This cohort study aims to describe the evolution of disease features and health-related quality of life per life stage in Dravet syndrome and other SCN1A-related non-Dravet seizure disorders which will enable treating physicians to provide tailored care. Health-related quality of life and disease features were assessed cross-sectionally in participants with a SCN1A-related seizure disorder, categorized per age group for Dravet syndrome, and longitudinally over seven years follow-up (2015-2022). Data were collected from questionnaires, medical records, and semi-structured telephonic interviews. Health-related quality of life was measured with the Paediatric Quality of Life Inventory, proxy-reported for participants with Dravet syndrome and for participants with non-Dravet aged younger than 18 years old and self-reported for participants with non-Dravet over 18 years old. Associations between health-related quality of life and disease features were explored with multivariable regression analyses, cross-sectionally in a cohort of 115 patients with Dravet and 48 patients with generalized epilepsy with febrile seizures plus and febrile seizures (non-Dravet) and longitudinally in a cohort of 52 Dravet patients and 13 non-Dravet patients. In the cross-sectional assessment in 2022, health-related quality of life was significantly lower in Dravet syndrome, compared to non-Dravet and normative controls. Health-related quality of life in the School and Psychosocial domain was significantly higher in older Dravet age groups. A higher health-related quality of life was associated with fewer behavioural problems [β = -1.1; 95% confidence interval (CI), (-1.4 to -0.8)], independent walking (β = 8.5; 95%CI (4.2-12.8)), compared to the use of a wheelchair), and fewer symptoms of autonomic dysfunction (β = -2.1, 95%CI (-3.2 to -1.0)). Longitudinally, health-related quality of life was significantly higher seven years later in the course of disease in Dravet participants (Δ8.9 standard deviation (SD) 18.0, P < 0.05), mediated by a lower prevalence of behavioural problems (β = -1.2, 95%CI (-2.0 to -0.4)), lower seizure frequency (β = -0.1, 95%CI (-0.2 to -0.0)) and older age (β = 0.03, 95%CI (0.01-0.04)). In summary, health-related quality of life was significantly higher at older age in Dravet syndrome. This finding may reflect the benefits of an advanced care strategy in recent years and a ceiling of severity of disease symptoms, possibly resulting in an increased wellbeing of parents and patients. The strong association with behavioural problems reinforces the need to incorporate a multidisciplinary approach, tailored to the age-specific needs of this patient group, into standard care.

Dravet syndrome (DS) is an infantile onset developmental and epileptic encephalopathy. Sodium channel blockers are known to exacerbate seizures in this syndrome. Due to its high incidence, the management of prolonged seizures is crucial for DS patients. There is still ambiguity regarding the use of intravenous phenytoin for prolonged seizure in DS patients mainly due to the lack of data, raising concern about the safety of it use. We conducted a retrospective study (from January 2009 to January 2020) aiming to assess the management of prolonged seizures in DS with a focus on the use of intravenous phenytoin. Data were collected for patients admitted to our hospital for seizures lasting >5 min. Among 52 identified patients in our database, 23 experienced 59 prolonged seizures managed in our hospital. Only four seizures ceased without rescue medication. Notably, the use of intravenous phenytoin was not associated with discernible adverse effects and was effective in stopping status epilepticus in 71% of cases. This study suggests the safety and efficacy of intravenous phenytoin for prolonged seizure in DS. There is a need for broader investigations of emergency treatments for evidence-based recommendations for the emergency plan of each patient.

OBJECTIVE: The current standard of care for Dravet syndrome (DS) includes polytherapy after inadequate seizure control with one or more monotherapy approaches. Treatment guidelines are often based on expert opinions, and finding an optimal balance between seizure control and adverse drug effects can be challenging. This study utilizes the efficacy and pharmacokinetic assessment of a second-line treatment regimen that combines clobazam and sodium valproate with an add-on drug as a proof-of-principle approach to establish an effective therapeutic regimen in a DS mouse model.
METHODS: We evaluated the efficacy of add-on therapies stiripentol, cannabidiol, lorcaserin, or fenfluramine added to clobazam and sodium valproate against hyperthermia-induced seizures in Scn1aA1783V/WT mice. Clobazam, N-desmethyl clobazam (an active metabolite of clobazam), sodium valproate, stiripentol, and cannabidiol concentrations were quantified in plasma and brain using liquid chromatography-tandem mass spectrometry for the combinations deemed effective against hyperthermia-induced seizures. The concentration data were used to calculate pharmacokinetic parameters via noncompartmental analysis in Phoenix WinNonLin.
RESULTS: Higher doses of stiripentol or cannabidiol, in combination with clobazam and sodium valproate, were effective against hyperthermia-induced seizures in Scn1aA1783V/WT mice. In Scn1aWT/WT mice, brain clobazam and N-desmethyl clobazam concentrations were higher in the triple-drug combinations than in the clobazam monotherapy. Stiripentol and cannabidiol brain concentrations were greater in the triple-drug therapy than when given alone.
CONCLUSIONS: A polypharmacy strategy may be a practical preclinical approach to identifying efficacious compounds for DS. The drug-drug interactions between compounds used in this study may explain the potentiated efficacy of some polytherapies.

Dravet syndrome (DS) presents a multifaceted clinical picture marked by epilepsy, cognitive impairments and behavioral disorders that progresses throughout development. Behavioral disorders include impairments in social relationships and communication, with frequent diagnosis of autism spectrum disorder. This study focused on comprehensively evaluating and comparing social communication profiles among a group of 43 children with Dravet syndrome, 30 children with level 1 autism spectrum disorder, 36 with social (pragmatic) communication disorder, and 18 with intellectual disability. Using validated tools like the Childhood Autism Spectrum Test and Children\'s Communication Checklist, distinct patterns of social communication deficits were delineated. Our findings indicate that children with Dravet syndrome experience challenges in social relationships, primarily due to difficulties in use of pragmatic language. Areas such as range of interests and social interaction are less affected compared to those with ASD, emphasizing differing profiles between the conditions. While children with DS and ID may have similar intellectual functioning, the different social communication deficits in DS indicate their role in the DS phenotype beyond ID. These results underscore the unique social communication profile of DS and emphasizes the importance of tailored interventions and deep phenotyping efforts for effective DS management.

OBJECTIVE: Protocadherin-19 (PCDH19) epilepsy is a rare female restricted epilepsy syndrome with early onset seizures and developmental delay caused by a change or mutation of the PCDH19 gene on the X chromosome. SCN1A-negative patients with a Dravet-like phenotype may have a gene mutation in PCDH19. The aim of this case series was to characterize the phenotype of epileptic patients according to PCDH19 mutations, antiseizure medications, brain images and mutation types in Taiwan.
METHODS: We retrospectively reviewed the medical records of patients with PCDH19 epilepsy from July 2017 to December 2021 from multiple centers in Taiwan. We analyzed the patients\' clinical data and genetic reports.
RESULTS: Fifteen female patients (age 3-23 years) were enrolled. Seizure onset was at 4 months to 2 years 7 months of age with generalized tonic-clonic or focal seizures. Seizure frequency tended to be in clusters rather than single longer seizures. The patients had varying degrees of intellectual disability, however 3 had no impairment. Two patients had abnormal brain images including mesial temporal sclerosis, subcortical and periventricular white matter lesions. On average, the patients received 4 antiseizure medications (range 3-6), including 9 patients who were seizure free, and 3 who received sodium channel blockers without aggravation. Missense and truncating variants (frameshift and nonsense variants) accounted for 40% and 46.7% of all mutations. The mutations of 13 patients were located on EC1 to EC4, and EC5 to cytoplasmic domain in 2 patients.
CONCLUSIONS: PCDH19 epilepsy has distinct phenotypes and an unusual X-linked pattern of expression in which females manifest core symptoms. Psychiatric and behavioral problems are frequently part of the clinical picture. Patients are usually treated with a wide array of standard antiseizure medications, with no preferred antiseizure medication class. No strong correlations between phenotype and location of variant mutations were found in our patients.

BACKGROUND: SCN1A channelopathy is the most well-known cause for epileptic encephalopathies and contributes to a wide phenotypic spectrum. The variable expressivity is troublesome for the interpretation of clinical significance and prognoses. To investigate the clinical manifestations, medications and outcomes of patients with SCN1A channelopathies, we conducted this observation retrospective study in Taiwan.
METHODS: A cohort consisting of 16 patients (5 males and 11 females) from multiple centers with identified SCN1A variants was investigated and phenotypically relevant factors were recorded. The variants were identified using NGS and confirmed by Sanger sequencing. A panel of 90 epileptic-related genes was used to identify SCN1A variants and to evaluate some of the potential SCN1A modifier genes.
RESULTS: The mean age of seizure onset was 10.4 months. Twelve of the sixteen patients (75%) had different degrees of neurocognitive sequela and psychobehavioral comorbidity in our cohort. Cognitive impairment was noted in all ten patients with Dravet syndrome (DS) and in two of the patients with non-DS phenotypes. A lower response rate to medications was also noted in patients with DS. Notably, a medication-specific tendency towards valproic acid (VPA), clobazam (CLB), and levetiracetam (LEV) was observed, revealing the effective pharmacotherapies for SCN1A-related seizures. An asymptomatic carrier with a reported pathogenic SCN1A variant was reviewed along with her monozygotic twin sister with DS. Nine novel SCN1A mutations are herein reported, eight of which being classified as pathogenic.
CONCLUSIONS: Our study revealed unfavorable outcomes for patients with SCN1A variants. Some patients with SCN1A channelopathy showed specific responsiveness to the pharmacotherapies previously either recommended or contraindicated for these patients. Our study also expands the genotype and provides valuable prognostic insights in patients with SCN1A channelopathy.

Developmental and epileptic encephalopathies (DEEs) present significant treatment challenges due to frequent, drug-resistant seizures and comorbidities that impact quality of life. DEEs include both developmental encephalopathy from underlying pathology and epileptic encephalopathy where seizures exacerbate cognitive and behavioral impairments. Classification by syndrome and etiology is essential for therapy and prognosis, with common syndromes like infantile epileptic spasms syndrome and Dravet syndrome having specific first-line treatments. Etiologies are predominantly genetic, structural, or combined, with targeted therapies increasingly available. Surgery aims to improve seizure control but also may improve development, if the epileptic encephalopathy can be ameliorated. Timely intervention can reduce seizures and epileptiform discharges, maximizing developmental potential and allowing reduction in antiseizure medication. In cases requiring extensive resections, new deficits may be offset by developmental gains. Studies indicate that parents are generally willing to accept some deficits for significant seizure reduction.

Recent advances in genetic diagnosis have revealed the underlying etiology of many epilepsies and have identified pathogenic, causative variants in numerous ion and ligand-gated channel genes. This chapter describes the clinical presentations of epilepsy associated with different channelopathies including classic electroclinical syndromes and emerging gene-specific phenotypes. Also discussed are the archetypal epilepsy channelopathy, SCN1A-Dravet syndrome, considering the expanding phenotype. Clinical presentations where a channelopathy is suspected, such as sleep-related hypermotor epilepsy and epilepsy in association with movement disorders, are reviewed. Channelopathies pose an intriguing problem for the development of gene therapies. Design of targeted therapies requires physiologic insights into the often multifaceted impact of a pathogenic variant, coupled with an understanding of the phenotypic spectrum of a gene. As gene-specific novel therapies come online for the channelopathies, it is essential that clinicians are able to recognize epilepsy phenotypes likely to be due to channelopathy and institute early genetic testing in both children and adults. These findings are likely to have immediate management implications and to inform prognostic and reproductive counseling.

Sodium channelopathies are genetic disorders caused by mutations in genes, including sodium voltage-gated channel alpha subunit 1 (SCN1A), that lead to several epilepsy syndromes. Traditional treatments with sodium channel blockers often have limited effectiveness and side effects. Dravet syndrome (DS), a severe epilepsy starting in infancy, presents significant treatment challenges. Perampanel (PER), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, has shown promise for DS, reducing seizure frequency and improving quality of life (QoL). The limited availability of randomized controlled trials on PER among DS is challenging, but broader studies on refractory epilepsies offer insights. Real-world studies support PER\'s efficacy, underscoring its potential for managing refractory seizures in DS. Studies showed long-term effectiveness in reducing seizure frequency and enhancing QoL. While PER has minimal impact on cognitive development, it significantly improves seizure control. Numerous studies confirm the use of PER as an effective adjunctive treatment for DS; however, it is crucial to observe the safety profile, especially for pediatric sodium channelopathy patients. Common side effects include dizziness, drowsiness, and irritability, necessitating careful management. Long-term safety is generally favorable, but monitoring for behavioral and mood changes is essential. Additionally, the response to PER in DS varies widely, complicating its use. The limited clinical data and the need for careful dosage monitoring, especially in children, present significant challenges. Side effects, potential drug interactions, and high costs further complicate treatment. Despite increasing attention to its cost-effectiveness, accessibility remains limited in some regions, posing significant barriers for many families. In this paper, we review the role of PER in treating pediatric patients with DS, emphasizing clinical evidence and practical considerations.

UNASSIGNED: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy that presents with frequent and prolonged seizures resistant to treatment as well as cognitive problems such as behavioral and developmental delays. However, there is a lack of scientific literature on the impact of this condition on caregivers and the family unit.
UNASSIGNED: To find out the social and emotional impact of DS on the family unit, to provide a comprehensive understanding of the disease\'s effects on both the family and caregivers.
UNASSIGNED: A tailored online survey was administered to Spanish DS families, collecting data on the employment, financial, emotional, and social status of patients and caregivers.
UNASSIGNED: A total of 112 Spanish caregivers participated in the study. The mean age of the 112 parents was 46.61 years, and 77.68 % of them were mothers. The majority of caregivers had to quit their jobs or reduce their working hours to take care of their child with DS, being the most of them mothers. Most of the caregivers felt that they were not well-informed by healthcare professionals (HCPs) and the Spanish National Health System (NHS). Despite access to resources, families often face financial strain and challenges in obtaining sufficient support, highlighting the need for enhanced social, economic, and psychological backing. In addition, both sentimental and social relationships were negatively impacted in the vast majority of respondents.
UNASSIGNED: The study advocates for policy reforms, integrated social services, community programs, and multidisciplinary efforts to improve the quality of life and social integration for those affected by DS.