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Febrile seizures
Author: Marvin A Fishman, MD
Literature review current through: Fev 2012. | This topic last updated: Out 17, 2011. 
INTRODUCTION — Febrile seizures are a common cause of convulsions in young children. They occur in 2 to 4 percent of children younger than five years of age, but the incidence is as high as 15 percent in some populations. This incidence has been attributed to closer living arrangements among family members making detection more likely, but racial and geographic variations may also be important.
The generally accepted criteria for febrile seizures include:
A convulsion associated with an elevated temperature greater than 38°C
A child younger than six years of age
No central nervous system infection or inflammation
No acute systemic metabolic abnormality that may produce convulsions
No history of previous afebrile seizures
Febrile convulsions are divided into two categories, simple (benign), or complex, based upon clinical features. Simple febrile seizures are the most common and are characterized by seizures that last less than 15 minutes, have no focal features, and, if they occur in a series, the total duration is less than 30 minutes. Complex febrile seizures are characterized by episodes that last more than 15 minutes, have focal features or postictal paresis, and occur in a series with a total duration greater than 30 minutes.
ETIOLOGY AND PATHOGENESIS — It is not known how or why seizures are generated in response to fever; it may be that fever-induced factors (eg, interleukin-1beta) are proconvulsant in individuals who are susceptible based upon the stage of brain development and genetic susceptibility. Certain ion channels in the brain are temperature sensitive and may generate fever-associated synchronized neuronal activity. There is also evidence to suggest that hyperthermia-induced hyperventilation and alkalosis may play a role.
Infections — Febrile seizures can occur during both viral and bacterial infections. In one hospital based study, the incidence of febrile seizures was similar with influenza, adenovirus, and parainfluenza infections (6 to 18 percent), and somewhat less common with respiratory syncytial virus and rotavirus (4 to 5 percent). No specific virus was associated with risk of complex febrile seizures or later recurrence. Other studies have reported higher rates of febrile seizures (36 percent) in human herpesvirus (HHV)-6 infections and also a higher rate of complex features and recurrence.
Immunizations — The risk of febrile seizures is increased after administration of diphtheria, tetanus toxoid, and whole-cell pertussis (DTP) and measles, mumps, and rubella (MMR) vaccine. In a large cohort study, febrile seizures were significantly increased on the day of DTP vaccination and 8 to 14 days following MMR vaccination (adjusted relative risks 5.7 and 2.83, respectively). The risk for subsequent seizures or neurodevelopmental disabilities was comparable in children with febrile seizures whether or not they were associated with vaccination; however, because immunization and the clinical onset of neurodevelopmental syndromes occur in early childhood, there may be a perception that the vaccination is causative.
Predisposing factors — Susceptibility to febrile seizures has been linked with abnormalities in neurotransmitters. However, whether observed abnormalities were primary events or were secondary to the convulsions is unclear. As an example, the cerebrospinal fluid (CSF) concentration of gamma-aminobutyric acid (GABA), an inhibitory transmitter, was reduced in one series of children who were studied after their first or second febrile seizure; the samples were obtained after the convulsion and, thus, may be the effect rather than the cause of the seizure. Furthermore, low CSF GABA was not confirmed in other studies of children with febrile seizures.
CSF neopterin concentrations may be elevated in children with febrile seizures. Because neopterin is secreted by activated macrophages, this observation suggests immune activation within the central nervous system.
Iron insufficiency may play a role in pathogenesis. In a prospective study of 150 children, mean ferritin levels were significantly lower in children with a first febrile seizure than in matched controls with febrile illness but no convulsions (29.5 versus 53.3 mcg/L). Plasma ferritin levels ≤30 mcg/L occurred in a significantly greater proportion of children with seizures than controls (65 versus 32 percent). Further studies will be required to confirm this preliminary finding.
Genetic susceptibility — Genetic and familial factors appear to be important factors in the expression of febrile convulsions and the subsequent development of epilepsy in some children. Among first-degree relatives of children with febrile seizures, 10 to 20 percent of parents and siblings also have had or will have febrile seizures. In addition, monozygotic twins have a much higher concordance rate than do dizygotic twins, in whom the rate is similar to that of other siblings.
Susceptibility to febrile seizures has been linked to several genetic loci in different families, including the long arm of chromosome 8q13-21 (FEB1), chromosome 19p (FEB2), chromosome 2q23-24 (FEB3), chromosome 5q14-15 (FEB4), chromosome 6q22-q24 (FEB5), chromosome 6q16.3-22.31, chromosome 21q22, and perhaps chromosome 18p11.2. The trait is transmitted in an autosomal dominant fashion. However, susceptibility genes have not been identified in most patients with febrile seizures.
Genetic factors are also believed to be important in nonmendelian forms of febrile seizures. One study suggests that common polymorphism in a sodium channel gene (splice site variant SCN1A) is a common risk factor for febrile seizures. However, this finding was not replicated in a follow-up study.
A syndrome of generalized epilepsy with febrile seizures plus (GEFS+) also has been described. The most common phenotype consists of children who had seizures with fever in early childhood that, unlike typical febrile seizures, continued beyond six years of age or were associated with afebrile tonic clonic seizures as well as other seizure types. The epilepsy typically remitted by mid-adolescence. This disorder is usually autosomal dominantly inherited. Family members who inherit the mutation may only have nonfebrile seizures.
Among different families with GEFS+, a variety of gene loci and mutations have been identified, including chromosome 19q with mutations in the beta-1-subunit of the neuronal sodium channel, chromosome 2q with mutations in the alpha-1-subunit of the neuronal sodium channel, chromosome 8p23-p21 and a mutation in the gamma-2 subunit of the GABA-A recepto. A mutation in the last gene has also been identified in a family with febrile seizures without associated epilepsy.
These observations link febrile seizures with afebrile seizures in some families in an autosomal dominant fashion. In addition, previous studies have shown that siblings and parents of patients with febrile seizures have a 4 to 10 percent incidence of epilepsy.
Hippocampal lesions — Another approach linking febrile seizures and epilepsy was suggested from an evaluation of two families with familial febrile convulsions. Magnetic resonance imaging (MRI) was performed in family members who had no seizures, febrile convulsions only, and febrile convulsions with the subsequent development of temporal lobe epilepsy. All subjects with febrile convulsions who did not develop epilepsy and six clinically unaffected relatives showed asymmetry in the size of the hippocampi. In addition to a difference in the size between the right and left hippocampi were changes in the internal architecture of the hippocampal bodies. The authors concluded that a subtle preexisting hippocampal malformation that was present may facilitate febrile convulsions and contribute to the development of subsequent hippocampal sclerosis, which was seen in the patients who developed temporal