Genotypes and phenotypes of DNM1 encephalopathy.

BACKGROUND: Variants in the dynamin-1 (DNM1) gene typically cause synaptopathy, leading to developmental and epileptic encephalopathy (DEE). We aimed to determine the genotypic and phenotypic spectrum of DNM1 encephalopathy beyond DEE. METHODS: Electroclinical phenotyping and genotyping of patients with a DNM1 variant were conducted for patients undergoing next-generation sequencing at our centre, followed by a systematic review. RESULTS: Six patients with heterozygous DNM1 variants were identified in our cohort. Three had a typical DEE phenotype characterised by epileptic spasms, tonic seizures and severe-to-profound intellectual disability with pathogenic variants located in the GTPase or middle domain. The other three patients had atypical phenotypes of milder cognitive impairment and focal epilepsy. Genotypically, two patients with atypical phenotypes had variants located in the GTPase domain, while the third patient had a novel variant (p.M648R) in the linker region between pleckstrin homology and GTPase effector domains. The third patient with an atypical phenotype showed normal development until he developed febrile status epilepticus. Our systematic review on 55 reported cases revealed that those with GTPase or middle domain variants had more severe intellectual disability (p<0.001) and lower functional levels of ambulation (p=0.001) or speech and language (p<0.001) than the rest. CONCLUSION: DNM1-related phenotypes encompass a wide spectrum of epilepsy and neurodevelopmental disorders, with specific variants underlying different phenotypes.

Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish.

Leukodystrophy with vanishing white matter (VWM), also called Childhood Ataxia with Central Nervous System Hypomyelination, is caused by mutations in the subunits of the eukaryotic translation initiation factor, EIF2B1, EIF2B2, EIF2B3, EIF2B4 or EIF2B5. However, little is known regarding the underlying pathogenetic mechanisms, and there is no curative treatment for VWM. In this study, we established the first EIF2B3 animal model for VWM disease in vertebrates by CRISPR mutagenesis of the highly conserved zebrafish ortholog eif2b3. Using CRISPR, we generated two mutant alleles in zebrafish eif2b3, 10- and 16-bp deletions, respectively. The eif2b3 mutants showed defects in myelin development and glial cell differentiation, and increased expression of genes in the induced stress response pathway. Interestingly, we also found ectopic angiogenesis and increased VEGF expression. Ectopic angiogenesis in the eif2b3 mutants was reduced by the administration of VEGF receptor inhibitor SU5416. Using the eif2b3 mutant zebrafish model together with in silico protein modeling analysis, we demonstrated the pathogenicity of 18 reported mutations in EIF2B3, as well as of a novel variant identified in a 19-month-old female patient: c.503 T > C (p.Leu168Pro). In summary, our zebrafish mutant model of eif2b3 provides novel insights into VWM pathogenesis and offers rapid functional analysis of human EIF2B3 gene variants.

Emotional and behavioral profiles of adolescents with epilepsy: Associations with parental perception of epilepsy-related stigma.

PURPOSE: We evaluated self-reported psychopathology in adolescents with epilepsy (AWE) and determined which types of psychopathology were associated with the parental perception of stigma towards AWE. METHODS: This was a cross-sectional, multicenter study of 289 adolescents aged 11 to 18 years. Psychopathology was evaluated using the Youth Self-Report scale, which consists of eight narrowband and three broadband syndrome scales. We analyzed the raw score and T-score of each syndrome scale. The parental perception of stigma was assessed using the modified three-item Epilepsy Stigma Scale. RESULTS: Of the 289 AWE (180 boys and 109 girls), 18.3% had at least one emotional or behavioral problem in the clinical range. Social problems were the most common (10.0%), followed by attention problems (6.9%) and aggressive behaviors (4.2%). Externalizing problems (11.8%) were two times more common than internalizing problems (6.2%). Females and older AWE had a higher level of internalizing problems. Social problems were more common in girls (15.6%) than in boys (6.7%), whereas thought problems were more common in boys (3.9%) than in girls (0%). Epilepsy-related factors, especially antiseizure medication polytherapy, were significantly associated with various emotional and behavioral problems. A quarter of parents felt stigma towards their children with epilepsy. Male sex, antiseizure medication polytherapy, and longer duration of epilepsy were more likely to be associated with the parental perception of stigma. Parental perception of stigma was significantly associated with psychopathology in AWE, particularly externalizing problems and social problems. CONCLUSIONS: Emotional and behavioral problems in AWE are common and vary depending on demographic, clinical, and parental factors. Early identification and proper management of these problems are crucial for decreasing comorbid psychopathology in AWE.

Disparate treatment outcomes according to presence of pathogenic mutations in West syndrome.

OBJECTIVE: It has been known that West syndrome (WS) patients with an unknown etiology have better clinical outcomes than patients with an identified etiology of any kind. However, after the exponential discovery of genes with mutations responsible for developmental and epileptic encephalopathy (DEE), a significant proportion of patients with a previously unknown etiology have been reclassified as having a genetic etiology, requiring reinvestigation of this concept. Therefore, this study investigated clinical outcomes of WS patients with genetic and unknown etiologies. METHODS: Patients diagnosed with WS without structural or metabolic abnormalities were included in this study. The DEE gene panel, comprising 172 genes, was performed for all patients. All patients were treated using the same treatment protocol for vigabatrin and high-dose prednisolone add-on therapy. Favorable responders were defined as patients who were seizure-free and whose electroencephalogram showed Burden of Amplitudes and Epileptiform Discharges scores of 2 or less. RESULTS: Of the 58 patients included in the study, 17 (29.3%) patients had an identified genetic etiology. There was no significant difference in rates of favorable response at 1 and 3 months after treatment, but significantly higher proportions of patients exhibited favorable responses among those with an unknown etiology at long-term follow-up (41.2% vs. 78.0%, p = .006 at 6 months; 29.4% vs. 65.9%, p = .011 at 1 year; 23.5 vs. 65.9%, p = .003 at 2 years). Moreover, the mental, psychomotor, and social age quotients of the patients with an identified genetic etiology were reduced to a significantly greater degree since diagnosis compared with those of the patients with an unknown etiology. SIGNIFICANCE: WS patients with genetic and unknown etiologies did not initially exhibit significantly different response rates to the vigabatrin and high-dose prednisolone add-on treatment. However, patients with a genetic etiology exhibited significantly higher relapse rates and significantly poorer long-term responses.

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in MTOR account for 15%-25% of FCD type II (FCDII), characterized by cortical dyslamination and dysmorphic neurons. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 100×-20,012×) of five important mTOR pathway genes-PIK3CA, PIK3R2, AKT3, TSC1, and TSC2-by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T [p.Arg22Trp] and c.610C>T [p.Arg204Cys]) and TSC2 (c.4639G>A [p.Val1547Ile]), and these results were reproducible on two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1-TSC2 complex. Furthermore, in utero CRISPR-Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures, as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.

Cannabidiol for Treating Lennox-Gastaut Syndrome and Dravet Syndrome in Korea.

BACKGROUND: For the first time in Korea, we aimed to study the efficacy and safety of cannabidiol (CBD), which is emerging as a new alternative in treating epileptic encephalopathies. METHODS: This study was conducted retrospectively with patients between the ages of 2-18 years diagnosed with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) were enrolled from March to October 2019, who visited outpatient unit at 3 and 6 months to evaluate medication efficacy and safety based on caregiver reporting. Additional evaluations, such as electroencephalogram and blood tests, were conducted at each period also. CBD was administered orally at a starting dose of 5 mg/kg/day, and was maintained at 10 mg/kg/day. RESULTS: We analyzed 34 patients in the LGS group and 10 patients in the DS group between the ages of 1.2-15.8 years. In the 3-month evaluation, the overall reduction of seizure frequency in the LGS group was 52.9% (>50% reduction in 32.3% of the cases), and 29.4% in the 6-month evaluation (more than 50% reduction in 20.6%). In DS group, the reduction of seizure frequency by more than 50% was 30% and 20% in the 3-month and 6-month evaluation, respectively. Good outcomes were defined as the reduction of seizure frequency by more than 50% and similar results were observed in both LGS and DS groups. Adverse events were reported in 36.3% of total patients of which most common adverse events were gastrointestinal problems. However, no life-threatening adverse event was reported in both LGS and DS during the observation period. CONCLUSION: In this first Korean study, CBD was safe and tolerable for use and could be expected to potentially reduce the seizure frequency in pediatric patients with LGS or DS.

Precise detection of low-level somatic mutation in resected epilepsy brain tissue.

Low-level somatic mutations have been shown to be the major genetic etiology of intractable epilepsy. The extents thereof, however, have yet to be systematically and accurately explored in a large cohort of resected epilepsy brain tissues. Moreover, clinically useful and precise analysis tools for detecting low-level somatic mutations from unmatched formalin-fixed paraffin-embedded (FFPE) brain samples, the most clinically relevant samples, are still lacking. In total, 446 tissues samples from 232 intractable epilepsy patients with various brain pathologies were analyzed using deep sequencing (average read depth, 1112x) of known epilepsy-related genes (up to 28 genes) followed by confirmatory site-specific amplicon sequencing. Pathogenic mutations were discovered in 31.9% (74 of 232) of the resected epilepsy brain tissues and were recurrently found in only eight major focal epilepsy genes, including AKT3, DEPDC5, MTOR, PIK3CA, TSC1, TSC2, SCL35A2, and BRAF. Somatic mutations, two-hit mutations, and germline mutations accounted for 22.0% (51), 0.9% (2), and 9.1% (21) of the patients with intractable epilepsy, respectively. The majority of pathogenic somatic mutations (62.3%, 33 of 53) had a low variant allelic frequency of less than 5%. The use of deep sequencing replicates in the eight major focal epilepsy genes robustly increased PPVs to 50-100% and sensitivities to 71-100%. In an independent FCDII cohort of only unmatched FFPE brain tissues, deep sequencing replicates in the eight major focal epilepsy genes identified pathogenic somatic mutations in 33.3% (5 of 15) of FCDII individuals (similar to the genetic detecting rate in the entire FCDII cohort) without any false-positive calls. Deep sequencing replicates of major focal epilepsy genes in unmatched FFPE brain tissues can be used to accurately and efficiently detect low-level somatic mutations, thereby improving overall patient care by enriching genetic counseling and informing treatment decisions.

Clobazam as an adjunctive treatment for infantile spasms.

Infantile spasms constitute a catastrophic epileptic condition. Seizures in approximately half of children with infantile spasms fail to improve with initial treatment attempts; at present, data regarding alternative treatments are limited. We assessed the efficacy of clobazam as an adjunctive therapy in patients whose seizures failed to respond to initial regimens of standard treatment for infantile spasms. All patients from Severance Children's Hospital who received clobazam as adjunctive therapy for infantile spasms were selected for the study. The efficacy of clobazam was evaluated by assessing the daily spasm frequency. Patients were categorized as complete responders if the spasms disappeared within 2 weeks of introducing clobazam, and the patients became spasm-free during weeks 3 and 4. Tolerability was gauged by analyzing adverse events and discontinuation rates. In all, 171 patients qualified for the analysis. Clobazam was introduced after the administration of 2.6 (median; interquartile range [IQR], 1.0-4.0) failed antiepileptic drugs (AEDs), at the age of 8.2 months (IQR, 6.0-10.0 months). After clobazam therapy was initiated, 38 (22.2%) patients became spasm-free for ≥2 weeks. Thirteen out of the 38 complete responders remained spasm-free until the last follow-up and did not require the administration of other AEDs. In 10 patients, the electroencephalogram (EEG) tracings were also within normal limits. These patients were successfully weaned off of all AEDs. Patients with conditions of unknown etiology, who had fewer prior exposures to AEDs, and had not received prior adrenocorticotropic hormone (ACTH)/steroids were more likely to have complete spasm control than the others. Adverse effects were minor, and only 6 of 101 (6%) patients who experienced adverse events had their treatments discontinued during the 3-month follow-up period. The most common adverse events observed were hypersalivation, sedation, and sleep disturbance. Thus, clobazam might be an effective and safe alternative therapeutic option in patients whose seizures failed to respond to initial regimens of standard treatment for infantile spasms. Further prospective studies on clobazam for infantile spasms, focusing on specific good response groups, dosing protocols, and long-term outcome are needed.

Interregional metabolic connectivity of 2-deoxy-2[18 F]fluoro-D-glucose positron emission tomography in vagus nerve stimulation for pediatric patients with epilepsy: A retrospective cross-sectional study.

OBJECTIVE: With the recognition of epilepsy as a network disease that disrupts the organizing ability of resting-state brain networks, vagus nerve stimulation (VNS) may control epileptic seizures through modulation of functional connectivity. We evaluated preoperative 2-deoxy-2[18 F]fluoro-D-glucose (FDG) positron emission tomography (PET) in VNS-implanted pediatric patients with refractory epilepsy to analyze the metabolic connectivity of patients and its prognostic role in seizure control. METHODS: Preoperative PET data of 66 VNS pediatric patients who were followed up for a minimum of 1 year after the procedure were collected for the study. Retrospective review of the patients' charts was performed, and five patients with inappropriate PET data or major health issues were excluded. We conducted an independent component analysis of FDG-PET to extract spatial metabolic components and their activities, which were used to perform cross-sectional metabolic network analysis. We divided the patients into VNS-effective and VNS-ineffective groups (VNS-effective group, ≥50% seizure reduction; VNS-ineffective group, <50% reduction) and compared metabolic connectivity differences between groups using a permutation test. RESULTS: Thirty-four (55.7%) patients showed >50% seizure reduction from baseline frequency 1 year after VNS. A significant difference in metabolic connectivity evaluated by preoperative FDG-PET was noted between groups. Relative changes in glucose metabolism were strongly connected among the areas of brainstem, cingulate gyrus, cerebellum, bilateral insula, and putamen in patients with <50% seizure control after VNS. SIGNIFICANCE: This study shows that seizure outcome of VNS may be influenced by metabolic connectivity, which can be obtained from preoperative PET imaging. This study of metabolic connectivity analysis may contribute in further understanding of the mechanism of VNS in intractable seizures.

Altered brain functional connectivity induced by physical exercise may improve neuropsychological functions in patients with benign epilepsy.

OBJECTIVE: The objective of this study was to elucidate alteration in functional connectivity (FC) in patients with benign epilepsy with centrotemporal spikes (BECTS) as induced by physical exercise therapy and their correlation to the neuropsychological (NP) functions. METHODS: We analyzed 115 artifact- and spike-free 2-second epochs extracted from resting state EEG recordings before and after 5weeks of physical exercise in eight patients with BECTS. The exact Low Resolution Electromagnetic Tomography (eLORETA) was used for source reconstruction. We evaluated the cortical current source density (CSD) power across five different frequency bands (delta, theta, alpha, beta, and gamma). Altered FC between 34 regions of interests (ROIs) was then examined using lagged phase synchronization (LPS) method. We further investigated the correlation between the altered FC measures and the changes in NP test scores. RESULTS: We observed changes in CSD power following the exercise for all frequency bands and statistically significant increases in the right temporal region for the alpha band. There were a number of altered FC between the cortical ROIs in all frequency bands of interest. Furthermore, significant correlations were observed between FC measures and NP test scores at theta and alpha bands. CONCLUSION: The increased localization power at alpha band may be an indication of the positive impact of exercise in patients with BECTS. Frequency band-specific alterations in FC among cortical regions were associated with the modulation of cognitive and NP functions. The significant correlation between FC and NP tests suggests that physical exercise may mitigate the severity of BECTS, thereby enhancing NP function.

Efficacy of the classic ketogenic and the modified Atkins diets in refractory childhood epilepsy.

OBJECTIVE: We aimed to compare the efficacy, safety, and tolerability of a modified Atkins diet (MAD) with the classic ketogenic diet (KD) for the treatment of intractable childhood epilepsy. METHODS: From March 2011 to March 2014, 104 patients aged 1-18 years who had refractory epilepsy were randomly assigned to each diet group (ClinicalTrials.gov, number NCT2100501). A seizure diary record was used to compare seizure frequencies with the baseline prediet seizure frequency at the third and sixth months after diet therapy initiation. RESULTS: Fifty-one patients were assigned to the KD and 53 patients to the MAD. The KD group had a lower mean percentage of baseline seizures compared with the MAD group at 3 months (38.6% for KD, 47.9% for MAD) and 6 months (33.8% for KD, 44.6% for MAD), but the differences were not statistically significant (95% confidence interval [CI] 24.1-50.8, p = 0.291 for 3 months; 95% CI 17.8-46.1, p = 0.255 for 6 months). Instead, for patients aged 1-2 years, seizure outcomes were consistently much more favorable in patients consuming the KD compared with those consuming the MAD. The rate of seizure freedom at 3 months after diet therapy initiation was significantly higher (53% for KD, 20% for MAD, p = 0.047) in these patients. The MAD had advantages with respect to better tolerability and fewer serious side effects. SIGNIFICANCE: The MAD might be considered as the primary choice for the treatment of intractable epilepsy in children, but the classic KD is more suitable as the first line of diet therapy in patients <2 years of age.

Family factors contributing to emotional and behavioral problems in Korean adolescents with epilepsy.

PURPOSE: We aimed to determine whether different aspects of family functioning are associated with emotional and behavioral problems in adolescents with epilepsy and, if not, to document any indirect associations mediated by other family factors. METHODS: This was a cross-sectional, multicenter study. A total of 297 adolescents with epilepsy and their parents participated. Adolescent psychopathology was measured using the Youth Self-Report. Family factors were classified into proximal (parent-child interaction), distal (parent characteristics), and contextual factors (family characteristics) in accordance to their level of proximity to the adolescent's everyday life. Regression analyses were used to analyze the unique and combined predictive power of family factors in relation to psychopathology. RESULTS: In total, 44 (14.8%) and 51 (17.2%) adolescents with epilepsy scored above the borderline cutoff (T-score ≥ 60) of internalizing and externalizing problems, respectively. Proximal and distal factors were independently associated with both internalizing and externalizing problems. High levels of parental depressive mood and parental overcontrol were the strongest factors contributing to internalizing and externalizing problems, respectively. Contextual factors were indirectly associated with both internalizing and externalizing problems through more proximal factors. CONCLUSIONS: Both proximal and distal family factors affect psychopathology in Korean adolescents with epilepsy. Parental feelings of depression and parental overcontrol are the strongest factors contributing to internalizing and externalizing problems, respectively.

Changing name of epilepsy in Korea; cerebroelectric disorder (noi-jeon-jeung,ë‡Œì „ì¦,): my epilepsy story.

Public misconception of epilepsy may lead to significant stigma to the disease itself, thereby causing impaired quality of life in people with epilepsy. Traditionally, epilepsy has been considered to be the consequence of evanescent spiritual forces, and even demonic possession (in many countries). The names of epilepsy in some East Asian countries originated from China, and include madness in their meaning. We recently changed the Korean name of epilepsy, gan-jil (간질, : a crazy, convulsive disease having meaning similar to ), to a neutral and scientifically explainable name: noi-jeon-jeung (뇌전증; ; cerebroelectric disorder). We expect that changing the stigmatized name of epilepsy to a neutral and scientific term with the meaning of cerebroelectric disorder will reduce the social stigma by understanding of epilepsy as one of the neurologic disorders.

The impact of an exercise therapy on psychosocial health of children with benign epilepsy: a pilot study.

OBJECTIVES: The purposes of the current study were to test the feasibility of exercise therapy for children with benign epilepsy with centrotemporal spikes (BECTS) and to collect pilot data about the impact of exercise therapy on neurocognitive, emotional, and behavioral outcomes. METHODS: Ten children with BECTS (9.7±1.42 years) participated in a therapeutic exercise program consisting of ten supervised exercise sessions and home-based exercises for five weeks. Electroencephalography (EEG), seizure frequency, and neurocognitive and psychological factors, including attention, executive function, depression, anxiety, behavioral problems, and quality of life, were assessed before and after the exercise program. RESULTS: No clinical symptoms were observed to worsen during the study, demonstrating that the exercise therapy was safe and also feasible. After five weeks of exercise therapy, significant improvements in neurocognitive domains such as simple visual and auditory attention, sustained attention, divided attention, psychomotor speed, and inhibition-disinhibition were observed. Furthermore, parent ratings of internalizing behavioral problems and social problems and mood-related well-being from quality of life improved after exercise therapy. Although not statistically significant, trends were noted toward improvement in children's self-reports of negative mood/somatization, parent reports of somatic complaints, and general health on a quality-of-life measure. CONCLUSIONS: A five-week structured exercise program was successfully implemented, with preliminary data suggesting beneficial impact on neurocognitive and psychobehavioral function. Exercise therapy should be further evaluated as a part of a comprehensive treatment program for children with benign epilepsy.

Epilepsy-related clinical factors and psychosocial functions in pediatric epilepsy.

PURPOSE: The aim of this study was to identify the different influencing patterns of demographic and epilepsy-related variables on various aspects of psychosocial function in pediatric epilepsy. METHOD: Five hundred ninety-eight patients with pediatric epilepsy between the ages of 4 and 18 years (boys=360, 60% and girls=238, 40%) and their parents participated in the study. Parents completed the Social Maturity Scale (SMS), the Korean version of the Child Behavior Checklist (K-CBCL), and the Korean version of the Quality of Life in Childhood Epilepsy Questionnaire (K-QOLCE) to assess daily living function, behavior, and quality of life. The Children's Global Assessment Scale (CGAS) was completed by clinicians to assess general adaptive function. Demographic variables, such as age and sex of child, and epilepsy-related clinical variables, including seizure type, seizure frequency, duration of epilepsy, and number of medications, were obtained from medical records. RESULTS: Demographic and epilepsy-related clinical variables had a strong influence (22-32%) on the cognition-related domain such as general adaptive function, school/total competence, and quality of life for cognitive function while a comparatively smaller effect (2-16%) on the more psychological domain including behavioral, emotional, and social variables. Younger age, shorter duration of illness, and smaller number of medications showed a strong positive impact on psychosocial function in pediatric epilepsy, particularly for adaptive function, competence, and quality-of-life aspects. CONCLUSION: Given the wide range of impact of demographic and clinical variables on various facets of psychosocial functions, more specific understanding of the various aspects of factors and their particular pattern of influence may enable more effective therapeutic approaches that address both the medical and psychological needs in pediatric epilepsy.

Genetic Diagnosis in Neonatal Encephalopathy With Hypoxic Brain Damage Using Targeted Gene Panel Sequencing.

BACKGROUND AND PURPOSE: Neonatal encephalopathy (NE) is a neurological syndrome that presents with severe neurological impairments and complications. Hypoxic-ischemic encephalopathy is a major contributor to poor outcomes, being responsible for 50%-80% of admissions to neonatal intensive care units. However, some cases of NE accompanied by hypoxic brain damage cannot be solely attributed to hypoxia-ischemia. We aimed to identify diverse pathogenic genetic variations that may be associated with cases of NE accompanied by hypoxic brain damage rather than hypoxia-ischemia. METHODS: We collected data from 34 patients diagnosed with NE accompanied by hypoxic brain damage over a 10-year period. Patients with the following specific conditions were excluded: 1) premature birth (<32 weeks), 2) no history of hypoxic events, 3) related anomalies, 4) neonatal infections, 5) antenatal or perinatal obstetrical complications, 6) severe hypoxia due to other medical conditions, and 7) early death (within 1 week). A comprehensive review of clinical and radiological features was conducted. RESULTS: A genetic diagnosis was made in 11 (32.4%) patients, with pathogenic variants being identified in the following 9 genes: CACNA1A (n=2), KCNQ2 (n=2), SCN2A (n=1), SCN8A (n=1), STXBP1 (n=1), NSD1 (n=1), PURA (n=1), ZBTB20 (n=1), and ENG (n=1). No specific treatment outcomes or clinical features other than preterm birth were associated with the results of the genetic analyses. Personalized treatments based on the results of genetic tests were attempted, such as the administration of sodium-channel blockers in patients with KCNQ2 or SCN8A variants and the implementation of a ketogenic diet in patients with STXBP1 or SCN2A mutations, which demonstrated some degree of effectiveness in these patients. CONCLUSIONS: Genetic analyses may help in diagnosing the underlying etiology of NE and concurrent hypoxic brain damage, irrespective of the initial clinical features.

Functional brain network analysis using electroencephalography in late-onset Lennox-Gastaut syndrome.

OBJECTIVE: We aimed to explore the clinical characteristics and functional network properties of patients with late-onset Lennox-Gastaut syndrome (LGS). METHODS: Late-onset LGS was defined by the appearance of LGS features after 8 years of age. We reviewed the medical charts of 9 patients with late-onset LGS, and performed electroencephalography connectivity analysis using graph theory. We assessed the clustering coefficient (CC) and characteristic path length (CPL), which are common basic measures of functional networks that represent local segregation and global integration. The characteristics and brain parameters of late-onset LGS were compared with a typical age-onset LGS group. RESULTS: Late onset LGS subjects were older than typical age onset LGS at the time of testing, but otherwise there were no significant differences in clinical characteristics. The late-onset group showed higher median CC values in the alpha (p = 0.045) and beta (p < 0.001) bands over brain regions implicated in cognitive processing. There were no significant differences in CPL between the LGS groups. CONCLUSIONS: Higher clustering coefficient values, in alpha/beta bands over brain regions implicated in cognitive processing, are consistent with increased cognitive network segregation in late onset LGS compared to typical age-onset LGS. Given network segregation is a normal aspect of brain maturation, these results imply that this process is less disturbed when the LGS process begins later in childhood.

Identification of etiologies according to baseline clinical features of pediatric new-onset refractory status epilepticus in single center retrospective study.

PURPOSE: New-onset refractory status epilepticus (NORSE) is defined as a state of prolonged seizure activity that does not improve despite the appropriate administration of medications, with underlying causes unknown after the initial diagnosis of status epilepticus. Because episodes of NORSE are accompanied by severe complications and a high risk of mortality, the prompt identification of the underlying cause is crucial for effective treatment and outcome prediction. This study assessed the relationship of NORSE etiologies with baseline clinical features in pediatric population. METHODS: Seventy-one pediatric patients, under 18 years of age at the initial diagnosis (4.50 ± 4.04, mean ± standard deviation), who experienced at least one episode of NORSE and underwent a comprehensive diagnostic evaluation between January 2005 and June 2020 at our center, were retrospectively selected. We reviewed clinical features at disease onset and long-term follow-up data. Uniform manifold approximation and projection (UMAP) was used to distinguish etiological clusters according to baseline clinical characteristics, and further analysis was performed based on underlying etiologies. RESULTS: Two distinct etiological groups-genetic and non-genetic-were identified based on the UMAP of clinical characteristics. Dravet syndrome (12/15, 80%) was more predominant in patients with a genetic diagnosis, whereas cryptogenic NORSE and encephalitis were prevalent in patients without a genetic diagnosis. The analysis of etiological categories revealed that age at the onset of status epilepticus (P=0.021) and progression to super refractory status epilepticus (SRSE) (P=0.038) were independently associated with differences in etiologies. CONCLUSION: Several clinical features in patients with NORSE, including the age of onset and the development of SRSE, can help identify underlying causes, which necessitate prompt and adequate treatment.

Efficacy of enteral feeding by gastrostomy tube placement in patients with Lennox-Gastaut syndrome on body weight and days of hospitalization: A retrospective case series.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is a severe form of drug-resistant epilepsy that begins during childhood and frequently leads to significant neurological impairments. Patients with LGS are likely to receive improper oral nutrition because of issues such as dysphagia and aspiration risk, potentially resulting in long-term tube feeding and eventual gastrostomy tube placement. Therefore, we investigated the effects of gastrostomy tube placement on nutrition outcomes and frequency of hospitalization in LGS. METHODS: We retrospectively examined 67 patients diagnosed with LGS who had undergone gastrostomy tube placement between January 2005 and August 2022. Comprehensive clinical data and complications arising from the procedure were collected. Patients' nutrition condition and frequency of hospitalizations were analyzed before and after gastrostomy tube placement. RESULTS: Gastrostomy tube placement was performed for the following reasons: high risk of aspiration (50 out of 67, 74.6%), dysphagia (13 out of 67, 25.4%), persistent nasogastric tube feeding (2 out of 67, 3.0%), and severe malnutrition (2 out of 67, 3.0%). After the procedure, z scores for weight-for-age improved significantly, shifting from -3.35 ± 3.57 to -2.54 ± 2.70 over a 2-year interval (P < 0.001). Additionally, the total days of hospitalization and days of hospitalization due to respiratory symptoms reduced significantly from 41.94 ± 51.76 to 15.27 ± 26.68 (P < 0.001) and from 23.75 ± 36.92 to 10.52 ± 22.98 (P = 0.009), respectively. Among the patients, 50 (74.6%) experienced complications resulting from gastrostomy, with a relatively small proportion of major complications (11 out of 67, 16.4%) and no mortality. CONCLUSION: Gastrostomy tube placement is a relatively safe procedure with favorable effects on nutrition status and hospitalization rates in patients with LGS.

Long-term efficacy and safety of adjunctive perampanel in pediatric patients aged 4-19 years with epilepsy: a real-world study.

This study determined the 24-month outcomes of perampanel treatment in children and adolescents with epilepsy. The percentage of ≥ 50% responders was 47.3% (139/294) at 12 months and 49.0% (144/294) at 24 months. A 100% reduction in seizures for more than 12 months was observed in 12.2% (36/294). Discontinuation occurred in 39.8% (117/294). The most common reason for discontinuation was adverse events (29.1%, 34/117). Baseline seizure frequency was higher in children aged < 12 years than in patients aged ≥ 12 years; however, the percentage of seizure reduction and ≥ 50% responders did not significantly differ between the two groups. The rate of early discontinuation was higher (p < 0.001) and the duration of perampanel treatment was shorter in children aged < 12 years (p = 0.001). Most children aged < 12 years discontinued PER due to inadequate effectiveness, while adverse event was the most common reason in patients aged ≥ 12 years (p = 0.045). Only slow titration was significantly associated with ≥ 50% of responders. In conclusion, this study showed that perampanel can be utilized effectively and safely for a prolonged period in pediatric patients aged 4 to < 12 years, as well as in patients aged 12 years and older.