Tiagabine add‐on for drug‐resistant partial epilepsy

Cochrane Database Syst Rev. 2002;(3):CD001908. Tiagabine add-on for drug-resistant partial epilepsy. Pereira J, Marson AG, Hutton JL. Servico de Neurologia, Hospital de Santo Antonio, Largo Prof. Abel Salazar, 4099-001 Porto, Portugal. [email protected] Abstract BACKGROUND: Epilepsy is a common neurological condition, affecting almost 0.5 to 1 per cent of the population. Nearly 30 per cent of people with epilepsy are resistant to currently available drugs. Tiagabine is one of the newer antiepileptic drugs and its effects as an adjunct (add-on) to standard drugs is assessed in this review. OBJECTIVES: To evaluate the effects of add-on treatment with tiagabine upon seizures, side effects, cognition and quality of life for people with drug-resistant localization related seizures. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trials register (28 March 2002), the Cochrane Controlled Trials Register (Cochrane Library Issue 1, 2002), MEDLINE (1966 to November 2001). In addition, we contacted Sanofi~Synthelabo (makers of tiagabine) and experts in the field to seek any unpublished or ongoing studies. SELECTION CRITERIA: Randomized placebo controlled add-on trials of people of any age with localization related seizures, in which an adequate method of concealment of randomization was used. The studies could be double, single or unblinded and be of parallel or crossover design. They had to have a minimum treatment period of eight weeks. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted data. Any disagreements were resolved by discussion. Outcomes investigated included 50 per cent or greater reduction in seizure frequency; treatment withdrawal; side effects; effects on cognition and quality of life. The primary analyses were by intention-to-treat. Worst case and best case analyses were also calculated for seizure outcomes. Dose response was evaluated in regression models. MAIN RESULTS: Three parallel group and two crossover group trials were included. The overall relative risk (RR) for a 50 per cent or greater reduction in seizure frequency (tiagabine versus placebo) was 3.16(95% confidence interval 1.97 to 5.07). Due to differences in response rates among trials, regression models were unable to provide reliable estimates of responses to individual doses. The RR for treatment withdrawal was 1.81(95% confidence interval 1.25 to 2.62). The 99% confidence interval for the following side effects: dizziness; fatigue; nervousness and tremor did not include unity, indicating that they are significantly associated with tiagabine. For cognitive and quality of life outcomes the limited data available suggested that there were no significant effects on cognition and mood and adjustment. REVIEWER'S CONCLUSIONS: Tiagabine reduces seizures frequency but is associated with some side effects when used as an add-on for people with drug-resistant localization related seizures. PMID: 12137637 [PubMed - indexed for MEDLINE] Publication Types, MeSH Terms, SubstancesPublication Types: Review MeSH Terms: Anticonvulsants/adverse effects Anticonvulsants/therapeutic use* Drug Resistance Epilepsies, Partial/drug therapy* Humans Nipecotic Acids/adverse effects Nipecotic Acids/therapeutic use* Substances: Anticonvulsants Nipecotic Acids tiagabine LinkOut - more resource

'Seizure First Aid Training' for people with epilepsy who attend emergency departments, and their family and friends: study protocol for intervention development and a pilot randomised controlled trial.

INTRODUCTION: People with chronic epilepsy (PWE) often make costly but clinically unnecessary emergency department (ED) visits. Offering them and their carers a self-management intervention that improves confidence and ability to manage seizures may lead to fewer visits. As no such intervention currently exists, we describe a project to develop and pilot one. METHODS AND ANALYSIS: To develop the intervention, an existing group-based seizure management course that has been offered by the Epilepsy Society within the voluntary sector to a broader audience will be adapted. Feedback from PWE, carers and representatives from the main groups caring for PWE will help refine the course so that it addresses the needs of ED attendees. Its behaviour change potential will also be optimised. A pilot randomised controlled trial will then be completed. 80 PWE aged ≥16 who have visited the ED in the prior 12 months on ≥2 occasions, along with one of their family members or friends, will be recruited from three NHS EDs. Dyads will be randomised to receive the intervention or treatment as usual alone. The proposed primary outcome is ED use in the 12 months following randomisation. For the pilot, this will be measured using routine hospital data. Secondary outcomes will be measured by patients and carers completing questionnaires 3, 6 and 12 months postrandomisation. Rates of recruitment, retention and unblinding will be calculated, along with the ED event rate in the control group and an estimate of the intervention's effect on the outcome measures. ETHICS AND DISSEMINATION: Ethical approval: NRES Committee North West-Liverpool East (Reference number 15/NW/0225). The project's findings will provide robust evidence on the acceptability of seizure management training and on the optimal design of a future definitive trial. The findings will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: ISRCTN13 871 327

Seizure first aid training for people with Epilepsy (SAFE) frequently attending emergency departments and their significant others : results of a UK multi-centre randomised controlled pilot trial

Objective To determine the feasibility and optimal design of a randomised controlled trial (RCT) of Seizure First Aid Training For Epilepsy (SAFE). Design Pilot RCT with embedded microcosting. Setting Three English hospital emergency departments (EDs). Participants Patients aged ≥16 with established epilepsy reporting ≥2 ED visits in the prior 12 months and their significant others (SOs). Interventions Patients (and their SOs) were randomly allocated (1:1) to SAFE plus treatment-as-usual (TAU) or TAU alone. SAFE is a 4-hour group course. Main outcome measures Two criteria evaluated a definitive RCT’s feasibility: (1) ≥20% of eligible patients needed to be consented into the pilot trial; (2) routine data on use of ED over the 12 months postrandomisation needed securing for ≥75%. Other measures included eligibility, ease of obtaining routine data, availability of self-report ED data and comparability, SAFE’s effect and intervention cost. Results Of ED attendees with a suspected seizure, 424 (10.6%) patients were eligible; 53 (12.5%) patients and 38 SOs consented. Fifty-one patients (and 37 SOs) were randomised. Routine data on ED use at 12 months were secured for 94.1% patients. Self-report ED data were available for 66.7% patients. Patients reported more visits compared with routine data. Most (76.9%) patients randomised to SAFE received it and no related serious adverse events occurred. ED use at 12 months was lower in the SAFE+TAU arm compared with TAU alone, but not significantly (rate ratio=0.62, 95% CI 0.33 to 1.17). A definitive trial would need ~674 patient participants and ~39 recruitment sites. Obtaining routine data was challenging, taking ~8.5 months. Conclusions In satisfying only one predetermined ‘stop/go’ criterion, a definitive RCT is not feasible. The low consent rate in the pilot trial raises concerns about a definitive trial’s finding’s external validity and means it would be expensive to conduct. Research is required into how to optimise recruitment from the target population

A Caenorhabditis elegans assay of seizure-like activity optimised for identifying antiepileptic drugs and their mechanisms of action

BACKGROUND: Epilepsy affects around 1% of people, but existing antiepileptic drugs (AEDs) only offer symptomatic relief and are ineffective in approximately 30% of patients. Hence, new AEDs are sorely needed. However, a major bottleneck is the low-throughput nature of early-stage AED screens in conventional rodent models. This process could potentially be expedited by using simpler invertebrate systems, such as the nematode Caenorhabditis elegans. NEW METHOD: Head-bobbing convulsions were previously reported to be inducible by pentylenetetrazol (PTZ) in C. elegans with loss-of-function mutations in unc-49, which encodes a GABAA receptor. Given that epilepsy-linked mutations in human GABAA receptors are well documented, this could represent a clinically-relevant system for early-stage AED screens. However, the original agar plate-based assay is unsuited to large-scale screening and has not been validated for identifying AEDs. Therefore, we established an alternative streamlined, higher-throughput approach whereby mutants were treated with PTZ and AEDs via liquid-based incubation. RESULTS: Convulsions induced within minutes of PTZ exposure in unc-49 mutants were strongly inhibited by the established AED ethosuximide. This protective activity was independent of ethosuximide's suggested target, the T-type calcium channel, as a null mutation in the worm cca-1 ortholog did not affect ethosuximide's anticonvulsant action. COMPARISON WITH EXISTING METHOD: Our streamlined assay is AED-validated, feasible for higher throughput compound screens, and can facilitate insights into AED mechanisms of action. CONCLUSIONS: Based on an epilepsy-associated genetic background, this C. elegans unc-49 model of seizure-like activity presents an ethical, higher throughput alternative to conventional rodent seizure models for initial AED screens

Developing patient-centred, feasible alternative care for adult emergency department users with epilepsy : protocol for the mixed-methods observational ‘collaborate’ project

Introduction Emergency department (ED) visits for epilepsy are common, costly, often clinically unnecessary and typically lead to little benefit for epilepsy management. An ‘Alternative Care Pathway’ (ACP) for epilepsy, which diverts people with epilepsy (PWE) away from ED when ‘999’ is called and leads to care elsewhere, might generate savings and facilitate improved ambulatory care. It is unknown though what features it should incorporate to make it acceptable to persons from this particularly vulnerable target population. It also needs to be National Health Service (NHS) feasible. This project seeks to identify the optimal ACP configuration. Methods and analysis Mixed-methods project comprising three-linked stages. In Stage 1, NHS bodies will be surveyed on ACPs they are considering and semi-structured interviews with PWE and their carers will explore attributes of care important to them and their concerns and expectations regarding ACPs. In Stage 2, Discrete Choice Experiments (DCE) will be completed with PWE and carers to identify the relative importance placed on different care attributes under common seizure scenarios and the trade-offs people are willing to make. The uptake of different ACP configurations will be estimated. In Stage 3, two Knowledge Exchange workshops using a nominal group technique will be run. NHS managers, health professionals, commissioners and patient and carer representatives will discuss DCE results and form a consensus on which ACP configuration best meets users’ needs and is NHS feasible

Supporting the ambulance service to safely convey fewer patients to hospital by developing a risk prediction tool: Risk of Adverse Outcomes after a Suspected Seizure (RADOSS)—protocol for the mixed-methods observational RADOSS project

Introduction Ambulances services are asked to further reduce avoidable conveyances to emergency departments (EDs). Risk of Adverse Outcomes after a Suspected Seizure seeks to support this by: (1) clarifying the risks of conveyance and non-conveyance, and (2) developing a risk prediction tool for clinicians to use ‘on scene’ to estimate the benefits an individual would receive if conveyed to ED and risks if not. Methods and analysis Mixed-methods, multi-work package (WP) project. For WP1 and WP2 we shall use an existing linked data set that tracks urgent and emergency care (UEC) use of persons served by one English regional ambulance service. Risk tools are specific to clinical scenarios. We shall use suspected seizures in adults as an exemplar. WP1: Form a cohort of patients cared for a seizure by the service during 2019/2020. It, and nested Knowledge Exchange workshops with clinicians and service users, will allow us to: determine the proportions following conveyance and non-conveyance that die and/or recontact UEC system within 3 (/30) days; quantify the proportion of conveyed incidents resulting in ‘avoidable ED attendances’ (AA); optimise risk tool development; and develop statistical models that, using information available ‘on scene’, predict the risk of death/recontact with the UEC system within 3 (/30) days and the likelihood of an attendance at ED resulting in an AA. WP2: Form a cohort of patients cared for a seizure during 2021/2022 to ‘temporally’ validate the WP1 predictive models. WP3: Complete the ‘next steps’ workshops with stakeholders. Using nominal group techniques, finalise plans to develop the risk tool for clinical use and its evaluation. Ethics and dissemination WP1a and WP2 will be conducted under database ethical approval (IRAS 307353) and Confidentiality Advisory Group (22/CAG/0019) approval. WP1b and WP3 have approval from the University of Liverpool Central Research Ethics Committee (11450). We shall engage in proactive dissemination and knowledge mobilisation to share findings with stakeholders and maximise evidence usage

Erratum To: Quality Of Sweat Test (st) Based On The Proportion Of Sweat Sodium (na) And Sweat Chloride (cl) As Diagnostic Parameter Of Cystic Fibrosis: Are We On The Right Way?

During production of the original article [1] the Methods section included an incorrect sentence. The following sentence "For the analysis of variables with numerical distribution, Fisher's exact test and one-way analysis of variance were used" should be corrected as "For the analysis of variables with numerical distribution, Student's t-test and one-way analysis of variance were used". © The Author(s).12

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

ObjectiveGuidelines 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.MethodsWe 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.ResultsWe 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.SignificanceNo 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 SummaryUnderstanding 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.Paroxysmal Cerebral Disorder

Epilepsy and Pregnancy: For healthy pregnancies and happy outcomes. Suggestions for service improvements from the Multispecialty UK Epilepsy Mortality Group

Between 2009 and 2012 there were 26 epilepsy-related deaths in the UK of women who were pregnant or in the first post-partum year. The number of pregnancy-related deaths in women with epilepsy (WWE) has been increasing. Expert assessment suggests that most epilepsy-related deaths in pregnancy were preventable and attributable to poor seizure control. While prevention of seizures during pregnancy is important, a balance must be struck between seizure control and the teratogenic potential of antiepileptic drugs (AEDs). A range of professional guidance on the management of epilepsy in pregnancy has previously been issued, but little attention has been paid to how optimal care can be delivered to WWE by a range of healthcare professionals. We summarise the findings of a multidisciplinary meeting with representation from a wide group of professional bodies. This focussed on the implementation of optimal pregnancy epilepsy care aiming to reduce mortality of epilepsy in mothers and reduce morbidity in babies exposed to AEDs in utero. We identify in particular -What stage to intervene − Golden Moments of opportunities for improving outcomes -Which Key Groups have a role in making change -When − 2020 vision of what these improvements aim to achieve. -How to monitor the success in this field We believe that the service improvement ideas developed for the UK may provide a template for similar initiatives in other countries

Rare coding variants in genes encoding GABA(A) receptors in genetic generalised epilepsies : an exome-based case-control study

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABA(A) receptors and was compared to the respective GABA(A) receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABA(A) receptors in cases (odds ratio [OR] 2.40 [95% CI 1.41-4.10]; p(Nonsyn)=0.0014, adjusted p(Nonsyn)=0.019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1.46 [95% CI 1.05-2.03]; p(Nonsyn)=0.0081, adjusted p(Nonsyn)=0.016). Comparison of genes encoding GABA(A) receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABA(A) receptor genes in cases compared with controls (OR 1.46 [95% CI 1.02-2.08]; p(Nonsyn)=0.013, adjusted p(Nonsyn)=0.027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. Interpretation Functionally relevant variants in genes encoding GABA(A) receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.Peer reviewe