Febrile seizures are convulsions induced by a fever in infants or young children. They are the most common type of seizure during childhood. While febrile seizures are usually benign, they are often very upsetting to parents. There are several operational definitions of febrile seizures

1. 
   

   American Academy of Pediatrics Practice Parameter: “A simple febrile seizure is a generalized seizure occurring in an infant or child between the ages of six months and five years, lasting less than 15 minutes and occurring only once in 24 hours. The child should not have an intracranial infection or a severe metabolic disturbance.”1

   
   
2. 
   

   The International League Against Epilepsy (ILAE): “A seizure occurring in childhood after one month of age, associated with a febrile illness not caused by an infection of the central nervous system, without previous neonatal seizures or a previous unprovoked seizure, and not meeting criteria for other acute symptomatic seizures.”2

Both definitions exclude seizures with fever in children who have previously had seizures unrelated to fever and do not exclude children with prior neurological impairment. Although these two definitions are similar, there is a discrepancy regarding the lower age limit of first seizure onset (3 months versus 1 month). The three critical elements of febrile seizures are shown in Table 4-1.

Epidemiologic studies show that approximately 3% to 4% of children have at least one febrile seizure by 7 years of age.3 There is a regional variation of the cumulative incidence of febrile seizures in different countries (Table 4-2). Febrile seizures are slightly more common in boys than girls. In the United States, the prevalence of febrile seizures in African American children is 4.2% versus 3.5% in Caucasian children.3

The pathophysiology of febrile seizures is unknown. It is possible that the following three features interact, resulting in a febrile seizure:

• Immature brain
  
• Fever
  
• Genetic predisposition

Immature Brain

Febrile seizures rarely occur before ages 1 to 3 months, suggesting that a certain degree of myelination or network maturation is required for the clinical expression of febrile seizures. Animal studies have shown that immature neuronal networks tend to generate periodic discharge and this facilitates the generation of pathologic and pathogenic oscillations.4

Febrile seizures rarely occur after ages 5 to 6 years, so there is a clear relationship between febrile seizures and brain maturation. Several studies have suggested that there is enhanced neuronal excitability during normal brain maturation.5 It is well established that many factors contribute the increased excitability of the immature brain. The tendency of immature neurons to oscillate is due to their high input resistance, which helps the generation of action potentials and increases excitability. In addition, during the early postnatal period GABA exerts a paradoxical excitatory effect in all animal species including primates.6,7 The lack of efficient GABAergic inhibition increases excitability and can facilitate synchronicity.4 The delayed maturation of postsynaptic G protein mediated GABAB-mediated inhibition will also contribute to augment neuronal excitability. The prolonged NMDA-mediated excitatory postsynaptic currents in immature versus adult neurons promotes the generation of network-driven events. These properties also underscore the propensity of immature networks to generate early network-driven patterns such as giant depolarizing potentials.8 The transient exuberant formation of excitatory synapses may also contribute to increased excitability in more developed stages.9

Fever

Fever is associated with cytokine release. Activation of the cytokine network may increase the susceptibility to febrile seizures.10-12 It is also possible that circulating toxins and immune reaction products modulate neuronal excitability. Previous studies have suggested that interleukin-1β, a pyrogenic pro-inflammatory cytokine, and hyperpolarization-activated cyclic nucleotide-gated cation channels are involved in the generation of febrile seizures or enhanced seizure susceptibility in animals. Conversely, neuropeptide Y could prevent febrile seizures by increasing the seizure threshold.13

Variations in temperature have effects on most cellular events, and several neurological disorders are provoked by elevated temperature, including febrile seizures and febrile episodic ataxia (calcium channels, CACN1A).14Temperature changes have been shown to affect plasma membrane states15 and synaptic transmission.16 Synaptic vesicle recycling has been shown to be temperature dependent. The size of recycling vesicles is twice as large, and the speed of both endocytosis and exocytosis are faster at physiologic temperature than at room temperature.17 Although the dynamic temperature dependence of turnover of GABAA receptors is unclear, there is evidence that inhibitory synaptic strength can be modulated within 10 minutes through recruiting more functional GABAA receptor to the postsynaptic plasma membrane.18 Kang and associates19 discovered recently that GABAA receptors containing mutant gamma subunits were not as good at getting to the neuronal cell surface when they were exposed to high temperatures. When exposing cells expressing the mutant receptors to 40°C, simulating a “fever” of 104°F, the receptors disappeared from the cell surface. Fewer inhibitory GABAA receptors on the cell membrane could leave a neuron open to the excitation and repetitive firing that characterizes seizures. The investigators are currently studying where the receptors go when the temperature is raised. Are they taken inside the cell more quickly, degraded, or is their forward insertion into the cell membrane slowed?

Genetic Factors

Although the mode of inheritance is unknown, genetic factors are clearly important. These factors may be either causative or protective against febrile seizures. The literature describing the genetics of febrile seizures is extensive, continually expanding, and complicated, reflecting the complexity of the disorder. The risk of developing febrile seizures is higher in some families than in others. A positive family history for febrile seizures can be elicited in 25% to 40% of patients with febrile seizures, and the reported frequency in siblings of children with febrile seizures has ranged from 9% to 22%. Studies showing a higher concordance rate in monozygotic rather than in dizygotic twins also support a genetic contribution. Familial clustering studies indicate a doubling of risk in children when both parents, rather than one parent, had febrile seizures.20

While there is clear evidence for a genetic basis of febrile seizures, the mode of inheritance is unclear. The mode of inheritance is more likely polygenic or autosomal dominant with reduced penetration.21 The most convincing evidence has emerged from linkage studies with reported linkages on numerous chromosomes (Table 4-3) with the strongest linkage on chromosome 2q and specifically, linkage to the genes responsible for sodium channel receptors and specifically a mutation in the alpha (a) subunit of the first neuronal sodium channel gene (SCN1A). The linkage on chromosomes 2q and 19q associated with the phenotype of febrile seizures, generalized epilepsy (tonic-clonic, absence, and myoclonic) (GEFS+), shows evidence of sodium channel involvement. Clearly, febrile seizures are an extremely heterogeneous condition with a complicated and, as yet, unclear pathophysiologic and genetic basis. More than seven chromosome linkage sites have been associated with febrile seizures, suggesting locus heterogeneity. In addition, at least 5 genes have been identified as causal for epilepsy syndromes that include febrile seizures.22 This includes the unique syndrome of generalized epilepsy with febrile seizure plus (GEFS+), which is caused in most cases by an autosomal dominant defect in cerebral voltage-gated sodium channels subunits (SCN1B, SCN1A, and SCN2A) or a defect in the gamma 2 subunit of the GABAA receptor.23 Although GEFS+ includes seizure types other than febrile seizures, it may give insight into the biology of age-limited temperature-dependent seizure susceptibility. In these patients with genetic predisposition, a low-grade fever can cause febrile seizures.

Febrile seizures typically begin with a sudden contraction of muscles involving the face, trunk, arms, or legs on both sides of the body. The force of the muscle contraction may cause the child to emit an involuntary cry or moan. The seizures may be accompanied with loss of consciousness, tongue biting, urinary/bowel incontinence, fall, vomiting, and apnea; and followed by postictal sleepiness, confusion, or feelings of fear.

In some cases, the febrile seizure is the first clear symptom of illness, but the study by Berg and colleagues in 199724 found that only 21% of children experienced febrile seizures before or within an hour of recognized fever onset. Most patients (57%) had a seizure after 1 to 24 hours of recognized fever, and 22% had seizures more than 24 hours after the onset of fever.

The common causes of fever associated with febrile seizures are shown in Table 4-4. There are no recent studies of the nature of inciting infections preferably causing febrile seizures. While the widespread use of vaccines against Haemophilus influenzae, varicella, pneumococcus, and meningococcus have changed the background of infections in the pediatric population, the incidence of febrile seizures has not significantly changed, suggesting the specific inciting infectious pathogens are not responsible for febrile seizures. Only documented pathogen associated with febrile seizures is human herpes virus type 6 (HHV6).26 HHV6 causes infant roseola, a common infection of infants and toddlers that is usually associated with fever ≥103°F. It is postulated that direct viral invasion of the brain, combined with fever, causes the initial febrile seizure, and that the virus might be reactivated by fever during subsequent illnesses, causing recurrent febrile seizures.

Seizures occurring soon after vaccinations should not be regarded as a direct adverse effect of the vaccine.27 Such seizures are believed to be triggered by fever induced by the vaccine. Their subsequent clinical course is identical to other febrile seizures,28 with no increased risk for subsequent afebrile seizures or abnormal neurological development.29 The frequency of febrile seizures after diphtheria-pertussis-tetanus or measles vaccination is 6 to 9 and 24 to 25 per 100,000 children vaccinated, respectively. The newer acellular pertussis vaccines rarely induce a febrile reaction, and therefore fewer febrile seizures currently result from this immunization.30

Types of Febrile Seizures

Febrile seizures can be divided into simple or complex febrile seizures depending on the duration of seizure, seizure type, and number of seizures during a 24-hour period (Table 4-5).