Characterising people with focal drug-resistant epilepsy: A retrospective cohort study.

OBJECTIVES: To describe the demographics, clinical characteristics, drug treatment outcomes, healthcare resource utilization, and injuries among people with focal drug-resistant epilepsy (F-DRE) analysed separately for six European countries. METHODS: We used electronic medical record data from six European (Belgium, Spain, Italy, France, UK and Germany) primary care/specialist care databases to identify antiseizure medication (ASM) treatment-naïve people (aged ≥ 18 years at F-DRE diagnosis). They were followed from their epilepsy diagnosis until death, the date of last record available, or study end. We used descriptive analyses to characterise the F-DRE cohort, and results were reported by country. RESULTS: One-thousand-seventy individuals with F-DRE were included (mean age 52.5 years; 55.4 % female). The median follow-up time from the first diagnosis to the end of the follow-up was 95.5 months across all countries. The frequency of F-DRE diagnosis in 2021 ranged from 8.8 % in Italy to 18.2 % in Germany. Psychiatric disorders were the most common comorbidity across all countries. Frequently reported psychiatric disorders were depression (26.7 %) and anxiety (11.8 %). The median time from epilepsy diagnosis to the first ASM failure ranged from 5.9 (4.2-10.2) months in France to 12.6 (5.8-20.4) months in Spain. Levetiracetam and lamotrigine were the most commonly used ASM monotherapies in all countries. Consultation with a general practitioner is sought more frequently after F-DRE diagnosis than after epilepsy diagnosis, except in the UK. SIGNIFICANCE: No one ASM is optimal for all people with F-DRE, and the risks and benefits of the ASM must be considered. Comorbidities must be an integral part of the management strategy and drive the choice of drugs.

Alcohol and the central nervous system.

Ethanol use is common to most cultures but with varying doses and to varying extents. While research has focused on the effects on the liver, alcohol exerts a range of actions on the function and structure of the nervous system. In the central nervous system (CNS) it can provoke or exacerbate neurological and psychiatric disease; its effects on the peripheral nervous system are not included in this review. Sustained alcohol intake can predispose to acute neurochemical changes which, with continued ingestion and incomplete treatment, can lead to chronic structural changes in the CNS: these include generalised cortical and cerebellar atrophy, amnesic syndromes such as Korsakoff's syndrome, and specific white matter disorders such as central pontine myelinolysis and Marchiafava-Bignami syndrome. Alcohol in pregnancy commonly and significantly affects fetal health, though this receives less medical and political attention than other causes of fetal harm. This review looks at the range of disorders that can follow acute or chronic alcohol use, and how these should be managed, and we provide a practical overview on how neurologists might diagnose and manage alcohol addiction.

Enhancing departmental teaching in the digital age: as easy as 1-3-5.

We have recently introduced a new item to our neurology Grand Rounds-the '1-3-5 presentation'. The format comprises a presentation on one topic, using three slides and lasting no more than 5 minutes. This a useful way of covering brief single topics and introducing and sparking discussion on more complex ones. '1-3-5s' have proven popular in our department and we have compiled a library of these presentations that is hosted on a YouTube channel. This article discusses the benefits and prospects for this format and encourages other units to provide similar opportunities for teaching and learning among all clinical grades.

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 .

Delivery of care, seizure control and medication adherence in women with epilepsy during pregnancy.

PURPOSE: To evaluate service access for women with epilepsy (WWE) during pregnancy; to determine seizure frequency and rates of adherence to anti-seizure medication (ASM). METHODS: Between June 2019-June 2020, pregnant WWE within NHS Greater Glasgow and Clyde health-board were identified from the National Obstetric Register. A manual review of electronic patient records was undertaken to ensure diagnostic accuracy, as well as determine contact with epilepsy services and documented seizures. Medication dispensing records were obtained six months before and six months after midwifery booking and measures of ASM adherence calculated. RESULTS: Between June 2019-June 2020, 4592 women were registered with a pregnancy. Eighty-five (1.9%) were identified as having active epilepsy (generalised- 40/85 (47.0%), focal- 35/85 (41.2%), unclassified- 10/85 (11.8%)). Preconceptually, 42/85 WWE (49.4%) had input from epilepsy services. Only 59/85 (69.4%) were reviewed during pregnancy (First trimester- 21/59 (35.6%), Second trimester- 25/59 (42.4%) and Third trimester- 13/59 (22.0%)). Seizure occurrence was documented in 37/85 WWE (43.5%) during the antenatal/postnatal period. 71/85 WWE (83.5%) were prescribed ASM. Poor adherence was noted in 50/85 (58.9%) and a documented seizure recorded in 26/50 (52.0%) of these women. CONCLUSION: Too many WWE do not receive input from epilepsy services during pregnancy, leaving some with poor ASM adherence and continued seizures. We aim to use "near-live" obstetric and dispensing data to facilitate early identification of WWE, promoting timely access to epilepsy specialists. This will also provide an opportunity to address concerns regarding ASM safety and allow medication dose changes to be considered.

Impact of regulatory safety notices on valproate prescribing and pregnancy outcome among women of child-bearing potential in Scotland: a population-based cohort study.

OBJECTIVE: To examine the impact of Medicines and Healthcare products Regulatory Agency (MHRA) safety alerts on valproate prescribing among women aged 14-45 years in Scotland and examine trends in pregnancies exposed to valproate. DESIGN: Population-based cohort study. PARTICIPANTS: 21 983 women of all ages who received valproate between January 2011 and December 2019. METHODS: All valproate prescriptions issued to women in Scotland between January 2011 and December 2019 were identified and prevalence/incidence rates per 10 000 population derived. The impact of regulatory safety alerts on prescribing was analysed using Joinpoint models. Linked pregnancy records for January 2011 to September 2019 were identified and annual rates of pregnancy per 1000 valproate-treated women aged 14-45 years were calculated for each pregnancy outcome: live birth, stillbirth, miscarriage and termination. RESULTS: Annual prevalent and incident rates of valproate prescribing declined in women aged 14-45 years between 2011 and 2019 from 40.5 to 18.3 per 10 000 population (54.8% reduction) and 7.9 to 1.3 per 10 000 population (83.5% reduction), respectively. Statistically significant changes occurred around the times of the MHRA safety alerts. The number of valproate-exposed pregnancies conceived each year fell from 70 in 2011 to 20 in 2018, a 71.4% reduction, and the number of live births fell from 52 to 14, a 73.0% reduction. Expressed as a rate this was a 46.4% decrease from 15.3 to 8.2 per 1000 valproate-treated women aged 14-45 years in 2011 and 2018, respectively. Live birth was the most common pregnancy outcome. CONCLUSION: This study demonstrates, for the first time, the capabilities of national data sets to identify drug exposure and derive pregnancy outcome at scale across Scotland. Building on this as part of an evolving national/UK surveillance capability will continue efforts to minimise in-utero exposure to valproate; enabling ongoing surveillance to understand better long-term outcomes, and to inform better provision of health and wider support services.

Epilepsy and pregnancy: identifying risks.

Pregnancy is a time of physical, physiological and psychological challenge. For women with epilepsy, as well as its potential for joy and fulfilment, pregnancy may bring additional risks and difficulties. Clinicians must anticipate and prevent these complications, ensuring that pregnancy, delivery and motherhood proceed without obstetric or medical complications, using available evidence to balance individual risks of undertreatment and overtreatment. Here we review epilepsy management in pregnancy, identifying some of the known effects of epilepsy and its treatment on gestation, fetal malformation, delivery, and neurocognitive and behavioural development. We outline strategies to reduce obstetric and fetal complications in women with epilepsy, while recognising the sometimes competing need to maintain or improve seizure control. We reinforce the importance of identifying those at highest risk, who may require additional measures or safeguards.

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.

Measuring differential attainment: a longitudinal analysis of assessment results for 1512 medical students at four Scottish medical schools.

OBJECTIVE: To measure Differential Attainment (DA) among Scottish medical students and to explore whether attainment gaps increase or decrease during medical school. DESIGN: A retrospective analysis of undergraduate medical student performance on written assessment, measured at the start and end of medical school. SETTING: Four Scottish medical schools (universities of Aberdeen, Dundee, Edinburgh and Glasgow). PARTICIPANTS: 1512 medical students who attempted (but did not necessarily pass) final written assessment. MAIN OUTCOME MEASURES: The study modelled the change in attainment gap during medical school for four student demographical categories (white/non-white, international/Scottish domiciled, male/female and with/without a known disability) to test whether the attainment gap grew, shrank or remained stable during medical school. Separately, the study modelled the expected versus actual frequency of different demographical groups in the top and bottom decile of the cohort. RESULTS: The attainment gap grew significantly for white versus non-white students (t(449.39)=7.37, p=0.001, d=0.49 and 95% CI 0.34 to 0.58), for internationally domiciled versus Scottish-domiciled students (t(205.8) = -7, p=0.01, d=0.61 and 95% CI -0.75 to -0.42) and for male versus female students (t(1336.68)=3.54, p=0.01, d=0.19 and 95% CI 0.08 to 0.27). International, non-white and male students received higher marks than their comparison group at the start of medical school but lower marks by final assessment. No significant differences were observed for disability status. Students with a known disability, Scottish students and non-white students were over-represented in the bottom decile and under-represented in the top decile. CONCLUSIONS: The tendency for attainment gaps to grow during undergraduate medical education suggests that educational factors at medical schools may-however inadvertently-contribute to DA. It is of critical importance that medical schools investigate attainment gaps within their cohorts and explore potential underlying causes.

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.

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.

Managing epilepsy in Ramadan: Guidance for healthcare providers and patients.

Ramadan is a regularly recurring period of fasting that takes place in the ninth month of the Islamic calendar. For this period, adult Muslims refrain from eating and drinking between dawn and sunset. The variation in summer daylight hours means that at temperate latitudes, fasting can last up to 20 h. It is already recognized that epilepsy control can deteriorate during Ramadan, and this may be explained by fasting-related changes to adherence to antiseizure drug regimes. This article provides specific advice to help Muslim patients prepare for Ramadan and reduce chances of exacerbation in epilepsy. In addition to advice around sleep hygiene, it explores the use of drugs or preparations of drugs that will demonstrate reduced variation during periods of fasting.

Drug withdrawal in the epilepsy monitoring unit - The patsalos table.

Investigation of possible candidates for epilepsy surgery will usually require inpatient EEG to capture seizures and allow full operative planning. Withdrawal of antiepileptic drugs increases the yield of this valuable diagnostic information and the benefits of this should justify any increase in the risk of harm associated with these seizures This paper outlines our opinion on what would constitute proposed best practice for management of antiepileptic drug (AED) dosing when patients are admitted for monitoring of seizures to an epilepsy monitoring unit (EMU). In the vast majority of cases EMU admissions are safe and, even if seizures occur, will pass off without complication. Previous guidance has concentrated on ensuring practice around technical aspects of EEG monitoring itself and staffing within the unit. In this guidance we aim to outline optimally safe ways of ensuring that EMUs ensure the minimisation of risk to the patients admitted under their care. We propose an algorithm for enhancing the safety of AED withdrawal in VT admissions while ensuring adequate seizure yields. Risk minimisation requires planned management of drug dosing (with reduction if appropriate), provision of adequate rescue medication, and adequate supervision to allow rapid response to generalised seizures. This algorithm is accompanied by a table which uses knowledge of the clinical and pharmacological properties of each AED to ensure dose withdrawal and reduction is timely and safe taking into account the severity and frequency of the individual's seizures.

The view of the clinician and the scientist on the family experience of sudden epilepsy deaths.

A sudden epilepsy-associated death is a tragedy for the bereaved, a failure for the clinician and a challenge for a research scientist. Sudden death in epilepsy cannot be truly anticipated or prepared for by the bereaved, or the clinical team. Communications and provision of pastoral care following sudden unexpected death in epilepsy (SUDEP) is an important part of an epilepsy service where interaction with the family and specialist services for the bereaved can be rewarding. Sudden death and SUDEP are valid targets for research attention, but families may be less aware of opportunities to assist in life science research or conversely feel coerced at a vulnerable time. We have a responsibility to ensure that the SUDEP risk is minimized and that we maximize the learning potential from each death. Out of such tragedies some good must come, but this will take combined efforts from doctors, families, and the voluntary sector acting in league with scientific and academic funders. In this review, we set out to consider the dual viewpoints of the clinician and the scientist and how they consider the family experience of sudden deaths to provide advice for all parties. "This paper is for the Special Issue: Prevent 21: SUDEP Summit - Time to Listen".

Low serum magnesium and 1-year mortality in alcohol withdrawal syndrome.

BACKGROUND: In 2014, the WHO reported that 6% of all deaths were attributable to excess alcohol consumption. The aim of the present study was to examine the relationship between serum magnesium concentrations and mortality in patients with alcohol withdrawal syndrome (AWS). MATERIALS AND METHODS: A retrospective review of 700 patients with documented evidence of previous AWS indicating a requirement for benzodiazepine prophylaxis or evidence of alcohol withdrawal syndrome between November 2014 and March 2015. RESULTS: Of 380 patients included in the sample analysis, 64 (17%) were dead at 1 year following the time of treatment for AWS. The majority of patients had been prescribed thiamine (77%) and a proton pump inhibitor (66%). In contrast, the majority of patients had low circulating magnesium concentrations (<0.75 mmol/L) (64%) and had not been prescribed magnesium (90%). The median age of death at one year was 55 years (P = 0.002). On univariate analysis, age (P < 0.05), GMAWS (P < 0.05), BDZ (P < 0.05), bilirubin (P < 0.001), alkaline phosphatase (P < 0.001), albumin (P < 0.001), CRP (P < 0.05), AST:ALT ratio >2 (P < 0.001), sodium (P < 0.05), magnesium (P < 0.001), platelets (P < 0.05) and the use of proton pump inhibitor medication (P < 0.001) were associated with death at 1 year. On multivariate binary logistic regression analysis, age > 50 years (OR 3.37, 95% CI 1.52-7.48, P < 0.01), AST:ALT ratio >2 (OR 3.10, 95% CI 1.38-6.94, P < 0.01) and magnesium < 0.75 mmol/L (OR 4.11, 95% CI 1.3-12.8, P < 0.05) remained independently associated with death at 1 year. CONCLUSION: Overall, 1-year mortality was significantly higher among those patients who were magnesium deficient (<0.75 mmol/L) when compared to those who were replete (≥0.75 mmol/L; P < 0.001).

Hiding in Plain Sight: Functional Neurological Disorders in the News.

OBJECTIVE: Functional movement and seizure disorders are still widely misunderstood and receive little public and academic attention. This is in stark contrast to their high prevalence and levels of associated disability. In an exploratory observational study, the authors examined whether the relative lack of media coverage of functional neurological disorders is in part due to misidentification in "human interest" news stories. METHODS: Thirteen recent news stories from high-impact English-language media outlets that portrayed patients with complex symptoms either attributed to other diagnoses or presented as medical mysteries were identified using online keyword searches. All selected news stories contained video or still images displaying relevant symptoms. Cases were categorized into movement disorders or seizure disorders and were then independently assessed by 10 respective expert raters. For each category, one story of a patient whose symptoms were due to a well-recognized neurological disease was also included. Both the diagnostic category and the respective confidence level were reported by each rater for each case. The interrater agreement was calculated for each group of disorders. RESULTS: The raters confirmed almost unanimously that all presented news stories except the negative control cases portrayed misidentified functional movement or seizure disorders. The interrater agreement and average diagnostic confidence were high. CONCLUSIONS: Functional neurological disorders are often wrongly considered a rare medical curiosity of the past. However, these findings suggest that, while they are largely absent from public discourse, they often appear in the news incognito, hiding in plain sight.

Refractory status epilepticus in adults admitted to ITU in Glasgow 1995-2013 a longitudinal audit highlighting the need for action for provoked and unprovoked status epilepticus.

PURPOSE: Our primary objective was to determine incidence of status epilepticus in adults admitted to 5 ITU settings in Glasgow over 18 years. We wanted to investigate if there are any change in causes and outcomes of SE over last decade. We also compared outcomes of De Novo statuts Epilpeticus (DNSE) and Stauts Epilepticus in patients with previous Epilepsy (SEPE). METHODS: The NHS GGC Research Ethics Committee gave permission for this study to continue without a full ethics submission. Between 2013 and 2016, coding records were searched across NHS Greater Glasgow and Clyde for adults over the age of 16 years admitted to an Intensive Care Facility in any of the hospitals in Glasgow. RESULTS: 633 cases were included in study. Cases were separated depending on whether there had been previous epilepsy (SEPE n = 214) or De Novo Status Epilepticus (DNSE, n = 419). Causes in both groups were listed, with 52% of those with DNSE having some contribution from substance misuse. In SEPE, this was felt to play a role in 33.7%. Duration of stay in both groups was similar, but the longest in-patient stays were in the DNSE group. Admission mortality was significantly higher in DNSE than in SEPE (13.8% versus 7.5%). This mortality risk was most closely associated with substance misuse in the group with DNSE. CONCLUSION: DNSE has a worse prognosis than SEPE. A presentation with DNSE is sign of a system in peril, even where episodes are provoked by alcohol and or drug use. Such episodes should spark off a chain of multispecialty care in order to address this recurring and persisting public health catastrophe.