Unusual Voltage-Gated Sodium and Potassium Channelopathies Related to Epilepsy.

BACKGROUND AND PURPOSE: There is extensive literature on monogenic epilepsies caused by mutations in familiar channelopathy genes such as SCN1A. However, information on other less-common channelopathy genes is scarce. This study aimed to explore the genetic and clinical characteristics of patients diagnosed with unusual voltage-gated sodium and potassium channelopathies related to epilepsy. METHODS: This observational, retrospective study analyzed pediatric patients with epilepsy who carried pathogenic variants of unusual voltage-gated sodium and potassium channelopathy genes responsible for seizure-associated phenotypes. Targeted next-generation sequencing (NGS) panel tests were performed between November 2016 and June 2022 at Severance Children's Hospital, Seoul, South Korea. Clinical characteristics and the treatment responses to different types of antiseizure medications were further analyzed according to different types of gene mutation. RESULTS: This study included 15 patients with the following unusual voltage-gated sodium and potassium channelopathy genes: SCN3A (n=1), SCN4A (n=1), KCNA1 (n=1), KCNA2 (n=4), KCNB1 (n=6), KCNC1 (n=1), and KCNMA1 (n=1). NGS-based genetic testing identified 13 missense mutations (87%), 1 splice-site variant (7%), and 1 copy-number variant (7%). Developmental and epileptic encephalopathy was diagnosed in nine (60%) patients. Seizure freedom was eventually achieved in eight (53%) patients, whereas seizures persisted in seven (47%) patients. CONCLUSIONS: Our findings broaden the genotypic and phenotypic spectra of less-common voltage-gated sodium and potassium channelopathies associated with epilepsy.

Senescent Astrocytes Derived from Human Pluripotent Stem Cells Reveal Age-Related Changes and Implications for Neurodegeneration.

Astrocytes play a crucial role in maintaining brain homeostasis by regulating synaptic activity, providing metabolic support to neurons, and modulating immune responses in the central nervous system (CNS). During aging, astrocytes undergo senescence with various changes that affect their function and frequently lead to neurodegeneration. This study presents the first evidence of senescent astrocytes derived from human pluripotent stem cells (hPSCs). These senescent hPSC-derived astrocytes exhibited altered cellular and nuclear morphologies, along with increased expression of senescence-associated markers. Additionally, nuclear localization of NFκB, telomere shortening, and frequent signs of DNA damage were observed in these cells. Furthermore, senescent astrocytes showed defects in various critical functions necessary for maintaining a healthy CNS environment, including a reduced ability to support neuronal survival and clear neurotransmitters, synaptic debris, and toxic protein aggregates. Altered structural dynamics and reduced mitochondrial function were also observed in senescent astrocytes. Notably, treating hPSC-derived senescent astrocytes with chemicals targeting reactive oxygen species or an enzyme that regulates mitochondrial function can reverse senescence phenotypes. Thus, this study offers a valuable cellular model that can be utilized to investigate the mechanisms of brain aging and may present new avenues for discovering innovative therapeutic approaches for neurodegenerative diseases.

Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy.

Somatic mosaicism in a fraction of brain cells causes neurodevelopmental disorders, including childhood intractable epilepsy. However, the threshold for somatic mosaicism leading to brain dysfunction is unknown. In this study, we induced various mosaic burdens in focal cortical dysplasia type II (FCD II) mice, featuring mTOR somatic mosaicism and spontaneous behavioral seizures. The mosaic burdens ranged from approximately 1,000 to 40,000 neurons expressing the mTOR mutant in the somatosensory (SSC) or medial prefrontal (PFC) cortex. Surprisingly, approximately 8,000 to 9,000 neurons expressing the MTOR mutant, which are extrapolated to constitute 0.08-0.09% of total cells or roughly 0.04% of variant allele frequency (VAF) in the mouse hemicortex, were sufficient to trigger epileptic seizures. The mutational burden was correlated with seizure frequency and onset, with a higher tendency for electrographic inter-ictal spikes and beta- and gamma-frequency oscillations in FCD II mice exceeding the threshold. Moreover, mutation-negative FCD II patients in deep sequencing of their bulky brain tissues revealed somatic mosaicism of the mTOR pathway genes as low as 0.07% in resected brain tissues through ultra-deep targeted sequencing (up to 20 million reads). Thus, our study suggests that extremely low levels of somatic mosaicism can contribute to brain dysfunction.

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.

A computational clinical decision-supporting system to suggest effective anti-epileptic drugs for pediatric epilepsy patients based on deep learning models using patient's medical history.

BACKGROUND: Epilepsy, a chronic brain disorder characterized by abnormal brain activity that causes seizures and other symptoms, is typically treated using anti-epileptic drugs (AEDs) as the first-line therapy. However, due to the variations in their modes of action, identification of effective AEDs often relies on ad hoc trials, which is particularly challenging for pediatric patients. Thus, there is significant value in computational methods capable of assisting in the selection of AEDs, aiming to minimize unnecessary medication and improve treatment efficacy. RESULTS: In this study, we collected 7,507 medical records from 1,000 pediatric epilepsy patients and developed a computational clinical decision-supporting system for AED selection. This system leverages three multi-channel convolutional neural network (CNN) models tailored to three specific AEDs (vigabatrin, prednisolone, and clobazam). Each CNN model predicts whether a respective AED is effective on a given patient or not. The CNN models showed AUROCs of 0.90, 0.80, and 0.92 in 10-fold cross-validation, respectively. Evaluation on a hold-out test dataset further revealed positive predictive values (PPVs) of 0.92, 0.97, and 0.91 for the three respective CNN models, representing that suggested AEDs by our models would be effective in controlling epilepsy with a high accuracy and thereby reducing unnecessary medications for pediatric patients. CONCLUSION: Our CNN models in the system demonstrated high PPVs for the three AEDs, which signifies the potential of our approach to support the clinical decision-making by assisting doctors in recommending effective AEDs within the three AEDs for patients based on their medical history. This would result in a reduction in the number of unnecessary ad hoc attempts to find an effective AED for pediatric epilepsy patients.

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.

Aetiology and Prognosis of Encephalitis in Korean Children: A Retrospective Single-Centre Study, 2005-2020.

PURPOSE: Encephalitis is a heterogeneous syndrome that occurs in childhood and is not rare. However, epidemiological studies of encephalitis based on the International Encephalitis Consortium (ICS) and expert recommendations are lacking. We investigated the aetiology and prognosis of encephalitis in Korean children. MATERIALS AND METHODS: This retrospective study included children aged <19 years hospitalised for encephalitis at Severance Children's Hospital between 2005 and 2020. The 2013 ICS criteria were used to diagnose encephalitis, and causality was classified according to the site from which the specimen was obtained. Neurological sequelae were categorised using the modified Rankin Scale (mRS) score. RESULTS: In total, 551 children were included, with 7% classified as possible, 77% as probable, and 15% as proven cases. A cause was identified in 42% of the cases (n=222), with viruses being the most common (42%), followed by bacteria (38%) and autoimmune encephalitis (12%). In cases of proven/probable encephalitis (n=65), bacteria accounted for 52%, followed by viruses (25%) and autoimmune encephalitis (22%). In cases with a single pathogen, the anti-N-methyl-D-aspartate receptor autoantibody (n=14) was the most common, followed by Group B streptococcus (n=13), herpes simplex virus (n=11), enterovirus (n=4), and others. Approximately 37% of patients had severe sequelae (mRS score ≥3) at discharge, which decreased to 31% 6 months after discharge. CONCLUSION: This large-scale study showed that autoimmune and infectious causes accounted for a significant proportion of encephalitis in Korean children. Further studies are needed to determine whether early targeted treatment following early diagnosis leads to a favourable prognosis in these populations.

Common genes and recurrent causative variants in 957 Asian patients with pediatric epilepsy.

OBJECTIVE: We aimed to identify common genes and recurrent causative variants in a large group of Asian patients with different epilepsy syndromes and subgroups. METHODS: Patients with unexplained pediatric-onset epilepsy were identified from the in-house Severance Neurodevelopmental Disorders and Epilepsy Database. All patients underwent either exome sequencing or multigene panels from January 2017 to December 2019, at Severance Children's Hospital in Korea. Clinical data were extracted from the medical records. RESULTS: Of the 957 patients studied, 947 (99.0%) were Korean and 570 were male (59.6%). The median age at testing was 4.91 years (interquartile range, 1.53-9.39). The overall diagnostic yield was 32.4% (310/957). Clinical exome sequencing yielded a diagnostic rate of 36.9% (134/363), whereas the epilepsy panel yielded a diagnostic rate of 29.9% (170/569). Diagnostic yield differed across epilepsy syndromes. It was high in Dravet syndrome (87.2%, 41/47) and early infantile developmental epileptic encephalopathy (60.7%, 17/28), but low in West syndrome (21.8%, 34/156) and myoclonic-atonic epilepsy (4.8%, 1/21). The most frequently implicated genes were SCN1A (n = 49), STXBP1 (n = 15), SCN2A (n = 14), KCNQ2 (n = 13), CDKL5 (n = 11), CHD2 (n = 9), SLC2A1 (n = 9), PCDH19 (n = 8), MECP2 (n = 6), SCN8A (n = 6), and PRRT2 (n = 5). The recurrent genetic abnormalities included 15q11.2 deletion/duplication (n = 9), Xq28 duplication (n = 5), PRRT2 deletion (n = 4), MECP2 duplication (n = 3), SCN1A, c.2556+3A>T (n = 3), and 2q24.3 deletion (n = 3). SIGNIFICANCE: Here we present the results of a large-scale study conducted in East Asia, where we identified several common genes and recurrent variants that varied depending on specific epilepsy syndromes. The overall genetic landscape of the Asian population aligns with findings from other populations of varying ethnicities.

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.

A machine learning-based quantitative model (LogBB_Pred) to predict the blood-brain barrier permeability (logBB value) of drug compounds.

MOTIVATION: Efficient assessment of the blood-brain barrier (BBB) penetration ability of a drug compound is one of the major hurdles in central nervous system drug discovery since experimental methods are costly and time-consuming. To advance and elevate the success rate of neurotherapeutic drug discovery, it is essential to develop an accurate computational quantitative model to determine the absolute logBB value (a logarithmic ratio of the concentration of a drug in the brain to its concentration in the blood) of a drug candidate. RESULTS: Here, we developed a quantitative model (LogBB_Pred) capable of predicting a logBB value of a query compound. The model achieved an R2 of 0.61 on an independent test dataset and outperformed other publicly available quantitative models. When compared with the available qualitative (classification) models that only classified whether a compound is BBB-permeable or not, our model achieved the same accuracy (0.85) with the best qualitative model and far-outperformed other qualitative models (accuracies between 0.64 and 0.70). For further evaluation, our model, quantitative models, and the qualitative models were evaluated on a real-world central nervous system drug screening library. Our model showed an accuracy of 0.97 while the other models showed an accuracy in the range of 0.29-0.83. Consequently, our model can accurately classify BBB-permeable compounds as well as predict the absolute logBB values of drug candidates. AVAILABILITY AND IMPLEMENTATION: Web server is freely available on the web at http://ssbio.cau.ac.kr/software/logbb_pred/. The data used in this study are available to download at http://ssbio.cau.ac.kr/software/logbb_pred/dataset.zip.

Social Stigma and Discrimination Toward People With Drug Addiction: A National Survey in Korea.

OBJECTIVE: This study aims to understand the attitudes, stigma, and discrimination of the general adult population toward drug addiction. METHODS: We conducted a cross-sectional nationwide survey with 1,020 Korean adults using an Internet web-based panel. Self-reported data were collected on demographics, experience with substance abuse, perceptions of narcotic analgesic use, beliefs about the legalization of cannabis use, coping with substance abuse and addiction, and perceptions of drug risks. All statistical analysis in this study utilized the IBM SPSS Statistics 26 program. RESULTS: In this study, 1.6% of the participants reported abuse of opioid analgesics, 88.0% reported negative perceptions of drug addiction, and 76.9% reported agreeing to unfair treatment of drug addicts. Logistic regression analysis found that perceived stigma was more prevalent among women (odd ratio [OR]=2.087, p<0.01), old adults (OR=1.939, p<0.01), those with no personal experience of opioid misuse (OR=8.172, p<0.05), and those who were non-smoking (OR=2.011, p<0.01). In addition, the discriminatory attitude was more prevalent among participants with higher income (OR=1.989, p<0.001) and those who are non-smoking (OR=1.608, p<0.05). CONCLUSION: This study provides information and guidelines for public intervention in drug addiction by identifying factors influencing social stigma and discriminatory behaviors toward drug addiction. The findings suggest that education on drug addiction prevention for the general adult population is necessary, and this education should include knowledge on coping with drug addiction and reducing stigma and discrimination toward drug addicts.

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.

Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development.

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

A decrease in the incidence of encephalitis in South Korea during the COVID-19 pandemic: A nationwide study between 2010 and 2021.

Limited data are available on the impact of the coronavirus disease (COVID-19) pandemic on encephalitis. Therefore, we evaluated trends in encephalitis in South Korea between 2010 and 2021 using data from the National Health Insurance Service. During the pandemic (February 2020 to 2021), the monthly incidence of encephalitis declined by 0.027 per 100 000 population (95% confidence interval [CI]: -0.055 to 0.001, p = 0.062) compared to that before the pandemic. In subgroup analysis, the estimated coefficient for level change during the pandemic in the 0-4 and 5-9 years age groups were -2.050 (95% CI: -2.972 to -1.128, p < 0.001) and -0.813 (95% CI: -1.399 to -0.227, p = 0.008), respectively. The annual incidence of encephalitis during the pandemic period significantly decreased in the 0-4 and 5-9 years age groups (incidence rate ratio: 0.34 [p = 0.007] and 0.28 [p = 0.024], respectively). The intensive care unit admission rate (39.1% vs. 58.9%, p < 0.001) and cases of death (8.9% vs. 11.1%, p < 0.001) decreased significantly during the pandemic compared to the prepandemic. During the pandemic, the incidence of encephalitis decreased markedly in South Korea, particularly in children aged ≤9 years. In addition, there were changes in the clinical outcome of encephalitis during the COVID-19 pandemic.

Refractive Errors, Retinal Findings, and Genotype of Tuberous Sclerosis Complex: A Retrospective Cohort Study.

PURPOSE: To examine the refractive errors, retinal manifestations, and genotype in tuberous sclerosis complex (TSC) patients in a Korean population. MATERIALS AND METHODS: A total of 98 patients with TSC were enrolled in Severance Hospital for a retrospective cohort study. The number of retinal astrocytic hamartoma and retinal achromic patch within a patient, as well as the size, bilaterality, and morphological type were studied. In addition, the refractive status of patients and the comorbidity of intellectual disability and epilepsy were also examined. RESULTS: Retinal astrocytic hamartoma was found in 37 patients, and bilateral invasion was observed in 20 patients (54%). TSC1 mutation was associated with myopia (p=0.01), while TSC2 mutation was associated with emmetropia (p=0.01). Retinal astrocytic hamartoma was categorized into three morphological types and examined as follows: type I (87%), type II (35%), and type III (14%). Single invasion of retinal astrocytic hamartoma was identified in 32% of the patients, and multiple invasions in 68%. The TSC1/TSC2 detection rate was 91% (41/45). Among them, TSC1 variant was detected in 23 patients (54%), whereas TSC2 variant was detected in 18 patients (40%). The results showed that TSC2 mutations are correlated with a higher rate of retinal astrocytic hamartoma involvement (all p<0.05), and multiple and bilateral involvement of retinal hamartomas (all p<0.05). However, the size of retinal astrocytic hamartomas, comorbidity of epilepsy, or intellectual disability did not show correlation with the genetic variant. CONCLUSION: TSC1 variant patients were more myopic, while TSC2 variant patients showed association with more extensive involvement of retinal astrocytic hamartoma.