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Hyperosmolar hyperglycemic state (HHS), a life-threatening complication of diabetes mellitus, may initially manifest with a broad spectrum of neurological symptoms. These include encephalopathy, coma, chorea-hemiballismus and epileptic activity. Focal motor seizures are among the most common manifestations whilst aphasia has rarely been described so far. Based on a recent experience from our hospital, we herein report a rare case of a patient with nonketotic hyperglycemia-induced global aphasia, followed by focal motor seizures and attempt a comprehensive review of the literature with regards to the various neurological syndromes through which, undiagnosed diabetes and HHS may present. Neurological aspects of HHS are not so well-documented and are certainly under-represented in the literature.

Phase 2 studies showed that focal seizures could be detected by algorithms using heart rate variability (HRV) in patients with marked autonomic ictal changes. However, wearable surface electrocardiographic (ECG) devices use electrode patches that need to be changed often and may cause skin irritation. We report the first study of automated seizure detection using a subcutaneously implantable cardiac monitor (ICM; Confirm Rx, Abbott). For this proof-of-concept (phase 1) study, we recruited six patients admitted to long-term video-electroencephalographic monitoring. Fifteen-minute epochs of ECG signals were saved for each seizure and for control (nonseizure) epochs in the epilepsy monitoring unit (EMU) and in the patients' home environment (1–8 months). We analyzed the ICM signals offline, using a previously developed HRV algorithm. Thirteen seizures were recorded in the EMU, and 41 seizures were recorded in the home-monitoring period. The algorithm accurately identified 50 of 54 focal seizures (sensitivity = 92.6%, 95% confidence interval [CI] = 85.6%–99.6%). Twelve of the 13 seizures in the EMU were detected (sensitivity = 92.3%, 95% CI = 77.2%–100%), and 38 of the 41 seizures in the out-of-hospital setting were detected (sensitivity = 92.7%, 95% CI = 84.7%–100%). Four false detections were found in the 141 control (nonseizure) epochs (false alarm rate = 2.7/24 h). Our results suggest that automated seizure detection using a long-term, subcutaneous ICM device is feasible and accurate in patients with focal seizures and autonomic ictal changes.

Our objective was to provide expert consensus recommendations to improve treatment tolerability through dose adjustments of concomitant antiseizure medications (ASMs) during addition of cenobamate to existing ASM therapy in adult patients with uncontrolled focal seizures.A panel of seven epileptologists experienced in the use of ASMs, including cenobamate, used a modified Delphi process to reach consensus. The panelists discussed tolerability issues with concomitant ASMs during cenobamate titration and practical strategies for dose adjustments that may prevent or mitigate adverse effects. The resulting recommendations consider concomitant ASM dose level and specify proactive (prior to report of an adverse effect) and reactive (in response to report of an adverse effect) dose adjustment suggestions based on concomitant ASM pharmacokinetic and pharmacodynamic interactions with cenobamate. Specific dose adjustment recommendations are provided.We recommend proactively lowering the dose of clobazam, phenytoin, and phenobarbital due to their known drug-drug interactions with cenobamate, and lacosamide due to a pharmacodynamic interaction with cenobamate, to prevent adverse effects during cenobamate titration. Reactive lowering of a concomitant ASM dose is sufficient for other ASMs at standard dosing owing to quick resolution of adverse effects. For carbamazepine and lamotrigine doses exceeding the upper end of standard dosing (e.g., carbamazepine, greater than 1200 mg/day; lamotrigine, greater than 500 mg/day), we encourage consideration of proactive dose reduction at cenobamate 200 mg/day to prevent potential adverse effects. All dose reductions for adverse effects can be repeated every 2 weeks as dictated by the adverse effects. At cenobamate 200 mg/day, we recommend that patients be evaluated for marked improvement of seizures and further dose reductions be considered to reduce potentially unnecessary polypharmacy.The primary goal of the recommended dose reductions of concomitant ASMs is to prevent or resolve adverse effects, thereby allowing cenobamate to reach the optimal dose to achieve the maximal potential of improving seizure control.Some people with epilepsy need to take more than one seizure medicine as part of their treatment. Taking more than one seizure medicine, however, can increase the risk of unwanted side effects. One approach to preventing side effects when adding a new seizure medicine is to lower the amount (dose) of existing seizure medicines. Cenobamate is a newer seizure medicine available in the USA for adults with focal seizures (also referred to as partial-onset seizures). Cenobamate, like many seizure medicines, must be titrated over time to a target dose. A group of epilepsy specialists met and developed recommendations for when and how to change the doses of existing seizure medicines when adding cenobamate. The goal of these recommendations is to prevent or reduce side effects like sleepiness or dizziness. The authors recommend that the dose of specific seizure medicines, including clobazam, lacosamide, phenytoin, and phenobarbital, be lowered as cenobamate is started or as cenobamate’s dose is being increased (but before side effects occur). Regular doses of other seizure medicines can be lowered if a side effect occurs because reducing the dose of the other seizure medications can often stop the side effect. These recommendations may help patients successfully reach their optimal dose of cenobamate with fewer side effects, potentially improving their seizure control.

Gaetano Zaccara,1 Simona Lattanzi,2 Antonio Leo,3 Emilio Russo3 1Regional Health Agency of Tuscany, Firenze, Italy; 2Neurological Clinic, Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy; 3Science of Health Department, University Magna Grecia of Catanzaro, Catanzaro, 88100, ItalyCorrespondence: Gaetano ZaccaraRegional Health Agency of Tuscany, via Pietro Dazzi 1, Firenze, 50141, ItalyTel +39 055 2336851Email gaetanozaccara@yahoo.itAbstract: Cenobamate (CNB) is the latest antiseizure medication (ASM) authorized for the treatment of focal-onset seizures in adults. Although the precise mechanism of action of CNB is not yet fully understood, this drug inhibits the persistent, rather than transient, voltage-gated sodium channel currents and is a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, differently from benzodiazepines. CNB has a non-linear pharmacokinetic with a terminal half-life range of about 50/60 hours within the therapeutic dose range, which allows once daily administration. Cenobamate inhibits cytochrome P450 (CYP) 2C19 and induces CYP3A4 and 2B6, and hence can potentially interact with ASMs (eg, phenytoin, carbamazepine and clobazam) and no-ASMs drugs. In two randomized, double-blind, placebo-controlled trials in patients with focal epilepsies, CNB has shown a particularly good efficacy with a rate of seizure freedom of about 20% during the maintenance period in participants treated with the dose of 400 mg/day. The most common treatment-emergent adverse effects include central nervous system-related symptoms, like dizziness, diplopia, somnolence, and gait disturbances. Safety issues of particular interest are severe skin reactions (drug reaction with eosinophilia and systemic symptoms) and QT shortening, which contraindicates its use in subjects with familial short QT syndrome or in combination with other QT-shortening drugs. The recommended starting dose is 12.5 mg/day, which can be gradually titrated to the target dose (200 mg/day) and further increased up to 400 mg/day. There are several aspects of CNB that need to be still addressed, including the long-term efficacy and the efficacy in patients with generalized seizures. Ongoing studies will clarify these issues. The clinical relevance of the peculiar pharmacokinetics and the pattern of drug–drug interactions also require further investigation.Keywords: cenobamate, focal seizures, antiseizure medications, drug–drug interactions, safety, efficacy

PurposeThis study aims to propose a diagnostic algorithm for autoimmune epilepsy in a retrospective cohort and investigate its clinical utility.MethodsWe reviewed 60 patients with focal epilepsy with a suspected autoimmune etiology according to board-certified neurologists and epileptologists. To assess the involvement of the autoimmune etiology, we used the patients' sera or cerebrospinal fluid (CSF) samples to screen for antineuronal antibodies using rat brain immunohistochemistry. Positive samples were analyzed for known antineuronal antibodies. The algorithm applied to assess the data of all patients consisted of two steps: evaluation of clinical features suggesting autoimmune epilepsy and evaluation using laboratory and imaging findings (abnormal CSF findings, hypermetabolism on fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging abnormalities, and bilateral epileptiform discharges on electroencephalography). Patients were screened during the first step and classified into five groups according to the number of abnormal laboratory findings. The significant cutoff point of the algorithm was assessed using a receiver-operating characteristic curve analysis.ResultsFourteen of the 60 patients (23.3%) were seropositive for antineuronal antibodies using rat brain immunohistochemistry. Ten patients had antibodies related to autoimmune epilepsy/encephalitis. The cutoff analysis of the number of abnormal laboratory and imaging findings showed that the best cutoff point was two abnormal findings, which yielded a sensitivity of 78.6%, a specificity of 76.1%, and an area under the curve of 0.81.ConclusionThe proposed algorithm could help predict the underlying autoimmune etiology of epilepsy before antineuronal antibody test results are available.

On March 18, 2021, an online council of experts in the field of epilepsy treatment was held, dedicated to the use of perampanel in the additional therapy of focal seizures (FS) and primary generalized tonic-clonic seizures (PGTCS) in children 4–12 years old. During the event, the features of the use of perampanel in this group of patients were discussed, considering the specifics of everyday clinical practice, current possibilities of PGTCS and FS therapy in children, its goals, as well as unsolved problems in the treatment of pediatric patients with PGTCS and FS. Particular attention was paid to the role of perampanel in the treatment of PGTCS and FS in children and its effectiveness in specific types of focal seizures.

Background: Epilepsy affects about 50 million people worldwide and around 30% of these patients have refractory epilepsy, with potential consequences regarding quality of life, morbidity and premature mortality. Objective: The aim of treatment with antiseizure medications (ASMs) is to allow patients to remain without seizures, with good tolerability. Levetiracetam is a broad-spectrum ASM with a unique mechanism of action that differs it from other ASMs. It has been shown to be effective and safe for treating adults and children with epilepsy. Methods: This was a phase III, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of levetiracetam in children and adults (4-65 years) as an adjuvant treatment for focal-onset seizures. It was conducted among 114 patients undergoing treatment with up to three ASMs. The primary efficacy analysis was based on the proportion of patients who achieved a reduction of ≥ 50% in the mean number of focal seizures per week, over a 16-week treatment period. The patients were randomized to receive placebo or levetiracetam, titrated every two weeks from 20 mg/kg/day or 1,000 mg/day up to 60 mg/kg/day or 3,000 mg/day. Results: Levetiracetam was significantly superior to placebo (p = 0.0031); 38.7% of the participants in the levetiracetam group and 14.3% in the control group shows reductions in focal seizures. Levetiracetam was seen to have a favorable safety profile and an adverse event rate similar to that of placebo. Conclusion: Corroborating the results in the literature, levetiracetam was shown to be effective and safe for children and adults with refractory focal-onset epilepsy. RESUMO Introdução: A epilepsia afeta cerca de 50 milhões de pessoas em todo o mundo e aproximadamente 30% desses pacientes apresentam epilepsia refratária, com possíveis consequências na qualidade de vida, morbidade e mortalidade prematura. Objetivo: O objetivo do tratamento com fármacos antiepilépticos (FAEs) é permitir que os pacientes permaneçam sem crises epilépticas com boa tolerabilidade. O levetiracetam (LEV) é um FAE de amplo espectro, com mecanismo de ação único, diferente dos demais e que demonstra ser eficaz e seguro no tratamento de adultos e crianças. Métodos: Estudo de fase III, multicêntrico, randomizado, duplo-cego e controlado por placebo avalia a eficácia e a segurança do LEV em crianças e adultos (4-65 anos) como tratamento adjuvante para crises de início focal em 114 pacientes já tratados com até três FAEs. A análise de eficácia primária foi baseada na proporção de pacientes que apresentaram redução ≥50% no número médio de crises epilépticas focais semanais, durante 16 semanas. Os pacientes foram randomizados para receber placebo ou LEV, titulado a cada duas semanas de 20 mg/kg/dia ou 1.000 mg/dia até 60 mg/kg/dia ou 3.000 mg/dia. Resultados: LEV foi significativamente superior ao placebo (p=0,0031), com 38,7% dos participantes no grupo LEV e 14,3% no grupo controle que apresentaram redução das crises focais. LEV apresenta bom perfil de segurança com eventos adversos semelhantes ao placebo. Conclusão: Corroborando com os resultados da literatura, o levetiracetam mostra-se eficaz e seguro para crianças e adultos com epilepsia focal refratária.

Introduction: Brivaracetam (BRV) is an antiseizure medication (ASM), which has been approved as an adjunctive treatment in adults and pediatric patients aged four years and older with focal onset seizures. It is a second-generation levetiracetam (LEV) derivative, sharing the same mechanism of action, binding synaptic vesicles 2A (SV2A). BRV shows higher binding affinity and selectivity and higher brain permeability than LEV.Areas covered: This article reviews randomized controlled trials, retrospective and prospective studies published up to December 2020, searched in electronic databases MEDLINE, EMBASE and the Clinical Trial Database and provide an overview of efficacy, safety and tolerability of BRV in pediatric patients with partial epilepsy. Furthermore, the authors provide their expert opinion on the drug and give their future perspectives.Expert opinion: The analysis of the literature data has demonstrated the safety and efficacy of BRV in pediatric patients, with more evidence in children aged 4 to 16 years with an onset of focal seizures. However, a positive response was also achieved in patients affected by some encephalopathic epilepsies. Comparative efficacy studies between BRV and other ASMs, in addition to well-designed RCTs that include larger pediatric populations are needed to better define the role and potentiality of this ASM.

Introduction The aim of this study was to compare healthcare resource utilization (HCRU) before and after initiation of eslicarbazepine acetate (ESL) in the long-term care (LTC) setting (rehabilitation center, mental health center, LTC non-skilled nursing facility/assisted-living facility, home health, assisted living, nursing home, other/unknown). Methods This retrospective analysis used IQVIA’s New Data Warehouse, which includes deterministically linked LTC, prescription, and professional fee claims data and IQVIA Hospital Charge Data Master database. The study period was 1 April 2013 to 31 December 2019. The index date was the date of ESL initiation in the LTC setting. Inclusion criteria were: (1) ≥ 1 new ESL prescription between 1 April 2014 and 31 December 2018; (2) diagnosis of focal seizure (FS) during the 12 months pre-index date; and (3) no ESL prescription during the 12-month period pre-index. A 12-month pre-post analysis compared epilepsy-specific and all-cause HCRU before and after ESL initiation. Categorical variables were compared with McNemar’s tests. Results A total of 307 patients (mean age 52.2 years, 57.7% male) with FS were included, of whom 24.8% were in nursing homes. Patients used a mean of 3.1 antiseizure drugs prior to initiation of ESL, and 87.9% of patients initiated ESL as adjunctive treatment. There were significant reductions in proportion of patients with epilepsy specific physician office visits, emergency department (ED) visits, hospitalizations, and all-cause physician office visits and hospitalizations in the post-index period compared to the pre-index period (P

Darshan Mehta,1 Matthew Davis,2 Andrew J Epstein,3 Brian Wensel,1 Todd Grinnell,4 G Rhys Williams1 1Sunovion Pharmaceuticals Inc., Marlborough, MA, USA; 2Medicus Economics, LLC, Milton, MA, USA; 3Medicus Economics, LLC, Philadelphia, PA, USA; 4Medical Affairs, Sunovion Pharmaceuticals Inc., Marlborough, MA, USACorrespondence: Darshan MehtaAssociate Director, Health Economics and Outcomes Research, Sunovion Pharmaceuticals Inc, 84 Waterford Drive, Marlborough, MA, 01752, USATel +1-774-369-7913Email Darshan.Mehta@sunovion.comObjective: To examine the association between initiating first-line (1L) monotherapy with eslicarbazepine acetate (ESL) vs a generic antiseizure drug (ASD) and healthcare resource utilization (HCRU) and charges in adults with treated focal seizures (FS).Methods: This was a retrospective analysis of Symphony Health’s Integrated Dataverse® open-source claims data. Two cohorts were identified as having initiated 1L monotherapy with ESL or literature-defined generic ASDs. Linear regression models with person fixed effects and inverse probability treatment weights assessed the relative additional changes in HCRU and charges among patients who received ESL compared to generic ASD.Results: A total of 250 and 43,220 patients initiated ESL (48.3 years; 57.2% female) or a generic ASD (54.5 years; 58.1% female), respectively. Compared to patients initiating a generic ASD, patients treated with ESL had additional reductions of 11.8 percentage points in the likelihood of any all-cause outpatient visits (P< 0.001), 7.4 percentage points in the likelihood of any emergency department (ED) visits (P=0.013), and 22.7 percentage points in the likelihood of any FS-related outpatient visits (P< 0.001). Patients initiating ESL had greater reductions in mean charges for all-cause medical ($2620; P=0.002), outpatient ($1995; P=0.005), and non-FS-related medical ($2708; P< 0.001) services. Patients initiating ESL had greater relative increases in mean total prescription ($1368; P< 0.001) and ASD-related prescription ($1636; P< 0.001) charges, but greater relative reductions in non-ASD prescription ($269; P=0.032) charges. The increases in prescription charges were of a lower magnitude than the decreases in medical charges.Conclusion: Initiation of ESL as 1L monotherapy was associated with statistically significantly greater reductions in any use of several all-cause and FS-related services, number of visits, and charges compared to initiation of a generic ASD as 1L monotherapy in patients with FS. Initiation of a generic ASD as 1L monotherapy was associated with significantly smaller increases in total prescription charges and ASD-related prescription charges.Keywords: eslicarbazepine acetate, focal seizures, healthcare resource utilization, medical charges

Resumen Las convulsiones epilépticas focales se originan en una localización focal del cerebro con descargas eléctricas anormales que pueden suceder por distintas causas, y pueden ocurrir en un bajo porcentaje de animales; son signos diferentes a la típica mioclonía tónico-clónica. El objetivo del presente trabajo es exponer casos clínicos de perros que presentaron vómitos, sialorrea y regurgitación como signos clínicos de convulsiones epilépticas focales. Estos perros, además de presentar tales signos digestivos mencionados, no mostraron alteraciones reveladoras en los datos de laboratorio ni en los métodos complementarios de imágenes solicitados. Debido a la escasa respuesta terapéutica y al empeoramiento de la condición de los pacientes (pérdida de peso severa), luego de descartar causas periféricas de vómitos y/o regurgitación, se consideró la posibilidad de que el estímulo del vómito fuera central. Por lo tanto, se realizó un electroencefalograma (EEG). En todos los casos el trazado del EEG evidenció anomalías. Dada las condiciones clínicas descritas, se implementó el tratamiento con fenobarbital y la evolución de los tres casos clínicos fue favorable. Los perros con presencia de convulsiones epilépticas focales autonómicas pueden presentar una variada sintomatología clínica que depende de las regiones cerebrales dañadas que las producen. Por eso es importante tener en cuenta dentro de los diferenciales de signos clínicos que pueden tener origen central como el vómito, principalmente cuando la causa permanece sin ser diagnosticadas, la epilepsia focal autonómica. Abstract Focal seizures originate in a focal location of the brain with abnormal electric discharges due to different causes and may occur in a low percentage of animals and their signs are different from the typical tonic-clonic myoclony. This work aims to disclose some clinical cases of dogs with vomit, sialorrhea and regurgitation as clinical signs of focal seizures. In addition to these digestive signs, the dogs did not show any noteworthy alteration in the laboratory test results, neither in the complementary imaging methods included in the study. Due to the scant therapeutic response and as the dogs got worse (a serious loss of weight), having ruling out any peripheral cause of vomit and/or regurgitation, the possibility of a central cause was considered. The dogs underwent an electroencephalogram (EEG) and in all cases the EEG results showed anomalies. Due to the described clinical conditions, a phenobarbital treatment was administered and the three cases clinical cases evolved positively. Dogs with focal autonomic seizures may show various clinical symptoms depending on the damaged brain regions they come from. Therefore, it is important to consider a central cause -focal autonomic epilepsy- for the differential clinical signs such as the vomit, mostly when there is not a clearly diagnosed cause.

Aims This post hoc analysis assessed the efficacy and safety/tolerability of adjunctive perampanel in patients from China (aged ≥12 years) with focal seizures (FS), with/without focal to bilateral tonic‐clonic seizures (FBTCS), or generalized tonic‐clonic seizures (GTCS). Methods Study centers in China were identified using data from five double‐blind, randomized, phase III studies of adjunctive perampanel (2‐12 mg/day) and their open‐label extensions (OLEx). Efficacy assessments included median percent reduction in seizure frequency per 28 days, and 50% and 75% responder and seizure‐freedom rates. Safety/tolerability assessments included monitoring of treatment‐emergent adverse events (TEAEs). Results Overall, 277 patients (placebo, n = 79; perampanel, n = 198) were included in the double‐blind safety analysis set. The full analysis set comprised 274 patients (FS, n = 238 [placebo, n = 60; perampanel, n = 178]; FBTCS, n = 120 [placebo, n = 31; perampanel, n = 89]; GTCS, n = 36 [placebo, n = 18; perampanel, n = 18]). Median percent reductions in seizure frequency for placebo vs perampanel were as follows: 16.6% vs 32.4% (FS; P, Adjunctive perampanel was associated with greater median percent reductions in seizure frequency per 28 days vs placebo in Chinese patients with focal or generalized seizure types during double‐blind, randomized, phase III studies.During OLEx studies, adjunctive perampanel showed efficacy for up to 4 years for FS and FBTCS, and up to 2 years for GTCS.Perampanel was generally well tolerated during short‐ and long‐term treatment.

Introduction This study assessed the association between early initiation of eslicarbazepine acetate (ESL) as first-line therapy (1L cohort) or as first adjunctive regimen to either levetiracetam (LEV) or lamotrigine (LTG) (add-on cohort), and healthcare resource utilization (HCRU) and charges among adults with treated focal seizures (FS). Methods This retrospective, longitudinal cohort analysis used Symphony Health’s Integrated Dataverse (IDV®) claims data to identify patients aged ≥ 18 years with a diagnosis of FS who had a new prescription for ESL between April 2015 and June 2018. Baseline was the 90-day period immediately prior to the date of the first-dispensed claim for ESL (index date) with a follow-up of 1–4 consecutive 90-day periods. Linear regression models were estimated to assess changes in HCRU and charge outcomes. Results There were 274 and 153 patients who received ESL in the 1L cohort and add-on cohort, respectively. The 1L cohort experienced significant reductions from baseline during follow-up in all-cause inpatient (IP; P

Background. Comparative study of antiepileptic drugs allows to make the optimal choice in therapy.The aim of the study: a comparative analysis of the administration of two similar by chemical structure antiepileptic drugs (zonisamide and topiramate) in the outpatient practice in epilepsy in children, taking into account the efficacy and tolerability.Materials and methods. A retrospective analysis of outpatient charts of equal in number (n = 18) groups of patients with different forms of epilepsy treated with zonisamide and topiramate in monotherapy and in combined therapy was carried out.Results. In general, no statistically significant difference in the efficacy of zonisamide and topiramate was obtained (p = 0.692). Efficacy in structural focal epilepsy was also comparable (absence of seizures 54.6 % and 45.5 %, respectively). With comparable efficacy, zonisamide was administered to patients much later in the antiepileptic drugs (Me = 5) than topiramate (Me = 3). Side effects on zonisamide were registered in 27.8 %, side effects on topiramate – in 38.9 % (p = 0.480). The difference in the effect of these drugs on cognitive functions was noted.Conclusions. Zonisamide shows its effectiveness in different forms of epilepsy in children, despite the later appointment in practice. The drug is well tolerated and probably has less negative effect on children’s cognitive functions than topiramate.

Objectives: To evaluate cutaneous allergic reactions in clinical trials of adjunctive eslicarbazepine acetate (ESL) for focal seizures. Materials and methods: Data were analyzed from three phase III randomized, double-blind, placebo-controlled studies of adjunctive ESL in adults (placebo, n = 426; ESL, n = 1021) and two randomized, double-blind, placebo-controlled studies (and open-label extensions [OLEs]) of adjunctive ESL in children aged 4-17 years (placebo, n = 160; ESL, n = 202; OLE, n = 337). Results: Adult studies: Rash (ESL 1.9%, placebo 0.9%) and pruritus (ESL 1.2%, placebo 0.9%) were the most frequent rash-related treatment-emergent adverse events (TEAEs). Most rash-related TEAEs were mild or moderate in severity. Incidence of rash increased with increasing ESL dose, but was not higher for patients who initiated treatment with higher ESL doses. Pediatric studies: Allergic dermatitis (ESL 3.0%, placebo 0) and rash (controlled studies: ESL 1.0%, placebo 1.3%; OLE periods: ESL ≤1.2%) were the most frequent rash-related TEAEs. There was one case of DRESS in the ESL group. Most rash-related TEAEs were mild or moderate in severity and judged as not related to treatment with ESL. Conclusions: Serious skin rashes were rare during adult and pediatric clinical trials of ESL. Although the incidence of rash with ESL was low, it is important for patients/caregivers to be made aware of the potential signs and symptoms associated with serious skin rashes. Fil: Rogin, Joanne. Minneapolis Clinic of Neurology. Midwest Center for Seizure Disorders; Estados Unidos Fil: Resnick, Trevor. Florida International University; Estados Unidos Fil: Strom, Laura. University of Colorado Denver Health Sciences. Department of Neurology; Estados Unidos Fil: Ben Menachem, Elinor. Sahlgrenska Academy Institute of Neuroscience and Physiology; Suecia Fil: Kochen, Sara Silvia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina Fil: Blum, David. Sunovion Pharmaceuticals Inc; Estados Unidos Fil: Gama, Helena. São Mamede de Coronado. BIAL - Portela & Ca, S.A.; Portugal Fil: Soares da Silva, Patrício. São Mamede de Coronado. BIAL - Portela & Ca, S.A.; Portugal. Universidad de Porto; Portugal Fil: Li, Yan. Sunovion Pharmaceuticals Inc; Estados Unidos Fil: Grinnell, Todd. Sunovion Pharmaceuticals Inc; Estados Unidos

BACKGROUND The present study was conducted to determine the incidence of partial seizures in children 5 - 15 years of age and evaluate EEG and CT scan as diagnostic tools in partial seizures in children. METHODS This is a hospital based observational study done for 2 years among children in the age group of 5 - 15 years presenting with focal seizures. Children presenting to our hospital with focal seizures defined as per International League against Epilepsy Classification formed the study group. A total of 87 patients were included. Children were investigated for the aetiology of focal seizures with routine and specific investigations including Mantoux test, CSF analysis, blood sugar, neuroimaging CT scan and/or MRI and EEG. All the findings were recorded in a pre-designed proforma and results were analysed. MRI was done in cases where differentiating NCC from tuberculoma by CT scan was a diagnostic dilemma and also in cases where CT was inconclusive. EEG was done in all cases. In all these children, appropriate standard treatment protocol was carried out. RESULTS The incidence of focal seizures was more common in between 5-10 years of age. Female to Male ratio was 1.12:1. CT evaluation of the patient showed that 93% of the patients had a lesion in the brain. Infections were the major cause of focal seizures. NCC and Tuberculoma were the major causes. Abnormal EEG pattern was seen in majority of the cases of 66%. CONCLUSIONS Focal seizures are one of the commonest type of seizures seen in children, associated with a localized lesion in the brain. Infective causes are the major aetiological factors.

BACKGROUND: The management of epilepsy in older adults has become part of daily practice because of an aging population. Older patients with epilepsy represent a distinct and more vulnerable clinical group as compared with younger patients, and they are generally under-represented in randomized placebo-controlled trials. Real-world studies can therefore be a useful complement to characterize the drug's profile. Brivaracetam is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A and approved as adjunctive therapy for focal seizures in adults with epilepsy. OBJECTIVE: The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive brivaracetam in older patients (≥65 years of age) with epilepsy treated in a real-world setting. METHODS: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a 12-month retrospective multicenter study including adult patients prescribed adjunctive brivaracetam. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events and the incidence of adverse events. Data were compared for patients aged ≥65 years of age ('older') vs those aged

To assess how efficacy and safety outcomes were affected when cenobamate was co-administered with antiseizure medications (ASMs) that use either sodium channel blocker (SCB) or non-sodium channel blocker (non-SCB) mechanisms of action (MoAs) in patients with uncontrolled focal seizures. Methods: An exploratory post-hoc analysis of a randomized, double-blind, placebo-controlled clinical study (YKP3089C017) was conducted. Baseline concomitant ASMs were grouped as either those that employed an SCB or non-SCB MoA. Efficacy was examined by cenobamate dose (100 mg, 200 mg, and 400 mg/day) and concomitant ASM group using responder rates (≥50%, ≥75%, ≥90% seizure reduction; 100% seizure reduction/seizure freedom) during the maintenance phase and median percentage seizure reduction during the double-blind period. Treatment-emergent adverse events (TEAEs) were examined in the double-blind period. Results: When co-administered with SCBs or non-SCBs, significantly higher percentages of patients achieved ≥50%, ≥75%, and ≥90% responder rates with cenobamate 200 mg/day and/or 400 mg/day versus placebo. Additionally, significantly higher percentages of patients achieved seizure freedom with cenobamate 400 mg/day versus placebo (SCB group, 17.5% versus 1.2%; non-SCB group, 40.0% versus 0.0%). Patients receiving 200 mg/day and 400 mg/day and concomitant SCBs and all patients taking cenobamate combined with non-SCB concomitant ASMs had significantly greater median percentage reductions in focal seizure frequency versus placebo. TEAEs were similar across groups; however, dizziness was more frequently reported in the SCB group. Conclusion: Cenobamate is a highly effective new treatment option for patients with uncontrolled focal seizures when co-administered with SCB or non-SCB ASMs, Study C017 was funded by SK Life Science, Inc. (Paramus, NJ), a subsidiary of SK Biopharmaceuticals Co. Ltd., which contributed to the design, conduct, management, analysis, and data interpretation of the study. The current post-hoc analysis of C017 was funded by Angelini S.p.a. (Rome Italy), which contributed to the conceptual design and analysis and interpretation of data. Medical writing assistance, under the direction of the authors, was provided by MedVal Scientific Information Services, LLC (Princeton, NJ), and was funded by Angelini S.p.a. Angelini S.p.a. has licensed exclusive rights from SK Biopharmaceuticals to develop and commercialize cenobamate in Europe

Introduction: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Most real-world research on BRV has focused on refractory epilepsy. The aim of this analysis was to assess the 12-month effectiveness and tolerability of adjunctive BRV when used as early or late adjunctive treatment in patients included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). Methods: BRIVAFIRST was a 12-month retrospective, multicenter study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of sustained seizure response, sustained seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Data were compared for patients treated with add-on BRV after 1-2 (early add-on) and ≥ 3 (late add-on) prior antiseizure medications. Results: A total of 1029 patients with focal epilepsy were included in the study, of whom 176 (17.1%) received BRV as early add-on treatment. The median daily dose of BRV at 12months was 125 (100-200) mg in the early add-on group and 200 (100-200) in the late add-on group (p

International audience; Focal neuronal lipofuscinosis (FNL) is an uncommon epileptic disorder related to an excess of lipofuscin accumulation within dysmorphic-appearing neurons (DANs), whose epileptogenic mechanisms are still poorly understood. It shares some clinical and neuroimaging similarities with focal cortical dysplasia of type IIb (FCDIIb), but it represents a different pathological entity. Here, we identified two patients with FNL among a 10-year cohort of 323 patients who underwent neurosurgery for a focal pharmacoresistant epilepsy. We describe the electroclinical, metabolic and neuropathological features of both patients with FNL who benefited from a comprehensive presurgical investigation. While the previous reports showed frontal lobe localization of the lesion, FNL was identified in the temporal lobe, in one of our patients. EEG investigations in both patients showed striking focal and rich interictal activity resembling that described in FCDIIb. Besides focal intraneuronal lipofuscin accumulation, the neuropathological analysis demonstrated that somata of DANs were surrounded by a large amount of GABAergic presynaptic buttons, suggesting the involvement of interneurons in the epileptogenicity of FNL. To further explore the role of GABAergic transmission in the generation of epileptiform activity in FNL, we performed in vitro multi-electrode array recordings on the post-surgery tissue from one patient. Spontaneous interictal-like discharges (IILDs) were identified only in the restricted area displaying the highest density of lipofuscin-containing DANs, suggesting a close correlation between the density of lipofuscin-containing neurons and epileptogenicity. Moreover, IILDs were blocked by the GABAA receptor antagonist gabazine. All together, these findings showed how GABA signaling may contribute to the generation of interictal-like activity in FNL tissue.

Objective: Post-stroke epilepsy (PSE) is one of the most common causes of acquired epilepsy and accounts for about 10-15% of all newly diagnosed epilepsy cases. However, evidence about the clinical profile of antiseizure medications in the PSE setting is currently limited. Brivaracetam (BRV) is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A. The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive BRV in patients with PSE treated in a real-world setting. Methods: This was a subgroup analysis of patients with PSE included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). The BRIVAFIRST was a 12-month retrospective, multicentre study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure‐freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Results: Patients with PSE included in the BRIVAFIRST were 75 and had a median age of 57 (interquartile range, 42-66) years. The median daily doses of BRV at 3, 6, and 12 months from starting treatment were 100 (100-150) mg, 125 (100-200) mg and 100 (100-200) mg, respectively. At 12 months, 32 (42.7%) patients had a reduction in their baseline seizure frequency by at least 50%, and the seizure freedom rates was 26/75 (34.7%). During the 1-year study period, 10 (13.3%) patients discontinued BRV. The reasons of treatment withdrawal were insufficient efficacy in 6 (8.0%) patients and poor tolerability in 4 (5.3%) patients. Adverse events were reported by 13 (20.3%) patients and were rated as mild in 84.6% and moderate in 15.4% of cases. Significance: Adjunctive BRV was efficacious and generally well-tolerated when used in patients with PSE in clinical practice. Adjunctive BRV can be a suitable therapeutic option for patients with PSE.

The maintenance of seizure control over time is a clinical priority in patients with epilepsy. The aim of this study was to assess the sustained seizure frequency reduction with adjunctive brivaracetam (BRV) in real-world practice. Patients with focal epilepsy prescribed add-on BRV were identified. Study outcomes included sustained seizure freedom and sustained seizure response, defined as a 100% and a ≥50% reduction in baseline seizure frequency that continued without interruption and without BRV withdrawal through the 12-month follow-up. Nine hundred ninety-four patients with a median age of 45 (interquartile range = 32-56) years were included. During the 1-year study period, sustained seizure freedom was achieved by 142 (14.3%) patients, of whom 72 (50.7%) were seizure-free from Day 1 of BRV treatment. Sustained seizure freedom was maintained for ≥6, ≥9, and 12months by 14.3%, 11.9%, and 7.2% of patients from the study cohort. Sustained seizure response was reached by 383 (38.5%) patients; 236 of 383 (61.6%) achieved sustained ≥50% reduction in seizure frequency by Day 1, 94 of 383 (24.5%) by Month 4, and 53 of 383 (13.8%) by Month 7 up to Month 12. Adjunctive BRV was associated with sustained seizure frequency reduction from the first day of treatment in a subset of patients with uncontrolled focal epilepsy.

Cenobamate (CNB) is the latest antiseizure medication (ASM) authorized for the treatment of focal-onset seizures in adults. Although the precise mechanism of action of CNB is not yet fully understood, this drug inhibits the persistent, rather than transient, voltage-gated sodium channel currents and is a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, differently from benzodiazepines. CNB has a non-linear pharmacokinetic with a terminal half-life range of about 50/60 hours within the therapeutic dose range, which allows once daily administration. Cenobamate inhibits cytochrome P450 (CYP) 2C19 and induces CYP3A4 and 2B6, and hence can potentially interact with ASMs (eg, phenytoin, carbamazepine and clobazam) and no-ASMs drugs. In two randomized, double-blind, placebo-controlled trials in patients with focal epilepsies, CNB has shown a particularly good efficacy with a rate of seizure freedom of about 20% during the maintenance period in participants treated with the dose of 400 mg/day. The most common treatment-emergent adverse effects include central nervous system-related symptoms, like dizziness, diplopia, somnolence, and gait disturbances. Safety issues of particular interest are severe skin reactions (drug reaction with eosinophilia and systemic symptoms) and QT shortening, which contraindicates its use in subjects with familial short QT syndrome or in combination with other QT-shortening drugs. The recommended starting dose is 12.5 mg/day, which can be gradually titrated to the target dose (200 mg/day) and further increased up to 400 mg/day. There are several aspects of CNB that need to be still addressed, including the long-term efficacy and the efficacy in patients with generalized seizures. Ongoing studies will clarify these issues. The clinical relevance of the peculiar pharmacokinetics and the pattern of drug–drug interactions also require further investigation.

A 16-year-old male was referred by the primary care physician (PCP) for a second opinion. An initial evaluation in another sleep center suggested a working diagnosis of night terrors for the last two years. The child would wake up frequently screaming for few minutes before going back to sleep with no recollection of these events later. A video during the polysomnography (PSG) showed the patient having one of his typical events. He was eventually diagnosed with Sleep-related Hypermotor Epilepsy (SHE) seizures. This case highlights the importance of differentiating parasomnia and seizures, particularly for the sleep medicine providers that incorporate providers from different academic backgrounds. We will discuss the clinical challenges to make the distinction for the referring providers and demonstrate the importance of video-PSG to establish the diagnosis.

Purpose: To evaluate the efficacy and tolerability of adjunctive perampanel (PER) in Chinese patients with focal-onset seizures, with or without secondarily generalized tonic-clonic seizures.Methods: Fifty-six patients aged 14–72 years were recruited consecutively in this single-center prospective observational study. All patients received PER as add-on treatment on the basis of clinical judgment. Seizure frequency, adverse events (AEs), and retention rates were obtained at 3 and 6 months after PER introduction.Results: The overall response rates were 60 and 71.1% after 3 and 6 months, respectively, and the freedom of seizures at the same points were reached in 8 and 15.8%. The retention rates were 89.3% at the 3-month follow-up and 67.9% at the 6-month follow-up. The overall incidence of adverse events was 55.4%. The leading reported AEs were dizziness (39.3%) and somnolence (25%).Conclusions: Our study confirmed the efficacy and tolerability of adjunctive PER in Chinese patients in real-life conditions. Based on our treatment experience, a lower maintenance dose of PER would be needed in Chinese patients.

Rasmussen encephalitis (RE) is a rare disease of unknown etiology that causes severe chronic unihemispheric inflammatory disease of the central nervous system mainly in children. It leads to intractable seizures, cognitive decline and progressive neurological deficits in the affected hemisphere. We report two cases of RE, as defined by fulfillment of the 2005 Bien criteria. The diagnostic challenge of characterizing this rare disease will be highlighted by the extensive serum, CSF, MR imaging and EEG data in the two patients. In addition, we will review the various forms of therapy attempted in these two patients, namely anti-epileptic drug therapy and immunomodulatory therapy. Hemispherectomy was done for the second patient with favorable outcomes of controlling seizures, but unfortunately, he died because of meningitis. Until the causes of Rasmussen's encephalitis are known, it is difficult to anticipate how treatments will improve. Such a situation creates a therapeutic dilemma; hemispherectomy is not favored because of the inevitable postoperative functional deficits, but a real risk exists that treatments used to delay progression of the disease will defer definitive surgical treatment beyond the time when an optimum post-hemispherectomy outcome could be expected., Highlights • Rasmussen encephalitis (RE) causes severe chronic unihemispheric inflammatory disease. • RE should be suspected in any patient with refractory seizures. • Its recognition is important because early intervention with surgery can improve outcomes.

The study aimed to review the clinical, radiological, and pathological findings and electroencephalogram (EEG) of pediatric epilepsy patients with temporal onset focal seizures induced by intermittent photic stimulation (IPS). Four patients with temporal onset photosensitivity focal seizures were analyzed. Three (75%) of the four patients were female. The average age of seizure-onset was 4.4 years. The interictal EEG showed both generalized and focal spike and waves in one patient and focal or multifocal spike and waves alone in three patients. Photoparoxysmal response (PPR) was evoked in all patients and showed generalized discharges (patients 2–4), both generalized and posterior discharges (patient 1). Both generalized and focal discharges could coexist in interictal discharges and PPR. The sensitive frequencies of PPR and photoconvulsive response (PCR) were 12–30 and 10–16 Hz, respectively, which were close to the occipital rhythm. In all patients, the onset of PCR was recorded, namely, the left anterior and mesial temporal lobe (TL), the left posterior TL, and the whole left TL, which showed two forms: the seizure of two patients was the onset of slow waves in the temporal area without spreading generalized discharges (patients 1 and 4), and the other one was fast rhythmic activities in the temporal area, spreading to the occipital area or gradually evolving into the generalized discharges (patients 2 and 3). During follow-up, except for patient 3 who had occasional seizures, the seizures of the remaining patients were under control. Temporal onset focal seizures could be induced by IPS. Temporal onset photosensitivity seizures were mostly easy to control with antiseizure drugs.

Summary Objective This study was undertaken to examine long‐term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open‐label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968). Methods Patients who completed the 12‐week, multicenter, multinational, double‐blind, randomized, placebo‐controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment‐emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan–Meier analysis. Results One hundred forty‐nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4–7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50–400 mg). The probability of treatment continuation at 1–6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2–5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity. Significance Long‐term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment‐resistant focal seizures taking one to three ASMs.

Rasmussen's encephalitis (RE) is a chronic neurological disorder characterized by unilateral inflammation of the cerebral cortex leading to severe focal seizures, progressive loss of cognition, and neurological deficits in the affected hemisphere. We present a rare case of RE in a child with global developmental delay and cerebral atrophy. Neuroimaging helped in clinching the diagnosis of the disease. Immunomodulators may slow the progression of the disease; hence, it needs to be identified early and treated promptly. Functional cerebral hemispherectomy is the only treatment for drug-resistant seizures, but it has its functional compromise.

OBJECTIVE: To assess the feasibility and accuracy of seizure detection based on heart rate variability (HRV) using a wearable electrocardiography (ECG) device. Noninvasive devices for detection of convulsive seizures (generalized tonic-clonic and focal to bilateral tonic-clonic seizures) have been validated in phase 2 and 3 studies. However, detection of nonconvulsive seizures still needs further research, since currently available methods have either low sensitivity or an extremely high false alarm rate (FAR). METHODS: In this phase 2 study, we prospectively recruited patients admitted to long-term video-EEG monitoring (LTM). ECG was recorded using a dedicated wearable device. Seizures were automatically detected using HRV parameters computed off-line, blinded to all other data. We compared the performance of 26 automated algorithms with the seizure time-points marked by experts who reviewed the LTM recording. Patients were classified as responders if >66% of their seizures were detected. RESULTS: We recruited 100 consecutive patients and analyzed 126 seizures (108 nonconvulsive and 18 convulsive) from 43 patients who had seizures during monitoring. The best-performing HRV algorithm combined a measure of sympathetic activity with a measure of how quickly HR changes occurred. The algorithm identified 53.5% of the patients with seizures as responders. Among responders, detection sensitivity was 93.1% (95% CI: 86.6%-99.6%) for all seizures and 90.5% (95% CI: 77.4%-97.3%) for nonconvulsive seizures. FAR was 1.0/24 h (0.11/night). Median seizure detection latency was 30 s. Typically, patients with prominent autonomic nervous system changes were responders: An ictal change of >50 heartbeats per minute predicted who would be responder with a positive predictive value of 87% and a negative predictive value of 90%. SIGNIFICANCE: The automated HRV algorithm, using ECG recorded with a wearable device, has high sensitivity for detecting seizures, including the nonconvulsive ones. FAR was low during the night. This approach is feasible in patients with prominent ictal autonomic changes.

Objective To examine the frequency of hyponatremia and potentially related symptoms in clinical trials of eslicarbazepine acetate (ESL) in adults with focal‐ (partial‐) onset seizures. Methods This post hoc, exploratory analysis included data from three controlled phase 3 trials of adjunctive ESL (400‐1200 mg once daily), two phase 3 trials of ESL monotherapy (1200‐1600 mg once daily), and their open‐label extension studies. Exploratory endpoints included clinical laboratory measurements of serum sodium concentrations ([Na+]), incidences of hyponatremia‐related treatment‐emergent adverse events (TEAEs), and incidences of TEAEs that are potential symptoms of hyponatremia. Results The controlled trials of adjunctive ESL and ESL monotherapy included 1447 (placebo, n = 426; ESL, n = 1021) and 365 (ESL, n = 365) patients, respectively; 639 and 274 patients continued onto uncontrolled, open‐label extensions. In the controlled and uncontrolled trials ≤3.3% of patients taking ESL had a minimum postdose [Na+] measurement ≤125 mEq/L, 10 mEq/L decrease in [Na+] from baseline

The cellular activity underlying human focal seizures, and its relationship to key signatures in the EEG recordings used for therapeutic purposes, has not been well characterized despite many years of investigation both in laboratory and clinical settings. The increasing use of microelectrodes in epilepsy surgery patients has made it possible to apply principles derived from laboratory research to the problem of mapping the spatiotemporal structure of human focal seizures, and characterizing the corresponding EEG signatures. In this review, we describe results from human microelectrode studies, discuss some data interpretation pitfalls, and explain the current understanding of the key mechanisms of ictogenesis and seizure spread.

Objectives To compare frequency analysis to human raters and determine the interrater agreement of postictal EEG changes after focal seizures. Methods 24 focal seizures with and without impaired awareness recorded with scalp-EEG in the epilepsy monitoring unit were selected. Five board-certified neurophysiologists annotated seizure termination and end of postictal changes for all seizures. We assessed agreement using intraclass correlation, described the band-power changes by time-frequency analysis, and correlated these measures with the rater annotations. Results Interrater agreement on the duration of the postictal changes was moderate (0.64, 95% confidence interval: 0.36–0.82). The interrater agreement for seizure termination was excellent (1.00). Median duration of the postictal interval of seizures with impaired awareness was significantly shorter than for seizures with retained awareness (p = 0.0004). Mean postictal duration was 16.4 min. Seizure duration did not predict duration of the postictal changes. We found a strong correlation of 0.8 between the median human rater and the duration of the decrease in spectral edge frequency. Conclusions The agreement of neurophysiologists is moderate for duration of postictal changes and high for seizure termination. Rater determination of postictal duration is correlated with measures of EEG slowing. Significance Disagreement between neurophysiologists on postictal duration need to be considered.

Detection of epileptogenic focus based on electroencephalogram (EEG) signal screening is an important pre-surgical step to remove affected regions inside the human brain. Considering the fact above, in this work, a novel technique for detection of focal EEG signals is proposed using a combination of empirical mode decomposition (EMD) and Teager–Kaiser energy operator (TKEO). EEG signals belonging to focal (Fo) and non-focal (NFo) groups were at first decomposed into a set of intrinsic mode functions (IMFs) using EMD. Next, TKEO was applied on each IMF and two higher-order statistical moments namely skewness and kurtosis were extracted as features from TKEO of each IMF. The statistical significance of the selected features was evaluated using student's t-test and based on the statistical test, features from first three IMFs which show very high discriminative capability were selected as inputs to a support vector machine classifier for discrimination of Fo and NFo signals. It was observed that the classification accuracy of 92.65% is obtained in classifying EEG signals using a radial basis kernel function, which demonstrates the efficacy of proposed EMD-TKEO based feature extraction method for computer-based treatment of patients suffering from focal seizures.

This study was funded by Laboratorios Bial, S.A. (Madrid, Spain)., The authors thank Alejandro Pedromingo (Bio-estadistica. com, Madrid, Spain) for the statistical analysis, and Isabel San Andrés (Incimed, Madrid, Spain) for performing the literature search. Their participation has been funded by Laboratorios Bial, S.A. (Madrid, Spain)., Aim of the study To assess the effectiveness, overall tolerability of eslicarbazepine acetate (ESL) as an initial or early monotherapy treatment of adult patients with focal epilepsy under real-world practice conditions. Materials and methods We focused on real-world longitudinal studies that included or separately reported the results of at least one of the efficacy outcomes of interest. A DerSimonian-Laird random effects model was used with the presentation of the 95% confidence intervals of the estimate Results 5 studies met our selection criteria and were included in the quantitative synthesis. All studies were observational and uncontrolled studies, and all but one were retrospective studies. The pooled proportion of patients who were seizure-free for the entire study period was 64.6% (95% CI, 45.7 to 79.8) at month 6 and 56.6% (95% CI, 50.2 to 62.8) at month 12. Pooled retention rates were 95.0% (95% CI, 90.3 to 97.5) at 6 months and 83.6% (95% CI, 73.9 to 90.1) at 12 months. The pooled proportion of patients who reported at least one adverse event was 27.2% (95% CI, 21.7 to 33.6), and the pooled proportion of patients who discontinued ESL due to adverse events was 8.9% (95% CI 6.2 to 12.6). Conclusions Our results suggest that initial or early monotherapy with ESL is effective and well-tolerated for the management of adult patients with focal epilepsy in clinical practice, with results that are at least similar to those reported in the pivotal randomized clinical trial of ESL monotherapy. No new safety signals with ESL have been identified in this systematic review., Bial Group

Darshan Mehta,1 Matthew Davis,2 Andrew J Epstein,3 Brian Wensel,1 Todd Grinnell,4 G Rhys Williams1 1Sunovion Pharmaceuticals Inc., Marlborough, MA, USA; 2Medicus Economics, LLC, Milton, MA, USA; 3Medicus Economics, LLC, Philadelphia, PA, USA; 4Medical Affairs, Sunovion Pharmaceuticals Inc., Marlborough, MA, USACorrespondence: Darshan MehtaAssociate Director, Health Economics and Outcomes Research, Sunovion Pharmaceuticals Inc, 84 Waterford Drive, Marlborough, MA, 01752, USATel +1-774-369-7913Email Darshan.Mehta@sunovion.comObjective: To examine the association between initiating first-line (1L) monotherapy with eslicarbazepine acetate (ESL) vs a generic antiseizure drug (ASD) and healthcare resource utilization (HCRU) and charges in adults with treated focal seizures (FS).Methods: This was a retrospective analysis of Symphony Health’s Integrated Dataverse® open-source claims data. Two cohorts were identified as having initiated 1L monotherapy with ESL or literature-defined generic ASDs. Linear regression models with person fixed effects and inverse probability treatment weights assessed the relative additional changes in HCRU and charges among patients who received ESL compared to generic ASD.Results: A total of 250 and 43,220 patients initiated ESL (48.3 years; 57.2% female) or a generic ASD (54.5 years; 58.1% female), respectively. Compared to patients initiating a generic ASD, patients treated with ESL had additional reductions of 11.8 percentage points in the likelihood of any all-cause outpatient visits (P< 0.001), 7.4 percentage points in the likelihood of any emergency department (ED) visits (P=0.013), and 22.7 percentage points in the likelihood of any FS-related outpatient visits (P< 0.001). Patients initiating ESL had greater reductions in mean charges for all-cause medical ($2620; P=0.002), outpatient ($1995; P=0.005), and non-FS-related medical ($2708; P< 0.001) services. Patients initiating ESL had greater relative increases in mean total prescription ($1368; P< 0.001) and ASD-related prescription ($1636; P< 0.001) charges, but greater relative reductions in non-ASD prescription ($269; P=0.032) charges. The increases in prescription charges were of a lower magnitude than the decreases in medical charges.Conclusion: Initiation of ESL as 1L monotherapy was associated with statistically significantly greater reductions in any use of several all-cause and FS-related services, number of visits, and charges compared to initiation of a generic ASD as 1L monotherapy in patients with FS. Initiation of a generic ASD as 1L monotherapy was associated with significantly smaller increases in total prescription charges and ASD-related prescription charges.Keywords: eslicarbazepine acetate, focal seizures, healthcare resource utilization, medical charges

Focal seizures in neonates presenting to the emergency department can be potentially dangerous and life-threatening. Hypoparathyroidism is an exceedingly rare but treatable cause of focal neonatal seizures. Due to its weak association with neonatal seizures, hypoparathyroidism often remains undetected as a potential cause. We hereby elucidate a rare case of idiopathic hypoparathyroidism presenting as right-sided focal seizures in a 12-day-old female neonate with an uneventful birth history. Despite the administration of antibiotics and phenobarbitone, the seizures remained unabated. Laboratory workup revealed the diagnosis of late-onset hypocalcemia with severe hypoparathyroidism. The patient was subsequently treated with calcium supplements and alfacalcidol. Thereafter, the frequency of seizures gradually decreased and the same treatment regimen was continued until the patient was seizure-free. The patient continues to do well to date with complete remission of his clinical symptoms.

Brivaracetam (BRV) is indicated for adjunctive treatment of focal (partial-onset) seizures with or without secondary generalisation in patients 4 years of age and older in the European Union (EU). An ongoing 12-month, prospective, non-interventional post-marketing study (EP0077; NCT02687711) is collecting real-world information on patients receiving treatment with adjunctive BRV in Europe. In this study, BRV is prescribed according to routine clinical practice and the EU Summary of Product Characteristics. This second interim analysis assessed effectiveness, tolerability and health-related quality of life outcomes for up to 6 months of treatment.At the cut-off date (13 April 2018), 266 patients from five countries had attended Visit 1, 24.1 % (64/266) had completed the study, 37.6 % (100/266) were ongoing, and 38.3 % (102/266) had discontinued. In total, 261 patients had at least one dose of BRV and were included in the analyses. Patients had a mean time since epilepsy diagnosis of 23.2 years, a mean of eight lifetime AEDs (sum of AEDs discontinued prior to study entry and concomitant at study entry), and a median of five focal seizures per 28 days during the 3-month retrospective Baseline. 66.3 % of patients initiated BRV at a dose within the recommended starting range (50-100 mg/day) and 87.1 % of patients received BRV modal doses within the recommended dose range (50-200 mg/day) during the study. Retention rates were 79.1 % (N = 239) at 3 months and 62.1 % (N = 211) at 6 months. The 50 % responder rates for focal seizures were 46.8 % (N = 139) at 3 months and 53.6 % (N = 97) at 6 months. The proportions of patients who were seizure-free were 10.7 % (21/196) and 7.5 % (15/199) at 3 and 6 months of treatment, respectively. Median percent reductions in focal seizure frequency per 28 days from Baseline to 3 and 6 months were 34.6 % (N = 139) and 53.3 % (N = 97), respectively. Overall, 44.2 % of patients had an improvement and 15.4 % had a worsening in Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 total score from Baseline to 6 months (N = 52). At least one treatment-emergent adverse event (TEAE) was reported in 51.0 % (133/261) of patients, and 34.5 % (90/261) of patients had drug-related TEAEs. The most common drug-related TEAEs (>= 5% of patients) were drug ineffective (7.7 %), seizure (6.5 %), and fatigue (6.1 %).In this 6-month interim analysis, BRV showed effectiveness when used in clinical practice in five European countries. BRV was well tolerated, and no new safety signals were observed.

Hemimegalencephaly (HME) and its more localized form - posterior quadrantic dysplasia (PQD) - are rare malformations of cortical development (MCD) that normally manifest as refractory focal epilepsy and cognitive impairment in children. We report a case study of a 19-year-old woman who presented with seizure-like symptoms to the emergency department after discontinuing her seizure treatment having fled her country. MRI revealed typical signs of PQD. This case study demonstrates how an unusual mild clinical presentation led to the late diagnosis of this rare MCD.

We report the case of an adult psychiatric patient who developed new-onset focal bilateral motor seizures (FBMS) in the context of a severe benzodiazepine withdrawal syndrome. The patient was forced to interrupt chronic lormetazepam abuse and overdosed on amitriptyline (800 mg in an oral solution) before the onset of seizures. Typical signs of amitriptyline intoxication such as sedation and anticholinergic effects were not observed. Video-EEG recordings revealed a stereotypical ictal motor pattern with asymmetric tonic posturing and bilateral clonic movements of the upper limbs, but there were no abnormalities identified by EEG. Seizures recurred multiple times per day but resolved simultaneously when withdrawal symptomatology subsided eight days after onset. Nonepileptic seizures (NES) were considered in the differential diagnosis because of the patient's psychiatric history including preserved awareness during the bilateral convulsions, the absence of postictal confusion, and normal EEG. The present case indicates that FBMS may occur during benzodiazepine withdrawal in patients who overdosed on amitriptyline. The diagnosis may be challenging as FBMS may mimic NES in the absence of abnormal neurophysiologic findings. This may be especially challenging in patients with an underlying psychiatric disease., Highlights • Focal onset seizures may be observed in patients with benzodiazepine withdrawal syndrome. • Focal bilateral motor seizures may mimic nonepileptic seizures in psychiatric patients with normal EEG findings. • The use of lormetazepam in the form of an oral solution containing ethanol should be carefully monitored to prevent abuse.

Limb shaking is a paroxysmal involuntary hyperkinetic movement that may be a presentation of severe unilateral steno-occlusive carotid disease. This unusual form of transient ischemic attack (TIA) is often misdiagnosed as focal motor seizures, especially with frequent repetition. We present a case of 67-year-old man with severe unilateral carotid stenosis leading to frequent left arm shaking TIAs. Initial work-up did not reveal any abnormalities, and anticonvulsant was started. He readmitted again after few days with left side mild hemiparesis. Cerebrovascular evaluation showed recent watershed infarction with significant stenosis in the ipsilateral internal carotid artery (ICA). The patient underwent stenting of the right ICA with weakness improvement and no more limb-shaking TIA on follow-up. In conclusion, early recognition of limb-shaking TIAs and differentiating it from focal motor seizures can facilitate identification of pre-occlusive carotid stenosis, allowing for appropriate interventions to prevent further TIAs or disabling stroke.

OBJECTIVE: To assess feasibility and efficacy of subtraction ictal SPECT coregistered to MRI (SISCOM) for epilepsy localization in children who are candidates for resective surgery. METHODS: We retrospectively reviewed all patients ≤16 years with drug-resistant epilepsy screened for epilepsy surgery in the University Hospital of Leuven from January 2009 to January 2018. Fifty-eight hospitalizations for ictal SPECT and 51 SISCOM analyses in 44 patients were included. Mean age was 9.1 years. Hospitalizations for SISCOM were analyzed in terms of multiple variables affecting feasibility and efficacy. The localization of SISCOM was compared with the localization of the presumed epileptogenic zone (PEZ) as determined by video-EEG. RESULTS: SISCOM was feasible in terms of chronic medication management, rescue antiepileptic therapy during hospitalization, and operative timings. Radiotracer injection occurred within 30 seconds from seizure onset in 91.4% of the patients. ictal SPECT imaging was performed within two hours from injection in 100% of the patients (mean: 40 minutes). SISCOM was able to localize the PEZ in 51.0% (26/51) and to additionally lateralize the PEZ in 17.6% (9/51), achieving better localizations than ictal SPECT, FDG-PET, and MRI (P

Epileptic seizures (ES) are frequent in critically ill patients and their detection and treatment are mandatory. However, sometimes it is quite difficult to discriminate between ES and non-epileptic bursts of periodic activity (BPA). Our aim was to characterize ES and BPA by means of quantified electroencephalography (qEEG). Records containing either ES or BPA were visually identified and divided into 1 s windows that were 10% overlapped. Differential channels were grouped by frontal, parieto-occipital and temporal lobes. For every channel and window, the power spectrum was calculated and the area for delta (0&ndash, 4 Hz), theta (4&ndash, 8 Hz), alpha (8&ndash, 13 Hz), and beta (13&ndash, 30 Hz) bands and spectral entropy (Se) were computed. Mean values of percentage changes normalized to previous basal activity and standardized mean difference (SMD) for every lobe were computed. We have observed that BPA are characterized by a selective increment of delta activity and decrease in Se along the scalp. Focal seizures (FS) always propagated and were similar to generalized seizures (GS). In both cases, although delta and theta bands increased, the faster bands (alpha and beta) showed the highest increments (more than 4 times) without modifications in Se. We have defined the numerical features of ES and BPA, which can facilitate its clinical identification.

Epileptic seizures are generally classified as either focal or generalized. It had been traditionally assumed that focal seizures imply localized brain abnormalities, whereas generalized seizures involve widespread brain pathologies. However, recent evidence suggests that large-scale brain networks are involved in the generation of focal seizures, and generalized seizures can originate in localized brain regions. Herein we study how network structure and tissue heterogeneities underpin the emergence of focal and widespread seizure dynamics. Mathematical modeling of seizure emergence in brain networks enables the clarification of the characteristics responsible for focal and generalized seizures. We consider neural mass network dynamics of seizure generation in exemplar synthetic networks and we measure the variance in ictogenicity across the network. Ictogenicity is defined as the involvement of network nodes in seizure activity, and its variance is used to quantify whether seizure patterns are focal or widespread across the network. We address both the influence of network structure and different excitability distributions across the network on the ictogenic variance. We find that this variance depends on both network structure and excitability distribution. High variance, i.e., localized seizure activity, is observed in networks highly heterogeneous with regard to the distribution of connections or excitabilities. However, networks that are both heterogeneous in their structure and excitability can underlie the emergence of generalized seizures, depending on the interplay between structure and excitability. Thus, our results imply that the emergence of focal and generalized seizures is underpinned by an interplay between network structure and excitability distribution.

Rasmussen syndrome (RS) is a chronic encephalopathy with uncertain etiology and immune-mediated pathogenesis. The only definitive treatment is represented by functional hemispherectomy. We describe the case of a 6.5-year-old female patient who developed several episodes of focal, unilateral clonic seizures. Following laboratory and instrumental investigations, the patient was diagnosed as having RS. A treatment with corticosteroids, intravenous immunoglobulin, and the antiseizure medication (carbamazepine and levetiracetam) did not completely control the seizures. Therefore, the patient was treated with mycophenolate mofetil (MMF), showing a good clinical response, with reduction of the seizures, and stability of the radiological findings. This case suggests the potential utility of MMF in the immune approach to RS., Highlights • Rasmussen encephalitis (RE) is an immune-mediated disease of unknown etiology. • Current definitive treatment for RE is represented by hemispherectomy. • The immune approach of RE has been performed with several agents. • In this case, mycophenolate mofetil was successfully used in a patient with RE.

Objective: To assess the efficacy, safety, and tolerability of eslicarbazepine acetate (ESL) monotherapy during long-term treatment. Methods: An open-label extension (OLE) study was conducted in adults completing a phase 3, randomized, double-blind, noninferiority trial, during which they had received monotherapy with either once-daily ESL or twice-daily controlled-release carbamazepine (CBZ-CR) for newly diagnosed focal epilepsy. In the OLE study, all patients received ESL (800-1600 mg/d) for 2 years. Primary efficacy outcome was retention time (from baseline of the OLE study). Secondary efficacy assessments included seizure freedom rate (no seizures during the OLE study) and responder rate (≥50% seizure frequency reduction from baseline of double-blind trial). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs). Results: Of 206 randomized patients, 96 who received ESL in the double-blind trial (ESL/ESL) and 88 who received CBZ-CR in the double-blind trial (CBZ-CR/ESL) were treated with ESL monotherapy (89.3% overall). Treatment retention time was similar between groups, with low probability of ESL withdrawal overall (80% in both groups throughout the study. Incidence of serious TEAEs was similar between groups (7.3% vs 5.7%; 0% vs 1.1% possibly related), as were the incidences of TEAEs considered at least possibly related to treatment (17.7% vs 18.2%) and TEAEs leading to discontinuation (3.1% vs 4.5%). The types of TEAEs were generally consistent with the known safety profile of ESL. Significance: ESL monotherapy was efficacious and generally well tolerated over the long term, including in patients who transitioned from CBZ-CR monotherapy. No new safety concerns emerged. info:eu-repo/semantics/publishedVersion

Few studies have reported the impact of intensive exercise on seizure susceptibility. Here, we present a case in which a patient developed drug-resistant focal epilepsy after craniotomy for a low-grade glioma. She had a marked reduction in seizure frequency after switching from moderate exercise to a high-intensity exercise program. Psychological benefits of exhaustive exercise included decreased suicide ideation, in part mediated by fewer seizures., Highlights • A case who started high-intensity exercise had a decline in seizure frequency. • In conjunction with diet, high intensity exercise increased urine ketones. • High-intensity exercise decreased suicide ideation and improved quality of life.

Background. Adequate selection of the 1st antiepileptic drug (AED) is an obligatory condition for the successful treatment of epilepsy. It is well known that the first drug in the treatment of infantile spasms (IS) in tuberous sclerosis complex (TSC) is vigabatrin (VGB). With regard to focal seizures (FS) in TSC, there are certain differences: some authors insist on VGB (P. Curatolo, 2012), others as the first choice drugs are mentioning carbamazepine and valproate (A. Saxena, 2015). Data in general on the possible effectiveness of medical treatment of epilepsy in TSC, and the effectiveness of different AEDs are also contradictory.Objective: to make a comparative evaluation of the efficacy of various AEDs in the treatment of epilepsy in patients with TC.Materials and methods. Retrospective analysis of medical records of patients hospitalized with epilepsy and TSC in the Department of Epileptology and Psychoneurology, Research and Clinical Institute for Pediatrics named after Yu.E Vel’tishev of N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, for the last 2 years was completed. Efficacy analysis was conducted in 134 patients (91 (67.9 %) with FS and 43 (32.1 %) with IS). Efficacy was estimated as the remission of epileptic seizures during 6 months. The percentage of patients with remission was also evaluated (seizures were stopped for 1 year or more) and percentage of patients with a decrease in the number of seizures. The results of the first monotherapy and the subsequent administration of two and three AEDs were analyzed.Results. Low efficiency of AEDs in starting monotherapy was noted – the remission of seizures within 6 months on any AED was only 27.5 % (25 from 91) with FS, with IS – 13.9 % (6 from 43). Remission on any 1st AED was observed only in 13.2 % (12 from 91) and 6.9 % (3 from 43), respectively. The effectiveness of individual AED is low, especially in achieving stable remission. So, valproate caused remission of FS in 14 (22.2 %) from 63, but in the future remission was stable only in 11 (17.5 %) from 63. VGB as the first monotherapy proved to be effective in 5 from 6 patients with FS and in 4 from 6 patients with IS. The introduction of the 2nd drug added another 13.3 % and 38.6 % of patients with remission of seizures, the 3rd AED – 7.3 % and 7.7 % in FS and IS, respectively. Most often, an effective drug in additional therapy was VGB. The efficiency of VGB was reduced if it was used not as the first, but as the second and third AED. The percentage of unsuccessful treatment (including combined therapy) is estimated as 51.5 % and 47.8 % of patients with FS and IS, respectively.Conclusion. Epilepsy associated with TSC is less sensitive to AEDs and gives a smaller percentage of remissions. Perhaps in our country this is due to the difficulties of prescription of VGB as a starting therapy for epilepsy in the patients with tuberous sclerosis complex.

Ictal syncope is a rare phenomenon that occurs in association with 0.002–0.4% of seizures. In the absence of other symptoms, seizures presenting with syncope may be challenging to diagnose. We report a case of a previously healthy male who developed recurrent episodes of syncope with postictal confusion and was later diagnosed with temporal seizures. The patient was successfully treated with anti-seizure drugs and placement of a cardiac pacemaker. In a systematic review of literature, we summarize the clinical characteristics of patients with ictal asystole and isolated syncope. Seizures should be considered in patients with syncope of uncertain etiology., Highlights • Focal seizures leading to bradycardia-asystole can be accompanied by sudden atonia with loss of consciousness • Ictal syncope as the only symptom of seizure represents an exceptionally rare phenomena that may mimic other paroxysmal neurological events • Patients with recurrent syncopal events of uncertain etiology should have seizures considered in the differential diagnosis