The management of febrile seizures

Issue: BCMJ, vol. 53 , No. 6 , July August 2011 , Clinical Articles

Seizures during a febrile illness (“febrile seizures”) are common in children be­tween 3 months and 6 years of age. In most cases, a clinical history and physical examination can be used to determine the prognosis of a child presenting with a febrile seizure, which is usually excellent. Electroencephalography and neuroimaging are of limited value, and treatment with antiepi­leptic medications is rarely indicated.


Parents and caregivers should be reassured that after a febrile seizure the child’s risk of having an afebrile seizure or developing epilepsy is very low.


Seizures with fever occur in 3% to 5% of children in North America and Europe[1,2] and in up to 14% of children of Asian origin.[3] In most children, these seizures are the manifestation of an underlying genetic abnormality that is expressed over a relatively small number of years and is associated with an excellent prognosis. Very occasionally seizures that are due to an underlying brain lesion or infection, or to a more serious genetic abnormality, may also occur initially at a time of fever. 

A febrile seizure (FS) is a disorder that presents between 3 months and 6 years of age with convulsions and fever but without evidence of intracranial infection or defined cause.[4] Population studies have found the vast majority of children have an excellent prognosis after FS.[5,6] These studies demonstrate that the risk of developing epilepsy after FS is not much greater than in the general population; there is no evidence that the seizures influence cognitive functioning; and very few children require treatment with prophylactic antiepileptic medication.

These studies also demonstrate that clinical factors alone can be used to establish the prognosis and that laboratory investigations are of little value in this regard.[5,6]

Simple versus complex febrile seizure 
Two major population studies, the National Collaborative Perinatal Project (NCCP)5 and the Child Health and Education (CHES),6 have used certain clinical features to categorize febrile seizures as simple or complex. A febrile seizure is considered complex if the seizure is focal or prolonged (longer than 15 minutes), or if there is more than one seizure in 24 hours. 

These studies demonstrate that approx­imately 80% of febrile seizures are simple. Focal seizures occurred in 4% of all FS, and the seizure lasted more than 15 minutes in 8% of cases and more than 30 minutes in 4% to 5% of cases.[5,7] Recurrent seizures within 24 hours occurred in 16% of cases. Characterization of FS as complex is of limited value in predicting the risk of later epilepsy. Whereas a child with a simple FS has a 98% probability of not developing epilepsy, a child with a complex FS has an 85% to 95% probability of not developing epilepsy.[5,8]

When do investigations help?
Although febrile seizures are common and the prognosis is excellent in nearly all children, it is important to recognize that fever and seizures are symptoms of a variety of different diseases. Thus, the occurrence of a seizure during a febrile illness may be symptomatic of an acute infection that requires treatment, such as bacterial meningitis or viral encephalitis.

Lumbar puncture
A diagnosis of bacterial meningitis or viral encephalitis should be considered in those children presenting with clinical features of these diseases and in those who have received antibiotics that may have masked these clinical features.[9

A practice parameter recommends that a lumbar puncture (LP) be performed following a febrile sei­zure if meningeal signs are present.[10] The same parameter recommends that LP be strongly considered if the child is younger than 12 months of age or has received antibiotics prior to the seizure, and LP be considered if the child is younger than 18 months. 

Bacterial meningitis has been found in 1.8% to 5.4% of children presenting with a febrile seizure.[9] However, these studies were performed prior to the use of vaccines against the bacteria commonly associated with meningitis in children under 2 years of age, meaning that today the incidence of bacterial meningitis is much lower in areas where immunization is available. 

This decreased incidence also means that many physicians have limited experience in the diagnosis of bacterial meningitis and it would seem prudent to err on the side of caution. 

The clinical condition of the child, the length of time since the seizure oc­curred, and the experience of the physician are factors that will determine whether to perform a lumbar puncture. Treatment with meningitic doses of an appropriate antibiotic and acyclovir should be instituted when there is concern that the seizure may be due to meningitis or encephalitis.

Blood glucose
Blood glucose should be measured if the seizure is longer than 15 minutes in duration or ongoing when the patient is assessed, and if the patient has a depressed level of consciousness for a prolonged period following the seizure. Blood glucose should also be checked at the bedside and 5 mL/kg of 10% dextrose should be administered if the level is less than 3 mmol/L. 

Other laboratory tests
If the seizure is prolonged or ongoing when the patient is assessed, a blood culture and urine culture should also be performed and treatment with antibiotics for meningitis and with acyclovir should be strongly considered until an LP can be performed and the diagnosis clarified.

Laboratory investigations after a simple febrile seizure depend on the clinical condition of the child and should be guided by an appropriate clinical recommendations for children of that age presenting to the emergency department with fever.[11]

Neuroimaging
Imaging of the brain is not indicated after a simple febrile seizure.[11] A computed tomography head scan should be performed if there is a postictal neurological deficit persisting for more than a few hours. Elective neuroimaging should be considered when there are clinical features of a neurological disorder such as micro- or mac­rocephaly, neurocutaneous ab­normalities, pre-existing neurological deficit, or when there is recurrent complex FS, particularly where there is doubt whether the seizures are occurring at times of fever.[12]

Magnetic resonance imaging has a higher sensitivity than CT for brain lesions that present with seizures. 

Electroencephalography
Electroencephalography (EEG) is not helpful in children with simple FS. Epileptiform abnormalities are relatively common in children with be­nign FS. Generalized spike-wave discharges occur in 49% and photosensitivity in 42% of children with benign FS followed until 11 to 13 years of age.[13

Although these abnormalities occur most often between 5 and 6 years of age, a proportion will appear at an earlier age. Thus, epileptiform abnormalities are common in children with FS and are a poor predictor of later epilepsy. In addition, first febrile seizures occur before 3 years of age in 89% of children with FS6 and EEG has a low sensitivity in that age group.[14]

The role of EEG following a complex febrile seizure has received limited attention. In one study, EEG performed during the wake and sleep states within 1 week of a complex febrile seizure was normal in all 33 children.15 EEG may be helpful in children who remain encephalopathic for longer than normal following a febrile seizure or who experience a focal seizure lasting longer than 30 minutes.

Risk of further febrile seizures 
Approximately 30% to 40% of children who have a febrile seizure will have a recurrence,[16] usually within 12 months.[5,17] A higher risk of recurrence exists if the first seizure occurs when the patient is younger than 15 months,[16] there is a history of FS in a first-degree relative,[16] there is a shorter duration of fever prior to the seizure,17 and when the febrile seizure occurs at a lower temperature.[17

In contrast, the presence of a complex first febrile seizure, a history of developmental delay, and a family history of epilepsy have no influence on the recurrence rate of febrile seizures.[17] In addition, patients who have a febrile seizure lasting longer than 30 minutes had only a 2% risk of a second lengthy febrile seizure5 (see Table).

Risk of afebrile seizures 
The risk of having an afebrile seizure or developing epilepsy following a febrile seizure is very low. The risk of an afebrile seizure is 3% at 7 years of age,[5] 2.5% at 10 years of age,[2] and 5% at 20 years of age.[18] However, the risk of developing epilepsy in patients who have their first afebrile seizure following a febrile seizure is between 70% and 85%.[2,18

The most important factor influencing the risk of developing epilepsy following a febrile seizure is the neurological function of the child prior to the febrile seizure. Forty percent of children with cerebral palsy, mental retardation, or both prior to the febrile seizure developed epilepsy compared with 2.9% of those without neurological deficit.[18

In contrast, only 0.9% of children with normal neurological development and no history of epilepsy in the immediate family had an afebrile seizure by 7 years of age, a figure only slightly higher than in the general population.[5

The occurrence of a complex febrile seizure has only a limited effect on the risk of developing epilepsy by 7 years of age. Whereas 2% of children developed epilepsy following a simple febrile seizure, 4% to 12% developed epilepsy following a complex febrile seizure in the NCCP study.[5,8]

Neurological outcome 
Children with febrile seizures whose neurological development is normal at the time of the first seizure perform as well as other children in terms of their academic progress, intellectual function, and behavior at 10 years of age. 

This is true for children with both simple and complex FS and for those with recurrent FS.[19] Similarly, when children with febrile seizures are compared with their siblings at the age of 7 years, there are no differences in the mean full-scale IQ scores, and poor academic achievement is as common in siblings as in children who have had febrile seizures.[20

Furthermore, the mean IQ of those with recurrent sei­zures and those with seizures lasting 30 minutes or longer is not different from that of their siblings. Thus, the prognosis for neurological development is excellent.

Treatment 
Most febrile seizures are brief and the seizure has usually ended prior to the child being assessed. If the seizure has not stopped, treatment with intravenous lorazepam (0.1 mg/kg over 1 min; maximum dose 4 mg), intrave-nous diazepam (0.3 mg/kg over 2 min; maximum dose 5 mg in infants and 10 mg in older children) or buccal midazolam (0.5 mg/kg; maximum dose 10 mg) is indicated.[21

Rectal diazepam (0.5 mg/kg; maximum dose 10 mg) may also be administered, but is less effective than buccal midazolam.[21

A benign form of seizure that occurs in association with viral gastroenteritis, and in the absence of dehydration or electrolyte disturbance, has a prognosis similar to that of FS.[22] These seizures occur in children in the same age group affected by FS and may or may not be associated with fever. 

Such seizures appear to be unrelated to FS in that only 7% of patients have a family history of FS and only 5% have a history of FS. The seizures are brief and generalized and last less than 3 minutes in 87% of children. 

They occur in clusters over a period that can be as long as 24 hours in 75% of children and recurrent episodes are rare.[23] Treatment with antiepileptic drugs does not abort the cluster in most children.[23] A retrospective study reported that a single dose of chloral hydrate (50 mg/kg/d) was effective in stopping a cluster in 19 of 22 patients (86%), whereas di­azepam was effective in only 2 of 16 patients (13%).[24

Care must be taken in monitoring young children receiving chloral hydrate, which may cause excessive sedation, vomiting, hyperactivity, and respiratory complications.[25

The second step in management is to exclude a serious underlying cause such as meningitis. This can usually be achieved by clinical assessment, with the proviso that the characteristic features of meningitis may not be present in children under 18 months of age and may be masked in those who have received antibiotics. 

Treatment with meningitic doses of an appropriate antibiotic and acyclovir should be instituted when there is concern that the seizure may be due to meningitis or encephalitis. 

An integral part of the management of a first febrile seizure is reassurance of the family. A first seizure can be a terrifying experience for many parents, who may think initially that their child is dying. The challenge is to help the family deal with the emotional trauma and to appreciate the excellence of the prognosis. 

It is im­portant for the family to understand that there is no increased risk of intellectual delay or school difficulties and that febrile seizures less than 30 minutes in duration do not result in brain damage.

Similarly, the family should appreciate the low risk of developing epilepsy and the lack of benefit in using antiepileptic drug treatment to lower that risk. Finally, the family should understand that EEG and neuroimaging are of little value.

This information should be discussed with the family when the child is seen at the time of the febrile seizure. The ability of the family to fully understand all of the information at that time is likely to be limited by their emotional state, and it can be helpful for arrangements to be made for the family to receive further education at a later visit. 

It is important to provide the family with information on the risk of a further febrile seizure and how to deal with such an event. The information can be given in pamphlet form along with the addresses of reliable websites (e.g., www.epilepsy.com/epilepsy/epilepsy_febrilewww.patient.co.uk/showdoc/23068735/).

Prevention and treatment of recurrent febrile seizures 
Cooling the child and using antipyretics does not reduce the frequency of recurrent FS.26 Antipyretics can make the febrile child more comfortable but the parents should be dissuaded from the aggressive use of these drugs. 

Several medications have been found to reduce the risk of a recurrent febrile seizure. Most physicians consider that the benefit of reducing sei­zure frequency is usually outweigh­ed by the potential side effects of treatment. However, there may be situations where drug treatment has a role. Thus, in the very small number of children who have very frequent febrile seizures, reduction in the frequency of these episodes may reduce the stress on the family. 

Similarly, prophylactic treatment should be considered in children who live remote from medical help and who have a history of a prolonged febrile seizure. 

Daily oral phenobarbital reduces the frequency of recurrences, but has a high incidence of behavioral and cognitive side effects.[27] Furthermore, in a placebo-controlled study of children with FS, the mean IQ of those who had received daily phenobarbital was 7 points lower than controls after 2 years and 5 points lower after the medication had been discontinued.[28

Daily oral valproic acid is also effective in reducing the frequency of recurrent FS,[29] but the high incidence of fatal liver failure in infants and young children30 suggests that the risks of this drug outweigh the benefits in this situation. Daily carbama­zepine and phenytoin are not effective in preventing recurrences.[31]

Benzodiazepines may reduce the frequency of recurrent febrile sei­zures. Intermittent rectal diazepam administered at a dose of 5 mg every 8 hours when the temperature is above 38.4 °C is effective in reducing the frequency of recurrences.[32

Intermittent oral diazepam at a dose of 0.3 mg/kg every 8 hours when the child is febrile is also effective in prevention of recurrent FS, but drowsiness, ataxia, or both occur in 30% of the children and limit the usefulness of oral diazepam. 

Intermittent clobazam (given as soon as the fever occurs for 48 hours at a dose of 0.3 to 1.0 mg/kg up to a maximum dose of 10 mg b.i.d.) has been shown in a placebo-controlled study to be effective in reducing fe­brile sei­zure recurrence.33 Intermittent cloba­zam has also been shown to be associated with fewer side effects than intermittent oral diazepam in children with febrile seizures.[33,34]

Parents of children who have had a prolonged febrile seizure and families living at a significant distance from medical help can be taught how to administer rectal diazepam (0.3 mg/kg) or buccal midazolam (0.5 mg/kg; maximum dose 10 mg) at home if the seizure lasts longer than 5 minutes.

All parents should be informed that there is no evidence that treatment with antiepileptic drugs influences the risk of developing epilepsy.

Summary
Febrile seizures are a common disorder in children between 3 months and 6 years of age, and are associated with an excellent prognosis. The risk of developing epilepsy is very small and neurological development and school progress are unaffected by the sei­zures. EEG and neuroimaging are not helpful and treatment with an anti­epileptic drug is rarely indicated.

Competing interests
None declared.

Key points for management of febrile seizures
• Febrile seizures occur in 3% to 5% of children between 3 months and 5 years of age.
• When a child presents with a seizure and fever, it is important to rule out bacterial meningitis. 
• Children with febrile seizures do as well at school as their siblings who do not have febrile seizures.
• The risk of developing epilepsy is approximately 1% in children with simple febrile seizures.
• Use of prophylactic antiepi­leptic medication is not recommended.
• Electroencephalography and neuroimaging are not indicated in children with simple febrile seizures. 
• Counseling and reassurance of caregivers are very important aspects of management.


References

1. Nelson KB, Ellenberg JH. Prognosis in children with febrile seizures. Pediatrics 1978;61:720-727.
2. Verity CM, Golding J. Risk of epilepsy after febrile convulsions: A national cohort study. BMJ 1991;303:1373-1376.
3. Hauser W. The prevalence and incidence of convulsive disorders in children. Epilepsia 1994;35(suppl 2):S1-6.
4. Consensus statement. Febrile seizures: Long-term management of children with fever-associated seizures. Pediatrics 1980;66:1009-1012.
5. Nelson KB, Ellenberg JH. Predictors of epilepsy in children who have experienced febrile seizures. N Engl J Med 1976;295:1029.
6. Verity CM, Butler NR, Golding J. Febrile convulsions in a national cohort followed up from birth. II—Medical history and intellectual ability at 5 years of age. Br Med J (Clin Res Ed) 1985;290:1311-1315.
7. Verity CM, Ross EM, Golding J. Outcome of childhood status epilepticus and lengthy febrile convulsions: Findings of national cohort study. BMJ 1993;307:225-228.
8. Annegers JF, Hauser WA, Shirts SB, et al. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 1987;316:493-498.
9. Aicardi J. Epilepsy in children. New York: Raven Press; 1994.
10. Practice parameter: The neurodiagnostic evaluation of the child with a first simple febrile seizure. American Academy of Pediatrics. Provisional Committee on Quality Improvement, Subcommittee on Afebrile Seizures. Pediatrics 1996;97:769-772.
11. Practice parameter: A guideline for discontinuing antiepileptic drugs in seizure-free patients—Summary statement. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1996;47:600-602.
12. Waruiru C, Appleton R. Febrile seizures: An update. Arch Dis Child 2004;89:751-756.
13. Doose H, Ritter K, Volzke E. EEG longi­tudinal studies in febrile convulsions. Genetic aspects. Neuropediatrics 1983;14:81-87.
14. Shinnar S, Kang H, Berg AT, et al. EEG abnormalities in children with a first unprovoked seizure. Epilepsia 1994;35:471-476.
15. Maytal J, Steele R, Eviatar L, et al. The value of early postictal EEG in children with complex febrile seizures. Epilepsia 2000;41:219-221.
16. Berg AT, Shinnar S, Hauser WA, et al. Predictors of recurrent febrile seizures: A meta-analytic review. J Pediatr 1990;116:329-337.
17. Berg AT, Shinnar S, Hauser WA, et al. A prospective study of recurrent febrile seizures. N Engl J Med 1992;327:1122-1127.
18. Annegers JF, Hauser WA, Elveback LR, et al The risk of epilepsy following febrile convulsions. Neurology 1979;29:297-303.
19. Verity CM, Greenwood R, Golding J. Long-term intellectual and behavioral outcomes of children with febrile convulsions. N Engl J Med 1998;338:1723-1728.
20. Ellenberg JH, Nelson KB. Febrile seizures and later intellectual performance. Arch Neurol 1978;35:17-21.
21. McIntyre J, Robertson S, Norris E, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: A randomised controlled trial. Lancet 2005;366:205-210.
22. Narchi H. Benign afebrile cluster convulsions with gastroenteritis: An observational study. BMC Pediatr 2004;4:2.
23. Uemura N, Okumura A, Negoro T, et al. Clinical features of benign convulsions with mild gastroenteritis. Brain Dev 2002;24:745-749.
24. Enoki H, Yokota T, Nagasaki R, et al. Single-dose chloral hydrate for benign convulsions with mild gastroenteritis. Epilepsia 2007;48:1026-1028.
25. Merola C, Albarracin C, Lebowitz P, et al. An audit of adverse events in children sedated with chloral hydrate or propofol during imaging studies. Paediatr Anaesth 1995;5:375-378.
26. van Stuijvenberg M, Derksen-Lubsen G, Steyerberg EW, et al. Randomized, controlled trial of ibuprofen syrup administered during febrile illnesses to prevent febrile seizure recurrences. Pediatrics 1998;102:E51.
27. Camfield PR, Camfield CS, Shapiro SH, et al. The first febrile seizure—antipyretic instruction plus either phenobarbital or placebo to prevent recurrence. J Pediatr. 1980;97:16-21.
28. Farwell JR, Lee YJ, Hirtz DG, et al. Phenobarbital for febrile seizures—effects on intelligence and on seizure recurrence. N Engl J Med 1990;322:364-369.
29. 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.
30. Bryant AE 3rd, Dreifuss FE. Valproic acid hepatic fatalities. III. U.S. experience since 1986. Neurology 1996;46:465-469.
31. Camfield C, Camfield P. Febrile seizures. In: Roger J, Bureau M, Dravet C, et al. (eds). Epileptic syndromes in infancy, childhood and adolescence. 4th ed. Montrouge, France: John Libbey Eurotext; 2005. p. 159-169.
32. Knudsen F, Vestermark S. Prophylactic diazepam or phenobarbitone in febrile convusions: A prospective controlled study. Arch Dis Child 1978;53:660-663.
33. Rose W, Kirubakaran C, Scott JX. Intermittent clobazam therapy in febrile seizures. Indian J Pediatr 2005;72:31-33.
34. Khosroshahi N, Faramarzi F, Salamati P, et al. Diazepam versus clobazam for intermittent prophylaxis of febrile seizures. Indian J Pediatr 2011;78:38-40.


Dr Farrell is a neurologist at BC Children’s Hospital (BCCH) and a professor in the Department of Pediatrics at the University of British Columbia. Dr Goldman is division head and research director of the Division of Pediatric Emergency Medicine at BC Children’s Hospital and an associate professor in the Department of Pediatrics at the University of British Columbia.

Kevin Farrell, MBChB,, Ran D. Goldman, MD,. The management of febrile seizures. BCMJ, Vol. 53, No. 6, July, August, 2011, Page(s) - Clinical Articles.



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