Clinical Applicability and Safety of Conventional Frame-Based Stereotactic Techniques for Stereoelectroencephalography.

Objective: Stereoelectroencephalography (SEEG) is increasingly being recognized as an important invasive modality for presurgical evaluation of epilepsy. This study focuses on the clinical and technical considerations of SEEG investigations when using conventional frame-based stereotaxy, drawing on institutional experience and a comprehensive review of relevant literature. Methods: This retrospective observational study encompassed the surgical implantation of 201 SEEG electrodes in 16 epilepsy patients using a frame-based stereotactic instrument at a single tertiary-level center. We provide detailed descriptions of the operative procedures and technical nuances for bilateral and multiple SEEG insertions, along with several illustrative cases. Additionally, we present a literature review on the technical aspects of the SEEG procedure, discussing its clinical implications and potential risks. Results: Frame-based SEEG electrode placements were successfully performed through sagittal arc application, with the majority (81.2%) of cases being bilateral and involving up to 18 electrodes in a single operation. The median skin-to-skin operation time was 162 minutes (interquartile range [IQR], 145-200), with a median of 13 minutes (IQR, 12-15) per electrode placement for time efficiency. There were two occurrences (1.0%) of electrode misplacement and one instance (0.5%) of a postoperative complication, which manifested as a delayed intraparenchymal hemorrhage. Following SEEG investigation, 11 patients proceeded with surgical intervention, resulting in favorable seizure outcomes for nine (81.8%) and complete remission for eight cases (72.7%). Conclusion: Conventional frame-based stereotactic techniques remain a reliable and effective option for bilateral and multiple SEEG electrode placements. While SEEG is a suitable approach for selected patients who are strong candidates for epilepsy surgery, it is important to remain vigilant concerning the potential risks of electrode misplacement and hemorrhagic complications.

Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma.

BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1manifestations (e.g., neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase 2 trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥ 3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hrs for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22±5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥ 20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSION: Selumetinib decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.

Severe Neurological Manifestation Associated With Coronavirus Disease 2019 in Children During the Omicron Variant-Predominant Period.

BACKGROUND: The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to be more infectious and less severe than the other variants. Despite the increasing number of symptomatic patients, severe neurological complications in children with the Omicron variant have been reported rarely, unlike with wild-type or Delta variants. This study aimed to investigate severe neurological complications in children with Omicron variant infection. METHODS: We conducted a retrospective study of 17 pediatric patients with severe neurological manifestations associated with coronavirus disease 2019 in Korea during the Omicron variant prevalence, from January 1 to April 30, 2022. RESULTS: Among the 17 patients, 11 had pre-existing neurological disabilities and nine met the criteria for multisystem inflammatory syndrome in children (MIS-C). Four of the five vaccine-eligible patients (12 years and older) were unvaccinated. Severe neurological manifestations included acute necrotizing encephalopathy, acute fulminant cerebral edema, acute disseminated encephalomyelitis, basal ganglia encephalitis, unclassified severe encephalopathy/encephalitis, and refractory status dystonicus. Patients with MIS-C and underlying neurological disabilities had longer median hospital and intensive care unit stays compared with those without these conditions. Five patients survived with new neurological deficits at the one-year follow-up, and three died, all of whom had underlying neurological disabilities. CONCLUSIONS: This study shows that severe neurological complications in pediatric patients with the Omicron variant of SARS-CoV-2 occur infrequently but may lead to significant morbidity and mortality, especially among those with pre-existing neurological disabilities and unvaccinated individuals. Continued efforts are necessary to prevent and manage such complications in these vulnerable populations.

Clinical and genetic characteristics of three patients with congenital insensitivity to pain with anhidrosis: Case reports and a review of the literature.

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss-of-function mutations of the NTRK1 gene, affecting the autonomic and sensory nervous system. Clinical manifestation is varied and includes recurrent fever, pain insensitivity, anhidrosis, self-mutilating behavior, and intellectual disability. METHODS: Clinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing. RESULTS: CIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3-8 years). Two patients exhibited self-mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM_002529.3) mutations, c.851-33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574-156_850+1113del (exons 5-7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851-33T>A (p.?) mutations and compound heterozygous for c.851-33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574-156_850+1113del (exons 5-7 del) displayed a late onset and milder clinical manifestation. CONCLUSION: All three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity.

Early developmental changes in a rat model of malformations of cortical development: Abnormal neuronal migration and altered response to NMDA-induced excitotoxic injury.

Malformations of cortical development (MCDs) are caused by abnormal neuronal migration processes during the fetal period and are a major cause of intractable epilepsy in infancy. However, the timing of hyperexcitability or epileptogenesis in MCDs remains unclear. To identify the early developmental changes in the brain of the MCD rat model, which exhibits increased seizure susceptibility during infancy (P12-15), we analyzed the pathological changes in the brains of MCD model rats during the neonatal period and tested NMDA-induced seizure susceptibility. Pregnant rats were injected with two doses of methylazoxymethanol acetate (MAM, 15 mg/kg, i.p.) to induce MCD, while controls were administered normal saline. The cortical development of the offspring was measured by performing magnetic resonance imaging (MRI) on postnatal days (P) 1, 5, and 8. At P8, some rats were sacrificed for immunofluorescence, Golgi staining, and Western analysis. In another set of rats, the number and latency to onset of spasms were monitored for 90 min after the NMDA (5 mg/kg i.p.) injection at P8. In MCD rats, in vivo MR imaging showed smaller brain volume and thinner cortex from day 1 after birth (p < 0.001). Golgi staining and immunofluorescence revealed abnormal neuronal migration, with a reduced number of neuronal cell populations and less dendritic arborization at P8. Furthermore, MCD rats exhibited a significant reduction in the expression of NMDA receptors and AMPAR4, along with an increase in AMPAR3 expression (p < 0.05). Although there was no difference in the latency to seizure onset between MCD rats and controls, the MCD rats survived significantly longer than the controls. These results provide insights into the early developmental changes in the cortex of a MCD rat model and suggest that delayed and abnormal neuronal development in the immature brain is associated with a blunted response to NMDA-induced excitotoxic injury. These developmental changes may be involved in the sudden onset of epilepsy in patients with MCD or prenatal brain injury.

Deep learning-based, fully automated, pediatric brain segmentation.

The purpose of this study was to demonstrate the performance of a fully automated, deep learning-based brain segmentation (DLS) method in healthy controls and in patients with neurodevelopmental disorders, SCN1A mutation, under eleven. The whole, cortical, and subcortical volumes of previously enrolled 21 participants, under 11 years of age, with a SCN1A mutation, and 42 healthy controls, were obtained using a DLS method, and compared to volumes measured by Freesurfer with manual correction. Additionally, the volumes which were calculated with the DLS method between the patients and the control group. The volumes of total brain gray and white matter using DLS method were consistent with that volume which were measured by Freesurfer with manual correction in healthy controls. Among 68 cortical parcellated volume analysis, the volumes of only 7 areas measured by DLS methods were significantly different from that measured by Freesurfer with manual correction, and the differences decreased with increasing age in the subgroup analysis. The subcortical volume measured by the DLS method was relatively smaller than that of the Freesurfer volume analysis. Further, the DLS method could perfectly detect the reduced volume identified by the Freesurfer software and manual correction in patients with SCN1A mutations, compared with healthy controls. In a pediatric population, this new, fully automated DLS method is compatible with the classic, volumetric analysis with Freesurfer software and manual correction, and it can also well detect brain morphological changes in children with a neurodevelopmental disorder.

Specific inhibitor of Wnt/beta-catenin pathway can alter behavioral responses in young rats with malformed cortices.

The Wnt/beta-catenin pathway plays a crucial role in regulating cellular processes and has been implicated in neural activity-dependent learning as well as anxiety. However, the role of this pathway in young children with abnormal cortical development is unknown. Cortical malformations at early development, behavioral abnormalities, and a susceptibility to seizures have been reported in rats prenatally exposed to methylazoxymethanol. In this study, we aimed to investigate whether we could improve the behavioral deficits in young rats with malformed cerebral cortices by modulation of the Wnt/beta-catenin pathway. We found a small molecule Wnt/beta-catenin inhibitor (CWP) that increased exploratory behavior in the open field test (P9, CWP 100 ug treatment, peripheral exploration, P = 0.011) and social behavior test (P12, CWP 250 ug treatment, distance traveled in center, P = 0.033) and decreased anxiety in fear conditioning. However, it did not reduce the susceptibility to seizures. After high dose (250 ug) CWP treatment at P12, phosphocreatine and glutathione (GSH) were decreased in the cortex at P15 (P = 0.021). These findings suggest that the role of Wnt/beta-catenin signaling in exploratory behavior and anxiety during early development warrants further investigation.

Electrophysiological network predicts clinical response to vigabatrin in epileptic spasms.

Purpose: This study aimed to discover electrophysiologic markers correlated with clinical responses to vigabatrin-based treatment in infants with epileptic spasms (ES). Method: The study involved a descriptive analysis of ES patients from a single institution, as well as electroencephalogram (EEG) analyses of 40 samples and 20 age-matched healthy infants. EEG data were acquired during the interictal sleep state prior to the standard treatment. The weighted phase-lag index (wPLI) functional connectivity was explored across frequency and spatial domains, correlating these results with clinical features. Results: Infants with ES exhibited diffuse increases in delta and theta power, differing from healthy controls. For the wPLI analysis, ES subjects exhibited higher global connectivity compared to control subjects. Subjects who responded favorably to treatment were characterized by higher beta connectivity in the parieto-occipital regions, while those with poorer outcomes exhibited lower alpha connectivity in the frontal regions. Individuals with structural neuroimaging abnormalities exhibited correspondingly low functional connectivity, implying that ES patients who maintain adequate structural and functional integrity are more likely to respond favorably to vigabatrin-based treatments. Conclusion: This study highlights the potential utility of EEG functional connectivity analysis in predicting early response to treatments in infants with ES.

Insulin-Like Growth Factor-1 Promotes Synaptogenesis Signaling, a Major Dysregulated Pathway in Malformation of Cortical Development, in a Rat Model.

Malformation of cortical development (MCD) is one of the main causes of intractable epilepsy in childhood. We explored a treatment based on molecular changes using an infant rat model of methylazoxymethanol (MAM)-induced MCD established by injecting MAM at gestational day 15. The offspring were sacrificed on postnatal day (P) 15 for proteomic analysis, which revealed significant downregulation in the synaptogenesis signaling pathway in the cortex of MCD rats. Recombinant human insulin-growth factor-1 (rhIGF-1) was injected from P12 to P14 twice daily and the effect of IGF1 on N-methyl-D-aspartate (NMDA)-induced spasms (15 mg/kg of NMDA, i.p.) was tested; the onset of P15 single spasm was significantly delayed (p = 0.002) and the number of spasms decreased (p < 0.001) in rhIGF1-pretreated rats (n = 17) compared to those in VEH-treated rats (n = 18). Electroencephalographic monitoring during spasms showed significantly reduced spectral entropy and event-related spectral dynamics of fast oscillation in rhIGF-1 treated rats. Magnetic resonance spectroscopy of the retrosplenial cortex showed decreased glutathione (GSH) (p = 0.039) and significant developmental changes in GSH, phosphocreatine (PCr), and total creatine (tCr) (p = 0.023, 0.042, 0.015, respectively) after rhIGF1 pretreatment. rhIGF1 pretreatment significantly upregulated expression of cortical synaptic proteins such as PSD95, AMPAR1, AMPAR4, NMDAR1, and NMDAR2A (p < 0.05). Thus, early rhIGF-1 treatment could promote synaptic protein expression, which was significantly downregulated by prenatal MAM exposure, and effectively suppress NMDA-induced spasms. Early IGF1 treatment should be further investigated as a therapeutic strategy in infants with MCD-related epilepsy.

Comparison of febrile seizures in children with or without coronavirus disease-2019: A single-center observational study.

BACKGROUND: Febrile seizure (FS) is one of the most common neurological manifestations of coronavirus disease-2019 (COVID-19) in children. We compared the clinical characteristics of FS in patients with and without COVID-19 during the pandemic period. METHODS: This retrospective single-center study included patients aged 0-18 years who visited the pediatric emergency department (ED) with FS from January 1, 2022, to April 30, 2022. RESULTS: A total of 186 patients visited the pediatric ED with FS during the study period: 123 (66.1%) were positive for COVID-19 and 63 (33.9%) were negative. Patients with COVID-19 were predominantly male (70.7% vs. 50.8%, p = 0.007) and older (2.4 vs. 1.8 years, p = 0.005) than those without COVID-19. A higher proportion of patients with COVID-19 were of atypical age (age > 5 years or <6 months) than those without COVID-19 (26.8% vs. 9.5%, p = 0.006). This was especially true for those aged >5 years (22% vs. 4.8%, p = 0.003). Patients with COVID-19 had a higher probability of multiple episodes of convulsion within 24 h than those without COVID-19 (10.6% vs. 1.6%, p = 0.037). Among patients with COVID-19, males had a shorter fever-to-seizure duration than females (3 h vs. 6.5 h, p = 0.045). CONCLUSIONS: Patients with FS with COVID-19 tend to be predominantly male and have older age of onset than those without COVID-19. Because of the atypical age of onset and probability of multiple convulsion episodes, vigilance for FS is needed in patients with COVID-19, especially males.

Nusinersen demonstrates effectiveness in treating spinal muscular atrophy: findings from a three-year nationwide study in Korea.

Introduction: Nusinersen is the first drug approved for spinal muscular atrophy (SMA) treatment. In this study, we aimed to evaluate the long-term safety and efficacy of nusinersen, assess the therapeutic effects based on the treatment initiation timing and baseline motor function, and explore the perception of functional improvement from either parents or patients, utilizing 3-year nationwide follow-up data in South Korea. Methods: We enrolled patients with SMA who were treated with nusinersen under the National Health Insurance coverage, with complete motor score records available and a minimum treatment duration of 6 months. To evaluate the motor function of patients, the Hammersmith Infant Neurological Examination-2 (HINE-2) was used for type 1 and the Expanded Hammersmith Functional Motor Scale (HFMSE) was used for types 2 and 3 patients. A significant improvement was defined as a HINE-2 score gain ≥5 for patients with type 1 and an HFMSE score ≥ 3 for patients with types 2 and 3 SMA. Effects of treatment timing were assessed. Patients with type 2 were further categorized based on baseline motor scores for outcome analysis. We also analyzed a second dataset from five tertiary hospitals with the information on parents/patients-reported impressions of improvement. Results: The study comprised 137 patients, with 21, 103, and 13 patients representing type 1, 2, and 3 SMA, respectively. At the 3-year follow-up, the analysis encompassed 7 patients with type 1, 12 patients with type 2, and none with type 3. Nearly half of all enrolled patients across SMA types (42.8, 59.2 and 46.2%, respectively) reached the 2-year follow-up for analysis. Patients with type 1 SMA exhibited gradual motor function improvement over 1-, 2-, and 3-year follow-ups (16, 9, and 7 patients, respectively). Patients with type 2 SMA demonstrated improvement over 1-, 2-, and 3-year follow-ups (96, 61 and 12 patients, respectively). Early treatment from symptom onset resulted in better outcomes for patients with type 1 and 2 SMA. In the second dataset, 90.7% of 108 patients reported subjective improvement at the 1-year follow-up. Conclusion: Nusinersen treatment for types 1-3 SMA is safe and effective in long-term follow-up. Early treatment initiation was a significant factor affecting long-term motor outcome.

Rapamycin Cannot Reduce Seizure Susceptibility in Infantile Rats with Malformations of Cortical Development Lacking mTORC1 Activation.

The mechanistic target of the rapamycin (mTOR) pathway is involved in cortical development. However, the efficacy of mTOR inhibitors in malformations of cortical dysplasia (MCD) outside of the tuberous sclerosis complex is unknown. We selected the MCD rat model with prenatal MAM exposure to test the efficacy of mTOR inhibitors in MCDs. We explored the early cortical changes of mTOR pathway protein expression in rats aged P15. We also monitored the early treatment effect of the mTOR inhibitor, rapamycin, on N-methyl-D-aspartate (NMDA)-induced spasms at P15 and their behavior in the juvenile stage. In vivo MR spectroscopy was performed after rapamycin treatment and compared with vehicle controls. There was no difference in mTORC1 pathway protein expression between MAM-exposed MCD rats and controls at P15, and prolonged treatment of rapamycin had no impact on NMDA-induced spasms despite poor weight gain. Prenatal MAM-exposed juvenile rats treated with rapamycin showed increased social approaching and freezing behavior during habituation. MR spectroscopy showed altered neurometabolites, including Gln, Glu+Gln, Tau, and Cr. Despite behavioral changes and in vivo neurometabolic alteration with early prolonged rapamycin treatment, rapamycin had no effect on spasms susceptibility in prenatal MAM-exposed infantile rats with MCD without mTORC1 activation. For MAM-exposed MCD rats without mTORC1 activation, treatment options outside of mTOR pathway inhibitors should be explored.

Clinical and genetic analyses of patients with lateralized overgrowth.

BACKGROUND: The genetic features and treatment strategies of lateralized overgrowth have been elusive. We performed this study to analyze the genetic characteristics and treatment results of propranolol- or alpelisib-treated patients with lateralized overgrowth. METHODS: Fifteen patients with lateralized overgrowth were involved. Clinical characteristics and whole-body magnetic resonance imaging (WB-MRI) findings were evaluated. Targeted exome sequencing with a gene panel of affected tissue and peripheral white blood cells was performed. Propranolol was administered and treatment results were evaluated. The PIK3CA inhibitor alpelisib was prescribed via a managed access program. RESULTS: The identified mutations were PIK3CA (n = 7), KRAS (n = 2), PTEN (n = 1), MAP2K3 (n = 1), GNAQ (n = 1), TBC1D4 (n = 1), and TEK (n = 1). Propranolol was prescribed in 12 patients, and 7 experienced mild improvement of symptoms. Alpelisib was prescribed in two patients with a PIK3CA mutation, and the reduction of proliferated masses after 1 year of treatment was proved by WB-MRI. CONCLUSIONS: Targeted exome sequencing identified various genetic features of lateralized overgrowth. Propranolol could be applied as an adjuvant therapy for reducing vascular symptoms, but a PIK3CA inhibitor would be the primary therapeutic strategy for PIK3CA-related overgrowth syndrome.

Phenotypic and Genetic Complexity in Pediatric Movement Disorders.

The complex and evolving nature of clinical phenotypes have made genetically diagnosing pediatric patients with movement disorders difficult. Here, we describe this diverse complexity in the clinical and genetic features of a pediatric cohort examined by whole-exome sequencing (WES) and demonstrate the clinical benefit of WES as a diagnostic tool in a pediatric cohort. We evaluated 75 patients with diverse single or combined movement phenomenologies using WES. WES identified 42 variants in 37 genes (56.0%). The detection rate was highest in patients with dystonia (11/13, 84.6%), followed by ataxia (21/38, 55.3%), myoclonus (3/6, 50.0%), unspecified dyskinesia (1/4, 25.0%), tremor (1/1, 100%), respectively. Most genetically diagnosed patients (90.5%) were affected by other neurologic or systemic manifestations; congenital hypotonia (66.7%), and epilepsy (42.9%) were the most common phenotypes. The genetic diagnosis changed the clinical management for five patients (6.7%), including treatments targeting molecular abnormalities, and other systemic surveillance such as cancer screening. Early application of WES yields a high diagnostic rate in pediatric movement disorders, which can overcome the limitations of the traditional phenotype-driven strategies due to the diverse phenotypic and genetic complexity. Additionally, this early genetic diagnosis expands the patient's clinical spectrum and provides an opportunity for tailored treatment.

Alpha-power in electroencephalography as good outcome predictor for out-of-hospital cardiac arrest survivors.

This study aimed to investigate the utility of quantitative EEG biomarkers for predicting good neurologic outcomes in OHCA survivors treated with targeted temperature management (TTM) using power spectral density (PSD), event-related spectral perturbation (ERSP), and spectral entropy (SE). This observational registry-based study was conducted at a tertiary care hospital in Korea using data of adult nontraumatic comatose OHCA survivors who underwent standard EEG and treated with TTM between 2010 and 2018. Good neurological outcome at 1 month (Cerebral Performance Category scores 1 and 2) was the primary outcome. The linear mixed model analysis was performed for PSD, ESRP, and SE values of all and each frequency band. Thirteen of the 54 comatose OHCA survivors with TTM and EEG were excluded due to poor EEG quality or periodic/rhythmic pattern, and EEG data of 41 patients were used for analysis. The median time to EEG was 21 h, and the rate of the good neurologic outcome at 1 month was 52.5%. The good neurologic outcome group was significantly younger and showed higher PSD and ERSP and lower SE features for each frequency than the poor outcome group. After age adjustment, only the alpha-PSD was significantly higher in the good neurologic outcome group (1.13 ± 1.11 vs. 0.09 ± 0.09, p = 0.031) and had best performance with 0.903 of the area under the curve for predicting good neurologic outcome. Alpha-PSD best predicts good neurologic outcome in OHCA survivors and is an early biomarker for prognostication. Larger studies are needed to conclusively confirm these findings.

Arterial ischemic stroke in children with congenital heart diseases.

BACKGROUND: We describe the prevalence, thromboembolic risk factors, and neurologic outcomes in children with congenital heart disease (CHD) and arterial ischemic stroke (AIS). METHODS: We retrospectively analyzed the clinical data of children with CHD and AIS from 2000 to 2016. Demographics, procedural and postprocedural data, neuroimaging findings, details of antithrombotic treatment, and neurological status at last follow up were evaluated. RESULTS: Patients with cyanotic CHD accounted for 24 of 30 cases with AIS. The majority of AIS (70%) was procedure related, and the mean time from procedure to diagnosis of stroke was 9.7 (range, 1-30) days. At the time of AIS, 14 (46.7%) patients revealed coexistence of additional thromboembolic causes of AIS. Three patients (10.0%) experienced recurrent AIS and six patients (20.0%) were diagnosed with post-stroke epilepsy. The unfavorable outcomes were found in 13 patients (43.3%), including four deaths. The unfavorable outcome was significantly associated with the main branch involvement of middle cerebral artery (OR = 10.296, 95% CI = 1.335-79.439) and hemorrhagic transformation (OR = 16.264, 95% CI = 1.359-194.690). CONCLUSIONS: Additional thromboembolic risk factors such as systemic or cardiac thrombus, arrhythmia, and surgical procedures for cyanotic CHD were found in patients with CHD and AIS. The main branch involvement of middle cerebral artery and hemorrhagic transformation were significant predictors of unfavorable outcomes. Further studies are required to identify the target for stroke prevention and develop better prophylactic strategies to minimize AIS in patients with CHD.

Deep Convolutional Gated Recurrent Unit Combined with Attention Mechanism to Classify Pre-Ictal from Interictal EEG with Minimized Number of Channels.

The early prediction of epileptic seizures is important to provide appropriate treatment because it can notify clinicians in advance. Various EEG-based machine learning techniques have been used for automatic seizure classification based on subject-specific paradigms. However, because subject-specific models tend to perform poorly on new patient data, a generalized model with a cross-patient paradigm is necessary for building a robust seizure diagnosis system. In this study, we proposed a generalized model that combines one-dimensional convolutional layers (1D CNN), gated recurrent unit (GRU) layers, and attention mechanisms to classify preictal and interictal phases. When we trained this model with ten minutes of preictal data, the average accuracy over eight patients was 82.86%, with 80% sensitivity and 85.5% precision, outperforming other state-of-the-art models. In addition, we proposed a novel application of attention mechanisms for channel selection. The personalized model using three channels with the highest attention score from the generalized model performed better than when using the smallest attention score. Based on these results, we proposed a model for generalized seizure predictors and a seizure-monitoring system with a minimized number of EEG channels.

Cleft size and type are associated with development of epilepsy and poor seizure control in patients with schizencephaly.

PURPOSE: To investigate the relationship between the anatomical features of schizencephaly and characteristics of epilepsy. METHODS: We retrospectively evaluated patients diagnosed with schizencephaly using brain magnetic resonance imaging. Seizure outcomes were evaluated as drug-resistant epilepsy and frequent seizures (more than once a month) during the previous year. Development of epilepsy, seizure outcomes, and clinical variables were compared according to the anatomical features of schizencephaly, such as cleft type, size, bilaterality, presence of cortical dysplasia, and temporal lobe involvement. RESULTS: Of the 76 patients with schizencephaly-related epilepsy, 28 (36.8%) had open lip clefts, and 13 (17.1%) had bilateral clefts. The development of epilepsy was related to a larger cleft size and the presence of cortical dysplasia. The patients with medium-to-large clefts were younger at seizure onset than those with small clefts (9.7±7.8 vs. 20.8±10.4 years). Among the 64 patients whose outcomes were evaluated, 31 (48.4%) had drug-resistant epilepsy, and 21 (32.8%) met our definition of frequent seizures. In the univariate analysis, open lip, larger clefts, and the presence of cortical dysplasia were associated with poor seizure outcomes. Even after adjustment for covariates, open lip clefts were significantly related to drug-resistant epilepsy (odds ratio=13.036, P=0.001) and frequent seizures (odds ratio=7.682, P=0.008). CONCLUSION: Open lip clefts were associated with poor seizure outcomes. Further, a larger cleft was related to an earlier development of epilepsy. The anatomical features of schizencephaly should be considered in the treatment of epilepsy.

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay.

BACKGROUND: The diagnostic yield of whole-exome sequencing (WES) varies from 30%-50% among patients with mild to severe neurodevelopmental delay (NDD)/intellectual disability (ID). Routine retrospective reanalysis of undiagnosed patients has increased the total diagnostic yield by 10-15%. Here, we performed proband-only WES of 1065 patients with NDD/ID and applied a prospective, daily reanalysis automated pipeline to patients without clinically significant variants to facilitate diagnoses. METHODS: The study included 1065 consecutive patients from 1056 nonconsanguineous unrelated families from 10 multimedical centers in South Korea between April 2018 and August 2021. WES data were analyzed daily using automatically updated databases with variant classification and symptom similarity scoring systems. RESULTS: At the initial analysis, 402 patients from 1056 unrelated families (38.0%, 402/1,056 families) had a positive genetic diagnosis. Daily prospective, automated reanalysis resulted in the identification of 34 additional diagnostic variants in 31 patients (3%), which increased our molecular diagnostic yield to 41% (433/1056 families). Among these 31 patients, 26 were diagnosed with 23 different diseases that were newly discovered after 2019. The time interval between the first analysis and the molecular diagnosis by reanalysis was 1.2 ± 0.9 years, which was shorter in the patients enrolled during the latter part of the study period. CONCLUSION: Daily updated databases and reanalysis systems enhance the diagnostic performance in patients with NDD/ID, contributing to the rapid diagnosis of undiagnosed patients by applying the latest molecular genetic information.

Identification of FOXG1 mutations in infantile hypotonia and postnatal microcephaly.

ABSTRACT: FOXG1, located at chromosome 14q12, is critical for brain development, and patients with FOXG1 mutation exhibit developmental encephalopathy with high phenotypic variability, known as FOXG1 syndrome. Here, we report 3 cases of FOXG1 syndrome that presented with infantile hypotonia and microcephaly.A total of 145 children with developmental delay and/or hypotonia were evaluated by whole-exome sequencing (WES) in the pediatric neurology clinic and medical genetics center at Asan Medical Center Children's Hospital, from 2017 to 2019. Each FOXG1 mutation was confirmed by Sanger sequencing. The clinical findings of each patient with FOXG1 mutation were reviewed.WES identified de-novo, pathogenic, and heterozygous FOXG1 mutations in 3 of 145 patients in our patient cohort with developmental delay and/or hypotonia. The characteristics of brain magnetic resonance imaging (MRI) were reported as callosal anomaly, decrease in frontal volume, fornix thickening, and hypoplastic olfactory bulbs. A phenotype-genotype correlation was demonstrated as a patient with a novel missense mutation, c.761A > C (p.Tyr254Ser), in the forkhead domain had better outcome and milder brain abnormalities than the other 2 patients with truncating mutation in the Groucho binding domain site, c.958delC (p.Arg320Alafs), or N-terminal domain, c.506dup (p.Lys170GlnfsThe). Importantly, all 3 patients had hypoplastic olfactory bulbs on their brain MRI, which is a distinct and previously unrecognized feature of FOXG1 syndrome.This is the first report of FOXG1 syndrome in a Korean population; this condition accounts for 2% (3 of 145 patients) of our patient cohort with developmental delays and/or hypotonia. Our report contributes to understanding this extremely rare genetic condition in the clinical and genetic perspectives.