Spanish consensus on the management of concomitant antiseizure medications when using cenobamate in adults with drug-resistant focal seizures.

OBJECTIVE: Cenobamate is an antiseizure medication (ASM) associated with high rates of seizure freedom and acceptable tolerability in patients with focal seizures. To achieve the optimal cenobamate dose for maximal potential effectiveness while avoiding or minimizing drug-related adverse events (AEs), the administration of cenobamate with other ASMs must be managed through concomitant ASM load reduction. A panel of Spanish epilepsy experts aimed to provide a Spanish consensus on how to adjust the dose of concomitant ASMs in patients with drug-resistant epilepsy (DRE) in order to improve the effectiveness and tolerability of adjunctive cenobamate. METHODS: A three-stage modified Delphi consensus process was undertaken, including six Spanish epileptologists with extensive experience using cenobamate. Based on current literature and their own expert opinion, the expert panel reached a consensus on when and how to adjust the dosage of concomitant ASMs during cenobamate titration. RESULTS: The expert panel agreed that tailored titration and close follow-up are required to achieve the best efficacy and tolerability when initiating cenobamate in patients receiving concomitant ASMs. When concomitant clobazam, phenytoin, phenobarbital, and sodium channel blockers are taken at high dosages, or when the patient is receiving two or more sodium channel blockers, dosages should be proactively lowered during the cenobamate titration period. Other concomitant ASMs should be reduced only if the patient reports a moderate/severe AE at any stage of the titration period. SIGNIFICANCE: Cenobamate is an effective ASM with a dose-dependent effect. To maximize effectiveness while maintaining the best tolerability profile, co-medication management is needed. The recommendations included herein provide practical guidance for proactive and reactive management of co-medication in cenobamate-treated patients with DRE and a high drug load. PLAIN LANGUAGE SUMMARY: Patients with epilepsy may continue to have seizures even after treatment with several different antiseizure medications (ASMs). Cenobamate is an ASM that can reduce seizures in these patients. In this study, six Spanish experts in epilepsy discussed the best way to use cenobamate in drug-resistant epilepsy. They provide practical guidance on when and how the dose of other ASMs might be adjusted to reduce side effects and optimize the use of cenobamate.

What have we learned from the real-world efficacy of FFA in DS and LGS? A post-marketing study in clinical practice.

OBJECTIVE: To evaluate the effectiveness and tolerability of fenfluramine (FFA) in routine clinical practice treating real-world populations with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). METHODS: This was a retrospective analysis of patients with DS or LGS who initiated FFA treatment from 2018 to 2022 at a single center. Patient demographics, medical history, seizure characteristics, and treatment outcomes were collected from electronic medical records. Duration of FFA treatment, dosage regimens, seizure frequency, seizure severity, improvements in cognitive, social, and motor outcomes, and adverse events were extracted and analyzed. Effectiveness was assessed using ≥50 % sustained reduction in monthly seizure frequency vs baseline for ≥2 consecutive months at 12 months; seizure freedom was a secondary measure. RESULTS: Seizure frequency data was available for 56 of 68 patients included in the study. At 12 months, 50 patients (89.3 %) remained on FFA treatment; 58 % of these patients achieved a ≥50 % sustained response and 10 % experienced seizure freedom. Cognitive, motor, and social improvement were noted in 70.7 %, 36.2 %, and 27.6 % of patients, respectively. The total number of concomitant antiseizure medications was reduced by ≥1 in 29.4 % of patients. No differences were found between DS and LGS patients in these outcomes; age at start of FFA and age at the 12-month timepoint did not have an effect. At least one AE was experienced by 59.7% of patients; in 86.5% of the cases, AEs were plausibly related to treatment. While 70.3% of AEs were self-resolving and 81.8% of the remaining patients experienced mild AEs, 1 patient experienced a serious AE unrelated to FFA which resulted in the patient's death. There were no cases of pulmonary arterial hypertension or ventricular heart disease. SIGNIFICANCE: The effectiveness and tolerability of FFA treatment in patients with DS or LGS in this retrospective analysis of real-world data were consistent with those seen in randomized clinical trials.

Efficacy and tolerability of add-on stiripentol in real-world clinical practice: An observational study in Dravet syndrome and non-Dravet developmental and epileptic encephalopathies.

OBJECTIVE: To assess efficacy and tolerability of stiripentol (STP) as adjunctive treatment in Dravet syndrome and non-Dravet refractory developmental and epileptic encephalopathies (DREEs). METHODS: Retrospective observational study of all children and adults with DREE and prescribed adjunctive STP at Hospital Ruber Internacional from January 2000 to February 2023. Outcomes were retention rate, responder rate (proportion of patients with ≥50% reduction in total seizure frequency relative to baseline), seizure freedom rate, responder rate for status epilepticus, rate of adverse event and individual adverse events, reported at 3, 6, and 12 months and at final visit. Seizure outcomes are reported overall, and for Dravet and non-Dravet subgroups. RESULTS: A total of 82 patients (55 Dravet syndrome and 27 non-Dravet DREE) were included. Median age was 5 years (range 1-59 years), and median age of epilepsy onset was younger in the Dravet group (4.9 [3.6-6] months) than non-Dravet (17.9 [6-42.3], P < 0.001). Median follow-up time STP was 24.1 months (2 years; range 0.3-164 months) and was longer in the Dravet group (35.9 months; range 0.8-164) than non-Dravet (17 months range 0.3-62.3, P < 0.001). At 12 months, retention rate, responder rate and seizure free rate was 68.3% (56/82), 65% [48-77%] and 18% [5.7-29%], respectively. There were no statistically significant differences between groups on these seizure outcomes. Adverse events were reported in 46.3% of patients (38/82), without differences between groups. SIGNIFICANCE: In this population of patients with epileptic and developmental encephalopathies, outcomes with adjunctive STP were similar in patients with non-Dravet DREE to patients with Dravet syndrome.

Health care concerns in parents of children with different genetic developmental and epileptic encephalopathies: A qualitative study.

AIM: To describe the experiences and unmet medical care needs of a group of parents of children with developmental and epileptic encephalopathies (DEEs) caused by the SCN1A, KCNQ2, CDKL5, PCDH19, and GNAO1 variants. METHOD: A qualitative descriptive study was conducted. Participants were recruited using purposeful sampling. The inclusion criteria consisted of parents of children with DEEs caused by the SCN1A, KCNQ2, CDKL5, PCDH19, or GNAO1 variants, aged between 4 and 10 years old. In total, 21 parents were included. Data were acquired via researcher field notes and in-depth interviews. A thematic analysis was performed. RESULTS: Three main themes were identified: (1) managing symptoms: epileptic seizures are experienced with great uncertainty and are accompanied by cognitive, behavioural, and motor symptoms; (2) accepting treatment: the ideal medication regimen is a challenge and the decision to withdraw or start a new therapy falls on the parents; and (3) therapeutic relationship and medical care: behaviours related to the health professional can hinder the therapeutic relationship with the parents. Parents are apprehensive about going to the emergency department. INTERPRETATION: Professionals in emergency departments should acquire better knowledge of DEEs, welcome parents, and improve treatment for the children. The results of this study can serve as a starting point for a roadmap of relevant caregiver-reported outcomes in DEEs, to be implemented with new clinical trials and aetiology-targeted therapies. WHAT THIS PAPER ADDS: Epileptic seizures are the symptom that is most experienced and feared by parents. The medication regime has no defined protocol and the decision to withdraw a medication is frequently left to parents.

Preocupaciones sobre la atención sanitaria en progenitores de niños con diferentes encefalopatías epilépticas genéticas del desarrollo: Un estudio cualitativo.

OBJETIVO: Describir las experiencias y las necesidades de atención médica de un grupo de progenitores de niños con encefalopatías epilépticas y del desarrollo (EED) causadas por las variantes SCN1A, KCNQ2, CDKL5, PCDH19 y GNAO1. MÉTODO: Se realizó un estudio cualitativo descriptivo. Los participantes fueron reclutados mediante un muestreo intencional. Los criterios de inclusión consistieron en progenitores de niños con EED causadas por las variantes SCN1A, KCNQ2, CDKL5, PCDH19 o GNAO1, con edades comprendidas entre los 4 y los 10 años. En total, se incluyeron 21 progenitores. Los datos se obtuvieron mediante entrevistas en profundidad y notas de campo del investigador. Se realizó un análisis temático. RESULTADOS: Se identificaron tres temas principales: (1) Manejando los síntomas, las crisis epilépticas se viven con gran incertidumbre, y se acompañan de síntomas cognitivos, conductuales y motores que limitan la vida del niño; b) Aceptando el tratamiento, la pauta de la medicación idónea es un reto, la decisión de retirar o comenzar una nueva terapia recae en los progenitores; y c) Relación terapéutica y atención médica, existen comportamientos y acciones del profesional que facilitan o dificultan la relación terapéutica con los progenitores. Acudir al servicio de urgencias es vivido con recelo por los progenitores. INTERPRETACIÓN: Los profesionales de los servicios de urgencias deben conocer mejor las EED, acoger a los progenitores y mejorar el tratamiento de los niños. Los resultados de este estudio pueden servir como punto de partida para una hoja de ruta de los resultados relevantes reportados por los cuidadores de las EED, a implementar nuevos ensayos clínicos y terapias dirigidas a la etiología. QUÉ AÑADE ESTE DOCUMENTO: Las crisis epilépticas son el síntomas más experimentado y temido por los progenitores en las EED. La pauta de la medicación no tiene un protocolo definido y la decisión de retirar una medicación recae en las manos de los progenitores.

Developmental epileptic encephalopathy in DLG4-related synaptopathy.

OBJECTIVE: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. METHODS: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. RESULTS: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype-phenotype relationship even between individuals with the same DLG4 variants. SIGNIFICANCE: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requires proper investigation with sleep EEG.

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.

New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN.

Cell excitability and its modulation by hormones and neurotransmitters involve the concerted action of a large repertoire of membrane proteins, especially ion channels. Unique complements of coexpressed ion channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that are tailored for diverse physiological contributions, and dysfunction of any component may induce a disease state. A crucial parameter controlling cell excitability is the resting membrane potential (RMP) set by extra- and intracellular concentrations of ions, mainly Na+, K+, and Cl-, and their passive permeation across the cell membrane through leak ion channels. Indeed, dysregulation of RMP causes significant effects on cellular excitability. This review describes the molecular and physiological properties of the Na+ leak channel NALCN, which associates with its accessory subunits UNC-79, UNC-80, and NLF-1/FAM155 to conduct depolarizing background Na+ currents in various excitable cell types, especially neurons. Studies of animal models clearly demonstrate that NALCN contributes to fundamental physiological processes in the nervous system including the control of respiratory rhythm, circadian rhythm, sleep, and locomotor behavior. Furthermore, dysfunction of NALCN and its subunits is associated with severe pathological states in humans. The critical involvement of NALCN in physiology is now well established, but its study has been hampered by the lack of specific drugs that can block or agonize NALCN currents in vitro and in vivo. Molecular tools and animal models are now available to accelerate our understanding of how NALCN contributes to key physiological functions and the development of novel therapies for NALCN channelopathies.

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.

GPI-anchoring disorders and the heart: Is cardiomyopathy an overlooked feature?

Glycosylphosphatidylinositol anchoring disorders (GPI-ADs) are a subgroup of congenital disorders of glycosylation. GPI biosynthesis requires proteins encoded by over 30 genes of which 24 genes are linked to neurodevelopmental disorders. Patients, especially those with PIGA-encephalopathy, have a high risk of premature mortality which sometimes is attributed to cardiomyopathy. We aimed to explore the occurrence of cardiomyopathy among patients with GPI-ADs and to raise awareness about this potentially lethal feature. Unpublished patients with genetically proven GPI-ADs and cardiomyopathy were identified through an international collaboration and recruited through the respective clinicians. We also reviewed the literature for published patients with cardiomyopathy and GPI-AD and contacted the corresponding authors for additional information. We identified four novel and unrelated patients with GPI-AD and cardiomyopathy. Cardiomyopathy was diagnosed before adulthood and was the cause of early demise in two patients. Only one patients underwent cardiac workup after being diagnosed with a GPI-AD. All were diagnosed with PIGA-encephalopathy and three had a disease-causing variant at the same residue. The literature reports five additional children with GPI-AD related cardiomyopathy, three of which died before adulthood. We have shown that patients with GPI-ADs are at risk of developing cardiomyopathy and that regular cardiac workup with echocardiography is necessary.

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.

Deep Brain Stimulation of the Anterior Nucleus of the Thalamus in Drug-Resistant Epilepsy in the MORE Multicenter Patient Registry.

BACKGROUND AND OBJECTIVES: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice. METHODS: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes. RESULTS: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years (p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years (p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported. DISCUSSION: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy. TRIAL REGISTRATION INFORMATION: MORE ClinicalTrials.gov Identifier: NCT01521754, first posted on January 31, 2012.

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.

Patient profile, management, and quality of life associated with Dravet syndrome: a cross-sectional, multicentre study of 80 patients in Spain.

The aim of this study was to describe the profile of patients diagnosed with Dravet syndrome (DS), their clinical management, and the impact of DS on their quality of life (QoL) and family. Data of 80 patients from 11 centres in Spain was collected. Patients (47.5% female) were 12.7 (9.6) years on average (SD, standard deviation). Despite the first episode occurred when patients were a mean (SD) of 0.4 (0.2) years, DS was not diagnosed until they were 6.9 (10.1) years old. The majority (86.7%) had SCN1A gene mutations and 73.4% had seizures during the last year (mostly generalized motor seizures [47.8%]). The mean (SD) number of status epilepticus episodes was 3.6 (8.0) since diagnosis and 0.1 (0.5) in the last year. On the Health Utilities Index Mark (HUI) multi-attribute scale, the mean global score (SD) was 0.56 (0.24) in HUI2 and 0.32 (0.37) in HUI3. The impact of the disease was severe in most patients (HUI2, 81%; HUI3, 83.5%). In the Care-related QoL (CarerQol) the mean (SD) well-being score was 7.2 (2.1). Most caregivers (90%) were satisfied with their caregiving tasks, although 75% had difficulties combining these tasks with daily activities, 68.8% reported mental health problems and 61.2% physical problems.

Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study.

OBJECTIVE: This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome (LGS). METHODS: Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE; NCT03355209). All patients were initially started on .2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months. RESULTS: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2-4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was -28.6% over the entire OLE (n = 241) and -50.5% at Month 15 (n = 142, p < .0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was -45.9% (n = 192, p = .0038). Generalized tonic-clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p < .0001, n = 106) and 35.8% (p < .0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%-44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%-41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. SIGNIFICANCE: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS.

ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Outcomes from a Spanish Expanded Access Program on cannabidiol treatment in pediatric and adult patients with epilepsy.

AIM: To evaluate the effectiveness and tolerability of cannabidiol (CBD) in patients with developmental and epileptic encephalopathies, including Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS), in a Spanish Expanded Access Program (EAP). METHODS: This was a multicenter, retrospective, observational study of patients treated with purified CBD in 14 hospitals across Spain. Patients with (1) written informed consent and (2) at least 6 months follow-up before the closure of the database were included. Primary effectiveness endpoints included reductions (100 %, ≥75 %, ≥50 %, ≥25 %, or 0 %) or worsening in seizure frequency (all seizure types and most disabling seizures) at 1-, 3-, 6-, and 12-month visits and at the last visit, and median relative seizure reduction between baseline and last visit. Secondary effectiveness endpoints included retention rate, reduction in seizure severity, status epilepticus, healthcare utilization, and quality of life. Primary safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation. RESULTS: One hundred and two patients (DS 12 %; LGS 59 %; other epilepsy syndromes 29 %) with a mean age of 15.9 years were enrolled. Patients were highly refractory to antiseizure medications (ASMs); mean number of prior failed ASMs was 7.5 (SD 3.7). The mean CBD dose was 13.0 mg/kg/day at the last visit. The proportion of patients with ≥50 % reduction in the total number of seizures from baseline was 44.9 % at 6 months and 38.9 % at 12 months. The median number of total seizures per month reduced by 47.6 % from baseline to the last visit. At 12 months, seizure severity was lower in 33/54 patients (61.1 %) and unchanged in 17/54 patients (31.5 %). Quality of life, based on the CAVE scale, increased from a mean score of 17.9 ± 4.7 (n = 54) at baseline to 21.7 ± 5.5 (n = 51) at the last patient visit (21.2 % improvement). The mean treatment retention time was 10.3 months. There were no statistically significant changes in the number of status epilepticus episodes, but lower healthcare utilization was observed. Adverse events occurred in sixty-eight patients (66.7 %), and the most common were somnolence (34.3 %) and diarrhea (12.7 %). Cannabidiol was discontinued exclusively due to AEs in 7.8 % of patients, increasing to 25.5 % when both lack of efficacy and AEs were considered together. CONCLUSIONS: Cannabidiol demonstrated promising effectiveness and tolerability in patients with developmental and epileptic encephalopathies taking part in a Spanish EAP.