Prolonged Febrile Seizures Research Articles

SCN1A Variants in vaccine-related febrile seizures: A prospective study.

Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures, and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet syndrome. Following vaccination, febrile seizures may raise the specter of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination or unrelated to vaccination compared to controls. We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n = 69) or as non-vaccine proximate (n = 75), and children with no history of seizures (n = 90) recruited in Australian pediatric hospitals. We detected 2 pathogenic variants in vaccine-proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and 1 in a non-vaccine-proximate case (p.V947L) who had febrile seizures plus from 9 months. All had generalized tonic-clonic seizures lasting >15 minutes. We also found enrichment of a reported risk allele, rs6432860-T, in children with febrile seizures compared to controls (odds ratio = 1.91, 95% confidence interval = 1.31-2.81). Pathogenic SCN1A variants may be identified in infants with vaccine-proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome, SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine. ANN NEUROL 2020;87:281-288.

Glycemic Status in Febrile Seizures

AbstractStress hyperglycemia is commonly identified in children with severe illness and previously normal glucose homeostasis. In the pediatric population febrile seizures are reported among stress-related conditions associated with stress hyperglycemia. The objective of this prospective study was to evaluate the possible association between blood glucose level and febrile seizure severity defined by fever degree, seizure type, seizure duration and hospitalization length. Among 167 febrile seizures the prevalence of stress hyperglycemia (blood glucose concentration over 150mg/dl) was 13.22%. There was a highly significant statistical association between seizure duration (exceeding 15 minutes) and increased blood glucose concentration (p= 0.001). Prolonged febrile seizures combined with high fever were significant risk factors for stress hyperglycemia. Further analysis on acute fluctuation of glycemia, persistence of hyperglycemia should be taken in consideration as possible prebdictive factor for stress hyperglycemia, by comparison to the peak blood glucose concentration .

Transgenerational deep sequencing revealed hypermethylation of hippocampal mGluR1 gene with altered mRNA expression of mGluR5 and mGluR3 associated with behavioral changes in Sprague Dawley rats with history of prolonged febrile seizure.

The impact of febrile seizure has been shown to transcend immediate generation with the alteration of glutamatergic pathway being implicated. However, transgenerational effects of this neurological disorder particularly prolonged febrile seizure (PFS) on neurobehavioral study and methylation profile is unknown. We therefore hypothesized that transgenerational impact of prolonged febrile seizure is dependent on methylation of hippocampal mGluR1 gene. Prolonged febrile seizure was induced on post-natal day (PND) 14, by injecting lipopolysaccharide (LPS; 217μg/kg ip) and kainic acid (KA; 1.83 mg/kg ip). Sucrose preference test (SPT) and Forced swim test (FST) were carried out in the first generation (F0) of animals at PND37 and PND60. The F0 rats were decapitated at PND 14, 37 and 60 which corresponded to childhood, adolescent and adulthood respectively and their hippocampal tissue collected. The second generation (F1) rats were obtained by mating F0 generation at PND 60 across different groups, F1 rats were subjected to SPT and FST test on PND 37 only. Decapitation of F1rats and collection of hippocampal tissues were done on PND 14 and 37. Assessment of mGluR5 and mGluR3 mRNA was done with PCR while mGluR1 methylation profile was assessed with the Quantitative MassARRAY analysis. Results showed that PFS significantly leads to decreased sucrose consumption in the SPT and increased immobility time in the FST in both generations of rats. It also leads to significant decrease in mGluR5 mRNA expression with a resultant increased expression of mGluR3 mRNA expression and hypermethylation of mGluR1 gene across both generations of rats. This study suggested that PFS led to behavioral changes which could be transmitted on to the next generation in rats.

Prolonged and unprolonged complex febrile seizures differently affect frontal theta brain activity

ObjectiveStudies have identified mild but persistent cognitive and functional deficits, which could be linked to each other, in children with complex febrile seizures (FS). Our aim was to investigate differences in brain activity in children with a history of complex FS, through a study paradigm notably associated with the development of learning capacities and using electroencephalographic (EEG) signal. To further increase our understanding of these differences, complex FS were studied separately depending on their type. MethodEEG was recorded in 43 children with past FS. Brain activity associated with auditory learning was investigated using a habituation paradigm, in which repetition suppression (RS) is typically found following stimulus repetition. Auditory stimuli were repeated three times, and each presentation were analysed separately in the time-frequency (TF) domain. A mixed-analysis of variance was used to assess differences in spectral power between stimulus repetition and FS type (simple vs complex prolonged; CP vs complex unprolonged; CUP). ResultsRepetition effects were found in the 3–6 Hz during 150–600 ms time window after stimulus onset at frontal sites (F(2, 40) = 5.645, p = 0.007, η2p = 0.220). Moreover, an interaction effect between stimulus repetition and FS type (F(4, 80) = 2.607, p = 0.042, η2p = 0.115) was found. Children with CP FS showed greater increase in spectral power in response to the first stimulus presentation, while children with CUP FS failed to show a RS pattern. SignificanceOur results show distinct abnormalities in brain activity to a habituation paradigm. We argue that these changes suggest children with CP FS may be hyperexcitable, while children with CUP FS show impaired habituation processes. Still, these differences may be associated with other clinical features linked to complex FS as well. Hence, the role of these differences in complex FS incidence and prognosis should be the subject of future studies.

Effect of a novel prolonged febrile seizure model on GABA associated ion channels.

Prolonged febrile seizures are usually modelled in animals using hyperthermia as an inducer. In this study, a modified simple febrile seizure model using a combination of lipopolysaccharide (LPS) and kainic acid (KA) was used to develop a prolonged febrile seizure animal model, which we used to assess effects on the expression of the sodium- potassium-chloride cotransporter 1 (NKCC1) and potassium-chloride cotransporter 2 (KCC2) and their possible role in seizure exacerbation. At post-natal day (PND) 14, rat pups were divided into a saline (S), simple febrile seizure (FSA-), prolonged febrile seizure (FSB-), saline A (SA+) and saline B (SB+) groups. SA+ and SB+ groups received different concentrations of KA (1.75mg/kg, 1.83μg/kg respectively) but no LPS. Changes in temperature, seizure activity and duration were recorded. Gene and protein expression of NKCC1, KCC2 and KCC2 phosphorylated serine (KCC2 ser) 940 were measured 1h post seizure termination and on PND 15 using RT- PCR and western blot. There was an initial increase in temperature that was immediately followed by a temperature decrease and an increase in seizure severity and duration in the FSB- group. There was a decrease in KCC2 ser 940 protein expression. NKCC1 protein expression was increased in both FS groups suggesting decreased GABA receptor functionality. Therefore, the novel FSB- model resulted in more severe and sustained seizure activity by altering cotransporter gene and protein expression. This suggests that this model can be used to mimic prolonged febrile seizures and hence can be used to investigate the physiological changes accompanying this condition.

Dexamethasone Attenuates Hyperexcitability Provoked by Experimental Febrile Status Epilepticus.

The role of neuroinflammation in the mechanisms of epilepsy development is important because inflammatory mediators provide tractable targets for intervention. Inflammation is intrinsically involved in the generation of childhood febrile seizures (FSs), and prolonged FS [febrile status epilepticus (FSE)] precedes a large proportion of adult cases of temporal lobe epilepsy (TLE). As TLE is often refractory to therapy and is associated with serious cognitive and emotional problems, we investigated whether its development can be prevented using anti-inflammatory strategies. Using an immature rat model of FSE [experimental FSE (eFSE)], we administered dexamethasone (DEX), a broad anti-inflammatory agent, over 3 d following eFSE. We assessed eFSE-provoked hippocampal network hyperexcitability by quantifying the presence, frequency, and duration of hippocampal spike series, as these precede and herald the development of TLE-like epilepsy. We tested whether eFSE provoked hippocampal microgliosis, astrocytosis, and proinflammatory cytokine production in male and female rats and investigated blood–brain barrier (BBB) breaches as a potential contributor. We then evaluated whether DEX attenuated these eFSE sequelae. Spike series were not observed in control rats given vehicle or DEX, but occurred in 41.6% of eFSE-vehicle rats, associated with BBB leakage and elevated hippocampal cytokines. eFSE did not induce astrocytosis or microgliosis but provoked BBB disruption in 60% of animals. DEX significantly reduced spike series prevalence (to 7.6%) and frequency, and abrogated eFSE-induced cytokine production and BBB leakage (to 20%). These findings suggest that a short, postinsult intervention with a clinically available anti-inflammatory agent potently attenuates epilepsy-predicting hippocampal hyperexcitability, potentially by minimizing BBB disruption and related neuroinflammation.

Long-term outcomes after childhood convulsive status epilepticus.

It is widely accepted that childhood convulsive status epilepticus (CSE) has associated short-term and long-term mortality and morbidity. However, the role of CSE itself on subsequent adverse outcomes is still debated. In addition, whether prolonged seizures cause any long-term hippocampal injury and developmental or memory impairment is uncertain. In this review, we aim to provide an overview of long-term outcomes after childhood CSE, highlighting data from recent literature on this subject. Long-term outcome after childhood CSE is favorable in previously normal children, with low incidence of epilepsy, motor and intellectual disability, behavioral impairment and need for special educational provision. Mesial temporal sclerosis is uncommon in children after prolonged febrile seizures. There is substantial morbidity after childhood CSE, but this is seen primarily in children with symptomatic causes and preexisting neurological abnormalities. Cause is the primary determinant of outcomes after childhood CSE and the additional effect of CSE characteristics such as seizure duration seems to be less than previously believed. Childhood CSE is associated with substantial neurological, cognitive and behavioral morbidity. Early identification of these difficulties and appropriate intervention are likely to have a major positive impact on their quality of life.

Febrile Status Epilepticus

AbstractFebrile status epilepticus (FSE) is defined as a febrile seizure lasting 30 minutes or more and is considered the extreme end of the complex febrile seizure spectrum. It remains unclear why some children are predisposed to the development of FSE compared with others. FSE is considered as medical emergency and as such, early treatment is crucial. The consequences of FSE have been a topic of interest for many years, specially its association with temporal lobe epilepsy and hippocampal sclerosis. In this article, we review the epidemiology, risk factors, pathophysiology, treatment, and prognosis including findings from the “Consequences of Prolonged Febrile Seizures in Childhood” (FEBSTAT) study.

DNA methyltransferase isoforms expression in the temporal lobe of epilepsy patients with a history of febrile seizures

BackgroundTemporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) is a common pharmaco-resistant epilepsy referred for adult epilepsy surgery. Though associated with prolonged febrile seizures (FS) in childhood, the neurobiological basis for this relationship is not fully understood and currently no preventive or curative therapies are available. DNA methylation, an epigenetic mechanism catalyzed by DNA methyltransferases (DNMTs), potentially plays a pivotal role in epileptogenesis associated with FS. In an attempt to start exploring this notion, the present cross-sectional pilot study investigated whether global DNA methylation levels (5-mC and 5-hmC markers) and DNMT isoforms (DNMT1, DNMT3a1, and DNMT3a2) expression would be different in hippocampal and neocortical tissues between controls and TLE patients with or without a history of FS.ResultsWe found that global DNA methylation levels and DNMT3a2 isoform expression were lower in the hippocampus for all TLE groups when compared to control patients, with a more significant decrease amongst the TLE groups with a history of FS. Interestingly, we showed that DNMT3a1 expression was severely diminished in the hippocampus of TLE patients with a history of FS in comparison with control and other TLE groups. In the neocortex, we found a higher expression of DNMT1 and DNMT3a1 as well as increased levels of global DNA methylation for all TLE patients compared to controls.ConclusionTogether, the findings of this descriptive cross-sectional pilot study demonstrated brain region-specific changes in DNMT1 and DNMT3a isoform expression as well as global DNA methylation levels in human TLE with or without a history of FS. They highlighted a specific implication of DNMT3a isoforms in TLE after FS. Therefore, longitudinal studies that aim at targeting DNMT3a isoforms to evaluate the potential causal relationship between FS and TLE or treatment of FS-induced epileptogenesis seem warranted.

High incidence of status epilepticus and ongoing seizures on arrival to the hospital due to high prevalence of febrile seizures in Izumo, Japan: A questionnaire-based study

ObjectivesTo determine the incidence of prolonged febrile seizures and status epilepticus in the first three years of life. MethodsA questionnaire was sent to 1560 families between April 2016 and March 2017 before their child attended a routine health check at three years of age in Izumo, Shimane prefecture, Japan. The questionnaire included an overview of febrile seizures, including the age at which febrile seizures occurred, the duration, and how the condition was managed. ResultsWe received 1089 (69.8%) responses and these showed that 134 (12.3%) children had a history of febrile seizures. Fourteen children with febrile seizures (10.4%) had prolonged seizures lasting 10–30 min and six children (4.5%) had status epilepticus. Ongoing febrile seizures that did not terminate on arrival to the hospital were observed in 11 children (8.2%) with febrile seizures. The incidence rates of status epilepticus, prolonged febrile seizures including status epilepticus and ongoing febrile seizures were 184, 612 and 337 per 100,000 children aged 36 months or less, respectively. ConclusionsThere was a greater incidence of status epilepticus than previously thought, possibly due to the high prevalence of febrile seizures in Japan. Eight percent of children with febrile seizures were seizing on arrival to the hospital. These ongoing seizures requiring emergency interventions were almost twice more than status epilepticus. Thus, it is necessary to develop an early intervention for the termination of prolonged febrile seizures.

Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort

Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

Simple Febrile Seizures: A Benign Phenomena?

AbstractFebrile seizures are one of the most common neurological causes of visits to the emergency room. This article is a review of the current literature concerning the evaluation and treatment of children with febrile seizures. Longitudinal prospective studies such as the FEBSTAT study (consequences of prolonged febrile seizures in childhood) have contributed to elucidate the long-term outcome of patients with prolonged febrile seizures. Neurogenetic research also demonstrated the role of genetic mutations (mainly voltage-gated ion channels) in the etiology of febrile seizures. Most febrile seizures are self-limited events with low risk of injury or evolution into status epilepticus or sudden death. However, the use of rectal diazepam as acute abortive treatment for febrile seizures lasting 5 minutes or longer has gained acceptance as a first-line home intervention. Most patients with febrile seizures do not require extensive investigations, but the treatment involves a customized plan. Efforts should be directed to educate caregivers about prognosis and management of potential recurrences. In selected cases, appropriate use of preventive antiseizure medication may be a consideration.

Upregulation of hippocampal synaptophysin, GFAP and mGluR3 in a pilocarpine rat model of epilepsy with history of prolonged febrile seizure

Despite the increasing interest and efforts to prevent, treat, and control epilepsy and its clinical manifestation (seizure), the prevalence has not decreased due to incomplete understanding of its etiology. The present study aimed at determining the effect of prolonged febrile seizure (PFS) on the onset of seizure in pilocarpine rat model of temporal lobe epilepsy (TLE).After induction of PFS at postnatal day (PND) 14 in ten out of thirty pups, epilepsy was induced with 350 mg/kg of pilocarpine on PND 60 in the 10 rats with PFS and 10 from the saline group. Animals that met the criteria for TLE were then chosen for the study. Effects of PFS on status epilepticus and the development of spontaneous recurrent seizures (SRSs) were observed. The hippocampal synaptophysin, glial fibrillary acidic protein (GFAP) with metabotropic glutamate receptor 3 (mGluR3) expressions were also measured with LI Cor Tissue florescence, immunofluorescence and immunohistochemistry respectively.We found that PFS reduced the onset of status epilepticus, but had no influence on the development of SRSs. Also, there was no difference in the hippocampal expression of synaptophysin and GFAP between rats that had pilocarpine with or without background PFS. However, the mGluR3 expression was significantly higher in pilocarpine with PFS when compared to pilocarpine alone.Our result showed that PFS may lead to epilepsy. It is also obvious that epilepsy with or without PFS history affects neurochemical expression of synaptophysin, GFAP and mGluR3, hence these proteins may be good targets for drug therapy in reducing both the mortality and morbidity of the disease.

Acetylcholine receptor agonist effect on seizure activity and GABAergic mechanisms involved in prolonged febrile seizure development in an animal model

Febrile seizures are a paediatric condition which affects 2–5 % of children worldwide with prolonged febrile seizures (PFS) being found to cause long-term complications and predispose patients to other neurological conditions later in life. Febrile seizures occur due to an imbalance between the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA. α7-nicotinic acetylcholine receptors (α7-nAchRs) have been found to mediate GABA release as well as its neurotransmission. In this study, α7-nAchRs were activated by using PNU-282,987 (PNU), a selective α7-nAchR agonist, in order to evaluate their effect in seizure threshold as well as GABAergic parameters in a PFS rat model. PFS was induced on 14-day old Sprague-Dawley rat pups by administration of lipopolysaccharide (217 ug/kg, i.p) followed 2.5 h later by kainic acid (KA) (1.83 mg/kg, i.p). PNU was given prior to KA administration and Methyllycaconitine (MLA), an α7-nAchR antagonist, was given following KA injection. Seizure activity was recorded and monitored for one hour following seizure induction. Glutamate decarboxylase (GAD)1 and GAD 2 expression, as well as GABA concentration in the hippocampus, were assessed. Our results show that activating α7-nAchRs delays PFS progression and this delay was attenuated by the antagonist, MLA. Exposure to PFS reduced the expression of GAD1 and GABA concentration while PNU injection prevented this decrease. This suggests that specific nicotinic acetylcholine receptors may be used as therapeutic targets in the maintenance of adequate hippocampal GABA concentration for the prevention of PFS development.

Intelligence and memory outcomes within 10 years of childhood convulsive status epilepticus

Long-term intelligence and memory outcomes of children post convulsive status epilepticus (CSE) have not been systematically investigated despite evidence of short-term impairments in CSE. The present study aimed to describe intelligence and memory outcomes in children within 10 years of CSE and identify potential risk factors for adverse outcomes. In this cohort study, children originally identified by the population-based North London Convulsive Status Epilepticus in Childhood Surveillance Study (NLSTEPSS) were prospectively recruited between July 2009 and February 2013 and invited for neuropsychological assessments and magnetic resonance imaging (MRI) scans. Full-scale intelligence quotients (FSIQs) were measured using the Wechsler Abbreviated Scales of Intelligence (WASI), and global memory scores (GMS) was assessed using the Children's Memory Scale (CMS). The cohort was analyzed as a whole and stratified into a prolonged febrile seizures (PFS) and non-PFS group. Their performance was compared with population norms and controls. Regression models were fitted to identify predictors of outcomes. With a mean of 8.9 years post-CSE, 28.5% of eligible participants were unable to undertake testing because of their severe neurodevelopmental deficits. Children with CSE who undertook formal testing (N = 94) were shown to have significantly lower FSIQ (p = 0.001) and GMS (p = 0.025) from controls; the PFS group (N = 34) had lower FSIQs (p = 0.022) but similar memory quotients (p = 0.88) with controls. Intracranial volume (ICV), developmental delay at baseline, and active epilepsy at follow-up were predictive of long-term outcomes in the non-PFS group. The relationship between ICV and outcomes was absent in the PFS group despite its presence in the control and non-PFS groups. Post-CSE, survivors reveal significant intelligence and memory impairments, but prognosis differs by CSE type; memory scores are uncompromised in the PFS group despite evidence of their lower FSIQ whereas both are compromised in the non-PFS group. Correlations between brain volumes and outcomes differ in the PFS, non-PFS, and control groups and require further investigation.

Early administration of vitamins B1 and B6 and l-carnitine prevents a second attack of acute encephalopathy with biphasic seizures and late reduced diffusion: A case control study

BackgroundAcute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most prevalent encephalopathy in Japanese children. AESD is characterized by a prolonged febrile seizure on day 1 followed by secondary seizures and MRI abnormality on days 4–6, resulting in high incidence of neurological sequelae. We aimed to clarify whether early administration of vitamins (vitamin B1, vitamin B6, and l-carnitine) would improve the clinical course of AESD. MethodsWe retrospectively reviewed 34 patients with acute encephalopathy who were admitted to our hospital between January 2009 and August 2016. Of the retrospectively registered 34 patients, 22 (65%) since 2011 were treated with the drug cocktail (prescription group) within 24 h of onset, whereas 12 (35%) before 2011 were not (non-prescription group). We compared clinical course, laboratory data, and MRI findings historically in both groups. ResultsThe two groups did not differ in terms of laboratory findings except for blood lactate values. There were no differences between the two groups regarding duration of ICU admission, intubation, or the duration of seizures. Among the prescription group, two patients developed AESD while 20 had mild encephalopathy (single phasic). In contrast, seven patients inthe non-prescription group developed AESD while five did not. The incidence of AESD was lower in the prescription group (P = 0.004). As for outcomes, the rate of developmental delay and epilepsy was significantly lower in the prescription group. ConclusionsOur data suggested that early administration of vitamins would improve the clinical course of acute encephalopathy. Mitochondrial rescue and neuroprotection are thought to be responsible for the favorable results.

Prolonged febrile seizures induce inheritable memory deficits in rats through DNA methylation.

SummaryAimsFebrile seizures (FSs) are the most common types of seizures in young children. However, little is known whether the memory deficits induced by early‐life FSs could transmit across generations or not.MethodsThe memory functions of different generations of FS rats were behaviorally evaluated by morris water maze, inhibitory avoidance task, and contextual fear conditioning task. Meanwhile, molecular biology and pharmacological methods were used to investigate the role of DNA methylation in transgenerational transmission of memory defects.ResultsProlonged FSs in infant rats resulted in memory deficits in adult and transgenerationally transmitted to next generation, which was mainly through mothers. For these two generations, DNA methyltransferase (DNMT) 1 was upregulated, leading to transcriptional inhibition of the synaptic plasticity protein reelin but not the memory suppressor protein phosphatase 1. DNMT inhibitors prevented the high expression of DNMT1 and hypermethylation of reelin gene and reversed the transgenerationally memory deficits. In addition, enriched environment in juvenile rats rescued memory deficits induced by prolonged FSs.ConclusionsOur study demonstrated early experience of prolonged FSs led to memory deficits in adult rats and their unaffected offspring, which involved epigenetic mechanisms, suggesting early environmental experiences had a significant impact on the transgenerational transmission of neurological diseases.

The Pharmacological Assessment of GABAA Receptor Activation in Experimental Febrile Seizures in Mice.

Hyperthermia-induced febrile seizures (FSs) are the most common seizures during childhood, and prolonged complex FSs can result in the development of epilepsy. Currently, GABAA receptor modulators such as benzodiazepines and barbiturates are used as medications for FSs with the aim of enhancing GABA-mediated inhibition of neuronal activity. However, it is still up for debate whether these enhancers of GABAergic neurotransmission could depolarize immature neurons with relatively higher levels of the intracellular Cl− in the developing brain during FSs. Here, we performed simultaneous video-local field potential monitoring to determine whether benzodiazepines and barbiturates affect the phenotypes of FSs in postnatal day (P)11 and P14 mice. We found that low-dose administration of diazepam decreased the incidence of clonic seizures at P11. We also found that high-dose administration of diazepam and pentobarbital exacerbated the behavioral and electrophysiological phenotypes of the induction phase of experimental FSs at P11 but not at P14. We further found that the deteriorated phenotypes at P11 were suppressed when Na+K+2Cl− cotransporter isoform 1 (NKCC1), which mediates Cl− influx, was blocked by treatment with the diuretic bumetanide. Though our findings do not exclude the involvement of sedation effect of high-dose GABAA receptor modulators in worsening experimental FSs at P11, pharmacological enhancement of GABAergic signaling could aggravate seizure activity in the early phase of FSs.

Republication de : Évaluation d’un enfant après une crise fébrile : focus sur trois problèmes de pratique clinique

Febrile seizures (FS) are the most common seizures seen in the paediatric population in the out-of-hospital and emergency department settings, and they account for the majority of seizures seen in children younger than 5 years old. An FS is a seizure accompanied by fever, without central nervous system infection, occurring in children between 6 months and 5 years old. Five criteria have been used and taught to classify any FS as simple or complex FS. These factors do not bear the same significance for clinical practice, in particular, the decision to perform a lumbar puncture for cerebrospinal fluid analysis to rule out an intracranial infection. Moreover, epidemiological studies have illustrated that some factors are predictive of febrile seizure recurrence while others are predictive of epilepsy occurrence. On this basis, a workshop was organized to provide an answer to three clinical practice questions: when should a lumbar puncture be performed in a child who has experienced a seizure during a fever episode, is the prescription of a rescue drug required with a risk of a prolonged febrile seizure recurrence, when should a neurological consultation be requested (risk of later epilepsy)? Based on a review of the literature and on a 1-day workshop, we report here the conclusion of the working group. A lumbar puncture is required in any child with meningitis symptoms or septic signs or behaviour disturbance. A lumbar puncture should be discussed based on the clinical symptoms and their progression over time when a child has experienced a focal FS or repetitive FSs without signs of meningitis or sepsis or behaviour disturbance. The lumbar puncture is not necessary in case of simple FS without signs of meningitis, including in infants between 6 and 12 months old. An early clinical evaluation (at least 4 h after the first clinical assessment) could be helpful, in particular in infants younger than 12 months of age. A rescue drug might be prescribed when there is a high risk of prolonged FS (i.e., risk higher than 20 %): age at FS<12months OR a history of a previous febrile status epilepticus OR if the first FS was a focal seizure OR abnormal development/neurological exam/MRI OR a family history of nonfebrile seizure. A neurological consultation should be requested for any child who has experienced a prolonged FS before the age of 1 year, for children who have experienced prolonged and focal FS or repetitive (within 24h) focal FS, for children who have experienced multiple complex (focal or prolonged or repetitive) FS, for children with an abnormal neurological exam or abnormal development experiencing a FS. Although childhood febrile seizures in most cases are benign, witnessing such seizures is always a terrifying experience for the child's parents. Most parents feel that their child is dying or could have severe brain injury related to the episode. Therefore, the group also suggests a post-FS visit with the primary care physician.

Early-life hyperthermic seizures upregulate adenosine A2A receptors in the cortex and promote depressive-like behavior in adult rats

Febrile seizures (FS) represent one of the most frequent convulsive disorders in children which can be classified into simple and prolonged depending on the duration. Although simple FS are generally considered as benign, there is controversy about the outcome of prolonged FS. Here, we have used an animal model of prolonged FS to investigate persistent neurochemical and behavioral alterations in adult rats. Hyperthermic seizures were induced in 12-day-old rats using a warmed air stream from a hair dryer. Neonates exhibited arrest of heat-induced hyperkinesis followed by body flexion and rearing and falling over associated with hindlimb clonus seizures (stage 5 on Racine scale criteria) after hyperthermic induction. After 48 days, the animals were assayed on dark–light box and forced swim tests in order to detect if rats will show signs of anxiety or depression. Finally, animals were sacrificed 56 days after hyperthermia-induced seizures (HIS), and their effects on adenosine A2A receptor signaling and 5′-nucleotidase activity were studied in plasma membranes from the cerebral cortex by using radioligand-binding assay and by measuring the activities of adenylate cyclase and 5′-nucleotidase. Results obtained have shown that adult rats submitted to HIS during the neonatal period showed depressive-like behavior. Furthermore, animals exposed to hyperthermic insult showed an increase in A2A receptor level which was also accompanied by an increase in A2A receptor functionality.