is one of the most common serious brain disorders, characterised by seizures that severely affect a person's quality of life and, frequently, their cognitive and mental health. Although most existing work has examined chronic epilepsy, newly diagnosed patients present a unique opportunity to understand the underlying biology of epilepsy and predict effective treatment pathways. The objective of this prospective cohort study is to examine whether cognitive dysfunction is associated with measurable brain architectural and connectivity impairments at diagnosis and whether the outcome of antiepileptic drug treatment can be predicted using these measures. METHODS AND ANALYSIS: 107 patients with newly diagnosed focal epilepsy from two National Health Service Trusts and 48 healthy controls (aged 16-65 years) will be recruited over a period of 30 months. Baseline assessments will include neuropsychological evaluation, structural and functional Magnetic Resonance Imaging (MRI), Electroencephalography (EEG), and a blood and saliva sample. Patients will be followed up every 6 months for a 24-month period to assess treatment outcomes. Connectivity- and network-based analyses of EEG and MRI data will be carried out and examined in relation to neuropsychological evaluation and patient treatment outcomes. Patient outcomes will also be investigated with respect to analysis of molecular isoforms of high mobility group box-1 from blood and saliva samples. ETHICS AND DISSEMINATION: This study was approved by the North West, Liverpool East Research Ethics Committee (19/NW/0384) through the Integrated Research Application System (Project ID 260623). Health Research Authority (HRA) approval was provided on 22 August 2019. The project is sponsored by the UoL (UoL001449) and funded by a UK Medical Research Council (MRC) research grant (MR/S00355X/1). Findings will be presented at national and international meetings and conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: IRAS Project ID 260623.

Indications and expectations for neuropsychological assessment in epilepsy surgery in children and adults.

In our first paper in this series (Epilepsia 2015; 56(5): 674-681), we published recommendations for the indications and expectations for neuropsychological assessment in routine epilepsy care. This partner paper provides a comprehensive overview of the more specialist role of neuropsychological assessment in the pre and postoperative evaluation of epilepsy surgery patients. The paper is in two parts. The first part presents the framework for the mandatory role of neuropsychologists in the presurgical evaluation of epilepsy surgery candidates. A preoperative neuropsychological assessment should be comprised of standardised measures of cognitive function in addition to wider measures of behavioural and psychosocial function. The results from the presurgical assessment are used to: (1) establish a baseline against which change can be measured following surgery; (2) provide a collaborative contribution to seizure characterization, lateralization and localization; (3) provide evidence-based predictions of cognitive risk associated with the proposed surgery; and (4) provide the evidence base for comprehensive preoperative counselling, including exploration of patient expectations of surgical treatment. The second part examines the critical role of the neuropsychologist in the evaluation of postoperative outcomes. Neuropsychological changes following surgery are dynamic and a comprehensive, long-term assessment of these changes following surgery should form an integral part of the postoperative follow-up. The special considerations with respect to pre and postoperative assessment when working with paediatric populations and those with an intellectual disability are also discussed. The paper provides a summary checklist for neuropsychological involvement throughout the epilepsy surgery process, based on the recommendations discussed.