COVID-19 response in a long-term care facility for people with epilepsy.

OBJECTIVE: To assess asymptomatic rates and severity of SARS-CoV-2 infection in people with epilepsy and their healthcare workers in a long-term care facility which had implemented weekly surveillance testing between April 2020 and June 2022. METHODS: Questionnaires focused on objective and subjective COVID-19 symptoms for people with epilepsy residing in and their healthcare workers at the Chalfont Centre for Epilepsy in June 2022. Demographic information, comorbidities, and seizure frequency were gathered from medical records. We also collected responses on objective and subjective COVID-19 symptoms from healthcare workers who participated in a prospective study assessing the reaction to COVID-19 vaccinations (SAFER). RESULTS: Fifty-five out of 89 (62%) residents tested positive at least once on weekly PCR testing for SARS-CoV-2 during the period of interest; 20 of those (37%) were asymptomatic. In comparison, of those 63 healthcare workers who tested positive at least once on weekly testing during the same period, only four (6%) were asymptomatic. Of the 159 healthcare workers who also participated in the SAFER study, 41 tested positive at least once, and seven (17%) were completely asymptomatic during infection with SARS-CoV-2. SIGNIFICANCE: People with epilepsy living in a long-term care facility were more likely to present with asymptomatic SARS-CoV-2 infections than healthcare workers at the same facility. Despite possible bias in the reporting of subjective symptoms due to management-by-proxy, there is no evidence that vulnerable people living in an epilepsy long-term care facility showed reduced resilience towards infections. PLAIN LANGUAGE SUMMARY: People with epilepsy living in care home facilities had a surprisingly high degree of asymptomatic infections with SARS-CoV-2. Very few residents had severe or fatal outcomes. This is in stark contrast to the widely reported bad outcomes for people without epilepsy in other care homes. People with epilepsy reported significantly less symptoms than their healthcare workers. No changes in seizure frequency during or after infection were observed.

Mood disorders in adults with epilepsy: a review of unrecognized facts and common misconceptions.

Epilepsy is one of the most common neurologic conditions. Its clinical manifestations are not restricted to seizures but often include cognitive disturbances and psychiatric disorders. Prospective population-based studies have shown that people with epilepsy have an increased risk of developing mood disorders, and people with a primary mood disorder have an increased risk of developing epilepsy. The existence of common pathogenic mechanisms in epilepsy and mood disorders may explain the bidirectional relation between these two conditions. Recognition of a personal and family psychiatric history at the time of evaluation of people for a seizure disorder is critical in the selection of antiseizure medications: those with mood-stabilizing properties (e.g., lamotrigine, oxcarbazepine) should be favoured as a first option in those with a positive history while those with negative psychotropic properties (e.g., levetiracetam, topiramate) avoided. While mood disorders may be clinically identical in people with epilepsy, they often present with atypical manifestations that do not meet ICD or DSM diagnostic criteria. Failure to treat mood disorders in epilepsy may have a negative impact, increasing suicide risk and iatrogenic effects of antiseizure medications and worsening quality of life. Treating mood disorders in epilepsy is identical to those with primary mood disorders. Yet, there is a common misconception that antidepressants have proconvulsant properties. Most antidepressants are safe when prescribed at therapeutic doses. The incidence of seizures is lower in people randomized to antidepressants than placebo in multicenter randomized placebo-controlled trials of people treated for a primary mood disorder. Thus, there is no excuse not to prescribe antidepressant medications to people with epilepsy.

Quality indicators for epilepsy management in China: The development of a tool to assess care and first three-year report.

OBJECTIVES: Epilepsy care in China has expanded considerably in the last decade but still remains largely unknown; we developed an easy-to-use tool to assess its quality. METHODS: We adapted the Epilepsy Update Quality Measurement, produced by the American Academy of Neurology (AAN) for use in China: The Quality Indicator for Epilepsy Treatment-China National Action (QUIET-CHINA). This tool incorporates a standardized case report form initially for logging quality indicators for people with epilepsy during in-patient stays. Nine quality indicators covered seizures, drugs, diagnostics, screening for co-morbid conditions, counseling for woman of child bearing age, and a composite indicator was further proposed by total number of interventions performed divided by the total number of people eligible in each indicator. The tool also has an electronic reporting and data feedback system. 96 epilepsy centers in 31 jurisdictions in mainland China have been piloted since 2017. RESULTS: Data from 11,600 individuals with epilepsy in the first 3-year study period were analyzed. The median age was 31; 60% were male. The composite indicators were 74%. Seizure freedom rate was less than 25% in all epilepsy types and post-surgical seizure freedom rate was 21%. 90% had seizure type and frequency, antiepileptic drugs recorded, while only 70% with active epilepsy were on regular antiepileptic drugs treatment. Investigations for diagnosis and etiology were performed in around 90% but screening for co-morbid conditions and counseling for women of childbearing potential was 38% and 15% respectively. Severe side effect happened in 2% individuals during the treatment. CONCLUSION: The preliminary results of the national action provided some baseline information. Except for an overall improvement, a significant treatment gap still exists, and psychiatric co-morbidities or issues affecting women are not seen as a priority. QUIET-CHINA will be expanded to more and other levels of hospitals, to help narrow the treatment gap and equalize the comprehensive epilepsy care on the national level.

Magnetic resonance imaging findings in Kenyans and South Africans with active convulsive epilepsy: An observational study.

OBJECTIVE: Focal epilepsy is common in low- and middle-income countries. The frequency and nature of possible underlying structural brain abnormalities have, however, not been fully assessed. METHODS: We evaluated the possible structural causes of epilepsy in 331 people with epilepsy (240 from Kenya and 91 from South Africa) identified from community surveys of active convulsive epilepsy. Magnetic resonance imaging (MRI) scans were acquired on 1.5-Tesla scanners to determine the frequency and nature of any underlying lesions. We estimated the prevalence of these abnormalities using Bayesian priors (from an earlier pilot study) and observed data (from this study). We used a mixed-effect modified Poisson regression approach with the site as a random effect to determine the clinical features associated with neuropathology. RESULTS: MRI abnormalities were found in 140 of 240 (modeled prevalence = 59%, 95% confidence interval [CI]: 53%-64%) of people with epilepsy in Kenya, and in 62 of 91 (modeled prevalence = 65%, 95% CI: 57%-73%) in South Africa, with a pooled modeled prevalence of 61% (95% CI: 56%-66%). Abnormalities were common in those with a history of adverse perinatal events (15/23 [65%, 95% CI: 43%-84%]), exposure to parasitic infections (83/120 [69%, 95% CI: 60%-77%]) and focal electroencephalographic features (97/142 [68%, 95% CI: 60%-76%]), but less frequent in individuals with generalized electroencephalographic features (44/99 [44%, 95% CI: 34%-55%]). Most abnormalities were potentially epileptogenic (167/202, 82%), of which mesial temporal sclerosis (43%) and gliosis (34%) were the most frequent. Abnormalities were associated with co-occurrence of generalized non-convulsive seizures (relative risk [RR] = 1.12, 95% CI: 1.04-1.25), lack of family history of seizures (RR = 0.91, 0.86-0.96), convulsive status epilepticus (RR = 1.14, 1.08-1.21), frequent seizures (RR = 1.12, 1.04-1.20), and reported use of anti-seizure medication (RR = 1.22, 1.18-1.26). SIGNIFICANCE: MRI identified pathologies are common in people with epilepsy in Kenya and South Africa. Mesial temporal sclerosis, the most common abnormality, may be amenable to surgical correction. MRI may have a diagnostic value in rural Africa, but future longitudinal studies should examine the prognostic role.

Neurological complications during the Omicron COVID-19 wave in China: A cohort study.

BACKGROUND AND PURPOSE: The aim was to investigate the neurological complications associated with coronavirus disease 19 (COVID-19) during the 2022 Omicron wave. METHODS AND ANALYSIS: The medical records of a cohort of people admitted to neurological wards of three participating tertiary centres in Sichuan from 12 December 2022 to 12 January 2023 were reviewed. Demographics and clinical data were obtained and analysed with an interest in COVID-19-related new-onset or worse neurological symptoms. The current data were also compared in two centres with similar data from the same period 12 months earlier. RESULTS: In all, 790 people were enrolled, of whom 436 were positive for COVID-19. Ninety-nine had new onset COVID-related neurological problems, or their known neurological condition deteriorated during the wave. There was a significant difference in demographics from the findings amongst admissions 12 months earlier as there was an increase in the average age, the incidence of encephalitis and encephalopathy, and mortality rates. One hundred and one received COVID-specific antivirals, intravenous glucocorticoids and intravenous immunoglobulin therapy. No differences were seen between these and those who did not use them. CONCLUSION: New-onset neurological conditions, particularly encephalitis and encephalopathy, increased significantly during this period. Deterioration of existing neurological conditions, such as seizure exacerbation, was also observed. A large-scale treatment trial of people with COVID-19 infection presenting with neurological disorders is still needed.

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.

Identification of different MRI atrophy progression trajectories in epilepsy by subtype and stage inference.

Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. Here we analyse a cross-sectional multicentre structural MRI dataset of 696 people with epilepsy and 118 control subjects. We use an innovative machine-learning algorithm, Subtype and Stage Inference, to develop a novel data-driven disease taxonomy, whereby epilepsy subtypes correspond to distinct patterns of spatiotemporal progression of brain atrophy.In a discovery cohort of 814 individuals, we identify two subtypes common to focal and idiopathic generalized epilepsies, characterized by progression of grey matter atrophy driven by the cortex or the basal ganglia. A third subtype, only detected in focal epilepsies, was characterized by hippocampal atrophy. We corroborate external validity via an independent cohort of 254 people and confirm that the basal ganglia subtype is associated with the most severe epilepsy.Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualized prognostics and targeted therapeutics.

Validation of the Georgian version of a Stigma Scale of Epilepsy.

INTRODUCTION: Stigma Scale of Epilepsy (SSE), initially developed in Brazil, is accepted worldwide as a sensitive tool for assessing epilepsy-related stigma. We adapted and validated a Georgian version of SSE. MATERIALS AND METHODS: The SSE originated in Brazil and was translated into Georgian by three independent experts through forward and backward translation. The final version was generated for validation after handling gross or conceptual inconsistencies between the source and the new format. We used Cronbach's alpha to assess the internal consistency of the Georgian version of SSE. To explore the construct of SSE subscales in the Georgian version, we used principal components and factor analysis. Varimax rotation was applied. The Kaiser-Meyer-Olkin Measure and Bartlett's test of sphericity were employed to assess the sampling adequacy. A probability <0.05 was considered statistically significant. RESULTS: 87 adults, 32 (37 %) with epilepsy and 55 (63 %) without epilepsy were enrolled. The overall mean score of SSE was 19.5 (SD 10.1; min. 2, max. 53), and the differences between people with [20.7 (SD 8.9; min. 2, max. 53)] and without epilepsy [17.5 (SD 10.4; min. 3, max. 42)] were not statistically significant. Cronbach's alpha for the overall sample was 0.854; for the epilepsy cohort it was 0.876, and for individuals without epilepsy 0.823, indicating good SSE internal consistency. Kaiser-Meyer-Olkin Measure was 0.705 and Bartlett's test of sphericity was 926.2 (df 276; p < 0.001), suggesting acceptable sample adequacy. DISCUSSION: The Georgian version of the SSE is a valid and reliable measurement tool for assessing epilepsy-related stigma determinants among the country's population.

Implementing WHO's Intersectoral Global Action Plan for epilepsy and other neurological disorders in Southeast Asia: a proposal.

The World Health Assembly approved the Intersectoral Global Action Plan for epilepsy and neurological disorders. Member states, including those in Southeast Asia, must now prepare to achieve IGAP's strategic targets by embracing novel approaches and strengthening existing policies and practices. We propose and present evidence to support four such processes. The opening course should engage all stakeholders to develop people-centric instead of outcome-centric approaches. Rather than caring for convulsive epilepsy alone, as currently done, primary care providers should also be skilled in diagnosing and treating focal and non-motor seizures. This could reduce the diagnostic gap as over half of epilepsies present with focal seizures. Currently, primary care providers lack knowledge and skills to manage focal seizures. Technology-enabled aids can help overcome this limitation. Lastly, there is need to add newer "easy to use" epilepsy medicines to Essential Medicines lists in light of emerging evidence for better tolerability, safety and user-friendliness.

Association of Mortality and Risk of Epilepsy With Type of Acute Symptomatic Seizure After Ischemic Stroke and an Updated Prognostic Model.

Importance: Acute symptomatic seizures occurring within 7 days after ischemic stroke may be associated with an increased mortality and risk of epilepsy. It is unknown whether the type of acute symptomatic seizure influences this risk. Objective: To compare mortality and risk of epilepsy following different types of acute symptomatic seizures. Design, Setting, and Participants: This cohort study analyzed data acquired from 2002 to 2019 from 9 tertiary referral centers. The derivation cohort included adults from 7 cohorts and 2 case-control studies with neuroimaging-confirmed ischemic stroke and without a history of seizures. Replication in 3 separate cohorts included adults with acute symptomatic status epilepticus after neuroimaging-confirmed ischemic stroke. The final data analysis was performed in July 2022. Exposures: Type of acute symptomatic seizure. Main Outcomes and Measures: All-cause mortality and epilepsy (at least 1 unprovoked seizure presenting >7 days after stroke). Results: A total of 4552 adults were included in the derivation cohort (2547 male participants [56%]; 2005 female [44%]; median age, 73 years [IQR, 62-81]). Acute symptomatic seizures occurred in 226 individuals (5%), of whom 8 (0.2%) presented with status epilepticus. In patients with acute symptomatic status epilepticus, 10-year mortality was 79% compared with 30% in those with short acute symptomatic seizures and 11% in those without seizures. The 10-year risk of epilepsy in stroke survivors with acute symptomatic status epilepticus was 81%, compared with 40% in survivors with short acute symptomatic seizures and 13% in survivors without seizures. In a replication cohort of 39 individuals with acute symptomatic status epilepticus after ischemic stroke (24 female; median age, 78 years), the 10-year risk of mortality and epilepsy was 76% and 88%, respectively. We updated a previously described prognostic model (SeLECT 2.0) with the type of acute symptomatic seizures as a covariate. SeLECT 2.0 successfully captured cases at high risk of poststroke epilepsy. Conclusions and Relevance: In this study, individuals with stroke and acute symptomatic seizures presenting as status epilepticus had a higher mortality and risk of epilepsy compared with those with short acute symptomatic seizures or no seizures. The SeLECT 2.0 prognostic model adequately reflected the risk of epilepsy in high-risk cases and may inform decisions on the continuation of antiseizure medication treatment and the methods and frequency of follow-up.

Transcranial magnetic stimulation-evoked electroencephalography responses as biomarkers for epilepsy: A review of study design and outcomes.

Transcranial magnetic stimulation (TMS) with electroencephalography (EEG), that is TMS-EEG, may assist in managing epilepsy. We systematically reviewed the quality of reporting and findings in TMS-EEG studies on people with epilepsy and healthy controls, and on healthy individuals taking anti-seizure medication. We searched the Cochrane Library, Embase, PubMed and Web of Science databases for original TMS-EEG studies comparing people with epilepsy and healthy controls, and healthy subjects before and after taking anti-seizure medication. Studies should involve quantitative analyses of TMS-evoked EEG responses. We evaluated the reporting of study population characteristics and TMS-EEG protocols (TMS sessions and equipment, TMS trials and EEG protocol), assessed the variation between protocols, and recorded the main TMS-EEG findings. We identified 20 articles reporting 14 unique study populations and TMS methodologies. The median reporting rate for the group of people with epilepsy parameters was 3.5/7 studies and for the TMS parameters was 13/14 studies. TMS protocols varied between studies. Fifteen out of 28 anti-seizure medication trials in total were evaluated with time-domain analyses of single-pulse TMS-EEG data. Anti-seizure medication significantly increased N45, and decreased N100 and P180 component amplitudes but in marginal numbers (N45: 8/15, N100: 7/15, P180: 6/15). Eight articles compared people with epilepsy and controls using different analyses, thus limiting comparability. The reporting quality and methodological uniformity between studies evaluating TMS-EEG as an epilepsy biomarker is poor. The inconsistent findings question the validity of TMS-EEG as an epilepsy biomarker. To demonstrate TMS-EEG clinical applicability, methodology and reporting standards are required.

Development and validation of a diagnostic aid for convulsive epilepsy in sub-Saharan Africa: a retrospective case-control study.

BACKGROUND: Identification of convulsive epilepsy in sub-Saharan Africa relies on access to resources that are often unavailable. Infrastructure and resource requirements can further complicate case verification. Using machine-learning techniques, we have developed and tested a region-specific questionnaire panel and predictive model to identify people who have had a convulsive seizure. These findings have been implemented into a free app for health-care workers in Kenya, Uganda, Ghana, Tanzania, and South Africa. METHODS: In this retrospective case-control study, we used data from the Studies of the Epidemiology of Epilepsy in Demographic Sites in Kenya, Uganda, Ghana, Tanzania, and South Africa. We randomly split these individuals using a 7:3 ratio into a training dataset and a validation dataset. We used information gain and correlation-based feature selection to identify eight binary features to predict convulsive seizures. We then assessed several machine-learning algorithms to create a multivariate prediction model. We validated the best-performing model with the internal dataset and a prospectively collected external-validation dataset. We additionally evaluated a leave-one-site-out model (LOSO), in which the model was trained on data from all sites except one that, in turn, formed the validation dataset. We used these features to develop a questionnaire-based predictive panel that we implemented into a multilingual app (the Epilepsy Diagnostic Companion) for health-care workers in each geographical region. FINDINGS: We analysed epilepsy-specific data from 4097 people, of whom 1985 (48·5%) had convulsive epilepsy, and 2112 were controls. From 170 clinical variables, we initially identified 20 candidate predictor features. Eight features were removed, six because of negligible information gain and two following review by a panel of qualified neurologists. Correlation-based feature selection identified eight variables that demonstrated predictive value; all were associated with an increased risk of an epileptic convulsion except one. The logistic regression, support vector, and naive Bayes models performed similarly, outperforming the decision-tree model. We chose the logistic regression model for its interpretability and implementability. The area under the receiver operator curve (AUC) was 0·92 (95% CI 0·91-0·94, sensitivity 85·0%, specificity 93·7%) in the internal-validation dataset and 0·95 (0·92-0·98, sensitivity 97·5%, specificity 82·4%) in the external-validation dataset. Similar results were observed for the LOSO model (AUC 0·94, 0·93-0·96, sensitivity 88·2%, specificity 95·3%). INTERPRETATION: On the basis of these findings, we developed the Epilepsy Diagnostic Companion as a predictive model and app offering a validated culture-specific and region-specific solution to confirm the diagnosis of a convulsive epileptic seizure in people with suspected epilepsy. The questionnaire panel is simple and accessible for health-care workers without specialist knowledge to administer. This tool can be iteratively updated and could lead to earlier, more accurate diagnosis of seizures and improve care for people with epilepsy. FUNDING: The Wellcome Trust, the UK National Institute of Health Research, and the Oxford NIHR Biomedical Research Centre.

KCNH2 variants in a family with epilepsy and long QT syndrome: A case report and literature review.

OBJECTIVE: Genes associated with Long QT syndromes (LQTS), such as KCNQ1, KCNH2, and SCN5A, are common causes of epilepsy. The Arg 744* variant of KCNH2 has been previously reported in people with epilepsy or LQTS, but none of these patients were reported to simultaneously suffer from epilepsy and LQTS. Herein, we report the case of a family with epilepsy and cardiac disorders. METHOD: The proband, a 25-year-old woman, with a family history of epilepsy and LQTS was followed at West China Hospital. The proband experienced her first seizure at the age of seven. Video electroencephalograms (vEEGs) showed epileptic discharges. Her 24-h dynamic electrocardiograms 2 (ECGs) showed QTc prolongation. The proband's mother, who is 50 years old, had her first generalized tonic-clonic seizure (GTCS) at the age of 18 years old. After she gave birth at the age of 25, the frequency of seizures increased, so antiepileptic therapy was initiated. When she was 28 years old, she complained of palpitations and syncope for the first time, and QTc prolongation was detected on her 24-h dynamic ECGs. The proband's grandmother also had complaints of palpitations and syncope at the age of 73. Her 24-h dynamic ECGs indicated supraventricular arrhythmia, with the lowest heart rate being 41 bpm, so she agreed to a pacemaker. Considering the young patient's family history, blood samples of the patient and her parents were collected for genetic analysis. RESULTS: A heterozygous variant of KCNH2 [c.2230 (exon9) C>T, p. Arg744Ter, 416, NM_000238, rs189014161] was found in the proband and her mother. According to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, we classified the KCNH2 variant as pathogenic. SIGNIFICANCE: This study expands the clinical phenotype of the Arg 744* KCNH2 pathogenic variant. In the context of channelopathies, because of the genetic susceptibility of the brain and the heart, the risk of comorbidity should be considered. This also indicates the importance of precise antiepileptic drug (AED) management and regular ECG monitoring for patients with channelopathies.

TMS-evoked EEG potentials demonstrate altered cortical excitability in migraine with aura.

Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine.We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses.Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters.This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements.

Cost-effectiveness of cenobamate for focal seizures in people with drug-resistant epilepsy.

OBJECTIVE: This study was undertaken to estimate the cost-effectiveness of add-on cenobamate in the UK when used to treat drug-resistant focal seizures in adults who are not adequately controlled with at least two prior antiseizure medications, including at least one used adjunctively. METHODS: We estimated the cost per quality-adjusted life-year (QALY) for cenobamate compared to brivaracetam, eslicarbazepine, lacosamide, and perampanel in the UK National Health Service over a lifetime time horizon. We used a Markov cohort structure to determine response to treatment, using pooled data from three long-term studies of cenobamate. A network meta-analysis informed the likelihood of response to therapy with brivaracetam, eslicarbazepine, lacosamide, and perampanel relative to cenobamate. Once individuals discontinued treatment, they transitioned to subsequent treatment health states, including other antiseizure medicines, surgery, and vagus nerve stimulation. Costs included treatment, administration, routine monitoring, event management, and adverse events. Published evidence and expert opinion informed the likelihood of response to subsequent treatments, associated adverse events, and costs. Utility data were based on Short-Form six-dimension form utility. Discounting was applied at 3.5% per annum as per National Institute for Health and Care Excellence guidance. Uncertainty was explored through deterministic and probabilistic sensitivity analyses. RESULTS: In the base case, cenobamate led to cost savings of £51 967 (compared to brivaracetam), £21 080 (compared to eslicarbazepine), £33 619 (compared to lacosamide), and £28 296 (compared to perampanel) and increased QALYs of 1.047 (compared to brivaracetam), 0.598 (compared to eslicarbazepine), 0.776 (compared to lacosamide), and 0.703 (compared to perampanel) per individual over a lifetime time horizon. Cenobamate also dominated the four drugs across most sensitivity analyses. Differences were due to reduced seizure frequency with cenobamate relative to comparators. SIGNIFICANCE: Cenobamate improved QALYs and was less costly than brivaracetam, eslicarbazepine, lacosamide, and perampanel. Therefore, cenobamate may be considered as a cost-effective adjunctive antiseizure medication for people with drug-resistant focal seizures.

Prognosis of adults and children following a first unprovoked seizure.

BACKGROUND: Epilepsy is clinically defined as two or more unprovoked epileptic seizures more than 24 hours apart. Given that, a diagnosis of epilepsy can be associated with significant morbidity and mortality, it is imperative that clinicians (and people with seizures and their relatives) have access to accurate and reliable prognostic estimates, to guide clinical practice on the risks of developing further unprovoked seizures (and by definition, a diagnosis of epilepsy) following single unprovoked epileptic seizure. OBJECTIVES: 1. To provide an accurate estimate of the proportion of individuals going on to have further unprovoked seizures at subsequent time points following a single unprovoked epileptic seizure (or cluster of epileptic seizures within a 24-hour period, or a first episode of status epilepticus), of any seizure type (overall prognosis). 2. To evaluate the mortality rate following a first unprovoked epileptic seizure. SEARCH METHODS: We searched the following databases on 19 September 2019 and again on 30 March 2021, with no language restrictions. The Cochrane Register of Studies (CRS Web), MEDLINE Ovid (1946 to March 29, 2021), SCOPUS (1823 onwards), ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). CRS Web includes randomized or quasi-randomized, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. In MEDLINE (Ovid) the coverage end date always lags a few days behind the search date. SELECTION CRITERIA: We included studies, both retrospective and prospective, of all age groups (except those in the neonatal period (< 1 month of age)), of people with a single unprovoked seizure, followed up for a minimum of six months, with no upper limit of follow-up, with the study end point being seizure recurrence, death, or loss to follow-up. To be included, studies must have included at least 30 participants. We excluded studies that involved people with seizures that occur as a result of an acute precipitant or provoking factor, or in close temporal proximity to an acute neurological insult, since these are not considered epileptic in aetiology (acute symptomatic seizures). We also excluded people with situational seizures, such as febrile convulsions. DATA COLLECTION AND ANALYSIS: Two review authors conducted the initial screening of titles and abstracts identified through the electronic searches, and removed non-relevant articles. We obtained the full-text articles of all remaining potentially relevant studies, or those whose relevance could not be determined from the abstract alone and two authors independently assessed for eligibility. All disagreements were resolved through discussion with no need to defer to a third review author. We extracted data from included studies using a data extraction form based on the checklist for critical appraisal and data extraction for systematicreviews of prediction modelling studies (CHARMS). Two review authors then appraised the included studies, using a standardised approach based on the quality in prognostic studies (QUIPS) tool, which was adapted for overall prognosis (seizure recurrence). We conducted a meta-analysis using Review Manager 2014, with a random-effects generic inverse variance meta-analysis model, which accounted for any between-study heterogeneity in the prognostic effect. We then summarised the meta-analysis by the pooled estimate (the average prognostic factor effect), its 95% confidence interval (CI), the estimates of I² and Tau² (heterogeneity), and a 95% prediction interval for the prognostic effect in a single population at three various time points, 6 months, 12 months and 24 months. Subgroup analysis was performed according to the ages of the cohorts included; studies involving all ages, studies that recruited adult only and those that were purely paediatric. MAIN RESULTS: Fifty-eight studies (involving 54 cohorts), with a total of 12,160 participants (median 147, range 31 to 1443), met the inclusion criteria for the review. Of the 58 studies, 26 studies were paediatric studies, 16 were adult and the remaining 16 studies were a combination of paediatric and adult populations. Most included studies had a cohort study design with two case-control studies and one nested case-control study. Thirty-two studies (29 cohorts) reported a prospective longitudinal design whilst 15 studies had a retrospective design whilst the remaining studies were randomised controlled trials. Nine of the studies included presented mortality data following a first unprovoked seizure. For a mortality study to be included, a proportional mortality ratio (PMR) or a standardised mortality ratio (SMR) had to be given at a specific time point following a first unprovoked seizure. To be included in the meta-analysis a study had to present clear seizure recurrence data at 6 months, 12 months or 24 months. Forty-six studies were included in the meta-analysis, of which 23 were paediatric, 13 were adult, and 10 were a combination of paediatric and adult populations. A meta-analysis was performed at three time points; six months, one year and two years for all ages combined, paediatric and adult studies, respectively. We found an estimated overall seizure recurrence of all included studies at six months of 27% (95% CI 24% to 31%), 36% (95% CI 33% to 40%) at one year and 43% (95% CI 37% to 44%) at two years, with slightly lower estimates for adult subgroup analysis and slightly higher estimates for paediatric subgroup analysis. It was not possible to provide a summary estimate of the risk of seizure recurrence beyond these time points as most of the included studies were of short follow-up and too few studies presented recurrence rates at a single time point beyond two years. The evidence presented was found to be of moderate certainty. AUTHORS' CONCLUSIONS: Despite the limitations of the data (moderate-certainty of evidence), mainly relating to clinical and methodological heterogeneity we have provided summary estimates for the likely risk of seizure recurrence at six months, one year and two years for both children and adults. This provides information that is likely to be useful for the clinician counselling patients (or their parents) on the probable risk of further seizures in the short-term whilst acknowledging the paucity of long-term recurrence data, particularly beyond 10 years.

Verbal fluency functional magnetic resonance imaging detects anti-seizure effects and affective side effects of perampanel in people with focal epilepsy.

Perampanel, a noncompetitive antagonist of the postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor, is effective for controlling focal to bilateral tonic-clonic seizures but is also known to increase feelings of anger. Using statistical parametric mapping-derived measures of activation and task-modulated functional connectivity (psychophysiologic interaction), we investigated 14 people with focal epilepsy who had verbal fluency functional magnetic resonance imaging (fMRI) twice, before and after the add-on treatment of perampanel. For comparison, we included 28 people with epilepsy, propensity-matched for clinical characteristics, who had two scans but no change in anti-seizure medication (ASM) regimen in-between. After commencing perampanel, individuals had higher task-related activations in left orbitofrontal cortex (OFC), fewer task-related activations in the subcortical regions including the left thalamus and left caudate, and lower task-related thalamocaudate and caudate-subtantial nigra connectivity. Decreased task-related connectivity is observed between the left OFC and precuneus and left medial frontal lobe. Our results highlight the brain regions associated with the beneficiary therapeutic effects on focal to bilateral tonic-clonic seizures (thalamus and caudate) but also the undesired affective side effects of perampanel with increased anger and aggression (OFC).