Febrile Seizures

Masanori Takeoka

EPIDEMIOLOGY AND CLINICAL FEATURES

A febrile seizure is defined by ILAE (International League Against Epilepsy) as “a seizure in association with absence of an infection (of the central nervous system) or acute electrolyte imbalance in children older than 1 month of age, without prior non-febrile seizures.”¹ Febrile seizures are most commonly seen between 6 months and 5 years, with a peak incidence of approximately 18 months.² Simple febrile seizures are relatively brief (< 15 minutes), generalized, and do not recur during the same febrile illness. In contrast, complex febrile seizures have focal features, long duration, or recurrence within 24 hours. Prior neurological condition is not part of this classification.¹

The prevalence of febrile seizures is 2% to 4% in the United States and Western Europe, and higher in Japan at 9% to 10%, and Guam at 14%. The highest incidence of febrile seizures is at approximately 18 months of age.² Febrile seizures tend to be more common during winter months, when children are prone to have systemic illnesses.

Risk factors for febrile convulsions include family history, daycare attendance, and underlying developmental abnormality.³ However, most children with febrile convulsions are developmentally normal and do not have any prior brain insults.

Most patients have simple febrile seizures, and the seizures are often seen shortly after onset of fever; many febrile seizures occur before parents are aware that the child has a fever. Certain childhood diseases, such as roseola from human herpes virus-6 infection, appear to be more prone to be associated with febrile seizures.^4,5

ETIOLOGY/GENETIC FACTORS

Susceptibility to febrile convulsions appears to be strongly influenced by genetic factors. Approximately 25% to 40% of affected children have a positive family history, and siblings have a 9% to 22% risk for febrile seizures.⁶ Such observations support the concept that susceptibility to febrile seizures is the result of the interaction of several genes. Linkage studies have identified many loci associated with febrile seizures. These loci include 8q13-q21 (FEB1), 19p (FEB2), 2q23-q24 (FEB3), 5q14-q15 (FEB4), 6q22-q24 (FEB5), and 18p11 (FEB6).⁷ In particular, there are families with strong autosomal-dominant penetrance of febrile seizures, some members with febrile seizures beyond the typical age, even some with epilepsy (mostly generalized); this condition has been described as generalized epilepsy with febrile seizure plus (GEFS Plus)⁸ or autosomal dominant epilepsy with febrile seizures (ADEFS).⁹ Some of these have been associated with mutations in alpha 1, alpha 2, and beta 1 subunits of the sodium channel (SCN1A, SCN2A, and SCN1B), or gamma-2 subunit of the GABA_A receptor (GABRG2).⁷

DIAGNOSIS

History and careful physical and neurological examination will be necessary to identify the source of fever. The main concern in children with febrile seizures is to evaluate for infection of the central nervous system, such as meningitis and encephalitis. This may require neuroimaging studies and lumbar puncture with examination of cerebrospinal fluid, especially in cases of prolonged and focal seizures, or prolonged postictal drowsiness with lethargy. In cases of complex febrile seizures, especially with focal features of the seizure or focal neurological examination, neuroimaging such as head computerized tomography (CT), may be considered before the lumbar puncture because of concerns of focal brain lesions. Such focal lesions may cause asymmetric or uneven distribution of intracranial pressure, which may potentially be affected by removal of cerebral spinal fluid.¹⁰ In one study, up to 18% of the children with complex febrile seizures had bacterial meningitis.¹¹ If the child is already receiving antibacterial therapy for a known infection such as otitis media, signs and symptom of bacterial meningoencephalitis can be masked; in such cases, lumbar puncture should be considered.¹²

Depending on clinical circumstances, evaluation of serum electrolytes and glucose may be advisable, especially with diarrhea, vomiting, poor appetite, and signs of dehydration, or if the source of fever is not apparent.¹³ Prolonged seizures and postictal sedation may occur with hypoglycemia. Identification of electrolyte imbalance and hypoglycemia is essential, as these are easily corrected but also may result in further complications if unrecognized and untreated.

Head CT or brain magnetic resonance imaging (MRI) may be considered in children with complex febrile seizures, especially with prolonged postictal sedation, focal features of the seizure, focal neurological exam, or with a history of preexisting, undiagnosed neurodevelopmental abnormality.¹⁴ In particular, children who present with prolonged febrile seizures followed by encephalopathy, with restricted diffusion on diffusion-weighted MRI, had a high incidence of neurological sequelae.¹⁵

Electroencephalogram (EEG) is of limited value in evaluation of children with simple febrile seizures. Nonspecific abnormalities, such as admixed slowing and disorganization of background activity may be evident, especially in the first 24 to 48 hours after the seizure, but these do not have prognostic significance.¹² Among children with complex febrile seizures, focal slowing may be noted acutely, frequently with a return to baseline within a week.¹⁶ Prospective studies on prolonged febrile seizures, including EEG findings and prognostic significance for epilepsy, are currently underway.¹⁷ In febrile status epilepticus with delayed recovery of consciousness, EEG can be helpful in evaluating for persisting nonconvulsive status epilepticus.

TREATMENT

Acute Management

Most febrile seizures end spontaneously within a few minutes, with no apparent permanent damage to the brain. Initial management of febrile seizures includes maintaining a clear airway and providing supplemental oxygen as necessary. Ventilatory assistance is usually not necessary for brief seizures. For ongoing seizure activity, diazepam rectal gel and intravenous diazepam are effective.^18,19

Febrile status epilepticus is defined as a single febrile seizure, or a series of febrile seizures without recovery to baseline neurological status between attacks, lasting more than 30 minutes.

Febrile status epilepticus should be managed, as with any other episode of status epilepticus, as a life-threatening medical emergency. (See Chapter 561.)

Prevention

The first febrile seizure—even when relatively brief—can be a significantly frightening experience to the witnessing parents, appearing as a life-threatening episode.²⁰ It is important to educate the parents about the natural history of the condition, including the expected benign outcome, especially in simple febrile seizures.

Most physicians recommend vigorous efforts to control fever, including use of antipyretic agents, as febrile seizures do not occur without associated fever; however, the merit of this approach has not been proven.²¹

The benefit in preventing recurrent febrile seizures has also not been proven, as the expected outcome is benign, especially in simple febrile seizures. Many factors need to be included in weighing risks and benefits in treatment for preventing febrile seizures; such may include anxiety, comfort level and expectation of the parents, and impact on the childís activities of daily life. In some specific situations, prevention may be considered.²² Children who have frequent recurrences of febrile seizures, resulting in emergency room visits, those who are baseline medically unstable, or those presenting with prolonged seizures, may be medically and socioeconomically at risk and may therefore be more likely candidates for consideration of prevention.

Intermittent treatment with oral diazepam (0.33 mg/kg) given at the first indication of fever has been shown to reduce the risk of febrile convulsion recurrence.²³ A similar approach with rectal diazepam suppository (0.5 mg/kg) was used in Japan, where the diazepam suppository is available.²⁴ When parents can detect fever before the onset of the seizure, this approach is preferable to daily prophylaxis with antiepileptic drugs such as phenobarbital because of less concern regarding compliance of daily administration, and less adverse reactions. Some children may be more sensitive to sedation with diazepam, and the dose may need to be adjusted individually in case of such excessive sedation. Duration of intermittent treatment with diazepam should be limited to up to 48 hours, due to sedation from accumulation of diazepam in the central nervous system. Respiratory suppression with oral or rectal administration of the usual recommended dose is not expected to cause respiratory suppression. Sedation from diazepam may complicate the assessment of the mental state; it is important that the family be alerted to notify the physician of such effects of diazepam.

Diazepam rectal gel has been approved for use in children with prolonged seizures and can also be used for frequent serial febrile seizures. Use of diazepam rectal gel should be limited to children with a history of prolonged febrile seizures, and it is advisable that parents be instructed in cardiopulmonary resuscitation.²⁵

Regarding daily prophylaxis, compliance and risk for adverse reactions may also need to be carefully weighed. Phenobarbital substantially lowers the recurrence risk of febrile seizures, but adverse reactions such as hyperactivity and irritability can be seen in a substantial proportion of treated children. Phenobarbital may also have a subtle but long-lasting effect on intellectual development. Daily prophylaxis with phenobarbital and other agents may still be recommended for selected high-risk children, such as with recurrent status epilepticus, or with underlying medical conditions that can have life-threatening consequences with seizures. This should be discussed with the family on an individual basis, weighing the potential risks and benefits. Effectiveness of antiepileptic drugs other than phenobarbital in preventing recurrence of febrile seizures has not been extensively evaluated. Valproic acid may reduce the recurrence rate of febrile seizures, but the risk of serious hepatotoxicity limits its use in young children. Carbamazepine and phenytoin appear ineffective for prevention of recurrent febrile seizures.² The effectiveness of other antiepileptic drugs used for generalized seizures, such as zonisamide and levetiracetam, has not been assessed for febrile seizures.

PROGNOSIS

About one third of children with an initial febrile seizure will experience another febrile seizure, and half of children with a second febrile seizure will experience a third seizure. In a group of children presenting to an emergency room with an initial febrile seizure, risk factors for recurrence included young age (< 18 months), relatively modest temperature elevation (< 40°C), and short duration of fever prior to the seizure.²⁶

Outcome of febrile seizures is usually favorable, but 2% to 10% of children with febrile seizures experience subsequent epilepsy, defined as recurrent, untriggered seizures. Risk factors for epilepsy include complex features of the initial attack (complex febrile seizures) and underlying neurodevelopmental abnormality.²

Approximately 15% of childhood epilepsy is preceded by febrile seizures,²⁷ but the nature of this relationship is controversial. In many cases, febrile seizures appear to reflect a nonspecific susceptibility to seizures, which may be genetically determined in most cases, but also may be related to other subtle brain abnormality, such as focal cortical dysplasia.

Febrile status epilepticus may contribute to development of mesial temporal sclerosis, which frequently occurs in older children and adults with temporal lobe epilepsy. These individuals often have a prior history of prolonged, focal febrile seizures.²⁸ Developmental delay and mental retardation occur at slightly increased rates among children with complex but not simple febrile seizures.²⁹

REFERENCES

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