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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., Competing Interests: Hoon-Chul Kang, a contributing editor of the Journal of Clinical Neurology, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Korean Neurological Association.)

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., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (© 2024 American Society for Parenteral and Enteral Nutrition.)

Objective: To investigate the surgical outcomes of patients with drug-resistant epilepsy and bilateral brain magnetic resonance imaging (MRI) abnormalities who had undergone various epilepsy surgeries., Methods: Patients with drug-resistant epilepsy and bilateral brain abnormalities on MRI who underwent epilepsy surgery at the Severance Children's Hospital between October 2003 and December 2021 were included. The age of seizure onset was 18 years or younger. Engel's classification was used to assess seizure outcomes at 1, 2, and 5 years after surgery., Results: A total of 40 patients met the inclusion criteria. The median age at surgery was 10.9 years (interquartile range [IQR] 6.9-15.1); the median interval to surgery was 7.1 years (IQR 2.7-11.5). One year after surgery, a favorable outcome of Engel class I-II was observed in 53% (21/40) of patients. At the 2- and 5-year follow-ups, 56% (20/36) and 63% (17/27) of patients showed good postoperative outcomes, respectively., Conclusions: Approximately, half of the patients with bilateral brain MRI abnormalities achieved seizure freedom after epilepsy surgery. The existence of bilateral brain MRI abnormalities should not hinder resective epilepsy surgery., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Everolimus is an inhibitor of mammalian target of rapamycin complex 1. As mutations in TSC1 and TSC2 , which cause partial-onset seizures associated with TSC, were found in focal cortical dysplasia type Ⅱ (FCD Ⅱ) patients, a clinical trial has been performed to explore the efficacy and safety of everolimus in FCD patients. However, no dosage regimen was determined to treat FCD II. To recommend an optimal dose regimen for FCD patients, a population pharmacokinetic model of everolimus in FCD patients was developed. Methods: The data of everolimus were collected from September 2017 to May 2020 in a tertiary-level hospital in Korea. The model was developed using NONMEM ® software version 7.4.1 (Icon Development Solutions, Ellicott City, MD, United States). Results: The population pharmacokinetics of everolimus was described as the one-compartment model with first-order absorption, with the effect of BSA on clearance. The final model was built as follows: TVCL = 12.5 + 9.71 × (BSA/1.5), TVV = 293, and TVKA = 0.585. As a result of simulation, a dose higher than 7 mg/m 2 is needed in patients with BSA 0.5 m 2 , and a dose higher than 6 mg/m 2 is needed in patients with BSA 0.7 m 2 . A dose of 4.5 mg/m 2 is enough in the population with BSA higher than 1.5 m 2 to meet the target trough range of 5-15 ng/mL. Conclusion: Based on the developed pharmacokinetics model, the optimal dose of everolimus in practice was recommended by considering the available strengths of Afinitor disperz ® , 2 mg, 3 mg, and 5 mg., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Park, Kim, Hahn, Kang, Lee, Kim and Chang.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2023. Springer Nature Limited.)

Growing evidence indicates that early and late postzygotic mosaicism can cause neurodevelopmental disorders (NDDs), but detection of low variant allele frequency (VAF) mosaic variants from blood remains a challenge. Data of 2162 patients with NDDs who underwent conventional genetic tests were reviewed and a deep sequencing was performed using a specifically designed mosaic next-generation sequencing (NGS) panel in the patients with negative genetic test results. Forty-four patents with neurocutaneous syndrome, malformation of cortical development, or nonlesional epileptic encephalopathies were included. In total, mosaic variants were detected from blood in 1.2% (25/2162) of the patients. Using conventional NGS panels, 22 mosaic variants (VAF, 8.8% to 29.8%) were identified in 18 different genes. Using a specifically designed mosaicism NGS panel, three mosaic variants of the NF1, TSC2, and AKT3 genes were identified (VAF, 2.0% to 11.2%). Mosaic variants were found frequently in the patients who had neurocutaneous syndrome (2/7, 28.6%), whereas only one or no mosaic variant was detected for patients who had malformations of cortical development (1/20, 5%) or nonlesional epileptic encephalopathies (0%, 0/17). In summary, mosaic variants that contribute to the spectrum of NDDs can be detected from blood via conventional NGS and specifically designed mosaicism NGS panels, and detection of mosaic variants using blood will increase diagnostic yield., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Trio test has been widely used for diagnosis of various hereditary disorders. We aimed to investigate the contribution of trio test in genetically diagnosing neurodevelopmental disorders (NDD)., Methods: We retrospectively reviewed 2,059 NDD cases with genetic test results. The trio test was conducted in 563 cases. Clinical usefulness, optimal timing, and methods for the trio test were reviewed., Results: Pathogenic or likely pathogenic variants were detected in 112 of 563 (19.9%) patients who underwent the trio test. With trio test results, the overall diagnostic yield increased by 5.4% (112/2,059). Of 165 de novo variants detected, 149 were pathogenic and we detected 85 novel pathogenic variants. Pathogenic, de novo variants were frequently detected in CDKL5 , ATP1A3 , and STXBP1 ., Conclusion: The trio test is an efficient method for genetically diagnosing NDD. We identified specific situations where a certain trio test is more appropriate, thereby providing a guide for clinicians when confronted with variants of unknown significance of specific genes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Kim, Kwon, Lee, Kim, Lee, Choi, Shin and Kang.)

Objective: We aimed to investigate the effects of ketogenic diet (KD) and modified Atkins diet (MAD) in patients with epileptic encephalopathy, caused by the STXBP1 (syntaxin-binding protein 1) gene mutation., Methods: We retrospectively evaluated the data of patients with STXBP1-related epileptic encephalopathy who were started on either KD or MAD between January 1, 2005, and June 30, 2021, in Severance Children's Hospital., Results: Twelve patients were examined. The median age of seizure onset was 1.5 months [interquartile range (IQR): 0-3] with a median age of dietary therapy initiation at 4.5 months (IQR: 3.0-9.3) and a median diet duration of 6.5 months (IQR: 2.8-13.3). The patients had various epilepsy syndromes: nine (75 %) patients had early infantile developmental and epileptic encephalopathy, two (16.7 %) had infantile epileptic spasms syndrome, and one (8.3 %) had developmental and epileptic encephalopathy. Three patients (25 %) were definite KD responders who achieved seizure freedom within the median of 2 months from KD initiation and remained seizure-free for a median of 36 months (IQR: 29.5-60.0). One patient (8.3 %) was a possible KD responder, seizure-free with KD initiation and steroid therapy while 8 were non-responders (66.7 %). The definite KD responders shared similar clinical characteristics as the rest, except that there were significantly more patients that had seizure onset at ≥ 6 months (p = 0.045) in the definite KD responder group., Conclusion: We demonstrated dietary therapy was highly effective for some patients with STXBP1-related epileptic encephalopathy, especially those with later onset., Competing Interests: Conflict of Interests The authors have no financial conflict of interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Ketogenic dietary therapy (KDT) is used as an effective treatment for epilepsy. However, KDT carries the risk of bone health deterioration; therefore, vitamin D supplementation is required. Vitamin D replacement therapy in KDT has not been established because it may be related to hypercalciuria/urolithiasis, which are common adverse effects of KDT. Hence, this study aimed to evaluate the dose-dependent association between vitamin D 3 and hypercalciuria/urolithiasis in patients undergoing KDT and dose optimization for renal complications., Materials and Methods: Overall, 140 patients with intractable childhood epilepsy started 3:1 KDT (lipid to non-lipid ratio) at the Severance Children's Hospital from January 2016 to December 2019. Regular visits were recommended after KDT initiation. Participants were assessed for height, weight, serum 25-hydroxyvitamin D (25-OH-D 3 ) level, parathyroid hormone level, and ratio of urinary excretion of calcium and creatinine (Uca/Ucr). Kidney sonography was conducted annually. Patients who already had urolithiasis and were taking hydrochlorothiazide before KDT, failed to maintain KDT for 3 months, did not visit the pediatric endocrine department regularly, did not take prescribed calcium and vitamin D3 properly, or needed hospitalization for > 1°month because of serious medical illness were excluded. Data from patients who started diuretic agents, e.g., hydrochlorothiazide, were excluded from that point because the excretion of calcium in the urine may be altered in these patients., Result: In total, 49 patients were included in this study. Uca/Ucr ratio significantly decreased with increasing levels of 25-OH-D 3 ( p = 0.027). The odds ratio for hypercalciuria was 0.945 (95% confidence interval, 0.912-0.979; p = 0.002) per 1.0 ng/mL increment in 25-OH-D 3 level. Based on findings of receiver operating characteristic curve analysis and Youden's J statistic, the cut-off 25-OH-D 3 level for preventing hypercalciuria was > 39.1 ng/mL at 6 months. Furthermore, the vitamin D 3 supplementation dose cut-off was > 49.5 IU/kg for hypercalciuria prevention., Conclusion: An inverse relationship between Uca/Ucr ratio and 25-OH-D 3 level was noted, which means that vitamin D supplementation is helpful for preventing hypercalciuria related to KDT. We suggest that the recommended 25-OH-D 3 level is > 40 ng/mL for hypercalciuria prevention and that KDT for children with epilepsy can be optimized by vitamin D 3 supplementation at 50 IU/kg., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Lee, Song, Choi, Suh, Kim, Chae, Kang, Lee, Kim, Kim and Kwon.)

Background and Purpose: Data regarding the effects of cannabidiol (CBD) on the quality of life (QOL) are currently inadequate. We assessed the QOL of pediatric patients with epilepsy who were treated with CBD., Methods: This prospective, open-label study included pediatric and adolescent patients (aged 2-18 years) with Dravet syndrome or Lennox-Gastaut syndrome. Oral CBD was administered at 10 mg/kg/day. The Korean version of the Quality Of Life in Childhood Epilepsy (QOLCE) questionnaire was administered when CBD treatment began and again after 6 months. Adaptive behavior was measured using the Korean versions of the Child Behavior Checklist (K-CBCL) and the second edition of the Vineland Adaptive Behavior Scales (Vineland-II)., Results: This study included 41 patients (11 with Dravet syndrome and 30 with Lennox-Gastaut syndrome), of which 25 were male. The median age was 4.1 years. After 6 months, 26.8% (11/41) of patients experienced a ≥50% reduction in the number of seizures. The total score for the QOLCE questionnaire did not change from baseline to after 6 months of CBD treatment (85.71±39.65 vs. 83.12±48.01, respectively; p =0.630). The score in the motor skills domain of Vineland-II reduced from 48.67±13.43 at baseline to 45.18±14.08 after 6 months of treatment ( p =0.005). No other Vineland-II scores and no K-CBCL scores had changed after 6 months of CBD treatment., Conclusions: CBD is an efficacious antiseizure drug used to treat Dravet syndrome and Lennox-Gastaut syndrome. However, it did not improve the patient QOL in our study, possibly because all of our patients had profound intellectual disabilities., Competing Interests: Hoon-Chul Kang, a contributing editor of the Journal of Clinical Neurology, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Korean Neurological Association.)

Objective: For patients with drug-resistant focal epilepsy, intracranial monitoring remains the gold standard for surgical intervention. Focal cortical dysplasia (FCD) is the most common cause of pharmacoresistant focal epilepsy in pediatric patients who usually develop seizures in early childhood. Timely removal of the epileptogenic zone (EZ) is necessary to achieve lasting seizure freedom and favorable developmental and cognitive outcomes to improve the quality of life. We applied brain network analysis to investigate potential biomarkers for the diagnosis of EZ that will aid in the resection for pediatric focal epilepsy patients with FCD type II., Methods: Ten pediatric patients with focal epilepsy diagnosed as FCD type II and that had a follow-up after resection surgery (Engel class I [ n = 9] and Engel class II [ n = 1]) were retrospectively included. Time-frequency analysis of phase transfer entropy, graph theory analysis, and power spectrum compensation were combined to calculate brain network parameters based on interictal epileptiform discharges from ECoG., Results: Clustering coefficient, local efficiency, node out-degree, and node out-strength with higher values are the most reliable biomarkers for the delineation of EZ, and the differences between EZ and margin zone (MZ), and EZ and normal zone (NZ) were significant ( p < 0.05; Mann-Whitney U -test, two-tailed). In particular, the difference between MZ and NZ was significant for patients with frontal FCD (MZ > NZ; p < 0.05) but was not significant for patients with extra-frontal FCD., Conclusions: Brain network analysis, based on the combination of time-frequency analysis of phase transfer entropy, graph theory analysis, and power spectrum compensation, can aid in the diagnosis of EZ for pediatric focal epilepsy patients with FCD type II., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Noh, Kim, Yang, Yang, Kim, Hur and Kim.)

Background: Multimodal treatment approaches are often considered for patients with Lennox-Gastaut syndrome (LGS). Creating an algorithm that can guide healthcare providers in selecting treatment options for patients with LGS remains a challenge. Herein, we assessed the long-term seizure-free and neurodevelopmental outcomes of stepwise multimodal treatment in patients with LGS., Objective: Herein, we assess the long-term seizure-free and neurodevelopmental outcomes of stepwise multimodal treatment in patients with LGS., Methods: We retrospectively examined the data of 371 patients with LGS who underwent stepwise multimodal treatment, including antiseizure medication (ASM) therapy, dietary therapy (DT), resective epilepsy surgery (R-ES), and palliative epilepsy surgery (P-ES). The seizure-free outcome was considered to be the effect of the final treatment according to the treatment algorithm, and the percentage of patients who remained seizure-free in each treatment group was calculated. ASM treatment, DT, R-ES, and P-ES were applied to 371 (100%), 201 (54.2%), 112 (30.2%), and 115 (31.0%) patients with LGS, respectively. We evaluated the stepwise multimodal treatment outcomes in these patients., Results: One hundred sixty-eight patients (45.3%) remained seizure-free for at least 1 year (seizure-free-for-1-year group), 61 of whom (16.5%) remained seizure-free for more than 5 years (remained-seizure-free group). Among the patients treated with ASM therapy, DT, R-ES, and P-ES, 41 (11.1%), 53 (14.3%), 56 (15.1%), and 29 (7.8%), respectively, remained seizure-free for 1 year. In addition, 15 (4.1%), 15 (4.1%), 19 (5.1%), and 12 (3.2%) patients in the ASM, DT, R-ES, and P-ES treatment groups, respectively, remained seizure-free for more than 5 years. Both the seizure-free-for-1-year and remained-seizure-free groups showed significant improvement in electroencephalography findings and neurodevelopmental status following treatment., Conclusion: This study provides an update on the long-term seizure outcomes and neurodevelopmental improvements in a large cohort of patients with LGS following comprehensive multimodal treatment. We emphasize that the active combination of multiple ASMs, DT, and surgical treatment could provide long-term seizure-free outcomes and significant neurological benefits to patients with LGS., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Introduction: Subdural grid monitoring (SDG) has the advantage to provide continuous coverage over a larger area of cortex, direct visualization of electrode location and functional mapping. However, SDG can cause direct irritation of the cortex or postoperative headaches due to cerebrospinal fluid (CSF) leakage. Epidural grid monitoring (EDG) without opening the dura is thought to reduce the possibility of these complications. We report our experience with EDG., Methods: We described our surgical technique of EDG in invasive intracranial electroencephalography (iEEG) monitoring. A retrospective review of 30 patients who underwent grid placement of iEEG between March 2019 and December 2020 was performed to compare SDG and EDG., Results: Of the 30 patients, 10 patients underwent SDG and 20 patients underwent EDG. There was no difference in age between SDG and EDG groups (p = 0.13). Also, there was no difference in the number of grid electrodes, craniotomy size, number of electrodes per craniotomy area and postoperative complication rate (p = 0.32, 0.84, 0.58 and 0.40). However, the maximum number of electrodes that have been undermined from the bone margin was much higher in SDG group (SDG 4.6 ± 2.2 vs. EDG 2.0 ± 0.9; p = 0.001). The demand for postoperative analgesics was significantly lower in EDG group (SDG 13.4 ± 9.1 vs. EDG 4.1 ± 4.3; p = 0.012); and the demand for postoperative antiemetics also tended to be low (SDG 4.6 ± 3.6 vs. EDG 1.8 ± 1.6; p = 0.078)., Conclusions: There was no significant difference in craniotomy and electrode insertion between the two groups; however, the EDG group showed less postoperative headache and nausea. Though not in direct contact with the cortex, the quality of the electrophysiological signal received through the electrode in EDG is comparable to that of the SDG. The EDG enables to detect the onset of seizure and delineate the epileptogenic zone sufficiently. Moreover, functional mapping is possible with EDG. Therefore, EDG has the sufficient potential to replace SDG for monitoring of the lateral surface of brain., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Whether epilepsy surgery, such as corpus callosotomy is effective in patients with pediatric intractable epilepsy with mitochondrial dysfunction is controversial, and there is a paucity of literature on this issue., Objective: This study aimed to assess and describe the effective application of corpus callosotomy for treating pediatric patients with intractable epilepsy with mitochondrial dysfunction in a single institution in Korea., Methods: This was a retrospective study of pediatric patients with intractable epilepsy and mitochondrial dysfunction who underwent corpus callosotomy in a single tertiary care center. Ten patients with intractable epilepsy with mitochondrial dysfunction were included, and 10 patients with intractable epilepsy with non-mitochondrial dysfunctions were included as a control group. The outcomes of corpus callosotomy in the two groups were evaluated and compared., Results: Corpus callosotomy was safely performed and was efficacious in reducing seizure frequency in both groups. The group with non-mitochondrial dysfunction showed slightly better treatment outcomes, with greater reductions in overall seizures, traumatic falling seizures, and electroencephalography improvements, but the differences in treatment effects were not statistically significant., Conclusions: Our study is meaningful as it identified the use of corpus callosotomy as a means to save lives and improve quality of life by reducing the frequency of seizures and those associated with traumatic falling in pediatric patients with intractable epilepsy with mitochondrial dysfunction. Larger multicenter studies are necessary to confirm the efficacy of the procedure., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

The ketogenic diet (KD) is a high-fat, low-carbohydrate diet, in which fat, instead of glucose, acts as a major energy source through the production of ketone bodies. The KD was formally introduced in 1921 to mimic the biochemical changes associated with fasting and gained recognition as a potent treatment for pediatric epilepsy in the mid-1990s. Recent clinical and scientific knowledge supports the use of the KD in drug-resistant epilepsy patients for its anti-seizure efficacy, safety, and tolerability. The KD is also receiving growing attention as a potential treatment option for other neurological disorders. This article will review on the recent updates on the KD, focusing on its mechanisms of action, its alternatives, expansion on its use in terms of age groups and different regions in the world, and future issues., Competing Interests: Conflicts of interest There is no competing interest among the authors., (Copyright © 2021 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: A multifactorial antiepileptic mechanism underlies the ketogenic diet (KD), and one of the proposed mechanisms of action is that the KD inhibits the mammalian target of rapamycin (mTOR) pathway. To test this clinically, this study aimed to determine the efficacy of the KD in patients with pathologically confirmed focal cortical dysplasia (FCD) due to genetically identifiable mTOR pathway dysregulation., Methods: A cohort of patients with pathologically confirmed FCD after epilepsy surgery and who were screened for the presence of germline and somatic mutations related to the mTOR pathway in peripheral blood and resected brain tissue was constructed prospectively. A retrospective review of the efficacy of the prior KD in these patients was performed., Results: Twenty-five patients with pathologically confirmed FCD and who were screened for the presence of detectable somatic mTOR pathway mutations had received a sufficient KD. Twelve of these patients (48.0%) had germline or somatic detectable mTOR pathway mutations. A response was defined as a ≥50% reduction in seizure frequency. The efficacy of the KD after 3 months of dietary therapy was superior in patients with detectable mTOR pathway mutations than in patients without detectable mTOR pathway mutations, although the difference was not statistically significant (responder rates of 58.3% vs. 38.5%, p =0.434)., Conclusions: A greater proportion of patients with mTOR pathway responded to the KD, but there was no statistically significant difference in efficacy of the KD between patients with and without detectable mTOR pathway mutations. Further study is warranted due to the smallness of the sample and the limited number of mTOR pathway genes tested in this study., Competing Interests: Hoon-Chul Kang, an assoicate editor of the Journal of Clinical Neurology, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Korean Neurological Association.)

Objective: Lennox-Gastaut syndrome (LGS) is a severe form of developmental and epileptic encephalopathy that is highly resistant to treatment with conventional anti-epileptic drugs and non-pharmacological therapies. In the present study, we aimed to investigate the efficacy of long-term, high-dose steroid therapy and its effect on prognosis in children with LGS., Methods: This prospective study included patients with LGS who received long-term, high-dose steroid therapy beginning in November 2016. Prednisolone (60 mg per day) was administered for 2 weeks, following which the dosage was reduced to 60 mg on alternate days for 12 weeks. The drug was then slowly tapered over the next 3 months. The primary outcome was a reduction in seizure frequency relative to baseline at 14 weeks. The secondary outcome was whether patients had become seizure-free at 1 year., Results: Among 44 patients, 30 (68.2%) experienced a reduction in seizure frequency of more than 50%, including 26 (59.1%) with complete seizure control who were classified as the responder group. The remaining 14 (31.8%) were classified as the non-responder group after 14 weeks of treatment. Twenty patients (45.5%, 20/44) remained seizure-free after 1 year of treatment. However, 10 patients (33.3%, 10/30) in the responder group relapsed within a year. Improvements in electroencephalography (EEG) findings tended to be consistent with seizure outcomes. All patients had side effects of weight gain and Cushing's face, but most adverse effects were mild and transient., Conclusion: Long-term, high-dose steroid therapy can be considered an effective treatment option for children with intractable LGS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: This study aimed to assess the long-term outcomes of vagus nerve stimulation (VNS) in children with pharmaco-resistant Dravet syndrome (DS)., Methods: We enrolled 22 patients with pharmaco-resistant DS who underwent VNS implantation at Severance Children's Hospital from March 2005 to October 2020. Efficacy and tolerability were assessed at 3, 6, 12, 18, 24, 30, and 36 months after VNS implantation. Efficacy was measured as the percentage reduction in seizure frequency at each follow-up compared with the baseline (pre-implantation) values., Results: Median patient age at VNS implantation was 10.0 years (interquartile range 7.7-13.3). The median follow-up period was 4.3 years (interquartile range 3.0-6.5) after VNS implantation. All cases were followed up for ≥2 years after VNS implantation. Three (13.6 %) patients maintained seizure freedom for ≥1 year. Among them, one achieved seizure freedom after 30 months of VNS. More than 50 % reduction in seizure frequency was observed in 36.4 % (8/22), 54.5 % (12/22), and 63.2 % (12/19) of the patients at 12, 24, and 36 months, respectively. The median percent reduction in seizure frequency was 18.8 %, 50.6 %, and 60.0 % at 12, 24, and 36 months, respectively. Compared with the baseline value, the seizure frequency was significantly lower at 24, 30, and 36 months, as well as at the longest follow-up period (p < 0.05, Wilcoxon signed-rank test). The symptom that was mostly associated with adverse events was hoarseness (4/22, 18.2 %); however, they had temporary or minimal effects on activities of daily living., Conclusions: Our findings demonstrate that VNS therapy allows long-term, progressive, and time-dependent improvement in seizure control for pharmaco-resistant DS. Clinicians should be aware of the delayed VNS efficacy over the years and should encourage long-term VNS maintenance by patients., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2021 International League Against Epilepsy.)

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., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Purpose: New diagnostic criteria for pediatric autoimmune encephalitis (AIE) have been introduced recently. A substantial proportion of cases of pediatric AIE are diagnosed as seronegative based on these criteria, and so the clinical characteristics of this group remain to be investigated., Methods: This study included 46 pediatric patients younger than 18 years with suspected AIE. Clinical features, laboratory or radiological findings, and treatment outcomes were compared between seronegative and seropositive patients., Results: Nine (19.6%) of the 46 patients were diagnosed as seropositive AIE. All of the patients with seropositive AIE had anti-N-methyl-D-aspartate receptor antibodies. Commonly identified neuropsychiatric symptoms were altered mental status, cognitive dysfunction, seizure, speech dysfunction, and psychotic disorder in both the seronegative and seropositive groups. Immunotherapy produced favorable treatment outcomes in both the seropositive ( n =7, 77.8%) and seronegative ( n =35, 94.6%) AIE patients. Treatment outcomes for first-line immunotherapy were better in seronegative AIE than seropositive AIE patients ( p =0.003), and hence a smaller proportion of seronegative patients required second-line treatment ( p =0.015)., Conclusions: Pediatric seronegative AIE patients showed clinical presentations similar to those of seropositive AIE patients, with favorable treatment outcomes after immunotherapy., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2021 Korean Neurological Association.)

Purpose: KCNQ2 mutations are associated with benign familial neonatal epilepsy (BFNE) or developmental and epileptic encephalopathy (DEE). In this study, we aimed to delineate the phenotype of KCNQ2 encephalopathy and evaluate the treatment response., Methods: Thirteen patients of KCNQ2 encephalopathy were included in the study. Characteristics of KCNQ2 mutations, electroclinical features, clinical course, and response to the treatment were analyzed., Results: Age range of the thirteen patients was between 3 months and 20.9 years. The onset of seizures in 11 patients ranged from 1 to 3 days of age, while in the other two patients it was 7 and 40 days, respectively. Most common initial seizure types were tonic seizures. Initial EEGs were suppression burst pattern in seven patients and slow and disorganized background with multifocal epileptiform discharges in six patients. Initial epilepsy syndrome was Ohtahara syndrome in seven patients, neonatal focal seizure in five patients, and focal epilepsy beyond neonatal period in one patient. Sodium channel blockers including oxcarbazepine (OXC) (n = 3), lamotrigine (LTG) (n = 3), phenytoin (PHT) (n = 2), topiramate (TPM) (n = 2), and zonisamide (ZNS) (n = 1) were tried and found effective in eleven patients. Ultimately, 12 of 13 patients became seizure-free. However, developmental outcomes were poor., Conclusions: Sodium channel blockers are effective in seizure control in these patients with KCNQ2 encephalopathy. Early recognition of KCNQ2 encephalopathy and early use of sodium channel blockers might be helpful in seizure control., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

Purpose: The observation of mild malformation of cortical development (mMCD) has yet to have a major clinical impact due to the lack of clinical and research data. We characterized the clinical features, surgical outcomes, and postoperative seizure control patterns in pediatric patients with mMCD., Methods: We examined 40 patients with isolated mMCD who underwent resective surgery during a 10-year period., Results: The median age at seizure onset was 1.2 years, and the median age at surgery was 7.9 years. Twenty-seven patients (67.5%) presented with childhood-onset epileptic encephalopathy (21 Lennox-Gastaut syndrome, 6 West syndrome), and 13 patients (32.5%) presented with intractable focal epilepsy (10 extratemporal lesions, 3 temporal lesions). Twenty-one patients (52.5%) showed "suspected focal cortical malformation" on MRI, whereas 16 patients (40.0%) and 3 patients (7.5%) showed normal MRI findings or mild brain atrophy, respectively. The most common surgical procedures were two lobar resections (18 patients, 45.0%), followed by unilobar resections (12 patients, 30.0%) and resections exceeding two lobar boundaries (10 patients, 25.0%). As a final surgical outcome, 24 patients (60.0%) were ILAE Class 1-3. Discontinuation of all AEDs was possible for 36.8% of ILAE Class 1 patients. Regarding the seizure control pattern, fluctuating seizure control was observed most frequently (21 patients, 52.5%)., Conclusion: Our results suggest that mMCD is an important pathological finding in children related to a significant degree of epileptogenicity, and resective surgery can have positive outcomes. However, these patients showed unstable postoperative seizure control patterns with a high rate of late recurrence, suggesting difficulties in the surgical treatment of intractable epilepsy., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Aims: We aimed to delineate the phenotypic spectrum of SCN2A-related developmental and epileptic encephalopathy (DEE) and determine the effectiveness of various treatment modalities, including sodium channel blockers and the ketogenic diet., Methods: Eleven patients with SCN2A-related DEE were included in the study. The characteristics of SCN2A mutations, electroclinical features, clinical course, and response to treatment modalities were analysed., Results: The 11 patients were aged between 0.4 and 9.7 years. The onset of seizures ranged from neonate (six patients) to infant (four patients), to childhood (one patient). Epilepsy presented as Ohtahara syndrome, West syndrome, epilepsy of infancy with migrating focal seizures (EIMFS), and focal epilepsy in neonatal- to infantile-onset patients. The only childhood-onset patient in our study presented with focal epilepsy with autism. Neonatal-to infantile-onset patients had drug-resistant epilepsy (9/10), however, sodium channel blockers were effective in all treated patients (9/9). The ketogenic diet (6/8) and high-dose steroid treatment (4/5) were also effective. The seizures in the childhood-onset patient worsened during treatment with sodium channel blockers. All mutations in neonatal- to infantile-onset patients were missense mutations, whereas the mutation in the childhood-onset patient was a truncation mutation., Conclusions: These results support earlier observations regarding the epilepsy syndromes and response to antiepileptic drugs in patients with SCN2A-related DEE.

Objective: For epilepsy with tuberous sclerosis complex (TSC), ketogenic diet (KD) therapy has been consistently reported to be more beneficial than the average KD therapy response. Herein, we aimed to investigate the long-term outcomes of a KD on patients with TSC and intractable epilepsy., Methods: This study included 31 patients with intractable epilepsy and TSC who were treated with the KD, and an intention-to-treat analysis was performed., Results: Overall, 21 of the 31 patients (67.7%) had >50% reduction in seizures at 3 months after initiating the KD. Thirteen of the 31 patients (41.9%) were seizure-free for at least 3 months, but 10 of these 13 patients (76.9%) experienced seizure recurrence during the 24-month follow-up period. Finally, at 24 months of the KD observational period, there was >50% response in 10 of the 31 patients (32.3%), including seizure-free patients (6 of 31 patients, 19.4%). Most of the patients (12 of 13, 92.3%) who experienced seizure freedom had >50% reduction in seizures within 1 month after initiating the KD, and this result was the only factor associated with seizure freedom in the current study., Conclusion: The KD appeared to be an effective therapeutic modality for intractable pediatric epilepsy in TSC, but it did not exhibit guaranteed efficacy over a long-term period., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose relevant to this article., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Early-onset epileptic encephalopathies with burst suppression (EOEE-BS) are a group of neonatal epileptic syndromes characterized by intractable epilepsy and severe psychomotor delay with structural and metabolic factors accounting for major etiologies. However, recent advances in gene sequencing have identified that genetic factors might also play a significant role in the development of EOEE-BS. Herein, we used various genetic tests to identify pathogenic genetic variants in EOEE-BS irrespective of structural malformations and analyzed the clinical features associated with each different etiology., Methods: A total of 48 patients with EOEE-BS were included. Except for patients with severe hypoxic damage, patients with structural malformations were included in our patient cohort. Clinical features of the patients were reviewed, and etiological diagnoses were made based on several genetic tests, metabolic studies, and radiological findings., Result: A genetic diagnosis was made in 31 (64.6 %) patients, with the most commonly diagnosed gene being STXBP1 (n = 13, 27.1 %), followed by KCNQ2 (n = 5, 10.4 %), SCN2A (n = 5, 10.4 %), DEPDC5 (n = 3, 6.3 %), CASK (n = 1, 2.1 %), CDKL5 (n = 1, 2.1 %), GNAO1 (n = 1, 2.1 %), SLC6A8 (n = 1, 2.1 %), and LIS1 deletion (n = 1, 2.1 %). Other than the classification of epilepsy syndrome, no clinical features were associated with the genetically diagnosed group. Among eight patients with structural malformations, genetic diagnosis was achieved in five (62.5 %), and those patients had pathogenic mutations in DEPDC5 and CASK or LIS1 deletion, indicating the significance of gene sequencing irrespective of structural abnormalities. Treatment responses to a variety of medications and the ketogenic diet differed by etiology, and surgical resection proved to be effective in patients with cortical dysplasia., Conclusion: Genetic etiologies are an important factor in EOEE-BS irrespective of structural malformations and the treatment options may differ by etiology., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Vagus nerve stimulation (VNS) is a nonpharmacologic therapeutic option for patients who have pharmaco-resistant Dravet syndrome (DS). Plentiful efforts have been made for delivering VNS to DS patients, but its effectiveness still requires further verification. We investigated the effectiveness of the VNS treatment of DS patients using brain connectivity analysis with electroencephalography (EEG)., Approach: Twenty pharmaco-resistant DS patients were selected to undergo VNS implantation and classified into responder and non-responder groups after 24 months post-VNS. The effect of VNS between 6 months pre- and 6, 12, and 24 months post-VNS in all patients, responders, and non-responders on four different frequency categories of four brain parameters were compared using resting-state EEG., Main Results: In alpha and beta bands, all patients showed positive results for characteristic path length (CPL), global efficiency (GE), and transitivity after VNS treatment, and changes in betweenness centrality (BC) were not significant. The difference in transitivity between responders and non-responders is more pronounced than those in CPL and GE are, in both the alpha (p < 0.015) and beta (p < 0.001) bands. There was an obvious change in BC, especially in the alpha band, as the hubs tended to move from frontal lobe to parietal lobe for responders; however, there was no change for the non-responders., Significance: We investigated the alteration in brain connectivity of DS patients in alpha and beta bands during a long-term follow-up and found the responders have a decreased transitivity after the VNS treatment. Moreover, the hubs with high values in the alpha band tended to move from frontal lobe to parietal lobe for responders after VNS treatment.

Background: Early-onset developmental and epileptic encephalopathy (DEE) is characterized by repeated seizures beginning within 3 months of birth and severe interictal epileptiform discharge, including burst suppression. This study assessed the utility of targeted gene panel sequencing in the genetic diagnosis of this disease., Materials and Methods: Targeted gene panel sequencing was performed in 150 early infantile-onset DEE patients (≤3 months of age), and we extensively reviewed their clinical characteristics, including therapeutic efficacy, according to genotype., Results: Of the early infantile-onset DEE patients, 70 were neonatal-onset DEE and the other 80 patients began experiencing seizures from 1 to 3 months after birth. There were 11 different pathogenic or likely pathogenic variants among 34.7% (52/150) of patients with early infantile-onset DEE, in whom KCNQ2, STXBP1, CDKL5, and SCN1A were the major pathogenic variants. Among the neonatal-onset DEE patients, pathological genes were identified in 42.9% (30/70), indicating a significantly higher diagnostic yield than in 27.5% (22/80) of patients who experienced seizure onset 1 to 3 months after birth (p = 0.048). Among the neonatal-onset DEE group, variants in KCNQ2, STXBP1, and CDKL5 were detected at high frequencies, accounting for 66.7% (20/30) of the pathogenic or likely pathogenic variants found in this study., Conclusion: Targeted gene panel sequencing demonstrated a high yield of pathogenic variants in the diagnosis of early-onset epileptic encephalopathy, especially in those with neonatal-onset DEE. Early diagnosis of early-onset epileptic encephalopathy may improve the prognosis of patients by earlier selection of appropriate treatment based on pathogenic variant., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background: Lennox-Gastaut syndrome (LGS) is a typical intractable form of epilepsy that most often occurs between the second and sixth year of life. This study aimed to evaluate the clinical efficacy and safety of ketogenic diet therapies (DTs) for LGS with mitochondrial dysfunction., Methods: This was a retrospective study involving 20 LGS patients with mitochondrial dysfunction who received several DTs from 2004 to 2014 at a single tertiary care center. Seizure reduction rate, cognitive function, retention rate, electroencephalography (EEG) changes, and adverse effects were examined before and after DTs., Results: The retention rates at 1 and 2 years after initiation of DTs were 45% and 40%, respectively. After 1-year follow up, we observed seizure freedom in two patients, 75% seizure reduction in two patients, 50% reduction in three patients, and 25% reduction in one patient. After 2-year follow up, the outcomes were seizure freedom in two patients, 90% seizure reduction in one patient, 75% reduction in two patients, and 50% reduction in two patients. EEG findings improved in nine patients. Nine patients were treated with DTs for 1 year; all patients demonstrated improved cognitive status. Eight patients were treated with DTs for 2 years, of whom seven had improved cognitive status. Poor tolerability of DTs was due to poor oral intake and gastrointestinal problems., Conclusions: We demonstrate that, in LGS with mitochondrial dysfunction, improvement of seizures and cognitive function are not inferior to those in other patients treated with DTs. This study showed that DTs are efficacious and feasible for LGS patients with mitochondrial dysfunction and can significantly improve their prognosis., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Background: Malformations of cortical development comprise phenotypically heterogeneous conditions, and the diagnostic value of genetic testing in blood still remains to be elucidated. We used targeted gene sequencing to identify malformations of cortical development caused by germline mutations and characteristics associated with pathogenic mutations., Methods: A total of 81 patients with malformations of cortical development were included. Genomic DNA was isolated from peripheral blood. Ninety-six genes were assessed using a targeted next-generation sequencing panel. Single-nucleotide variants and exonic and chromosomal copy number variations were examined with our customized pipeline., Results: Genetic causes were identified from blood in 19 (23.5%) patients with malformations of cortical development; 14 patients had pathogenic or likely pathogenic single-nucleotide variants in seven genes, including DCX (n = 5), DEPDC5 (n = 2), PAFAH1B1 (n = 3), TUBA1A (n = 1), TUBA8 (n = 1), TUBB2B (n = 1), and TUBB3 (n = 1). Five patients had pathogenic copy number variations. Multifocal involvement of the lesion (tangential distribution, P < 0.001) and concurrent involvement of multiple structures such as the cortex, white matter, and ventricle (radial distribution, P = 0.003) were more commonly found in patients with identified genetic causes. Intellectual disability was also more commonly associated with pathogenic mutations (P = 0.048). In a multivariable regression analysis, both tangential and radial radiological distribution of malformations of cortical development were independently associated with positive germline test results., Conclusion: We identified germline mutations in almost one-fourth of our patients with malformations of cortical development by using targeted gene sequencing. Germline abnormalities were more likely found in patients who had multifocal malformations of cortical development., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Surgery has been and is now a well-established treatment indicated for adults and children with drug-resistant epilepsy (DRE). The surgical landscape for children with DRE appears to be expanding, and surgical cases of pediatric epilepsy have increased significantly in the past decade, contrary to adult epilepsy. Several fundamental changes have led to the widespread surgical treatment for DRE in children, based on a risk-benefit analysis of pediatric epilepsy surgery, and a change in our overall approach to evaluation. There are unique and age-related differences associated with pediatric epilepsy surgery, characterized by different types of etiologies, concerns for developmental progress, and safety issues. Indications for "pediatric epilepsy surgery" have been broadened to include a wide spectrum of etiologies without excluding children with "generalized" seizures, "generalized or multifocal eletroencephlography", or patients with contra-lateral epileptiform activity or magnetic resonance imaging abnormalities. Furthermore, epilepsy surgery is increasingly considered in infancy and early childhood, which has similar surgical outcomes as the case of late childhood, in an effort to improve the eventual development outcome. Seizure freedom, or at least seizure reduction, is an excellent result with resolution of the associated epileptic encephalopathy, normalization of the EEG, and decrease in the total epileptic burden in the pediatric field., (Copyright © 2019 Korean Epilepsy Society.)

Objective: We aim to delineate the genetic and clinical features of SCN8A developmental and epileptic encephalopathy., Methods: Nine patients with SCN8A developmental and epileptic encephalopathy were included in this study. Genetic and clinical features and effectiveness of sodium channel blockers were assessed in patients who were confirmed with SCN8A mutations., Results: The onset of seizures ranged from the neonatal period to 18 months of age. Seizure types were diverse and predominantly involved focal seizures or spasms. The most common initial epilepsy syndrome was West syndrome in four patients, followed by neonatal-onset focal seizures in three patients and unclassified focal epilepsy in two patients. Electroencephalograms (EEGs) showed slow and disorganized background and epileptiform abnormalities with occipital predominance. Six patients presented intractable seizures including one patient with recurrent nonconvulsive status epilepticus. Sodium channel blockers were effective in seven patients among eight patients given them. All patients showed developmental delay or regression. Severe hypotonia or ataxia was also presented in some patients. Microcephaly was also characteristic. De novo missense mutations in SCN8A were found in the inactivation gate, C-terminal, loop 2, and transmembrane segments (S1, 4, 5, and 6). There was no correlation between the location of the mutation in the protein and phenotype or response to sodium channel blockers., Conclusion: SCN8A developmental and epileptic encephalopathy presents intractable seizures including spasms, focal seizures, neonatal status epilepticus, and nonconvulsive status epilepticus. Sodium channel blockers were effective irrelevant to the location of the mutation in the protein., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.

Hormone therapies and vigabatrin are first-line agents in infantile spasms, but more than one-third of patients fail to respond to these treatments. This was a retrospective study of patients with infantile spasms who were treated between January 2005 and December 2017. We analyzed the response rates of initial treatment and second-line treatment. Responders were defined as those in whom cessation of spasms was observed for a period of at least one month, within 2 weeks of treatment initiation. Regarding the response rate to initial treatment, combination therapy of vigabatrin with prednisolone showed a significantly better response than that of vigabatrin monotherapy (55.3% vs. 39.1%, p = 0.037). Many drugs, such as clobazam, topiramate, and levetiracetam, were used as second-line agents after the failure of vigabatrin. Among these, no antiepileptic drug showed as good a response as prednisolone. For patients who used prednisolone, the proportion of responders was significantly higher in the higher-dose group (≥40 mg/day) than in the lower-dose group (66.7% vs. 12.5%, p = 0.028). Further studies of combination therapy to assess dosage protocols and long-term outcomes are needed., Competing Interests: The authors declare no conflict of interest.

Purpose: It is important to determine whether specific etiology is more effective to dietary treatment so that the diet can be started earlier for infants. We evaluated etiology-specific, seizure-free outcomes of dietary treatment in infants <1 year of age., Methods: We conducted a 10-year, retrospective, longitudinal observational study of 115 infants treated with ketogenic diet (KD) or modified Atkins diet (MAD)., Results: Most patients (70%) received classical KD; 30% received MAD. During follow-up, 90%, 73%, and 61% of the patients remained on the diet at 3, 6, and 12 months, respectively. Seizure-free outcomes were reported in 50%, 44%, and 50% of the patients at 3, 6, and 12 months, respectively. Long-term seizure-free outcomes over 12 months were reported in 43 (74%) of 58 infants who were seizure-free at 3 months. Etiologies were mostly symptomatic (structural brain abnormalities, genetic, or metabolic) in 83 (72%) of 115 patients. According to underlying etiology, long-term seizure-free outcomes were observed in 14 (33%) of 42 patients with structural brain abnormalities, 7 (33%) of 21 with genetic etiologies, 7 (35%) of 20 with metabolic etiologies, and 15 (47%) of 32 with unknown etiologies. There were no etiology-based differences with respect to long-term seizure-free outcomes (P = 0.63)., Conclusion: The high rate of long-term seizure-free outcomes can be predicted based on the seizure freedom at 3 months regardless of etiology. Early dietary treatment is beneficial, even in infants <1 year of age with specific symptomatic etiologies such as genetic, structural brain abnormalities, and metabolic etiology., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Whole exome sequencing on family trios gives the highest diagnostic yield, but high cost limits its application. Here, we performed proband-only clinical exome sequencing in a population of patients with neurodevelopmental disabilities and tested the diagnostic yield., Methods: This observational, retrospective study included 108 unrelated patients with neurodevelopmental disabilities who underwent clinical exome sequencing at the outpatient clinics of the Severance Children's Hospital, Seoul, South Korea, between March 2017 and May 2018. Clinical exome sequencing targeted 4503 disease-causing genes., Results: The overall diagnostic rate was 38.0% (41 of 108) when proband-only clinical exome sequencing was performed without additional parental testing. Four sequence variants were reclassified as likely pathogenic after parental testing, representing an additional 3.7% of the diagnostic yield. The final diagnostic rate was 41.7% (45 of 108). Of 45 patients with genetic abnormalities, a total of 38 sequence variations were detected in 33 (30.6%) patients with five homozygous cases, and 13 chromosomal copy number variants were detected in 12 (11.1%) patients. Novel variants of known causal genes for neurodevelopmental disabilities were detected in 18 (16.7%) patients. These were variants that could be reclassified as likely pathogenic if the de novo nature of the mutation was confirmed after testing of parental samples., Conclusions: Proband-only clinical exome sequencing is a practical diagnostic tool that may be implemented in the clinical setting for patients with neurodevelopmental disabilities. A cost-effective approach to neurodevelopmental disabilities would be a proband-only clinical exome sequencing followed by parental testing of selective candidate variants., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Low-grade epilepsy-associated tumors (LEATs) are associated with childhood seizures that are typically drug-resistant, necessitating surgical interventions. In this study, we aimed to investigate the efficacy of surgical intervention in children with LEATs and to identify factors associated with seizure and cognitive outcomes., Methods: We reviewed 58 children less than 18 years of age who underwent epilepsy surgery due to histopathologically confirmed LEATs and had a minimum postoperative follow-up duration of 24 months., Results: Of the 58 patients who were followed for a median duration of 5.6 (IQR 3.2 to 10.0) years, 51 (87.9%) were seizure-free after surgery. In univariate analysis, shorter epilepsy duration, fewer antiepileptic drugs at time of surgery, gross total resection, and unilobar tumor involvement were associated with seizure freedom. In multivariate analysis, gross total resection was independently associated with seizure freedom. The preoperative and postoperative full-scale intelligence quotient (FSIQ) scores were 78.9 ± 27.1 and 80.9 ± 28.7, respectively. In univariate analysis, younger age at seizure onset, longer epilepsy duration, more antiepileptic drugs at time of surgery, multilobar tumor involvement, and presence of generalized epileptic discharges were associated with lower preoperative FSIQ. In multivariate analysis, longer epilepsy duration was independently associated with lower preoperative FSIQ scores. Postoperative FSIQ scores were significantly influenced by preoperative FSIQ scores., Conclusions: Epilepsy surgery for LEATs in children resulted in excellent seizure outcome. Gross total resection was the only independent factor associated with favorable seizure outcome. Preoperative and postoperative cognitive abilities were significantly influenced by epilepsy duration, so early surgical intervention should be considered., (Copyright © 2018. Published by Elsevier Inc.)

Objective: To identify whether somatic mutations in SLC35A2 alter N-glycan structures in human brain tissues and cause nonlesional focal epilepsy (NLFE) or mild malformation of cortical development (mMCD)., Methods: Deep whole exome and targeted sequencing analyses were conducted for matched brain and blood tissues from patients with intractable NLFE and patients with mMCD who are negative for mutations in mTOR pathway genes. Furthermore, tissue glyco-capture and nanoLC/mass spectrometry analysis were performed to examine N-glycosylation in affected brain tissue., Results: Six of the 31 (19.3%) study patients exhibited brain-only mutations in SLC35A2 (mostly nonsense and splicing site mutations) encoding a uridine diphosphate (UDP)-galactose transporter. Glycome analysis revealed the presence of an aberrant N-glycan series, including high degrees of N-acetylglucosamine, in brain tissues with SLC35A2 mutations., Conclusion: Our study suggests that brain somatic mutations in SLC35A2 cause intractable focal epilepsy with NLFE or mMCD via aberrant N-glycosylation in the affected brain.

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., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Purpose: The treatment options for Lennox-Gastaut syndrome (LGS), a pediatric epileptic syndrome, are limited, especially in younger children. Rufinamide tablets were safe and effective as an add-on treatment in Korean children and adolescents <20 years of age with LGS. This subgroup analysis aimed to evaluate the efficacy and safety of rufinamide tablets in LGS pediatric patients aged 1-4 years., Methods: This was a retrospective, observational study in LGS patients aged 1-4 years who received 12 weeks of treatment with rufinamide orally as an adjuvant treatment between April and June 2010. The proportion of responders (patients with a ≥50% reduction in seizure frequency after rufinamide treatment) was evaluated according to the type of seizure. The proportion of patients who were seizure-free was also evaluated. Adverse events (AEs) were evaluated after 12 weeks of treatment., Results: Among the 15 patients evaluated, one discontinued treatment because of worsening seizures 4 weeks after administration of rufinamide. Seven (46.67%) patients were responders and four patients were seizure-free. There were four responders with convulsive seizures, one each for myoclonic seizures and drop attacks, and spasms. The responder rate was increased to 69.23% by long-term treatment of rufinamide. AEs were experienced by three patients. One patient each experienced somnolence, fatigue, and rash., Conclusion: Rufinamide tablets were efficacious and well tolerated in LGS patients aged 1-4 years, at doses up to 1000 mg per day, when given as add-on therapy to other antiepileptic drugs., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: We aimed to evaluate the long-term outcome of resective epilepsy surgery in patients with Lennox-Gastaut syndrome (LGS)., Methods: We reviewed the case reports of 90 patients with LGS who had undergone resective surgery between 2003 and 2014 at the Severance Children's Hospital and managed them for a minimum period of 2 years., Results: At the time of surgery, the patients were between 3.0 and 23.5 years old (mean ± SD: 9.3 ± 4.4). The time from seizure onset to surgery ranged from 0.7 to 20.1 years (7.2 ± 4.3). On postoperative follow-up for an average period of 6.1 ± 2.2 years (range: 2.1-11.4 years), 45 patients (50.0%) had no seizures, and 15 (16.7%) reported infrequent seizures. Seizure-free outcomes were achieved in 15 of the 21 (71.4%) hemispherectomies, 23 of the 51 (45.1%) multilobar resections, and 7 of the 18 (38.9%) single lobar resections. On high-resolution MRIs, 20 patients (22.2%) had negative findings, 8 of whom (40.0%) became seizure-free after resective surgery. Malformation of cortical development was the most common pathologic finding and was noted in 57 patients (63.3%). Seizure-free patients achieved better adaptive behavior and social competence than did patients with persistent seizures at the second (2-3 years after surgery) and third (4-6 years after surgery) follow-ups, as indicated by social quotients ( P < .05)., Conclusions: Resective surgery is a viable option in some patients to treat seizures that are associated with LGS, with a high probability of seizure control and better adaptive function., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Objective: Hormonal therapy and vigabatrin are now accepted as the first-line or standard therapies for West syndrome (WS). However, the superiority of these drugs in terms of monotherapy or combination therapy is still in question. In this study, we designed a treatment protocol for WS and prospectively assessed the efficacy of these therapies in controlling spasms, stabilizing electroencephalography (EEG), and allowing for developmental catch-up., Methods: In patients diagnosed with WS, vigabatrin was first administered alone for 2 weeks, and then prednisolone was administered in combination with vigabatrin if patients did not respond to vigabatrin. The detailed drug administration protocol was as follows: vigabatrin 50 mg/kg/day for 1 day, followed by vigabatrin 100 mg/kg/day for 3 days, vigabatrin 150 mg/kg/day if spasms were still present or the burden of amplitudes and epileptiform discharges (BASED) score on EEG was ≥3 on day 5; 40 mg/day of prednisolone was added if spasms were still present or the BASED score was ≥3 on day 14. The prednisolone dose was increased to 60 mg/day if spasms were still present or the BASED score was ≥3 on day 21., Results: Sixty-six patients newly diagnosed with WS (median seizure onset age: 5.7 [IQR, 4.1-7.1] months, median age at diagnosis: 6.6 [IQR, 5.4-8.1] months, n = 40 [60.6%] boys) were subjected to the vigabatrin and prednisolone therapy protocol. Of the 66 patients, 22 (33.3%) patients showed resolution of spasms and a BASED score of ≤2 after vigabatrin alone, and 26 (39.4%) patients showed resolution of spasms and a BASED score of ≤2 after a combination of vigabatrin and prednisolone, for a total of 48 (72.7%) patients who were responsive to the protocol without relapse for at least 7 months after WS diagnosis. The mental and psychomotor age quotients were higher at the time of diagnosis and remained significantly higher 6 months after the diagnosis in responsive patients (p <  0.001). No serious adverse reactions leading to discontinuation or reduction of drug doses were observed., Conclusion: Using a treatment protocol involving vigabatrin and prednisolone for WS, 72.7% of patients showed resolution of spasms and a BASED score of ≤2. This study also found that this drug administration protocol was safe. However, further studies are warranted as this study describes results from observational study with limited sample size., (Copyright © 2018 Elsevier B.V. All rights reserved.)