Focal Onset Seizures Research Articles

Multi-centric Phase III, single-arm, open-label clinical study to assess clinical safety, tolerability, and efficacy of intravenous lacosamide in focal onset seizures

Background: In hospitalized seizure patients and during clinical seizure emergencies, parenteral administration of antiepileptic therapy (AED) is primary treatment modality. Appropriate selection and administration of AED is essential for immediate seizure control. The purpose of this study was to evaluate the safety, tolerability, and efficacy of lacosamide injection in adult patients with focal onset seizures (FOS) with or without secondary generalized tonic-clonic seizures or focal to bilateral tonic-clonic seizures. Methods: In this Phase 3 study, we enrolled 60 patients (≥18 years) with FOS and maintained on stable doses of oral lacosamide. Patients were switched to intravenous (i.v.) lacosamide (10 mg/ml); daily i.v. dosage and frequency were kept equivalent to oral lacosamide per patient. Lacosamide was infused intravenously over for 30 to 60 minutes at 12 hourly intervals for five consecutive days. Primary outcome was evaluating the safety and secondary outcome included measuring the seizure frequency during the treatment (day 1- 5) and at follow-up (day 12). Results: All patients enrolled completed the study. No significant changes in vital signs, or laboratory parameters, were observed at the end of treatment or follow-up when compared to baseline. The frequency analysis for all the components of electrocardiogram (ECG) was within the normal limits at all times. There were no serious adverse events (AEs) reported in this study. Overall, 26.66% of patients had mild to moderate AE intensity that resolved spontaneously without any other intervention. Most common AEs (frequency=5%) were abdominal pain upper, injection site pruritus, and nausea. The anti-seizure activity for lacosamide was maintained despite oral to i.v. switch of lacosamide. Conclusions: The study showed that i.v. lacosamide is a safe and effective strategy in patients with FOS and can be co-administered with other anti-epileptic drugs (AEDs), especially in acute settings with primary generalized tonic-clonic seizures. Registration: CTRI (CTRI/2011/07/001888; 14th July 2011).

Heterogeneity of clinical features, EEG and brain imaging findings in anti-leucine-rich glioma-inactivated protein 1 autoimmune encephalitis: a retrospective case series study and review of the literature

BackgroundAnti-leucine-rich glioma-inactivated 1 (LGI-1) autoimmune encephalitis (AE), characterized by rapid decline of memory, seizures, and neuropsychiatric abnormalities, is a rare but devastating disorder. Early diagnosis and treatment are essential to prevent long-term sequelae. In this report, we provide a detailed description of clinical characteristics, laboratory test results, imaging, and electroencephalography (EEG) findings, as well as treatment responses of eight patients with anti-LGI-1 AE treated at our center.Case presentationAt the onset, all eight patients presented with confusion/memory deterioration, seizures (including faciobrachial dystonic seizures or other types of seizure), and behavioral changes such as hallucination, paranoia, and anxiety. Four patients were found with severe hyponatremia. Anti-LGI1 antibodies were detected in the cerebrospinal fluid and/or serum of all patients. For patients with faciobrachial dystonic seizures, no discernible scalp EEG change was detected, while EEG recording of patients experiencing other types of seizure showed focal slowing, focal epileptiform discharges, and focal onset seizures. All patients showed abnormal brain magnetic resonance imaging signals, mainly involving the mesial temporal lobe and the hippocampus. In addition, one patient also experienced fulminant cerebral edema during the acute phase of the illness. All patients received immunotherapy and anti-seizure medications and achieved good seizure control. Nevertheless, these patients continued to experience cognitive impairment during their long-term follow-ups.ConclusionsThe care of anti-LGI1 AE patients requires rapid evaluation, prompt initiation of immunotherapy, and long-term follow-up. The long-term presence of neurocognitive complications observed in these patients underline the importance of developing reliable biomarkers that can distinguish between different subtypes of this disease with heterogeneous clinico-electrographico-radiological features. Further research is needed to understand the molecular mechanisms underlying the heterogeneity, in order to facilitate development of more effective treatments for anti-LGI1 AE.

Focal Onset Seizures: New Treatment Options in The Clinical Practice

This symposium took place during the 2023 Congress of the European Academy of Neurology (EAN). Mar Carreño, Director, Epilepsy Unit, Hospital Clínic and Instituto Clavel, Barcelona, Spain, presented the definition of drug-resistant epilepsy (DRE), and stressed that uncontrolled epilepsy does not necessarily indicate DRE. Before a diagnosis of DRE is made in a patient not responding to medication, questions should be asked regarding the initial epilepsy diagnosis. Carreño discussed paroxysmal events that may mimic epilepsy, and presented three cases of misdiagnosed DRE that were subsequently correctly identified as cardiac syncope, a psychogenic event, and use of inappropriate medication in a patient with generalised epilepsy. The second part of Carreño’s presentation focused on patients with confirmed DRE. They outlined the complications of DRE, including sudden unexpected death in epilepsy (SUDEP), which should be discussed with the patient. Carreño finished their lecture with a discussion of comorbid conditions, including neuropsychiatric comorbidities, which affect one in three patients with epilepsy. Bernhard J. Steinhoff, Medical Director, Kork Epilepsy Center, Kehl, Germany, then discussed the clinical approach to patients with DRE, including treatment options, the range of anti-seizure medications (ASM), and the reasons for failure of first-line treatment, noting that the probability of achieving seizure freedom decreases with each failed ASM. Steinhoff explored the options of substitution monotherapy or combination therapy after failure of the first ASM, before describing cenobamate (CNB) add-on therapy. A randomised, placebo-controlled, dose-response trial showed that adjunctive CNB reduced focal (partial)-onset seizure frequency in a dose-related fashion. Several papers have been published providing real-world evidence to show that adjunctive CNB therapy is associated with improved seizure outcomes, and that the number of concomitant ASMs could be reduced. The symposium concluded with a question and answer session.

Epilepsy Due to Solitary Calcified Cysticercus Granuloma.

The calcified stage of the neurocysticercosis (NCC) is the common cause of acquired epilepsy in low and middle income countries in people aged > 20 years. Approximately 30% of adult onset seizures and epilepsy are attributable to NCC. In India and some of the Latin American countries, epilepsy due to solitary calcified NCC is the common adult onset epilepsy. The current evidence suggests that the calcified cysticercus granuloma is probably the epileptogenic focus. The mechanisms involved in the epileptogenic process are not well understood; Focal-onset seizures with or without impaired awareness are the common seizure type. Focal-onset seizure can evolve to bilateral tonic-clonic seizure. Seizure outcome with anti-seizure medication, most often with monotherapy, is very good. The seizure disorders associated with various stages of NCC can be preventable.

Cenobamate (YKP3089) and Drug-Resistant Epilepsy: A Review of the Literature.

Cenobamate (CNB), ([(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl], is a novel tetrazole alkyl carbamate derivative. In November 2019, the Food and Drug Administration approved Xcopri®, marketed by SK Life Science Inc., (Paramus, NJ, USA) for adult focal seizures. The European Medicines Agency approved Ontozry® by Arvelle Therapeutics Netherlands B.V.(Amsterdam, The Neatherlands) in March 2021. Cenobamate is a medication that could potentially change the perspectives regarding the management and prognosis of refractory epilepsy. In this way, this study aims to review the literature on CNB's pharmacological properties, pharmacokinetics, efficacy, and safety. CNB is a highly effective drug in managing focal onset seizures, with more than twenty percent of individuals with drug-resistant epilepsy achieving seizure freedom. This finding is remarkable in the antiseizure medication literature. The mechanism of action of CNB is still poorly understood, but it is associated with transient and persistent sodium currents and GABAergic neurotransmission. In animal studies, CNB showed sustained efficacy and potency in the 6 Hz test regardless of the stimulus intensity. CNB was revealed to be the most cost-effective drug among different third-generation antiseizure medications. Also, CNB could have neuroprotective effects. However, there are still concerns regarding its potential for abuse and suicidality risk, which future studies should clearly assess, after which protocols should be changed. The major drawback of CNB therapy is the slow and complex titration and maintenance phases preventing the wide use of this new agent in clinical practice.

Value contribution of cenobamate for the treatment of Focal-Onset Seizures (FOS) in patients with drug-resistant epilepsy (DRE) in Spain through reflective Multi-Criteria Decision Analysis (MCDA)

IntroductionEpilepsy is one of the most common neurological conditions worldwide. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, despite the availability of many anti-seizure medications, including the latest options, called third-generation anti-seizure medications (ASMs), approximately 40% of people with epilepsy present drug-resistant epilepsy (DRE). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. In a chronic disease with a portfolio of available ASMs, the decision to introduce a new therapeutic alternative must follow a holistic evaluation of value provided. Reflective Multi-Criteria Decision Analysis (MCDA) methodology allows to determine the value contribution of a treatment in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner from the perspective of relevant stakeholders. PurposeThe aim of this study was to determine the relative value contribution of cenobamate in the treatment of FOS in patients with DRE compared with third-generation ASMs using reflective MCDA-based methodology. MethodsA systematic literature review (combining biomedical databases and grey literature sources) was performed to populate the Evidence and Value: Impact on DEcisionMaking (EVIDEM) MCDA framework adapted to determine what represents value in the management of FOS in patients with DRE in Spain. The study was conducted in two phases. The first took place in 2021 with a multi-stakeholder group of eight participants. The second phase was conducted in 2022 with a multi-stakeholder group of 32 participants. Participants were trained in MCDA methodology and scored four evidence matrices (cenobamate vs. brivaracetam, vs. perampanel, vs. lacosamide and vs. eslicarbazepine acetate). Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. ResultsDRE is considered a very severe condition associated with many important unmet needs, mainly with regard to the lack of more effective treatments to achieve the ultimate goal of treatment. Compared to third-generation ASMs, cenobamate is perceived to have a better efficacy profile based on improvements in responder rate and seizure freedom. Regarding safety, it is considered to have a similar profile to alternatives and a positive quality-of-life profile. Cenobamate results in lower direct medical costs (excluding pharmacological) and indirect costs. Overall, cenobamate is regarded as providing a high therapeutic impact and supported by high-quality evidence. ConclusionsBased on reflective MCDA methodology and stakeholders’ experience in clinical management of epilepsy in Spain, cenobamate is perceived as a value-added option for the treatment of patients with DRE when compared with third-generation ASMs.

Efficacy and tolerability of immediate switch from sodium channel blockers to Lacosamide

Lacosamide (LCM) is a new-generation anti-seizure medication approved for monotherapy and add-on therapy for focal-onset epilepsy. It has novel pharmacodynamics and favorable pharmacokinetic qualities with good clinical response. This study aims to evaluate the effectiveness and tolerability of LCM when used in the immediate switch from sodium channel blockers in patients with focal-onset and generalized-onset epilepsies. This retrospective, multicenter observational study was conducted with adult patients who received LCM as mono- or polytherapy through immediate switch with 6 to 52 months follow-up. The clinical data obtained during the follow-up period were analyzed to assess retention rate, seizure freedom, more than 50% seizure reduction, and adverse effects. A total of 32 patients (eight females, 24 males) with a median age of 49.75 (range, 23–86) years, median age at epilepsy onset of 32.58 (range, 0.5–85) years, and median epilepsy duration of 17.17 (range, 1–46) years were included in this study. Seizure frequency was between 1 and 90 in the past 6 months. Seven (21.9%) of the patients had structural brain lesions and 27 (84.4%) of the patients had EEG abnormalities. The adverse effects leading to switching were hyponatremia, rash, elevated liver enzymes, pain, and erectile dysfunction. At 14.34 (range, 6–52) months follow-up, 30 (93.75%) patients in total retained LCM, 20 (66.7%) of them were seizure-free, and 13 were on LCM monotherapy. Responder rate was 81.25%. Eight (25%) of the patients experienced adverse effects after the immediate switch. One patient with generalized-onset epilepsy needed to quit LCM due to an increase in seizures. Seizure frequency did not change in three patients in the focal-onset group. Immediate switch to LCM showed favorable outcomes with a significant reduction in seizure frequency, high retention rates, and tolerable adverse effect profiles in both focal-onset and generalized-onset seizures.

Potential efficacy and safety of eslicarbazepine acetate oral loading in patients with epilepsy.

Eslicarbazepine acetate (ESL) is a new antiseizure medication (ASM) approved as an adjunctive therapy or monotherapy for focal onset seizures. We performed this study to explore the potential efficacy and safety of ESL oral loading in selected patients with epilepsy. Thirty adult patients with status epilepticus or acute repetitive seizures were enrolled, and ESL was administered at a single loading dosage of 30 mg/kg. Plasma levels of an active metabolite of ESL, monohydroxy derivative (MHD), were measured at 2, 4, 6, 12, and 24 h after ESL oral loading. Two thirds of the patients reached a therapeutic level of MHD 2 h after ESL loading, and most of the patients achieved a therapeutic range within 12 h after loading. Plasma MHD levels did not rise above the supratherapeutic level in any patient throughout the study. The reported adverse effects included one patient with gaze-evoked nystagmus and another patient with a rash. No serious adverse events leading to drug discontinuation occurred. There was no discernible difference in sodium levels before and after ESL oral loading. Our study findings suggest that ESL oral loading could be a useful therapeutic option for patients with epilepsy who need rapid elevations in the therapeutic levels of ASMs.

Efficacy and safety of perampanel monotherapy in patients with focal-onset seizures:A real-world experience in eastern China

ObjectiveTo assess the effectiveness and tolerability of perampanel (PER) monotherapy in real-world practice for the treatment of focal-onset seizures (FOS) in eastern China. MethodThis is a single-center, retrospective study of patients with FOS, aged ≥ 4 years, who had been prescribed PER as monotherapy. Outcomes included retention, seizure-free, and responder rates at 3, 6 and 12 months and adverse events (AEs) throughout the follow-up period. The efficacy and AEs of PER monotherapy in patients with aged < 14 years old and ≥ 14 years old were also compared. ResultsSixty-seven patients with FOS who received PER monotherapy and completed a one-year follow-up were included in the analysis. The median maintenance dose was 4 mg. Modified intent-to-treat analysis demonstrated that the retention rates of PER monotherapy at follow-up of 3, 6 and 12months were 75%, 70% and 63%, respectively. At the same points, seizure-free rates of PER monotherapy were 69%, 63% and 52%, and responder rates were 69%, 66% and 61%, respectively. Patients with sleep-related seizures had higher seizure-free rates at 12 months of follow-up. No significant difference in seizure-free and responder rates was found between the aged < 14 years old and the aged ≥ 14 years old. Twenty-one patients (31.3%) had AEs and five patients discontinued using PER because of intolerant AEs. Common AEs were dizziness, irritability and somnolence. The AEs rate in patients < 14 years was 17.9%, significantly lower than patients ≥ 14 years. ConclusionsOur findings revealed the real-world data of patients in eastern China with FOS using PER as monotherapy. Patients had good retention, seizure-free and responder rates, and relatively low AEs rate at a low dose of PER treatment.

Report of three patients with extensive neurocysticercosis in rural southern Tanzania: neurological, serological and neuroradiological findings

BackgroundNeurocysticercosis (NCC) is common in eastern Africa, but disease presentation varies considerably. Most patients have single or few NCC-typical lesions in their brain but some present with a large number of lesions. We present three patients with positive antibody-based serology for Taenia solium cysticercosis screened at the Vwawa district hospital, Mbozi district, southern Tanzania, in whom extensive NCC was confirmed by neuroimaging.Case presentationsPatient 1 was a 55-year-old female from the tribe Malila smallholder farmer who has had four generalized tonic–clonic epileptic seizures over a period of 11 years and one episode of transient left hemiparesis one year before seizure onset. The patient also reported monthly to weekly episodes of severe, progressive, unilateral headache. The computed tomography (CT) scan of the brain showed 25 NCC lesions of which 15 were in the vesicular stage. Patient 2 was a 30-year-old male from tribe Nyha mechanic who reported monthly episodes of moderate to severe, progressive, bilateral headache, but no epileptic seizures. The CT scan showed 63 NCC lesions of which 50 were in the vesicular stage. Patient 3 was a 54-year-old female from the tribe Malila smallholder farmer who suffered from frequent generalized tonic–clonic epileptic seizures with potential signs of focal seizure onset. She also reported weekly to daily episodes of severe, progressive, unilateral headache. The CT scan showed 29 NCC lesions of which 28 were in the vesicular stage.ConclusionsClinical presentation of NCC with multiple brain lesions varies considerably ranging from few epileptic seizures and severe headache to severe epilepsy with frequent epileptic seizures. Individuals with neurological signs/symptoms that may be due to NCC, based for example on epidemiological criteria or serological evidence of cysticercosis, are recommended to undergo neuroimaging before anthelminthic treatment is considered.

Equipotency of lacosamide to levetiracetam in new onset focal epilepsy: A randomized controlled trial.

Levetiracetam (LEV) is a well-established broad spectrum antiseizure medication (ASM) effective in focal, generalized, and myoclonic seizures whereas lacosamide (LCM) is a comparatively newer ASM currently approved only as an add-on agent in focal seizures. The aim of the study was to assess the efficacy and the tolerability of oral LCM as monotherapy in adult people with epilepsy (PWE) with new onset focal onset epilepsy compared with those receiving LEV. In this open-label single-center non-inferiority trial, PWE aged between 16 and 65 years suffering from new onset focal seizures, with or without secondary generalization were put on LCM monotherapy or LEV monotherapy. Data regarding demographic characteristics, seizure type and etiology, LCM and LEV daily dose, seizure frequency at baseline and at 6 months of follow-up, and seizure freedom rates were recorded. Thirty-five PWE on LCM (24 males), their mean age: 38.20 ± 16.62 years and 35 PWE on LEV (25 males, mean age: 38.91 ± 17.13 years) were enrolled. The most common type of seizure observed was focal to bilateral tonic-clonic seizure >70% followed by focal impaired awareness seizure and focal awareness seizure. Structural epilepsy was found in 21 among LCM group and 22 of LEV group. In the LCM group, the seizure frequency decreased from 3.33 ± 1.88 to 0.85 ± 1.09 (P = 0.001) at 6 months and from 3.61 ± 3.12 to 0.94 ± 1.24 (P = 0.001) in LEV group, intergroup difference (P = 0.74). At 6-month follow-up period, 78.9% in LCM arm and 87.9% in the LEV arm had experienced a 50% of reduction in seizure frequency while seizure freedom was attained in 43.3% of PWE in both the arms (P = 1). The most common treatment emergent adverse effects in the LCM group were fatiguability, dyspepsia, headache, and dizziness, while in the LEV group; somnolence and behavioral abnormality. Treatment with LCM met the non-inferiority criteria when compared with LEV. Therefore, it might be useful as first-line monotherapy for adults with newly diagnosed focal epilepsy.

Safety and effectiveness of perampanel monotherapy after adjunctive therapy through retention rate in subjects with focal-onset seizures with or without focal to bilateral tonic-clonic seizures: A multicenter retrospective study in Korea

ObjectiveTo assess the effectiveness and tolerability of perampanel monotherapy following conversion from adjunctive therapy. MethodsThis was a multicenter, retrospective, non-interventional study of Korean patients aged ≥12 years with focal-onset seizures (FOS) with or without focal to bilateral tonic-clonic seizures. Data were extracted from electronic medical records of perampanel-treated patients from 1 February 2016 to 31 October 2020. Kaplan–Meier estimated retention rates, effectiveness, and safety were recorded. ResultsSubjects (n = 66, mean age 46.2 years) were mostly male (68.2%) with focal to bilateral tonic-clonic seizure (71.2%). Mean duration of illness was 86.3 months. Retention rates after conversion to perampanel monotherapy at 3, 6, and 12 months (primary outcome) were 96.0%, 96.0%, and 75.6%, respectively. Overall retention rates in patients receiving perampanel as adjunctive or monotherapy at 3, 6, 12, 18, and 24 months after perampanel add-on were 100%, 98.3%, 95.9%, 92.6%, and 92.6%, respectively. Mean retention duration was 41.2 months (overall perampanel administration) and 21.4 months (monotherapy). Mean seizure frequency/28 days in the Full Analysis Set (n = 61) was comparable for adjunctive and monotherapy (0.2 ± 0.79 vs 0.2 ± 0.64; change between adjunctive and monotherapy periods: 0.0 ± 0.59; p = 0.498). Perampanel was well tolerated and no new safety signals were identified. Dizziness (4.6%), only reported during adjunctive therapy, was the most common treatment-emergent adverse event. ConclusionsConversion to perampanel monotherapy from adjunctive therapy showed promising results in subjects with FOS with/without focal to bilateral tonic-clonic seizures; further studies in a larger population are needed to confirm these encouraging data.

Efficacy and Safety of Perampanel in Children with Drug-Resistant Focal-Onset Seizures: A Retrospective Review

Background: Epilepsy is one of the most common neurological disorders. Existing antiseizure medications (ASMs) are still unable to control seizures in one-third of these patients, making the discovery of antiseizure therapies with novel mechanisms of action a necessity. Aim of the Study: This study aimed to determine the safety and efficacy of perampanel (PER) as an adjuvant treatment for children with drug-resistant focal-onset seizures with or without focal to bilateral tonic-clonic seizures. Patients and methods: This is a single-center retrospective study of 38 epileptic pediatric patients, aged 2 to 14, at King Faisal Specialist Hospital and Research Center whose seizures were pharmaco-resistant to more than two antiseizure medications and followed for at least three months after PER adjuvant therapy initiation. Efficacy was assessed by the PER response rate at 3-, 6-, and 12-month follow-up evaluations, and side effects were also reported. Results: Multiple seizure types were reported. Myoclonic seizures were the predominant type of epilepsy in 17 children (44.7%). At 3 months, 6 months, and 12 months of follow-up, approximately 23.4%, 23.4%, and 18.4% of the patients were seizure-free at these time points, respectively. Adverse events were documented in 14 patients (35.7%) and led to the discontinuation of PER in 26.3%, 31.6%, and 36.8% of the studied group at the 3-, 6-, and 12-month follow-ups, respectively. The most common adverse events included dizziness or drowsiness, irritability, gait disturbance, and confusion; however, all were transient, and no serious adverse effects occurred. Conclusion: Our findings confirm the therapeutic efficacy of adjunctive PER in the treatment of drug-resistant epilepsy in children. As an adjunctive treatment for epilepsy, perampanel demonstrated sufficient effectiveness and tolerability.

Open-label study to investigate the safety and efficacy of adjunctive perampanel in pediatric patients (aged 4 to

PurposeTo evaluate the safety and tolerability of adjunctive perampanel in a Japanese subpopulation of Study 311 (NCT02849626), which was a global, multicenter, open-label, single-arm study of children (aged 4 to <12 years) with inadequately controlled focal-onset seizures (FOS), with or without focal to bilateral tonic-clonic seizures (FBTCS) or generalized tonic-clonic seizures (GTCS). MethodsStudy 311 comprised a Core Study, Extension A, and Extension B; this report focuses on the Japanese patient subgroup in the Core Study only. In the Core Study, Japanese patients (FOS only) received adjunctive perampanel ≤12 mg/day in a 23-week Treatment Phase. Endpoints included safety/tolerability (primary) and median percent change in seizure frequency per 28 days from baseline. Patients were stratified by age and concomitant enzyme-inducing anti-seizure medication (EIASM) use. ResultsOf 65 enrolled Japanese patients, 56 completed the Core Study and nine withdrew. The most common reason for discontinuation was adverse events (AEs) (n = 4 [6.2%]). The mean (standard deviation) daily dose of perampanel in Japanese FOS patients was 5.8 (2.2) mg/day. During the Core Study, treatment-emergent AEs (TEAEs) were reported by 89% of Japanese patients, most commonly nasopharyngitis (28%) and somnolence (28%). The median percent reduction in seizure frequency per 28 days from baseline was 37% and the lower limit of the 95% CI was greater than 10.5%, satisfying the pre-defined efficacy criteria. Perampanel was effective regardless of age or concomitant EIASM use. ConclusionPerampanel as adjunctive therapy is generally safe, well-tolerated, and efficacious in Japanese children aged 4 to <12 years with FOS (with/without FBTCS).

De novo ADGRV1 variant in a patient with ictal asystole provides novel clues for increased risk of SUDEP

BackgroundVarious cardiac and autonomic manifestations are frequently reported during seizures. Among the seizure-related arrhythmia, ictal tachycardia is the most common, followed by ictal bradycardia, with ictal asystole being the rarest. The occurrence of ictal asystole may obscure the clinical presentation and delay the diagnosis, representing a life-threatening presentation of epilepsy, with an elevated risk of sudden unexpected death in epilepsy patients (SUDEP). These cardiac abnormalities are being increasingly recognized as the key to elucidating the mechanisms of SUDEP.Case presentationWe present a 35-year-old man with a history of focal-onset seizures with impaired consciousness since his mid-20 s. He developed different types of seizures for 2 years, described as tonic seizure and atonic seizure (drop attack). During such clinical events, he suffered from falls and cardiac arrest. However, thorough cardiac electrophysiology and imaging workup failed to reveal a cardiac etiology. Subsequent video electroencephalograph (EEG) monitoring was performed, and ictal bradycardia and ictal asystole were discovered. A cardiac pacemaker was implanted, and at 3-year follow-up, the patient did not suffer more atonic seizures, or falls. Genetic tests discovered a de novo variant of Adhesion G Protein-Coupled Receptor V1 (ADGRV1), which may provide a clue for the patient’s ictal asystole and the increased risk of SUDEP.ConclusionsConsidering the important impact of ictal bradycardia and asystole on the morbidity and potential mortality of epileptic patients, it is important to simultaneously utilize EEG and electrocardiogram to confirm the diagnosis. This case report highlights the link between the de novo variant of ADGRV1 and the ictal bradycardia/asystole phenotype and implicates the importance of genetic testing in adult epilepsy patients.

Real-world safety and effectiveness of cenobamate in patients with focal onset seizures: Outcomes from an Expanded Access Program.

This study investigated early, real-world outcomes with cenobamate (CNB) in a large series of patients with highly drug-resistant epilepsy within a Spanish Expanded Access Program (EAP). This was a multicenter, retrospective, observational study in 14 hospitals. Inclusion criteria were age ≥18 years, focal seizures, and EAP authorization. Data were sourced from patient clinical records. Primary effectiveness endpoints included reductions (100%, ≥90%, ≥75%, and ≥50%) or worsening in seizure frequency at 3-, 6-, and 12-month visits and at the last visit. Safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation. The study included 170 patients. At baseline, median epilepsy duration was 26 years and median number of seizures/month was 11.3. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 12 and 3, respectively. Mean CNB dosages/day were 176 mg, 200 mg, and 250 mg at 3, 6, and 12 months. Retention rates were 98.2%, 94.5%, and 87% at 3, 6, and 12 months. At last available visit, the rate of seizure freedom was 13.3%; ≥90%, ≥75%, and ≥50% responder rates were 27.9%, 45.5%, and 63%, respectively. There was a significant reduction in the number of seizures per month (mean: 44.6%; median: 66.7%) between baseline and the last visit (P < 0.001). Responses were maintained regardless of the number of prior or concomitant ASMs. The number of concomitant ASMs was reduced in 44.7% of patients. The cumulative percentage of patients with AEs and AEs leading to discontinuation were 68.2% and 3.5% at 3 months, 74.1% and 4.1% at 6 months, and 74.1% and 4.1% at 12 months. The most frequent AEs were somnolence and dizziness. In this highly refractory population, CNB showed a high response regardless of prior and concomitant ASMs. AEs were frequent but mostly mild-to-moderate, and few led to discontinuation.

Clinical features and drug-resistance in pediatric epilepsy with co-occurring autism: A retrospective comparative cohort study

ObjectiveWe conducted a retrospective comparative cohort study to determine the phenotypic and real-world management differences in children with epilepsy and co-occurring autism as compared to those without autism. MethodsClinical variables, EEG, brain MRI, genetic results, medical and non-medical treatment were compared between 156 children with both epilepsy and autism, 156 randomly selected and 156 demographically matched children with epilepsy only. Logistic regression analyses were conducted to determine predictors of drug-resistant epilepsy (DRE). ResultsAs compared to the’matched’ cohort, more patients with autism had generalized motor seizures although not statistically significant after Benjamini-Hochberg correction (54.5%, vs 42.3%, p = .0314); they had a lower rate of electroclinical syndromes (12.8%, vs 30.1%, p = .0002). There were more incidental MRI findings but less positive MRI findings to explain their epilepsy in children with autism (26.3%, vs 13.8% and 14.3%, vs 34.2%, respectively; p = .0003). In addition, LEV, LTG, and VPA were the most common ASMs prescribed to children with autism, as opposed to LEV, OXC, and LTG in children without autism. No difference in the major EEG abnormalities was observed. Although the rates of DRE were similar (24.8%, vs 26.6%, p = .7203), we identified two clinical and five electrographic correlates with DRE in children with both epilepsy and autism and a final prediction modeling of DRE that included EEG ictal findings, focal onset seizures, generalized motor seizures, abnormal EEG background, age of epilepsy onset, and history of SE, which were distinct from those in children without autism. SignificanceOur study indicates that detailed seizure history and EEG findings are the most important evaluation and prediction tools for the development of DRE in children with epilepsy and co-occurring autism. Further studies of epilepsy in specific autism subgroups based on their etiology and clinical severity are warranted.

Multisite thalamic recordings to characterize seizure propagation in the human brain.

Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important uncertainty is to what extent thalamic subregions other than the ANT could be recruited more prominently in the propagation of focal onset seizures. We designed the current study to simultaneously monitor the engagement of the ANT, mediodorsal (MD) and pulvinar (PUL) nuclei during seizures in patients who could be candidates for thalamic neuromodulation. We studied 11 patients with clinical manifestations of presumed temporal lobe epilepsy (TLE) undergoing invasive stereo-encephalography (sEEG) monitoring to confirm the source of their seizures. We extended cortical electrodes to reach the ANT, MD and PUL nuclei of the thalamus. More than one thalamic subdivision was simultaneously interrogated in nine patients. We recorded seizures with implanted electrodes across various regions of the brain and documented seizure onset zones (SOZ) in each recorded seizure. We visually identified the first thalamic subregion to be involved in seizure propagation. Additionally, in eight patients, we applied repeated single pulse electrical stimulation in each SOZ and recorded the time and prominence of evoked responses across the implanted thalamic regions. Our approach for multisite thalamic sampling was safe and caused no adverse events. Intracranial EEG recordings confirmed SOZ in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites, highlighting the importance of invasive monitoring for accurate localization of SOZs. In all patients, seizures with the same propagation network and originating from the same SOZ involved the same thalamic subregion, with a stereotyped thalamic EEG signature. Qualitative visual reviews of ictal EEGs were largely consistent with the quantitative analysis of the corticothalamic evoked potentials, and both documented that thalamic nuclei other than ANT could have the earliest participation in seizure propagation. Specifically, pulvinar nuclei were involved earlier and more prominently than ANT in more than half of the patients. However, which specific thalamic subregion first demonstrated ictal activity could not be reliably predicted based on clinical semiology or lobar localization of SOZs. Our findings document the feasibility and safety of bilateral multisite sampling from the human thalamus. This may allow more personalized thalamic targets to be identified for neuromodulation. Future studies are needed to determine if a personalized thalamic neuromodulation leads to greater improvements in clinical outcome.

Characteristics of febrile seizures with SARS-CoV-2 infection in the Omicron era.

While the pandemic of coronavirus disease 2019 (COVID-19) is ongoing, the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been dominant recently. The Omicron variant causes more seizures in pediatric patients compared with previously circulated variants. This study aimed to investigate the incidence and clinical features of febrile seizure (FS) in pediatric patients with COVID-19 during the Omicron era. The medical records of pediatric patients (≤18 years of age) diagnosed with COVID-19, who presented with FS between February 2020 and June 2022, were reviewed retrospectively to analyze clinical characteristics of FS in seven university-affiliated hospitals of Korea. Of 664 pediatric patients with COVID-19 during the study period, 46 during the pre-Omicron period and 589 during the Omicron period were included in the study analysis; 29 patients during the transition period were excluded. Among the included patients, 81 (12.8%) had concomitant FS, and most (76.5%) experienced simple FS. All FS episodes occurred during the Omicron period and none of them during pre-Omicron period (P=0.016). Sixty-five (80.2%) and 16 (19.8%) patients were categorized as FS (patient age ≤60 months) and late-onset FS (patient age >60 months), respectively. Underlying neurologic disease (P=0.013) and focal onset seizure (P=0.012) were more common in the late-onset FS group than in the FS group; however, overall clinical manifestations and outcomes including seizures consistent with characteristics of complex FS and subsequent epilepsy were similar between the two groups. As the COVID-19 pandemic persists, the incidence of FS has increased with the emergence of the Omicron variant. About one-fifth of the patients experiencing FS due to infection by the Omicron variant of SARS-CoV-2 were aged >60 months; however, clinical characteristics and outcomes were favorable. More information and long-term prognoses in patients with FS due to COVID-19 should be acquired.

Anti-seizure efficacy of perampanel in two established rodent models of early-life epilepsy

Early-life seizures can be refractory to conventional antiseizure medications (ASMs) and can also result in chronic epilepsy and long-term behavioral and cognitive deficits. Treatments targeting age-specific mechanisms contributing to epilepsy would be of clinical benefit. One such target is the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subtype of excitatory glutamate receptor, which is upregulated in the developing brain. Perampanel is a non-competitive, selective AMPAR antagonist that is FDA-approved for focal onset seizures (FOS) or primary generalized tonic-clonic seizures (PGTC) in children and adults. However, the efficacy of perampanel treatment in epilepsy patients younger than 4 years has been less documented. We thus tested the efficacy of perampanel in two early-life seizure models: (1) a rat model of hypoxia-induced neonatal seizures and (2) a mouse model of Dravet syndrome with hyperthermia-induced seizures. Pretreatment with perampanel conferred dose-dependent protection against early-life seizures in both experimental models. These findings suggest that AMPAR-mediated hyperexcitability could be involved in the pathophysiology of early-life seizures, which may be amenable to treatment with perampanel.