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Objective: There is currently scarce data on the electroclinical characteristics of epilepsy associated with synapsin 1 (SYN1) pathogenic variations. We examined clinical and electro‐encephalographic (EEG) features in patients with epilepsy and SYN1 variants, with the aim of identifying a distinctive electroclinical pattern. Methods: In this retrospective multicenter study, we collected and reviewed demographic, genetic, and epilepsy data of 19 male patients with SYN1 variants. Specifically, we analyzed interictal EEG data for all patients, and electro‐clinical data from 10 epileptic seizures in 5 patients, using prolonged video‐EEG monitoring recordings. Inter‐ictal EEG functional connectivity parameters and frequency spectrum of the 10 patients over 12 years of age, were computed and compared with those of 56 age‐ and sex‐matched controls. Results: The main electroclinical features of epilepsy in patients with SYN1 were (1) EEG background and organization mainly normal; (2) interictal abnormalities are often rare or not visible on EEG; (3) more than 60% of patients had reflex seizures (cutaneous contact with water and defecation being the main triggers) isolated or associated with spontaneous seizures; (4) electro‐clinical semiology of seizures was mainly temporal or temporo‐insulo/perisylvian with a notable autonomic component; and (5) ictal EEG showed a characteristic rhythmic theta/delta activity predominating in temporo‐perisylvian regions at the beginning of most seizures. Comparing patients with SYN1 to healthy subjects, we observed a shift to lower frequency bands in power spectrum of interictal EEG and an increased connectivity in both temporal regions. Interpretation: A distinct epilepsy syndrome emerges in patients with SYN1, with a rather characteristic clinical and EEG pattern suggesting predominant temporo‐insular involvement. ANN NEUROL 2025;97:34–50 [ABSTRACT FROM AUTHOR]

Objective: EEG patterns and quantitative EEG (qEEG) features have been poorly explored in monogenic epilepsies. Herein, we investigate regional differences in EEG frequency composition in patients with STXBP1 developmental and epileptic encephalopathy (STXBP1‐DEE). Methods: We conducted a retrospective study collecting electroclinical data of patients with STXBP1‐DEE and two control groups of patients with DEEs of different etiologies and typically developing individuals matched for age and sex. We performed a (1) visual EEG assessment, (b) qEEG analysis, and (c) electrical source imaging (ESI). We quantified the relative power (RP) of four frequency bands (α β, θ, δ), in two electrode groups (anterior/posterior), and compared their averages and dynamics (standard deviation [SD] over time). The ESI was performed by applying the standard Distributed Source Modeling algorithm. Results: We analyzed 42 EEG studies in 19 patients with STXBP1‐DEE (10 female), with a median age at recordings of 9.6 years (range 9 months to 29 years). The δRP was higher in recordings of STXBP1‐DEE (p <.001) compared to both control groups, suggesting the pathogenicity and STXBP1‐specificity of these findings. In STXBP1‐DEE, the δRP was significantly higher in the anterior electrode group compared to the posterior one (p =.003). There was no correlation between the anterior δRP and the epilepsy focus, age at recordings, and concomitant medications The ESI modeling of this activity showed a widespread involvement of the dorsomesial frontal cortex, suggesting a large corticosubcortical pathologic network. Finally, we identified two groups of recordings: cluster.1 with higher anterior δRP and low dynamics and cluster.2 with lower δRP and higher dynamics. Patients in cluster.1 had a more severe epilepsy and neurological phenotype compared to patients in cluster 2. Significance: The qEEG analysis showed a predominant frontal slow activity as a specific STXBP1 feature that correlates with the severity of the phenotype and may represent a biomarker for prospective longitudinal studies of STXBP1‐DEE. [ABSTRACT FROM AUTHOR]

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL. We enrolled individuals with BPTF -related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed. We studied 11 individuals with a null variant in BPTF , including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases. Our study provides the first characterization of BPTF -related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare. [ABSTRACT FROM AUTHOR]

Objective: We aimed to develop consensus for diagnosis/management of SCN8A‐related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A‐related disorders. Methods: A Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process. Twenty‐eight expert clinicians, one researcher, and 13 caregivers from 16 countries participated in the subsequent three survey rounds. We defined consensus as follows: strong consensus, ≥80% fully agree; moderate consensus, ≥80% fully/partially agree, <10% disagree; and modest consensus, 67%–79% fully/partially agree, <10% disagree. Results: Early diagnosis is important for long‐term clinical outcomes in SCN8A‐related disorders. There are five phenotypes: three with early seizure onset (severe developmental and epileptic encephalopathy [DEE], mild/moderate DEE, self‐limited (familial) infantile epilepsy [SeL(F)IE]) and two with later/no seizure onset (neurodevelopmental delay with generalized epilepsy [NDDwGE], NDD without epilepsy [NDDwoE]). Caregivers represented six patients with severe DEE, five mild/moderate DEE, one NDDwGE, and one NDDwoE. Phenotypes vary by age at seizures/developmental delay onset, seizure type, electroencephalographic/magnetic resonance imaging findings, and first‐line treatment. Gain of function (GOF) versus loss of function (LOF) is valuable for informing treatment. Sodium channel blockers are optimal first‐line treatment for GOF, severe DEE, mild/moderate DEE, and SeL(F)IE; levetiracetam is relatively contraindicated in GOF patients. First‐line treatment for NDDwGE is valproate, ethosuximide, or lamotrigine; sodium channel blockers are relatively contraindicated in LOF patients. Significance: This is the first‐ever global consensus for the diagnosis and treatment of SCN8A‐related disorders. This consensus will reduce knowledge gaps in disease recognition and inform preferred treatment across this heterogeneous disorder. Consensus of this type allows more clinicians to provide evidence‐based care and empowers SCN8A families to advocate for their children. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to develop consensus on comorbidities (frequency, severity, and prognosis) and overall outcomes in epilepsy, development, and cognition for the five phenotypes of SCN8A‐related disorders. Methods: A core panel consisting of 13 clinicians, 1 researcher, and 6 caregivers was formed and split into three workgroups. One group focused on comorbidities and prognosis. All groups performed a literature review and developed questions for use in a modified‐Delphi process. Twenty‐eight clinicians, one researcher, and 13 caregivers from 16 countries participated in three rounds of the modified‐Delphi process. Consensus was defined as follows: strong consensus ≥80% fully agree; moderate consensus ≥80% fully or partially agree, <10% disagree; and modest consensus 67%–79% fully or partially agree, <10% disagree. Results: Consensus was reached on the presence of 14 comorbidities in patients with Severe Developmental and Epileptic Encephalopathy (Severe DEE) spanning non‐seizure neurological disorders and other organ systems; impacts were mostly severe and unlikely to improve or resolve. Across Mild/Moderate Developmental and Epileptic Encephalopathy (Mild/Moderate DEE), Neurodevelopmental Delay with Generalized Epilepsy (NDDwGE), and NDD without Epilepsy (NDDwoE) phenotypes, cognitive and sleep‐related comorbidities as well as fine and gross motor delays may be present but are less severe and more likely to improve compared to Severe DEE. There was no consensus on comorbidities in the SeL(F)IE phenotype but strong conesensus that seizures would largely resolve. Seizure freedom is rare in patients with Severe DEE but may occur in some with Mild/Moderate DEE and NDDwGE. Significance: Significant comorbidities are present in most phenotypes of SCN8A‐related disorders but are most severe and pervasive in the Severe DEE phenotype. We hope that this work will improve recognition, early intervention, and long‐term management for patients with these comorbidities and provide the basis for future evidence‐based studies on optimal treatments of SCN8A‐related disorders. Identifying the prognosis of patients with SCN8A‐related disorders will also improve care and quality‐of‐life for patients and their caregivers. [ABSTRACT FROM AUTHOR]

Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype-phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype-phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations. [ABSTRACT FROM AUTHOR]

Vinpocetine is a synthetic derivative of the alkaloid vincamine and has been used as a dietary supplement for decades. Following a positive report of the use of vinpocetine in a patient with a loss‐of‐function GABRB3 variant, we here describe another patient with a loss‐of‐function GABRA1 variant (p.(Arg112Gln)) who benefited from vinpocetine treatment. This patient was diagnosed with autism spectrum disorder, psychiatric complications, and therapy‐resistant focal epilepsy. Upon add‐on treatment with 40 mg vinpocetine daily for 16 months, the patient experienced an overall improved quality of life as well as seizure freedom. Our findings corroborate that vinpocetine can attenuate epilepsy‐associated behavioral issues in patients with loss‐of‐function GABAA receptor gene variants. [ABSTRACT FROM AUTHOR]

Purpose : Heterozygous variants in PRRT2 are mostly associated with benign phenotypes, being the major genetic cause of benign familial infantile seizures (BFIS), as well as in paroxysmal disorders. We report two children from unrelated families with BFIS that evolved to encephalopathy related to status epilepticus during sleep (ESES). Methods and results: Two probands presented with focal motor seizures at 3 months of age, with a limited course. Both children presented, at around 5 years of age, with centro-temporal interictal epileptiform discharges with a source in the frontal operculum, markedly activated by sleep, and associated with stagnation on neuropsychological development. Whole-exome sequencing and co-segregation analysis revealed a frameshift mutation c.649dupC in the proline-rich transmembrane protein 2 (PRRT2) in both probands and all affected family members. Conclusion: The mechanism leading to epilepsy and the phenotypic variability of PRRT2 variants remain poorly understood. However, its wide cortical and subcortical expression, in particular in the thalamus, could partially explain both the focal EEG pattern and the evolution to ESES. No variants in the PRRT2 gene have been previously reported in patients with ESES. Due to the rarity of this phenotype, other possible causative cofactors are likely contributing to the more severe course of BFIS in our probands. [ABSTRACT FROM AUTHOR]

Pathogenic variants in CWF19L1 lead to a rare autosomal recessive form of hereditary ataxia with only seven cases reported to date. Here, we describe four additional unrelated patients with biallelic variants in CWF19L1 (age range: 6–22 years) and provide a comprehensive review of the literature. The clinical spectrum was broad, including mild to profound global developmental delay; global or motor regression in infancy or adolescence; childhood‐onset ataxia and cerebellar atrophy; and early‐onset epilepsy. Since only two previously reported patients were adults, our cohort expands our understanding of the evolution of symptoms from childhood into early adulthood. Taken together, we describe that CWF19L1‐related disorder presents with developmental and epileptic encephalopathy with treatment‐resistant seizures and intellectual disability in childhood followed by progressive ataxia and other extrapyramidal movement disorders in adolescence. [ABSTRACT FROM AUTHOR]

Background: Several EEG criteria have been proposed for diagnosis of non-convulsive status epilepticus (NCSE), but none have been clinically validated. We aimed to assess the diagnostic accuracy of the EEG criteria proposed by a panel of experts at the fourth London-Innsbruck Colloquium on Status Epilepticus in Salzburg, 2013 (henceforth called the Salzburg criteria).Methods: We did a retrospective, diagnostic accuracy study using EEG recordings from patients admitted for neurological symptoms or signs to three centres in two countries (Danish Epilepsy Centre, Dianalund, Denmark; Aarhus University Hospital, Aarhus, Denmark; and Paracelsus Medical University, Salzburg, Austria). Participants were included from the Danish centres if they were aged 4 months or older, and from the Austrian centre if aged 18 years or older. Participants were sorted into two groups: consecutive patients under clinical suspicion of having NCSE (the clinical validation group) or consecutive patients with abnormal EEG findings but no clinical suspicion of NCSE (the control group). Two raters blinded to all other patient data retrospectively analysed the EEG recordings and, using the Salzburg criteria, categorised patients as in NCSE or not in NCSE. By comparing with a reference standard inferred from all clinical and para-clinical data, therapeutic response, and the final outcome, we calculated sensitivity, specificity, overall diagnostic accuracy, positive and negative predictive values, and inter-rater agreement for the Salzburg criteria. The reference standard was inferred by two raters who were blinded to the scorings of the Salzburg criteria.Findings: We retrospectively reviewed EEG data from 220 patients. EEGs in the clinical validation group were recorded in 120 patients between Jan 1, and Feb 28, 2014 (Austria), and Aug 1, 2014, and Jan 31, 2015 (Denmark). EEGs in the control group were recorded in 100 patients between Jan 13 and Jan 22, 2014 (Austria) and Jan 12 and Jan 26, 2015 (Denmark). According to the reference standard, 43 (36%) of the 120 patients in the validation group had NCSE. In the validation cohort sensitivity was 97·7% (95% CI 87·9-99·6) and specificity was 89·6% (80·8-94·6); overall accuracy was 92·5% (88·3-97·5). Positive predictive value was 84·0% (95% CI 74·1-91·5) and negative predictive value was 98·6% (94·4-100). Three people in the control group (n=100) fulfilled the Salzburg criteria and were therefore false positives (specificity 97·0%, 95% CI 91·5-99·0; sensitivity not calculable). Inter-rater agreement was high for both the Salzburg criteria (k=0·87) and for the reference standard (k=0·95). Therapeutic changes occurred significantly more often in the group of patients fulfilling Salzburg criteria (42 [84%] of 50 patients) than in those who did not (11 [16%] of 70; p<0·0001).Interpretation: The Salzburg criteria for diagnosis of NCSE have high diagnostic accuracy and excellent inter-rater agreement, making them suitable for implementation in clinical practice.Funding: None. [ABSTRACT FROM AUTHOR]

Objective: To determine the duration of epileptic seizure types in patients who did not undergo withdrawal of antiseizure medication. Methods: From a large, structured database of 11 919 consecutive, routine video‐electroencephalograpy (EEG) recordings, labeled using the SCORE (Standardized Computer‐Based Organized Reporting of EEG) system, we extracted and analyzed 2742 seizures. For each seizure type we determined median duration and range after removal of outliers (2.5–97.5 percentile). We used surface electromyography (EMG) for accurate measurement of short motor seizures. Results: Myoclonic seizures last <150 ms, epileptic spasms 0.4–2 s, tonic seizures 1.5–36 s, atonic seizures 0.1–12,5 s, when measured using surface EMG. Generalized clonic seizures last 1–24 s. Typical absence seizures are rarely longer than 30 s (2.75–26.5 s) and atypical absences last 2–100 s. In our patients, the duration of focal aware (median: 27 s; 1.25–166 s) and impaired awareness seizures (median: 42.5 s; 9.5–271 s) was shorter than reported previously in patients undergoing withdrawal of antiseizure medication. All focal seizures terminated within 10 min. Median duration of generalized tonic–clonic seizures was 79.5 s (57–102 s) and of focal‐to‐bilateral tonic–clonic seizures was 103.5 (77.5–237 s). All tonic–clonic seizures terminated within 5 min. Significance: This comprehensive list of seizure durations provides important information for characterizing seizures and diagnosing patients with epilepsy. The upper limits of seizure durations are helpful in early recognition of imminent status epilepticus. [ABSTRACT FROM AUTHOR]

Individuals with no significant seizure reduction (defined as >= 50 % reduction in seizure frequency after 3 months of treatment) with maximum daily dosage of pyridoxine were offered a switch from oral pyridoxine to oral P5P. Seizure types included bilateral tonic-clonic seizures ( I n i = 4), absence seizures ( I n i = 2), focal seizures with or without impaired awareness ( I n i = 3), focal to bilateral tonic-clonic seizures ( I n i = 2), myoclonic seizures ( I n i = 2), and tonic seizures ( I n i = 1). Although the treatment period was too short to observe any convincing changes in the first two seizure types, a drastic reduction in focal seizures (>90%) was seen during the last 8-10 weeks of pyridoxine treatment. ABBREVIATIONS ASM Antiseizure medication GPI Glycosylphosphatidylinositol P5P Pyridoxal 5-phosphate TNSALP Tissue non-specific alkaline phosphatase Introduction The glycolipid glycosylphosphatidylinositol (GPI) plays an important role in both embryonic development and neurogenesis.1,2 GPI is synthesized in the endoplasmic reticulum, transferred to proteins, and later modified in the Golgi apparatus.3 At least 31 genes are involved in this multistep pathway and, to date, pathogenic variants in 22 of these genes have been associated with human disease.4 The pattern of inheritance is autosomal recessive in all but one gene; I PIGA i is located on the X chromosome and inheritance is X-linked recessive. [Extracted from the article]

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p = 0.001) and females (OR = 3.0, p < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p = 0.001), absence seizures (OR = 6.0, p < 0.001) and stress-precipitated seizures (OR = 5.3, p = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation. [ABSTRACT FROM AUTHOR]

• We compared the long-term occurrence of spikes and seizures. • Modulation of spiking associated with seizures was seen in 37% of spike-clusters. • Both increasing and decreasing spiking-patterns were recorded. To test the hypothesis that significant changes in the occurrence of interictal epileptiform electroencephalography (EEG) discharges (EDs) are associated with seizures: while some EDs are pro-convulsive, increasing at seizure-occurrence, others are protective, showing decrease related to seizures. We analyzed 102 consecutive, long-term video-EEG monitoring sessions, from 98 patients. Using a semi-automated spike-detection method, we quantified the occurrence of EDs, grouped according to their location and morphology (clusters) and we constructed graphical representation of data, showing changes in time of the spiking patterns (spike-histograms). We compared the spike-histograms with the time-points of the seizures (pre-, peri- and postictal changes). Totally 179 ED-clusters were identified. Modulation of the spiking pattern, associated with seizures, was observed in 66 clusters (37%), from 47 patients (48%). Most of these changes (40 clusters; 61%) were related to increase in the spiking-pattern. Changes in spiking-pattern were associated with more than one third of the EDs. Both increasing and decreasing patterns were observed. EDs are more often pro-convulsive, with increasing spiking patterns associated with seizures. However, in more than one third of the ED clusters modulated by seizures, the spiking pattern decreased, raising the possibility of an anticonvulsive function of these discharges. [ABSTRACT FROM AUTHOR]

• We characterized photoparoxysmal response (PPR) in a SCORE database of 10,671 EEG recordings. • Using standardized intermittent photic stimulation protocol and definitions, the prevalence of PPR was 4%. • The most common PPR type was activation of preexisting epileptogenic area. To characterize photoparoxysmal EEG response (PPR) using a standardized protocol of intermittent photic stimulation (IPS) and standardized definitions for PPR, classified into six types. Using the SCORE system (Standardized Computer-Based Organized Reporting of EEG) we prospectively built a large database of standardized EEG annotations. In this study, we extracted the features related to PPR from the structured dataset consisting of 10,671 EEG recordings with IPS, from 7,188 patients. The standardized IPS protocol elicited PPR in 375 recordings (3.5%), in 288 patients (4%), with a preponderance among young (11–20 years) and female patients (67%). PPR was persistent in patients with multiple recordings. The most frequent type of PPR was activation of preexisting epileptogenic area (58%), followed by generalized-PPR limited to the stimulus train (22%). We could not find any recording with self-sustained posterior response. Seizures were elicited in 27% of patients with PPR, most often myoclonic seizures and absences, in patients with self-sustained generalized PPR. The most common type of PPR was accentuation of preexisting epileptogenic area. Self-sustained posterior response could not be documented. Self-sustained generalized-PPR had the highest association with seizures. Using standardized stimulation protocol and definitions for PPR types, IPS provides high diagnostic yield. [ABSTRACT FROM AUTHOR]

• Worsening of epilepsy associated with increment of awake spike-wave-index. • A frontal topography of sleep EEG epileptic activity in the active phase of ESES. • Language disorder due to speech/oro-motor dyspraxia. To investigate the clinical and EEG features of Encephalopathy with Status Epilepticus during slow Sleep (ESES) related to CNKSR2 pathogenic variants. Detailed clinical history, repeated wakefulness/overnight sleep EEGs, brain MRI were collected in five patients, including one female, with CNKSR2 -related ESES. Neurodevelopment in infancy was normal in two patients, delayed in three. Epilepsy onset (age range: 2–6 years) was associated with appearance or aggravation of cognitive impairment, language regression and/or behavioral disorders. Worsening of epilepsy and of cognitive/behavioral disturbances paralleled by enhancement of non-rapid eye movement (NREM) sleep-related, frontally predominant, EEG epileptic discharges [spike-wave-index (SWI): range 60–96%] was consistent with ESES. In three patients, episodes of absence status epilepticus or aggravation of atypical absences occurred, in this latter case associated with striking increment of awake SWI. Speech/oro-motor dyspraxia was diagnosed in four patients. In two patients, long-term follow-up showed epilepsy remission and persistence of mild/moderate cognitive disorders and behavioral disturbances into adulthood. Novel findings of our study are occurrence also in females, normal neurodevelopment before epilepsy onset, epilepsy aggravation associated with enhanced awake SWI, mild/moderate evolution in adulthood and language disorder due to speech/oro-motor dyspraxia. Our findings expand the phenotypic spectrum of CNKSR2 -related ESES. [ABSTRACT FROM AUTHOR]

The objective of the study was to investigate electroclinical and neuropsychological features, genetic background, and evolution of children with idiopathic encephalopathy with status epilepticus during slow sleep (ESES), including Landau–Kleffner syndrome (LKS). All children diagnosed with idiopathic ESES at the Danish Epilepsy Centre between March 2003 and December 2014 were retrospectively reviewed. Repeated 24-hour electroencephalography (24-h EEG) recordings, neuropsychological assessments, and clinical–neurological evaluation were performed throughout the follow-up in all patients. In 13 children, genetic investigations were performed. We collected 24 children (14 males and 10 females). Mean age at ESES diagnosis was 6 years, and mean ESES duration was 2 years and 7 months. Twenty-one children had epileptic seizures. Three children had LKS. Topography of sleep-related EEG epileptic abnormalities was diffuse in 3 subjects, hemispheric in 6, multifocal in 9, and focal in 6. During the active phase of ESES, all children presented with a heterogeneous combination of behavioral and cognitive disturbances. In 14 children, a parallel between severity of the clinical picture and spike–wave index (SWI) was observed. We could not find a strict correlation between the type and severity of neurobehavioral impairment and the side/topography of sleep-related EEG discharges during the active phase of ESES. At the last follow-up, 21 children were in remission from ESES. Complete recovery from neurobehavioral disorders was observed in 5 children. Genetic assessment, performed in 13 children, showed GRIN2A variant in two (15.4%). Our patients with idiopathic ESES showed a heterogeneous pattern of epileptic seizures, neurobehavioral disorders, and sleep EEG features. Only one-fourth of children completely recovered from the neuropsychological disturbances after ESES remission. Lack of correlation between severity/type of cognitive derangement and SWI and/or topography of sleep EEG epileptic abnormalities may suggest the contribution of additional factors (including impaired sleep homeostasis due to epileptic activity) in the neurobehavioral derangement that characterize ESES. • Patients with idiopathic ESES show a variety of seizures, neurobehavioral disorders, and EEG features. • Only one-fourth of children completely recovered after ESES remission. • Protracted sleep-related epileptiform activity is harmful in the developmental age. • Impairment of sleep homeostasis might play a role in ESES pathophysiology. • Idiopathic ESES is a model of epileptic encephalopathy due to protracted epileptic activity. [ABSTRACT FROM AUTHOR]

Objectives: Developmental and epileptic encephalopathies (DEEs) caused by pathogenic variants in SCN8A are associated with difficult-to-treat and early-onset seizures, developmental delay/intellectual disability, impaired quality of life, and increased risk of early mortality. High doses of sodium channel blockers are typically used to treat SCN8A-DEE caused by gain-of-function (GoF) variants. However, seizures are often drug resistant, and only a few patients achieve seizure freedom. In this retrospective study, the effect of cenobamate was assessed in patients with SCN8A-DEE., Methods: Across multiple centers and through collaborations with SCN8A patient advocacy organizations, patients with SCN8A-DEE treated with cenobamate for ≥6 months were identified. Data were obtained from patients' caregivers or treating physicians through a (Research Electronic Data Capture) REDCap survey. The functional effect of the SCN8A variants was obtained from the literature or assessed by prediction tools., Results: Twelve patients (3-25 years of age (median 8 years), 9 females) with presumed GoF SCN8A variants were treated with cenobamate for a mean period of 17 months (range 6-42 months). Countable motor seizures were meaningfully reduced in 10 of 12 patients (83%). Six patients experienced a seizure reduction above 70%, of which two achieved seizure freedom. In addition, two patients achieved a reduction in seizures ranging between 50% and 70%. An increase in seizure-free days per patient was also reported. Rescue medication was decreased in six of seven patients (85%) in need. Furthermore, 80% of patients reported non-seizure-related improvements, which included increased alertness, better sleep, and improved muscle tone. Adverse effects were reported by 50% of patients, and half resolved spontaneously or through the reduction of concomitant antiseizure medications., Significance: Our data suggest that cenobamate is a promising and safe treatment for SCN8A-DEE, even during early childhood. As a potential precision approach to treatment, cenobamate significantly reduced seizure burden and improved non-seizure-related symptoms. These positive outcomes may also be achieved in patient cohorts with GoF variants in other voltage-gated sodium channel genes., (© 2025 International League Against Epilepsy.)

Knowledge of the natural history of CDKL5 deficiency disorder (CDD) is limited to the results of cross-sectional analysis of largely pediatric cohorts. Assessment of outcomes in adulthood is critical for clinical decision-making and future precision medicine approaches but is challenging because of the diagnostic gap and duration of follow-up that would be required for prospective studies. We aimed to delineate the natural history retrospectively from adulthood. We analyzed clinical data about an international cohort of 67 adults with CDD. We analyzed demographic, phenotypic, CDKL5 Developmental Score (CDS), and treatment data, and tested associations with genetic factors, sex, and a positive or negative history of neonatal seizures, as an early predictor of prognosis. All but one of 67 adults (55 females, median age of 24 years at last follow-up) had epilepsy, typically beginning with epileptic spasms or tonic seizures before 4 months of age. Focal-onset and non-motor seizures emerged later. Fewer than a third had been documented as having bilateral tonic-clonic seizures or status epilepticus. Seizures often improved with age, but 73% had never experienced more than 6 months of seizure-freedom. Clobazam, sodium valproate, and lamotrigine were the most frequently prescribed antiseizure medications, but no specific treatment demonstrated superiority. Common comorbidities included movement disorders, visual impairment, sleep disorders, constipation, and scoliosis. All participants had intellectual disability, 75% had not acquired speech and 45% had regressed developmentally. 16% never achieved any CDS skill, but most attained at least three, and 28% attained six or all seven. By adulthood, half of those who had achieved any CDS skill retained all their CDS skills. The skills most frequently lost were independent walking and standing. Those with a history of neonatal seizures tended to attain fewer CDS skills and were more likely to have abnormal muscle tone in adulthood, atrioventricular conduction delay, and potential complications of their illness and treatment. Individuals carrying missense variants attained more CDS skills than those with other variants and were more likely to lose skills in adulthood and develop anxiety, possibly reflecting the limited neurodevelopment of those with non-missense variants, who manifested a more multisystemic disorder. In summary, retrospective data from adulthood elucidates the evolution of symptoms, variation in developmental outcomes, and the treatment landscape in CDKL5 deficiency disorder. Presence a non-missense variants or a history of neonatal seizures indicates a more complex disorder and lower developmental trajectory. Our findings will inform management decisions, prognostication, and the design of clinical trials in CDKL5 Deficiency Disorder.

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

Introduction: Pathogenic variants in STXBP1 cause a spectrum of disorders mainly consisting of developmental and epileptic encephalopathy (DEE), often featuring drug-resistant epilepsy. An increased mortality risk occurs in individuals with drug-resistant epilepsy and DEE, with sudden unexpected death in epilepsy (SUDEP) often the major cause of death. This study aimed to identify the rate and causes of mortality in STXBP1-related disorders., Methods: Through an international call, we analyzed data on individuals with STXBP1 pathogenic variants, who passed away from causes related to their disease., Results: We estimated a mortality rate of 3.2% (31/966), based on the STXBP1 Foundation and the STXBP1 Global Connect registry. In total, we analyzed data on 40 individuals (23 males) harboring pathogenic STXBP1 variants, collected from different centers worldwide. They died at a median age of 13 years (range: 11 months-46 years). The most common cause of death was SUDEP (36%), followed by pulmonary infections and respiratory complications (33%). The incidence of SUDEP peaked in mid-childhood, while non-SUDEP causes were more frequent in early childhood or adulthood (p = 0.006). In the most severe phenotypes, death was related to non-SUDEP causes (p = 0.018)., Conclusion: We found a mortality rate in STXBP1-related disorders similar to other DEEs, with an early age at death and SUDEP as well as pulmonary infections as the main cause of death. These findings assist in prognostic evaluation and genetic counseling for the families. They help to define the mortality risk of STXBP1-related disorders and implement preventative strategies., (© 2024. The Author(s).)

Objective: DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature., Methods: Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains., Results: DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum., Significance: We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy., (© 2024 International League Against Epilepsy.)

Pathogenic variants in CACNA1E are associated with early-onset epileptic and developmental encephalopathy (DEE). Severe to profound global developmental delay, early-onset refractory seizures, severe hypotonia, and macrocephaly are the main clinical features. Patients harboring the recurrent CACNA1E variant p.(Gly352Arg) typically present with the combination of early-onset DEE, dystonia/dyskinesia, and contractures. We describe a 2-year-and-11-month-old girl carrying the p.(Gly352Arg) CACNA1E variant. She has a severe DEE with very frequent drug-resistant seizures, profound hypotonia, and episodes of dystonia and dyskinesia. Long-term video-EEG-monitoring documented subsequent tonic asymmetric seizures during wakefulness and mild paroxysmal dyskinesias of the trunk out of sleep which were thought to be a movement disorder and instead turned out to be focal hyperkinetic seizures. This is the first documented description of the EEG findings in this disorder. Our report highlights a possible overlap between cortical and subcortical phenomena in CACNA1E-DEE. We also underline how a careful electro-clinical evaluation might be necessary for a correct discernment between the two disorders, playing a fundamental role in the clinical assessment and proper management of children with CACNA1E-DEE., (© 2024 The Author(s). Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Recording seizures on video-EEG has a high diagnostic value. However, bilateral convulsive seizures constitute a risk for the patients. Our aim was to investigate the diagnostic yield and associated risks of provocation methods in short-term video-EEGs., Methods: We extracted data on seizures and provocation methods from a large database of short-term video-EEGs with standardized annotations using SCORE (Standardized Computer-based Organized reporting of EEG)., Results: 2742 paroxysmal clinical episodes were recorded in 11 919 consecutive EEGs. Most epileptic seizures (54%) were provoked. Hyperventilation provoked most of typical absence seizures (55%), intermittent photic stimulation (IPS) provoked myoclonic seizures (25%) and most of bilateral convulsive seizures (55%), while 43% of focal seizures were precipitated by sleep. All but one of the 16 bilateral convulsive seizures were provoked by IPS or sleep. Latency between start of generalized photoparoxysmal EEG response and bilateral convulsive seizures were ≤3 s in all but one patient., Significance: The large, structured database provides evidence for the diagnostic utility of various provocation methods in short-term video-EEGs. The risk of bilateral convulsive seizures is relatively small, but it cannot be prevented by stopping IPS after 3 s. A priori knowledge about seizure semiology helps planning patient-tailored provocation strategy in short-term video-EEGs., (© 2024 International League Against Epilepsy.)

Pathogenic variants in SCN8A are associated with a broad phenotypic spectrum, including Self-Limiting Familial Infantile Epilepsy (SeLFIE), characterized by infancy-onset age-related seizures with normal development and cognition. Movement disorders, particularly paroxysmal kinesigenic dyskinesia typically arising after puberty, may represent another core symptom. We present the case of a 1-year-old girl with a familial disposition to self-limiting focal seizures from the maternal side and early-onset orofacial movement disorders associated with SCN8A-SeLFIE. Brain MRI was normal. Genetic testing revealed a maternally inherited SCN8A variant [c.4447G > A; p.(Glu1483Lys)]. After the introduction of valproic acid, she promptly achieved seizure control as well as complete remission of strabismus and a significant decrease in episodes of tongue deviation. Family history, genetic findings, and epilepsy phenotype are consistent with SCN8A-SeLFIE. Movement disorders are an important part of the SCN8A phenotypic spectrum, and this case highlights the novel early-onset orofacial movement disorders associated with this condition. The episodes of tongue deviation and protrusion suggest focal oromandibular (lingual) dystonia. Additionally, while infantile strabismus or esophoria is a common finding in healthy individuals, our case raises the possibility of an ictal origin of the strabismus. This study underscores the importance of recognizing and addressing movement disorders in SCN8A-SeLFIE patients, particularly the rare early-onset orofacial manifestations. It adds to the growing body of knowledge regarding the diverse clinical presentations of SCN8A-associated disorders and suggests potential avenues for clinical management and further research., (© 2024 The Authors. Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., (© 2023 International League Against Epilepsy.)

Background: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia., Methods: We collected genetic and electro-clinical data of ten individuals from nine unrelated families carrying novel SCN8A variants associated with chronic progressive or episodic ataxia. Electrophysiological characterizations of these variants were performed in ND7/23 cells and cultured neurons., Findings: Variants associated with chronic progressive ataxia either decreased Na + current densities and shifted activation curves towards more depolarized potentials (p.Asn995Asp, p.Lys1498Glu and p.Trp1266Cys) or resulted in a premature stop codon (p.Trp937Ter). Three variants (p.Arg847Gln and biallelic p.Arg191Trp/p.Asp1525Tyr) were associated with episodic ataxia causing loss-of-function by decreasing Na + current densities or a hyperpolarizing shift of the inactivation curve. Two additional episodic ataxia-associated variants caused mixed gain- and loss-of function effects in ND7/23 cells and were further examined in primary murine hippocampal neuronal cultures. Neuronal firing in excitatory neurons was increased by p.Arg1629His, but decreased by p.Glu1201Lys. Neuronal firing in inhibitory neurons was decreased for both variants. No functional effect was observed for p.Arg1913Trp. In four individuals, treatment with sodium channel blockers exacerbated symptoms., Interpretation: We identified episodic or chronic ataxia as predominant phenotypes caused by variants in SCN8A. Genotype-phenotype correlations revealed a more pronounced loss-of-function effect for variants causing chronic ataxia. Sodium channel blockers should be avoided under these conditions., Funding: BMBF, DFG, the Italian Ministry of Health, University of Tuebingen., Competing Interests: Declaration of interests MK reports a doctoral grant from DAAD. JDOE is coordinator of the Chorea and Huntington Disease Group (ERN-RND). EB has received funding from the Dutch Epilepsy Foundation, on behalf of the Dravet syndrome Foundation Netherlands/Flanders, the JANIVO foundation and the K.F. Hein Foundation. LS declares grants from the German Research Foundation, German Ministry of Heath, European Commission, and Innovationsfond, and has received consulting fees from Vico Therapeutics and Novartis. RSM has received consulting and speaker fees from UCB and Orion and speaker fees from EISAI and Angelini Pharma. All other authors report no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10 -9 ) and 10p11.21 (P = 3.6 × 10 -8 ). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10 -3 ). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10 -3 ) and increased seizure-like events (P = 6.8 × 10 -7 ). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10 -3 ). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease., (© 2023. Springer Nature Limited and Centre of Excellence in Genomic Medicine Research, King Abdulaziz University.)

Objective: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyze the electroclinical features and the functional effects of GABRA1 variants to establish genotype-phenotype correlations., Methods: Genetic and electroclinical data of 27 individuals (22 unrelated and 2 families) harboring 20 different GABRA1 variants were collected and accompanied by functional analysis of 19 variants., Results: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile onset epilepsy (focal seizures, fever sensitivity, and electroencephalographic posterior epileptiform discharges) was described for variants in the extracellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects, and the patients generally had a favorable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF variants were associated with severe early onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy., Interpretation: Our data expand the genetic and phenotypic spectrum of GABRA1 epilepsies and permit delineation of specific subphenotypes for LoF and GoF variants, through the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the pathomechanism and a precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. ANN NEUROL 2023., (© 2023 American Neurological Association.)

IRF2BPL has recently been described as a novel cause of neurodevelopmental disorders with multisystemic regression, epilepsy, cerebellar symptoms, dysphagia, dystonia, and pyramidal signs. We describe a novel IRF2BPL phenotype consistent with progressive myoclonus epilepsy (PME) in three novel subjects and review the features of the 31 subjects with IRF2BPL-related disorders previously reported. Our three probands, aged 28-40 years, harbored de novo nonsense variants in IRF2BPL (c.370C > T, p.[Gln124*] and c.364C > T; p.[Gln122*], respectively). From late childhood/adolescence, they presented with severe myoclonus epilepsy, stimulus-sensitive myoclonus, and progressive cognitive, speech, and cerebellar impairment, consistent with a typical PME syndrome. The skin biopsy revealed massive intracellular glycogen inclusions in one proband, suggesting a similar pathogenic pathway to other storage disorders. Whereas the two older probands were severely affected, the younger proband had a milder PME phenotype, partially overlapping with some of the previously reported IRF2BPL cases, suggesting that some of them might be unrecognized PME. Interestingly, all three patients harbored protein-truncating variants clustered in a proximal, highly conserved gene region around the "coiled-coil" domain. Our data show that PME can be an additional phenotype within the spectrum of IRF2BPL-related disorders and suggest IRF2BPL as a novel causative gene for PME., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Importance: Electroencephalograms (EEGs) are a fundamental evaluation in neurology but require special expertise unavailable in many regions of the world. Artificial intelligence (AI) has a potential for addressing these unmet needs. Previous AI models address only limited aspects of EEG interpretation such as distinguishing abnormal from normal or identifying epileptiform activity. A comprehensive, fully automated interpretation of routine EEG based on AI suitable for clinical practice is needed., Objective: To develop and validate an AI model (Standardized Computer-based Organized Reporting of EEG-Artificial Intelligence [SCORE-AI]) with the ability to distinguish abnormal from normal EEG recordings and to classify abnormal EEG recordings into categories relevant for clinical decision-making: epileptiform-focal, epileptiform-generalized, nonepileptiform-focal, and nonepileptiform-diffuse., Design, Setting, and Participants: In this multicenter diagnostic accuracy study, a convolutional neural network model, SCORE-AI, was developed and validated using EEGs recorded between 2014 and 2020. Data were analyzed from January 17, 2022, until November 14, 2022. A total of 30 493 recordings of patients referred for EEG were included into the development data set annotated by 17 experts. Patients aged more than 3 months and not critically ill were eligible. The SCORE-AI was validated using 3 independent test data sets: a multicenter data set of 100 representative EEGs evaluated by 11 experts, a single-center data set of 9785 EEGs evaluated by 14 experts, and for benchmarking with previously published AI models, a data set of 60 EEGs with external reference standard. No patients who met eligibility criteria were excluded., Main Outcomes and Measures: Diagnostic accuracy, sensitivity, and specificity compared with the experts and the external reference standard of patients' habitual clinical episodes obtained during video-EEG recording., Results: The characteristics of the EEG data sets include development data set (N = 30 493; 14 980 men; median age, 25.3 years [95% CI, 1.3-76.2 years]), multicenter test data set (N = 100; 61 men, median age, 25.8 years [95% CI, 4.1-85.5 years]), single-center test data set (N = 9785; 5168 men; median age, 35.4 years [95% CI, 0.6-87.4 years]), and test data set with external reference standard (N = 60; 27 men; median age, 36 years [95% CI, 3-75 years]). The SCORE-AI achieved high accuracy, with an area under the receiver operating characteristic curve between 0.89 and 0.96 for the different categories of EEG abnormalities, and performance similar to human experts. Benchmarking against 3 previously published AI models was limited to comparing detection of epileptiform abnormalities. The accuracy of SCORE-AI (88.3%; 95% CI, 79.2%-94.9%) was significantly higher than the 3 previously published models (P < .001) and similar to human experts., Conclusions and Relevance: In this study, SCORE-AI achieved human expert level performance in fully automated interpretation of routine EEGs. Application of SCORE-AI may improve diagnosis and patient care in underserved areas and improve efficiency and consistency in specialized epilepsy centers.

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

SCN8A-developmental and epileptic encephalopathy is caused by pathogenic variants in the SCN8A gene encoding the Na v 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., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Objectives: Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence., Methods: In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible., Results: Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living., Discussion: STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To determine the prevalence and characteristics of normal variants in EEG recordings in a large cohort, and provide readers with typical examples of all normal variants for educational purposes., Methods: Using the SCORE EEG system (Standardized Computer-Based Organized Reporting of EEG), we prospectively extracted EEG features in consecutive patients. In this dataset, we analyzed 3050 recordings from 2319 patients (mean age 38.5 years; range: 1-89 years)., Results: The distribution of the normal variants was as follows: sharp transients 19.21% (including wicket spikes), rhythmic temporal theta of drowsiness 6.03%, temporal slowing of the old 2.89%, slow fused transients 2.59%, 14-and 6-Hz bursts 1.83%, breach rhythm 1.25%, small sharp spikes 1.05%, 6-Hz spike and slow wave 0.69% and SREDA 0.03%., Conclusions: The most prevalent normal variants are the sharp transients, which must not be over-read as epileptiform discharges., Significance: EEG readers must be familiar with the normal variants to avoid misdiagnosis and misclassification of patients referred to clinical EEG recordings., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Harald Aurlien is Chief Medical Officer and minority shareholder in Holberg EEG AS. The remaining authors do not have conflicts of interest related to this work., (© 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)