Febrile Seizures in Children at the Departmental Teaching Hospital of OuéméPlateau: Etiologies and Risk Factors for Death

Background: Febrile seizures are the most frequent neurological disorder in pediatrics. They have multiple etiologies and require urgent management. The aim of this survey was to study febrile seizures in children at the Departmental Teaching Hospital of Ouémé Plateau (DTH/OP). Method: This was a cross-sectional survey, conducted from January 1, 2020, to December 31, 2020, in the pediatric department of the DTH/OP. Children aged 1 month to 18 years, hospitalized for febrile seizures recognized at the anamnesis and/or during the physical examination were included in this study. Results: The frequency of seizures was 17.08% (510/2986). The male to female ratio was equal to 1.4. The mean age was 44.27 ± 40.75 months. The seizure was generalized tonic-clonic in 77.9% of cases and localized in 11.6% of cases. The main etiologies were severe malaria (75.5%), sepsis (21.6%), enteric infections (14.9%) and pneumonia (10.2%). Diazepam was the anticonvulsant treatment used in the first intention (79.7%). Most of the children were hospitalized for 3 to 7 days. The recovery rate was 82.3% and the fatality rate was equal to 17.7%. Eight children presented sequelae. There was a statistically significant link between the children’s clinical outcome and age (p < 0.001);severe malaria (p < 0.001);sepsis (p < 0.001) and enteric infections (p = 0.003). Conclusion: Febrile seizures were frequent in the pediatric emergency department of the DTH/OP. There is a need to intensify sensitization on malaria prevention measures in the community and improve case management at the hospital.

IL-1β: an important cytokine associated with febrile seizures?

Febrile seizures （FSs） are the most common convulsions in childhood. Studies have demonstrated a significant relationship between a history of prolonged FSs during early childhood and temporal sclerosis, which is responsible for intractable mesial temporal lobe epilepsy. It has been shown that interleukin-1β （IL-1β） is intrinsically involved in the febrile response in children and in the generation of FSs. We summarize the gene polymorphisms, changes of IL-1β levels and the putative role of IL-1β in the generation of FSs. IL-1β could play a role either in enhancing or in reducing neural excitability. If the enhancing and reducing effects are balanced, an FS does not occur. When the enhancing effect plays the leading role, an FS is generated. A mild imbalance can cause simple FSs while a severe imbalance can cause complex FSs and febrile status epilepticus. Therefore, anti-IL-1β therapy may help to treat FSs.

Generation of Febrile Seizures and Subsequent Epileptogenesis

Febrile seizures（FSs） occur commonly in children aged from 6 months to 5 years. Complex（repetitive or prolonged） FSs, but not simple FSs, can lead to permanent brain modification. Human infants and immature rodents that have experienced complex FSs have a high risk of subsequent temporal lobe epilepsy. However, the causes of FSs and the mechanisms underlying the subsequent epileptogenesis remain unknown. Here, we mainly focus on two major questions concerning FSs： how fever triggers seizures, and how epileptogenesis occurs after FSs. The risk factors responsible for the occurrence of FSs and the epileptogenesis after prolonged FSs are thoroughly summarized and discussed. An understanding of these factors can provide potential therapeutic targets for the prevention of FSs and also yield biomarkers for identifying patients at risk of epileptogenesis following FSs.

Effects of febrile seizures in mesial temporal lobe epilepsy with hippocampal sclerosis on gene expression using bioinformatical analysis

Background:To investigate the effect of long-term febrile convulsions on gene expression in mesial temporal lobe epilepsy with hippocampal sclerosis(MTLE-HS)and explore the molecular mechanism of MTLE-HS.Methods:Microarray data of MTLE-HS were obtained from the Gene Expression Omnibus database.Differentially expressed genes(DEGs)between MTLE-HS with and without febrile seizure history were screened by the GEO2R software.Pathway enrichment and gene ontology of the DEGs were analyzed using the DAVID online database and FunRich software.Protein–protein interaction(PPI)networks among DEGs were constructed using the STRING database and analyzed by Cytoscape.Results:A total of 515 DEGs were identified in MTLE-HS samples with a febrile seizure history compared to MTLEHS samples without febrile seizure,including 25 down-regulated and 490 up-regulated genes.These DEGs were expressed mostly in plasma membrane and synaptic vesicles.The major molecular functions of those genes were voltage-gated ion channel activity,extracellular ligand-gated ion channel activity and calcium ion binding.The DEGs were mainly involved in biological pathways of cell communication signal transduction and transport.Five genes(SNAP25,SLC32A1,SYN1,GRIN1,and GRIA1)were significantly expressed in the MTLE-HS with prolonged febrile seizures.Conclusion:The pathogenesis of MTLE-HS involves multiple genes,and prolonged febrile seizures could cause differential expression of genes.Thus,investigations of those genes may provide a new perspective into the mechanism of MTLE-HS.

Gender difference in acquired seizure susceptibility in adult rats after early complex febrile seizures

Gender differences are involved in many neurological disorders including epilepsy. However, little is known about the effect of gender difference on the risk of epilepsy in adults with a specific early pathological state such as complex febrile seizures（FSs） in infancy. Here we used a well-established complex FS model in rats and showed that：（1） the susceptibility to seizures induced by hyperthermia, pentylenetetrazol（PTZ）, and maximal electroshock（MES） was similar in male and female rat pups, while males were more susceptible to PTZ- and MES-induced seizures than age-matched females in normal adult rats;（2） adult rats with complex FSs in infancy acquired higher seizure susceptibility than normal rats; importantly, female FS rats were more susceptible to PTZ and MES than male FS rats; and（3） the protein expression of interleukin-1β, an infl ammatory factor associated with seizure susceptibility, was higher in adult FS females than in males, which may reflect a gender-difference phenomenon of seizure susceptibility. Our results provide direct evidence that the acquired seizure susceptibility after complex FSs is gender-dependent.

Early hypoactivity of hippocampal rhythms during epileptogenesis after prolonged febrile seizures in freely-moving rats

Prospective and experimental studies have shown that individuals with early-life complex/prolonged febrile seizures （FSs） have a high incidence of temporal lobe epilepsy during adulthood, revealing a close relationship between FSs and epilepsy. However, little is known about how epileptogenesis develops after FSs. The present study was designed to investigate acquired seizure susceptibility and analyze local field potentials during the latent period after FSs. We found that the seizure susceptibility decreased in 35-day- old （P35） FS rats but increased in P60 FS rats. Consistently, hippocampal electroencephalogram （EEG） power in every band was decreased at P35 but increased at P60 in FS rats. Our results provide direct evidence for hypoactivity but not hyperactivity during the early phase of the latent period, displaying a broad decrease in hippocampal rhythms. These characteristic EEG changes can be a useful biomarker for the early diagnosis of epileptogenesis induced by FSs.

Association between GABRG2 rs211037 polymorphism and febrile seizures:a metaanalysis

Background:Emerging evidence has implied that the GABRG2 gene play a role in the mechanism of febrile seizure(FS),however,the relationship between GABRG2 rs211037 polymorphism and the risk of FS remains controversial.This meta-analysis was conducted to investigate the relationship of GABRG2 rs211037 polymorphism with the susceptibility to FS.Methods:MEDLINE,Embase,Cochrane Library and CNKI databases were searched(until April 6,2019)for eligible studies on the relationship between GABRG2 rs211037 polymorphism and FS.We calculated the odds ratios(ORs)by a fixed or random model with the STATA 15.0 software.Subgroup analyses for the ethnicity,the source of the control,and age and sex matching of controls were conducted.Results:A total of 8 studies consisting of 775 FS patients and 5162 controls were included in this study.Based on the overall data,he GABRG2 rs211037 polymorphism was not significantly associated with the risk of FS(TT+CT vs CC:OR=0.95,95%CI 0.64–1.41,P=0.80).Notably,the GABRG2 rs211037 variant was significantly associated with decreased risk of FS in Asian populations(TT vs CT+CC:OR=0.63,95%CI 0.45–0.88,P=0.006),but increased risk in Caucasian populations(CT vs CC:OR=1.56,95%CI 1.14–2.15,P=0.006).Significant associations were also detected when healthy controls out of the whole controls were employed for comparison(TT vs CT+CC:OR=0.59,95%CI 0.45–0.77,P<0.001)and when data from studies with age-and sex-matched controls were used(TT+CT vs CC:OR=0.60,95%CI 0.43–0.86,P=0.001).Conclusion:The GABRG2 rs211037 polymorphism may decrease the risk of FS in Asian populations,while increasing the risk in Caucasian populations.Further well-designed studies with large sample sizes are essential to verify the conclusions in other ethnicities.

Febrile seizure, but not hyperthermia alone, induces the expression of heme oxygenase-1 in rat cortex

Background Febrile seizure （FS） is the most common seizure disorders. Approximately one third of children with a febrile seizure have recurrent events. The mechanism of FS remains unclear. Heme oxygenase-1 （HO-1） is a member of the heat shock proteins family and can be induced in the brain by various stresses, including hyperthemia and seizure. This study aimed at investigating the changes of HO-1 in the cortex of rats after recurrent FS. Methods FS in rats was induced ten times, once every 2 days. In a bath of warm water, developing rats were randomly divided into two groups： control group （n=16） and warm water-treated group （n=50）. The latter group was subdivided into hyperthermia group （n=19） and FS group （n=23）. The expression and content of HO-1 mRNA in cortex were observed using in situ hybridization and quantitative reverse transcription-polymerase chain reaction （RT-PCR）. The content of HO- 1 protein in cortex was measured using Western blotting. Results HO-1 mRNA expression of cortex neurons in FS group was markedly increased in comparison with those in hyperthermia and control groups （P=0.00）, however, there was no statistic difference bftween hyperthermia group and control group （P=0.16）. The relative amount of HO- 1 mRNA in cortex in FS group was increased by 53.13% and 96% in comparison with those in hyperthermia group and control group respectively （P=0.00）, but there was no obvious difference between the later two groups （P=0.051）. Western blotting analysis showed that the HO-1 protein content in cortex in FS group was increased by 198% and 246% in comparison with those in hyperthermia group and control group respectively （P=0.00）. There was no obvious difference in HO-1 protein content between the later two groups （P=0.09）. Conclusions Recurrent FS in rats can cause the increase of HO-1 mRNA and protein in cortex which may be involved in the mechanism of FS. The short-time recurrent hyperthermia can not induce the increase of HO-1 mRNA and protein.

Temporal lobe epilepsy associated with human herpes virus 6

Human herpes virus 6(HHV-6)is a ubiquitous and most common pathogen that affects humans.Human herpes virus 6B(HHV-6B)is a wide spread human herpesvirus that infects most people when they are children,establishes latent infections in the central nervous system(CNS),especially in the hippocampus and amygdala,and induces neurologic diseases.HHV-6 can establish a latent infection and be reactivated by various stimuli.Recently,viral genomic DNA of HHV-6B has been detected in surgically removed brain tissues of intractable epilepsy patients,suggesting the involvement of HHV-6B in the pathogenesis of epilepsy.Temporal lobe epilepsy(TLE)has been shown to be closely related with HHV-6B.TLE patients with HHV-6B in their brains suffer from reiterative attacks of febrile seizures and hippocampal sclerosis.However,the mechanisms underlying the contribution of this virus to the development of TLE remains unknown.The direct damage and immune activation caused by the virus are involved in the process of neuron damage,abnormal neural circuit formation and glial cell proliferation.In addition,some cytokines like interleukin-17A(IL-17A),nuclear factor-kappa B(NF-κb),transforming growth factor-β(TGF-β),mitogen-activated protein kinase(MAPK)and phospholipase A2 are up-regulated and involved in the pathological process of TLE.More studies are needed to clarify the mechanisms underlying the link between HHV-6B and epilepsy,and identify biomarkers to recognize different patient groups for anti-inflammatory or immunomodulatory therapies.