Body temperature predicts recurrent febrile seizures in the same febrile illness

BackgroundThe incidence of recurrent febrile seizures during the same febrile illness (RFS) is 14–24%. A pilot study found that body temperature and male sex were predictors of RFS. This study sought to validate body temperature as a predictor of RFS, calculate the optimal cut-off body temperature for predicting RFS, and identify the other predictors of RFS.MethodsThis prospective cohort study enrolled children with febrile seizures aged 6–60 months who visited the emergency department at Atsugi City Hospital, Japan, between March 1, 2019, and February 29, 2020. Children who had multiple seizures, diazepam administration before the emergency department visit, seizures lasting >15 min, underlying diseases, or who could not be followed up were excluded. The optimal cut-off body temperature was determined using a receiver-operating characteristic curve.ResultsA total of 109 children were enrolled, of whom 13 (11.9%) had RFS. A lower body temperature was significantly associated with RFS (P = 0.02). The optimal cut-off body temperature for predicting RFS was 39.2 °C. Children with RFS also had significantly lower C-reactive protein and blood glucose levels (P = 0.01 and 0.047, respectively), but none of the other factors considered were significantly associated with RFS.ConclusionsThis large prospective study confirmed that body temperature is a predictor of RFS. The optimal cut-off body temperature for predicting RFS was 39.2 °C. Low C-reactive protein level and blood glucose level might be predictors of RFS, but this needs to be confirmed in prospective multicenter studies.     

Short-term neurodevelopmental outcomes of focal febrile seizures

ObjectiveThe effect of complex febrile seizures (FS), specifically focal FS, on long-term neurodevelopmental outcome is not well known. The aim of this study was to assess the association between complex FS and neurodevelopmental outcome.MethodsA single-center, retrospective, cohort study was performed. The study included 282 children aged 6–60 months who experienced FS. Of these, 61 (22%) experienced recurrent FS, 33 (12%) prolonged FS, and 17 (6%) focal FS. The effect of these complex FS on subsequent need for special neurodevelopmental support was investigated. The neurodevelopmental status after FS was evaluated by a questionnaire.ResultsDuring a median follow-up period of 3 years post FS, 12 children (4.3%) required special neurodevelopmental support. Univariate analysis demonstrated a significant association between focal FS and the need for subsequent special neurodevelopmental support, as well as a correlation between prolonged FS and pre-existing neurodevelopmental abnormality. Multiple logistic regression analysis demonstrated that focal FS (odds ratio [OR]: 12.27; 95% confidence interval [CI]: 2.11–71.22) and pre-existing neurodevelopmental abnormality (OR: 262; 95% CI: 17–3944) were significantly associated with the need for subsequent special support.ConclusionAn association was found between focal FS and subsequent neurodevelopmental impairment; therefore, close follow-up with particular attention to neurodevelopmental status is required for children who experience focal FS.     

The effects of antihistamines on the semiology of febrile seizures

Objective

The aim of this study was to clarify the effects of antihistamines on the semiology of febrile seizures.

A case report of a family with overlapping features of autosomal dominant febrile seizures and GEFS+

Familial febrile seizures occur in both generalized epilepsy with febrile seizures plus (GEFS+) and autosomal dominant febrile seizures (ADFS). The literature largely separates families with GEFS+ from those with ADFS. However, there is clinical overlap, and families with ADFS also include individuals with afebrile seizures. The phenotypic spectrum of GEFS+ is broader now than when first described, resulting in unclear boundaries between these two familial syndromes. The purpose of this report is to highlight the phenotypic similarities of GEFS+ and ADFS. A multigenerational family with febrile and afebrile seizures is described and the clinical features are compared to those of previously reported GEFS+ and ADFS families. This family meets the requirements for both ADFS and the broader definition of GEFS+. Linkage analysis has shown no clear linkage to known febrile seizure or GEFS+ loci. Despite locus heterogeneity, identified mutations in reported GEFS+ have so far all been in sodium channel or γ-aminobutyric acid (GABA)–receptor genes, with other modifier genes postulated to affect individual phenotypes. The two mutations identified in families with ADFS are in genes implicated in GEFS+, SCN1A , and GABRG2 . We conclude that it is inappropriate to separate GEFS+ and ADFS at present given the clinical and genotypic overlap.     

Febrile seizures: treatment and prognosis

Recent epidemiologic data indicate that the vast majority of children with febrile seizures have a normal longterm outcome. A precise knowledge of the short- and long-term outcome with or without treatment, and short- and long-term side effects is an important prerequisite for assessing the various treatment strategies. We focus on the impact of short-term or prophylactic treatment on the short- and long-term outcome of various types of febrile seizures. There is universal agreement that daily prophylaxis with antiepileptic agents should never be used routinely in simple febrile seizures, but only in highly selected cases, if at all. Intermittent diazepam (DZP) prophylaxis at times of fever may or may not reduce the recurrence rate, but it does not appear to improve the long-term outcome as compared with short-term seizure control. The treatment may be used to reduce the recurrence rate for a small arbitrarily defined group with multiple simple febrile seizures, complex febrile seizures, especially focal, prolonged or both, febrile status, and when parental anxiety is severe. However, there is no evidence that treatment of simple febrile seizures can prevent the rare cases of later epilepsy, and many children with complex febrile seizures have a benign long-term outcome, even without treatment. Many prefer a "wait and see" policy. An attractive alternative is to treat new febrile seizures with rectal DZP in solution at seizure onset, given by the parents at home to prevent febrile status. Newer, less well documented short-term strategies include nasal, oral, or rectal administration of other benzodiazepines. Short-term seizure control of febrile status and careful parental counseling are the two most important targets of treatment.     

Epilepsy duration, febrile seizures, and cerebral glucose metabolism

PURPOSE: Studies using magnetic resonance imaging have shown that reduced hippocampal volume is associated with a history of febrile seizures, the duration of epilepsy, and the number of generalized tonic-clonic seizures. It is uncertain whether these factors have the same influence on functional as on structural measures of the integrity of the epileptogenic zone. METHODS: We used positron emission tomography (PET) with fluorine 18 2-deoxyglucose to study 91 patients with temporal lobe seizure foci localized by ictal video-EEG. PET was performed in the awake interictal resting state with ears plugged and eyes patched. We recorded surface EEG during injection (5 mCi) and the 30-min uptake period. We used a standard template to analyze PET scans. RESULTS: A significant negative relation was found between the duration of epilepsy and hippocampal glucose metabolism ipsilateral to the epileptic focus. Patients with a history of either any febrile seizures, or complex, or prolonged febrile seizures, did not have greater hypometabolism ipsilateral to the epileptic focus than did patients without a febrile seizure history. We found no effect of generalized tonic-clonic seizure history. CONCLUSIONS: Longer epilepsy duration is associated with greater hypometabolism, suggesting that epilepsy is a progressive disease.     

Increased levels of NLRP3 in children with febrile seizures

ObjectiveFebrile seizures (FS) are the most common convulsions in childhood. Interleukin-1beta (IL-1β) is proposed to play an important role in the development of FS, from in vitro data and data from peripheral blood samples. IL-1β secretion is needed for activation of the NLR family, pyrin-domain containing 3(NLRP3) inflammasome. However, whether NLRP3 play a role in the development of FS remains unknown. This study aimed to investigate the role of NLRP3 in FS.MethodsThirty-two FS cases and twenty-two matched controls were included in this study. Control samples were collected from children with febrile illness without seizures. We detected their levels of IL-1β and NLRP3 by Enzyme linked immunosorbent assay and Western blot, respectively.ResultsSerum IL-1β levels were significantly higher in FS patients (Median = 301.64 pg/ml) than in fever only controls (Median = 159.48 pg/ml) (P < 0.05). Additionally, NLRP3 protein levels of peripheral blood mononuclear cells (PBMC) were significantly higher in typical FS than in fever only controls (P < 0.05). Moreover, serum levels of IL-1β were significantly correlated with levels of NLRP3 protein (r = 0.787, P < 0.001).ConclusionsIn this study, our results firstly indicated that NLRP3 protein was significantly up-regulated in the typical FS children compared in fever only controls. Increased NLRP3 can mediate IL-1β secretion that is responsible for the occurrence of FS.     

Treatment of febrile seizures: Historical perspective,current opinions,and potential future directions

Although most febrile seizures do no harm and two-thirds of initial cases have no witnessed recurrence, the seizures cause much family anxiety, and are sometimes prolonged. In rare cases they are the first evidence of important epilepsy syndromes or are implicated in the development of epilepsy with mesial temporal sclerosis in later life. There have been trials of prophylactic treatment with antiepileptic drugs including carbamazepine, diazepam, phenobarbital, phenytoin, and sodium valproate. Several strategies have been employed with these drugs, including continuous secondary prophylaxis, intermittent secondary prophylaxis in response to later episodes of fever, and rescue medication early in the course of further seizures. Another treatment strategy has been using one or more antipyretic agents in early response to fever using agents such as acetaminophen and ibuprofen. Over the years, researchers have identified a variety of clinical, genetic, and environmental risk factors for more severe or prolonged febrile seizures and higher risk of recurrence. This review evaluates the rationale for secondary prophylaxis of febrile seizures, the potential effectiveness of such treatment, and whether it can be recommended as a general approach to treating febrile seizures or as an approach to be used in groups identified to be at increased risk.     

Interleukin-10 is associated with resistance to febrile seizures: Genetic association and experimental animal studies

Purpose:   Febrile seizures (FS) are the most common form of childhood convulsions. Many reports have shown that a proinflammatory cytokine, interleukin-1 (IL-1) β, may have a facilitatory effect on the development of FS. We have previously shown that the IL1B -511C/T single nucleotide polymorphism (SNP) is associated with simple FS of sporadic occurrence. The balance between pro- and antiinflammatory cytokines influences the regulation of infections and could, therefore, play a role in the pathogenesis of FS. Here, to determine whether pro- and antiinflammatory cytokine genes are responsible for the susceptibility to FS, we have performed an association study on functional SNPs of cytokine genes in FS patients and controls.
Methods:   The promoter SNPs of four inflammatory cytokine genes ( IL6 -572C/G, IL8 -251A/T, IL10 -592A/C and TNFA -1037C/T) were examined in 249 patients with FS (186 simple and 63 complex FS) and 225 controls. Because the IL10 -592 SNP showed a positive association with FS, two additional SNPs ( IL10 -1082A/G and -819T/C) were subjected to haplotype analysis. Furthermore, we examined the in vivo role of IL-10 in hyperthermia-induced seizures using immature animal models.
Results:   The frequencies of the IL10 -592C allele and -1082A/-819C/-592C haplotype were significantly decreased in FS as compared with in controls (p = 0.014 and 0.013, respectively). The seizure threshold temperature in the IL-10–administered rats was significantly higher than that in the saline-treated control ones (p = 0.027).
Conclusions:   The present study suggests that IL-10 is genetically associated with FS and, contrary to IL-1β, confers resistance to FS.     

TRPV1 promotes repetitive febrile seizures by pro-inflammatory cytokines in immature brain

Febrile seizure (FS) is the most common seizure disorder in children, and children with FS are regarded as a high risk for the eventual development of epilepsy. Brain inflammation may be implicated in the mechanism of FS. Transient receptor potential vanilloid 1 (TRPV1) is believed to act as a monitor and regulator of body temperature. The role of inflammation in synaptic plasticity mediation indicates that TRPV1 is relevant to several nervous system diseases, such as epilepsy. Here, we report a critical role for TRPV1 in a febrile seizure mouse model and reveal increased levels of pro-inflammatory factors in the immature brain. Animals were subjected to hyperthermia for 30 min, which generates seizures lasting approximately 20 min, and then were used for experiments. To invoke frequently repetitive febrile seizures, mice are exposed to hyperthermia for three times daily at an interval of 4 h between every time induced seizure, and a total of 4 days to induce. Behavioral testing for febrile seizures revealed that a TRPV1 knock-out mouse model demonstrated a prolonged onset latency and a shortened duration and seizure grade of febrile seizure when compared with wild type (WT) mice. The expression levels of both TRPV1 mRNA and protein increased after a hyperthermia-induced febrile seizure in WT mice. Notably, TRPV1 activation resulted in a significant elevation in the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and HMGB1) in the hippocampus and cortex. These data indicate that the reduction of TRPV1 expression parallels a decreased susceptibility to febrile seizures. Thus, preventative strategies might be developed for use during febrile seizures.     

全面性癫(癎)伴热性惊厥附加症的临床与分子遗传学研究

目的 探讨全面性癫痫伴热性惊厥附加症（generalized epilepsy with febrile seizures plus，GEFS＋）的临床特点与分子遗传学特征。方法 收集1个GEFS＋家系所有成员的血样标本，选择3种候选基因（SCN1B、SCN1A、GABRG2）附近的11个微卫星标记物D19S414、D19S220、D19S902、D2S156、D2S142、D2S2330、D2S335、D2S364、D5s436、D5S422和D5S400，应用PCR得到扩增产物片段，根据相应产物大小的不同，得到每个样本的基因型；用连锁分析软件的MLINK程序计算每个标记的LOD值，根据两点间的LOD值判断连锁关系，探讨GEFS＋的可能致病基因与染色体19q13．1、2q24以及5q31．1-q33．1区域的连锁关系。连锁分析限定性定位后再进行GABRG2基因突变分析。结果 （1）GEFS＋家系临床特征：家系成员4代共20人。第Ⅱ～Ⅳ代中患者6例（男女各3例）；发作表型为热性惊厥（FS）1例、热性惊厥附加症（FS＋）3例、Fs＋伴失神发作1例，发作类型不详1例，未见严重发作类型。（2）GEFS＋基因连锁分析结果：①D2S335因不能进行基因分型，给予舍弃；②D19S和D2S多个LOD值小于0，在重组率为0．0时D19S220、D19s902、D2S364处的LOD值均小于-2；D19S414、D2S142、D2S156、D2S2330、D5S422处的LOD值小于0，基本可以排除连锁关系；③D5S436、D5$400处的LOD值在重组率为0．0时大于-2，但小于3，既不能排除也不能肯定其连锁关系；该家系致病基因与报道的GEFS＋定位区域19q13．1和2q24区域没有连锁关系；与5q31．1．q33．1区域的连锁关系有待于进一步明确。（3）GABRG2基因的测序结果（先证者）：显示11外显子一处同义突变（c．1420C〉T），未见GABRG2基因致病突变。结论 该GEFS＋家系呈现不同的临床表型，其疾病基因与3种候选基因SCN1A、SCN1B、GABARG2的突变无关；表明GFFS＋具有表型的异质性与遗传的异质性，其病因学有待进一步研究。     

Genetic susceptibility to febrile seizures: Case-control association studies

Objective: A genetic predisposition to febrile seizures (FS) has long been recognized. The inheritance appears to be polygenic in small families or sporadic cases of FS encountered in daily clinical practice. To determine whether candidate genes are responsible for the susceptibility to FS, we have performed genetic association studies in FS patients and controls. Methods: The single-nucleotide polymorphisms (SNPs) of genes involved in immune response (interleukin (IL) 1B), endocannabinoid signaling (CNR1), acid–base balance (SLC4A3, SLC9A1, SLC9A3), gap junction channel (CX43), and GABA_A receptor trafficking (PRIP1) were examined in 249 FS patients (186 simple and 63 complex FS) and 225 controls. Results: There were no significant differences in the allele frequencies of the SNPs between controls and all FS, simple FS, and complex FS patients. When the simple FS patients were divided into two groups according to either having (familial) or not having a family history of FS in close relatives (sporadic), there was a significant association between IL1B −511 SNP and sporadic simple FS (p = 0.003). Conclusions: These data suggest that cytokine genes may act as enhancers or attenuators of FS susceptibility. Genetic association study may be an effective approach to understanding the molecular basis of FS at least in a subgroup of patients.     

A BFIS-like syndrome with late onset and febrile seizures: suggestive linkage to chromosome 16p11.2-16q12.1

Benign familial infantile seizures (BFIS) is a dominant idiopathic epilepsy with partial and secondarily generalized seizures with age of onsetr between 3 and 12 months. Here we describe a four-generation family with some characteristic features of BFIS but with unusual clinical signs, in eight affected members with an unusual clinical phenotype. Onset was consistently between 14 and 20 months of age with clusters of complex-partial or generalized tonic-clonic seizures and a high rate of febrile seizures, which have not been described for BFIS previously. All affected members showed multifocal interictal epileptiform discharges in the EEG. The known loci for benign familial neonatal/infantile seizures (BFNS/BFNIS), generalized epilepsy with febrile seizures plus (GEFS+) and the BFIS locus on chromosome 19q were excluded. Further genetic analysis showed suggestive linkage to the major BFIS locus on chromosome 16 between markers D16S690 and D16S3136. This ;;BFIS-like' syndrome may enlarge the phenotypic spectrum of diseases linked to the chromosome 16 region.     

Cognitive dysfunction after experimental febrile seizures

While the majority of children with febrile seizures have an excellent prognosis, a small percentage are later discovered to have cognitive impairment. Whether the febrile seizures produce the cognitive deficits or the febrile seizures are a marker or the result of underlying brain pathology is not clear from the clinical literature. We evaluated hippocampal and prefrontal cortex function in adult rats with a prior history of experimental febrile seizures as rat pups. All of the rat pups had MRI brain scans following the seizures. Rats subjected to experimental febrile seizures were found to have moderate deficits in working and reference memory and strategy shifting in the Morris water maze test. A possible basis for these hippocampal deficits involved abnormal firing rate and poor stability of hippocampal CA1 place cells, neurons involved in encoding and retrieval of spatial information. Additional derangements of interneuron firing in the CA1 hippocampal circuit suggested a complex network dysfunction in the rats. MRI T2 values in the hippocampus were significantly elevated in 50% of seizure-experiencing rats. Learning and memory functions of these T2-positive rats were significantly worse than those of T2-negative cohorts and of controls. We conclude that cognitive dysfunction involving the hippocampus and prefrontal cortex networks occur following experimental febrile seizures and that the MRI provides a potential biomarker for hippocampal deficits in a model of prolonged human febrile seizures.     

Infant febrile seizures: Changes in declarative memory as revealed by event-related potentials

Objective

According to a widespread opinion the vast majority of infant febrile seizures (IFS) are harmless. However, IFS are often associated with hippocampal sclerosis, which should lead to deficient episodic memory with spared context-free semantic memories. Although IFS represent the most common convulsive disorder in children, these consequences are rarely examined.

Methods

We measured the hippocampal volume of 17 IFS children (7–9 years old) and an age-matched control group on the basis of MR images. Furthermore, we examined episodic and semantic memory performance with standardized neuropsychological tests. Two processes underlying recognition memory, namely familiarity and recollection, were assessed by means of event-related potentials (ERP).

Results

The IFS children did not show a decreased hippocampus volume. Intelligence, working memory, semantic and episodic memory were intact. However, ERP indices of recognition memory subprocesses revealed deficits in recollection-based remembering that presumably relies on the integrity of the hippocampus, whereas familiarity-based remembering seemed to be intact.

Conclusions

Although hippocampus volume remains unaffected, IFS seems to induce functional changes in the MTL memory network, characterized by a compensation of recollection by familiarity-based remembering.

Significance

This study significantly adds to the debate on the consequences of IFS by differentiating the impact on memory processing.     

Bilateral hippocampal atrophy in temporal lobe epilepsy: effect of depressive symptoms and febrile seizures

Purpose: Neuroimaging studies suggest a history of febrile seizures, and depression, are associated with hippocampal volume reductions in patients with temporal lobe epilepsy (TLE). Methods: We used radial atrophy mapping (RAM), a three‐dimensional (3D) surface modeling tool, to measure hippocampal atrophy in 40 patients with unilateral TLE, with or without a history of febrile seizures and symptoms of depression. Multiple linear regression was used to single out the effects of covariates on local atrophy. Key Findings: Subjects with a history of febrile seizures (n = 15) had atrophy in regions corresponding to the CA1 and CA3 subfields of the hippocampus contralateral to seizure focus (CHC) compared to those without a history of febrile seizures (n = 25). Subjects with Beck Depression Inventory II (BDI‐II) score ≥14 (n = 11) had atrophy in the superoanterior portion of the CHC compared to subjects with BDI‐II <14 (n = 29). Significance: Contralateral hippocampal atrophy in TLE may be related to febrile seizures or depression.     

Failure to detect association between polymorphisms of the sodium channel gene SCN1A and febrile seizures in Chinese patients with epilepsy

A recent study in Caucasians found an association between the single nucleotide polymorphism (SNP) of SCN1A, IVS5N +5 G>A (rs3812718), and febrile seizures (FS). We examined whether this and other tagging SNPs of SCN1A were associated with an increased risk of FS in Han Chinese. A total of 728 Han Chinese patients with focal epilepsy were recruited: 97 had a history of FS (58% male, mean age 35 ± 12 years) and 631 did not (50% male, mean age 40 ± 15 years). Genotyping was performed for IVS5N +5 G>A and seven other tagging SNPs selected from the HapMap database. Genotyping was also performed in 848 ethnically matched population controls (50% male, mean age 37 ± 17 years). There was no statistically significant difference in either allele or genotype frequency of any of the SNPs studied between epilepsy patients with and without FS, and between epilepsy patients with FS and controls. The results do not suggest that SCN1A SNPs are susceptibility factors for FS in Han Chinese.     

Unprovoked seizures after complex febrile convulsions

Children with complex febrile convulsions bear a higher risk of developing epilepsy than children with simple febrile convulsions. Complex febrile convulsions are defined by the presence of prolonged seizures, partial seizures and multiple seizures occurring during the same day. The aim of this study is to delineate the relative significance of each of the three criteria defining complex febrile convulsions. Fifty-seven out of 477 children (12%) admitted for febrile convulsions had complex febrile convulsions and normal neurological examination. Follow-up was available for 48 (84%) of them. Thirteen of these 48 (27%) had epilepsy at follow-up. The mean age of seizure onset among the patients with subsequent afebrile seizures was significantly lower than the rest (10.8 months versus 16.8 months). The patients with partial febrile convulsions showed a trend toward a higher risk (45%) of developing epilepsy than the patients with multiple febrile convulsions (21%).