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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, prolonged 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, the syndrome of febrile seizures can be viewed as a syndrome of reactive seizures, and not as a true epileptic syndrome where seizures are unprovoked (Engel 2001).

Clinical manifestations

A febrile seizure is frequently the first symptom of illness to parents. The first febrile seizure is complex in approximately 20% 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).

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. All could contribute.

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 are widely available against Haemophilus influenzae, varicella, pneumococcus or meningococcus. 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). They 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) and does not increase the risk for subsequent afebrile seizures or abnormal neurologic development (Barlow 2001). The frequency of febrile seizures after vaccination is 6 to 9 and 24 to 25 per 100,000 children vaccinated. Newer pertussis vaccines rarely have a febrile reaction, so that fewer febrile seizures currently result from this immunization.

Although the mode of inheritance is unknown, genetic factors are clearly important. 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). As well, monozygotic twins have high concordance as compared with dizygotic twins who have the same rate as their siblings. 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), suggesting locus heterogeneity. In addition, a new unique syndrome of “febrile seizures plus” has recently been described that is caused by an autosomal dominant defect in cerebral voltage gated sodium channels (Berkovic 1998). This disorder accounts for only a small fraction of febrile seizures.

Pathogenesis and pathophysiology

The pathophysiology of febrile seizures is unknown. The role of cytokine network activation is presently being studied along with an increased susceptibility to febrile seizures associated with specific interleukin alleles (Tsai et al 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 and Schechter 1982) and a limited capacity to increase cellular energy metabolism at elevated temperatures have been suggested as contributory factors (Holtzman et al 1981).

A recently documented pathogen associated with febrile seizures is human Herpes virus type 6 (Suga 2000). This is the etiologic agent for infant roseola, a common infection of infants and toddlers usually associated with fever greater than or equal to 103°F. It is postulated that the direct viral invasion of the brain or 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 and Golding 1991). They are slightly more common in boys and black (4.2%) versus white 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 et al 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.

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 a febrile seizure (Rutter 1978; Camfield 1980; Uhari et al 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 et al 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 of Ibuprofen syrup administered during a febrile illness to prevent febrile seizure recurrences also was ineffective (van Stuijvenberg et al 1998). Therefore, the compulsive use of antipyretics cannot be recommended other than to make the child more comfortable. Sponging with tepid water or alcohol is ineffective also (Newman 1985). Although these interventions may lower the body temperature, which is elevated in response to pyrogens, they do not change the hypothalamic “set point.”

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

Differential diagnosis

Since febrile seizures are usually short, the diagnosis must be made from the history. A frequent diagnostic error is “febrile” syncope (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 complete 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).

Determination of serum electrolytes (particularly sodium), glucose, blood urea nitrogen, calcium, and phosphorus levels should be reserved for when there is a reasonable suspicion that one or more may be abnormal (Hirtz 1989). It should be noted that a serum sodium under less than 135 umol/l is associated with recurrent febrile seizures within the same illness (Hugen et al 1995). Rates of bacteremia are low, 2% (Shah 2002), as is serious bacterial illness. Therefore, blood cultures and complete blood count are not routinely necessary.

Lumbar puncture should be performed only when there is clinical evidence of possible 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).

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 test is not necessary. Furthermore, studies of children with complex febrile seizures have not shown the EEG to be predictive of the development of epilepsy.

Neuroimaging studies (CT or MRI), likewise, should not be routinely obtained. Consideration should be given when the child has significant focal neurologic abnormality, developmental abnormalities, neurocutaneous lesions or abnormal head size.

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 (Freeman 1980; Berg and Shinnar 1996). 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 more likely is a recurrence, particularly if the onset is under 12 months of age. Children with a first febrile seizure before 1 year of age have a 50% chance of recurrence, compared with a recurrence risk of only 20% if the first seizure is after age 3 years (Verity et al 1985b).

A family history of febrile seizures is consistently associated with recurrences (Bethune et al 1993; van Esch et al 1994); however, a family history of afebrile seizures has inconsistently demonstrated a relationship (Berg et al 1992; Nelson and Ellenberg 1978; Offringa et al 1992). When febrile seizures are complex, they are not more frequently associated with recurrences (Nelson and Ellenberg 1978; Verity et al 1985a; Berg and Shinnar 1996).

Berg has nicely shown that a shorter duration of temperature before the first seizure and a lower temperature at the time of the first seizure increase the chance of recurrence (Berg et al 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 et al 1990).

Based on the work of Berg and colleagues (Berg et al 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 et al 1985b; Annegers et al 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 et al 1987). 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 et al 1987; Camfield et al 1994).

Approximately 15% of children with epilepsy have one or more preceding febrile seizures, regardless of the cause of the epilepsy (Camfield et al 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, nor those having the onset of febrile seizures after the age of 5 years (Webb 1999).

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; only one of the children had previous 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 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, there has been a important connection between prolonged febrile seizures, mesial temporal sclerosis and intractable temporal lobe epilepsy. While there is controversy about the cause and effect issues in this hypothesis, it is clear that the sequence is uncommon, not more than one of 75,000 children.

Management

Febrile seizures are usually brief and self-limited. When the seizure occurs, the child should be placed on its side or stomach 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 still active, 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 et al 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. No support was found for a shared susceptibility hypothesis. Several studies have documented the magnitude of parental anxiety and improvement with education, understanding and reassurance (van Stuijvenberg et al 1999; Huang et al 2001; 2002).

Only rarely is any kind of medication indicated (Camfield et al 1997). 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 recurrent febrile seizure (Camfield 1980; Freeman 1980). Valproate has a similar effect (Mamelle et al 1984). Concerns about reports of fatal hepatitis in this age range 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. A recent meta analysis of phenobarbital suggests that it cannot be recommended (Offringa and Moyer 2001).

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 appear to 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 et al 1989). The benefit 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 a child with only a few caretakers. A dose of 0.2 mg/kg per dose of oral diazepam has been shown to be ineffective (Uhari et al 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

polygenic

simple seizures

Minor keyword descriptors

convulsions

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

central nervous system infection

meningitis

encephalitis