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Background: Idiopathic generalized epilepsy (IGE) is a collection of generalized nonlesional epileptic network disorders. Around 20-40% of patients with IGE are refractory to antiseizure medication, and mechanisms underlying refractoriness are poorly understood. Here, we characterize structural brain network alterations and determine whether network alterations differ between patients with refractory and nonrefractory IGE. Methods: Thirty-three patients with IGE (10 nonrefractory and 23 refractory) and 39 age- and sex-matched healthy controls were studied. Network nodes were segmented from T1-weighted images, while connections between these nodes (edges) were reconstructed from diffusion magnetic resonance imaging (MRI). Diffusion networks of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and streamline count (Count) were studied. Differences between all patients, refractory, nonrefractory, and control groups were computed using network-based statistics. Nodal volume differences between groups were computed using Cohen's d effect size calculation. Results: Patients had significantly decreased bihemispheric FA and Count networks and increased MD and RD networks compared with controls. Alterations in network architecture, with respect to controls, differed depending on treatment outcome, including predominant FA network alterations in refractory IGE and increased nodal volume in nonrefractory IGE. Diffusion MRI networks were not influenced by nodal volume. Discussion: Although a nonlesional disorder, patients with IGE have bihemispheric structural network alterations that may differ between patients with refractory and nonrefractory IGE. Given that distinct nodal volume and FA network alterations were observed between treatment outcome groups, a multifaceted network analysis may be useful for identifying imaging biomarkers of refractory IGE.

Monogenic epilepsies are rare but often severe. Because of their rarity, they are neglected by traditional drug developers. Hence, many lack effective treatments. Treatments for a disease can be discovered more quickly and economically by computationally predicting drugs that can be repurposed for it. We aimed to create a computational method to predict the efficacy of drugs for monogenic epilepsies, and to use the method to predict drugs for Dravet syndrome, as (1) it is the archetypal monogenic catastrophic epilepsy; (2) few antiseizure medications are efficacious in Dravet syndrome; and (3) predicting the effect of drugs on Dravet syndrome is challenging, because Dravet syndrome is typically caused by an SCN1A mutation, but some antiseizure medications that are efficacious in Dravet syndrome do not affect SCN1A, and some antiseizure medications that affect SCN1A aggravate seizures in Dravet syndrome.We have devised a computational method to predict drugs that could be repurposed for a monogenic epilepsy, based on a combined measure of drugs' effects upon (1) the function of the disease's causal gene and other genes predicted to influence its phenotype, (2) the transcriptomic dysregulation induced by the casual gene mutation, and (3) clinical phenotypes.Our method correctly predicts drugs that are more effective, less effective, ineffective, and aggravating for seizures in people with Dravet syndrome. Our method correctly predicts the positive "hits" from large-scale screening of compounds in an animal model of Dravet syndrome. We predict the relative efficacy of 1462 drugs. At least 38 drugs are ranked higher than one or more of the antiseizure drugs currently used for Dravet syndrome and have existing evidence of antiseizure efficacy in animal models.Our predictions are a novel resource for identifying new treatments for seizures in Dravet syndrome, and our method can be adapted for other monogenic epilepsies.

It is well established that abnormal thalamocortical systems play an important role in the generation and maintenance of primary generalised seizures. However, it is currently unknown which thalamic nuclei and how nuclear‐specific thalamocortical functional connectivity are differentially impacted in patients with medically refractory and non‐refractory idiopathic generalised epilepsy (IGE). In the present study, we performed structural and resting‐state functional magnetic resonance imaging (MRI) in patients with refractory and non‐refractory IGE, segmented the thalamus into constituent nuclear regions using a probabilistic MRI segmentation method and determined thalamocortical functional connectivity using seed‐to‐voxel connectivity analyses. We report significant volume reduction of the left and right anterior thalamic nuclei only in patients with refractory IGE. Compared to healthy controls, patients with refractory and non‐refractory IGE had significant alterations of functional connectivity between the centromedian nucleus and cortex, but only patients with refractory IGE had altered cortical connectivity with the ventral lateral nuclear group. Patients with refractory IGE had significantly increased functional connectivity between the left and right ventral lateral posterior nuclei and cortical regions compared to patients with non‐refractory IGE. Cortical effects were predominantly located in the frontal lobe. Atrophy of the anterior thalamic nuclei and resting‐state functional hyperconnectivity between ventral lateral nuclei and cerebral cortex may be imaging markers of pharmacoresistance in patients with IGE. These structural and functional abnormalities fit well with the known importance of thalamocortical systems in the generation and maintenance of primary generalised seizures, and the increasing recognition of the importance of limbic pathways in IGE., We report that patients with idiopathic generalised epilepsy have different patterns of thalamic structural and functional connectivity alterations depending on whether they are refractory or not to anti‐seizure medication. Only refractory patients showed evidence of atrophy of the anterior (limbic) thalamic nuclei and increased functional connectivity between the ventral lateral posterior nuclei and cortex bilaterally.

BACKGROUND Due to the COVID-19 pandemic, scientific congresses are increasingly being organised as virtual congresses. In May 2020, the European Academy of Neurology (EAN) held a VC, free-of-charge. In the absence of systematic studies on this topic, the aim of this study is to evaluate the attendance and perceived quality of the 2020 EAN virtual congress (VC) compared to the 2019 EAN face-to-face congress (FFC). METHODS Analysis of demographic data of participants obtained from the online registration collected. Comparison of the two congresses based on a survey with questions on the perception of speakers' performance, quality of networking, and other aspects. RESULTS Of 43,596 registered participants, 20,694 active participants attended the VC. Compared to 2019, the number of participants tripled (6916 in 2019) and the cumulated number of participants attending the sessions was five times higher (169,334 in 2020 vs 33,024 in 2019). Out of active participants 55% were from outside Europe, 42% were board-certified neurologists (FFC: 80%), and 21% were students (FFC: 0.6%). The content of the congress was evaluated as 'above expectation' by 56% of the attendees (FFC: 41%). Out of the respondents who had been exposed to earlier EAN congresses 73% preferred the FFC congress compared to the VC (17%). CONCLUSION The VC fulfilled the main mission of organizing high quality EAN congresses despite the restrictions of the impersonal format. The geographical distribution of the participants prove the expected higher inclusivity of a VC. The large participation of students and neurologists in training opens new educational potentials for the EAN.

Epileptic seizures are increasingly recognized as part of the clinical phenotype of patients with Alzheimer’s disease (AD). However, the evidence base on which to make treatment decisions for such patients is slim, there being no clear recommendation based on systematic review of the few existing studies of anti-seizure drugs in AD patients. Here the authors examine the potential implications for the treatment of seizures in AD of the results of the recently published SANAD II pragmatic study, which examined the effectiveness of levetiracetam, zonisamide, or lamotrigine in newly diagnosed focal epilepsy, and of valproate and levetiracetam in generalized and unclassifiable epilepsy.

Introduction: Systematic reviews (SR) and systematic reviews with meta-analysis (SRMA) can constitute the highest level of research evidence. Such evidence syntheses are relied upon heavily to inform the clinical knowledge base and to guide clinical practice for meningioma. This review evaluates the reporting and methodological quality of published meningioma evidence syntheses to date. Methods: Eight electronic databases/registries were searched to identify eligible meningioma SRs with and without meta-analysis published between January 1990 and December 2020. Articles concerning spinal meningioma were excluded. Reporting and methodological quality were assessed against the following tools: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), A MeaSurement Tool to Assess systematic Reviews (AMSTAR 2), and Risk Of Bias in Systematic reviews (ROBIS). Results: 116 SRs were identified, of which 57 were SRMAs (49.1%). The mean PRISMA score for SRMA was 20.9 out of 27 (SD 3.9, 77.0% PRISMA adherence) and for SR without meta-analysis was 13.8 out of 22 (SD 3.4, 63% PRISMA adherence). Thirty-eight studies (32.8%) achieved greater than 80% adherence to PRISMA. Methodological quality assessment against AMSTAR 2 revealed that 110 (94.8%) studies were of critically low quality. Only 21 studies (18.1%) were judged to have a low risk of bias against ROBIS. Conclusion: The reporting and methodological quality of meningioma evidence syntheses was poor. Established guidelines and critical appraisal tools may be used as an adjunct to aid methodological conduct and reporting of such reviews, in order to improve the validity and transparency of research which may influence clinical practice.

BackgroundPrevious neuroimaging studies reported functional and structural impairments of the upper basal ganglia (specifically, the striatum) in idiopathic generalised epilepsy (IGE). However, these studies often overlook lower basal ganglia structures located in and adjacent to the midbrain due to poor contrast on clinically acquired volumetric T1-weighted scans. Here, we acquired 3D isotropic T1-weighted, T2-weighted and resting state functional MR images to investigate differences in volume, estimated myelin content and functional connectivity in three midbrain and midbrain-adjacent structures in patients with IGE: the substantia nigra (SN), subthalamic nuclei (SubTN) and red nuclei (RN).MethodsA total of 33 patients with IGE (23 refractory, 10 non-refractory) and 39 age and sex matched healthy controls underwent MR imaging. The SN, SubTN and RN were automatically segmented from T2-weighted images. Estimated median myelin content for each structure was determined using a previously described T1-weighted/T2-weighted ratio method. Functional connectivity analysis between midbrain structures and the rest of the brain was performed using seed-based resting state fMRI analysis and compared between participant groups using the CONN toolbox running in SPM12 (pFDRResultsAn increased volume of the right RN was found in patients with IGE relative to healthy controls. Structural volumes of the right SubTN differed between patients with non-refractory and refractory IGE. No myelin alterations of midbrain structures were found in patients with IGE or between treatment outcome groups. Functional connectivity alterations were found for all midbrain regions in patients with IGE, including significantly decreased functional connectivity between the left SN and the thalamus compared to controls, and significantly increased functional connectivity observed between the right SubTN and the left superior frontal gyrus in patients with IGE relative to controls. Connectivity alterations specific to patients with non-refractory IGE were also found.ConclusionWe report volumetric and functional connectivity alterations of midbrain and lower basal ganglia structures in patients with IGE. We postulate that an increased structural volume of the RN in patients is due to increased iron deposition that impacts on T2-weighted contrast. These findings are consistent with previous experiential work demonstrating pathophysiological abnormalities of the lower basal ganglia in animal models of generalised epilepsy.

The Patient Information Leaflet (PIL) is an authoritative document that all people with epilepsy in the EU receive when prescribed antiseizure medication (ASM). We undertook the first independent, comprehensive assessment to determine how understandable they are. Regulators state that when patients are asked comprehension questions about them, ≥80% should answer correctly. Also, recommended is that PILs have a maximum reading requirement of US grade 8.Study 1: We obtained 140 current ASM PILs written in English. "Readability" was assessed using four tests, with and without adjustment for influence of familiar, polysyllabic words. A total of 179 online materials on epilepsy were also assessed. Study 2: Two PILs from Study 1 were randomly selected (Pregabalin Focus; Inovelon) and shown to 35 people from the UK epilepsy population. Their comprehension was assessed. Study 3: To understand whether the student population provides an accessible alternative population for future examination of ASM PILs, Study 3 was completed, using the same methods as Study 2, except that participants were 262 UK university students.Study 1: No PIL had a reading level of grade 8. Median was grade 11. Adjusting for context, the PILs were still at grade 10.5. PILs for branded ASMs were most readable. PILs were no more readable than (unregulated) online materials. Study 2: Users struggled to comprehend the PILs' key messages. The eight questions asked about pregabalin were typically answered correctly by 54%. For Inovelon, it was 62%. Study 3: Most student participants comprehended the PILs' key messages. The questions about Inovelon were answered correctly by 90%; for pregabalin it was 86%.This is the first independent and comprehensive examination of ASM PILs. It found that PILs being used fail to meet recommendations and regulatory requirements and risk not being understandable to a substantial proportion of users. In finding that people from the epilepsy population differ markedly in comprehension of PILs compared to students, this study highlights the importance of completing user testing with the target population.

Core Outcome Sets (COS) define minimum outcomes to be measured and reported in clinical effectiveness trials for a particular health condition/health area. Despite recognition as critical to clinical research design for other health areas, none have been developed for neuro-oncology. COS development projects should carefully consider: scope (how the COS should be used), stakeholders involved in development (including patients as both research partners and participants), and consensus methodologies used (typically a Delphi survey and consensus meeting), as well as dissemination plans. Developing COS for neuro-oncology is potentially challenging due to extensive tumor subclassification (including molecular stratification), different symptoms related to anatomical tumor location, and variation in treatment options. Development of a COS specific to tumor subtype, in a specific location, for a particular intervention may be too narrow and would be unlikely to be used. Equally, a COS that is applicable across a wider area of neuro-oncology may be too broad and therefore lack specificity. This review describes why and how a COS may be developed, and discusses challenges for their development, specific to neuro-oncology. The COS under development are briefly described, including: adult glioma, incidental/untreated meningioma, meningioma requiring intervention, and adverse events from surgical intervention for pediatric brain tumors.

IntroductionMeningioma is the most common primary intracranial tumour in adults. The majority are non-malignant, but a proportion behave more aggressively. Incidental/minimally symptomatic meningioma are often managed by serial imaging. Symptomatic meningioma, those that threaten neurovascular structures, or demonstrate radiological growth, are usually resected as first-line management strategy. For patients in poor clinical condition, or with inoperable, residual or recurrent disease, radiotherapy is often used as primary or adjuvant treatment. Effective pharmacotherapy treatments do not currently exist. There is heterogeneity in the outcomes measured and reported in meningioma clinical studies. Two ‘Core Outcome Sets’ (COS) will be developed: (COSMIC: Intervention) for use in meningioma clinical effectiveness trials and (COSMIC: Observation) for use in clinical studies of incidental/untreated meningioma.Methods and analysisTwo systematic literature reviews and trial registry searches will identify outcomes measured and reported in published and ongoing (1) meningioma clinical effectiveness trials, and (2) clinical studies of incidental/untreated meningioma. Outcomes include those that are clinician reported, patient reported, caregiver reported and based on objective tests (eg, neurocognitive tests), as well as measures of progression and survival. Outcomes will be deduplicated and categorised to generate two long lists. The two long lists will be prioritised through two, two-round, international, modified eDelphi surveys including patients with meningioma, healthcare professionals, researchers and those in caring/supporting roles. The two final COS will be ratified through two 1-day online consensus meetings, with representation from all stakeholder groups.Ethics and disseminationInstitutional review board (University of Liverpool) approval was obtained for the conduct of this study. Participant eConsent will be obtained prior to participation in the eDelphi surveys and consensus meetings. The two systematic literature reviews and two final COS will be published and freely available.Trial registration numberCOMET study ID 1508

Highlights • Model predicts risk of seizure recurrence after single fit or epilepsy diagnosis. • Model performs well in independent data. • Future work required to ensure the model is adopted in clinical practice. • Model can improve the lives of people with single seizures and early epilepsy., Purpose Following a single seizure, or recent epilepsy diagnosis, it is difficult to balance risk of medication side effects with the potential to prevent seizure recurrence. A prediction model was developed and validated enabling risk stratification which in turn informs treatment decisions and individualises counselling. Methods Data from a randomised controlled trial was used to develop a prediction model for risk of seizure recurrence following a first seizure or diagnosis of epilepsy. Time-to-event data was modelled via Cox's proportional hazards regression. Model validity was assessed via discrimination and calibration using the original dataset and also using three external datasets – National General Practice Survey of Epilepsy (NGPSE), Western Australian first seizure database (WA) and FIRST (Italian dataset of people with first tonic-clonic seizures). Results People with neurological deficit, focal seizures, abnormal EEG, not indicated for CT/MRI scan, or not immediately treated have a significantly higher risk of seizure recurrence. Discrimination was fair and consistent across the datasets (c-statistics: 0.555 (NGPSE); 0.558 (WA); 0.597 (FIRST)). Calibration plots showed good agreement between observed and predicted probabilities in NGPSE at one and three years. Plots for WA and FIRST showed poorer agreement with the model underpredicting risk in WA, and over-predicting in FIRST. This was resolved following model recalibration. Conclusion The model performs well in independent data especially when recalibrated. It should now be used in clinical practice as it can improve the lives of people with single seizures and early epilepsy by enabling targeted treatment choices and more informed patient counselling.

Aims Carbamazepine can cause hypersensitivity reactions in ~10% of patients. An immunogenic effect can be produced by the electrophilic 10,11-epoxide metabolite but not by carbamazepine. Hypothetically, certain single nucleotide polymorphisms might increase the formation of immunogenic metabolites, leading ultimately to hypersensitivity reactions. This study explores the role of clinical and genetic factors in the pharmacokinetics (PK) of carbamazepine and 3 metabolites known to be chemically reactive or formed through reactive intermediates. Methods A combination of rich and sparse PK samples were collected from healthy volunteers and epilepsy patients. All subjects were genotyped for 20 single nucleotide polymorphisms in 11 genes known to be involved in the metabolism or transport of carbamazepine and carbamazepine 10,11-epoxide. Nonlinear mixed effects modelling was used to build a population-PK model. Results In total, 248 observations were collected from 80 subjects. A 1-compartment PK model with first-order absorption and elimination best described the parent carbamazepine data, with a total clearance of 1.96 L/h, central distribution volume of 164 L and absorption rate constant of 0.45 h-1 . Total daily dose and coadministration of phenytoin were significant covariates for total clearance of carbamazepine. EPHX1-416G/G genotype was a significant covariate for the clearance of carbamazepine 10,11-epoxide. Conclusion Our data indicate that carbamazepine clearance was affected by total dose and phenytoin coadministration, but not by genetic factors, while carbamazepine 10,11-epoxide clearance was affected by a variant in the microsomal epoxide hydrolase gene. A much larger sample size would be required to fully evaluate the role of genetic variation in carbamazepine pharmacokinetics, and thereby predisposition to carbamazepine hypersensitivity.

Purpose Epilepsy is associated with costly unplanned health service use. The UK’s National Audits of Seizure Management in Hospital found use was often clinically unnecessary, avoidable and typically led to little benefit for epilepsy management. We systematically identified how services have responded to reduce such use. Methods We invited England’s ambulance services, neuroscience and neurology centres and a random sample of Emergency Departments (EDs) to complete a survey. It asked what innovations they (or services they worked with) had made in the past 5 years or were making, the priority afforded to them, user involvement, what comprised usual practice, and barriers to change. Results 72/87 of invited (82.8 %) services responded. EDs ascribed less priority to reducing emergency hospital use for epilepsy and convulsions, than other service types. Overall, 60 % of services reported a change(s) and/or were planning one. Neurology/neuroscience sites (93.8 %) were most likely to report change; EDs (15.4 %) least likely. Eleven types of change were identified; 5 sought to promote proactive epilepsy care and avert the need for emergency care; 3 focused on the care received from emergency services; and 3 focused on follow-up care ED attendees received. Most were for those with established, rather than new epilepsy and targeted known limitations to current care provision. Conclusion Reducing emergency hospital use by PWE is a high priority for most health services in England and a number of new services have been developed. However, they have not been consistently implemented and innovation is lacking in some areas of care.

Objective:\ud \ud Genetic variants in STXBP1 , which encodes the conserved exocytosis protein Munc18‐1, are associated with a variety of infantile epilepsy syndromes. We aimed to develop an in vivo Caenorhabditis elegans model that could be used to test the pathogenicity of such variants in a cost‐effective manner.\ud \ud Methods:\ud \ud The CRISPR/Cas9 method was used to introduce a null mutation into the unc‐18 gene (the C. elegans orthologue of STXBP1 ), thereby creating a paralyzed worm strain. We subsequently rescued this strain with transgenes encoding the human STXBP1/Munc18‐1 protein (wild‐type and eight different epilepsy‐associated missense variants). The resulting humanized worm strains were then analyzed via behavioral, electrophysiological, and biochemical approaches.\ud \ud Results:\ud \ud Transgenic expression of wild‐type human STXBP1 protein fully rescued locomotion in both solid and liquid media to the same level as the standard wild‐type worm strain, Bristol N2. Six variant strains (E59K, V84D, C180Y, R292H, L341P, R551C) exhibited impaired locomotion, whereas two (P335L, R406H) were no different from worms expressing wild‐type STXBP1. Electrophysiological recordings revealed that all eight variant strains displayed less frequent and more irregular pharyngeal pumping in comparison to wild‐type STXBP1‐expressing strains. Four strains (V84D, C180Y, R292H, P335L) exhibited pentylenetetrazol‐induced convulsions in an acute assay of seizure‐like activity, in contrast to worms expressing wild‐type STXBP1. No differences were seen between wild‐type and variant STXBP1 strains in terms of mRNA abundance. However, STXBP1 protein levels were reduced to 20%‐30% of wild‐type in all variants, suggesting that the mutations result in STXBP1 protein instability.\ud \ud Significance:\ud \ud The approach described here is a cost‐effective in vivo method for establishing the pathogenicity of genetic variants in STXBP1 and potentially other conserved neuronal proteins. Furthermore, the humanized strains we created could potentially be used in the future for high‐throughput drug screens to identify novel therapeutics.

BACKGROUND: This is an updated version of the Cochrane Review last published in Issue 7, 2019; it includes two additional studies. Epilepsy is a common neurological disease that affects approximately 1% of the UK population. Approximately one‐third of these people continue to have seizures despite drug treatment. Pregabalin is one of the newer antiepileptic drugs that has been developed to improve outcomes. In this review we summarised the current evidence regarding pregabalin when used as an add‐on treatment for drug‐resistant focal epilepsy. OBJECTIVES: To assess the efficacy and tolerability of pregabalin when used as an add‐on treatment for drug‐resistant focal epilepsy. SEARCH METHODS: For the latest update we searched the following databases on 16 November 2020: Cochrane Register of Studies (CRS Web), and MEDLINE (Ovid, 1946 to 16 November 2020). CRS Web includes randomised or quasi‐randomised, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organisation International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups, including Epilepsy. We imposed no language restrictions. We contacted the manufacturers of pregabalin and authors in the field to identify any relevant unpublished studies. SELECTION CRITERIA: We included randomised controlled trials comparing pregabalin with placebo or an alternative antiepileptic drug as an add‐on for people of any age with drug‐resistant focal epilepsy. Double‐blind and single‐blind trials were eligible for inclusion. The primary outcome was 50% or greater reduction in seizure frequency; secondary outcomes were seizure freedom, treatment withdrawal for any reason, treatment withdrawal due to adverse effects, and proportion of individuals experiencing adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted the relevant data. Primary analyses were intention‐to‐treat (ITT). We presented summary risk ratios (RRs) and odds ratios (ORs) with 95% confidence intervals (CIs). We evaluated dose response in regression models. We carried out a risk of bias assessment for each included study using the Cochrane risk of bias tool and assessed the overall certainty of evidence using the GRADE approach. MAIN RESULTS: We included 11 randomised controlled trials (3949 participants). Nine trials compared pregabalin to placebo. For the primary outcome, participants randomised to pregabalin were significantly more likely to attain a 50% or greater reduction in seizure frequency compared to placebo (RR 1.95, 95% CI 1.40 to 2.72, 9 trials, 2663 participants, low‐certainty evidence). The odds of response doubled with an increase in dose from 300 mg/day to 600 mg/day (OR 1.99, 95% CI 1.74 to 2.28), indicating a dose‐response relationship. Pregabalin was significantly associated with seizure freedom (RR 3.94, 95% CI 1.50 to 10.37, 4 trials, 1125 participants, moderate‐certainty evidence). Participants were significantly more likely to withdraw from pregabalin treatment than placebo for any reason (RR 1.33, 95% CI 1.10 to 1.60; 9 trials, 2663 participants; moderate‐certainty evidence) and for adverse effects (RR 2.60, 95% CI 1.86 to 3.64; 9 trials, 2663 participants; moderate‐certainty evidence). Three trials compared pregabalin to three active‐control drugs: lamotrigine, levetiracetam and gabapentin. Participants allocated to pregabalin were significantly more likely to achieve a 50% or greater reduction in seizure frequency than those allocated to lamotrigine (RR 1.47, 95% CI 1.03 to 2.12; 1 trial, 293 participants) but not those allocated to levetiracetam (RR 0.94, 95% CI 0.80 to 1.11; 1 trial, 509 participants) or gabapentin (RR 0.96, 95% CI 0.82 to 1.12; 1 trial, 484 participants). We found no significant differences between pregabalin and lamotrigine for seizure freedom (RR 1.39, 95% CI 0.40 to 4.83). However, significantly fewer participants achieved seizure freedom with add‐on pregabalin compared to levetiracetam (RR 0.50, 95% CI 0.30 to 0.85). No data were reported for this outcome for pregabalin versus gabapentin. We detected no significant differences in treatment withdrawal rate for any reason or due to adverse effects, specifically, during either pooled analysis or subgroup analysis. Ataxia, dizziness, somnolence, weight gain, headache and fatigue were significantly associated with pregabalin than in active control. We rated the overall risk of bias in the included studies as low or unclear due to the possibility of publication bias and lack of methodological details provided. We assessed all the studies to be at a high risk of funding bias as they were all sponsored by Pfizer. We rated the certainty of the evidence as very low to moderate using the GRADE approach. AUTHORS' CONCLUSIONS: For people with drug‐resistant focal epilepsy, pregabalin when used as an add‐on treatment was significantly more effective than placebo at producing a 50% or greater seizure reduction and seizure freedom. Results demonstrated efficacy for doses from 150 mg/day to 600 mg/day, with increasing effectiveness at 600 mg doses, although there were issues with tolerability at higher doses. However, the trials included in this review were of short duration, and longer‐term trials are needed to inform clinical decision‐making. This review focused on the use of pregabalin in drug‐resistant focal epilepsy, and the results cannot be generalised to add‐on treatment for generalised epilepsies. Likewise, no inference can be made about the effects of pregabalin when used as monotherapy.

Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial epilepsy syndrome characterized by distinctive phenotypic heterogeneity within families. The SCN1B c.363C>G (p.Cys121Trp) variant has been identified in independent, multi-generational families with GEFS+. Although the variant is present in population databases (at very low frequency), there is strong clinical, genetic, and functional evidence to support pathogenicity. Recurrent variants may be due to a founder event in which the variant has been inherited from a common ancestor. Here, we report evidence of a single founder event giving rise to the SCN1B c.363C>G variant in 14 independent families with epilepsy. A common haplotype was observed in all families, and the age of the most recent common ancestor was estimated to be approximately 800 years ago. Analysis of UK Biobank whole-exome-sequencing data identified 74 individuals with the same variant. All individuals carried haplotypes matching the epilepsy-affected families, suggesting all instances of the variant derive from a single mutational event. This unusual finding of a variant causing an autosomal dominant, early-onset disease in an outbred population that has persisted over many generations can be attributed to the relatively mild phenotype in most carriers and incomplete penetrance. Founder events are well established in autosomal recessive and late-onset disorders but are rarely observed in early-onset, autosomal dominant diseases. These findings suggest variants present in the population at low frequencies should be considered potentially pathogenic in mild phenotypes with incomplete penetrance and may be more important contributors to the genetic landscape than previously thought.

Currently no sensitive and specific biomarkers exist to predict drug-resistant epilepsy. We determined whether blood levels of high-mobility group box 1 (HMGB1), a mediator of neuroinflammation implicated in drug-resistant epilepsies, identifies patients with drug-resistant seizures. Patients with drug-resistant epilepsy express significantly higher levels of blood HMGB1 than those with drug-responsive, well-controlled seizures and healthy controls. No correlation existed between blood HMGB1 levels and total pretreatment seizure count or days since last seizure at new epilepsy diagnosis, indicating that blood HMGB1 does not solely reflect ongoing seizures. HMGB1 distinguishes with high specificity and selectivity drug-resistant versus drug-responsive patients. This protein therefore has potential clinical utility to act as a biomarker for predicting response to therapy, which should be addressed in prospective clinical studies.

Background This is an updated version of the original Cochrane Review published in 2014. Epilepsy is a common neurological condition characterised by recurrent seizures. Pharmacological treatment remains the first choice to control epilepsy. Sulthiame (STM) is widely used as an antiepileptic drug in Europe and Israel. In this review, we have presented a summary of evidence for the use of STM as monotherapy in epilepsy. Objectives To assess the efficacy and side effect profile of STM as monotherapy when compared with placebo or another antiepileptic drug for people with epilepsy. Search methods We searched the following databases on 13 April 2020: the Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 10 April 2020). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including Cochrane Epilepsy. We imposed no language restrictions. We contacted the manufacturers of STM and researchers in the field to ask about ongoing and unpublished studies. Selection criteria Randomised controlled monotherapy trials of STM in people of any age with epilepsy of any aetiology. Data collection and analysis We followed standard Cochrane methodology. Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: treatment withdrawal; seizure-free at six months; adverse effects; and quality of life scoring. We conducted the primary analyses by intention-to-treat where possible, and presented a narrative analysis of the data. Main results We included four studies involving a total of 355 participants: three studies (209 participants) with a diagnosis of benign epilepsy of childhood with centrotemporal spikes (BECTS), and one study (146 participants) with a diagnosis of generalised tonic-clonic seizures (GTCS). STM was given as monotherapy compared with placebo and with levetiracetam in the BECTS studies, and compared with phenytoin in the GTCS study. An English translation of the full text of one of the BECTS studies could not be found, and analysis of this study was based solely on the English translation of the abstract. For the primary outcome, the total number of dropouts caused either by seizure recurrence or adverse reaction was significantly higher in the levetiracetam treatment arm compared to the STM treatment arm (RR 0.32, 95% Cl 0.10 to 1.03; 1 study, 43 participants; low-certainty evidence). For the secondary outcomes for this comparison, results for seizure freedom were inconclusive (RR 1.12, 95% Cl 0.88 to 1.44; 1 study, 43 participants; low-certainty evidence). Reporting of adverse effects was incomplete. Participants receiving STM were significantly less likely to develop gingival hyperplasia than participants receiving phenytoin in the GTCS study (RR 0.03, 95% CI 0.00 to 0.58; 1 study, 146 participants; low-certainty evidence). No further statistically significant adverse events were noted when STM was compared with phenytoin or placebo. The most common adverse events were related to behavioural disturbances when STM was compared with levetiracetam (RR 0.95, 95% Cl 0.59 to 1.55; 1 study, 43 participants; low-certainty evidence), with the same incidence in both groups. No data were reported for quality of life. Overall, we assessed one study at high risk of bias and one study at unclear bias across the seven domains, mainly due to lack of information regarding study design. Only one trial reported effective methods for blinding. The risk of bias assessments for the other two studies ranged from low to high. We rated the overall certainty of the evidence for the outcomes as low using the GRADE approach. Authors' conclusions This review provides insufficient information to inform clinical practice. Small sample sizes, poor methodological quality, and lack of data on important outcome measures precluded any meaningful conclusions regarding the efficacy and tolerability of sulthiame as monotherapy in epilepsy. More trials, recruiting larger populations, over longer periods, are needed to determine whether sulthiame has a clinical use.

ObjectiveNeuroimaging research is providing insights into epilepsy as a disorder of brain connectivity linked to functional impairments which may have an identifiable genetic component. This case-control study aims to identify imbalances in a functional connectome dimension spanning from unimodal to transmodal networks and explore the potential genetic basis of such alterations in patients with newly diagnosed focal epilepsy (NDfE).MethodsWe used gradient-based analysis of resting-sate fMRI data comparing cortical gradient maps in patients with NDfE (n = 27) to age and sex-matched controls (n = 36). Using a brain-wide gene expression dataset, gene combinations associated with altered brain regions were then entered into an enrichment analysis.ResultsWe found an increased differentiation of connectivity profiles between unimodal and transmodal networks in NDfE, which was particularly pronounced in the patients with persistent seizures at 12-months follow-up (n=10). Differences corresponded to gradient score reductions in a visual network and increases in limbic and default mode systems which subserve higher-level cognition. Cortical difference maps were spatially correlated with regional expression of a weighted gene combination. These genes were enriched for disease and ontology terms and pathways previously associated with epilepsy and seizure susceptibility.InterpretationsLarge-scale functional hierarchy may be altered from in focal epilepsy from diagnosis and correlate with response to treatment. Combining functional neuroimaging and transcriptional data analysis may provide a framework for understanding the wide-ranging impairments associated with the disorder and mechanistic insight into how gene processes may drive alterations in brain function mediating the genetic risk of epilepsy.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the efficacy and tolerability of valproate when used as add‐on therapy for people with drug‐resistant focal epilepsy.

Background Routinely recorded data held in electronic health records can be used to inform the conduct of randomised controlled trials (RCTs). However, limitations with access and accuracy have been identified. Objective: Using epilepsy as an exemplar condition, we assessed the attributes and agreement of routinely recorded data compared to data collected using case report forms in a UK RCT assessing antiepileptic drug treatments for individuals newly diagnosed with epilepsy. Methods The case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK multicentre RCT assessing the clinical and cost-effectiveness of antiepileptic drugs as treatments for epilepsy. Ninety-eight of 470 eligible participants provided consent for access to routinely recorded secondary care data that were retrieved from NHS Digital Hospital Episode Statistics (N=71) and primary and secondary care data from The Secure Anonymised Information Linkage Databank (N=27). We assessed data items relevant to the identification of individuals eligible for inclusion in SANAD II, baseline and follow-up visits. The attributes of routinely recorded data were assessed including the degree of missing data. The agreement between routinely recorded data and data collected on case report forms in SANAD II was assessed using calculation of Cohen’s kappa for categorical data and construction of Bland-Altman plots for continuous data. Results There was a significant degree of missing data in the routine record for 15 of the 20 variables assessed, including all clinical variables. Agreement was poor for the majority of comparisons, including the assessments of seizure occurrence and adverse events. For example, only 23/62 (37%) participants had a date of first-ever seizure identified in routine datasets. Agreement was satisfactory for the date of prescription of antiepileptic drugs and episodes of healthcare resource use. Conclusions There are currently significant limitations preventing the use of routinely recorded data for participant identification and assessment of clinical outcomes in epilepsy, and potentially other chronic conditions. Further research is urgently required to assess the attributes, agreement, additional benefits, cost-effectiveness and ‘optimal mix’ of routinely recorded data compared to data collected using standard methods such as case report forms at clinic visits for people with epilepsy. Trial registration Standard and New Antiepileptic Drugs II (SANAD II (EudraCT No: 2012-001884-64, registered 05/09/2012; ISRCTN Number: ISRCTN30294119, registered 03/07/2012))

Better drugs are needed for common epilepsies. Drug repurposing offers the potential of significant savings in the time and cost of developing new treatments. In order to select the best candidate drug(s) to repurpose for a disease, it is desirable to predict the relative clinical efficacy that drugs will have against the disease. Common epilepsy can be divided into different types and syndromes. Different antiseizure medications are most effective for different types and syndromes of common epilepsy. For predictions of antiepileptic efficacy to be clinically translatable, it is essential that the predictions are specific to each form of common epilepsy, and reflect the patterns of drug efficacy observed in clinical studies and practice. These requirements are not fulfilled by previously published drug predictions for epilepsy. We developed a novel method for predicting the relative efficacy of drugs against any common epilepsy, by using its Genome-Wide Association Study summary statistics and drugs’ activity data. The methodological advancement in our technique is that the drug predictions for a disease are based upon drugs’ effects on the function and abundance of proteins, and the magnitude and direction of those effects, relative to the importance, degree and direction of the proteins’ dysregulation in the disease. We used this method to predict the relative efficacy of all drugs, licensed for any condition, against each of the major types and syndromes of common epilepsy. Our predictions are concordant with findings from real-world experience and randomized clinical trials. Our method predicts the efficacy of existing antiseizure medications against common epilepsies; in this prediction, our method outperforms the best alternative existing method: area under receiver operating characteristic curve (mean ± standard deviation) 0.83 ± 0.03 and 0.63 ± 0.04, respectively. Importantly, our method predicts which antiseizure medications are amongst the more efficacious in clinical practice, and which antiseizure medications are amongst the less efficacious in clinical practice, for each of the main syndromes of common epilepsy, and it predicts the distinct order of efficacy of individual antiseizure medications in clinical trials of different common epilepsies. We identify promising candidate drugs for each of the major syndromes of common epilepsy. We screen five promising predicted drugs in an animal model: each exerts a significant dose-dependent effect upon seizures. Our predictions are a novel resource for selecting suitable candidate drugs that could potentially be repurposed for each of the major syndromes of common epilepsy. Our method is potentially generalizable to other complex diseases., Mirza et al. develop and use a novel genomic method to predict the relative efficacy of drugs for each of the major types and syndromes of common epilepsy. This dataset is a novel and valuable resource for selecting the best candidate drug(s) to repurpose for these epilepsies., Graphical Abstract Graphical Abstract

Summary When developing a new medicine for children, the potential to extrapolate from adult efficacy data is well recognized. However, significant assumptions about the similarity of adults and children are needed for extrapolations to be biologically plausible. One such assumption is that of similar exposure–response (E–R-) relationships. Motivated by applications to antiepileptic drug development, we consider how data that are available from existing trials of adults and adolescents can be used to quantify prior uncertainty about whether E–R-relationships are similar in adults and younger children. A Bayesian multivariate meta-analytic model is fitted to existing E–R-data and adjusted for external biases that arise because these data are not perfectly relevant to the comparison of interest. We propose a strategy for eliciting expert prior opinion on external biases. From the bias-adjusted meta-analysis, we derive prior distributions quantifying our uncertainty about the degree of similarity between E–R-relationships for adults and younger children. Using these we calculate the prior probability that average pharmacodynamic responses in adults and younger children, both on placebo and at an effective concentration, are sufficiently similar to justify a complete extrapolation of efficacy data. A simulation study is performed to evaluate the operating characteristics of the approach proposed.

OBJECTIVE: Classification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks. METHODS: We used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes. RESULTS: A total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types. SIGNIFICANCE: Quantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.

Introduction Psychological interventions hold promise for the epilepsy population and continue to be trialed to determine their efficacy. Such interventions present opportunities for variance in delivery. Therefore, to accurately interpret a trial's estimate of effect, information on implementation fidelity (IF) is required. We present a novel 3-part study. Part 1 systematically rated trials for the extent to which they reported assessing whether the intervention was delivered as intended (adherence) and with what sort of skill (competence). Part 2 identified barriers to reporting and assessing on fidelity perceived by trialists. Part 3 determined what journals publishing epilepsy trials are doing to support IFs reporting. Methods Articles for 50 randomized controlled trials (RCTs)/quasi-RCTs of psychological interventions identified by Cochrane searches were rated using the Psychotherapy Outcome Study Methodology Rating Form's fidelity items. The 45 corresponding authors for the 50 trials were invited to complete the ‘Barriers to Treatment Integrity Implementation Survey’. ‘Instructions to Authors’ for the 17 journals publishing the trials were reviewed for endorsement of popular reporting guidelines which refer to fidelity (Consolidated Standards of Reporting Trials (CONSORT) statement or Journal Article Reporting Standards [JARS]) and asked how they enforced compliance. Results Part 1: 15 (30%) trials reported assessing for adherence, but only 2 (4.3%) gave the result. Four (8.5%) reported assessing for competence, 1 (2.1%) gave the result. Part 2: 22 trialists – mostly chief investigators – responded. They identified ‘lack of theory and specific guidelines on treatment integrity procedures’, ‘time, cost, and labor demands’, and ‘lack of editorial requirement’ as “strong barriers”. Part 3: Most (15, 88.2%) journals endorsed CONSORT or JARS, but only 5 enforced compliance. Conclusions Most trials of psychological interventions for epilepsy are not reported in a transparent way when it comes to IF. The barriers' trialists identify for this do not appear insurmountable. Addressing them could ultimately help the field to better understand how best to support the population with epilepsy.

The widening range of treatment options for epilepsy, and their potential outcomes, mean decisions about treatment for people with epilepsy (PWE) are often complex. While antiepileptic drugs (AEDs) represent the mainstay of treatment, other potential nondrug interventions are gaining in importance. These treatments all have the potential for harming those using them, as well as bringing benefits. This study examined the views and experiences of PWE about a range of treatment options. We used both qualitative and quantitative approaches - a series of depth-narrative interviews, followed by a large-scale survey. Treatment options and healthcare priorities deemed important by at least 10% of interview participants were then addressed as a series of statements in the follow-on survey questionnaire. Quantitative responses supported healthcare priorities identified through the qualitative interviews. The key goal of treatment among study participants was to be able to live 'a normal life'. Important physical, psychological, and life benefits of treatment were identified - most being the direct consequence of improved seizure control. One psychological benefit, reduced worry, was also identified as an important treatment goal. All participants viewed AEDs as appropriate first-line treatment; and since adverse effects of AEDs had implications for individual levels of daily function and wellbeing, their appropriate management was considered important. In contrast, surgery was almost always regarded as the treatment of last resort. Despite lack of research evidence supporting their use, participants were interested in complementary therapies as adjunctive treatment and a means of coping with having epilepsy, with yoga and meditation of particular interest. An important finding was the desire for targeted services to help with memory problems, as was the call to increase availability of psychological/counseling services. Our findings emphasize the importance of providing treatment responsive to the life context of individual patients. They highlight not only the level of demand for specific treatment options, but also the need for high-quality evidence to support future investment in their provision.

This protocol for a Cochrane Review is out of date and has been withdrawn in order to adhere to Cochrane policy.

Introduction The National Audit of Seizure Management in Hospitals (NASH) identified low referral rates to neurology and epilepsy services after an emergency department attendance or admission with a seizure. Methods National Health Service Secondary Users Service (SUS) data were used to assess the impact of a seizure pathway at seven hospitals in Cheshire & Merseyside, which was implemented in 2014. Three of these hospitals also had a nurse employed part-time to support the pathway. Patients admitted with a seizure between 2011 and 2018 inclusive were identified using an algorithm based on ICD-10 codes, and the primary outcome was a neurology referral within 3 months of admission. Regression models were used to assess the impact of age, deprivation and comorbidity on post admission clinic referral rates. Results 13,285 admissions with seizure were included in the analysis. 5,677 had not attended a neurology clinic appointment in the 12 months before the admission. The percentage of whom that were offered an appointment following the admission was: 16.0% before the pathway and 35.9% with the nurse-supported pathway, which was significant in the regression model. 4,700 admissions had attended a neurology clinic appointment in the 12 months before the admission. Of this group, the percentage of whom that were offered an appointment following the admission was: 55.2% before the pathway and 62.4% with the nurse-supported pathway, an increase that was not significant in the regression model. The regression models identified significant health inequalities whereby older patients, those with comorbidities and those living in deprived areas were significantly less likely to be referred. Conclusion Neurology out-patient appointment rates following an admission with seizures are low, worryingly so for those with no neurology appointment in the previous 12 months. A nurse-supported pathway can improve appointment rates, but the effect is modest. Further service redesign is required; the impact of which should be rigorously evaluated.

Objective: Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation.Methods: A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance.Results: We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs.Significance: This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale.

Multicompartment diffusion magnetic resonance imaging (MRI) approaches are increasingly being applied to estimate intra‐axonal and extra‐axonal diffusion characteristics in the human brain. Fiber ball imaging (FBI) and its extension fiber ball white matter modeling (FBWM) are such recently described multicompartment approaches. However, these particular approaches have yet to be applied in clinical cohorts. The modeling of several diffusion parameters with interpretable biological meaning may offer the development of new, noninvasive biomarkers of pharmacoresistance in epilepsy. In the present study, we used FBI and FBWM to evaluate intra‐axonal and extra‐axonal diffusion properties of white matter tracts in patients with longstanding focal epilepsy. FBI/FBWM diffusion parameters were calculated along the length of 50 white matter tract bundles and statistically compared between patients with refractory epilepsy, nonrefractory epilepsy and controls. We report that patients with chronic epilepsy had a widespread distribution of extra‐axonal diffusivity relative to controls, particularly in circumscribed regions along white matter tracts projecting to cerebral cortex from thalamic, striatal, brainstem, and peduncular regions. Patients with refractory epilepsy had significantly greater markers of extra‐axonal diffusivity compared to those with nonrefractory epilepsy. The extra‐axonal diffusivity alterations in patients with epilepsy observed in the present study could be markers of neuroinflammatory processes or a reflection of reduced axonal density, both of which have been histologically demonstrated in focal epilepsy. FBI is a clinically feasible MRI approach that provides the basis for more interpretive conclusions about the microstructural environment of the brain and may represent a unique biomarker of pharmacoresistance in epilepsy., Bryant et al. used fiber ball imaging to measure intra‐axonal and extra‐axonal white matter diffusion in patients with longstanding focal epilepsy. It is reported that extra‐axonal diffusion is different between patients with refractory and nonrefractory epilepsy and may represent a novel imaging biomarker of pharmacoresistance.

Summary Background The optimal invasive treatment for sciatica secondary to herniated lumbar disc remains controversial, with a paucity of evidence for use of non-surgical treatments such as transforaminal epidural steroid injection (TFESI) over surgical microdiscectomy. We aimed to investigate the clinical and cost-effectiveness of these options for management of radicular pain secondary to herniated lumbar disc. Methods We did a pragmatic, multicentre, phase 3, open-label, randomised controlled trial at 11 spinal units across the UK. Eligible patients were aged 16–65 years, had MRI-confirmed non-emergency sciatica secondary to herniated lumbar disc with symptom duration between 6 weeks and 12 months, and had leg pain that was not responsive to non-invasive management. Participants were randomly assigned (1:1) to receive either TFESI or surgical microdiscectomy by an online randomisation system that was stratified by centre with random permuted blocks. The primary outcome was Oswestry Disability Questionnaire (ODQ) score at 18 weeks. All randomly assigned participants who completed a valid ODQ at baseline and at 18 weeks were included in the analysis. Safety analysis included all treated participants. Cost-effectiveness was estimated from the EuroQol-5D-5L, Hospital Episode Statistics, medication usage, and self-reported resource-use data. This trial was registered with ISRCTN, number ISRCTN04820368, and EudraCT, number 2014-002751-25. Findings Between March 6, 2015, and Dec 21, 2017, 163 (15%) of 1055 screened patients were enrolled, with 80 participants (49%) randomly assigned to the TFESI group and 83 participants (51%) to the surgery group. At week 18, ODQ scores were 30·02 (SD 24·38) for 63 assessed patients in the TFESI group and 22·30 (19·83) for 61 assessed patients in the surgery group. Mean improvement was 24·52 points (18·89) for the TFESI group and 26·74 points (21·35) for the surgery group, with an estimated treatment difference of −4·25 (95% CI −11·09 to 2·59; p=0·22). There were four serious adverse events in four participants associated with surgery, and none with TFESI. Compared with TFESI, surgery had an incremental cost-effectiveness ratio of £38 737 per quality-adjusted life-year gained, and a 0·17 probability of being cost-effective at a willingness-to-pay threshold of £20 000 per quality-adjusted life-year. Interpretation For patients with sciatica secondary to herniated lumbar disc, with symptom duration of up to 12 months, TFESI should be considered as a first invasive treatment option. Surgery is unlikely to be a cost-effective alternative to TFESI. Funding Health Technology Assessment programme of the National Institute for Health Research (NIHR), UK.

BACKGROUND: Depressive disorders are the most common psychiatric comorbidity in patients with epilepsy, affecting around one‐third, with a significant negative impact on quality of life. There is concern that patients may not be receiving appropriate treatment for their depression because of uncertainty regarding which antidepressant or class works best and the perceived risk of exacerbating seizures. This review aims to address these issues and inform clinical practice and future research. OBJECTIVES: We aimed to review and synthesise evidence from randomised controlled trials of antidepressants and prospective non‐randomised studies of antidepressants used for treating depression in patients with epilepsy. The primary objectives were to evaluate the efficacy and safety of antidepressants in treating depressive symptoms and the effect on seizure recurrence. SEARCH METHODS: We conducted a search of the following databases: the Cochrane Epilepsy Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 5), MEDLINE (Ovid), SCOPUS, PsycINFO, www.clinicaltrials.gov and conference proceedings, including studies published up to 31 May 2014. There were no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and prospective non‐randomised cohort controlled and uncontrolled studies investigating children or adults with epilepsy treated with an antidepressant for depressive symptoms. The intervention group consisted of patients receiving an antidepressant drug in addition to an existing antiepileptic drug regimen. The control group(s) consisted of patients receiving a placebo, comparative antidepressant, psychotherapy or no treatment in addition to an existing antiepileptic drug regimen. DATA COLLECTION AND ANALYSIS: We extracted data on trial design factors, patient demographics and outcomes for each study. The primary outcomes were changes in depression scores (proportion with a greater than 50% improvement or mean difference) and change in seizure frequency (mean difference or proportion with a seizure recurrence or episode of status epilepticus, or both). Secondary outcomes included the number of patients withdrawing from the study and reasons for withdrawal, as well as any adverse events. Two authors undertook data extraction separately for each included study. We then cross‐checked the data extraction. We assessed risk of bias using a version of the extended Cochrane Collaboration tool for assessing risk of bias in both randomised and non‐randomised studies. We presented binary outcomes as risk ratios (RRs) with 95% confidence intervals (CIs). We presented continuous outcomes as standardised mean differences (SMDs) with 95% CIs, and mean differences (MDs) with 95% CIs. If possible we intended to use meta‐regression techniques to investigate possible sources of heterogeneity however this was not possible due to lack of data. MAIN RESULTS: We included in the review eight studies (three RCTs and five prospective cohort studies) including 471 patients with epilepsy treated with an antidepressant. The RCTs were all single‐centre studies comparing an antidepressant versus active control, placebo or no treatment. The five non‐randomised prospective cohort studies reported on outcomes mainly in patients with partial epilepsy treated for depression with a selective serotonin reuptake inhibitor (SSRI). We rated all the RCTs and one prospective cohort study as having unclear risk of bias. We rated the four other prospective cohort studies as having high risk of bias. We were unable to perform any meta‐analysis for the proportion with a greater than 50% improvement in depression scores because the studies reported on different treatment comparisons. The results are presented descriptively and show a varied responder rate of between 24% and 97%, depending on the antidepressant given. For the mean difference in depression score we were able to perform a limited meta‐analysis of two prospective cohort studies of citalopram, including a total of 88 patients. This gave low quality evidence for the effect estimate of 1.17 (95% CI 0.96 to 1.38) in depression scores. Seizure frequency data were not reported in any RCTs and we were unable to perform any meta‐analysis for prospective cohort studies due to the different treatment comparisons. The results are presented descriptively and show that treatment in three studies with a selective serotonin reuptake inhibitor did not significantly increase seizure frequency. Patients given an antidepressant were more likely to withdraw due to adverse events than inefficacy. Reported adverse events for SSRIs included nausea, dizziness, sedation, gastrointestinal disturbance and sexual dysfunction. Across three comparisons we rated the evidence as moderate quality due to the small sizes of the contributing studies and only one study each contributing to the comparisons. We rated the evidence for the final comparison as low quality as there was concern over the study methods in the two contributing studies. AUTHORS' CONCLUSIONS: Existing evidence on the effectiveness of antidepressants in treating depressive symptoms associated with epilepsy is very limited. Only one small RCT demonstrated a statistically significant effect of venlafaxine on depressive symptoms. We have no high quality evidence to inform the choice of antidepressant drug or class of drug in treating depression in people with epilepsy. This review provides low quality evidence of safety in terms of seizure exacerbation with SSRIs, but there are no available comparative data on antidepressant classes and safety in relation to seizures. There are currently no comparative data on antidepressants and psychotherapy in treating depression in epilepsy, although psychotherapy could be considered in patients unwilling to take antidepressants or where there are unacceptable side effects. Further comparative clinical trials of antidepressants and psychotherapy in large cohorts of patients with epilepsy and depression are required to better inform treatment policy in the future.