Fenfluramine treatment in pediatric patients with Dravet syndrome reduces seizure burden and overall healthcare costs: A retrospective and observational real-world study.

OBJECTIVES: Dravet syndrome is a developmental and epileptic encephalopathy characterized by early onset epilepsy with multiple seizure types often intractable to treatment. Randomized clinical trials have demonstrated how treatment with fenfluramine significantly reduces seizure frequency in patients with Dravet syndrome. The study aims to (1) describe the efficacy and tolerability of fenfluramine in a Danish cohort of patients with Dravet syndrome; and (2) evaluate whether treatment with fenfluramine reduces epilepsy-related hospital contacts administrated by pediatricians or epilepsy-trained nurses. METHODS: A retrospective registry-based cohort study at the Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark, enrolled 30 pediatric patients with Dravet syndrome treated with fenfluramine between 2017 and 2023. RESULTS: Thirty patients with Dravet syndrome (aged 3-21 years, 12 females) with a verified pathogenic SCN1A variant were included. They were treated with fenfluramine at a mean duration of 29 months with a mean maintenance dose of 0.5 mg/kg/day. The number of patient-years on treatment was 75 years. At last follow-up, 6 patients had discontinued treatment due to lack of efficacy or adverse effects. In the remaining 24 patients, generalized tonic-clonic seizures were reduced by ≥30% in 83%, by ≥50% in 67%, and by 100% in 25%. Additionally, 71% of the patients were reduced in concomitant anti-seizure medication, and 75% experienced a reduction (mean reduction at 52%, range 11%-94%) in epilepsy-related hospital contacts from baseline to the end of the treatment period. SIGNIFICANCE: Treatment with fenfluramine effectively reduced seizure frequency and concomitant antiseizure medication in patients with Dravet syndrome. Furthermore, a decrease in epilepsy-related contacts by 80% was observed over 6 years of treatment, which may indicate cost-effective benefits. PLAIN LANGUAGE SUMMARY: Patients with Dravet syndrome suffer from severe epileptic seizures that are difficult to treat with medication. Earlier, treatment with fenfluramine (an anti-seizure medication) has been documented to decrease the total number of seizures in patients with Dravet syndrome. This publication summarizes the experiences with fenfluramine in children with Dravet syndrome at the Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark. Our publication also illustrates that treatment with fenfluramine may reduce the patients' number of yearly contacts with doctors and nurses specialized in epilepsy treatment, which may indicate cost-effectiveness.

Evaluation of GFAP, S100B, and UCHL-1 Levels in Children With Refractory Epilepsy.

INTRODUCTION: A number of biomarkers are used to evaluate the duration of the epileptic seizure and the interictal period following neuronal injury. Invasive diagnostic methods are increasingly being replaced by peripheral or minimally invasive biomarkers that give results faster and are more secure. PURPOSE: We aimed to evaluate serum glial fibrillary acidic protein (GFAP), S100B, and ubiquitin C-terminal hydrolase (UCHL-1) levels in children with epilepsy. METHODS: Our study included 3 groups: a nonrefractory epilepsy group, a refractory epilepsy group, and a control group. The GFAP, S100B, and UCHL-1 levels in serum samples collected 2-24 hours after the last seizure were analyzed using enzyme-linked immunosorbent assays. RESULTS: A total of 69 children participated in the study, with 35 participants in the refractory epilepsy group, 18 in the nonrefractory epilepsy group, and 16 in the control group. The GFAP values in the refractory (25.4 ng/mL) and nonrefractory (26.1 ng/mL) epilepsy groups were found to be statistically significantly higher than those in the control group (17.9 ng/mL; P = .001). The S100B values were found to be significantly higher in the refractory epilepsy group (34.13 pg/mL) than in both the control group and the nonrefractory epilepsy group (28.05 pg/mL; P = .028). No significant differences were observed in the UCHL-1 levels between the 3 groups. CONCLUSIONS: We conclude that the observed differences may be due to the increased expression of S100B and GFAP caused by increased and repetitive neuronal damage in refractory epilepsies compared with nonrefractory epilepsies.

A Complex Presentation: Psychosis in a Patient Diagnosed With Lennox-Gastaut Syndrome.

Lennox-Gastaut syndrome (LGS) is a form of severe childhood epilepsy, with most children experiencing seizures before reaching the age of eight. Typically, patients have multiple types of seizures, making an accurate diagnosis challenging. While it can be secondary to other causes, often, it is idiopathic. Over time, children develop cognitive impairment, leading to intellectual disability. The mainstay of treatment and management is seizure control. However, management remains challenging due to the complexity of the syndrome, as it is associated with multiple seizure types, intellectual deterioration, and other psychiatric comorbidities. We present the case of a 19-year-old male diagnosed with LGS and treated with various available therapies, who demonstrated multiple breakthrough seizures, significant neurocognitive disabilities, and behavior challenges. Additionally, the patient displayed psychotic features of auditory hallucinations, aggression, and attempts at self-mutilation, a rare clinical presentation in LGS.

Investigation of patients with childhood epilepsy in single center: Comprehensive genetic testing experience.

INTRODUCTION: Epilepsy is a common multifactorial neurological disease usually diagnosed during childhood. In this study, we present the contribution of consecutive genetic testing to the genetic diagnostic yield of childhood epilepsy. METHODS: In 100 children (53 female, 47 male) with epilepsy, targeted sequencing (TS) and clinical exome sequencing (CES) were performed. All cases (n = 100) included in the study were epilepsy patients. In addition, we investigated the genetic diagnosis rates according to the associated co-occurring findings (including developmental delay/intellectual disability, brain malformations, macro-/microcephaly, and dysmorphic features). RESULTS: The overall diagnostic rate in this study was 33% (n = 33 patients). We identified 11 novel variants in WDR45, ARX, PCDH19, SCN1A, CACNA1A, LGI1, ASPM, MECP2, NF1, TSC2, and CDK13. Genetic diagnosis rates were as follows: cases with developmental delay/intellectual disability 38.7% (24/62) and without developmental delay/intellectual disability 23.6% (9/38); cases with brain malformations 46.8% (15/32) and without brain malformations 25% (16/64); cases with macro-/microcephaly 50% (6/12) and without macro-/microcephaly 28.4% (25/88); and cases with dysmorphic features 48.2% (14/29) and without dysmorphic features 23.9% (17/71). CONCLUSION: Genotype-phenotype correlation is even more important in diseases such as epilepsy, which include many genes and variants of these genes in etiopathogenesis. We presented the clinical findings of the cases carrying 11 novel variants in detail, including dysmorphic features, accompanying neurodevelopmental disorders, EEG results, and brain MRI results.

Structure-function interrelationships and associated neurotransmitter profiles in drug-naïve benign childhood epilepsy with central-temporal spikes patients.

OBJECTIVES: To explore the interrelationships between structural and functional changes as well as the potential neurotransmitter profile alterations in drug-naïve benign childhood epilepsy with central-temporal spikes (BECTS) patients. METHODS: Structural magnetic resonance imaging (sMRI) and resting-state functional MRI data from 20 drug-naïve BECTS patients and 33 healthy controls (HCs) were acquired. Parallel independent component analysis (P-ICA) was used to identify covarying components among gray matter volume (GMV) maps and fractional amplitude of low-frequency fluctuations (fALFF) maps. Furthermore, we explored the spatial correlations between GMV/fALFF changes derived from P-ICA and neurotransmitter maps in JuSpace toolbox. RESULTS: A significantly positive correlation (p < 0.001) was identified between one structural component (GMV_IC6) and one functional component (fALFF_IC4), which showed significant group differences between drug-naïve BECTS patients and HCs (GMV_IC6: p < 0.01; fALFF_IC4: p < 0.001). GMV_IC6 showed increased GMV in the frontal lobe, temporal lobe, thalamus, and precentral gyrus as well as fALFF_IC4 had enhanced fALFF in the cerebellum in drug-naïve BECTS patients compared to HCs. Moreover, significant correlations between GMV alterations in GMV_IC6 and the serotonin (5HT1a: p < 0.001; 5HT2a: p < 0.001), norepinephrine (NAT: p < 0.001) and glutamate systems (mGluR5: p < 0.001) as well as between fALFF alterations in fALFF_IC4 and the norepinephrine system (NAT: p < 0.001) were detected. CONCLUSION: The current findings suggest co-altered structural/functional components that reflect the correlation of language and motor networks as well as associated with the serotonergic, noradrenergic, and glutamatergic neurotransmitter systems. CLINICAL RELEVANCE STATEMENT: The relationship between anatomical brain structure and intrinsic neural activity was evaluated using a multimodal fusion analysis and neurotransmitters which might provide an important window into the multimodal neural and underlying molecular mechanisms of benign childhood epilepsy with central-temporal spikes. KEY POINTS: Structure-function relationships in drug-naïve benign childhood epilepsy with central-temporal spikes (BECTS) patients were explored. The interrelated structure-function components were found and correlated with the serotonin, norepinephrine, and glutamate systems. Co-altered structural/functional components reflect the correlation of language and motor networks and correlate with the specific neurotransmitter systems.

From brain connectivity to cognitive function: Dissecting the salience network in pediatric BECTS-ESES.

BACKGROUND: Benign childhood epilepsy with centrotemporal spikes (BECTS), a common pediatric epilepsy, may lead to cognitive decline when compounded by Electrical Status Epilepticus during Sleep (ESES). Emerging evidence suggests that disruptions in the Salience Network (SN) contribute significantly to the cognitive deficits observed in BECTS-ESES. Our study rigorously investigates the dynamic functional connectivity (dFC) within the SN and its correlation with cognitive impairments in BECTS-ESES, employing advanced neuroimaging and neuropsychological assessments. METHODS: In this research, 45 patients diagnosed with BECTS-ESES and 55 age-matched healthy controls (HCs) participated. We utilized resting-state functional magnetic resonance imaging (fMRI) and Independent Component Analysis (ICA) to identify three fundamental SN nodes: the right Anterior Insula (rAI), left Anterior Insula (lAI), and the Anterior Cingulate Cortex (ACC). A two-sample t-test facilitated the comparison of dFC between these pivotal regions and other brain areas. RESULTS: Significantly, the BECTS-ESES group demonstrated increased dFC, particularly between the ACC and the right Middle Occipital Gyrus, and from the rAI to the right Superior Parietal Gyrus and Cerebellum, and from the lAI to the left Postcentral Gyrus. Such dFC augmentations provide neural insights potentially explaining the neuropsychological deficits in BECTS-ESES children. Employing comprehensive neuropsychological evaluations, we mapped these dFC disruptions to specific cognitive impairments encompassing memory, executive functioning, language, and attention. Through multiple regression analysis and path analysis, a preliminary but compelling association was discovered linking dFC disturbances directly to cognitive impairments. These findings underscore the critical role of SN disruptions in BECTS-ESES cognitive dysfunctions. LIMITATION: Our cross-sectional design and analytic methods preclude definitive mediation models and causal inferences, leaving the precise nature of dFC's mediating role and its direct impact by BECTS-ESES partially unresolved. Future longitudinal and confirmatory studies are needed to comprehensively delineate these associations. CONCLUSION: Our study heralds dFC within the SN as a vital biomarker for cognitive impairment in pediatric epilepsy, advocating for targeted cognitive-specific interventions in managing BECTS-ESES. The preliminary nature of our findings invites further studies to substantiate these associations, offering profound implications for the prognosis and therapeutic strategies in BECTS-ESES, thereby underlining the importance of this research in the field of pediatric neurology and epilepsy management.

Children and Young Adults with Epilepsy Exhibit an Interictal Autonomic Dysfunction: A Prospective Exploratory Study.

Dysautonomic disorders are an increasingly studied group of conditions, either as isolated diseases or associated with other neurological disorders. There is growing interest in understanding how dysautonomia affects people with epilepsy, who may report autonomic symptoms before, during and after seizures. Furthermore, autonomic abnormalities appear to play a role in sudden unexpected death in epilepsy, likely contributing to the increased mortality rate described in epilepsy. To better understand the association between epilepsy and dysautonomia, we explored electrochemical skin conductance in a group of 18 children and young adults with epilepsy compared to 15 age- and sex-matched healthy controls by the SudoscanTM test. We found a significant difference in terms of electrochemical skin conductance, suggesting that people with epilepsy suffer significantly reduced conductance in small nerve fibers. Within patients, values were significantly different according to the type of epilepsy and to neuroimaging results, with lower conductance values in epilepsies of unknown origin and in patients with morphological abnormalities of the brain. Using a non-invasive test, we identified altered conductance of small sympathetic nerve fibers in children and young adults with epilepsy, suggesting underlying dysautonomia. Further studies are needed to investigate this association and to clarify its neurobiological substrates.

Systematically altered connectome gradient in benign childhood epilepsy with centrotemporal spikes: Potential effect on cognitive function.

OBJECTIVE: Benign childhood epilepsy with centrotemporal spikes (BECTS) affects brain network hierarchy and cognitive function; however, itremainsunclearhowhierarchical changeaffectscognition in patients with BECTS. A major aim of this study was to examine changes in the macro-network function hierarchy in BECTS and its potential contribution to cognitive function. METHODS: Overall, the study included 50 children with BECTS and 69 healthy controls. Connectome gradient analysis was used to determine the brain network hierarchy of each group. By comparing gradient scores at each voxel level and network between groups, we assessed changes in whole-brain voxel-level and network hierarchy. Functional connectivity was used to detect the functional reorganization of epilepsy caused by these abnormal brain regions based on these aberrant gradients. Lastly, we explored the relationships between the change gradient and functional connectivity values and clinical variables and further predicted the cognitive function associated with BECTS gradient changes. RESULTS: In children with BECTS, the gradient was extended at different network and voxel levels. The gradient scores frontoparietal network was increased in the principal gradient of patients with BECTS. The left precentral gyrus (PCG) and right angular gyrus gradient scores were significantly increased in the principal gradient of children with BECTS. Moreover, in regions of the brain with abnormal principal gradients, functional connectivity was disrupted. The left PCG gradient score of children with BECTS was correlated with the verbal intelligence quotient (VIQ), and the disruption of functional connectivity in brain regions with abnormal principal gradients was closely related to cognitive function. VIQ was significantly predicted by the principal gradient map of patients. SIGNIFICANCE: The results indicate connectome gradient disruption in children with BECTS and its relationship to cognitive function, thereby increasing our understanding of the functional connectome hierarchy and providing potential biomarkers for cognitive function of children with BECTS.

Epilepsy as a Novel Phenotype of BPTF-Related Disorders.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Importance of Genetic Testing in Children With Generalized Epilepsy.

INTRODUCTION: Epilepsy is a neurological disorder characterized by the predisposition for recurrent unprovoked seizures. It can broadly be classified as focal, generalized, unclassified, and unknown in its onset. Focal epilepsy originates in and involves networks localized to one region of the brain. Generalized epilepsy engages broader, more diffuse networks. The etiology of epilepsy can be structural, genetic, infectious, metabolic, immune, or unknown. Many generalized epilepsies have presumed genetic etiologies. The aim of this study is to compare the role of genetic testing to brain MRI as diagnostic tools for identifying the underlying causes of idiopathic (genetic) generalized epilepsy (IGE). METHODS:  We evaluated the diagnostic yield of these two categories in children diagnosed with IGE. Data collection was completed using ICD10 codes filtered by TriNetX to select 982 individual electronic medical records (EMRs) of children in the Penn State Children's Hospital who received a diagnosis of IGE. The diagnosis was confirmed after reviewing the clinical history and electroencephalogram (EEG) data for each patient. RESULTS: From this dataset, neuroimaging and genetic testing results were gathered. A retrospective chart review was done on 982 children with epilepsy, of which 143 (14.5%) met the criteria for IGE. Only 18 patients underwent genetic testing. Abnormalities that could be a potential cause for epilepsy were seen in 72.2% (13/18) of patients with IGE and abnormal genetic testing, compared to 30% (37/123) for patients who had a brain MRI with genetic testing. CONCLUSION: This study suggests that genetic testing may be more useful than neuroimaging for identifying an etiological diagnosis of pediatric patients with IGE.

Risk Factor Predictors for Developing Epilepsy in Cerebral Palsy Patients in a Tertiary Hospital in Saudi Arabia: A Retrospective Study.

Background Cerebral palsy (CP) is a major cause of childhood motor impairment worldwide. The prevalence of CP related to preterm births has increased consistently. Perinatal hypoxic-ischemic encephalopathy, intra- or periventricular haemorrhage, cerebral dysgenesis and intracranial infections are among the factors contributing to CP onset. Several studies have explored epilepsy-related morbidity among children with CP, finding notable correlations between the two conditions. Worldwide, there are multiple studies highlighting the high prevalence of epilepsy among children with CP and its association with specific CP subtypes and neurologic insults. However, research on the risk factors for epilepsy in CP children is limited, particularly in the Middle East and Saudi Arabia. Aim This study aims to address this gap by analysing potential prenatal, antenatal, and postnatal risk factors associated with epilepsy development in children with CP. Methods A retrospective cohort analysis of 152 children aged 1-14 years diagnosed with CP at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, was conducted. Results The study showed a significant prevalence of epilepsy (68.4%), with generalised seizures being the most common type. Quadriplegia was notably common among CP children with epilepsy, indicating a potential correlation between motor impairment severity and epilepsy risk. Furthermore, CP children with epilepsy exhibited a higher prevalence of co-morbidities, emphasising the multifaceted nature of this condition. Perinatal and neonatal factors, such as hypoxic events, mechanical ventilation, perinatal asphyxia, neonatal convulsions, and microcephaly, were identified as significant risk factors for epilepsy in children with CP. While speech and hearing disorders were present in CP children with and without epilepsy, a slightly higher prevalence of impaired speech was observed in those with epilepsy. However, the difference between the two groups was not significant. Conclusion This study provides valuable insights into the epidemiology, clinical characteristics and potential risk factors associated with epilepsy among children diagnosed with CP in Saudi Arabia. The findings underscore the complexity of managing epilepsy in this population and highlight the need for further research to elucidate the underlying mechanisms and support the development of targeted interventions to improve patient outcomes.

Efficacy and Safety of Pulse Intravenous Methylprednisolone in Pediatric Epileptic Encephalopathies: Timing and Networks Consideration.

Background: Epileptic encephalopathies (EE) are characterized by severe drug-resistant seizures, early onset, and unfavorable developmental outcomes. This article discusses the use of intravenous methylprednisolone (IVMP) pulse therapy in pediatric patients with EE to evaluate its efficacy and tolerability. Methods: This is a retrospective study from 2020 to 2023. Inclusion criteria were ≤18 years at the time of IVMP pulse therapy and at least 6 months of follow-up. Efficacy and outcome, defined as seizure reduction > 50% (responder rate), were evaluated at 6 and 9 months of therapy, and 6 months after therapy suspension; quality of life (QoL) was also assessed. Variables predicting positive post-IVMP outcomes were identified using statistical analysis. Results: The study included 21 patients, with a responder rate of 85.7% at 6 and 9 months of therapy, and 80.9% at 6 months after therapy suspension. Variables significantly predicting favorable outcome were etiology (p = 0.0475) and epilepsy type (p = 0.0475), with the best outcome achieved in patients with genetic epilepsy and those with encephalopathy related to electrical status epilepticus during slow-wave sleep (ESES). All patients evidenced improvements in QoL at the last follow-up, with no relevant adverse events reported. Conclusions: Our study confirmed the efficacy and high tolerability of IVMP pulse therapy in pediatric patients with EE. Genetic epilepsy and ESES were positive predictors of a favorable clinical outcome. QOL, EEG tracing, and postural-motor development showed an improving trend as well. IVMP pulse therapy should be considered earlier in patients with EE.

Evaluation of the Effect of Parenting Style and Parental Mealtime Actions on the Eating Behavior of Children with Epilepsy.

BACKGROUND: Research on the interaction of parenting style, parents' mealtime behaviors, and children's eating behavior in the presence of chronic disease is limited. This study aimed to investigate the impact of parenting style and parental mealtime actions on the eating behavior of children with epilepsy. METHODS: Thirty-one children with epilepsy, thirty-one healthy children (aged 4-9 years), and their parents were included. The Multidimensional Assessment of Parenting Scale (MAPS), Parent Mealtime Action Scale, Children's Eating Behavior Questionnaire, and Healthy Eating Index (HEI)-2015 were applied. The MAPS, HEI-2015 scores, and body mass index for age Z scores were similar in both groups (p > 0.05). In the epilepsy group, the food approach behavior score was higher, and positive correlations were noted between broadband negative parenting and food approach behavior, and the HEI-2015 score and broadband positive parenting (p < 0.05). Regression analysis showed that broadband negative parenting and snack modeling increased the food approach behavior in the epilepsy group. Owing to the chronic disease, the effects of parent-child interaction on the child's eating behavior in the epilepsy group differed from those of healthy children reported in the literature.

Early onset absence epilepsy of childhood: Epidemiologic data, treatment and outcome in a sample of 56 patients born between 2000 and 2018.

PURPOSE: The aim of our work is to describe the characteristics of Early Onset Absence Epilepsy (EOAE) and to observe whether specific anamnestic, clinical or electroencephalographic characteristics can influence the drug sensitivity of this pathology. METHODS: We carried out a retrospective study of patients affected by absence epilepsy with onset under four years of age, born between January 1st 2000 and December 31st 2018, who were reffered to the Regional Epilepsy Center of Spedali Civili of Brescia. We then divided the sample into three groups based on the age of onset. RESULTS: Our sample is composed of 56 patients. Among the children with epilepsy onset under two years of age (11), all were still on therapy after three and six years of follow-up, and 64 % of them required polytherapy. Among patients with epilepsy onset between two and three years of age (24), 87 % were still on therapy after three years of follow-up and 68 % after six years of follow-up; 46 % of these subjects required polytherapy. Among patients with epilepsy onset between three and four years of age (21), 89 % were still on therapy after three years of follow-up and 38 % after six years of follow-up; 38 % of them required polytherapy. CONCLUSIONS: We observe that patients with an earlier epilepsy onset have a worse outcome and a lower drug sensitivity. This may allow to predict in which cases it would be appropriate to maintain antiseizure therapy for a prolonged period.

Prophylactic antiseizure medications for recurrent status epilepticus in nonsyndromic childhood epilepsy.

PURPOSE: The management of status epilepticus (SE) has mainly focused on the termination of ongoing SE episodes. However, long-term therapeutic strategies for the prevention of SE are lacking. This study aimed to investigate the effectiveness of prophylactic antiseizure medications (ASMs) for SEs in nonsyndromic childhood epilepsy. METHODS: This retrospective study was conducted at Jikei University Hospital. Patients <18 years of age, diagnosed with epilepsy, and experiencing three or more SE episodes within 1 year between April 1, 2017, and October 1, 2021, were included. ASMs introduced for seizure types that developed into SE were evaluated. The effectiveness of ASMs was determined by using the "Rule of Three": An ASM was determined effective if patients were free of SE for a duration at least three times that of their longest SE interval in 12 months prior to intervention. RESULTS: The investigation included a total of 32 ASMs administered to 13 patients. The longest interval between SE episodes before ASM administration was 28-257 d. The first SE interval after ASM administration was 12-797 d. Levetiracetam (LEV) and clobazam (CLB) showed effectiveness in 2/10 and 5/6 patients, respectively. Other ASMs were ineffective. The leading etiology of epilepsy was perinatal brain injury, identified in four patients, and CLB was effective in all of them. CONCLUSIONS: The present study suggests that CLB and LEV may prolong the SE interval in some cases of nonsyndromic childhood epilepsy. CLB may be beneficial, particularly in patients with perinatal brain injury.

Genetic variant interpretation for the neurologist - A pragmatic approach in the next-generation sequencing era in childhood epilepsy.

Genetic advances over the past decade have enhanced our understanding of the genetic landscape of childhood epilepsy. However a major challenge for clinicians ha been understanding the rationale and systematic approach towards interpretation of the clinical significance of variant(s) detected in their patients. As the clinical paradigm evolves from gene panels to whole exome or whole genome testing including rapid genome sequencing, the number of patients tested and variants identified per patient will only increase. Each step in the process of variant interpretation has limitations and there is no single criterion which enables the clinician to draw reliable conclusions on a causal relationship between the variant and disease without robust clinical phenotyping. Although many automated online analysis software tools are available, these carry a risk of misinterpretation. This guideline provides a pragmatic, real-world approach to variant interpretation for the child neurologist. The focus will be on ascertaining aspects such as variant frequency, subtype, inheritance pattern, structural and functional consequence with regard to genotype-phenotype correlations, while refraining from mere interpretation of the classification provided in a genetic test report. It will not replace the expert advice of colleagues in clinical genetics, however as genomic investigations become a first-line test for epilepsy, it is vital that neurologists and epileptologists are equipped to navigate this landscape.

Risk factors of electrical status epilepticus during sleep in children with benign childhood epilepsy with centro-temporal spikes.

Objective: To explore risk factors of electrical status epilepticus during sleep in children with benign childhood epilepsy with centro-temporal spikes (BECT). Methods: This is a clinical comparative study. The subjects of study were 67 children with BECT from the Outpatient Department of Pediatric Neurology in Xingtai People's Hospital from January 2019 to January 2022. According to the occurrence of ESES, the enrolled children were divided into control group which included BECT children without ESES and the observation group which included BECT children with ESES. Compared differences of the two groups in the age of first seizure, the frequency of seizures before treatment, the classification of treatment drugs, cranial MRI, and discharge side of electroencephalogram (EEG). Results: There was no statistical difference between the two groups in the frequency of seizures before treatment, the classification of treatment drugs, cranial MRI, and the distribution of EEG discharges in the left and right cerebral areas(P>0.05). Statistical differences were observed in the age of the first seizure, whether the seizures occurred after treatment, and EEG discharges in unilateral/bilateral cerebral areas (P<0.05). Furthermore, the collinearity test and Logistic regression analysis showed that the age of the first seizure, the frequency of seizures before treatment, and whether the seizures occurred after treatment were independent risk factors for the occurrence of ESES in BECT (P<0.05). Conclusion: Clinically, the occurrence of ESES in children with BECT may be related to the younger age of the first seizure, higher frequency of seizures before treatment, and the occurrence of seizures after treatment.

Cognitive development in children with new-onset Rolandic epilepsy and Rolandic discharges without seizures: Focusing on intelligence, visual perception, working memory and the role of parents' education.

PURPOSE: Our aim was to assess intelligence, visual perception and working memory in children with new-onset Rolandic epilepsy (RE) and children with Rolandic discharges without seizures (RD). METHODS: The participants in the study were 12 children with RE and 26 children with RD aged 4 to 10 years (all without medication and shortly after diagnosis) and 31 healthy controls. Their cognitive performance was assessed using the German versions of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), the Wechsler Intelligence Scale for Children (WISC-IV), the Developmental Test of Visual Perception-2 (DTVP-2), the Developmental Test of Visual Perception-Adolescent and Adult (DTVP-A) (each according to age) and the Word Order, Hand Movements and Spatial Memory subtests of the German version of the Kaufman Assessment Battery for Children (K-ABC). RESULTS: The comparison of the entire group of children with RE/RD and the control group conducted in the first step of our analysis revealed a weaker performance of the children with RE/RD in all cognitive domains. Significant deficits, however, were found exclusively in the RD group. Compared to the controls, they performed significantly weaker regarding IQ (full scale IQ: p < 0.001; verbal IQ: p < 0.001; performance IQ: p = 0.002; processing speed: p = 0.005), visual perception (general visual perception: p = 0.005; visual-motor integration: p = 0.002) and working memory (WISC working memory: p = 0.002 and K-ABC Word Order (p = 0.010) and Hand Movements (p = 0.001) subtests. Also, the children without seizures scored significantly lower than those with seizures on the WISC Working Memory Index (p = 0.010) and on the K-ABC Word Order (p = 0.021) and Hand Movements (p = 0.027) subtests. Further analysis of our data demonstrated the particular importance of the family context for child development. Significant cognitive deficits were found only in children with RD from parents with lower educational levels. This group consistently scored lower compared to the control group regarding IQ (full scale IQ: p < 0.001; verbal IQ: p < 0.001; performance IQ: p = 0.012; processing speed: p = 0.034), visual perception (general visual perception: p = 0.018; visual-motor integration: p = 0.010) and auditory working memory (WISC working memory: p = 0.014). Furthermore, compared to the children with RE, they performed significantly weaker on verbal IQ (p = 0.020), auditory working memory consistently (WISC working memory: p = 0.027; K-ABC: Word Order: p = 0.046) as well as in one of the K-ABC spatial working memory subtests (Hand Movements: p = 0.029). Although we did not find significant deficits in children with new-onset RE compared to healthy controls, the performance of this group tended to be weaker more often. No statistically significant associations were observed between selected clinical markers (focus types: centrotemporal/other foci/laterality of foci and spread of Rolandic discharges) and cognitive test results. Except for spatial working memory, we also found no evidence that the age of our patients at the time of study participation was of significant importance to their cognitive performance. CONCLUSIONS: Our study provides some evidence that children with Rolandic discharges, with and without seizures, may be at higher risk of cognitive impairment. In addition to medical care, we emphasise early differentiated psychosocial diagnostics to provide these children and their families with targeted support if developmental problems are present.

Efficacy and safety of corticosteroids and ACTH in epileptic syndromes beyond Infantile Epileptic Spasms Syndrome (IESS): A systematic review and meta-analysis.

We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52-0.67) and 0.56 (95% CI 0.43-0.68). The relapse rate was high (PP 0.33, 95% CI 0.27-0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and "symptomatic" etiology. Obesity and Cushing's syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48-0.89) or corticosteroids (PP 0.72, 95% CI 0.54-0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02-0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support.

Pharmacogenetic study of phosphatase and tensin homolog polymorphism (rs701848) in childhood epilepsy: relation to circulating Wnt signaling.

OBJECTIVE: The present study aimed at evaluating the potential contribution of Phosphatase and Tensin Homolog (PTEN) and its gene polymorphism (PTEN rs701848 T/C) in relation to Wingless/integrase-1 (Wnt) signaling in childhood epilepsy and the impact of antiepileptic medications on their serum levels. METHODS: This study included 100 children with epilepsy (50 pharmacoresistant and 50 pharmacoresponsive) and 50 matched controls. All subjects had their genotypes for the PTEN rs701848T/C polymorphism assessed using TaqManTM assays and real-time PCR. By using the sandwich ELISA technique, the blood concentrations of PTEN and Wnt3a were measured. RESULTS: Serum Wnt3a levels in epileptic patients were significantly higher than in the control group, p < 0.001. Children with epilepsy who received oxcarbazepine had considerably lower serum Wnt3a levels than those who didn't, p < 0.001.With an AUC of 0.71, the cutoff value for diagnosing epilepsy as serum Wnt3a > 6.2 ng/mL has a sensitivity of 55% and a specificity of 80%. When compared to controls, epileptic children had considerably more (TT) genotype and less (TC and CC) genotypes, p < 0.05 for all. Epileptic children had significantly higher (T) allele frequency than controls, p = 0.006 with OR (95%CI) = 1.962(1.206-3.192). Pharmacoresistant epileptic children had significantly higher (TT) genotype compared to pharmacoresponsive type (p = 0.020). CONCLUSION: We originally found a strong association between PTEN rs701848 T/C and childhood epilepsy, in particular pharmacoresistant type. Serum Wnt3a levels increased in epilepsy, but were not significantly different between different alleles of PTEN. In pharmaco-responsive children Wnt3a levels differed significantly between the different PTEN genotypes. Antiepileptics may affect Wnt3a levels.