dravet

Dravet syndrome is an intractable epilepsy with a high seizure burden that is resistant to current anti-seizure medications. There is evidence that neuroinflammation plays a role in epilepsy and seizures, however few studies have specifically examined neuroinflammation in Dravet syndrome under conditions of a higher seizure burden. Here we used an established genetic mouse model of Dravet syndrome (Scn1a+/- mice), to examine whether a higher seizure burden impacts the number and morphology of microglia in the hippocampus...

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is an underestimated complication of epilepsy. Previous studies have demonstrated that enhancement of serotonergic neurotransmission suppresses seizure-induced sudden death in evoked seizure models. However, it is unclear whether elevated serotonin (5-HT) function will prevent spontaneous seizure-induced mortality (SSIM), which is characteristic of human SUDEP. We examined the effects of 5-HT-enhancing agents that act by three different pharmacological mechanisms on SSIM in Dravet mice, which exhibit a high incidence of SUDEP, modeling human Dravet syndrome...

OBJECTIVE: Several clinical trials have suggested that fenfluramine (FFA) is effective for the treatment of epilepsy in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). However, the exploration of its optimal target dose is ongoing. This study aimed to summarize the best evidence to inform this clinical issue. MATERIALS AND METHODS: We searched PubMed, Embase (via Ovid), and Web of Science for relevant literature published before December 1st, 2023. Randomized, double-blind, placebo-controlled studies that evaluated the efficacy, safety, and tolerability of FFA in DS and LGS were identified and meta-analysis was performed according to doses...

L'intérêt envers l'utilisation des produits du cannabis à des fins médicales chez les enfants de moins de 18 ans augmente. De nombreux produits du cannabis à des fins médicales contiennent du cannabidiol, du delta-9-tétrahydrocannabinol ou ces deux produits. Malgré les nombreuses prétentions thérapeutiques, peu d'études rigoureuses guident la posologie, l'innocuité et l'efficacité du cannabis à des fins médicales en pédiatrie clinique...

Interest in using cannabis products for a medical purpose in children under the age of 18 years is increasing. There are many medical cannabis products available that can include cannabidiol (CBD) or delta-9-tetrahydrocannabinol (THC), or both. Despite many therapeutic claims, there are few rigorous studies to inform the dosing, safety, and efficacy of medical cannabis in paediatric clinical practice. This statement reviews the current evidence and provides recommendations for using medical cannabis in children...

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction...

OBJECTIVE: To explore the correlation between clinical phenotypes and genotypes among 46 children with SCN1A-related developmental epileptic encephalopathy (DEE). METHODS: Clinical data of 46 children with DEE and SCN1A variants identified at the Guangzhou Women and Children's Medical Center between January 2018 and June 2022 were collected. The children were grouped based on their age of onset, clinical manifestations, neurodevelopmental status, and results of genetic testing...

INTRODUCTION: Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC)-associated epilepsy are rare conditions associated with severe childhood-onset epilepsy. Caregivers play a critical role in the patients' care and may experience significant psychosocial and socioeconomic burden. This cross-sectional study determined the burden of caring for patients with these rare epilepsy conditions in Japan. METHODS: A quantitative online survey was used to assess patients' and caregivers' characteristics and the caregivers' emotional state, among others...

Fenfluramine (Fintepla® ) is approved for the treatment of seizures associated with the rare epileptic encephalopathies Dravet syndrome and Lennox-Gastaut syndrome. Fenfluramine is extensively metabolized; thus, patients with hepatic impairment (HI) might experience changes in exposure to fenfluramine or its metabolites. In this phase 1 study, we investigated the pharmacokinetics (PK) and safety of a single oral dose of 0.35 mg/kg fenfluramine in subjects with mild (n = 8), moderate (n = 8), or severe (n = 7) HI (Child-Pugh A/B/C, respectively) and healthy control subjects (n = 22) matched for sex, age, and BMI...

PCDH19 clustering epilepsy (PCDH19-CE) is an X-linked epilepsy disorder associated with intellectual disability (ID) and behavioral disturbances, which is caused by PCDH19 gene variants. PCDH19 pathogenic variant leads to epilepsy in heterozygous females, not in hemizygous males and the inheritance pattern is unusual. The hypothesis of cellular interference was described as a key pathogenic mechanism. According to that, males do not develop the disease because of the uniform expression of PCDH19 (variant or wild type) unless they have a somatic variation...

BACKGROUND: A pathogenic variant in SCN1A can result in a spectrum of phenotypes, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS + ) syndrome. Dravet syndrome (DS) is associated with refractory seizures, developmental delay, intellectual disability (ID), motor impairment, and challenging behavior(1,2). GEFS + is a less severe phenotype in which cognition is often normal and seizures are less severe. Challenging behavior largely affects quality of life of patients and their families...

BACKGROUND: Dravet Syndrome (DS) is a rare and severe form of childhood epilepsy that is often refractory to conventional antiepileptic drugs. Emerging evidence suggests that Cannabidiol (CBD) offer therapeutic benefits for DS. This review aims to evaluate the efficacy and safety of CBD in pediatric patients with DS based on data from ten clinical trials. METHODS: A review was conducted to identify clinical trials assessing the efficacy and safety of CBD in pediatric patients diagnosed with DS...

Genetic factors contribute to the aetiology of epilepsy in >50% of cases, and information on the use of antiseizure medications in people with specific aetiologies will help guide treatment decisions. The PERMIT Extension study pooled data from two real-world studies (PERMIT and PROVE) to investigate the effectiveness and safety/tolerability of perampanel (PER) when used to treat people with focal and generalised epilepsy in everyday clinical practice. This post-hoc analysis of PERMIT Extension explored the use of PER when used to treat individuals presumed to have epilepsy with a genetic aetiology...

BACKGROUND: Preimplantation genetic testing for monogenic disorders (PGT-M) is now widely used as an effective strategy to prevent various monogenic or chromosomal diseases. MATERIAL AND METHODS: In this retrospective study, couples with a family history of hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes and/or carrying the pathogenic genes underwent PGT-M to prevent children from inheriting disease-causing gene mutations from their parents and developing known genetic diseases...

OBJECTIVE: Individuals with Dravet syndrome (DS) exhibit progressive gait disturbance. No quantitative studies have been conducted to evaluate the effectiveness of medication for gait disturbance. Therefore, the aim of this study was to evaluate the effectiveness of levodopa for pathological gait in people with DS using three-dimensional gait analysis (3DGA). METHODS: Nine individuals with DS, ages 6-20 years, participated in a crossover study of levodopa and were randomly assigned to the levodopa precedence or no levodopa precedence group...

Soticlestat (TAK-935) is a first-in-class, selective inhibitor of cholesterol 24-hydroxylase (CH24H) under phase III development for the treatment of the developmental and epileptic encephalopathies (DEEs), Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS). A previous model characterized the pharmacokinetics (PKs), CH24H enzyme occupancy (EO), and pharmacodynamics (PDs) of soticlestat in healthy volunteers. The present study extended this original model for patients with DEEs and investigated sources of variability...

Stiripentol (Diacomit® ) (STP) is an orally active antiseizure medication (ASM) indicated as adjunctive therapy, for the treatment of seizures associated with Dravet syndrome (DS), a severe form of childhood epilepsy, in conjunction with clobazam and, in some regions valproic acid. Since the discovery of STP, several mechanisms of action (MoA) have been described that may explain its specific effect on seizures associated with DS. STP is mainly considered as a potentiator of gamma-aminobutyric acid (GABA) neurotransmission: (i) via uptake blockade, (ii) inhibition of degradation, but also (iii) as a positive allosteric modulator of GABAA receptors, especially those containing α3 and δ subunits...

Dravet syndrome (DS) is a neurodevelopmental disorder characterized by epilepsy, developmental delay/intellectual disability, and features of autism spectrum disorder, caused by heterozygous loss-of-function variants in SCN1A encoding the voltage-gated sodium channel α subunit Nav1.1. The dominant model of DS pathogenesis is the "interneuron hypothesis," whereby GABAergic interneurons (INs) express and preferentially rely on Nav1.1-containing sodium channels for action potential generation. This has been shown for three of the major subclasses of cerebral cortex GABAergic INs: those expressing parvalbumin, somatostatin, and vasoactive intestinal peptide...

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic disorder resulting from loss of function of the voltage-gated sodium channel, NaV 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that NaV s abundant in the brain also occur in the heart, suggesting that the very molecular mechanisms underlying epilepsy could also precipitate cardiac arrhythmias and sudden death...

OBJECTIVES: Stiripentol, fenfluramine, and cannabidiol are licensed add-on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing their full licensed dose regimens, across different jurisdictions, as first-line add-on therapies in DS. METHODS: We conducted a systematic review and frequentist network meta-analysis (NMA) of randomized controlled trial (RCT) data for licensed add-on DS therapies. We compared the proportions of patients experiencing: reductions from baseline in monthly convulsive seizure frequency (MCSF) of ≥50% (clinically meaningful), ≥75% (profound), and 100% (seizure-free); serious adverse events (SAEs); discontinuations due to AEs...