Identifying risk for status epilepticus with the ADAN scale: a prospective multicenter validation study. / Escala ADAN para la identificación del estado epiléptico: estudio de validación prospectivo y multicéntrico.

OBJECTIVES: Status epilepticus (SE) is a serious event associated with high mortality. This study aims to validate the recently developed ADAN (Abnormal speech, ocular Deviation, Automatisms, and Number of motor epileptic seizures) scale for detecting high risk for SE. MATERIAL AND METHODS: Prospective, multicenter, observational study in adults with suspected epileptic seizures. Consecutive recruitment took place over a 27-month period in 4 hospital emergency departments (EDs). The main endpoint was the proportion of patients with criteria for SE based on the collection and analysis of clinical characteristics and the ADAN scale criteria on arrival at the ED. RESULTS: Of the 527 patients recruited, 203 (38.5%) fulfilled the criteria that predicted SE. Multiple regression analysis demonstrated that the 4 ADAN criteria were the only variables independently associated with a final diagnosis of SE (P .001). The predictive power of the scale was 90.9% (95% CI, 88.4%-93.4%) for a final SE diagnosis. We established 3 risk groups based on ADAN scores: low (score, 0-1: 8.7%), moderate (2, 46.6%), and high (> 2, 92.6%). A cut point of more than 1 had a sensitivity of 88.2% for predicting SE, specificity of 77.8%, positive predictive value of 71.3%, and negative predictive value of 91.3%. CONCLUSION: The ADAN scale is a prospectively validated, simple clinical tool for identifying patients in the ED who are at high risk for SE.

OBJETIVO: El estado epiléptico (EE) es una enfermedad grave con elevada mortalidad. Este estudio tiene como objetivo validar la escala ADAN, propuesta recientemente para identificar pacientes con alto riesgo de desarrollar un EE. METODO: Se realizó un estudio prospectivo, multicéntrico y observacional que incluyó a pacientes adultos con sospecha de crisis epilépticas. Se llevó a cabo un reclutamiento consecutivo durante 27 meses en los servicios de urgencias (SU) de cuatro hospitales. La variable principal fue la proporción de pacientes que cumplían criterios para EE. Se han recopilado y analizado las características clínicas y la puntuación en la escala ADAN a su llegada al SU. RESULTADOS: Se reclutaron 527 pacientes, de los cuales 203 (38,5%) cumplieron criterios de EE. En el análisis de regresión múltiple, se demostró que el habla anormal, la desviación ocular, los automatismos y el número de crisis epilépticas motoras fueron las únicas variables independientemente asociadas con un diagnóstico final de EE (p 0,001). La capacidad predictiva de la escala fue del 90,9% (intervalo de confianza del 95%, 88,4-93,4) para identificar el EE como diagnóstico final. Se establecieron tres grupos de riesgo: bajo (0 1 puntos: 8,7%), moderado (2: 46,6%) y alto (> 2: 92,6%). Una puntuación de corte > 1 punto proporcionó una sensibilidad del 88,2%, especificidad del 77,8%, valor predictivo positivo del 71,3% y valor predictivo negativo del 91,3% para predecir el EE. CONCLUSIONES: La escala ADAN es una herramienta clínica simple y validada de manera prospectiva para identificar, en los SU, a los pacientes con elevado riesgo de EE.

The usefulness of NDDI-E and QOLIE-10 scales for the screening of major depressive disorders in patients with epilepsy in video-EEG units.

OBJECTIVE: Mood disorders in patients with epilepsy are common, with depression being the most prevalent. However, this comorbidity is often underdiagnosed. The systematic use of scales such as NDDI-E and QOLIE-10 in prolonged video-EEG monitoring units could be a useful tool for the detection of this comorbidity. METHODS: Descriptive cross-sectional study of a series of patients with epilepsy evaluated in a prolonged video-EEG monitoring unit. RESULTS: Three hundred forty-nine patients were included. The mean age was 49.1 years, and 49.3% were female. 66.2% had focal epilepsy. 20.4% had pharmacoresistant epilepsy. 38.7% of patients had NDDI-E > 13. 43% of patients with focal epilepsy had NDDI-E > 13 versus 21.8% of patients with idiopathic generalized epilepsy (p = .015). Patients with focal temporal epilepsy had the highest rate of NDDI-E > 13 (48.5%). Significant association was found between patient-perceived mood and NDDI-E score (p < .001). However, in the group of patients with NDDI-E > 13, 37.6% had reported feeling "very good" or "good" in mood. Likewise, in the group that had reported feeling "very good" or "good" 21.6% had NDDI-E > 13. In 50.5% of patients with NDDI-E > 13 some kind of therapeutic intervention aimed at this comorbidity was performed. Perceived quality of life as measured by the QOLIE-10 scale was lower in patients with NDDI-E > 13 (p < .001). SIGNIFICANCE: The use of scales such as the NDDI-E and QOLIE-10 at the time of admission in video-EEG monitoring units allows screening for major depressive disorders in patients with epilepsy, which subsequently needs to be confirmed by formal assessment by a psychiatrist. Their systematic use in these units prevents some patients from going undiagnosed. Detection of these disorders allows targeted therapeutic intervention.

Corticosteroids versus clobazam for treatment of children with epileptic encephalopathy with spike-wave activation in sleep (RESCUE ESES): a multicentre randomised controlled trial.

BACKGROUND: Epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) is a rare syndrome associated with cognitive and behavioural regression. On the basis of mostly small observational and retrospective studies, corticosteroids and clobazam are often considered the most effective treatments for this syndrome. We aimed to compare cognitive outcomes of children with EE-SWAS 6 months after starting treatment with either corticosteroids or clobazam. METHODS: We did a multicentre, randomised controlled trial at eight tertiary referral centres for rare epilepsies in seven European countries. Children were eligible to participate if they were aged 2-12 years, were diagnosed with EE-SWAS within 6 months before inclusion, and had not been treated with corticosteroids or clobazam previously. Participants were randomly assigned (1:1) to treatment with corticosteroids (either continuous treatment with 1-2 mg/kg per day of prednisolone orally or pulse treatment with 20 mg/kg per day of methylprednisolone intravenously for 3 days every 4 weeks) or clobazam (0·5-1·2 mg/kg per day orally). The primary outcome was cognitive functioning after 6 months of treatment, which was assessed by either the intelligence quotient (IQ) responder rate (defined as improvement of ≥11·25 IQ points) or the cognitive sum score responder rate (defined as improvement of ≥0·75 points). Safety was assessed by number of adverse events and serious adverse events. Data were analysed in the intention-to-treat population, which included all children as randomised who had primary outcome data available at 6 months. The trial is registered with the Dutch Trial Register, Toetsingonline, NL43510.041.13, and the ISRCTN registry, ISRCTN42686094. The trial was terminated prematurely because enrolment of the predefined number of 130 participants was deemed not feasible. FINDINGS: Between July 22, 2014, and Sept 3, 2022, 45 children were randomly assigned to either corticosteroids (n=22) or clobazam (n=23); two children assigned clobazam dropped out before 6 months and were excluded from the intention-to-treat analysis. At the 6-month assessment, an improvement of 11·25 IQ points or greater was reported for five (25%) of 20 children assigned corticosteroids versus zero (0%) of 18 assigned clobazam (risk ratio [RR] 10·0, 95% CI 1·2-1310·4; p=0·025). An improvement of 0·75 points or more in the cognitive sum score was recorded for one (5%) of 22 children assigned corticosteroids versus one (5%) of 21 children assigned clobazam (RR 1·0, 95% CI 0·1-11·7, p=0·97). Adverse events occurred in ten (45%) of 22 children who received corticosteroids, most frequently weight gain, and in 11 (52%) of 21 children who received clobazam, most often fatigue and behavioural disturbances. Occurrence of adverse events did not differ between groups (RR 0·8, 95% CI 0·4-1·4; p=0·65). Serious adverse events occurred in one child in the corticosteroid group (hospitalisation due to laryngitis) and in two children in the clobazam group (hospitalisation due to seizure aggravation, and respiratory tract infection). No deaths were reported. INTERPRETATION: The trial was terminated prematurely, and the target sample size was not met, so our findings must be interpreted with caution. Our data indicated an improvement in IQ outcomes with corticosteroids compared with clobazam treatment, but no difference was seen in cognitive sum score. Our findings strengthen those from previous uncontrolled studies that support the early use of corticosteroids for children with EE-SWAS. FUNDING: EpilepsieNL, WKZ fund, European Clinical Research Infrastructure Network, and Ming fund.

Epileptogenic focal lesions in Dravet syndrome: A warning to investigators.

OBJECTIVE: Most patients with Dravet syndrome (DS) have unremarkable neuroimaging studies. However, a small number of patients exhibit focal abnormalities that may modify the epilepsy phenotype. We report a case series of DS patients carrying SCN1A variants concurrent with additional focal brain lesions, aiming to provide details regarding their clinical course, electrographic findings, and imaging features. METHODS: We reviewed the electronic medical records of patients with developmental and epileptic encephalopathies in our center, from January 2000 to December 2022, identifying 90 patients with DS resulting from SCN1A variants. Of these, patients displaying focal brain lesions were eligible. RESULTS: Five patients (4 males and 1 female), with median age of 26 years, were included. All exhibited clinical and electroencephalographic features consistent with the DS spectrum. Sequencing analysis of the SCN1A gene identified pathogenic variants. Magnetic resonance imaging (MRI) revealed focal cortical dysplasia (FCD) in two patients, while the remaining three had cystic lesions. Three patients had previously undergone resective epilepsy surgery in other centers, with no improvement in seizure frequency. Neuropathology studies revealed the presence of FCD type IIA, intracranial teratomas, and dysembryoplastic neuroepithelial tumor (DNET). SIGNIFICANCE: When an individual with an established diagnosis of genetic epilepsy and a focal lesion on MRI is undergoing preoperative evaluation, it is crucial to conduct a comprehensive analysis to understand the relevance of the focal finding for the patient's phenotype and thus anticipate potential surgical outcomes. In instances where epilepsy in DS patients is influenced by a specific focal structural lesion, resective surgery should be carefully considered after precise pharmacological treatment, acknowledging the persistent influence of an SCN1A variant on expected outcomes.

Cenobamate in patients with highly refractory focal epilepsy: A retrospective real-world study.

PURPOSE: To determine the effectiveness and safety outcomes of cenobamate in a cohort of patients with highly refractory focal epilepsy in routine clinical practice. METHODS: Observational, retrospective, phase 4 study on subjects receiving cenobamate in three Spanish centers. The primary endpoint was the retention rate at the last follow-up. The main secondary endpoints were the 50%-responder  and seizure-free rates at three months and the last follow-up. Other secondary endpoints were Global Clinical Impressions-Improvement (CGI-I) scores and treatment-emergent adverse events (TEAEs). RESULTS: Fifty-one patients with highly refractory focal epilepsy with 24.7 years of disease evolution, ten previously tried ASM, and a 23.5% of previous epilepsy surgery were included. The retention rate at the last follow-up was 80.4%. The 50% responder rate in focal seizures at three months was 56.5% (median reduction per month 51%, 0-74.6; p < 0.0001) and in focal to bilateral tonic-clonic seizures was 63.6% (median reduction per month 89%, 0-100; p = 0.022). A total of 54.3% of subjects reported a reduction in the intensity of focal seizures, and 66% manifested clinically significant satisfaction. Cenobamate allowed a significant decrease in concomitant ASM, especially sodium channel blockers. TEAEs were reported in 43.1% of individuals, 85% of whom resolved or improved, with no new safety findings. CONCLUSION: In this analysis of patients with highly refractory focal epilepsy treated with cenobamate according to standard clinical practice, there was evidence of a high reduction in both seizure frequency and intensity, with a manageable safety profile.

Real-life evidence about the use of intravenous brivaracetam in urgent seizures: The BRIV-IV study.

PURPOSE: Urgent seizures are a medical emergency for which new therapies are still needed. This study evaluated the use of intravenous brivaracetam (IV-BRV) in an emergency setting in clinical practice. METHODS: BRIV-IV was a retrospective, multicenter, observational study. It included patients ≥18 years old who were diagnosed with urgent seizures (including status epilepticus (SE), acute repetitive seizures, and high-risk seizures) and who were treated with IV-BRV according to clinical practice in 14 hospital centers. Information was extracted from clinical charts and included in an electronic database. Primary effectiveness endpoints included the rate of IV-BRV responder patients, the rate of patients with a sustained response without seizure relapse in 12 h, and the time between IV-BRV administration and clinical response. Primary safety endpoints were comprised the percentage of patients with adverse events and those with adverse events leading to discontinuation. RESULTS: A total of 156 patients were included in this study. The mean age was 57.7 ± 21.5 years old with a prior diagnosis of epilepsy for 57.1% of patients. The most frequent etiologies were brain tumor-related (18.1%) and vascular (11.2%) epilepsy. SE was diagnosed in 55.3% of patients. The median time from urgent seizure onset to IV treatment administration was 60.0 min (range: 15.0-360.0), and the median time from IV treatment to IV-BRV was 90.0 min (range: 30.0-2400.0). Regarding dosage, the mean bolus infusion was 163.0 ± 73.0 mg and the mean daily dosage was 195.0 ± 87.0 mg. A total of 77.6% of patients responded to IV-BRV (66.3% with SE vs. 91% other urgent seizures) with a median response time of 30.0 min (range: 10.0-60.0). A sustained response was achieved in 62.8% of patients. However, adverse events were reported in 14.7%, which were predominantly somnolence and fatigue, with 4.5% leading to discontinuation. Eighty-six percent of patients were discharged with oral brivaracetam. CONCLUSION: IV-BRV in emergency settings was effective, and tolerability was good for most patients. However, a larger series is needed to confirm the outcomes.

D-galactose Supplementation for the Treatment of Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE): A Pilot Trial of Precision Medicine After Epilepsy Surgery.

MOGHE is defined as mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Approximately half of the patients with histopathologically confirmed MOGHE carry a brain somatic variant in the SLC35A2 gene encoding a UDP-galactose transporter. Previous research showed that D-galactose supplementation results in clinical improvement in patients with a congenital disorder of glycosylation due to germline variants in SLC35A2. We aimed to evaluate the effects of D-galactose supplementation in patients with histopathologically confirmed MOGHE, with uncontrolled seizures or cognitive impairment and epileptiform activity at the EEG after epilepsy surgery (NCT04833322). Patients were orally supplemented with D-galactose for 6 months in doses up to 1.5 g/kg/day and monitored for seizure frequency including 24-h video-EEG recording, cognition and behavioral scores, i.e., WISC, BRIEF-2, SNAP-IV, and SCQ, and quality of life measures, before and 6 months after treatment. Global response was defined by > 50% improvement of seizure frequency and/or cognition and behavior (clinical global impression of "much improved" or better). Twelve patients (aged 5-28 years) were included from three different centers. Neurosurgical tissue samples were available in all patients and revealed a brain somatic variant in SLC35A2 in six patients (non-present in the blood). After 6 months of supplementation, D-galactose was well tolerated with just two patients presenting abdominal discomfort, solved after dose spacing or reduction. There was a 50% reduction or higher of seizure frequency in 3/6 patients, with an improvement at EEG in 2/5 patients. One patient became seizure-free. An improvement of cognitive/behavioral features encompassing impulsivity (mean SNAP-IV - 3.19 [- 0.84; - 5.6]), social communication (mean SCQ - 2.08 [- 0.63; - 4.90]), and executive function (BRIEF-2 inhibit - 5.2 [- 1.23; - 9.2]) was observed. Global responder rate was 9/12 (6/6 in SLC35A2-positive). Our results suggest that supplementation with D-galactose in patients with MOGHE is safe and well tolerated and, although the efficacy data warrant larger studies, it might build a rationale for precision medicine after epilepsy surgery.

Artificial intelligence system, based on mjn-SERAS algorithm, for the early detection of seizures in patients with refractory focal epilepsy: A cross-sectional pilot study.

Around one-third of epilepsy patients develop drug-resistant seizures; early detection of seizures could help improve safety, reduce patient anxiety, increase independence, and enable acute treatment. In recent years, the use of artificial intelligence techniques and machine learning algorithms in different diseases, including epilepsy, has increased significantly. The main objective of this study is to determine whether the mjn-SERAS artificial intelligence algorithm developed by MJN Neuroserveis, can detect seizures early using patient-specific data to create a personalized mathematical model based on EEG training, defined as the programmed recognition of oncoming seizures before they are primarily initiated, usually within a period of a few minutes, in patients diagnosed of epilepsy. Retrospective, cross-sectional, observational, multicenter study to determine the sensitivity and specificity of the artificial intelligence algorithm. We searched the database of the Epilepsy Units of three Spanish medical centers and selected 50 patients evaluated between January 2017 and February 2021, diagnosed with refractory focal epilepsy who underwent video-EEG monitoring recordings between 3 and 5 days, a minimum of 3 seizures per patient, lasting more than 5 s and the interval between each seizure was greater than 1 h. Exclusion criteria included age <18 years, intracranial EEG monitoring, and severe psychiatric, neurological, or systemic disorders. The algorithm identified pre-ictal and interictal patterns from EEG data using our learning algorithm and was compared to a senior epileptologist's evaluation as a gold standard. Individual mathematical models of each patient were trained using this feature dataset. A total of 1963 h of 49 video-EEG recordings were reviewed, with an average of 39.26 h per patient. The video-EEG monitoring recorded 309 seizures as subsequently analyzed by the epileptologists. The mjn-SERAS algorithm was trained on 119 seizures and split testing was performed on 188 seizures. The statistical analysis includes the data from each model and reports 10 false negatives (no detection of episodes recorded by video-EEG) and 22 false positives (alert detected without clinical correlation or abnormal EEG signal within 30 min). Specifically, the automated mjn-SERAS AI algorithm achieved a sensitivity of 94.7% (95 %; CI 94.67-94.73), and an F-Score representing specificity of 92.2% (95 %; CI 92.17-92.23) compared to the reference performance represented by a mean (harmonic mean or average) and a positive predictive value of 91%, with a false positive rate of 0.55 per 24 h in the patient-independent model. This patient-specific AI algorithm for early seizure detection shows promising results in terms of sensitivity and false positive rate. Although the algorithm requires high computational requirements on specialized servers cloud for training and computing, its computational load in real-time is low, allowing its implementation on embedded devices for online seizure detection.

Levetiracetam, from broad-spectrum use to precision prescription: A narrative review and expert opinion.

Levetiracetam (LEV) is an antiseizure medication (ASM) whose mechanism of action involves the modulation of neurotransmitters release through binding to the synaptic vesicle glycoprotein 2A. It is a broad-spectrum ASM displaying favorable pharmacokinetic and tolerability profiles. Since its introduction in 1999, it has been widely prescribed, becoming the first-line treatment for numerous epilepsy syndromes and clinical scenarios. However, this might have resulted in overuse. Increasing evidence, including the recently published SANAD II trials, suggests that other ASMs are reasonable therapeutic options for generalized and focal epilepsies. Not infrequently, these ASMs show better safety and effectiveness profiles compared to LEV (partially due to the latter's well-known cognitive and behavioral adverse effects, present in up to 20% of patients). Moreover, it has been shown that the underlying etiology of epilepsy is significantly linked to ASMs response in particular scenarios, highlighting the importance of an etiology-based ASM choice. In the case of LEV, it has demonstrated an optimal effectiveness in Alzheimer's disease, Down syndrome, and PCDH19-related epilepsies whereas, in other etiologies such as malformations of cortical development, it may show negligible effects. This narrative review analyzes the current evidence related to the use of LEV for the treatment of seizures. Illustrative clinical scenarios and practical decision-making approaches are also addressed, therefore aiming to define a rational use of this ASM.

Morphometric and microstructural characteristics of hippocampal subfields in mesial temporal lobe epilepsy and their correlates with mnemonic discrimination.

Introduction: Pattern separation (PS) is a fundamental aspect of memory creation that defines the ability to transform similar memory representations into distinct ones, so they do not overlap when storing and retrieving them. Experimental evidence in animal models and the study of other human pathologies have demonstrated the role of the hippocampus in PS, in particular of the dentate gyrus (DG) and CA3. Patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HE) commonly report mnemonic deficits that have been associated with failures in PS. However, the link between these impairments and the integrity of the hippocampal subfields in these patients has not yet been determined. The aim of this work is to explore the association between the ability to perform mnemonic functions and the integrity of hippocampal CA1, CA3, and DG in patients with unilateral MTLE-HE. Method: To reach this goal we evaluated the memory of patients with an improved object mnemonic similarity test. We then analyzed the hippocampal complex structural and microstructural integrity using diffusion weighted imaging. Results: Our results indicate that patients with unilateral MTLE-HE present alterations in both volume and microstructural properties at the level of the hippocampal subfields DG, CA1, CA3, and the subiculum, that sometimes depend on the lateralization of their epileptic focus. However, none of the specific changes was found to be directly related to the performance of the patients in a pattern separation task, which might indicate a contribution of various alterations to the mnemonic deficits or the key contribution of other structures to the function. Discussion: we established for the first time the alterations in both the volume and the microstructure at the level of the hippocampal subfields in a group of unilateral MTLE patients. We observed that these changes are greater in the DG and CA1 at the macrostructural level, and in CA3 and CA1 in the microstructural level. None of these changes had a direct relation to the performance of the patients in a pattern separation task, which suggests a contribution of various alterations to the loss of function.

Effect of fenfluramine on seizures and comorbidities in SCN8A-developmental and epileptic encephalopathy: A case series.

SCN8A-developmental and epileptic encephalopathy is caused by pathogenic variants in the SCN8A gene encoding the Nav 1.6 sodium channel, and is characterized by intractable multivariate seizures and developmental regression. Fenfluramine is a repurposed drug with proven antiseizure efficacy in Dravet syndrome and Lennox-Gastaut syndrome. The effect of fenfluramine treatment was assessed in a retrospective series of three patients with intractable SCN8A epilepsy and severe neurodevelopmental comorbidity (n = 2 females; age 2.8-13 years; 8-16 prior failed antiseizure medications [ASM]; treatment duration: 0.75-4.2 years). In the 6 months prior to receiving fenfluramine, patients experienced multiple seizure types, including generalized tonic-clonic, focal and myoclonic seizures, and status epilepticus. Overall seizure reduction was 60%-90% in the last 3, 6, and 12 months of fenfluramine treatment. Clinically meaningful improvement was noted in ≥1 non-seizure comorbidity per patient after fenfluramine, as assessed by physician-ratings of ≥"Much Improved" on the Clinical Global Impression of Improvement scale. Improvements included ambulation in a previously non-ambulant patient and better attention, sleep, and language. One patient showed mild irritability which resolved; no other treatment-related adverse events were reported. There were no reports of valvular heart disease or pulmonary arterial hypertension. Fenfluramine may be a promising ASM for randomized clinical trials in SCN8A-related disorders.

Anakinra and tocilizumab in the chronic phase of febrile infection-related epilepsy syndrome (FIRES): Effectiveness and safety from a case-series.

PURPOSE: There is scarce evidence of effective treatments for the chronic phase of Febrile infection-related epilepsy syndrome (FIRES). This study aimed to analyze the outcomes of treatment with anakinra and tocilizumab. METHODS: Retrospective study including patients receiving either anti-interleukin-1 (anti-IL-1, anakinra) or anti-IL-6 (tocilizumab) during the chronic phase of FIRES. We evaluated seizure outcomes, non-seizure comorbidities, and adverse events. Additionally, an indirect control group including patients during the chronic phase of FIRES non-treated with-IL therapies was evaluated. RESULTS: Five patients were included; three females. Median age at FIRES: 8 years (IQR: 6-10). Five patients received anakinra; one patient switched to tocilizumab after ineffectiveness. Median treatment duration was 9months (IQR: 7-20). While no patients became seizure-free, 20-50% reduction in seizure frequency was reported in 3/5 patients after 6 months with anakinra. Retention rate was 100% at 6 months and 40% at 12months. Three patients reported reduced seizure intensity and rescue medication needed, and better behavior/communication. Similar improvement was reported for the patient switching to tocilizumab. Patients with the best response received anti-IL a median of 9 years after acute phase. All discontinuations were due to ineffectiveness. There were none relevant adverse events apart from one patient presenting transient seizure aggravation. Nine patients were included in the control group; none of them showed relevant improvement in seizure outcomes or cognitive/behavioral comorbidities. Only one presented mild improvement in seizure frequency during the 6-months follow-up. CONCLUSION: This study provides promising data on effectiveness/safety of anakinra and tocilizumab in the chronic phase of FIRES. These findings warrant prospective/larger studies.

Onset of efficacy and adverse events during Cenobamate titration period.

OBJECTIVES: Cenobamate is an antiseizure medication (ASM) approved in Europe as adjunctive therapy for adults with inadequately controlled focal seizures. This post hoc analysis reports onset of efficacy and characterizes time to onset, duration, and severity of the most common treatment-emergent adverse events (TEAEs) during cenobamate titration. MATERIALS & METHODS: Adult patients with uncontrolled focal seizures taking 1 to 3 concomitant ASMs were randomized to receive adjunctive cenobamate or placebo (double-blind studies C013 and C017) or cenobamate (open-label study C021). Outcome assessments included efficacy (median percentage change in seizure frequency and onset [studies C013 and C017]) and safety (onset, duration, and severity of TEAEs [all studies]). RESULTS: Onset of efficacy was observed by Weeks 1 to 4 of titration in studies C013 and C017 which used a faster titration schedule than study CO21. In study C013, the median percentage seizure frequency reduction was 36.7% in patients receiving cenobamate versus 16.3% in those taking placebo (p = .002); in study C017, significant differences in seizure frequency emerged in Week 1 and continued throughout titration between all cenobamate groups and placebo (p < .001). The most commonly reported TEAEs were somnolence, dizziness, fatigue, and headache, with first onset of each reported as early as Week 1; however, the majority resolved. CONCLUSIONS: Reductions in seizure frequency occurred during titration with initial efficacy observed prior to reaching the target dose. These reductions were regarded as clinically meaningful because they may indicate early efficacy at lower doses than previously expected and had a considerable impact on patient quality of life. Long-term treatment with adjunctive cenobamate was generally safe and well-tolerated.

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies.

This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes. They generally have a pediatric presentation, but patients frequently reach adulthood still undiagnosed. Identifying the etiology is essential, because there lies the key for precision medicine. Phenotypes modify according to age, and although deep phenotyping has allowed to outline certain entities, genotype-phenotype correlations are still poor, commonly leading to long-lasting diagnostic odysseys and ineffective therapies. Recent adult series show that the target patients to be identified for genetic testing are those with epilepsy and different risk factors. The clinician should take active part in the assessment of the pathogenicity of the variants detected, especially concerning variants of uncertain significance. An accurate diagnosis implies precision medicine, meaning genetic counseling, prognosis, possible future therapies, and a reduction of iatrogeny. Up to date, there are a few tens of gene mutations with additional concrete treatments, including those with restrictive/substitutive therapies, those with therapies modifying signaling pathways, and channelopathies, that are worth to be assessed in adults. Further research is needed regarding phenotyping of adult syndromes, early diagnosis, and the development of targeted therapies.

Headache education and management in Cameroon: a healthcare provider study.

Headache disorders are the most prevalent neurological conditions in the Sub-Saharan Africa and the second cause of disability. In this study, we analyze the knowledge about headache disorders and their management among Cameroonian healthcare providers. We conducted an interventional study with a prospective cohort design. Cameroonian health care providers from the whole country were invited. The evaluation was based on a questionnaire that was done before and after a 4-day educational course. The study included 42 participants, 52.4% female, aged 36.8 years. Participants treated a median of 240 monthly patients. Headache was reported as the most frequent neurological condition in their clinics (34%). Mean number of neurological patients seen per week was 69.3, among them 20 were headache patients. At baseline, only 35.8% correctly mentioned at least one primary headache, increasing to 78.6% after the course (p = 0.002). Secondary headaches were correctly identified by 19.0% at baseline and 40.5% after the course (p = 0.01). Clinical history was considered sufficient for headache diagnosis by 57.1% before and 78.6% after (p = 0.5). Correct red flags were mentioned at baseline by only 14.3% of participants, increasing to 40.5% after the course (p = 0.005). At baseline, the preferred symptomatic was paracetamol (47.6%) and Non-Steroidal Anti-Inflammatory Drugs (9.5%), changing to 23.8 and 66.7% after the course (p = 0.05 and < 0.001). Headache was reported as the most frequent neurological disorders. Knowledge about primary headache disorders and their etiology was scarce, and the clinical concept of red flags was limited. The acute drug of choice was paracetamol.