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Complex febrile seizures (CFS), a subset of paediatric febrile seizures (FS), have been studied for their prognosis, epileptogenic potential and neurocognitive outcome. We evaluated their functional connectivity differences with simple febrile seizures (SFS) in children with recent-onset FS. Resting-state fMRI (rs-fMRI) datasets of 24 children with recently diagnosed FS (SFS-n = 11; CFS-n = 13) were analysed. Functional connectivity (FC) was estimated using time series correlation of seed region–to-whole-brain-voxels and network topology was assessed using graph theory measures. Regional connectivity differences were correlated with clinical characteristics (FDR corrected p  < 0.05). CFS patients demonstrated increased FC of the bilateral middle temporal pole (MTP), and bilateral thalami when compared to SFS. Network topology study revealed increased clustering coefficient and decreased participation coefficient in basal ganglia and thalamus suggesting an inefficient-unbalanced network topology in patients with CFS. The number of seizure recurrences negatively correlated with the integration of Left Thalamus (r = − 0.58) and FC of Left MTP to 'Right Supplementary Motor and left Precentral' gyrus (r = − 0.53). The FC of Right MTP to Left Amygdala, Putamen, Parahippocampal, and Orbital Frontal Cortex (r = 0.61) and FC of Left Thalamus to left Putamen, Pallidum, Caudate, Thalamus Hippocampus and Insula (r 0.55) showed a positive correlation to the duration of the longest seizure. The findings of the current study report altered connectivity in children with CFS proportional to the seizure recurrence and duration. Regardless of the causal/consequential nature, such observations demonstrate the imprint of these disease-defining variables of febrile seizures on the developing brain.

Studies using experimental animal models have demonstrated IL-1[beta] expression in microglia and astrocytes after seizures and that IL-1[beta] itself can enhance neuronal excitability. 4 Based on these findings, a hypothesis has been proposed that the vicious cycle consisting of seizure activity and inflammation contribute to the further progression of inflammation-mediated status epilepticus. 1 However, this paradigm has not been definitively demonstrated in human status epilepticus. [...]the present study unveiled a previously unrecognised relationship between a group of proinflammatory cytokines/chemokines and refractory status epilepticus in a human disease.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common subtype of acute encephalopathy in Japan and is difficult to differentiate from prolonged febrile seizures (PFSs). This study aimed to explore the capability of machine learning to differentiate AESD from PFSs on the basis of early electroencephalogram (EEG) analyses. Sixty one children with AESD ( n  = 20) or PFS ( n  = 41) were included. Digital EEG data with bipolar montage collected within 48 h (1–48 h) after seizure onset were analyzed using absolute power spectrum (APS) and phase lag index (PLI) values in each EEG frequency band. The APS values in the theta, alpha, beta, and gamma bands were lower for AESD than those for PFS. By contrast, the mean PLI values for all frequency bands were higher for AESD than for PFS. Machine learning analysis revealed that the APS value in the beta bands provided the highest differentiation accuracy and positive predictive value for AESD (68.8%). The mean APS values across all electrodes in the beta band may be a useful tool for differentiating between early-phase AESD and PFS. This study demonstrates the potential for early automated diagnosis of AESD and PFS using EEG analysis.

Febrile seizures are common in children and can lead to neurological deficits like motor impairments, memory problems, and cognitive decline. Research on dimethyl itaconate aims to mitigate these effects and improve the quality of life for affected people. By exploring its potential as a protective agent against oxidative stress during seizures, this study in adult male rats measures the activity of key enzymes related to oxidative stress and behavioral performance. Pregnant rats were divided into control, sham, DMI, febrile seizure, and DMI + febrile seizure groups. Seizure severity was evaluated through threshold and frequency measurements, while memory, motor function, and balance were assessed using shuttle box, rotarod, open field, and wire hanging tests. After that, the hippocampus tissue was removed from the brain and the levels of MDA, SOD, GSH, TAC, GR, GPx, and catalase were measured through biochemical methods. Results show that dimethyl itaconate raised the seizure threshold and reduced tonic-clonic seizures. The DMI + febrile seizure group also showed improved memory, movement, and balance compared to the febrile seizure group (p < 0.05 in all cases). Overall, dimethyl itaconate decreased oxidative stress and improved neurological outcomes in fever-affected rats.

Extreme heat caused by climate change is increasing the transmission of infectious diseases, resulting in a sharp rise in heat-related illness and mortality. Understanding the mechanistic link between heat, inflammation, and disease is thus important for public health. Thermal hyperpnea, and consequent respiratory alkalosis, is crucial in febrile seizures and convulsions induced by heat stress in humans. Here, we address what causes thermal hyperpnea in neonates and how it is affected by inflammation. Transient receptor potential cation channel subfamily V member 1 (TRPV1), a heat-activated channel, is sensitized by inflammation and modulates breathing and thus may play a key role. To investigate whether inflammatory sensitization of TRPV1 modifies neonatal ventilatory responses to heat stress, leading to respiratory alkalosis and an increased susceptibility to hyperthermic seizures, we treated neonatal rats with bacterial LPS, and breathing, arterial pH, vagus nerve activity, and seizure susceptibility were assessed during heat stress in the presence or absence of a TRPV1 antagonist (AMG-9810) or shRNA-mediated TRPV1 suppression. LPS-induced inflammatory preconditioning lowered the threshold temperature and latency of hyperthermic seizures. This was accompanied by increased tidal volume, minute ventilation, expired CO , and arterial pH (alkalosis). LPS exposure also elevated vagal spiking and intracellular calcium concentrations in response to hyperthermia. TRPV1 inhibition with AMG-9810 or shRNA reduced the LPS-induced susceptibility to hyperthermic seizures and altered the breathing pattern to fast shallow breaths (tachypnea), making each breath less efficient and restoring arterial pH. These results indicate that inflammation exacerbates thermal hyperpnea-induced respiratory alkalosis associated with increased susceptibility to hyperthermic seizures, primarily mediated by TRPV1 localized to vagus neurons.

Febrile seizures during childhood are linked to the development of chronic epilepsy. Now, Ryuta Koyama and colleagues show that febrile seizures are associated with enhanced GABAergic excitation and ectopic granule cell migration in the hippocampus. Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA A receptors (GABA A -Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA A -Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na + K + 2Cl − co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABA A -R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.

Febrile seizures (FSs) are the most common convulsion in infancy and childhood. Considering the limitations of current treatments, it is important to examine the mechanistic cause of FSs. Prompted by a genome-wide association study identifying TMEM16C (also known as ANO3) as a risk factor of FSs, we showed previously that loss of TMEM16C function causes hippocampal neuronal hyperexcitability [Feenstra et al., Nat. Genet. 46, 1274–1282 (2014)]. Our previous study further revealed a reduction in the number of warm-sensitive neurons that increase their action potential firing rate with rising temperature of the brain region harboring these hypothalamic neurons. Whereas central neuronal hyperexcitability has been implicated in FSs, it is unclear whether the maximal temperature reached during fever or the rate of body temperature rise affects FSs. Here we report that mutant rodent pups with TMEM16C eliminated from all or a subset of their central neurons serve as FS models with deficient thermoregulation. Tmem16c knockout (KO) rat pups at postnatal day 10 (P10) are more susceptible to hyperthermia-induced seizures. Moreover, they display a more rapid rise of body temperature upon heat exposure. In addition, conditional knockout (cKO) mouse pups (P11) with TMEM16C deletion from the brain display greater susceptibility of hyperthermia-induced seizures as well as deficiency in thermoregulation. We also found similar phenotypes in P11 cKO mouse pups with TMEM16C deletion from Ptgds-expressing cells, including temperature-sensitive neurons in the preoptic area (POA) of the anterior hypothalamus, the brain region that controls body temperature. These findings suggest that homeostatic thermoregulation plays an important role in FSs.

Febrile seizures (FS) are a common childhood neurological condition triggered by fever in children without prior neurological disorders. While generally benign, some individuals, particularly those with complex FS or genetic predispositions, may develop epilepsy or other neurological comorbidities. The mechanisms underlying this transition remain unclear. Mutations in SCN1A , encoding the Na V 1.1 sodium channel α-subunit, have been linked to several epilepsy syndromes associated with FS. This study examines phenotypic variability in individuals carrying the same SCN1A c.434T > C mutation, using induced pluripotent stem cell (iPSC)-derived neurons from two siblings with FS. Despite sharing the mutation, only the older sibling developed temporal lobe epilepsy (TLE). Transcriptomic analysis revealed downregulation of GABAergic pathway genes in both siblings’ neurons, aligning with SCN1A -associated epilepsy. However, neurons from the sibling with TLE exhibited additional abnormalities, including altered AMPA receptor subunit composition, changes in GABA A receptor subunits and chloride cotransporters expression, and reduced brain-derived neurotrophic factor (BDNF) levels, indicative of developmental immaturity. Voltage-clamp recordings confirmed impaired GABAergic and AMPA receptor-mediated synaptic activity. These findings suggest that combined GABAergic dysfunction, aberrant AMPA receptor composition, and reduced BDNF signaling contribute to the more severe phenotype and increased epilepsy susceptibility.

It remains unclear how infantile febrile seizures (FS) enhance adult seizure susceptibility. Here we showed that the transient increase of interleukin-1β (IL-1β) after prolonged FS promoted adult seizure susceptibility, which was blocked by interleukin-1 receptor antagonist (IL-1Ra) within a critical time window. Postnatal administered IL-1β alone mimicked the effect of FS on adult seizure susceptibility. IL-1R1 knockout mice were not susceptible to adult seizure after prolonged FS or IL-1β treatment. Prolonged FS or early-life IL-1β treatment increased the expression of cannabinoid type 1 receptor (CB1R) for over 50 days, which was blocked by IL-1Ra or was absent in IL-1R1 knockout mice. CB1R antagonist, knockdown and endocannabinoid synthesis inhibitor abolished FS or IL-1β-enhanced seizure susceptibility. Thus, this work identifies a pathogenic role of postnatal IL-1β/IL-1R1 pathway and subsequent prolonged prominent increase of endocannabinoid signaling in adult seizure susceptibility following prolonged FS and highlights IL-1R1 as a potential therapeutic target for preventing the development of epilepsy after infantile FS.

A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene, SCN9A encoding Na(v)1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine Scn9a ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous Scn9a(N641Y/N641Y) knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the SCN9A p.N641Y mutation as disease-causing in this family. To confirm the role of SCN9A in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Na(v)1.7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome (severe myoclonic epilepsy of infancy), we sequenced the SCN1A gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Na(v)1.7 missense variants (8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with SCN9A missense variants also harbored either missense or splice site SCN1A mutations and three had no SCN1A mutations. This study provides evidence for a role of SCN9A in human epilepsies, both as a cause of FS and as a partner with SCN1A mutations.