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Current thumbnail: Febrile seizures are common and have a benign outcome. The genetic basis of this syndrome of reactive seizures is under intense investigation. Evidence-based guidelines suggest minimal investigations are needed for diagnosis and most children do not require intermittent or long-term or treatment..

Historical note and nomenclature

Febrile seizures (febrile convulsions) are the most common convulsive events in human experience. They were recognized as distinct from other seizures in the mid-19th century, and at that time, treatment was redirected to the underlying causes of fever rather than the symptom of a seizure. With the introduction of the thermometer at the end of the 1800s, fever was understood to be the primary factor producing the convulsion. Until the early 20th century, infantile convulsions were thought to be severe and often fatal. Unfortunately, few effective treatments were available. Sentinel studies in the 1940s by Lennox and Livingston investigated risk factors for recurrence and later epilepsy (Livingston et al 1947; Lennox 1949). In the 1970s two population-based studies formed the foundation of the current view of febrile seizures (van den Berg 1969; Nelson and Ellenberg 1978): they are common, many recur, developmental outcome is not altered, and few children later develop epilepsy. In the late 1990s two evidence-based practice parameters by the American Academy of Pediatrics Committee on Quality Improvement Committee on Quality Improvement, Subcommittee on Febrile Seizures were published reflecting the current evidence diagnosis and treatment of febrile seizures (Anonymous 1996; 1999).

About 3% to 4% of all children will have at least one febrile seizure (Nelson and Ellenberg 1976). Although the seizures are associated with fever (greater than 38.5°C), those provoked by central nervous system infection are excluded. The peak age for febrile seizures is 18 to 22 months with a range between about 6 months and 5 years (Anonymous 1996).

Febrile seizures can be subdivided into “simple” (generalized tonic-clonic, duration less than 15 minutes, and without recurrence within the next 24 hours) or “complex” (focal, duration more than 15 minutes, or occurring in a cluster of 2 or more convulsions within 24 hours). Febrile seizures are now known to be benign and only 2% to 3% of children will later develop epilepsy (Nelson and Ellenberg 1976). The risk of epilepsy following a simple febrile seizure is about 2% and following a complex febrile seizure still only 5% to 10%. Therefore, febrile seizures can be viewed as a syndrome of reactive seizures, and not as a true epileptic syndrome (Engel 2001).

Clinical manifestations

In many cases, the febrile seizure is the first clear symptom of illness. The first febrile seizure is complex in approximately 25% of cases. About 75% of febrile convulsions are “simple.” In the National Collaborative Perinatal Project study of 55,000 infants, 1706 experienced a first febrile seizure and were followed to age 7 years. Twenty-eight percent of the initial febrile seizures were “complex”: 4% focal, 8% prolonged greater than 15 minutes, and 16% with recurrence within 24 hours. A Todd’s paresis (transient focal post-ictal weakness) occurred in 0.4% (Nelson and Ellenberg 1978). In another prospective cohort study of first febrile seizures, 35% of 428 children had one or more features of a complex febrile seizure (Berg and Shinnar 1996). A retrospective study from Singapore reported similar findings (Lee 2004). Prolonged (greater than 30 minutes) post-ictal unconsciousness, while rare, has been associated with seizures that are focal or last longer than five minutes (Okumura et al 2004).

Clinical vignette

No information was provided by the author.

Etiology

Three features interact to bring on a febrile seizure: immature brain, fever and genetic predisposition.
Febrile seizures rarely occur before age 6 months or after ages 4 years to 5 years, so there is a clear relationship with brain maturation. The nature of this maturation process is unclear and could be related to increasing myelination, “dying back” of excessive neurons or increasing synaptic complexity.

Causes of fever vary and include upper respiratory tract infection or pharyngitis (38%), otitis media (23%), pneumonia (15%), gastroenteritis (7%), roseola infantum (5%), and noninfectious illness (12%) (Nelson and Ellenberg 1978; Lewis 1979). There are no recent studies of the nature of inciting infections, since vaccines against Haemophilus influenzae, varicella, pneumococcus, and meningococcus are in widespread use. Seizures occurring soon after immunization with whole cell diphtheria-pertussis-tetanus and measles vaccines should not be regarded as a direct adverse effect of the vaccine (Hirtz et al 1983). Such seizures are believed to be triggered by fever induced by the vaccine. Their subsequent clinical course is identical to other febrile seizures (Hirtz and Nelson 1983), with no increased risk for subsequent afebrile seizures or abnormal neurologic development (Barlow 2001). 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. Newer acellular pertussis vaccines rarely induce a febrile reaction, and fewer febrile seizures currently result from this immunization (Le Saux 2003).

Although the mode of inheritance is unknown, genetic factors are clearly important. These factors may be either causative or protective against febrile seizures. Monozygotic twins have high concordance as compared with dizygotic twins, who have the same rate as their siblings. Autosomal recessive inheritance is unlikely, as there is an excess of parents affected and the risk to siblings is approximately 25% (Nelson and Ellenberg 1978). The mode of inheritance is more likely polygenic or autosomal dominant with reduced penetrance (Annegers 1982; Tsuboi 1991). More than seven chromosome linkage sites have been associated with febrile seizures (Wallace 1996; Johnson et al 1998; Kugler et al 1998; Peiffer 1999; Nakayama 2000; Nabbout 2002; Iwasaki 2002; Nakayama 2004), suggesting locus heterogeneity. In addition, at least 5 genes have been identified as causal for epilepsy syndromes which include febrile seizures (Winawer and Hesdorffer 2004). This includes the unique syndrome of generalized epilepsy with febrile seizures 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 (Berkovic 1998). Although GEFS+ includes seizure types other than febrile seizures, it may give insight into the biology of age-limited temperature-dependent seizure susceptibility.

Pathogenesis and pathophysiology

The pathophysiology of febrile seizures is unknown. The role of activation of the cytokine network is presently being studied. There appears to be increased susceptibility to febrile seizures associated with specific interleukin alleles (Tsai 2002; Virta 2002; Kanemoto 2003). Circulating toxins, immune reaction products, and viral or bacterial invasion of the central nervous system have been implicated, together with relative lack of myelination in the immature brain and increased oxygen consumption during the febrile episode (Hirtz and Nelson 1983). Immaturity of thermoregulatory mechanisms (McCaughran 1982) and a limited capacity to increase cellular energy metabolism at elevated temperatures have been suggested as contributory factors (Holtzman 1981).

A recently documented pathogen associated with febrile seizures is human herpes virus type 6 (HHV6) (Suga 2000). 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.

Epidemiology

By 7 years of age, 3% to 4% of children have one or more febrile seizures (Nelson and Ellenberg 1978; Verity 1991). They are slightly more common in boys and in black (4.2%) versus white North American children (3.5%) (Nelson and Ellenberg 1978).

Risk factors for a first febrile convulsion have been studied in comparison with age-matched febrile and afebrile controls (Bethune 1993). The risk of a first febrile seizure is about 30% if a child has two or more of the following independent risk factors: (1) a first or second degree relative with febrile seizures, (2) delayed neonatal discharge of greater than 28 days of age, (3) parental report of slow development, and (4) day care attendance. It may be reasonable to offer anticipatory guidance (familiarization with febrile seizures, first aid, and types of management) to families at high risk.

For 7 years after a first “simple” febrile seizure, children have the same health care utilization as age matched febrile and afebrile controls, except for a minor increase in referrals to ear, nose, and throat services shortly after the febrile seizure (Gordon 2000). Children with febrile seizures do not seem to be more vulnerable to illness and their parents apparently are not so concerned about the child’s health to excessively consult a physician.

Prevention

Because fever is an essential element for the genesis of febrile seizures, it would seem intuitively correct that antipyretic medications would prevent the first or recurrent febrile convulsions. However, several studies have shown that appropriate, rigorous use of antipyretic medication does not prevent febrile seizures (Rutter 1978; Camfield 1980; Uhari 1995). A Finnish study randomized children to receive placebo or acetaminophen (10 mg/kg) at the time of illness for 2 years following a first febrile seizure (Uhari 1995). Those receiving placebo had recurrent febrile seizures during 8.2% of febrile illnesses, compared with 5.2% for those receiving acetaminophen. A similar randomized study showed that administration of ibuprofen syrup during a febrile illness to do not prevent febrile seizure recurrences (van Stuijvenberg 1998). Therefore, the compulsive use of antipyretics for prevention of febrile seizures cannot be recommended. Sponging with tepid water or alcohol is also ineffective (Newman 1985). Although these interventions may lower the body temperature, they do not change the hypothalamic “set point,” which is elevated in response to pyrogens.

Dutch investigators (van Stuijvenberg 1999) followed a group of children who experienced a first febrile seizure. Those with more frequent fever episodes during the following 6 months had more recurrent febrile seizures than those with fewer fevers (OR 1.8). However, we are unaware of any study that proves that efforts to reduce bouts of febrile illness result in fewer febrile seizures.

Differential diagnosis

Since febrile seizures are usually short, the diagnosis must be made from the history. Frequent diagnostic errors include febrile syncope and febrile myoclonus (Stevenson 1990).

Other provoking causes for the seizure must be excluded, especially a central nervous system infection. About 15% of children with meningitis will have seizures, but virtually none are neurologically normal shortly after the seizure (Gerber and Berliner 1981). In older children with meningitis, there are constitutional symptoms such as headache, and signs such as nuchal rigidity. However, children under one year of age may not have such obvious signs of meningeal irritation. As the American Academy of Pediatrics Committee on Quality Improvement Committee on Quality Improvement states, “The clinical evaluation of young febrile children requires skills that vary among examiners. In all children younger than 12 months, performance of a lumbar puncture should be strongly considered. In a child between 12 to 18 months of age, a lumbar puncture should be considered because clinical signs and symptoms of meningitis may be subtle. In a child older than 18 months, although a lumbar puncture is not routinely warranted, it is recommended in the presence of meningeal signs and symptoms” (Anonymous 1996). In addition, if the child has previously been treated with antibiotics, the clinician should be aware that the signs and symptoms of CNS infection may become masked, and lumbar puncture should be strongly considered in such cases.

Diagnostic workup

The initial workup of a febrile seizure should include a thorough history from a reliable witness and a careful pediatric and neurologic examination (Freeman 1980). If the cause of fever can be identified and if the child presents no disturbance of consciousness, it is usually not necessary to obtain further laboratory evaluation (Anonymous 1996).

Measurements of serum electrolytes (particularly sodium), glucose, blood urea nitrogen, calcium, and phosphorus levels should be reserved for children for whom there is a reasonable suspicion that one or more may be abnormal (Hirtz 1989). It should be noted that a serum sodium less than 135 umol/l has been associated with recurrent febrile seizures within the same illness (Hugen 1995), although another study found no difference in serum sodium levels between children with initial single simple and recurrent (within 24 hours) simple febrile seizures (Thoman 2004). Rates of bacteremia are low, 2% (Shah 2002), as are other serious bacterial illnesses. Therefore, blood cultures and complete blood count are not routinely necessary.

As quoted above, lumbar puncture should be performed only when there is clinical evidence of meningitis, although indications for lumbar puncture are less rigid in children under the age of two, where the usual clinical signs can be absent.

Neuroimaging should not be performed in the routine evaluation of child with a first simple febrile seizure. A CT or MRI should be performed only when an underlying structural lesion is suspected (Anonymous 1996; Hirtz et al 1997). Neuroimaging might be considered when the child has significant focal neurologic abnormalities, developmental abnormalities, neurocutaneous lesions or abnormal head size.

An EEG should not be routinely performed in the evaluation of a neurologically healthy child with a first simple febrile seizure, either at the time of presentation or within the following month. Because abnormal EEGs do not reliably predict the development of epilepsy or recurrent febrile seizures, a routine EEG is not necessary. Furthermore, studies of children with complex febrile seizures have not shown the EEG to be predictive of the development of epilepsy.

Prognosis and complications

There are two significant risks associated with febrile seizures: recurrent febrile seizures and later epilepsy (Freeman 1980).

Recurrent febrile seizures occur in about 30% to 40% of children, usually within a year of the first seizure (Freeman 1980; Berg 1996; Lee 2004). Predictors of recurrence include age, family history, duration of illness, and temperature at the time of the seizure.

The earlier the age of onset, the greater is the risk of recurrence. Children with a first febrile seizure before one year of age have a 50% chance of recurrence, compared with 20% if the first seizure is after age 3 years (Verity 1985b).

A family history of febrile seizures is consistently associated with recurrences (Bethune 1993; van Esch 1994). However, a family history of afebrile seizures has inconsistently demonstrated this relationship (Berg 1992; Nelson and Ellenberg 1978; Offringa 1992). Compared to simple febrile seizures, complex febrile seizures are not more frequently associated with recurrences (Nelson and Ellenberg 1978; Verity 1985a; Berg and Shinnar 1996).
A shorter duration of fever before the first seizure and a lower temperature at the time of the first seizure increase the chance of recurrence (Berg 1992). In addition, a meta-analysis by Berg has shown that young age of onset and family history of febrile seizures are the strongest predictors of another seizure (Berg 1990).

Based on the work of Berg and colleagues (Berg 1997), risk factors can be combined to provide a useful prediction scheme. They followed 428 children who presented to an urban emergency room with a first febrile seizure. Over the next 2 years, 32% recurred. The recurrence risk for those with none of the four risk factors (age less than 18 months, family history of febrile seizures, low temperature at the time of the seizure and short duration of illness) was 4%, with one factor 23%, with two 32%, with three 62%, and with all four 76%.

Only 2% to 4% of children with a first febrile convulsion subsequently develop epilepsy (Nelson and Ellenberg 1976; Verity 1985b; Annegers 1987). Risk factors for later epilepsy include (1) an abnormal neurologic or developmental status prior to the first febrile seizure, (2) a family history of afebrile seizures, and (3) a complex febrile seizure. Sixty percent of children with a first febrile seizure have none of these risk factors and a subsequent risk of epilepsy of only 0.9%. About 2% of children with one risk factor (34% of children with febrile seizures) and 10% of those with two or more risk factors (6% of children with febrile seizures) will develop epilepsy (Nelson and Ellenberg 1978; Annegers 1987). As well, those having the onset of febrile seizures after the age of 5 years do not have an increased risk of epilepsy (Webb 1999). Therefore, risk factors in the individual child are not useful clinical predictors of epilepsy. When epilepsy does develop, the seizures can be of virtually any type, although the highest association is with generalized, rather than partial, seizures (Rocca 1987; Camfield 1994).

Approximately 15% of children with epilepsy have one or more preceding febrile seizures, regardless of the cause of the epilepsy (Camfield 1994). This observation suggests that the tendency for febrile seizures plays an important role in a person’s seizure threshold. However, there is no evidence that one or multiple febrile seizures cause epilepsy.

There is no evidence that a short febrile convulsion damages the brain. The National Collaborative Perinatal Project study included 431 sibling pairs discordant for febrile seizures (Ellenberg 1978). Psychometric testing at age 7 years included the Wechsler Intelligence Scale for Children as a measure of overall intelligence and the Wide Range Achievement Test as a measure of academic achievement. For those known to be normal before the first febrile seizure, there was no difference in intelligence or school achievement between sibling pairs, even in the 27 with febrile seizures lasting more than 30 minutes. Chang and colleagues (Chang et al 2001) conducted another study utilizing a prospective, population-based, case-control method to assess the learning, spatial, and sequential working memory of 87 school-aged children with a previous febrile seizure and 87 randomly selected age-matched control subjects. The febrile seizure group performed significantly and consistently better than control subjects on mnemonic capacity and had more flexible mental processing abilities than their age-matched controls.

Starting with the sentinel work of Murray Falconer, an important connection has been drawn between prolonged febrile seizures, mesial temporal sclerosis, and intractable temporal lobe epilepsy. The cause and effect relationship has been a source of intense controversy. It has been suggested that “two hits” are required for this sequence of events--the first an initial injury or malformation of the temporal lobe and the second a vulnerability factor (? genetic) unique to the child that allows the febrile seizure to occur. Fortunately, the sequence of a prolonged febrile seizure, mesial temporal sclerosis and intractable temporal lobe epilepsy is uncommon, occurring in not more than one of 75,000 children (Camfield 1994).

Management

Febrile seizures are usually brief and self-limited. When the seizure occurs, the child should be placed in a prone position or on his/her side on a protected surface, observed carefully, and brought to an emergency facility if the seizure lasts longer than 10 minutes (Hirtz 1989). In most cases, a feverish child is taken to a medical facility after the seizure has ended. If the convulsion is prolonged, however, the child's airway should be kept clear, oxygenation maintained, and intravenous or rectal anticonvulsants such as diazepam, midazolam, or lorazepam given to halt the seizure.

Parents should be counseled that family routines will be disrupted for several weeks, but that life will continue and their child will do well. The only serious sequela appears to be parental anxiety and subsequent labeling of the child as “vulnerable.” Often parents worry about the potential association of febrile seizures and sudden infant death. Vestergaard and colleagues (Vestergaard 2002) compared the risk of sudden infant death syndrome in 9977 siblings of children with a febrile seizure and 20,177 siblings who never had febrile seizures. These data did not support a shared susceptibility hypothesis. Several studies have documented the magnitude of parental anxiety and improvement with education, understanding and reassurance (van Stuijvenberg 1999; Huang 2001; 2002).

Only rarely is any kind of prophylactic medication indicated for a child with one or more febrile seizures (Camfield 1997; Anonymous 1999). Prophylactic daily therapy with phenobarbital or valproate may reduce the recurrence of febrile seizures. Daily administration of phenobarbital at a dosage sufficient to achieve a blood level of 15 µg/ml can effectively reduce the risk of a recurrent febrile seizure (Camfield 1980; Freeman 1980). However, a recent meta analysis of phenobarbital suggests that it cannot be recommended (Offringa and Moyer 2001). Valproate has a similar effect (Mamelle 1984). Concerns about reports of fatal hepatitis in children under two years or of pancreatitis, although rare, make valproate an inadvisable choice. Compliance with daily medication is often problematic. Daily use of carbamazepine or phenytoin has been found to be ineffective treatment for prevention of febrile seizures.

There does not seem to be any compelling reason to treat children with daily prophylactic medication after one or more febrile seizures (Anonymous 1999). The potential side effects of drugs outweigh the benefits.

If treatment is offered, we recommend liquid diazepam 0.5 mg/kg/dose given rectally at home at the time of an actual seizure (Knudsen 1978; Camfield 1989). Nasal midazolam shows promise and its use may supplant liquid diazepam, because of its ease of delivery, although more study is needed. The benefit of an intermittent treatment is the prevention of a prolonged febrile seizure; however, this approach is only appropriate for a well-organized family with a few individuals caring for the child. Alternatively, intermittent oral diazepam at the time of illness might be considered to prevent a recurrent febrile seizure. For success, there must be excellent compliance and few caretakers. A dose of 0.2 mg/kg per dose of oral diazepam has been shown to be ineffective (Uhari 1995). A mild reduction in recurrence risk is seen with 0.3 mg/kg per dose, but at this dose about one-third of children will have significant side effects of somnolence or ataxia (Rosman et al 1993; Camfield et al 1995). It has been estimated that 14 children with a first febrile seizure would have to be treated with intermittent oral diazepam to prevent one recurrent febrile seizure.

The inefficacy of antipyretic medications is outlined in the Prevention section of the topic.

Pregnancy

Not applicable.

Anesthesia

Not applicable.

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Abbreviations

CT:computed tomography
EEG:electroencephalogram
MRI:magnetic resonance imaging

ICD-9 code

780.3

Synonyms

Febrile convulsions

Subtopics

Complex seizures
Simple seizures

Major keyword descriptors

complex seizures
delayed neonatal discharge
dominant with incomplete penetrance
febrile seizures plus
fever
focal seizures
generalized tonic-clonic seizures
grand mal
Herpes virus type 6
immature brain
mesial temporal sclerosis
neurocutaneous lesions
polygenic
simple seizures

Minor keyword descriptors

abnormal head size
convulsions
developmental abnormalities
infection
seizures
slow development

Age of presentation

01-23 months
02-05 years

Age of typical presentation

01-23 months
02-05 years

Population groups preferentially affected

none selectively affected

Occupation groups preferentially affected

none selectively affected

Sex

male=female

Family history

family history may be obtained

Heredity

none

Glossary

Febrile convulsions:otherwise unprovoked seizures that occur in the setting of fever in neonates and children between 3 months and 5 years of age.

Permuted topic, synonyms, subtopics

Febrile seizures
seizures, Febrile
convulsions, Febrile

Related topics

Epilepsy
Neonatal seizures

Differential diagnosis

febrile syncope
febrile myoclonus
central nervous system infection
meningitis
encephalitis

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