Simple FS Complex FS Extended FS Onset during extreme febrile seizures Throughout mild to moderate febrile seizures Intermittent or continuous FSs Duration Few minutes Prolonged (10 minutes) Zero type Generalized tonic-clonic seizures Hemilateral or focal seizures Nil Other FS Recurrent Non Recurrent Most recurrent events None Some prolonged Todd’s palsy Nil Previous neurological signs Absent Possible presence Nil Clinical outcome Adequate apyretic convulsions 10–15% cases Nil Table 1: Simple FS differs from complex and extensive FS.

Methodology

The methodology of this research is an exhaustive review of the literature searched from PubMed, Elsevier, ResearchGate, Medline, Embase, The Cochrane Library and other major databases.

Epidemiology

Between the ages of five months and five years, FS is most common and peaks at 18 months. About 20-30% of FS are complex, with the majority being simple [14,15]. Compared to the general population, families of children with FS have an increased rate of epilepsy. According to the results of one study, 9.2% of FS patients had first-degree relatives who had epilepsy [16]. The incidence of FS in children in Western Europe and the United States ranges from 2% to 5%, and the peak age at onset is 18 months [17,18]. Children of various ethnic backgrounds may present with FS. However, some populations have a higher prevalence than others, consisting of Japanese (6%) and Indians (5-10%) [18]. 50% of all children with FS are between 12 and 30 months of age, while only 6-15% of children experience their first episode after four [19].

Etiology and pathophysiology

Certain viruses have been found to cause FS. Influenza A and B, respiratory syncytial virus, adenovirus, human metapneumovirus, parainfluenza viruses 1, 2, 3, 4a and 4b, rhinovirus, rotavirus, human herpesvirus 6, enterovirus and human metapneumovirus are the viruses most commonly associated with FS virus in young children. Upper respiratory tract infections (URTIs) and common viruses that cause URTIs, such as influenza viruses and respiratory syncytial virus, have been associated with FS in numerous studies. This association is supported by the autumn/winter seasonality of these events [20,21]. Peaks in FS frequencies correlate with increases in summer diagnoses of gastroenteritis in children, particularly enteroviruses [22]. Various vaccines, such as rotavirus vaccine, measles vaccine, diphtheria pertussis vaccine, and influenza virus vaccine, are associated with the development of FS. Although the specific pathogenesis of FS is uncertain, it is commonly accepted that these events are caused by a confluence of environmental exposures (fever and its cause) and genetic predisposition. Fever and induction of seizures According to one theory, increasing brain temperature will promote neuronal firing and increase the likelihood of synchronized neuronal activity, which causes seizures [23]. Stressors during pregnancy and the first months after birth may affect limbic epileptogenesis by altering central nervous system neuroplasticity [24]. By attracting astrocytes and microglia to the site of injury, early life trauma is thought to alter the excitability of circuits (for example, infection in the mother, prenatal maternal or environmental stress, perinatal hypoxic-ischemic injury, or any infection after the baby is born, convulsion or trauma leading to brain damage). After this lowering of the seizure threshold in the developing brain, a second hit (like, say, a fever) may be enough to trigger a seizure [25]. The inflammasome pathway of the immune system, which produces the cytokines interleukin (IL)-1, tumor necrosis factor alpha (TNF-α), IL-6, and interferon, can also be activated by fever. The anti-inflammatory cytokine, IL-10, is also produced in response to IL-1, IL-6 and TNF-α [26]. IL-1β and IL-10 are increased in FS [26,27]. Antipyretics that block prostaglandins do not reduce the length or frequency of FS. This demonstrates that prostaglandins (generated as a result of cytokine release in response to fever, as shown in Figure 1) [4] do not trigger seizures in febrile illnesses [28,29]. Figure 1: A condensed version of the pro-cytokines that promote an anti-inflammatory as well as febrile response. TNF-a: tumor necrosis factor alpha. INF-γ: interferon gamma; IL: interleukin; PGE2: prostaglandin E2. Image credit: Authors. Genetic predisposition Twin and family studies suggest that the etiology of FS has a significant genetic component febrile seizures 1 (FEB1). Parametric linkage analysis of a large family revealed the locations of FEB1 on chromosome 8q13-21, febrile convulsions 2 (FEB2) on 19p133, and febrile convulsions 3 (FEB3) on 2q23-24. A variety of 47 tiny families were subjected to a non-parametric evaluation and febrile convulsions 4 (FEB4) was discovered on 5q14-15 [30]. The genes encoding sodium channel alpha 1 subunit (SCN1A), voltage-gated sodium channel alpha subunit 2 (SCN2A), and gamma-aminobutyric acid (GABA) receptor subunit have mutations in FS. In 25-40% of cases where a child has FS, a positive family history of FS can be found [31,32]. The chance of a sibling developing FS depends on how much FS a child has. In many twin registries, monozygotic twins have significantly higher concordance rates for FS than dizygotic twins [33]. Children who have FS and later develop generalized epilepsy without having specific status epilepticus may be explained by the FS plus phenotype. These individuals or their family members have a background of FS, which is generally complex and appears after the age of five. Epilepsy can manifest later in childhood or adolescence in various types of seizures. These families have been linked to mutations in SCN1A, SCN1B, and gamma-aminobutyric acid type A subunit of receptor gamma2 subunit, among other genes. The clinical phenotypes of epilepsy that comprise the putative genetic syndrome known as generalized epilepsy with FS plus (GEFS+) range from mild to severe, with myoclonic ataxia being the most severe. [34,35]. There are two mutations associated with genetic susceptibility to FS. Voltage-gated sodium ion channels In neurons, voltage-gated sodium channels play an important role in the propagation of action potentials. It is supported by the discovery of multiple sodium channel subtypes that there are variations in the genes responsible for making the sodium channel protein [36]. SCN1B gene mutations have been found in all individuals with seizures, including FS, in studies of GEFS+ families [37]. Additionally, a recent study linked two families with GEFS+ syndromes to mutations in the SCN1A gene [38]. Other SCN protein mutations have been discovered and shown to exist in families with similar phenotypes [39]. However, GEFS+ is a rare cause of FS, making it difficult to identify the exact impact these mutations have. Cyclic cyclic nucleotides activated by hyperpolarization Seizure development depends on hyperpolarization-activated cyclic nucleotides (HCNs), which promote neuronal excitability [40]. In people with seizures and epilepsy, mutations in hyperpolarization genes activate cyclic nucleotide-gated channels,…