Additive interaction between birth asphyxia and febrile seizures on autism spectrum disorder: a population-based study.

BACKGROUND: Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder that can significantly impact an individual's ability to socially integrate and adapt. It's crucial to identify key factors associated with ASD. Recent studies link both birth asphyxia (BA) and febrile seizures (FS) separately to higher ASD prevalence. However, investigations into the interplay of BA and FS and its relationship with ASD are yet to be conducted. The present study mainly focuses on exploring the interactive effect between BA and FS in the context of ASD. METHODS: Utilizing a multi-stage stratified cluster sampling, we initially recruited 84,934 Shanghai children aged 3-12 years old from June 2014 to June 2015, ultimately including 74,251 post-exclusion criteria. A logistic regression model was conducted to estimate the interaction effect after controlling for pertinent covariates. The attributable proportion (AP), the relative excess risk due to interaction (RERI), the synergy index (SI), and multiplicative-scale interaction were computed to determine the interaction effect. RESULTS: Among a total of 74,251 children, 192 (0.26%) were diagnosed with ASD. The adjusted odds ratio for ASD in children with BA alone was 3.82 (95% confidence interval [CI] 2.42-6.02), for FS alone 3.06 (95%CI 1.48-6.31), and for comorbid BA and FS 21.18 (95%CI 9.10-49.30), versus children without BA or FS. The additive interaction between BA and FS showed statistical significance (P < 0.001), whereas the multiplicative interaction was statistically insignificant (P > 0.05). LIMITATIONS: This study can only demonstrate the relationship between the interaction of BA and FS with ASD but cannot prove causation. Animal brain experimentation is necessary to unravel its neural mechanisms. A larger sample size, ongoing monitoring, and detailed FS classification are needed for confirming BA-FS interaction in ASD. CONCLUSION: In this extensive cross-sectional study, both BA and FS were significantly linked to ASD. The coexistence of these factors was associated with an additive increase in ASD prevalence, surpassing the cumulative risk of each individual factor.

An overview of risk factors in children with febrile seizures.

INTRODUCTION: Febrile seizures (FS) are the most common neurologic disorder seen in children. Caused mainly by fever without any damage to the central nervous system (CNS). The associations of several factors, which we can find in the inflammatory response and genetic predisposition, are involved in the occurrence of FS. AIM: This review provides insight into risk factors, particularly the involvement of the inflammatory response and genetic susceptibility in the occurrence of FS. METHODS: A PubMed search was performed using the keywords « febrile seizures ¼, « inflammatory response ¼, « Pro-inflammatory cytokines ¼, «And anti-inflammatory cytokines ¼. The search strategy included meta-analyses, prospective case-control studies, clinical trials, observational studies, and reviews. RESULTS: Febrile seizures with a peak incidence of 18 months usually occur between 6 months and 5 years. A variety of genetic, inflammatory, and environmental factors, including viruses and vaccines, trigger FS. A positive family history of febrile seizures increases the risk for FS occurrence with (20%) in siblings and (33%) in one parent. The involvement of inflammatory response genes, including the cytokine genes IL1B, IL1R, IL6, and IL4. According to these findings, FS is associated with the activation of a cascade of pro- and anti-inflammatory cytokines and the unbalance between these cytokines in the inflammation regulation plays a role in the development of FS. CONCLUSION: Current knowledge suggests that genetic susceptibility and inflammatory response dysregulation contribute to FS's genesis.

Higher Risk of Psychiatric Disorders in Children With Febrile Seizures: A Nationwide Cohort Study in Taiwan.

BACKGROUND: Febrile seizures occur commonly in children aged between six months and six years. A previous Danish study found a positive correlation between febrile seizures and the overall incidence of psychiatric disorders. This population-based nationwide observational study was conducted to investigate the association between febrile seizures and different psychiatric disorders in Taiwan and the associated risk factors. METHODS: This cohort study used data from the National Health Insurance Research Database in Taiwan-a nationwide claims database covering >99% of the Taiwanese population. The study period was from January 2000 to December 2015; the overall median follow-up time was 11.04 ± 10.95 years. Overall, 2464 children with febrile seizures diagnosed between 2000 and 2015 met the inclusion criteria, and 7392 children without febrile seizures matched by index year, age, and sex were included in the control cohorts. Febrile seizures and psychiatric disorders were measured as the exposure and main outcomes, respectively. RESULTS: Children with febrile seizures (n = 2463) were at a high risk of psychiatric disorders (adjusted hazard ratio, 4.70; 95% confidence interval [CI], 2.44 to 7.30; P < 0.001). The risk for anxiety was the highest (adjusted hazard ratio, 21.92; 95% CI, 11.40 to 34.05; P < 0.001). CONCLUSIONS: When treating children with febrile seizures, particular attention should be paid to the symptoms of psychiatric disorders, as early referral may be beneficial for these children.

Ascorbic acid mitigates the impact of oxidative stress in a human model of febrile seizure and mesial temporal lobe epilepsy.

Prolonged febrile seizures (FS) in children are linked to the development of temporal lobe epilepsy (MTLE). The association between these two pathologies may be ascribed to the long-term effects that FS exert on neural stem cells, negatively affecting the generation of new neurons. Among the insults associated with FS, oxidative stress is noteworthy. Here, we investigated the consequences of exposure to hydrogen peroxide (H2O2) in an induced pluripotent stem cell-derived neural stem cells (iNSCs) model of a patient affected by FS and MTLE. In our study, we compare the findings from the MTLE patient with those derived from iNSCs of a sibling exhibiting a milder phenotype defined only by FS, as well as a healthy individual. In response to H2O2 treatment, iNSCs derived from MTLE patients demonstrated an elevated production of reactive oxygen species and increased apoptosis, despite the higher expression levels of antioxidant genes and proteins compared to other cell lines analysed. Among the potential causative mechanisms of enhanced vulnerability of MTLE patient iNSCs to oxidative stress, we found that these cells express low levels of the heat shock protein HSPB1 and of the autophagy adaptor SQSTM1/p62. Pre-treatment of diseased iNSCs with the antioxidant molecule ascorbic acid restored HSBP1 and p62 expression and simultaneously reduced the levels of ROS and apoptosis. Our findings suggest the potential for rescuing the impaired oxidative stress response in diseased iNSCs through antioxidant treatment, offering a promising mechanism to prevent FS degeneration in MTLE.

Predicting factors for acute encephalopathy in febrile seizure children with SARS-CoV-2 omicron variant: a retrospective study.

BACKGROUND: SARS-CoV-2 posed a threat to children during the early phase of Omicron wave because many patients presented with febrile seizures. The study aimed to investigate predicting factors for acute encephalopathy of children infected by SARS-CoV-2 Omicron variant presenting with febrile seizures. METHODS: The retrospective study analyzed data from pediatric patients who visited the emergency department of Chang Gung Memorial Hospital in Taiwan between April and July 2022. We specifically focused on children with COVID-19 who presented with febrile seizures, collecting demographic, clinical, and laboratory data at the pediatric emergency department, as well as final discharge diagnoses. Subsequently, we conducted a comparative analysis of the clinical and laboratory characteristics between patients diagnosed with acute encephalopathy and those with other causes of febrile seizures. RESULTS: Overall, 10,878 children were included, of which 260 patients presented with febrile seizures. Among them, 116 individuals tested positive for SARS-CoV-2 and of them, 14 subsequently developed acute encephalopathy (12%). Those with acute encephalopathy displayed distinctive features, including older age (5.1 vs. 2.6 years old), longer fever duration preceding the first seizure (1.6 vs. 0.9 days), cluster seizure (50% vs. 16.7%), status epilepticus (50% vs. 13.7%) and occurrences of bradycardia (26.8% vs. 0%) and hypotension (14.3% vs. 0%) in the encephalopathy group. Besides, the laboratory findings in the encephalopathy group are characterized by hyperglycemia (mean (95% CI) 146 mg/dL (95% CI 109-157) vs. 108 mg/dL (95% CI 103-114) and metabolic acidosis (mean (95% CI) pH 7.29(95% CI 7.22-7.36) vs. 7.39 (95%CI 7.37-7.41)). CONCLUSIONS: In pediatric patients with COVID-19-related febrile seizures, the occurrence of seizures beyond the first day of fever, bradycardia, clustered seizures, status epilepticus, hyperglycemia, and metabolic acidosis should raise concerns about acute encephalitis/encephalopathy. However, the highest body temperature and the severity of leukocytosis or C-reactive protein levels were not associated with poor outcomes.

[Analysis of three Chinese pedigrees affected with Genetic epilepsy with febrile seizures plus due to variants of SCN1A gene].

OBJECTIVE: To analyze the clinical and genetic characteristics of three Chinese pedigrees affected with Genetic epilepsy with febrile seizures plus (GEFS+). METHODS: Three GEFS+ probands and their pedigree members presented at the Children's Hospital of Zhengzhou University from January 2020 to December 2021 were selected as the study subjects. Clinical data of the pedigrees were collected. Whole exome sequencing was carried out for the probands, and Sanger sequencing was used to verify the candidate variants. RESULTS: Proband 1 was a 3-year-and-2-month-old male with febrile seizure plus. His father, two aunts, grandmother, aunt grandmother, uncle grandfather, and paternal great-grandmother also had onset of febrile seizures at 1 ~ 2 years of age with remission before 6 years old. Proband 2 was a 1-year-and-4-month-old male with complex febrile seizure. His mother, maternal uncle, and maternal grandmother also had febrile seizures before 5 ~ 6 years of age. Proband 3 was a 3-year-and-11-month-old male with febrile seizure plus. His father and grandfather also had febrile seizures plus with remission at 7 ~ 8 years of age. Genetic testing revealed that proband 1 had harbored a paternally derived heterozygous SCN1A: c.1613T>C variant, proband 2 had harbored a maternally derived heterozygous SCN1A: c.2804A>G variant, and proband 3 had harbored a paternally derived heterozygous SCN1A: c.1271T>C variant. All of the three variants were predicted as likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (PM1+PM2_Supporting+PP1+PP3+PP4). CONCLUSION: The c.1613T>C, c.2804A>G and c.1271T>C variants probably underlay the pathogenesis of GEFS+ in these pedigrees.

Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies.

OBJECTIVE: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood. METHODS: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. RESULTS: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ2 = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS. SIGNIFICANCE: Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.

Neurological and immunological adverse events after pneumococcal conjugate vaccine in children using national immunization programme registry data.

BACKGROUND: Despite the general consensus on the safety of pneumococcal conjugate vaccine (PCV), safety concerns unveiled during post-licensure surveillance need to be addressed. We investigated whether there is a transient increased risk following a three-dose series of pneumococcal conjugate vaccine (PCV) administered at 2, 4 and 6 months of age. METHODS: This was a population-based cohort study using the Korea immunization registry data linked to nationwide administrative claims data. Self-controlled risk interval analysis was conducted for PCV recipients who had an outcome of interest within pre-defined risk and control intervals between 2018 and 2022. The outcomes were anaphylaxis, asthma, encephalopathy, febrile seizure, Kawasaki disease and thrombocytopenia. We used conditional Poisson regression model to estimate the incidence rate ratios (IRRs) and 95% confidence intervals (CIs) comparing the outcomes in the risk and control intervals. RESULTS: Of 1 114 096 PCV recipients, 8661 had outcomes either in the risk or control intervals. Their mean age at Dose 1 was 10.0 weeks, 58.3% were boys, and 85.3% received 13-valent PCV. PCV was not associated with an increased risk of any outcomes except for febrile seizure. There were 408 (56.0%) cases of febrile seizure in the risk interval, corresponding to an IRR of 1.27 (95% CI 1.10-1.47). CONCLUSIONS: It is reassuring to note that there was no increased risk of the potential safety concerns following PCV administration. Despite the transient increased risk of febrile seizure, absolute numbers of cases were small. Febrile seizure is generally self-limiting with a good prognosis, and should not discourage parents or caregivers from vaccinating their children.

A Systematic Review and Clinical Presentation of Central Nervous System Complications of Severe Acute Respiratory Syndrome Coronavirus 2 in Hospitalized Pediatric Patients During the Coronavirus Disease 2019 Pandemic in Israel.

BACKGROUND: Coronavirus disease-associated central nervous system complications (CNS-C) in hospitalized children, especially during the Omicron wave, and in comparison with influenza associated CNS-C, are not well understood. METHODS: The study population included 755 children aged <18 years hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at Sheba Medical Center, during March 2020 to July 2022. A comparative cohort consisted of 314 pediatric patients with influenza during the 2018-2019 and 2019-2020 influenza seasons. RESULTS: Overall, 5.8% (n = 44) of patients exhibited CNS-C. Seizures at presentation occurred in 33 patients with COVID-19 (4.4%), with 2.6% (n = 20) experiencing nonfebrile seizures, 1.1% (n = 8) febrile seizures, and 0.7% (n = 5) status epilepticus. More patients with CNS-C experienced seizures during the Omicron wave versus the pre-Omicron period (77.8% vs 41.2%, P = 0.03). Fewer patients were admitted to the intensive care unit in the Omicron wave (7.4%) versus prior waves (7.4% vs 41.2%, P = 0.02). Fewer patients with SARS-CoV-2 experienced CNS-C (5.8%) versus patients with influenza (9.9%), P = 0.03. More patients with SARS-CoV-2 experienced nonfebrile seizures (2.6% vs 0.6%, P = 0.06), whereas more patients with influenza experienced febrile seizures (7.3% vs 1.1%, P < 0.01). CONCLUSIONS: The Omicron wave was characterized by more seizures and fewer intensive-care-unit admissions than previous waves. Pediatric patients with SARS-CoV-2 experienced fewer CNS-C and more nonfebrile seizures compared with patients with influenza.

Developmental patterning function of GNOM ARF-GEF mediated from the cell periphery.

The GNOM (GN) Guanine nucleotide Exchange Factor for ARF small GTPases (ARF-GEF) is among the best studied trafficking regulators in plants, playing crucial and unique developmental roles in patterning and polarity. The current models place GN at the Golgi apparatus (GA), where it mediates secretion/recycling, and at the plasma membrane (PM) presumably contributing to clathrin-mediated endocytosis (CME). The mechanistic basis of the developmental function of GN, distinct from the other ARF-GEFs including its closest homologue GNOM-LIKE1 (GNL1), remains elusive. Insights from this study largely extend the current notions of GN function. We show that GN, but not GNL1, localizes to the cell periphery at long-lived structures distinct from clathrin-coated pits, while CME and secretion proceed normally in gn knockouts. The functional GN mutant variant GNfewerroots, absent from the GA, suggests that the cell periphery is the major site of GN action responsible for its developmental function. Following inhibition by Brefeldin A, GN, but not GNL1, relocates to the PM likely on exocytic vesicles, suggesting selective molecular associations en route to the cell periphery. A study of GN-GNL1 chimeric ARF-GEFs indicates that all GN domains contribute to the specific GN function in a partially redundant manner. Together, this study offers significant steps toward the elucidation of the mechanism underlying unique cellular and development functions of GNOM.

Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes.

Mutations of the SCN1A gene, which encodes the voltage-dependent Na+ channel's α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes' variability in the family of five SCN1A gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing SCN1A-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype.

Feeding metformin during pregnancy and lactation periods improved learning and memory impairment in the rat offspring exposed to febrile seizure: Role of oxidative stress and inflammatory response.

BACKGROUND: Many clinical evidences have reported the higher risk of seizure in young children and infants after exposure to hyperthermia, which more likely can cause brain damage and affect cognitive function, so, many researches were focused on prevention or treatment of febrile seizure (FS) with minimal adverse effects. Considering the potential effects of oxidative stress as a prominent trigger in FS, and demonstrating the anti-oxidant effects of metformin, the present study aimed to investigate the protective effect of metformin administration in prenatal and lactation periods in rat pups exposed to hyperthermia by which induced seizure. METHOD AND MATERIALS: Pregnant rats were divided into six groups: (1) vehicle: pregnant rats received normal saline during pregnancy and lactation; (2) FS: pregnant rats received normal saline during pregnancy and lactation; (3-5) FS-Met50/100/150 mg/kg: pregnant rats received different doses of metformin including 50, 100 and 150 mg/kg during pregnancy and lactation; (6) Met150 mg/kg: pregnant rats received Met150 mg/kg during pregnancy and lactation. The male pups born to mothers received in all FS groups exposed to hyperthermia. All experimental groups were allowed to grow up, and after the lactation period, they were subjected for behavioural tests and biochemical analysis. RESULTS: According to the present findings, the prenatal and lactation exposure to the highest dose of metformin demonstrated significant difference with FS group in both behavioural and biochemical test analyses. Although the remaining doses of metformin were also effective, the much better results were reported with the highest dose of metformin (150 mg/kg). Interestingly, the highest dose of metformin administered alone demonstrated better result than vehicle in probe trial test. CONCLUSION: Considering the present research and related study in relation to metformin in ameliorating the epilepsy symptoms, there are numerous evidences on positive effect of metformin on seizure. Although the exact mechanism is unclear, the anti-oxidant effect of metformin is strongly supported.

Video Analyses of Sudden Unexplained Deaths in Toddlers.

BACKGROUND AND OBJECTIVES: More than 2,900 US children aged younger than 4 years die from unknown causes each year, accounting for more than 219,000 life years lost annually. They are mostly sleep-related and unwitnessed with unremarkable autopsies, limiting our understanding of death mechanisms. We sought to understand potential mechanisms of death by evaluating videos of sudden deaths in toddlers. METHODS: In our registry of 301 sudden unexplained child deaths, a series of 7 consecutively enrolled cases with home video recordings of the child's last sleep period were independently assessed by 8 physicians for video quality, movement, and sound. RESULTS: Four boys and 3 girls (13-27 months at death) with terminal videos shared similar demographic features to the 293 other registry cases without video recordings. Five video recordings were continuous and 2 were triggered by sound or motion. Two lacked audio. All continuous recordings included a terminal convulsive event lasting 8-50 seconds; 4 children survived for >2.5 minutes postconvulsion. Among discontinuous videos, time lapses limited review; 1 suggested a convulsive event. Six were prone with face down, and 1 had autopsy evidence of airway obstruction. Primary cardiac arrhythmias were not supported; all 7 children had normal cardiac pathology and whole-exome sequencing identified no known cardiac disease variants. DISCUSSION: Audio-visual recordings in 7 toddlers with unexplained sudden deaths strongly implicate that deaths were related to convulsive seizures, suggesting that many unexplained sleep-related deaths may result from seizures.

Epilepsy in dystrophinopathies: A retrospective cohort and review of the literature.

OBJECTIVE: This study aimed to assess the prevalence and characteristics of epilepsy in dystrophinopathies within a cohort of 142 patients at a tertiary neuromuscular center in Istanbul, Turkey. METHODS: We recorded the age at seizure onset, seizure type, family history, history of febrile seizures, treatment, and EEG results. Epilepsy was classified according to the latest International League Against Epilepsy (ILAE) classification. RESULTS: Of the 142 DMD patients, 8 experienced epileptic seizures (5.6 %). The median age of the patients was 11 years (8.0-15.2). The median age for the first DMD symptoms was 24 months (16.5-37.5). All seizures were consistent with generalized tonic-clonic seizures. Three patients are currently on anti-seizure medication. SIGNIFICANCE: The prevalence of epilepsy in our study (5.6 %) exceeds that of the general pediatric population (0.5-1 %). However, the frequency of febrile seizures in children with dystrophinopathy is similar to that of the general population.

Seizures and Sudden Death Beyond SUDEP.

Many physicians and researchers are familiar with the tragic phenomenon known as sudden infant death syndrome (SIDS), the leading cause of postneonatal mortality in high-resource countries. A less familiar category of unexplained deaths is the problem of sudden unexplained death in childhood (SUDC), a more rare and unusual presentation of sudden death in children who are no longer infants and whose reasons for death defy explanation. A substantial body of research in SUDC now supports the possibility of an overlap with epilepsy and associated sudden death in that context (SUDEP). Stemming from the first contemporary reports of SUDC, we have learned that a disproportionate number of these children have personal and/or family histories of febrile seizures,1 in many cases, inherited in an autosomal dominant manner.2 Their febrile seizures can be associated with abnormalities in their temporal lobes,3,4 including bilamination of the dentate gyrus and other findings conventionally associated with temporal lobe epilepsy, implicating potential epilepsy-related mechanisms.5 Further evaluation of this emerging epilepsy-related phenotype has led to the identification of genetic variants in SCN1A and other epilepsy-associated genes,6,7 moving SUDC away from being considered an unexplained phenomenon to one where the working hypothesis includes a role for genetic predisposition and epilepsy-like mechanisms in the deaths, even without an established history of epilepsy. Nonetheless, because the terminal events of these seemingly healthy children are unexpected and unobserved, the clinical manifestations of whatever underlying vulnerabilities exist-generally discovered posthumously-remain a matter of speculation.

Increased expression of NLRP3 associated with elevated levels of HMGB1 in children with febrile seizures: a case-control study.

BACKGROUND: High mobility group box-1 (HMGB1) is an endogenous danger signal that mediates activation of the innate immune response including NLR pyrin domain containing 3 (NLRP3) inflammasome activation and proinflammatory cytokine release. Although HMGB1 and NLRP3 have been implicated in the pathophysiology of seizures, the correlation between HMGB1 and NLRP3 expression has not been determined in children with febrile seizures (FS). To explore the relationship between extra-cellular HMGB1 and NLRP3 in children with FS, we analyzed serum HMGB1, NLRP3, caspase-1, and proinflammatory cytokines in patients with FS. METHODS: Thirty children with FS and thirty age-matched febrile controls were included in this study. Blood was obtained from the children with FS within 1 h of the time of the seizure; subsequently, the serum contents of HMGB1, NLRP3, caspase-1, interleukin (IL)-1ß, interleukin (IL)-6, and tumour necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. The Mann‒Whitney U test was used to compare serum cytokine levels between FS patients and controls. Spearman's rank correlation coefficient was calculated to detect significant correlations between cytokine levels. RESULTS: Serum levels of HMGB1, NLRP3, caspase-1, IL-1ß, IL-6, and TNF-α were significantly higher in FS patients than in febrile controls (p < 0.05). Serum levels of HMGB1 were significantly correlated with levels of NLRP3 and caspase-1 (both, p < 0.05). Serum levels of caspase-1 were significantly correlated with levels of IL-1ß (p < 0.05). Serum levels of IL-1ß were significantly correlated with levels of IL-6 and TNF-α (p < 0.05). CONCLUSIONS: HMGB1 is up-regulated in the peripheral serum of FS patients, which may be responsible, at least in part, for the increased expression of NLRP3 and Caspase-1. Increased expression of caspase-1 was significantly associated with elevated serum levels of IL-1ß. Given that activated Caspase-1 directly regulates the expression of mature IL-1ß and positively correlates with activation of the NLRP3 inflammasome, our data suggest that increased levels of peripheral HMGB1 possibly mediate IL-1ß secretion through the activation of the NLRP3 inflammasome in children with FS. Thus, both HMGB1 and NLRP3 might be potential targets for preventing or limiting FS.

Impact of Respiratory Viruses and SARS-CoV-2 on Febrile Seizures in Saudi Children: Insights into Etiologies, Gender, and Familial Associations.

BACKGROUND Childhood febrile seizures occur between 5 months and 6 years of age in children without a previous history of seizure and are associated with high temperature in the absence of intracranial infection. This retrospective study identified 71 children aged 6 months to 5 years with febrile seizures between 2017 and 2021 at a single center in Saudi Arabia and aimed to identify an association between common respiratory virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MATERIAL AND METHODS Pediatric nasopharyngeal specimens were tested using a multiplex PCR respiratory panel detecting human coronaviruses (NL63, 229E, OC43, HKU1), influenza A/B, human adenovirus, parainfluenza viruses 1-4, respiratory syncytial virus, human metapneumovirus, rhinovirus/enterovirus, Middle East respiratory syndrome coronavirus, and, as of September 2021, SARS-CoV-2, confirmed using the Cepheid Xpert Xpress SARS-CoV2 RT-PCR kit. RESULTS In a cohort of 71 pediatric patients (median age, 19 months; 54.9% female), dominant pathogens included human rhinovirus/enterovirus (23.9%), influenza A/B (26.8%), and SARS-CoV-2 (14.1%). Concurrent infections were noted in 28.2%. Simple seizures occurred in 69%, and complex seizures in 31%. Females exhibited an 8.18-fold increased risk for complex seizures. Each additional fever day reduced complex seizure risk by 36%. Familial seizure history increased risk 8.76-fold. Human rhinovirus/enterovirus or parainfluenza infections inversely affected complex seizure likelihood compared with adenovirus. CONCLUSIONS In Saudi children with febrile seizures, distinct viral etiologies, sex, and familial links play pivotal roles. Given regional viral variations, region-tailored diagnostic and therapeutic strategies are paramount. A multicenter prospective cohort study is essential for comprehensive understanding.

Distinctive Clinico-electrographic and Radiological Profile of Childhood and Adolescent Seizures.

AIM: Electroencephalogram (EEG) is specific, but not sensitive, for the diagnosis of epilepsy. This study aimed to correlate the clinico-electrographic and radiological features of seizure disorders in children attending a tertiary care centre in northern India. METHODS: Children aged between one to 18 years with seizure episodes were included. Clinical details, including historical as well as physical findings, were evaluated along with EEG and neuroimaging (Magnetic resonance imaging). Details were noted on pre-designed proforma. Variables were analysed by using appropriate statistical methods. RESULTS: A total of 110 children with seizures were enrolled in the study. Male to female ratio was 1.6: 1, and the mean age of the study children was 8 years. The majority of the children were symptomatic for more than one year. The most common seizure type was Generalised Tonic Clonic Seizure (GTCS), and Hypoxic-ischemic Encephalopathy (HIE) sequelae was the most commonly attributed etiology, followed by neurocysticercosis. EEG and neuroimaging findings were found to correlate well with seizure semiology from history. The incidence of febrile seizures was 10% in this study, with nearly three-fourths of them being simple febrile seizures. CONCLUSION: Microcephaly and developmental delay were the most distinctive clinical correlates in children with seizures. There was a fair agreement between the types of seizures described in history and depicted on EEG with Cohen's kappa of 0.4. Also, there was a significant association between the type of seizures on EEG and the duration of symptoms.

A nationwide survey of adenovirus-associated encephalitis/encephalopathy in Japan.

BACKGROUND: Adenovirus is a major pathogen causing febrile illness among children. It may also cause acute encephalitis/encephalopathy. This study aimed to elucidate the clinical features of adenovirus-associated encephalitis/encephalopathy (AdVE) among children in Japan. METHODS: A nationwide survey of children with AdVE was conducted. An initial survey was distributed among pediatricians to obtain information about children with AdVE treated between January 2014 and March 2019. A second survey was used to obtain the clinical information of children with AdVE from hospitals that responded to the initial survey and those identified from a literature search of the reported cases. We collected demographic data and information about symptoms of infection, neurological symptoms, laboratory parameters, treatment, and outcomes. Outcomes were determined using the Pediatric Cerebral Performance Category Score. RESULTS: Clinical information was available for 23 children with a median age of 39 months. Two had preexisting neurological disorders and six had a history of febrile seizures. The outcome was good in 15 patients and poor in eight patients. Serum lactate dehydrogenase, glucose, and ammonia levels were higher among children with a poor outcome compared to those with a good outcome. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion was the most common type (n = 8), followed by acute encephalopathy with biphasic seizures and late reduced diffusion (n = 7). CONCLUSION: A prior history of febrile seizures was frequent in children with AdVE. Several different subtypes of acute encephalopathy were seen in children with AdVE, and the outcome was poor in those with acute encephalopathy with biphasic seizures and late reduced diffusion and hemorrhagic shock and encephalopathy syndrome. Elevated lactate dehydrogenase, glucose, and ammonia levels on admission were found to correlate with a poor outcome.