Febrile seizures are a common cause of pediatric emergencies and the most common type of seizure in children between 6 months to 5 years of age, always associated with fever.
These seizures can be classified as simple, complex, or febrile status epilepticus, depending on several factors, and usually do not cause any long-term harm. These types of episodes can be very alarming for parents.
Likely multifactorial and caused by a rise in body temperature, but the exact mechanism is still being investigated. Risk factors for febrile seizures include age, high fever, viruses, genetics, and vaccines.
Diagnosis should aim at finding the cause of the high fever. MRI and CT are not recommended, and the use of EEG helps diagnose epilepsy in children with recurrent episodes. Treatment typically involves managing the fever and its underlying cause.
Introduction to Febrile Seizures in Children
References: (1, 2, 3, 4)
Frequently perceived by parents as a life-threatening event, febrile seizures (FS) are one of the most common causes of pediatric emergency department visits. Presenting in young children, usually occurring between 6 months and 5 years of age (1-3), that is accompanied by fever (100.4 F/ 38.5 C or greater) with a 2-5% incidence in Western countries (2), without central nervous system infection.
Most FS have favorable outcomes leading to the widely held view that they are benign. Although this may be true in most cases, recent studies have identified relationships between FS and psychiatric disease and sudden unexplained death in childhood (SUDC). It has also been discussed that prolonged seizures can damage the brain and lead to negative consequences.
Only a subset of children experiences FS, even though almost all children will experience a significant fever during early childhood. The cause is likely multifactorial, propagated by a variety of genetic and environmental factors, including viruses and vaccines, that as clinicians, we should take into consideration when assessing, diagnosing, and treating a child presenting with fevers and seizures, as well as to be able to explain the sequelae to concerned parents of the child.
Parents should be educated on the benign nature of this condition in children and provided with practical guidance to practice at home in case another episode happens.
In this article review, we discuss the definition of this clinical entity, have a quick overview of its etiology, epidemiology, and pathophysiology, and have a glance at the different classifications, appropriate information for parents, and address the evaluation, treatment, and prognosis of FS.
Definitions of Febrile Seizures in Children
References: (2, 3, 5, 6, 7)
A febrile seizure is a fit or convulsion caused by a sudden change in the child’s body temperature and is usually associated with a fever above 101 degrees Fahrenheit (38.3 ºC). Seizures may happen during a viral infection, such as a cold, the flu, or an ear infection, and commonly occur in children between 6 months and 5 years old.
According to the definition of the American Academy of Pediatrics, the International League Against Epilepsy states that FS can occur from 1 month of age, having an implication regarding the likelihood of genetic epilepsy such as Dravet syndrome or PCDH19 (3). In some cases, a child may not have a fever at the time of the seizure but will develop one a few hours later.
The American Academy of Pediatrics defines a febrile seizure as a convulsion occurring in the context of a fever without central nervous system infection in a child without prior history of afebrile seizures, known neurological disorder, or a pre-existing disorder that predisposes to an increased risk of seizures.
In contrast, the International League Against Epilepsy does not exclude children with neurological disorders that predispose them to a greater risk of seizure (e.g., cerebral palsy) (3). These definitions exclude seizures occurring in the presence of an underlying central nervous system infection or a metabolic disturbance. Children with a pathological history of afebrile seizure are excluded from the group of children with FS as the febrile illness is considered a trigger of a pre-existing predisposition to epilepsy.
Most FS stop without any treatment and don’t cause other health problems. Symptoms may include loss of consciousness or passing out, uncontrollable shaking, eye-rolling, or rigid limbs. Rarely can a child become rigid or have twitches in only a part of the body (focal features). After the convulsion, some kids might feel drowsiness, while others feel no lasting effects.
Classification of Febrile Seizures in Children
References: (1, 2, 3, 4, 8, 9)
FS has been classified as simple, complex, and febrile status epilepticus based on duration, the presence of focal features, and recurrence. Approximately 70% of febrile seizures are simple, 25% are complex, and 5% are classified as febrile status epilepticus (8). Febrile status epilepticus is the most common cause of status epilepticus in children (accounts for 25-52% of all status epilepticus in children) (2).
Simple febrile seizures (SFS) are characterized by a generalized seizure that lasts less than 15 minutes and does not recur within 24 hours. Complex febrile seizures (CFS) are characterized by the presence of at least one of the following: focality, duration longer than 15 minutes, and a recurrence within 24 hours.
Febrile status epilepticus (FSE) or “prolonged febrile seizure” is defined as at least 30 minutes of continuous seizure activity or 30 minutes of recurrent seizures without full recovery of consciousness in between seizures. However, in 2015, an International League Against Epilepsy redefined the time periods, including 5 minutes for generalized tonic-clonic seizures, 10 minutes for focal seizures, and 10-15 minutes for absence seizures. (3)
Children who have FSE have a greater risk of future adverse events, with up to 41% subsequently having febrile seizure recurrence. Nevertheless, the overall mortality and morbidity of febrile status epilepticus are low. (2)
Table 1: Classification of FS (9)
|Simple||Complex||Febrile Status Epilepticus|
|Duration||Less than 15 minutes||Seizures lasting more than 15 minutes and those lasting less than 15 minutes which stop with anticonvulsive medication||Seizures lasting more than 30 minutes or 30 minutes of recurring seizures without recovery of consciousness in between.|
|Presence of focal features||Generalized without focal features||Seizures with focal features||Nil|
|Recurrence||No recurrence in 24 hs||Recurrent seizures within 24 hours||Nil|
|Onset||During bouts of extreme febrility||Throughout mild- to-moderate febrile bouts||Intermittent or ongoing FSs|
|Post-ictal effect||None||Some lingering, Todd’s paralysis||Nil|
|Previous neurological signs||Absence||Potential presence||Nil|
|Outcome||Decent||Afebrile seizures 5-10% of cases||Nil|
Epidemiology of Febrile Seizures in Children
FS are the most common cause of seizures in childhood, with a 2-5% incidence in European and American children, there has been found a higher incidence in Japan (7-10%) and Guam (14%) (2). Some studies have found a higher incidence in males, and others haven’t found a difference between genders. (4)
As we said before, the common age is between 6 months and 5 years, though it has been reported in children up to 7 years and younger as 3 months old. The peak incidence of a first episode is in children aged 12-18 months old (accounting for up to 4% of children in this age group) (8), with 90% of children that have had a previous episode by the age of 3 years.
FS are most commonly reported in winter, corresponding with a peak in febrile illnesses in young children, with some of them having a single event and others having multiple events over early childhood.
Etiology of Febrile Seizures in Children
The cause of a febrile seizure is unknown, although they are linked to various factors like genetics, viruses, vaccines, and the start of a high temperature.
Pathogens (2, 4, 8): The incidence of this condition has been strongly associated with certain viruses. Most commonly Influenza, Parainfluenza, Respiratory Syncytial Virus (mostly in winter/fall associated with upper respiratory tract infections), Enterovirus, and Adenovirus (mostly in the summer, associated with gastrointestinal diseases).
Human Herpesvirus type 6 (HHV-6) infection, also known as roseola infantum or sixth disease, is an important virus historically implicated in the disease. While children infected with this virus may experience respiratory or gastrointestinal symptoms, exanthema is a common finding.
Viral infections are documented in up to 80% of FS, although bacterial pathogens can also cause it, most commonly in the context of otitis media.
Genetics: There is an association between approximately one-third to one-half of children with FS having a family history. (4)
High temperature (8, 10): The highest fever temperature depends on the threshold of each child, as it varies from individual to individual. While the degree of fever is ultimately the most significant factor in FS, these episodes often occur while the temperature is rising, with the presence of fever greater than 38 º C/100.4 ºF appearing after the manifestation of the seizure. One study found the risk of having a febrile seizure nearly doubled with each increase in degrees Fahrenheit above 101ºF. (11)
Vaccines (2, 4): Febrile reactions following vaccinations are common in young children. FS may occur after the administration of certain vaccines, most commonly those containing measles, combined diphtheria-tetanus toxoids-pertussis, pneumococcal conjugate vaccine (PCV 13), and influenza vaccines, presenting within 2 weeks post-vaccination (4).
Although vaccination may cause a minimal risk for FS in a short period after administration, vaccination reduces the risk by preventing infection by common viruses that cause FS and, therefore, reducing the risk overall.
Pathophysiology of Febrile Seizures in Children
References: (2, 8)
As we know, seizures occur due to synchronized, prolonged, and unchecked activation of clusters of neurons and arise out of a mismatch in excitatory and inhibitory activity in the brain. The exact pathophysiology of FS is not understood; however, it is assumed that multifactorial and genetic predisposition and environmental factors trigger the event.
One exploratory study showed that children with hippocampal and amygdala volume atrophy, marked asymmetry, and hippocampal malformation, had more prevalence in FS than those who didn’t.
There have also been studies about the role of voltage-gated sodium ion channels, and Hyperpolarization activated cyclic nucleotide-gated channels (HNC). Variations in gene coding of the sodium channel protein have been found in children with seizures, including FS in families GEFS +. And mutations to HNC have been found in patients with seizures and epilepsy. Further specific HNC2 channel mutations have been found in association with FS and GEFS+ patients. Nevertheless, while these ion channel mutations play a role in disease production, they are shown to have low penetrance; therefore, a second factor may be necessary for seizure propagation.
Studying the fever and seizure induction, early life trauma (such as maternal infection, prenatal maternal or environmental stress, traumatic brain injury, etc.) is thought to lead to modification of circuit excitability by recruiting astrocytes and microglia at the site of insult, being the fever a sufficient trigger to start a seizure activity.
Hyperthermia can increase the excitability of pyramidal and dentate granule cells, as well as that of inhibitory interneurons. Seizures may also lead to ectopic granule cells that render the brain excitability, which could explain the increased risk of FS recurrence after the first one. These mechanisms will explain the rise in seizure activity since it increases the excitability, which reduces the seizure threshold, and the increased inhibition of the interneurons augments the synchronicity of cells.
In addition to affecting neural pathways, fever may trigger seizures via the inflammatory pathway, with IL-10 as an anti-inflammatory cytokine produced in response to IL-1B, IL-6, and TNF- alpha. Both IL-1B and IL-10 are elevated in FS. Prostaglandins produced due to cytokine release do not initiate seizures in febrile illnesses; this is why antipyretics that inhibit prostaglandins do not reduce the duration or recurrence of FS.
Risk Factors Associated with Febrile Seizures
References: (1, 2, 6, 7, 10)
About one in every 25 children will have at least one febrile seizure, and the older the child is when this episode occurs, the less likely that the child will have more due to not being in the age group at risk. Certain factors increase the risk for FS, including:
- Family history of FS;
- Age between 12-18 months old (risk group);
- Already had one febrile seizure in their life;
- Having their first febrile seizure younger than 15 months old;
- FS is the first sign of illness before any other symptom;
- The first febrile seizure was with a relatively low temperature;
- Previously having a CFS.
Other risk factors include the ones described in the etiology and pathophysiology segments: being exposed in utero to stress or maternal infections, certain gene mutations, family history of FS, certain viral infections, particularly those associated with high fevers, and certain vaccines.
We can also mention that being in the neonatal intensive care unit for more than 28 days, developmental delay, and daycare attendance (because of the increased chance of developing common childhood infections) have been proven to increase the risk of having a febrile seizure in children (1).
Signs and Symptoms of Febrile Seizures in Children
References: (4, 5, 6, 10)
Usually, FS happen when the temperature of the child goes up suddenly and typically occur within the first 24 hours of an illness, often within an hour of fever onset. The seizure is the first sign of a febrile illness in 25-50% of cases. (4)
As we said before in this article, there are different types of FS and with them, different symptoms and signs.
In SFS, a child may lose consciousness, have irregular breathing, pallor or cyanosis, foam at the mouth, roll his eyes or fix his gaze, vomit or urination during a convulsion, or have generalized twitching.
When experiencing a CFS, the difference will be that the child will experience generalized or focal twitching and jerking of extremities and that these manifestations could happen more than once in 24 hours.
After the seizure, a postictal period of drowsiness, fussiness, or confusion may occur for up to one hour. A postictal palsy (Todd’s paralysis) may occur.
Anticipatory Guidance for Parents
References: (1, 5, 6, 10)
Anticipatory guidance for parents should focus on reassurance, emphasizing the benign nature of FS and the overall excellent prognosis, even if the seizure recurs.
Physicians may also provide parents with guidance on the initial management of FS, stating that the most important thing is to stay calm, place the child on the floor, lying on their side, they should try to time how long the seizure lasts, loosen any clothing around their head and neck, remove any nearby objects, and watch of signs of any breathing problem.
Parents should avoid restraining the child, putting any medication in their mouth while they are having the seizure, putting the child in cold water to reduce the fever, and putting their hands on their children’s mouth (there’s a common belief that they might choke or swallow their tongue).
Parents should be aware that the child may be sleepy following the seizure and should take their child to the hospital or call an ambulance if is having a seizure for the first time, the seizure last longer than 5 minutes and shows no signs of stopping, suspect the seizure is being caused by another serious illness, and the child has breathing difficulties.
References: (1, 2, 4, 7, 8, 10)
The first step in diagnosis is to know the characteristics of the episode since the convulsion is usually over when the child is brought to the physician. Parents should be able to tell us how long the seizure lasted, how long it took for the child to recover from the seizure, if it is the first time that this happened, and what were the characteristics of the seizure (if it was generalized or focal, tonic-clonic, with/out loss of consciousness, duration, and accompanying features.)
In addition, healthcare providers will review a child’s medical history looking for personal or family history of seizure or epilepsy, recent illness or antibiotic use, recent vaccinations, and immunization status for Haemophilus influenza type b and Streptococcus pneumoniae. The physician should also perform a thorough physical examination checking for focal neurological signs or Todd’s paralysis. Physicians should keep in mind that severe diarrhea or vomiting can cause seizures due to dehydration and electrolyte imbalances.
In this first examination, the differential diagnosis that should be discarded before settling with the diagnosis of FS should be:
- Aseptic meningitis;
- Bacterial meningitis;
- Tonic-clonic seizures.
Hospital admission is usually not required for children with SFS, although factors to consider when making the decision include younger age, the need for further observation because of abnormal examination findings, or unreliable follow-up.
A patient with a normal general and neurological exam, whose history is consistent with an SFS, does not need a further laboratory, imaging, or neurophysiologic evaluation. It has been proven that infants with an SFS don’t have a higher risk of urinary tract infections, bacteremia, pneumonia, or bacterial meningitis.
Full blood count, serum electrolytes, calcium, magnesium, phosphorous, and blood glucose levels should only be performed if other clinical features indicate the need for these investigations, such as prolonged post-ictal drowsiness or suspicion of bacteremia.
A febrile seizure in an infant or child raises the concern for meningitis. However, there is no evidence that a well-appearing child with only an SFS has an increased risk of bacterial meningitis. The American Academy of Pediatrics (AAP) does not recommend a routine lumbar puncture for well-appearing children with an SFS.
However, in children under 18 months old, clinical signs of meningism are unreliable, so in infants 6-12 months old presenting with fever and seizure, a lumbar puncture is indicated if there is no Hib or pneumococcal vaccinations (or if history is unknown) or if the patient was pretreated with antibiotics (this may affect the presentation of bacterial meningitis), and to discard meningitis or other intracranial infection when there is clinical suspicion.
Lumbar puncture performed in the evaluation of CFS varies by practitioner. Two guidelines published in the post-vaccine era have suggested performing a lumbar puncture on children with a CFS only if they are 12 months of age or younger. Another recently published guideline suggests performing a lumbar puncture after a CFS only if the child’s clinical examination is suggestive of meningitis.
Children with FSE are at high risk for meningitis compared to those with SFS and CFS. Studies have described rates of bacterial meningitis as 12% and 17% with FSE. Two recently published guidelines recommend performing a lumbar puncture on all children with FSE.
Decisions about diagnostic testing may not be as straightforward in children with CFS because these are more heterogeneous. The neurological examination is crucial when deciding whether to perform a lumbar puncture. Children with signs and symptoms of bacterial meningitis should undergo the procedure.
Children with FSE should raise concerns for bacterial infection, intracranial abnormality, or toxic ingestion.
No data have been published that support or negate the need for neuroimaging, specifically computed tomography (CT) or magnetic resonance imaging (MRI), in the evaluation of children with SFS. The AAP discourages the use of routine neuroimaging in patients with SFS.
CT and MRI are only indicated to exclude other pathology as suspected, including focal lesions, structural defects, or head injury. One study has suggested the value of MRI after FSE to predict future epilepsy. However, MRI is not required on an emergency basis in the evaluation of febrile status epilepticus (12).
Electroencephalography (EEG) has no role in the acute management of FS and does not predict recurrence. While EEGs may show slow or focal abnormalities in 34% of children with FSE, the absence of epileptiform activity does not exclude seizures. Therefore, is not considered useful for routine diagnosis (2). Outpatient electroencephalography should be performed in children with multiple risk factors for epilepsy because of the risk of subsequent nonfebrile seizures.
Management of Febrile Seizures
References: (2, 4, 8, 13)
There is no specific treatment for SFS or CFS other than appropriate treatment for underlying etiologies driving the ongoing febrile illness.
Most FS will resolve spontaneously before presentation to the hospital. For those that have not resolved, international consensus is that an anticonvulsant drug should be administered for any tonic-clonic seizure that has been ongoing for more than 5 minutes.
The prophylactic use of antiepileptic drugs in children with FS to raise seizure threshold has been found to work in reducing recurrence rates of FS with intermittent diazepam and continuous phenobarbitone, but given the benign nature of these seizures, and the high prevalence of adverse effects of these drugs (in up to 30% of cases, including respiratory depression) they are infrequently used.
Febrile status epilepticus can occur in less than 10% of children during the first febrile seizure. Rectal or intravenous diazepam or intravenous lorazepam should be administered for any child with FSE. In the absence of intravenous access, midazolam, given intranasally or intramuscularly, or diazepam, given intranasally or rectally, are reasonable alternatives.
FSE rarely stops spontaneously and often requires more than 1 antiepileptic medication. Repeat doses of benzodiazepines can be administered after 5 minutes. Second-line antiseizure medications such as levetiracetam, fosphenytoin, valproate, or phenobarbital may be necessary.
Despite the established link between the febrile immune response and FS, antipyretics benefits are generally limited to providing comfort to the child and do not affect the risk of future recurrence or severity.
Some studies have shown a tendency for low levels of zinc in the blood and cerebrospinal fluid in children with FS.
Long-term Outcomes of Febrile Seizures in Children
References: (2, 3, 4, 8, 10)
FS can be frightening for parents and families; despite being considered by professionals as essentially “benign.” Studies looking at the parental reactions to FS have documented behaviors and physiological manifestations affecting the carers’ physical, psychological, and behavioral responses as well as disruption in the family’s quality of life. A key concern among parents is the possibility of long-term neurological sequelae, but there is no evidence that hospitalization of children after a febrile seizure, merely to reassure parents, is of any benefit.
It is estimated that children with a history of SFS have a 1-2% chance of developing epilepsy later in life than the general population. Children with a history of CFS have a 5-10% chance of developing epilepsy, compared to 1 to 2 in 100 chances in people who have not had FS (8, 10). For children with FSE, in a 9-year follow-up study, the incidence of epilepsy after FSE is 14%, with a diagnosis of epilepsy being made 2 years post-FSE. (14)
There is no evidence that FS have a causative relationship with mesial temporal sclerosis. A prospective cohort study in the UK found no difference in academic progress, intellect, and behavior at 10 years of age in children who had an SFS or CFS compared with control patients. In a UK study, within 6 weeks and persisting at 1-year post-FS, children showed similar cognition, motor, and language scores that control population on the Bayley Scales of Infant Development but lower scores than typically developing controls. (2)
Also, the risk of mental illness was 30% in children with FS compared to 17% in unaffected individuals. It is notable that there is a stepwise increase in the risk of epilepsy and psychiatric disease with each additional febrile seizure. Children with a single febrile seizure had a sevenfold increased risk of epilepsy diagnosis before 5 years of age, while three or more febrile seizures elevated this risk 42-fold. The interpretation of these numbers is that each febrile seizure is causing brain injury and that this injury is cumulative. (3)
A recent retrospective study assessed the potential role of FS in Sudden Unexplained Death in Childhood (SUDC). The findings were of a significantly higher prevalence of FS among cases of SUDC and also in sudden explained death in childhood. However, FS in this study was defined broadly and is likely to have children with other significant neurological impairments. It is unlikely that FS per se is responsible for this outcome, but it is possible that there is an underlying genetic predisposition to both FS and SUDC. (3)
The author does not report any conflict of interest
This information is for educational purposes, not to treat disease or supplant professional medical judgment. Physicians should follow local policy regarding the diagnosis and management of medical conditions.
Exanthematous Disease of Childhood
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