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.

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.

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.

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.

Population pharmacokinetics of everolimus in patients with seizures associated with focal cortical dysplasia.

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/m2 is needed in patients with BSA 0.5 m2, and a dose higher than 6 mg/m2 is needed in patients with BSA 0.7 m2. A dose of 4.5 mg/m2 is enough in the population with BSA higher than 1.5 m2 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.

Acute Necrotizing Myelitis Associated with COVID-19.

Acute ascending hemorrhagic longitudinally extensive transverse myelitis is a rare inflammatory demyelinating disorder, which invades several vertebral segments and progresses rapidly and manifests severe symptoms. We present a case of acute necrotizing myelitis associated with COVID-19 infection. A 10-year-old female, with no previous medical history and no prior administration of COVID-19 vaccination, contracted COVID-19 in early April 2022. Two weeks later, she suffered from severe posterior neck pain and also presented with motor weakness and numbness in both lower extremities, making it difficult to walk independently and spontaneously void urine. Initial spinal cord MR showed longitudinally segmental extensive T2 hyperintensities. Cerebrospinal fluid (CSF) analysis revealed elevated red blood cell, normal white blood cell, and elevated protein levels and absence of oligoclonal bands. CSF culture and viral polymerase chain reaction were negative. Autoimmune work-up was negative. She was started on intravenous methylprednisolone 1g/day for 5 days and immunoglobulin (Ig) 2 g/kg for 5 days. She was also treated with six courses of therapeutic plasma exchange. Nevertheless, her pain and motor weakness persisted. She eventually developed respiratory failure. Follow-up MR presented a newly noted small hemorrhagic component. She was consequently treated with two additional courses of methylprednisolone and Ig. At 6-months follow-up, neurological examination showed improvement with normal sensory function and motor grade IV function in both upper extremities. We present the case of acute necrotizing myelitis associated with COVID-19 infection. Multiple courses of methylprednisolone and Ig showed mild improvement in motor and sensory function. However, poor prognosis was unavoidable due to rapid progression of the disease.

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.

Surgical Treatment of Epilepsy with Bilateral MRI Abnormalities.

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.

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.

Detecting Low-Variant Allele Frequency Mosaic Pathogenic Variants of NF1, TSC2, and AKT3 Genes from Blood in Patients with Neurodevelopmental Disorders.

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.

Erratum: Effects of Cannabidiol on Adaptive Behavior and Quality of Life in Pediatric Patients With Treatment-Resistant Epilepsy.

This corrects the article on p. 547 in vol. 18, PMID: 36062772.

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.

Association of hypercalciuria with vitamin D supplementation in patients undergoing ketogenic dietary therapy.

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 D3 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-D3) 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-D3 (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-D3 level. Based on findings of receiver operating characteristic curve analysis and Youden's J statistic, the cut-off 25-OH-D3 level for preventing hypercalciuria was > 39.1 ng/mL at 6 months. Furthermore, the vitamin D3 supplementation dose cut-off was > 49.5 IU/kg for hypercalciuria prevention. Conclusion: An inverse relationship between Uca/Ucr ratio and 25-OH-D3 level was noted, which means that vitamin D supplementation is helpful for preventing hypercalciuria related to KDT. We suggest that the recommended 25-OH-D3 level is > 40 ng/mL for hypercalciuria prevention and that KDT for children with epilepsy can be optimized by vitamin D3 supplementation at 50 IU/kg.

Effects of Cannabidiol on Adaptive Behavior and Quality of Life in Pediatric Patients With Treatment-Resistant Epilepsy.

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.

Treatment strategies for Lennox-Gastaut syndrome: outcomes of multimodal treatment approaches.

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.

Effects of the ketogenic diet therapy in patients with STXBP1-related encephalopathy.

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.

Brain network analysis of interictal epileptiform discharges from ECoG to identify epileptogenic zone in pediatric patients with epilepsy and focal cortical dysplasia type II: A retrospective study.

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.

Effective application of corpus callosotomy in pediatric intractable epilepsy patients with mitochondrial dysfunction.

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.

Epidural grid, a new methodology of invasive intracranial EEG monitoring: A technical note and experience of a single center.

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.

Efficacy of the Ketogenic Diet for Pediatric Epilepsy According to the Presence of Detectable Somatic mTOR Pathway Mutations in the Brain.

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.