Wirrell, Elaine C

Abstract Objective Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high seizure burden and mortality risk. Stiripentol, one of the first DS‐specific therapies, received FDA approval in 2018 but its real‐world use and impact post‐approval in the USA remain insufficiently characterized. The STIRUS study aimed to assess treatment patterns, clinical efficacy, and quality of life outcomes associated with stiripentol in a contemporary US cohort. Methods STIRUS was a retrospective, multicenter chart review of 98 DS patients who initiated stiripentol after FDA approval and were treated for at least 3 months. Data were collected from 10 USA epilepsy centers on seizure types and frequency, status epilepticus (SE), rescue medication use, emergency room visits, and quality of life, at baseline and during the first and final 3 months on stiripentol. Changes over time were assessed using generalized estimating equation models. Results Initiation of stiripentol was associated with a significant reduction in bilateral convulsive seizure frequency (OR = 2.16, p < 0.006) and a nearly 50% decrease in SE episodes (OR = 2.9, p < 0.003). Importantly, there was a marked decline in rescue medication use and seizure‐related hospital visits: the proportion of patients requiring no rescue medications increased from 23% to over 53%, and those needing frequent emergency interventions dropped from 39% at baseline to 14% during the final 3 months. Quality of life improved in more than half of patients and caregivers. Significance The STIRUS study supports the real‐world efficacy of stiripentol in reducing seizure burden and healthcare utilization in DS. Despite its demonstrated benefits and approval for use in infants, stiripentol remains underutilized and often introduced late in the treatment course. Early and broader adoption may help improve clinical outcomes and quality of life in this vulnerable population. Plain Language Summary The STIRUS study found that stiripentol, an anti‐seizure medication specifically approved for Dravet Syndrome, helped reduce seizures and hospital visits for children living with this severe form of epilepsy. Patients had fewer convulsive seizures, needed fewer rescue medicines, and reported better quality of life. Despite these benefits, stiripentol is still not widely used and often started too late in treatment, suggesting earlier use could further improve outcomes.

Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by drug‐resistant seizures and developmental slowing. Although cognitive and executive function deficits have been described, their early trajectory is not well understood. Methods The prospective ENVISION natural history study (NCT04537832) assessed cognitive, executive, and adaptive function in children younger than 5 years of age with SCN1A + DS every 6 months for up to 2 years using Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID‐III), Wechsler Preschool & Primary Scale of Intelligence, 4th Edition (WPPSI‐IV), Vineland Adaptive Behavior Scales, 3rd Edition (VABS‐3), Behavior Rating Inventory of Executive Function – Preschool Version (BRIEF‐P), and Pediatric Evaluation of Disability Inventory (PEDI). Results Fifty‐eight children were enrolled, with 47% younger than age 2 years. At least 80% of children did not achieve age‐appropriate milestones. Mean BSID‐III Cognitive raw scores increased minimally, with age‐equivalent gains of only 3 months over 1.5 years. Mean Cognitive Composite scores declined significantly by Month 12 (from 81.6 to 72.2; change: –11.0, 95% confidence interval [CI]: −15.3 to −6.8), signaling a widening gap compared with neurotypical development. Executive function worsened, with mean BRIEF‐P Global Executive Composite T‐scores increasing by 3.2 points/year. For some participants, scores were 5 standard deviations (SD) above the normative mean, reflecting abilities profoundly below age expectations (bottom .00003% of the population). Adaptive functioning worsened, with mean VABS‐3 Adaptive Behavior Composite decreasing from 78.7 to 68.1 over 1.5 years (change: –9.0, 95% CI: −11.9 to −6.1) and greater decline among children <2 years at enrollment, with scores decreasing by ~15 points (1 SD). Over half of children >3 years could not remove clothing independently; and when placed on a toilet, 48% could not use it. Significance Infants and young children with SCN1A + DS show significant and progressive developmental slowing across several domains, highlighting urgent need for therapies to mitigate the devastating impact on individuals and families.

Abstract Dravet syndrome is a severe developmental and epileptic encephalopathy caused by heterozygous, loss‐of‐function, pathogenic variants in the SCN1A gene. It is characterized by frequent, often prolonged convulsive seizures. Dravet syndrome is associated with diverse comorbid conditions, including developmental impairment, intellectual disability, and behavioral disturbances, in addition to high mortality rates. Prompt diagnosis and treatment initiation are essential to reduce seizure frequency, status epilepticus, and potentially improve neurodevelopmental outcomes. Currently available therapies such as fenfluramine, stiripentol, and cannabidiol have demonstrated significant reduction in convulsive seizure frequency, based on randomized controlled trials and real‐world studies; however, they have not markedly affected non‐seizure symptoms. Emerging therapies such as genetic modulation are promising given their potential for disease modification, seizure frequency reduction, and improvement of non‐seizure outcomes. This review of observational studies and randomized clinical trials provides an overview of the natural history of Dravet syndrome, current treatment guidelines with recently approved medications, addressing both safety and efficacy, and new therapeutic approaches, including disease‐modifying therapies. The therapeutic landscape in Dravet syndrome is evolving, with the use of new antiseizure agents and precision therapies that target the SCN1A variant. Goals of treatment include improvement of seizure burden, neurodevelopment, comorbidities, and quality of life in individuals with Dravet syndrome.

Abstract Objective To assess the localization and lateralization values of ictal emotional features and ictal defensive behaviors in pediatric and young adult patients with frontal lobe epilepsy (FLE). Methods Children and young adults with FLE were identified from a single institution's epilepsy surgery database. Two epileptologists determined by consensus the presence of ictal emotional features (positive‐ smile, laughter, humming, singing; negative‐ fear, crying, anger, disgust, contempt, sadness) and ictal defensive behaviors (freezing with a fearful facial expression, shielding the face with hands, burying the face in a pillow, or exhibiting hyperkinetic motor behaviors like attempting to escape from bed or resisting restraint) in each patient's first video EEG (vEEG). Historic seizure semiology and vEEG reports were compared with the consensus vEEG analysis. Longitudinal changes in ictal emotional features were defined by the emergence or resolution of ictal emotional features between historic seizure semiology and re‐review of presurgical vEEG analysis. Subgroup analyses were conducted according to the seizure lateralization (left vs. right) and sublobar localization (precentral, medial, lateral, extensive) based on surgical extent. Results Twenty‐three FLE patients were included (female 39%; mean age at vEEG analysis: 11.28 years, range 1.75–20.17). The inter‐rater reliability was very good for both ictal emotional features ( κ = 0.81, 95% CI: 0.59–1) and ictal defensive behaviors ( κ = 0.91, 95% CI: 0.79–1). Ictal emotional features were observed in 10 patients (43.4%), with negative emotions present in 70% (7/10) of these cases. vEEG reports lacked documentation of ictal emotional features in two patients. Although ictal emotional features showed no statistical correlation by sublobar regions, ictal defensive behaviors were consistently seen in medial compared to lateral FLE (100% vs. 16.6%; p = 0.004). Longitudinal changes in ictal emotional features were observed in 8 (34.7%) patients. Significance Ictal emotional features were common in pediatric and young adult FLE patients and were mainly negative. Ictal defensive behaviors were more likely associated with medial FLE. Longitudinal changes in ictal emotional features occurred in about a third of pediatric and young adult patients with FLE. Plain Language Summary This study examined emotional features and defensive behaviors during seizures in children and young adults with FLE. Negative emotions were commonly seen during seizures. Ictal defensive behaviors were more frequently observed in patients with medial FLE, and recognizing these signs could help clinicians localize the seizures. Changes in emotional features were seen over time in about one‐third of children and young adult patients.

Abstract Objective This study was undertaken to evaluate the response to second treatments for infantile epileptic spasms syndrome (IESS). Methods Infants aged 2–24 months with IESS were prospectively enrolled in the National Infantile Spasms Cohort study at 21 pediatric epilepsy centers in the United States from 2012 to 2018. We analyzed data from infants who initially received standard treatment (hormonal therapy [adrenocorticotropic hormone, high‐dose prednisolone] or vigabatrin), had continued or recurring epileptic spasms, and received a second treatment. We excluded those with tuberous sclerosis. Treatment groups included hormonal therapy followed by vigabatrin (reference), hormonal‐to‐hormonal, hormonal‐to‐nonstandard, vigabatrin‐to‐hormonal, and vigabatrin‐to‐nonstandard. Nonstandard treatments included other antiseizure medications and dietary therapy. Treatment groups were tested for differences in 3‐month clinical remission using a binary logistic regression to estimate odds ratios (ORs). Results There were 153 infants with IESS who received second treatments. The highest rates of 3‐month remission were among infants in the hormonal‐to‐vigabatrin (22/65, 34%) and vigabatrin‐to‐hormonal (9/26, 35%) groups, followed by vigabatrin‐to‐nonstandard (3/10, 30%), hormonal‐to‐hormonal (4/22, 18%), and hormonal‐to‐nonstandard (1/30, 3.3%). Compared to the hormonal‐to‐vigabatrin group (reference), fewer infants had remission in the hormonal‐to‐nonstandard group (OR = .07, 95% confidence interval [CI] = .01–.53), and there was a trend toward fewer infants in the hormonal‐to‐hormonal group (OR = .43, 95% CI = .13–1.4, p = .17). Following initial hormonal treatment, the number needed to treat was three infants for one additional infant to have remission when treated with vigabatrin compared to nonstandard therapy as the second treatment. Significance This updated analysis with an expanded sample size provided power for additional subgroup analysis. Overall response rates were low, and at best only one third had remission after second treatment. Results support a clinical strategy of switching mechanism of action when selecting a second medication for epileptic spasms (i.e., use vigabatrin after hormonal therapy, or hormonal therapy after vigabatrin). Our findings also support the use of standard over nonstandard therapies.

Abstract The International League Against Epilepsy (ILAE) has updated the operational classification of epileptic seizures, building upon the framework established in 2017. This revision, informed by the implementation experience, involved a working group appointed by the ILAE Executive Committee. Comprising 37 members from all ILAE regions, the group utilized a modified Delphi process, requiring a consensus threshold of more than two thirds for any proposal. Following public comments, the Executive Committee appointed seven additional experts to the revision task force to address and incorporate the issues raised, as appropriate. The updated classification maintains four main seizure classes: Focal, Generalized, Unknown (whether focal or generalized), and Unclassified. Taxonomic rules distinguish classifiers, which are considered to reflect biological classes and directly impact clinical management, from descriptors, which indicate other important seizure characteristics. Focal seizures and those of unknown origin are further classified by the patient's state of consciousness (impaired or preserved) during the seizure, defined operationally through clinical assessment of awareness and responsiveness. If the state of consciousness is undetermined, the seizure is classified under the parent term, that is, the main seizure class (focal seizure or seizure of unknown origin). Generalized seizures are grouped into absence seizures, generalized tonic–clonic seizures, and other generalized seizures, now including recognition of negative myoclonus as a seizure type. Seizures are described in the basic version as with or without observable manifestations, whereas an expanded version utilizes the chronological sequence of seizure semiology. This updated classification comprises four main classes and 21 seizure types. Special emphasis was placed on ensuring translatability into languages beyond English. Its aim is to establish a common language for all health care professionals involved in epilepsy care, from resource‐limited areas to highly specialized centers, and to provide accessible terms for patients and caregivers.

AbstractEpilepsy syndromes are distinct electroclinical entities which have been recently defined by the International League Against Epilepsy Nosology and Definitions Task Force. Each syndrome is associated with “a characteristic cluster of clinical and EEG features, often supported by specific etiologic findings”. Syndromes often present in an age‐dependent manner, carry both prognostic and treatment implications, and are associated with a specific range of comorbidities. Syndromes are most commonly identified in young children and are less frequent in adults. Syndrome identification assists clinicians in selecting the highest yield investigations, the most effective therapies, and allows them to give more accurate prognoses both with regards to seizure control and potential remission as well as expected, associated comorbidities. This review outlines how syndromes are organized and defined, highlighting the characteristic features of the more common entities.Plain Language SummaryEpilepsy syndromes are identifiable entities that are characterized by specific seizure type(s) and EEG findings. Identification of an epilepsy syndrome often provides a clue to the underlying cause, helps clinicians select the most effective treatments, and provides information on the likely outcome.

Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy. Diagnosis is clinical, but ~90% of patients have pathogenic variants in SCN1A . ATP6V0C has recently been proposed as a novel candidate gene for epilepsy, with or without developmental delay. Here we describe two adult patients with a clinical diagnosis of DS associated with ATP6V0C variants. Methods Patients with developmental and epileptic encephalopathies were evaluated by physicians who are experts in DS, and their clinical diagnosis was correlated with genetic findings. A subgroup of those patients with DS but without known genetic causes were evaluated through gene panels, whole exome sequencing, and chromosome microarray. Phenotype was determined by pediatric and adult chart reviews, interviews, and physical examinations. Results Of 753 patients with DS, two unrelated individuals with classic features of DS during childhood and adulthood were identified with heterozygous de novo missense variants in ATP6V0C (c.319G > C, p.(Gly107Arg) and c.284C > T, p.(Ala95Val), respectively). Both variants were absent in normal populations and computational prediction algorithms suggested deleterious effects on protein structure and/or function. No disease‐causing variants in other genes previously associated with DS were found. Significance Here we describe two adult patients with Dravet‐like syndrome and pathogenic/likely pathogenic variants in ATP6V0C . We propose that abnormal ATP6V0C function can, at the severe end of the clinical spectrum, be associated with Dravet‐like phenotype. This is relevant, as these patients would not qualify for disease‐modifying antisense nucleotide or gene therapies targeting SCN1A .