Association of perinatal factors with neurodevelopmental referrals in a population-based cohort study in Japan.

Although the causes of neurodevelopmental disorders remain unknown, several environmental risk factors have attracted considerable attention. We conducted a retrospective, longitudinal, population-based cohort study using data from infant health examinations of children born to mothers with pregnancies between April 1, 2014 and March 31, 2016 in Kobe City to identify the perinatal factors associated with neurodevelopmental referrals in 3-year-old children. There were 15,223 and 1283 children in the normal and referral groups, respectively. Neurodevelopmental referrals at the health checkup for 3-year-old children were significantly associated with the lack of social support during pregnancy (adjusted odds ratio [aOR] 1.99, 99% CI 1.14-3.45, p = 0.001), history of psychiatric consultation (aOR 1.56, 99% CI 1.10-2.22, p = 0.001), no social assistance post-delivery (aOR 1.49, 99% CI 1.03-2.16, p = 0.006), Edinburgh Post-natal Depression Scale (EPDS) score ≥ 9 (aOR 1.36, 99% CI 1.01-1.84, p = 0.008), infant gender (male) (aOR 2.51, 99% CI 2.05-3.06, p < 0.001), and cesarean delivery (aOR 1.39, 99% CI 1.11-1.75, p < 0.001). In conclusion, this exploratory study in the general Japanese population identified six perinatal factors associated with neurodevelopmental referrals in 3-year-old children: infant gender (male), cesarean section, maternal history of psychiatric consultation, EPDS score ≥ 9, lack of social support during pregnancy, and no social assistance post-delivery.

Association of early bedtime at 3 years of age with higher academic performance and better non-cognitive skills in elementary school.

This study investigated the relationship between sleep habits in early childhood and academic performance and non-cognitive skills in the first grade. We retrospectively analyzed a longitudinal population-based cohort from birth through early childhood, up to elementary school, in Amagasaki City, Japan. The primary outcome was academic performance in the first grade. Other outcomes were self-reported non-cognitive skills. Overall, 4395 children were enrolled. Mean national language scores for children with bedtimes at 18:00-20:00, 21:00, 22:00, and ≥ 23:00 were 71.2 ± 19.7, 69.3 ± 19.4, 68.3 ± 20.1, and 62.5 ± 21.3, respectively. Multiple regression analysis identified bedtime at 3 years as a significant factor associated with academic performance. However, sleep duration was not significantly associated with academic performance. Bedtime at 3 years also affected non-cognitive skills in the first grade. Diligence decreased with a later bedtime (21:00 vs. 18:00-20:00; odds ratio [OR]: 1.98, 95% confidence interval [CI] 1.27-3.09; 22:00 vs. 18:00-20:00; OR: 2.15, 95% CI 1.37-3.38; ≥ 23:00 vs. 18:00-20:00; OR: 2.33, 95% CI 1.29-4.20). Thus, early bedtime at 3 years may be associated with a higher academic performance and better non-cognitive skills in the first grade. Optimum early-childhood sleep habits may positively impact academic future.

Timing of therapeutic interventions against infection-triggered encephalopathy syndrome: a scoping review of the pediatric literature.

Our goal was to conduct a scoping review of the literature on the treatment of infection-triggered encephalopathy syndrome/acute encephalopathy in children, focusing on treatment targets and treatment initiation timing. We performed literature searches using PubMed for articles reporting treatments of infection-triggered encephalopathy syndrome/acute encephalopathy. We included articles describing specific treatments for acute encephalopathy with control groups. For the purpose of searching new therapies only experimentally tried in the case series, we also included case series studies without control groups in this review, if the studies contained at least two cases with clear treatment goals. Therapies were classified based on their mechanisms of action into brain protection therapy, immunotherapy, and other therapies. We operationally categorized the timing of treatment initiation as T1 (6-12 h), T2 (12-24 h), T3 (24-48 h), and T4 (>48 h) after the onset of seizures and/or impaired consciousness. Thirty articles were included in this review; no randomized control study was found. Eleven retrospective/historical cohort studies and five case-control studies included control groups with or without specific therapies or outcomes. The targeted conditions and treatment timing varied widely across studies. However, the following three points were suggested to be effective in multiple studies: (1) Careful seizure management and targeted temperature management within 12 h (T1) of onset of febrile seizure/prolonged impaired consciousness without multiple organ failure may reduce the development of acute encephalopathy with biphasic seizures and late reduced diffusion; (2) immunotherapy using corticosteroids, tocilizumab, or plasma exchange within 24 h (T1-T2) of onset of acute necrotizing encephalopathy may reduce sequelae; and (3) anakinra therapy and ketogenic diet demonstrate little evidence of neurologic sequelae reduction, but may reduce seizure frequency and allow for weaning from barbiturates, even when administered weeks (T4) after onset in children with febrile infection-related epilepsy syndrome. Although available studies have no solid evidence in the treatment of infection-triggered encephalopathy syndrome/acute encephalopathy, this scoping review lays the groundwork for future prospective clinical trials.

Dravet syndrome and hemorrhagic shock and encephalopathy syndrome associated with an intronic deletion of SCN1A.

OBJECTIVE: Hemorrhagic shock and encephalopathy syndrome (HSES) is a serious condition that requires intensive care and is associated with a high mortality rate. However, its pathogenesis remains unclear. In the present study, a genetic analysis was performed to determine the genetic background of patients with clinically suspected Dravet syndrome (DS) who developed HSES. METHODS: Whole exome sequencing was performed, followed by minigene analysis of the intron variant detected by whole exome sequencing to confirm its effect on splicing. RESULTS: Whole exome sequencing revealed a novel 21-bp deletion in intron 3 of SCN1A NM_001165963.4 (NC_000002.11:g.166073675_166073695del). This deletion was not found in the patient's parents and was proven to be de novo. Minigene analysis revealed an aberrant mRNA lacking 40 and 106 bp from the 5' end of exon 4 of SCN1A. Therefore, we diagnosed this case as DS due to the deletion in intron 3 of SCN1A. CONCLUSIONS: We report a case of DS with HSES caused by a 21-bp deletion in the intron of SCN1A that was confirmed by minigene analysis. The present case met Levin's criteria for HSES and the splicing analysis of SCN1A is an important finding. This study has important implications for understanding HSES pathogenesis.

Clinical and laboratory characteristics of complex febrile seizures in the acute phase: a case-series study in Japan.

BACKGROUND: Patients with complex febrile seizures (CFS) often display abnormal laboratory results, unexpectedly prolonged seizures, and/or altered consciousness after admission. However, no standardized values have been established for the clinical and laboratory characteristics of CFS in the acute phase, making the management of CFS challenging. This study aimed to determine the clinical and laboratory characteristics of children with CFS during the acute phase. In particular, the duration of impaired consciousness and the detailed distribution of blood test values were focused. METHODS: We retrospectively reviewed medical records of a consecutive pediatric cohort aged 6-60 months who were diagnosed with CFS and admitted to Kobe Children's Hospital between October 2002 and March 2017. During the study period, 486 seizure episodes with confirmed CFS were initially reviewed, with 317 seizure episodes included in the analysis. Detailed clinical and laboratory characteristics were summarized. RESULTS: Among 317 seizure episodes (296 children with CFS), 302 required two or fewer anticonvulsants to be terminated. In 296 episodes showing convulsive seizures, median seizure duration was 30.5 min. The median time from onset to consciousness recovery was 175 min. Impaired consciousness lasting > 6, 8, and 12 h was observed in 13.9%, 7.6%, and 1.9% patients with CFS, respectively. Additionally, the distribution of aspartate aminotransferase, lactate dehydrogenase, creatinine, and glucose were clarified with 3, 10, 50, 90, and 97 percentile values. CONCLUSION: This study detailed the clinical and laboratory findings of acute-phase CFS using the data of the largest 15-year consecutive cohort of children with CFS. These results provide important information for appropriate acute management of CFS.

Time course of serum cytokine level changes within 72 h after onset in children with acute encephalopathy and febrile seizures.

BACKGROUND: Cytokine levels have been measured in acute encephalopathy (AE) to determine its pathology or as a diagnostic biomarker to distinguish it from febrile seizures (FS); however, the dynamics of cytokine level changes have not yet been fully captured in these two neurological manifestations. Thus, we aimed to explore the time course of serum cytokine level changes within 72 h after onset in AE and FS. METHODS: We retrospectively measured cytokine level in residual serum samples at multiple timepoints in seven children whose final diagnoses were AE or FS. RESULTS: The levels of 13 cytokines appeared to increase immediately after onset and peaked within 12-24 h after onset: interleukin (IL)-1ß, IL-4 IL-5, IL-6, IL-8, IL-10, IL-17, eotaxin, fibroblast growth factor, granulocyte colony-stimulating factor, interferon gamma, interferon-inducible protein-10, and macrophage chemoattractant protein-1. There were no dynamic changes in the levels of three cytokines (IL-1 receptor agonist, macrophage inflammatory protein-1α, and platelet-derived growth factor-bb) 72 h after onset. Levels of some cytokines decreased to around control levels within 48 h after onset: IL-1ß, IL-4, IL-5, IL-17, fibroblast growth factor, and interferon gamma. The levels of most cytokines appeared to be higher in AE, especially in hemorrhagic shock encephalopathy syndrome, than in FS. CONCLUSIONS: Cytokine levels in both AE and FS change dynamically, such as the levels of several cytokines increased within a few hours after onset and decreased at 12-24 h after onset. Therefore, it will be desirable to make clinical decisions regarding the administration of anti-inflammatory therapy in 24 h after onset in AE.

Behavioral Therapy for Children with Avoidant/Restrictive Food Intake Disorder Dependent on Tube or Oral Enteral Nutrient Formula: A Feasibility Study.

In children with eating disorders, nutritional status and growth may depend on enteral nutrient formula. Ultimately, its goal is to introduce or reintroduce oral feeding. Japanese research on the treatment of tube or oral formula-dependent children is scarce. This study determined the feasibility of behavioral therapy for children with avoidant/restrictive food intake disorder and dependency on the tube or oral enteral nutrient formula in Japan. Medical records of children diagnosed with this disorder, dependent on the tube or oral enteral nutrient formula and who had received behavioral therapy intervention to withdraw from the formula were retrospectively investigated. We collected their characteristics at first visit and the caloric percentage from oral food intake six months after starting the treatment. In total, four patients (age range: 2-5 years) participated in this study. The feeding routes employed before the intervention were a nasogastric tube for one patient, a gastrostomy bottom for the other patient, and oral formula for the remaining patients (i.e., two children). At the sixth month of the behavioral treatment, none of the patients needed the formula, and the caloric percentage of required nutrition from oral food intake was 100%. Our data demonstrate that this behavioral therapy is feasible for children with avoidant/restrictive food intake disorder dependent on the tube or oral formula in Japan.

Prognostic effects of treatment protocols for febrile convulsive status epilepticus in children.

BACKGROUND: Febrile status epilepticus is the most common form of status epilepticus in children. No previous reports compare the effectiveness of treatment strategies using fosphenytoin (fPHT) or phenobarbital (PB) and those using anesthetics as second-line anti-seizure medication for benzodiazepine-resistant convulsive status epilepticus (CSE). We aimed to examine the outcomes of various treatment strategies for febrile convulsive status epilepticus (FCSE) in a real-world setting while comparing the effects of different treatment protocols and their presence or absence. METHODS: This was a single-center historical cohort study that was divided into three periods. Patients who presented with febrile convulsive status epilepticus for ≥60 min even after the administration of at least one anticonvulsant were included. During period I (October 2002-December 2006), treatment was performed at the discretion of the attending physician, without a protocol. During period II (January 2007-February 2013), barbiturate coma therapy (BCT) was indicated for FCSE resistant to benzodiazepines. During period III (March 2013-April 2016), BCT was indicated for FCSE resistant to fPHT or PB. RESULTS: The rate of electroencephalogram monitoring was lower in period I than period II+III (11.5% vs. 85.7%, p<0.01). Midazolam was administered by continuous infusion more often in period I than period II+III (84.6% vs. 25.0%, p<0.01), whereas fPHT was administered less often in period I than period II+III (0% vs. 27.4%, p<0.01). The rate of poor outcome, which was determined using the Pediatric Cerebral Performance Category scale, was higher in period I than period II+III (23.1% vs. 7.1%, p=0.03). The rate of poor outcome did not differ between periods II and III (4.2% vs. 11.1%, p=0.40). CONCLUSIONS: While the presence of a treatment protocol for FCSE in children may improve outcomes, a treatment protocol using fPHT or PB may not be associated with better outcomes.

Growth and differentiation factor-15 as a potential prognostic biomarker for status-epilepticus-associated-with-fever: A pilot study.

OBJECTIVE: Biomarkers predicting poor outcomes of status-epilepticus-associated-with-fever (SEF) at an early stage may contribute to treatment guidance. However, none have been reported thus far. We investigated the dynamics of serum growth and differentiation factor (GDF)-15 after seizure onset in patients with SEF and determined whether GDF-15 can predict poor outcomes, particularly in the first 6 h after seizure onset. METHODS: We enrolled 37 pediatric patients with SEF and eight patients with simple febrile seizures (SFS) and collected their blood samples within 24 h of seizure onset and eight febrile control patients between March 1, 2017 and September 30, 2020. All patients were aged ≤15 years. RESULTS: In the SEF group, the median post-seizure serum GDF-15 values were 1,065 (<6h), 2,720 (6-12 h), and 2,411 (12-24 h) pg/mL. The median serum GDF-15 in the first 6 h was measured in patients with SEF without a significant past medical history (n = 21) and was found to be statistically significantly higher (1,587 pg/mL) than in the febrile control (551 pg/mL) and SFS (411 pg/mL) groups. The median serum GDF-15 was statistically significantly higher in patients with SEF with sequelae (n = 5) and patients with acute encephalopathy with biphasic seizures/reduced diffusion/hemorrhagic shock and encephalopathy syndrome (n = 6) than in patients with SEF without sequelae (n = 16) (15,898 vs 756 pg/mL) and patients with prolonged FS (n = 15) (9,448 vs 796 pg/mL). CONCLUSIONS: This study demonstrates the dynamics of serum GDF-15 in patients with SEF and indicates the potential of GDF-15 as an early predictor of poor outcomes.

Genetic Analysis of UGT1A1 Polymorphisms Using Preserved Dried Umbilical Cord for Assessing the Potential of Neonatal Jaundice as a Risk Factor for Autism Spectrum Disorder in Children.

Neonatal jaundice has been suggested as a perinatal risk factor for autism spectrum disorder (ASD). We examined UGT1A1 polymorphisms to assess the potential of neonatal jaundice as a risk factor for ASD in children by using DNA extracted from preserved umbilical cord. In total, 79 children with ASD were genotyped for UGT1A1*28 (c.-41-40dup), UGT1A1*6 (c.211 G > A), and UGT1A1*27 (c.686 C > A). The allele frequency of UGT1A1*6 (OR = 1.34, p = 0.26) and UGT1A1*28 (OR = 0.80, p = 0.54) and the prevalence of UGT1A1*28/*6 diplotypes did not differ significantly from those in the control population. No UGT1A1*27 allele was detected in the subjects. ASD symptom assessment scores were not associated with UGT1A1*28/*6/*27 genotypes or UGT1A1*28/*6 diplotypes. These results suggest that neonatal jaundice is not significantly associated with ASD.

Early steroid pulse therapy for children with suspected acute encephalopathy: An observational study.

ABSTRACT: Steroid pulse therapy is widely used to treat virus-associated acute encephalopathy, especially the cytokine storm type; however, its effectiveness remains unknown. We sought to investigate the effectiveness of early steroid pulse therapy for suspected acute encephalopathy in the presence of elevated aspartate aminotransferase (AST) levels.We enrolled children admitted to Hyogo Children's Hospital between 2003 and 2017 with convulsions or impaired consciousness accompanied by fever (temperature >38°C). The inclusion criteria were: refractory status epilepticus or prolonged neurological abnormality or hemiplegia at 6 hours from onset, and AST elevation >90 IU/L within 6 hours of onset. We excluded patients with a neurological history. We compared the prognosis between the groups with or without steroid pulse therapy within 24 hours. A good prognosis was defined as a Pediatric Cerebral Performance Category Scale (PCPC) score of 1-2 at the last evaluation, within 30 months of onset. Moreover, we analyzed the relationship between prognosis and time from onset to steroid pulse therapy.Fifteen patients with acute encephalopathy and 5 patients with febrile seizures were included in this study. Thirteen patients received steroid pulse therapy within 24 hours. There was no between-group difference in the proportion with a good prognosis. There was no significant correlation between PCPC and timing of steroid pulse therapy (rs = 0.253, P = .405). Even after excluding 2 patients with brainstem lesions, no significant correlation between PCPC and steroid pulse therapy timing (rs = 0.583, P = .060) was noted. However, the prognosis tended to be better in patients who received steroid pulse therapy earlier.Steroid pulse therapy within 24 hours did not improve the prognosis in children with suspected acute encephalopathy associated with elevated AST. Still, even earlier administration of treatment could prevent the possible neurological sequelae of this condition.

Prediction of AESD and neurological sequelae in febrile status epilepticus.

OBJECTIVE: The clinical prediction rule (CPR) for acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was developed with an area under the receiver operating characteristic curve (AUC) of 0.95 - 0.96. Our objective was to verify the AESD CPR in a new cohort and compare the utilities of three CPRs of acute encephalopathy: the Tada, Yokochi, and Nagase criteria. METHODS: We reviewed the clinical data and medical charts of 580 consecutive patients (aged < 18 years) with febrile convulsive status epilepticus lasting for ≥ 30 min in 2002 - 2017 and measured the performance of the CPRs in predicting AESD and sequelae. RESULTS: The CPRs predicted AESD with an AUC of 0.84 - 0.88. The Tada criteria predicted AESD with a positive predictive value (PPV) of 0.25 and a negative predictive value (NPV) of 0.99. The Yokochi criteria predicted AESD with a PPV and NPV of 0.20 and 0.95, respectively, after 12 h. The Nagase criteria predicted AESD with a PPV and NPV of 0.14 and 1.00, respectively, after 6 h. The PPVs of the Tada, Yokochi, and Nagase criteria for sequelae were 0.28, 0.28, and 0.17, respectively; the corresponding NPVs were 0.97, 0.95, and 0.98, respectively. CONCLUSIONS: The effectiveness of the AESD CPR in a new cohort was lower than that in the derivation study. CPRs are not sufficient as diagnostic tests, but they are useful as screening tests. The Nagase criteria are the most effective for screening among the three CPRs due to their high NPV and swiftness.

Elevated cytokine, chemokine, and growth and differentiation factor-15 levels in hemorrhagic shock and encephalopathy syndrome: A retrospective observational study.

Patients with hemorrhagic shock and encephalopathy syndrome (HSES) have a high early mortality rate, which may be caused by a 'cytokine storm'. However, there is little information on how cytokines and chemokines change over time in these patients. We aimed to describe the characteristics of HSES by examining changes in serum biomarker levels over time. Six patients with HSES were included. We retrospectively evaluated their clinical course and imaging/laboratory data. We measured serum levels of multiple cytokines [interleukin 1ß (IL-1ß), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-gamma, and tumor necrosis factor alpha], chemokines (IL-8, monocyte chemoattractant protein-1, interferon-inducible protein-10), and growth and differentiation factor (GDF)-15. The highest cytokine and chemokine levels were noted in the first 24 h, and decreased thereafter. The GDF-15 level was markedly high. Cytokine, chemokine, and GDF-15 levels were significantly higher in patients with HSES than in controls in the first 24 h, except for IL-2 and IL-4. Patients with HSES have high inflammatory cytokine and chemokine levels, a high GDF-15 level in the first 24 h, and high lactate levels. Our study provides new insights on the pathophysiology of HSES, a detailed clinical picture of patients with HSES, and potential biomarkers.

Early non-convulsive seizures are associated with the development of acute encephalopathy with biphasic seizures and late reduced diffusion.

INTRODUCTION: Children with either febrile seizure or acute encephalopathy exhibit seizures and/or impaired consciousness accompanied by fever of unknown etiology (SICF). Among children with SICF, we previously reported those who have refractory status epilepticus or prolonged neurological abnormalities with normal AST levels are at a high risk for the development of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), considered to be caused by excitotoxicity. Non-convulsive seizures (NCS) are common in critically ill children and cause excitotoxic neuronal injury. The aim of this study was to elucidate the prevalence of NCS in the acute phase of children at a high risk for developing AESD and the relationship between NCS in the acute phase and neurological outcomes. METHODS: We studied 137 children with SICF at a high risk for developing AESD and who underwent continuous electroencephalogram monitoring (cEEG) upon admission to a tertiary pediatric care center at Hyogo Prefectural Kobe Children's Hospital between October 2007 and August 2018. Patient characteristics and outcomes were compared between patients with NCS and without NCS. RESULTS: Of the 137 children, NCS occurred in 30 children; the first NCS were detected in cEEG at the beginning in 63.3%, during the first hour in 90%, and within 12 h in 96.7%. Neurological sequelae were more common in NCS patients (20.0%) than in non-NCS patients (1.9%; p = 0.001). Five in 30 NCS patients (16.7%) and 3 in 107 non-NCS patients (2.8%) developed AESD (p = 0.013). CONCLUSION: The occurrence of NCS is associated with subsequent neurological sequelae, especially the development of AESD.

Prevalence of Wilson disease based on genome databases in Japan.

BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B gene. In 1984, Scheinberg and Sternlieb estimated the prevalence of WD to be 1:30 000. However, recent epidemiological studies have reported increasing prevalence rates in different populations. The carrier frequency of ATP7B variants and the prevalence of WD in the Japanese population have not been reported using multiple databases. METHODS: Multiple public databases were used. First, we included mutations in the ATP7B gene that were registered in the Human Gene Mutation Database (HGMD) Professional, where 885 ATP7B variants were identified as pathogenic. Next, we investigated the allele frequencies of these 885 variants in Japanese individuals using the Human Genetic Variation Database (HGVD) and the Japanese Multi Omics Reference Panel (jMorp). RESULTS: Of the 885 variants of ATP7B, 7 and 12 missense and nonsense variants, zero and three splicing variants, and zero and two small deletions were found in the HGVD and in jMorp, respectively. The total allele frequencies of the ATP7B mutations were 0.011 in the HGVD and 0.014 in the jMorp. According to these data, the carrier frequencies were 0.022 (2.2%) and 0.028 (2.8%), respectively, and patient frequencies were 0.000121 (1.21/10 000 individuals) and 0.000196 (1.96/10 000 individuals), respectively. CONCLUSIONS: This is the first study to report the carrier frequency of ATP7B variants and the prevalence of WD in Japan using multiple databases. The calculated prevalence of WD was comparatively higher than that of previous reports, indicating previous underdiagnosis or the existence of less severe phenotypes.

Seizure prevalence in children aged up to 3 years: a longitudinal population-based cohort study in Japan.

OBJECTIVE: To investigate the prevalence of seizures/febrile seizures in children up to 3 years of age and examine the effects of gestational age at birth on the risk for febrile seizures. DESIGN: Retrospective longitudinal population-based cohort study. SETTING: Kobe City public health center, Kobe, Japan, from 2010 to 2018. PARTICIPANTS: Children who underwent a medical check-up at 3 years of age. METHODS: Information regarding seizures was collected from the parents of 96 014 children. We identified the occurrence of seizure/febrile seizure in 74 017 children, whose gestational ages at birth were noted. We conducted a multivariate analysis with the parameter, gestational age at birth, to analyse the risk of seizure. We also stratified the samples by sex and birth weight (<2500 g or not) and compared the prevalence of seizure between those with the term and late preterm births. RESULTS: The prevalence of seizure was 12.1% (11.8%-12.3%), 13.2% (12.2%-14.4%), 14.6% (12.4%-17.7%) and 15.7% (10.5%-22.8%) in children born at 37-41, 34-36, 28-33 and 22-27 gestational weeks, respectively. The prevalence of febrile seizures was 9.0% (8.8%-9.2%), 10.5% (9.5%-11.5%), 11.8% (9.7%-14.5%) and 11.2% (6.9%-17.7%) in children born at 37-41, 34-36, 28-33 and 22-27 gestational weeks, respectively. Male was an independent risk factor for seizures (OR: 1.15, 95% CI 1.09 to 1.20; absolute risk increase 0.014, 95% CI 0.010 to 0.019) and febrile seizures (OR: 1.21, 95% CI 1.15 to 1.28; absolute risk increase 0.016, 95% CI 0.012 to 0.020), respectively. Late preterm birth was not associated with an increased risk of seizure/febrile seizure. CONCLUSIONS: Although very preterm birth may increase the risk of seizure/febrile seizure, the risk associated with late preterm birth is considerably small and less than that associated with male.

Thiamylal anaesthetic therapy for febrile refractory status epilepticus in children.

PURPOSE: To evaluate barbiturate anaesthetic therapy using thiamylal for febrile refractory status epilepticus (fRSE) in children. METHODS: This was a review of a prospectively-collected database between April 2012-March 2016 for fRSE cases treated with thiamylal anaesthetic therapy in a single paediatric hospital in Japan. The sample comprised 23 children (median age, 23 months) with fRSE that underwent thiamylal anaesthetic therapy for convulsive seizures lasting longer than 60 min, sustained after intravenous administration of benzodiazepine and non-benzodiazepine anticonvulsants. The intervention comprised protocol-based thiamylal anaesthetic therapy with bolus administration. We measured the dose and time required to achieve the burst suppression pattern (BSP) on electroencephalography, seizure recurrence, death, neurological sequelae, and complications. RESULTS: All patients except one reached the BSP. The thiamylal median dose until reaching the BSP was 27.5 mg/kg, and the median time from thiamylal administration to reaching the BSP was 109.5 min. There was one case of immediate treatment failure and one of withdrawal seizure, but no breakthrough seizure. No deaths occurred during treatment, and neurological sequelae occurred in four cases (17%). Vasopressors were administered in all cases. Other complications included 11 cases of pneumonia and one of enterocolitis. CONCLUSION: We revealed the time and dose required to reach the BSP with thiamylal anaesthetic therapy using bolus administration in children. Our results suggested that reaching the BSP with bolus administration requires markedly less time than without bolus administration, rarely causes seizure recurrence in paediatric fRSE, and causes haemodynamic dysfunction and infections as often as observed without bolus administration.

Detailed characteristics of acute encephalopathy with biphasic seizures and late reduced diffusion: 18-year data of a single-center consecutive cohort.

OBJECTIVE: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a syndrome characterized by biphasic seizures with impaired consciousness. AESD is rare outside Asia, and consecutive cohort studies are therefore scarce. Herein, we aimed to describe the detailed characteristics of AESD, including clinical course, electroencephalogram data, laboratory data, imaging findings, treatment, and outcomes. METHODS: We reviewed the clinical database and medical charts of 43 consecutive pediatric patients (<18 years old) who developed AESD between October 1, 2002, and September 30, 2019. RESULTS: We found that AESD occurred even though patients did not develop prolonged seizures. A comparison between the two groups (first seizure duration <30 min and first seizure duration ≥30 min) revealed three main findings: first, patients with AESD who had shorter seizures had better prognosis than those with prolonged seizures; second, patients with AESD who had shorter seizures tended to have earlier occurrence of a second seizure; and third, high signal intensity on diffusion-weighted magnetic resonance imaging was observed mainly in frontal areas, not diffusely, in patients with shorter seizures, and in a broader area in patients with prolonged seizures. CONCLUSIONS: Our description of the detailed clinical picture of AESD may add new insight into its pathophysiology.

Detailed clinical course of fatal acute encephalopathy in children.

OBJECTIVE: Although the mortality among previously healthy children with acute encephalopathy (AE) is approximately 5%, their detailed clinical course has not been clarified. The objective of the present study was to describe the detailed clinical course, in minutes, of fatal AE. METHODS: We retrospectively reviewed the medical records of five patients (from 6 months to 14 years of age) who previously had no neurological disorders and were diagnosed with brain death due to AE between 2002 and 2018 at Kobe Children's Hospital. RESULTS: The initial clinical symptoms were convulsion in three cases and impaired consciousness in two. The earliest noted brain imaging abnormality was 7.5 h after neurological symptom detection. Liver enzymes and creatinine levels increased at initial examination, and sodium elevated gradually. All patients met the criteria of systemic inflammatory response syndrome, disseminated intravascular coagulation, and shock within 14 h of symptom detection. High dose steroids and targeted temperature management were initiated 3.5-14 h after onset. Despite these therapies, patients were diagnosed with brain death from 16 h to 4 days after initial neurological symptoms. AE diagnoses were made between 4 h 29 min and 4 days after initial neurological symptoms and included hemorrhagic shock and encephalopathy syndromes, Reye-like syndrome, and acute necrotizing encephalopathy in two, two, and one patient(s), respectively. CONCLUSIONS: We revealed the time series' of clinical events (e.g. SIRS, shock, DIC, AE diagnosis, brain death, and treatments) and laboratory findings relative to initial neurological symptom in fatal AE.