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Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies. 5th edition. New York: Oxford University Press; 2024. doi: 10.1093/med/9780197549469.003.0069
The majority of seizures that arise with fever in infants and children are brief and cause few long-term consequences. A subset of the seizures is prolonged and, when lasting >30 minutes, are termed febrile status epilepticus (FSE). Human and experimental animal data indicate that FSE may be associated with injury to the hippocampus and subsequent temporal lobe epilepsy (TLE) and cognitive problems. Current clinical approaches in the treatment of febrile seizures recommend administration of benzodiazepines to abort the seizure and prevent the evolution of FSE. However, the minimal duration of FSE that leads to epilepsy and memory deficits is unclear, and the first FSE in a child—which is sufficient to provoke long-term consequences—is often difficult to anticipate and abort. Ongoing human and experimental animal studies are beginning to uncover the mechanisms by which FSE can lead to injury, epilepsy, and cognitive deficits in both normal and predisposed individuals. These mechanisms include neuroinflammation and large-scale changes in neuronal gene expression and synaptic connectivity within hippocampal circuits. Future therapy will focus on aborting adverse FSE-induced consequences using mechanism-based interventions.
Febrile seizures are one of the most common form of seizures, and 2%–5% of young children in Western countries experience at least one before the age of 6 (Stafstrom, 2002). These seizures should occur in children without a history of neurological illness (AAP Subcommittee on Febrile Seizures, 2008), but the exclusion of neurodevelopmental delay is not explicit. Febrile seizures take place in the setting of a febrile illness without acute electrolyte imbalance or central nervous system infection (AAP Subcommittee on Febrile Seizures, 2008). When the seizures are brief and nonfocal, they are classified as simple febrile seizures and are considered generally benign. The recommendations are to warn parents about the risk of repeat seizures with future febrile illnesses, and children are sent home from the emergency department without workup or further neurological follow-up (Steering Committee on Quality Improvement and Management: Subcommittee on Febrile Seizures, 2008). However, when a febrile seizure is long, lasting over 30 minutes, it is then classified as febrile status epilepticus (FSE) (although alternative definitions exist; Trinka et al., 2015). These children may be at significant risk of long-term neurological consequences (S. Seinfeld et al., 2016). FSE is often focal (though focality is not a requirement) and is frequently the first febrile seizure (Shinnar et al., 2008). Notably, FSE should be distinguished from new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) (Gaspard et al., 2018; Hirsch et al., 2018). Whereas FSE is less common than simple febrile seizures, it accounts for 5%–9% of all febrile seizures and affects 25,000–30,000 children per year (Berg and Shinnar, 1996; Hesdorffer et al., 2011; Shinnar et al., 1997). Thus, it is critical to develop an understanding of both the management recommendations of FSE as well as the current research on strategies to prevent long-term consequences.
It is often difficult to separate the relative contribution of genetics and environmental factors in the development of FSE. Genetic predisposition to prolonged febrile seizures and FSE is exemplified by Dravet syndrome, often resulting from a mutation in SCN1A, a gene encoding the alpha subunit of the voltage-gated sodium channel NaV1.1. A long febrile seizure is often the first manifestation of Dravet syndrome and occurs during the first months of life (Hirose et al., 2013; Scheffer and Nabbout, 2019). Other monogenic mutations such as PCDH19 may also present with long FS (Trivisano and Specchio, 2019), and familial associations indicate a genetic component in many infants and children with FS and FSE (Kasperavičiūtė et al., 2013). Studies on twins also support a strong concordance of the genetic influence on the development of FSE, although that relationship is less strong than genetic concordance of simple febrile seizures (Eckhaus et al., 2013; S. A. Seinfeld et al., 2016). Of note, many children have no family history of FSE and a normal prior development, supporting a robust environmental contribution to FSE and its consequences. The contributions of environmental factors to the development of FSE are also well established, with relative temperature of the fever and the type of viral source of fever seeming to play a role (Chin et al., 2006; Mohammadpour Touserkani et al., 2017; Theodore et al., 2008). It is likely that genetic and environmental factors both play a role in the development of FSE, and the spectrum of their relative contributions varies among individuals.
As mentioned above, individuals who experience simple febrile seizures have an excellent prognosis, both acutely and long term. There is a slightly increased risk of epilepsy, with a lifetime risk of 2%, compared to 1% in the general population (Annegers et al., 1987), and there has been an association with increased risk of psychiatric disease (Dreier et al., 2019), but intellectual development in general is normal (Baram and Shinnar, 2001; Chang et al., 2001; Verity et al., 1998; Vestergaard et al., 2007). This contrasts with the risks after FSE, which has a more guarded long-term prognosis. The short-term outcome following an episode of FSE is good, with a low risk of morbidity and mortality (Chungath and Shorvon, 2008; S. A. Seinfeld et al., 2016). In the long term, the risk is greater. In a child who has a single episode of FSE, the risk of epilepsy increases from 1% to up to 30%–40% (Annegers et al., 1987; Yokoi et al., 2019). Whereas the risk for epilepsy is higher in individuals with abnormal development at the time of the FSE, the increased risk (estimated at 14%; Mewasingh et al., 2020; Pujar et al., 2018) extends to children with no evidence of brain disease. The spontaneous, unprovoked seizures develop years after the initial FSE and may be generalized (Annegers et al., 1987) or originate from the temporal lobe (Abou-Khalil et al., 1993; French et al., 1993). Temporal lobe epilepsy (TLE) is characterized by seizures involving the hippocampus and is often associated with cognitive and emotional problems (Beghi et al., 2006; Nickels et al., 2016). TLE is often difficult to control with antiseizure medication, with ~30% of patients continuing to have seizures even with optimal medication management (Berg, 2008; Chen et al., 2018; Jobst and Cascino, 2015; Spencer, 2002; Wiebe et al., 2001). This makes understanding the mechanisms for FSE-related epileptogenesis important, because they hold the key for preventing the contribution of FSE to the development of TLE.
Prospective studies allow us to more clearly understand the long-term changes in the brain that occur following FSE. The largest of these studies is the ongoing FEBSTAT study, which has been following 199 children from the onset of FSE. It is the first prospective study of its size and combines early brain imaging, cognitive, and medical outcome measures. Due to the long timeline between the FSE and epileptogenesis, analysis of epilepsy outcomes is ongoing, but the project has published on the other long-term effects of FSE, including hippocampal injury (Lewis et al., 2014; McClelland et al., 2016; Provenzale et al., 2008; Shinnar et al., 2012).
Even in prospective studies, it is difficult in children to fully separate the contribution of FSE to epilepsy from the contributions of genetic factors and other inherent predispositions to both FSE and TLE. Experimental models can reveal clear causal relationships and may identify the responsible mechanisms. Several models of FSE have been reported in both mice (Chen et al., 2021; Tao et al., 2016; van Gassen et al., 2008) and rats (Baram et al., 1997; Dubé et al., 2010; Heida et al., 2004; Heida and Pittman, 2005; Reid et al., 2013; Scantlebury et al., 2005). Our immature rat model of experimental (e)FSE leads to limbic epilepsy (Dubé et al., 2006, 2010), allowing for further investigation into the potential mechanisms by which FSE promotes epilepsy. One-third of rats that undergo eFSE develop epilepsy, and epilepsy never develops in controls (Dubé et al., 2006, 2010), supporting the hypothesis that FSE alone is sufficient to induce epilepsy in an otherwise normal brain (Dubé et al., 2006, 2010; Choy et al., 2014).
It has long been understood that epilepsy provoking insults in adults can lead to functional neuropsychiatric changes, including deficits. However, it has been less clear whether SE and FSE contribute to outcome in children. Indeed, the preponderance of evidence in children suggests that the outcome of SE depends on its etiology (S. Seinfeld et al., 2016). There have also been studies showing an increased risk of schizophrenia and mood disorders following febrile seizures (Dreier et al., 2019). Prospective studies such as the FEBSTAT and the North London Study now provide evidence that FSE may lead to long-term cognitive deficits (Jobst et al., 2019; Martinos et al., 2012; Mewasingh et al., 2020; Shinnar et al., 2012). Importantly, cognitive deficits in children can arise following FSE prior to, and thus independent from, spontaneous seizures. Specifically, children tested 6 weeks and 1 year following FSE exhibited deficits in language, motor, and cognitive functions, even when they had no known developmental delays prior to FSE (Martinos et al., 2013; Weiss et al., 2016). This supports the hypothesis that FSE alone is sufficient to induce cognitive deficits, though it is possible that aberrant changes to the limbic/hippocampal networks underlie both the cognitive deficits and TLE. When these same children were given memory and intelligence question (IQ) test 10 years after FSE, they revealed decreased IQ compared to controls, but they did not identify memory problems (Martinos et al., 2019). The authors hypothesize that the normalization in memory together with decrease in IQ is due to differences in the memory strategies tested between the toddlers and older children.
Work in animal models of FSE has recapitulated the data found in children and has provided potential mechanisms. Rats that undergo eFSE early in life have deficits in their performance on the Morris Water Maze (Dubé et al., 2009) and active avoidance task (Patterson et al., 2017) compared to littermate controls. Notably, these deficits are independent of the development of epilepsy. These findings support the notion that FSE directly provokes enduring cognitive deficits, separate from epileptogenesis and independent of genetic contributions. Recent data from the FEBSTAT study have found significant overlap between the children with long-term memory problems and those with hippocampal injury apparent on neuroimaging following FSE (Jobst et al., 2019; Weiss et al., 2017), supporting the hypothesis that FSE may injure hippocampal circuits, inducing memory problems.
The contrast between the good short-term outcomes for children who experience FSE and the guarded long-term prognosis provides incentive for both acute management of FSE and the development of preventative treatments. The ideal management will include the combined strategies of aborting FSE to minimize damage and an intervention to prevent circuit changes within the limbic system that lead to TLE and cognitive deficits.
Treatment strategies for FSE have been based on two goals: stopping the seizure acutely and preventing the child from having repeat episodes of FSE (Fig. 69–1). The first step in seizure management prioritizes the ABCs of critical care: maintaining airway, breathing, and circulation; and then administration of a drug to abort the seizure (S. Seinfeld et al., 2016). Similar to afebrile seizures, benzodiazepines (BZDs) are widely accepted as the mainstay first-line medication for any febrile seizure lasting longer than 5 minutes (Chamberlain et al., 2014; Glauser et al., 2016; Silbergleit et al., 2012). If possible, this is best done in an emergency medical services setting, before the child arrives at hospital, though local regulations for BZD administration by emergency medical services vary (Silverman et al., 2017). To minimize time to treatment, minimally invasive routes of medication administration have been the focus of recent studies, especially when evaluating treatment in a prehospital setting. This has been supported in recent studies comparing midazolam to diazepam (which has been found to be similar in its IV form to IV lorazepam) (Chamberlain et al., 2014). The studies revealed similar rates of attaining seizure control between both buccal and intranasal midazolam and intravenous (IV) diazepam, and buccal midazolam was superior to rectal diazepam (Lahat et al., 2000; Nakken and Lossius, 2011; Scott et al., 1999). Interestingly, both buccal and intranasal midazolam achieved faster seizure control as compared to IV diazepam. This supports the argument that medical professionals should not wait for IV access for administration of BZDs during a prolonged febrile seizure, as noninvasive midazolam is comparable, if not superior, at quickly achieving seizure cessation. This is particularly important because a recent study found that delay of first-line BZD treatment of greater than 10 minutes after seizure onset in children is associated with increased risk of negative outcomes, including need for continuous infusions and even death (Gaínza-Lein et al., 2018). Achieving this sub-10-minute goal may require changes in the management and norms of emergency medical services, as is apparent in the FEBSTAT study cohort, where the median time to medication administration was 30 minutes after the seizure onset (Seinfeld et al., 2014). More recent studies have found an average of 15–20 minutes to first BZD administration, but that the timeline did not decrease following society guidelines emphasizing rapid administration (Sánchez Fernández et al., 2020). Additionally, an emerging consensus suggests that the onset of injury that might lead to epilepsy or cognitive problems is earlier than 30 minutes (Joshi and Goodkin, 2020; Sánchez Fernández et al., 2020). The most recent recommendations from the American Epilepsy Society recommend BZDs as first-line treatment, with the highest level of evidence supporting IV diazepam or IV lorazepam, and good evidence supporting the use of rectal diazepam, intramuscular midazolam, intranasal midazolam, and buccal midazolam (Glauser et al., 2016).
Overview of acute management strategies of febrile status epilepticus.
If seizure cessation cannot be achieved with BZD treatment, administration of additional medication is required, but there is less consensus on the best method. The 2016 status epilepticus guidelines of the American Epilepsy Society recommend either IV valproic acid, fosphenytoin, or levetiracetam, but state there is no clear evidence supporting one option over another (Glauser et al., 2016). A more recent retrospective study found similar efficacy in aborting seizures between IV fosphenytoin and continuous IV midazolam, though IV midazolam decreases likelihood of the patient requiring barbiturate-induced coma (Nishiyama et al., 2018). The ESETT trial was a randomized, controlled trial comparing second-line treatment in children with SE with IV fosphenytoin, levetiracetam, and valproic acid. They found similar seizure control among the three medications, but increased requirement for endotracheal intubation with fosphenytoin compared to the others (Chamberlain et al., 2020; Kapur et al., 2019).
When FSE fails to respond to first- and second-line therapies, it is categorized as refractory FSE. It should also be noted that electrographic epileptic activity may continue without clinical manifestations, suggesting the need for vigilance and additional electroencephalograms (EEGs) if subclinical seizures are suspected (Zehtabchi et al., 2020). A study found that continuous midazolam is inferior to barbiturate coma therapy with continuous EEG in children with refractory FSE, as patients treated with continuous midazolam are more likely to have breakthrough seizures and have worse functional outcomes 1 month after seizure onset (Nagase et al., 2014). Mild hypothermia (32ºC–35ºC) has been used as a treatment to decrease seizure burden in pediatric refractory status epilepticus, but it has not been systematically studied and remains experimental (Guilliams et al., 2013). The American Epilepsy Society does not have a recommendation of the best treatment for refractory FSE based on insufficient research comparing treatments (Glauser et al., 2016).
The required workup following FSE of infectious cause of the fever has been debated. By definition, simple febrile seizures and, by extension, FSE cannot occur in a child with a known central nervous system infection. SE with fever has been shown to be the only clinical symptom of bacterial meningitis (Chin et al., 2005, 2006), and thus there have been studies investigating the value of lumbar puncture in a child with fever, SE, and no meningeal signs. A study of children that received lumbar puncture after FSE found that status epilepticus is rarely the sole presenting symptom of bacterial meningitis in well-vaccinated communities and that lumbar puncture rarely changed diagnosis or management (Haro et al., 2018). There has been previous work revealing patients can have cerebrospinal fluid (CSF) pleocytosis following status epilepticus independent of meningitis or encephalitis (Barry and Hauser, 1994). Contrasting to this long-held belief, the FEBSTAT study found that pleocytosis was very uncommon following FSE, leading to the recommendation against abnormal CSF values after FSE being attributed to a postictal phenomenon alone and that they require careful investigation (Frank et al., 2012). An important consideration when evaluating the utility of lumbar puncture following FSE is the vaccination status of the community and individual patients, as the bacterial conjugate vaccine was first made available in the year 2000. Because of this, there has been a decrease in bacterial meningitis in this age group, decreasing the positive predictive value of pleocytosis and probability of CSF findings changing management (Haro et al., 2018). Accordingly, the recommendation of whether to pursue a lumbar puncture in a child with FSE is up to the individual clinician based on suspicion of meningitis or encephalitis. Pretest probability of an infectious pleocytosis in a lumbar puncture is low without meningeal symptoms in a patient age >12 months and up-to-date vaccinations (S. Seinfeld et al., 2016).
Reoccurrence rate of FSE is high, estimated at over 40% for another episode of any type of febrile seizure and a 10% chance of another episode of FSE (Hesdorffer et al., 2016). Because of this, there has been significant investigation into the utility of prophylactic intermittent or continuous drug treatment to prevent recurrent febrile seizures, with less work focusing specifically on children who have had FSE. Studies have looked at multiple time points and treatment strategies: antipyretic or prophylactic BZD use in current febrile illness, intermittent antipyretics or BZDs at onset of future febrile illnesses, and continuous antiseizure medication throughout the years the child is at risk of febrile seizures (Fig. 69–2). They have shown decreased risk of recurrent febrile seizures with continuous antipyretic use throughout the current illness, but there is no evidence to support continuous antipyretic use in future seizures (Hashimoto et al., 2021; Murata et al., 2018). Previously, the Japan Society of Child Neurology recommended immediate administration of prophylactic BZD to children presenting to the hospital following febrile seizures (Fukuyama et al., 1996). This guideline was changed in 2015, and recent retrospective studies reviewing outcomes of children prior to and following that change revealed that the reduction in prophylactic BZD use correlated with an increase in febrile seizures during the next 24 hours (Inoue et al., 2020). Thus, there may be some role in short-term prophylactic usage of BZD following febrile seizures in children particularly at risk of recurrence.
Overview of prophylactic treatment strategies for prevention of recurrent seizures following febrile seizures
Work investigating continuous phenobarbital prophylaxis or intermittent diazepam prophylaxis only during future febrile illnesses revealed a reduction in reoccurrence of febrile seizures with both treatment strategies. There was no similar benefit of intermittent antipyretics or the other antiseizure medications tested. Importantly, up to 30%–36% of the children in the intermittent BZD- and phenobarbital-treated groups experienced significant cognitive side effects compared to controls (Offringa et al., 2017). Other studies looked at efficacy of other mechanisms of prophylaxis, including intermittent melatonin, but these need to be studied in larger populations (Barghout et al., 2019).
Thus, based on the potential side effects of long-term or intermittent treatment with these medications, it is not recommended to widely prescribe them prophylactically. While it is not recommended to attempt to prevent all febrile seizures, there is risk of repeat FSE, which does entail increased risk. Thus, it is recommended that parents of children who experience FSE be prescribed a noninvasive BZD, such as rectal diazepam, to abort future prolonged febrile seizures (O’Dell et al., 2005).
Since the development of epilepsy and cognitive problems affect a subset of individuals that experience FSE, there has been significant investigation into developing a method to prognosticate long-term outcomes. These have included clinical, laboratory, and neuroimaging techniques. For example, Nagase et al. found that the combining measures of seizure response to treatment, neurological function 6 hours after seizure onset, and aspartate aminotransferase laboratory values, they were able to retrospectively predict outcomes at discharge (Nagase et al., 2013). More encouraging than combined laboratory measurements is direct measurement via visualization and quantification of brain structures through neuroimaging. Neuroimaging has become the primary method of measuring brain injury following FSE, particularly utilizing magnetic resonance imaging (MRI). MRI is widely clinical available, noninvasive (although requiring anesthesia), and can provide a direct reflection of underlying brain alterations.
Post-FSE imaging has found a higher preponderance of developmental structural changes in children with FSE that likely influenced the brain’s susceptibility to FSE, most specifically hippocampal malrotation (Chan et al., 2015), as well as temporal lobe and hippocampal size abnormalities (McClelland et al., 2016). Additionally, both children and experimental animal models have revealed increased T2 signals throughout the limbic system, and especially the hippocampus, days, weeks, and months after FSE, which likely reflect long-term injury (Dubé et al., 2004; Scott et al., 2003). Most exciting for prognostication is not the differences that were there long before or after FSE, but instead the changes measurable in the hours to days following FSE. These short-term MRI changes reflect the immediate effects of the insult, ideally giving a window into understanding the mechanisms of long-term changes to neuronal circuitry.
Early MRI changes in the brains of rats that undergo eFSE have proven particularly fruitful in predicting epileptogenesis. MRIs 2–6 hours after eFSE in immature rats revealed apparent decrease in T2 values throughout the limbic circuit and especially in hippocampus and amygdala. Remarkably, reduced T2 values within the basolateral amygdala (BLA) were strongly predictive of the subsequent development of epilepsy (Choy et al., 2014). This signal change was initially found on an 11.7T high magnetic field T2 MRI and was a T2* effect, which correlates with changes in deoxyhemoglobin (Chavhan et al., 2009). Using appropriate T2* sequences, these changes are measurable on lower strength scanners as well (Curran et al., 2018). Whether this approach predicts epileptogenesis in children is under current investigation.
Currently published clinical studies in children have analyzed MRIs days, rather than hours, following FSE and have begun to find important differences. A recent study found hippocampal hyperintensity in 27% of children in the days following FSE, which correlated with continued ipsilateral EEG changes after the cessation of FSE. The children who had hippocampal hyperintensity were significantly more likely to develop epilepsy when followed 13 years later than those without (Yokoi et al., 2019). The FEBSTAT study found increased hippocampal T2 signal following FSE in 12% of subjects 24–72 hours after seizure onset, though these changes have not yet been correlated with future risk of epilepsy (Lewis et al., 2014; Shinnar et al., 2012). The group did find that the hippocampi with increased T2 signal in the days following FSE shrank in the year following the seizure, meeting criteria for hippocampal sclerosis, an important risk factor for TLE (Lewis et al., 2014).
In addition to predicting future development of epilepsy, MRI changes have also been associated with future cognitive deficits. Animal models have revealed that T2 increases after eFSE are associated with impaired performance on active avoidance spatial task weeks later, specifically in the hippocampus and basolateral amygdala (Barry et al., 2015). Similarly, results from the FEBSTAT study have revealed that children with increased T2 in the days following FSE were more likely to develop deficits in receptive language skills (Weiss et al., 2016) and memory function (Jobst et al., 2019; Weiss et al., 2017).
The ability to predict which children are at risk for both epilepsy and cognitive deficits following FSE is important for counseling families with an accurate prognosis, but it is also critical for the study of the pathogenesis of those changes. Optimally, these predictions should be coupled with treatments aimed at preventing the processes culminating in spontaneous seizures or cognitive problems.
As a result of their role in the production of fever, inflammatory processes are inherently involved in the development of febrile seizures (Dubé et al., 2005; Eskilsson et al., 2014; Heida et al., 2009; Luheshi et al., 1997). Inflammatory modulators signal the hyperthermia that increases excitability of the brain and also have a direct role in increasing the likelihood of spontaneous seizures form the limbic circuit (Dubé et al., 2007; Patterson et al., 2015; Vezzani et al., 2011). Increased levels of inflammatory cytokines are also involved in epileptic seizures and have been measured in the brain of epileptic animals and in the brain tissue removed from patients with epilepsy (Aronica and Gorter, 2007; Balosso et al., 2013). Thus, inflammatory modulators are an enticing candidate for mediating the effects of FSE on both epileptogenesis and cognitive deficits.
In experimental models, increased expression of inflammatory cytokines is fairly rapid, measurable as early as 1 hour after the end of FSE and nearly completely disappearing by 96 hours post seizure (Dubé et al., 2010; Patterson et al., 2015). This rapid time course is encouraging because it allows for potential interventions early in the cascade, rather than interacting with the multitude of long-lasting downstream targets. In immature rodent models inflammatory processes increased most in the same limbic regions and in the same animals in which the epilepsy-predictive MRI signal was observed (Choy et al., 2014; Patterson et al., 2015). The increasing inflammatory mediators in one model included COX2, GFAP, TNF-α, Interleukin-1β (IL-1β), and Interleukin-1 Receptor 1 (IL-1R1) (Patterson et al., 2015). Without this increase in inflammation within the brain, particularly IL-1β, the brain is significantly more resistant to febrile seizure, as seen in mice deficient in IL-1β (Dubé et al., 2005). In other models, TNF-α was the predominant governor of future hyperexcitability (Heida and Pittman, 2005; Reid et al., 2013).
Similarly in children, increases in cytokines and chemokines have measured in the plasma and CSF following FSE, including TNF-α, CXCL9, CXCL10, CXCL11, and CCL19. The levels were increased not only compared to controls but also as compared to children who have experienced afebrile status epilepticus or chronic seizures (Ichiyama et al., 2008; Kothur et al., 2019). Interestingly, the FEBSTAT study found that IL-6 and IL-8 were significantly higher in the serum of patients that had exhibited T2 hippocampal hyperintensity on MRI following FSE, supporting the hypothesis that MRI changes and inflammatory markers measure overlapping processes inherent in epileptogenesis.
Inflammation is also an enticing target for treatment because of the many drugs that are clinically available or in development that directly interact with the inflammatory cascade. There have been studies that investigate the involvement of specific pathways, including IL-1β (Feng et al., 2016; Maroso et al., 2011; Noe et al., 2013; Ravizza et al., 2008), the cyclooxygenase and prostaglandin cascade (Holtman et al., 2010; Järvelä et al., 2011; Jiang et al., 2010, 2012, 2015; Polascheck et al., 2010; Rojas et al., 2014), high mobility group box 1 (HMGB1), a DNA binding protein critical for the initiation of the inflammatory cascade (Brennan et al., 2021; Choi et al., 2011; Li et al., 2013), and micro-RNA 124 (Brennan et al., 2016). Because of the complex and diverse inflammatory cascades involved, it is not surprising that the goal of preventing hyperexcitability following FSE has not been accomplished by blocking single inflammatory pathways. Rather, a short-term treatment with dexamethasone, a clinically available glucocorticoid receptor agonist which acts as a broad anti-inflammatory agent, has proven the most effective at preventing aberrant hippocampal hyperexcitability following FSE, as measured via EEG spike series, a precursor to spontaneous seizures (Garcia-Curran et al., 2019). These findings in experimental models are consistent with a clinical retrospective study that found that children with fever and refractory SE who received methylprednisolone (a similar glucocorticoid receptor agonist) and IV immunoglobulin (IVIG) had better short- and long-term outcomes than children who received IVIG alone or no immunotherapy (Lin et al., 2018).
In addition to provoking inflammatory changes, FSE may influence brain function via enduring changes in gene expression. A deleterious effect of FSE on cognitive outcomes might be a result of such enduring epigenetic processes. Animal experiments have begun to elucidate the potential mechanisms, and thus possible interventions, of these cognitive deficits. Transcriptomic analyses on the brains of rats that underwent eFSE revealed coordinated changes in the expression of multiple genes that govern neuronal behavior. The regulated genes included Neuron-Restrictive Silencing Factor (NRSF), a gene that was originally described in nonneuronal tissues where it played role suppressing neuron-specific genes (Chen et al., 1998; Schoenherr and Anderson, 1995). Since then, NRSF regulation has been shown to play an important role in both developing and mature neurons, including via suppressing genes during neuronal growth and maturation (Ballas and Mandel, 2005; Gao et al., 2011; Singh-Taylor et al., 2017). Seizures increase NRSF protein levels and activity (Brennan et al., 2016; Garriga-Canut et al., 2006; McClelland et al., 2014; Rodenas-Ruano et al., 2012; Roopra et al., 2001), and thus it was hypothesized that NRSF plays a unique role in FSE, due to its dual roles in development and following seizures. Granule cells of the dentate gyrus, a cell population required for learning and memory, are one of the populations of cells that are still differentiating at the developmental period FSE occurs and thus may be uniquely affected (Schlessinger et al., 1975; Thind et al., 2008). Blocking NRSF binding to the chromatin during a few days following FSE rescued the cognitive performance of eFSE rats in an active avoidance learning and memory task in adulthood, significantly better than rats without NRSF blockade (Patterson et al., 2017). The blockade not only prevented memory problems but also rescued the normal development of dentate gyrus granule cells following FSE, suggesting that NRSF regulation following FSE is a promising candidate for treatment (Hall et al., 2018; Patterson et al., 2017).
As we gain a greater understanding of the lifelong effects of even a single episode of FSE, the importance of acute treatment and long-term preventative strategies becomes clear. These strategies are two pronged. First, there are the established first- and second-line treatments to acutely abort prolonged febrile seizures to minimize the seizures’ ability to injure and alter the brain. The second is the true future of FSE management, namely, the accurate prediction of the long-term development of cognitive deficits and epilepsy, and then administration of targeted acute preventative treatments to abort the alterations in brain circuitry before they occur.
The current work studying the mechanisms and treatment strategies in animal models of FSE are the first steps toward future preventative strategies in children and is helping scientists understand the roles of inflammation, epigenetic modulation, and structural brain changes in long-term outcomes. This is critically important because of the major cost of TLE in terms of human potential and productivity. Though modern medicine has reduced the number of individuals that have febrile seizure progress to FSE, FSE is likely to continue as a major source of refractory TLE (Cloppenborg et al., 2019; Englot et al., 2012; Jehi et al., 2015), providing impetus to address its impact on the world’s future generations.
The authors’ work has been supported by NIH grants NS35439, NS108296, and T32 NS045540.
This is an open access publication, available online and distributed under the terms of a Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International licence (CC BY-NC-ND 4.0), a copy of which is available at https://creativecommons.org/licenses/by-nc-nd/4.0/. Subject to this license, all rights are reserved.
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