US Pharm. 2013;38(5):Epub.
ABSTRACT: Febrile seizures are the most common seizure disorder of childhood, occurring mostly between ages 6 months and 5 years. They are classified as simple (most common) or complex, depending on duration and presentation. It is important to rule out serious conditions, especially central nervous system infections. Up to 30% of patients experience recurrences, mostly during the year after the first episode. The vast majority of patients have excellent outcomes, although there is a slightly increased risk of epilepsy. Antiepileptic medications have shown benefit in preventing seizure recurrence, but they usually are not recommended for simple febrile seizures because of the increased incidence of side effects. The pharmacist can play an important role in reassuring and educating the patient’s family.
Febrile seizures are the most common seizure disorder of childhood. Although this type of seizure is associated with few adverse outcomes, it is a frightening event that causes great anxiety for parents and caregivers. Febrile seizures affect 3% to 7% of children aged up to 7 years in the United States and Western Europe.1,2
Febrile seizures are associated with fever (body temperature ≥38°C [100.4°F]) and occur in the absence of intracranial infection, metabolic imbalances, or history of afebrile seizures.3 These seizures typically occur between ages 6 months and 5 years, with peak incidence between 9 and 20 months. Onset after age 7 years is rare.2,4
It is important to ascertain whether the patient has a history of afebrile seizures or recurrent nonfebrile seizures (epilepsy), as the medical management of these conditions may differ from that of febrile seizures.4
Febrile seizures are classified as simple or complex.3,5 Simple febrile seizures, which are more common, are characterized by generalized tonic-clonic convulsions lasting less than 15 minutes. They resolve spontaneously and do not recur within 24 hours or within the same febrile illness.3 Complex febrile seizures, which account for about 30% of cases, are focal in nature, last longer than 15 minutes, and often recur within 24 hours or within the same febrile illness.3
Febrile status epilepticus, which occurs in less than 5% of all cases, is defined by seizures lasting longer than 30 minutes. It manifests either as one long episode or as a cluster of shorter events without consciousness being regained between the events.2,5
CAUSE OF FEBRILE SEIZURES
Febrile seizures are more likely to occur during a rise in body temperature. More than half of cases occur within 1 to 24 hours of fever onset. Another 20% to 22% of cases take place prior to, during the first hour after, or more than 24 hours after fever onset.5-7
The exact cause remains unclear, but it is thought that both genetic and environmental factors are involved in the pathogenesis of febrile seizures. A family history of febrile seizures is a definite risk factor. The most likely mode of inheritance appears to be polygenic, but some children may exhibit an autosomal-dominant pattern.2,5
Viral infections (human herpesvirus 6, influenza, parainfluenzae, and adenovirus) are frequent triggers of febrile seizures.8
Because fever is often a manifestation of an underlying infectious process, it is important to exclude infections, especially those involving the central nervous system. The patient should be promptly evaluated, with a detailed medical history taken and a careful physical and neurologic examination performed to eliminate the presence of meningitis, encephalitis, or other neurologic abnormalities.6
The medical history should include seizure duration and description; fever duration prior to seizure onset; history of recent illness; recent antibiotic use; immunization status; family history of febrile seizures; and history of epilepsy.6,8 Patients with underlying neurologic conditions may be more prone to experiencing seizures with fever and should not be classified as having simple febrile seizures.9 Routine laboratory testing usually is not necessary, unless the tests are performed to determine the source of the fever, rather than the source of the seizure itself.10
In a retrospective study of 503 cases of meningitis in subjects aged 2 months to 15 years, 93% of subjects presented with significantly altered mental status; the remaining 7% showed other signs of meningeal involvement.11 Signs included neck stiffness, bulging fontanel, complex febrile seizures, prolonged postictal phase, and status epilepticus. None of the subjects had bacterial meningitis that manifested strictly as a simple febrile seizure.2
The American Academy of Pediatrics (AAP) recommends that a lumbar puncture be performed in any child with signs or symptoms suggestive of meningitis. The procedure also should be considered in children aged 6 to 12 months with an unreliable or incomplete history of Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae immunization. When antibiotics are administered before the occurrence of febrile seizures, the typical meningitic signs and symptoms may be masked.10
Electroencephalography and other neuroimaging tests are not predictive of seizure recurrence or later development of epilepsy. Therefore, they are not indicated in otherwise healthy children with febrile seizures.8,10
RISK FACTORS AND OUTCOMES
Several risk factors have been associated with the occurrence of febrile seizure: history of febrile or afebrile seizures in first- or second-degree relatives, day care attendance, developmental delay, and neonatal nursery stay longer than 30 days. Children with two of these risk factors have a 28% chance of having at least one febrile seizure.5
Although rates of morbidity and mortality associated with febrile seizures are extremely low, concerns regarding long-term complications have been raised. These concerns include seizure recurrence, cognitive and developmental deficits, and the risk of epilepsy.
Recurrence of febrile seizures is common. In a cohort study of 136 children with simple febrile seizures, up to 32% experienced recurrent seizures. Seventy-five percent of seizures occurred within the first year.12 Early age (<18 months) at the time of the first febrile seizure, family history of febrile seizures, and fever height and duration prior to the first seizure have been identified as predictors of seizure recurrence.7
Lower body temperature and shorter duration of fever before the initial febrile seizure are associated with an increased risk of recurrence.7 Children with three or more risk factors have a 60% chance of multiple seizures within 2 years.2,6,8
The chance of developing epilepsy subsequent to febrile seizures is small, but was elevated in one study in which subjects with febrile seizures were compared with age-matched subjects without them (1.6% vs. 0.4%).13 Risk factors for epilepsy after a febrile seizure include preexisting neurologic abnormality, family history of epilepsy, complex febrile seizures, and fever duration of less than 1 hour before seizure onset.5,8 Children with no risk factors have a 2.4% chance of developing epilepsy, compared with a 1.4% risk in the general population.2
Large population-based studies found no correlation between simple febrile seizures and cognitive or learning deficits.1,14,15 A 7-year study assessed 431 pairs of siblings discordant for the presence of febrile seizures and found no significant differences in intellectual ability or academic performance. In a British study, 303 children with a history of febrile seizures did not differ from controls in terms of academic progress, intelligence, or behavior.14
Several studies have documented that there is no increased risk or incidence of death in patients with febrile seizures.2,16
FEBRILE SEIZURES AND VACCINATIONS
The link between febrile seizures and immunizations has generated much debate and investigation. Most seizure episodes occurring at the time of early-childhood immunization have been simple febrile seizures without long-term consequences.3,17
A cohort study involving nearly 680,000 children examined the risk of seizures and neurodevelopmental disability following the administration of diphtheria and tetanus toxoids and whole-cell pertussis (DTP) vaccine and measles, mumps, and rubella (MMR) vaccine. There was an elevated risk of febrile seizures on the day of DTP administration and 8 to 14 days after MMR administration. There were six to nine additional febrile seizures per 100,000 children vaccinated with DTP and 25 to 34 new cases per 100,000 children receiving the MMR vaccine. These results were consistent with those from previous reports. Compared with children who had febrile seizures unrelated to immunizations, these children did not have a greater risk of epilepsy or any other neurodevelopmental disorder. It was concluded that the benefits of DTP and MMR immunizations largely outweigh the transient increase in the risk of developing febrile seizures.18
The preceding study was published in 2001. The use of whole-cell pertussis in the U.S. and most other developed countries has since been replaced by the less reactogenic diphtheria and tetanus toxoids with acellular pertussis (DTaP) vaccine.17
A Danish study examined nearly 379,000 children who received the combined DTaP-inactivated poliovirus (IPV)-Hib vaccine during their first 5 years. Overall, 2.1% of children were diagnosed with febrile seizures before age 18 months. There was an increased risk of febrile seizures on the day of the first and second vaccinations, but the absolute risk remained extremely low (<4 per 100,000 vaccinations). DTaP-IPV-Hib vaccination was not associated with an increased risk of epilepsy.19
In addition to pertussis- and measles-containing products, other vaccines associated with fever can potentially cause febrile seizures. Using data from the Vaccine Safety Datalink project, the CDC investigated the records of more than 200,000 children aged 6 months to 4 years who were vaccinated during the 2010–2011 influenza season. Febrile seizures occurred after inactivated influenza vaccine and 13-valent pneumococcal conjugate vaccine at a rate of one additional seizure for every 2,000 to 3,000 children vaccinated. Seizures were more common between ages 12 and 23 months and when the two vaccines were administered at the same visit.20
Continuous Antiepileptic Therapy
Multiple studies have shown that daily administration of phenobarbital is effective for preventing subsequent febrile seizures. In a randomized study of 79 children, phenobarbital 5 mg/kg/day was more effective than placebo for preventing seizure recurrence (5% vs. 25% had recurrence). Irritability and transient sleep disturbances were more common in the phenobarbital group during the first year of treatment. There was no difference in IQ testing between the groups after 8 to 12 months of treatment.21 In another trial, phenobarbital and valproic acid were compared with placebo in infants with a first episode of simple febrile seizure. There were fewer recurrences in the phenobarbital (19%) and valproic acid groups (4.5%) compared with the placebo group (35%).22
Phenobarbital has been associated with irritability, short-term memory impairment, sleep-pattern disturbances, and decreased concentration. Behavior disturbances and sleep disorders necessitate discontinuation of therapy in up to 25% of patients.3,21 Although valproic acid is equally as effective as or more effective than phenobarbital in preventing subsequent simple febrile seizures, reports of severe liver and bone marrow toxicity outweigh its potential benefits.13 Additionally, phenytoin and carbamazepine are ineffective for preventing recurrent febrile seizures.5,14
In summary, the continuous prophylactic use of phenobarbital or valproic acid to prevent febrile seizure recurrence, although effective, is not recommended because of the potential risk of side effects and the usually benign course of febrile seizures.4
Although antipyretics may provide overall comfort to the febrile child, they do not reduce the risk of febrile seizures. Compared with placebo, neither acetaminophen nor nonsteroidal anti-inflammatory drugs reduced the recurrence of febrile seizures.3,5,23
The pre-emptive administration of benzodiazepines at the onset of fever has been explored as a method of preventing febrile seizure recurrence and avoiding the side effects associated with the continuous use of antiepileptic drugs. It is important to note that a seizure can occur before fever is apparent, which limits the usefulness of intermittent therapy.3
Several studies have shown that oral diazepam administered at fever onset significantly reduces the recurrence of febrile seizures compared with placebo. In a large randomized, placebo-controlled trial of oral diazepam (0.33 mg/kg every 8 hours) given during febrile illness, there was an 82% reduction in the risk of febrile seizures in the diazepam group. A higher incidence of mild-to-moderate side effects including hyperactivity, ataxia, and lethargy was reported in the diazepam group.24
The efficacy and safety of diazepam rectal gel have been documented in patients aged 2 to 17 years with acute repetitive seizures. Doses ranged from 0.2 to 0.5 mg/kg depending upon the age group. Somnolence was seen frequently in the treated group. No child experienced serious respiratory compromise.25 In a different study involving prophylactic rectal diazepam, no changes in long-term prognosis were observed in patients at the onset of fever or seizure.3
Alternative routes of administration for benzodiazepines have been explored as treatment for prolonged seizures. Intranasal midazolam (0.2 mg/kg) was shown to be as effective and safe as IV diazepam in children with prolonged (>10 minutes) febrile seizures.26
Because of the excellent long-term prognosis and minimal complications of simple febrile seizures and the risk of potential medication toxicities, the AAP does not recommend the use of continuous or intermittent anticonvulsants to treat simple febrile seizures.3 However, anticonvulsant prophylaxis may be considered in cases of complex febrile seizures, in the presence of abnormal neurologic development, or in the case of a history of nonfebrile seizures of genetic origin in a parent or sibling.4 Intermittent use of rectal diazepam also may be considered in patients at risk for prolonged or multiple febrile seizures.5
It has been suggested that intermittent oral or rectal diazepam at the onset of febrile illness could be considered in situations in which parental anxiety associated with febrile seizures is severe. Parents should be reminded, however, about the potential short-term side effects.14,23
ROLE OF THE PHARMACIST
Family education and parental counseling are essential when dealing with a child with febrile seizures. Parents’ and caregivers’ concerns and fears should be addressed, and pharmacists can play an important role in providing education and reassurance.
Family education should address the benign nature of febrile seizures, the excellent long-term prognosis, the likelihood of seizure recurrence, and the fact that febrile seizures do not increase the risk of developmental delay or other neurologic problems in otherwise healthy children. Parents and caregivers should be informed that the risks associated with anticonvulsant medications for preventing seizure recurrence generally outweigh the benefits. Pharmacists should provide education on the use of antipyretics for comfort, discuss appropriate age-specific dosing, and advise that antipyretics have not been shown to decrease the incidence of seizure recurrence.4,5,8 If intermittent therapy is prescribed, explicit instructions on dosage, administration, and proper monitoring should be provided.
It is also helpful to advise parents and caregivers about what to do during a seizure. The child should be placed on a protected surface on his or her side, and nothing should be placed in the child’s mouth. If the seizure lasts longer than 10 minutes, emergency medical services should be contacted. Also, parents and caregivers should be informed that any child experiencing a febrile seizure should be evaluated by a medical professional to determine the cause.27
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2. Cross JH. Fever and fever-related epilepsies. Epilepsia. 2012;53(suppl 4):3-8.
3. American Academy of Pediatrics Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures. Febrile seizures: clinical practice guidelines for the long-term management of the child with simple febrile seizures. Pediatrics. 2008;121:1281-1286.
4. Consensus statement. Febrile seizures: long-term management of children with fever-associated seizures. Pediatrics. 1980;66:1009-1012.
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10. American Academy of Pediatrics Subcommittee on Febrile Seizures. Febrile seizures: guideline for the neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics. 2011;127:389-394.
11. Green SM, Rothrock SG, Clem KJ, et al. Can seizures be the sole manifestation of meningitis in febrile seizures? Pediatrics. 1993;92:527-534.
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14. Baumann RJ, Duffner PK. Treatment of children with simple febrile seizures: the AAP practice parameter. American Academy of Pediatrics. Pediatr Neurol. 2000;23:11-17.
15. Knudsen FU. Febrile seizures: treatment and prognosis. Epilepsia. 2000;41:2-9.
16. Nelson KB, Ellenberg JH. Predictors of epilepsy in children who have experienced febrile seizures. N Engl J Med. 1976;295:1029-1033.
17. Cendes F, Sankar R. Vaccinations and febrile seizures. Epilepsia. 2011;52(suppl 3):23-25.
18. Barlow WE, Davis RL, Glasser JW, et al. The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine. N Engl J Med. 2001;345:656-661.
19. Sun Y, Christensen J, Hviid A, et al. Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type b. JAMA. 2012;307:823-831.
20. CDC. Update on febrile seizures in children following vaccination with influenza vaccines and pneumococcal vaccines. www.cdc.gov/vaccinesafety/Concerns/FebrileSeizures.html. Accessed February 9, 2013.
21. Camfield PR, Camfield CS, Shapiro SH, Cummings C. The first febrile seizure—antipyretic instruction plus either phenobarbital or placebo to prevent recurrence. J Pediatr. 1980;97:16-21.
22. Mamelle N, Mamelle JC, Plasse JC, et al. Prevention of recurrent febrile convulsions—a randomized therapeutic assay: sodium valproate, phenobarbital and placebo. Neuropediatrics. 1984;15:37-42.
23. Lux AL. Treatment of febrile seizures: historical perspective, current opinions, and potential future directions. Brain Dev. 2010;32:42-50.
24. Rosman NP, Colton T, Labazzo J, et al. A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures. N Engl J Med. 1993;329:79-84.
25. Kriel RL, Cloyd JC, Pellock JM, et al. Rectal diazepam gel for treatment of acute repetitive seizures. Pediatr Neurol. 1999;20:282-288.
26. Lahat E, Goldman M, Barr J, et al. Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study. BMJ. 2000;321:83-86.
27. National Institute of Neurological Disorders and Stroke. Febrile seizures fact sheet. www.ninds.nih.gov/disorders/febrile_seizures/detail_febrile_seizures.htm. Accessed March 24, 2013.
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