Dr. B. Talukdar*
Professor of Pediatrics, Maulana Azad Medical College.
Email: firstname.lastname@example.org *
Febrile seizure is a very common age-related acute seizure disorder in children provoked by a febrile illness. The disease has a high incidence, 2-4% (higher in Western hemisphere, about 8-10%) and unique age specificity. It has been defined as 'event in infancy and childhood, usually occurring between 3 months and 5 years of age, associated with fever but without intracranial infection or a defined cause (1). Seizure with fever in children who had suffered a previous non-febrile seizure are excluded. It is distinguished, from epilepsy which is a recurrent non-febrile seizure. Febrile seizure is called simple if it is brief, generalized and single and complex if it is prolonged for > 15 minutes, has focal features and has multiple recurrences within 24 hours. Recurrence is common and is the most vexed problem in this disease, so is the familial occurrence. The disease is relatively benign. There is hardly any role of
investigation for febrile seizure per se except for the purpose of finding any associated pathology if there be or for exclusion of certain serious condition like meningitis at times. There is no
specific treatment and management is primarily prophylactic. All these issues however continue to be subjects of intense research and has resulted in a few interesting developments in recent times.
|Occurrence and recurrence|
|The common age of occurrence is 3 months to 5 yrs. However occasional case has been seen to occur as early as 1 month of age and ILAE (International League Against Epilepsy) seeks to bring down the lower age limit to 1 month (2). The upper age limit also can go beyond 5 years.
Attendance at day care centre has been shown to increase the incidence of febrile seizure. It increases the chances of contact with kids suffering from an attack of URI. Other
important risk factors that have been well established are a presence of first or second degree relative with FS, neonatal nursery stay for > 30 days, developmental delay (3). Incidence of FS in offspring of individuals (male or female) with history of febrile seizure is 10%.
Other important risk factors that have been well established are a presence of first or second degree relative with FS, neonatal nursery stay for > 30 days, developmental delay (3).
Risk of recurrence of febrile seizure in another child is about 1 in 5 with one affected sibling. It is about 1 in 3 with both parents and previous child being affected. Abnormal EEG findings in probands are not related to increased risk in offsprings. Febrile status epilepticus is known to constitute about 25% of all cases of status epilepticus, and about 40% cases of first febrile seizure can be status. However febrile status epilepticus does not increase the risk of further febrile seizure or epilepsy in a neurodevelopmentally normal child (4).
|FS and epilepsy|
|Most evidence suggests no casual relationship with epilepsy, FS does not increase the risk of epilepsy unduly. Generally FS is usually followed by generalized and focal FS by focal/partial epilepsy (5). Factors that have been well established to have risk factors for development of epilepsy are |
neurodevelopmental abnormality before the attack of FC, family history of epilepsy, and complex FC (5).
Factors that have been well established to have risk factors for development of epilepsy are neurodevelopmental abnormality before the attack of FC, family history of epilepsy, and complex FC (5).
Viral infections, like roseola infantum, influenza has been known to be the commonest cause of the fever in FC, although documentation through virologic studies is few. With better diagnostic tools a few viruses have been added now, these are HSV 6, HSV 7, and influenza (6, 7). The advent of PCR has made it easier to detect these viruses.
Immunologic markers have been another area of intense investigation looking for the cause of fever in FS. Several immunologic markers have been shown to be of significance in the aetiopathogenesis of febrile seizure. Based on animal studies pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha), interleukin-1 alpha, Interleukin-1 beta and interleukin 1 Ra have been suspected to have role in precipitating febrile seizure by influencing neuronal excitability that may result in linking of fever and seizure activity. This role of activation of cytokine network in pathogenesis of febrile seizure has been supported by a few clinical studies. Elevated concentration of these CSF pro-inflammatory cytokines TNF-alpha, IL-1 beta, interleukin-1 alpha are seen in CSF. Recently, an association between a regulatory polymorphism in the genes encoding interleukin-1 beta and interleukin-1 Ra and febrile seizures was reported; however this has been contradicted by another recent study (10).
Zinc deprivation may play a role in
pathogenesis of FS. Serum and CSF zinc levels have been found to be low in many cases febrile seizures (11). Iron deficiency anemia has also been found to commoner in children with FS than controls and may have a role in pathogenesis of febrile seizures (12). Immunoglobulin deficiency also may play apart as it has been found to be low in FS (13). There is a possibility of immunological derangements in the cytokine and interferon axis in FS that may play a part in causation of febrile seizure (14).
Zinc deprivation may play a role in pathogenesis of FSW.
|Mesial temporal sclerosis|
|Mesial temporal sclerosis and FS has long been a debatable issue. Epidemiological data do not suggest that mesial temporal sclerosis is a cause of FS. It is more likely to be an association. A recent case control study using MRI volumetry of amygdale and hippocampus and qualitative analysis of mesial temporal structures show no association to FS (15). Recent clinicopathological studies have shown existence of multiple/other pathologies like dysplasias and migration defects in mesial temporal sclerosis, some of which can even be genetically determined (16).
Epidemiological data do not suggest that mesial temporal sclerosis is a cause of FS. It is more likely to be an association.
|Imaging, a common tempting investigation, is frequently asked for in febrile seizure. There is no need of these investigations to be done routinely. These may however be justifiable in cases with neurodevelopmentally abnormal child where some structural abnormality may be found, although not having any clinical or therapeutic usefulness. Here again imaging is basically for investigating of a child with neurodevelopmental abnormality and not febrile seizure say. Even after a first complex febrile seizure it is not routinely indicated as has been shown in a recent study that the risk of serious intracranial problem is low (17).
EEG, another tempting investigation is frequently asked for in cases of FS. It is also not routinely indicated as these are not useful for diagnosis or prognosis. Abnormal finding if any has no specificity and these disappear in time and are not helpful in predicting recurrence of FS or even future development of epilepsy and cannot be used as guide for use of ACT. There is no indication to undertake an early EEG irrespective of whether the febrile seizure is simple or complex. Recurrent simple or complex febrile also do not justify and EEG, as it is of no use in identifying a structural abnormality or in predicting further recurrence or future development of epilepsy (18).
|Familial occurrence is a strong factor in febrile seizure. About 9-22% of sibs and 8-14% of parents are found to have history of febrile seizures. High concordance rate in monozygotic twins has been well established. High incidence of occurrence in families, high concordance rate in monozygotic twins, familial clustering studies showing doubling of risk when both parents were affected all these suggest hereditary nature of the disease. The pattern of inheritance is however is not clear/controversial and variable from families to family and even within the same family. However the most commonly observed trait is autosomal dominant with reduced/incomplete penetrance.
However, the most commonly observed trait is autosomal dominant with reduced/incomplete penetrance.
It has long been recognized that there is a significant genetic component for susceptibility to FS. Work in this direction suggests that genetic abnormalities primarily mutations in several genes may be responsible for susceptibility to FS. (15-21). Six susceptibility FS loci have been identified on chromosomes 8q13-q21 9FEB1), 19p (FEB2), 2q23-q24 (FEB3), 5q14-q15 (FEB4), 6q22-q24 (FEB5), and 18 p11(FEB6) (19, 20, 21, 22). Furthermore, mutations in the voltage-gated sodium channel alpha-1, alpha-2 and beta-1 subunit genes (SCN1A, SCN2A and SCN1B) and the GABA (A) receptor gamma-2 subunit gene (GABRG2) have been identified in cases of febrile seizure (23, 24, 25, 26). Possibility of febrile seizure being primarily a channelopathy has been postulated in view of the mutations in the genes encoding ion channels in brain neurons like SCN1B.
Possibility of febrile seizure being primarily a channelopathy has been postulated in view of the mutations in the genes encoding ion channels in brain neurons like SCN1B.
Attempt has been made to find a relation between fever and the mutant gene; a recent study suggests that febrile seizures may be produced by a temperature-induced dynamic reduction of susceptible mutant surface GABAA receptors in response to fever (27). Thus several abnormal genes have been described in febrile seizures; however some of them specially those related to the ion channels are also seen to occur in afebrile seizures and epilepsies as well thereby complicating the specificity of these genes to febrile seizures alone. So far no consistent or convincing FS susceptibility genes have emerged and to find a true association, larger sample size and newer methodologic refinements are needed (22).
|Generalized epilepsy with febrile seizure plus (GEFS+)|
|An interesting finding of |
genetic abnormalities found in cases of FS continuing beyond the usual age of occurrence has led to the development of the concept of FEFS+, a genetic epilepsy syndrome. FEFS has a spectrum of phenotypes including febrile seizure and febrile seizure plus (28). The syndrome comprised a childhood onset (median 1 year) of multiple FC, but unlike the typical FC syndrome, attacks with fever, at times without fever, continue beyond 6 years of age. Mutations in the voltage-gated sodium channel alpha-1, alpha-2 and beta-1 subunit genes (SCN1A, SCN2A and SCN1B) and the GABA (A) receptor gamma-2 subunit gene (GABRG2) have been identified in cases of GEFS+. (23-26)
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- Okumura A, Takemoto K, Ozaki T. Serum beta 2-microglobulin and neopterin levels in children with febrile illness: their relation to influenza and febrile convulsion, J Pediatr Neurol 2003;1:35-38.
- Tilgen N, Pfeiffer H, Cobilanschi J, et al. Association analysis between the human interleukin 1 beta (-511) gene polymorphism and susceptibility to febrile convulsion. Neurosci Lett 2002;334:68-70.
- Haspolar S, Baysal Y, Interleukin -1beta, and interleukin-1Ra polymorphisms in febrile seizures. J Child Neurol. 2005 Jul;20(7):565-8.
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- Daoud AS, Batieha A, Abu-Ekteish FA, Gharaibeh N, Ajlouni S, Hijazi S. Iron status: a possible risk factor for the first febrile convulsion. Epilepsia 2002;43:740-743.
- Caksen H, Oner AF, Arslan, Kan MC, Cesur Y, Uner A. Immunoglobulin subgroup in children with febrile convulsion. Pediatr Int 2001;43:58-60.
- Vitra M, Hurme M, Helminen M. Increased plasma level of pro-and anti-inflammatory cytokines in patients with febrile convulsion. Epilepsia 2002;43:920-923.
- Tarkka R, Paakko E, Pyhitinen J, Uhari M, Rantala H. Febrile convulsion and mesial temporal sclerosis: No association in a long-term follow-up study. Neurology 2003;60:215-218.
- Porter BE, Judkins AR, Clancy RR et al. Dysplasia: a common finding in intractable pediatric temporal lobe epilepsy. Neurology 2003;61:265-8.
- Ng YT, McGregor AL, Duane DC, Jahnke HK, Bird CR, Wheless JW. Childhood mesial temporal sclerosis. J Child Neurol. 2006 Jun;21(6):512-7.
- Maytal J, Steele R, Eviatar I et al. The value of early post ictal EEG in children with complex febrile seizures. Epilepsia 2000; 41:219-221.
- Wallace RH, Berkovic SF, Howel RA et al. Suggestion of a major gene for familial febrile convulsions mapping to 8q12-q21. J Med Genet 1996;33:308-12.
- Johnson EW, Dubovsky J, Rich SS et al. Evidence for a novel gene for familial febrile Convulsion, FEB 2, linked to chromosome 19p in an extended family from mid west. Hum Genet 1998;7:63-7.
- Nabbout R, Prud'homme JF, Herman A, et al. A locus for simple pure febrile convulsion maps to chromosome 6q22-q24, Brain 2002;125:2668-2680.
- akayama J, Arinami T. Molecular genetics of febrile seizures. Epilepsy Res. 2006 Aug;70 (2-3 suppl):190-198.
- allace RH, Wang DW, Sigh R et al. Febrile seizure and generalized epilepsy associated with a mutation in Na+channel beta subunit SCN1B. Nat Genet 1998;19:366-70.
- Baulac S, Gourfinkel-An 1, Oicard F et al. A second look for familial generalized epilepsy with febrile seizure plus mapped to chromosome 2q21-q33. Am J Hum Genet 1999;65:1078-85.
- Wallace RH, Marini C, Petrou S. et al. Mutant GABA (A) receptor gamma2 subunit in childhood epilepsy and febrile seizure. Nat Genet 2001;28:49-52.
- Nakayama J, Hammono K, Gourfinkel-An 1 et al. First genetic evidence of GABA A receptor dysfunction in epilepsy: a mutation in the gamma2 gene. Nat age net 2001;28:46-48.
- Kang JQ, Shen W, Macdonald RL. Why does fever trigger febrile seizures? GABAA receptor gamma2 subunit mutations associated with idiopathic generalized epilepsies have temperature-dependent trafficking deficiencies J Beyriscu. 2006 Mar1;26(9):2590-7.
- Gerard F, Pereira S, Robaglia-Schlupp A, Genton P, Szepetowski P. Clinical and genetic analysis of a new multigenerational pedigree with GEFS+. Epilepsia 2002;43:581-586.
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|Talukdar B D.. Available From : http://www.pediatriconcall.com/fordoctor/ Conference_abstracts/report.aspx?reportid=399|