Incidence of Neonatal Seizures in China Based on Electroencephalogram Monitoring in Neonatal Neurocritical Care Units.

Importance: Neonatal seizures pose a significant challenge in critical care, and continuous video electroencephalography (cEEG) monitoring holds promise for early detection of seizures. However, large-scale data on the incidence of neonatal seizures and monitoring systems in China are lacking. Objectives: To determine the incidence of neonatal seizures in infants with high risk in China. Design, Setting, and Participants: A large, cross-sectional multicenter study was conducted from January 2017 to December 2018 in the neonatal intensive care units (NICUs) of 7 tertiary medical centers in China. Neonates with high risk were included, and cEEG monitoring was conducted. Data were collected between January 1, 2017, and January 31, 2020. The data were analyzed between January 2021 and January 2022. Main Outcomes and Measures: The incidence of neonatal seizures, categorized by etiology, and seizure burden. Results: A total of 20 310 neonates with high risk were included (10 495 [51.7%] male; mean [SD] postmenstrual age, 37.7 [3.7] weeks), and seizures were observed in 3423 infants (16.9%). The highest proportion of seizures was attributed to acute neonatal encephalopathy (1448 [42.3%]). The incidence of seizures decreased with postmenstrual age and birth weight, with the highest occurrence observed in neonates with postmenstrual age of less than 28 weeks (237 of 879 [27.0%]) or birth weight of less than 1.0 kg (269 of 914 [29.4%]). Preterm infants had a higher proportion of moderate and severe seizure burdens compared with full-term infants (moderate severity: 248 of 1199 [20.7%] vs 454 of 2224 [20.4%]), but no significant differences were observed in etiology. Seizure burden was highest with genetic syndromes (49 of 188 [26.1%]), central nervous system malformations (33 of 127 [26.0%]), and inborn errors of metabolism (27 of 113 [23.9%]). During hospitalization, 7.8% of neonates with seizures died (267 neonates), with 81.3% of these cases having a moderate or severe seizure burden (217 neonates). Mortality was generally higher in preterm vs full-term infants (98 of 1199 [8.2%] vs 169 of 2224 [7.6%]) and increased with the severity of seizure burden (217 of 267 neonates with moderate or severe burden [81.3%]). Conclusions and Relevance: This cross-sectional study of neonatal seizures underscores the substantial burden seizures pose to high-risk infants with brain injury in China, particularly those who are born prematurely or who have congenital conditions.

Use of medical exome sequencing for identification of underlying genetic defects in NICU: Experience in a cohort of 2303 neonates in China.

Emerging evidence demonstrates the clinical utility of genomic applications in newborn intensive care unit (NICU) patients with strong indications of Mendelian etiology. However, such applications' diagnostic yield and utility remain unclear for NICU cohorts with minimal phenotype selection. In this study, focused medical exome sequencing was used as a first-tier, singleton-focused diagnostic tool for 2303 unrelated sick neonates. Integrated analysis of single nucleotide variants (SNVs), small insertions and deletions (Indels), and large copy number variants (CNVs) was performed. The diagnostic rate in this NICU cohort is 12.3% (284/2303), with 190 probands with molecular diagnoses made from SNV/Indel analyses (66.9%), 93 patients with diagnostic aneuploidy/CNVs findings (32.8%), and 1 patient with both SNV and CNV (0.4%). In addition, 54 (2.3%) of patients had a reportable incidental finding. Multiple organ involvements, craniofacial abnormalities, and dermatologic abnormalities were the strongest positive predictors for a molecular diagnosis. Among the 190 cases with SNV/Indel defects, direct impacts on medical management were observed in 46.8% of patients after the results were reported. In this study, we demonstrate that focused medical exome sequencing is a powerful first-line diagnostic tool for NICU patients. Significant number of diagnosed NICU patients can benefit from more focused medical management and long-term care.

Development and validation of Auto-Neo-electroencephalography (EEG) to estimate brain age and predict report conclusion for electroencephalography monitoring data in neonatal intensive care units.

BACKGROUND: Electroencephalography (EEG) monitoring is widely used in neonatal intensive care units (NICUs). However, conventional EEG report generation processes are time-consuming and labor-intensive. Therefore, an automatic, objective, and comprehensive pipeline for brain age estimation and EEG report conclusion prediction is urgently needed to assist clinician's decision-making. METHODS: We recruited patients who underwent EEG monitoring from the NICU at Children's Hospital of Fudan University from Jan. 2016 to Mar. 2018. A total of 1,851 subjects were enrolled, including the patient's conceptional age (CA) and the clinical EEG report conclusion (normal, slightly abnormal, moderately abnormal, or severely abnormal). A total of 1,591 subjects were used to generate predictive models and 260 were used as the validation dataset. We developed Auto-Neo-EEG (an automatic prediction system to assist clinical neonatal EEG report generation), including signal feature extraction, supervised machine learning realized by gradient boosted models, to estimate brain age and predict EEG report conclusion. RESULTS: The predicted results from the validation dataset were compared with the clinical observations to assess the performance. In the independent validation dataset, the model could achieve accordance 0.904 on estimating brain age for neonates with normal clinical EEG report conclusion, and differences between the predicted and observed brain age were strongly related with EEG report conclusion abnormality. Further, as for the EEG report conclusion prediction, the model could achieve area under the curve (AUC) of 0.984 for severely abnormal situations, and 0.857 for moderately abnormal ones. CONCLUSIONS: The Auto-Neo-EEG has the high accuracy of estimating brain age and EEG report conclusion, which can potentially greatly accelerate the EEG report generation processes assist in clinical decision making.

Preoperative Vitamin D Deficiency Is Associated With Higher Vasoactive-Inotropic Scores Following Pediatric Cardiac Surgery in Chinese Children.

The relationship between vitamin D and cardiovascular health in children remains unclear. Vitamin D deficiency (VDD) is supposed to be a potential risk factor associated with poorer outcomes after congenital heart disease (CHD) surgery. The maximum vasoactive-inotropic use after cardiac surgery is considered to be a good predictor of adverse outcomes. We aimed to assess the correlation between preoperative VDD and the maximum vasoactive-inotropic score (VISmax) at 24 h postoperatively. Nine hundred children with CHD were enrolled in this study, and preoperative total serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured by liquid chromatography-tandem mass spectrometry. Related demographic and clinical characteristics were collected. A total of 490 boys (54.4%) and 410 girls (45.6%) with a mean age of 1 year (range: 6 months-3 years) were enrolled. The median 25(OH)D level was 24.0 ng/mL, with 32.6% of patients having VDD [25(OH)D < 20 ng/mL]. The univariate analysis indicated that VDD [odds ratio (OR): 2.27; 95% confidence interval (CI): 1.48-3.50] is associated with a risk of increased VISmax at 24 h postoperation. Multivariate analysis revealed that VDD (OR: 1.85; 95% CI: 1.09-3.02), a Risk-adjusted Congenital Heart Surgery score of at least three points (OR: 1.55; 95% CI: 1.09-2.19), and cardiopulmonary bypass time (OR: 1.02; 95% CI: 1.01-1.02) were independently associated with an increased VISmax within 24 h after cardiac surgery. VDD in pediatric patients before cardiac surgery is associated with the need for increased postoperative inotropic support at 24 h postoperation.

Amplitude of low-frequency fluctuation may be an early predictor of delayed motor development due to neonatal hyperbilirubinemia: a fMRI study.

BACKGROUND: Acute bilirubin encephalopathy or kernicterus is the worst consequence of brain damage caused by the elevation of total unbound serum bilirubin (TSB) in neonates. The present study aimed to visualize the characteristic brain regions of neonates with hyperbilirubinemia (HB) using functional magnetic resonance imaging (fMRI) and to measure the amplitude of low-frequency fluctuation (ALFF) values. METHODS: This was a prospective cohort study, which included newborns with HB who were hospitalized at the Children's Hospital of Fudan University. The control group included neonates admitted with neonatal simple wet lung or pneumonia without neurological disease or brain injury. Newborns were divided into a severe hyperbilirubinemia group (SHB), moderate HB group, and control group based on TSB levels. The newborns completed routine MRI combined with fMRI scans and brainstem auditory evoked potentials (BAEPs) during their hospitalization. RESULTS: A total of 251 newborns were included in this study. There were 45 patients in the SHB group, 65 in the HB group, and 141 in the control group. The average ALFF value in the basal ganglia region in the SHB group was the highest, which was greater than that in the HB and control groups (P<0.001). The ALFF increased with an increase in TSB concentration. Based on the results of the Bayley Scales of infant development assessment, we further found that the most significant difference in ALFF remained in the basal ganglia region between newborns with motor development scores above 70 (including 70) and below 70. Correlation analysis revealed a strong negative correlation between motor development scores and ALFF (r=-0.691, P<0.001). When ALFF alone was used to predict motor development, the sensitivity was 89%. When ALFF was combined with TSB and BEAP results, the area under the ROC curve was the largest (AUC =0.85). The sensitivity and specificity of the model were 67.86% and 90.77%, respectively. CONCLUSIONS: The ALFF value may be able to serve as an early imaging biomarker and has a greater sensitivity than TSB or BAEP results in predicting long-term motor development (18 m) in HB.

Data on mutations and Clinical features in SCN1A or SCN2A gene.

Mutations in SCN1A and SCN2A are associated with a wide spectrum of epilepsy related disorders in human. This dataset presented variants and clinical features of SCN1A and SCN2A genes. A total of 48 cases were presented, including 33 SCN1A mutations and 14 SCN2A mutations. While 22 mutations were novel in SCN1A and 11 were novel in SCN2A. The clinical features were included of gender, birth history, family history, seizure onset age, seizure types, frequency of seizures, initial and follow-up EEGs, brain MRI findings, antiepileptic drugs, prognosis and developmental data. The data can provide insights on novel mutations and different phenotypes of SCN1A and SCN2A.

Clinical and genetic spectrum of a large cohort of children with epilepsy in China.

PURPOSE: Genetic diagnosis for children suffering from epilepsy has important implications for treatment, prognosis, and development of precision medicine strategies. METHODS: We performed exome sequencing (ES) or targeted sequencing on 733 children with epilepsy onset within the first year of life. We subgrouped our patients based on the onset age of seizure into neonatal and before 1 year (1-12 months), to compare the clinical and genetic features. RESULTS: The subgroups with different onset age of seizure showed different pathogenic variant spectrum, and the 1-year age group was more likely to have developmental delays than the neonate group (p = 0.000614). The diagnostic rate was 26.7% for targeted sequencing using a 2742-gene panel, and 42% for ES. We identified 12 genes, which covered 48.7% of diagnostic cases. Our data revealed that 41.9% of patients in the neonate group and 49.7% patients in the 1-year group had treatment options based on molecular diagnosis. CONCLUSION: The 12 most commonly implicated genes in this cohort and the genes with treatment options should be considered as part of the essential panel for early diagnosis of epilepsy onset, if large medical exome analyses or ES are not feasible as first-tier analysis. Genetic results are beginning to improve therapy by antiepileptic medication selections and precision medicine approaches.

Association between SCN1A and SCN2A mutations and clinical/EEG features in Chinese patients from epilepsy or severe seizures.

BACKGROUND: We investigated the association between SCN1A and SCN2A mutations and clinical phenotype and electroencephalography (EEG) features. METHODS: In this study, 48 patients suffered from epilepsy or severe seizures with SCN1A and SCN2A mutations were recruited. Medical data and molecular diagnosis were analyzed. RESULTS: A total of 47 mutations were identified, including 33 novel mutations. The onset of most epilepsy caused by SCN1A mutations (1-6 m) was later than that of SCN2A mutations (neonatal). SCN1A mutations included truncating mutations and missense mutations occurred in the crucial region were associated with more severe phenotypes and developmental delay (85.7%, P = 0.020). De novo mutations or truncating mutations of SCN2A mutations are mainly associated with severe phenotypes. The proportion of initial abnormal EEG of SCN2A mutation was higher than that of SCN1A mutation (54.2%, 100%). Patients with SCN1A mutations showed more focal epileptiform discharges (69.2%), while patients with SCN2A mutations had more multifocal epileptiform discharges (53.8%). Sodium channel blockers were less effective for patients with SCN1A mutations and SCN2A mutations with early seizures onset. CONCLUSIONS: Our study expanded the mutation spectrum of the SCN1A and SCN2A, and led to a better understanding of the similarities and difference in the genetic and clinical features between the two genes.

Novel compound heterozygous mutations in the PEX1 gene in two Chinese newborns with Zellweger syndrome based on whole exome sequencing.

Peroxisome biogenesis disorders (PBDs) represent a spectrum of human genetic disorders that are characterized by damaged peroxisome assembly. In the newborn period, the characteristics of affected patients include dysmorphic facial features, neonatal hypotonia, seizures, ocular abnormalities, poor feeding, liver cysts with hepatic dysfunction and skeletal defects. These can be caused by a defect in at least 14 different PEX genes. In this study, whole-exome sequencing (WES) was performed on samples from two Chinese newborns with clinical features of Zellweger syndrome. WES identified two novel mutations (c.2416+1G>T and c.2489delT) in patient 1 and another two novel mutations (c.1483+1G>A and c.1727dupG) in patient 2 in the PEX1 gene. All four mutations have a serious influence on the protein function, which also highlights the power of WES, particularly in clinically challenging cases.

Executive Function Training for Children with Attention Deficit Hyperactivity Disorder.

BACKGROUND: Accumulating evidence indicates that attention deficit hyperactivity disorder (ADHD) is associated with core deficits in executive function (EF) which predicts poorer academic and occupational functioning. This makes early intervention targeting EF impairments important to prevent long-term negative outcomes. Cognitive training is a potential ADHD treatment target. The present study aimed to explore the efficacy, feasibility, and acceptability of a cognitive training program (targeting child's multiple EF components and involving parent support in daily life), as a nonpharmacological intervention for children with ADHD. METHODS: Forty-four school -age children with ADHD and their parents participated in 12 sessions of EF training (last for 12 weeks) and 88 health controls (HC) were also recruited. Training effects were explored using both neuropsychological tests (Stroop color-word test, Rey-Osterrieth complex figure test, trail making test, tower of Hanoi, and false-belief task) and reports of daily life (ADHD rating scale-IV, Conners' parent rating scale, and behavior rating inventory of executive function [BRIEF]) by analysis of paired sample t-test and Wilcoxon signed-rank test. The differences on EF performances between children with ADHD after training and HC were explored using multivariate analysis. RESULTS: The results (before vs. after EF training) showed that after intervention, the children with ADHD presented better performances of EF both in neuropsychological tests (word interference of Stroop: 36.1 ± 14.6 vs. 27.1 ± 11.1, t = 4.731, P < 0.001; shift time of TMT: 194.9 ± 115.4 vs. 124.8 ± 72.4, Z = -4.639, P < 0.001; false-belief task: χ2 = 6.932, P = 0.008) and reports of daily life (global executive composite of BRIEF: 148.9 ± 17.5 vs. 127.8 ± 17.5, t = 6.433, P < 0.001). The performances on EF tasks for children with ADHD after EF training could match with the level of HC children. The ADHD symptoms (ADHD rating scale total score: 32.4 ± 8.9 vs. 22.9 ± 8.2, t = 6.331, P < 0.001) and behavioral problems of the children as reported by parents also reduced significantly after the intervention. Participants reported that the EF training program was feasible to administer and acceptable. CONCLUSIONS: The EF training program was feasible and acceptable to children with ADHD and parents. Although replication with a larger sample and an active control group are needed, EF training program with multiple EF focus and parent involving in real-life activities could be a potentially promising intervention associated with significant EF (near transfer) and ADHD symptoms improvement (far transfer).