Febrile convulsion: review and update

Transcription

1 REVIEW ARTICLE Journal of Pediatric Neurology 2004; 2(1): : review and update Azhar Daoud Department of Neuroscience, Jordan University of Science and Technology and King Abdullah University Hospital, Irbid, Jordan Abstract s (FCs) are the most frequently occurring epilepsy syndrome experienced in infants/children between 6 months and 6 years of age and occur in 2-4%. It describes any seizure that occurs in response to a febrile stimulus in the absence of meningitis, encephalitis, serum electrolyte imbalance and other acute neurologic illnesses. There have been many recent reports on the molecular genetic and pathogenesis of FC. It has been recognized that there is significant genetic component for susceptibility of FC with different reported mutation. Others have tried to correlate FC to immunologic problem through interleukin, cytokines, immunoglobulin and interferon. Also, reports on correlations between FC and iron deficiency anemia, hypozincemia or to specific infections have been published. Children having first or second degree relatives with a history of FC, neonatal nursery stay of more than 30 days, developmental delay or attendance at a day care center are at increase risk of developing FC. A single simple FC does not seem to increase the risk of epilepsy and there is no causal relationship between FC and subsequent epilepsy. Viruses are the most common cause of illness in children admitted to the hospital with a first FC. Routine laboratory studies, electroencephalogram and neuroimaging are not indicated for patients who have FC, and should be performed only as part of the evaluation for a source of fever and/or in atypical cases. Prognosis is generally Correspondence: Azhar Daoud, M.D., Professor of Child Neurology College of Medicine Jordan University of Science and Technology King Abdullah University Hospital P. O. Box 3030 Irbid 22110, Jordan. Tel: , fax: daoud@just.edu.jo Received: July 30, Revised: September 08, Accepted: October 01, good and parents should be counseled about the benign nature of FC. Children with FC are at no greater risk of intellectual impairments than their peers. Maintenance therapy to prevent recurrence has not been shown to prevent later development of epilepsy, and therefore intermittent diazepam or lorazepam are the main drugs to be used. (J Pediatr Neurol 2004; 2(1): 9-14). Key words: febrile convulsion, review, update. Introduction s (FCs) are the commonest type of seizure in children occurring in 2-5% of all children (1). FCs are to be distinguished from epilepsy, which is characterized by recurrent non- FC (2). FCs are defined as an event in neurologically healthy infant/children between 6 months and 6 years of age with fever > 38 C (rectal temperature) but without evidence of intracranial infection as a cause and no history of prior a FC (2,3). Seizures with fever in children who have suffered a previous non-fc are excluded. This definition excludes seizures that accompany meningitis, electrolyte imbalance or toxic encephalopathy. Seizures in these instances may carry a more ominous prognosis than the benign course of FC owing to the effects of associated illness (4). History The mean age of onset of FC is months and they rarely occur before the age of 9 months or after the age of 5 years (3). FCs usually occur early in the course of a febrile illness and are often the first sign (4). These convulsions are associated with a rapidly rising temperature and usually develop when the core temperature reaches 39 C or higher. The seizures may be of any type but mainly simple FC occur in 80-85% of cases. Simple (benign) FCs are generalized tonic-clonic seizures, lasting less than 15 minutes, not recurring more than once

2 10 within 24 hours, and with no postictal neurological abnormalities. Complex FCs are focal, prolonged more than 15 minutes, recurrent more than once within 24 hours and/or associated with postictal focal neurological finding (2). These seizures constituted 15-20% of FCs. Febrile status is defined as seizures with duration of 30 minutes or more or a series of recurrent seizures without regaining consciousness (2). Epidemiology FCs are the most common form of convulsion, occurring in 2-5% of young children in North America and Europe and in 6-9% in Japan (3). They are slightly more common in males. The usual age of onset is between 12 and 15 months. Few children will have a first episode after 3 years. It has been found that 21% children had a convulsion either before or within one hour of onset of fever, 57% between 1-24 hours after onset of fever and 22% had a convulsion more than 24 hours after onset of fever (5). Risk factors for febrile seizures and for recurrences The following factors are associated with increased risk for FC: a. A first or second-degree relative with FC. b. A neonatal nursery stay of more than 30 days. c. Developmental delay. d. Attendance at a day care centre. Children with 2 of these risk factors have 28% chances of experiencing at least one FC (6). Approximately 30% of children with one FC will have a recurrence, 10% will have 3 or more episodes. Factors increasing the risk of recurrence are a family history of FC, age of first attack younger than 12 months, and the height and duration of the fever (5-7). The likelihood of a recurrence of FC varies with age. The younger the child at the first FC, the more likely is a recurrence. Fifty percent of those children whose first seizure occurs under the age of one year will have at least one recurrence, whereas only 20 percent of those who have their first FC after the age of 3 years will have a recurrence. Previous studies have shown an increase risk of recurrence to be associated with shorter duration of fever before the initial FC and a lower temperature (7). About 75 percent of recurrences take place within 1 year, and about 90 percent within 2 years. There is no increased likelihood of recurrence if the seizure is a complex one (7). Evaluation and management During the acute attack, the airway management, keeping the child in a semi-prone position to avoid aspiration, monitoring of the vital signs and other supportive care are the pillars of management. If seizures continue for more than few minutes then the administration of diazepam (0.2 mg/kg) or lorazepam (0.05 mg/kg) IV should be considered. The rectum may be used as an alternative to the IV route, since diazepam is readily absorbed. Rectal diazepam tubes are available as 5 mg for children aged 4-24 months and 10 mg for older children. Where rectal preparation are not available, the undiluted intravenous preparation is sucked in a small syringe and given through a polythene tube which is gently inserted 4-5 cm into the anus after lubricating with lignocaine jelly. This method has been found to be effective in aborting acute seizure at home and in a hospital setting. Strongly consider admission in the first attack of FC if one or more of the following factors are present: 1. Age under 18 months. 2. Presence of signs of meningitis. 3. The child is drowsy, irritable, systemically unwell or toxic. 4. Recent or current treatment with antibiotics. 5. Complex febrile convulsion. 6. Inadequate home circumstances. Routine laboratory studies are not indicated for patients who have FC and should be performed only as part of the evaluation for the source of fever (6-8). Management of the normal infant who has simple FC includes in addition to the physical, neurological and developmental assessment, a careful search for the cause of fever. Active measure to control the fever includes the use of antipyretics in appropriate doses, removing excess clothing. Reassurance of the parents about the benign course of FC, short-term anticonvulsant prophylaxis is not indicated except to terminate a prolonged seizure. Investigation for a child with FC should be focused on investigating the cause of fever and excluding meningitis: a. In children under the age of 12 months strongly consider lumbar puncture as signs and symptoms of bacterial meningitis may be minimal or absent in this age group. b. In children between the ages of months signs of meningitis may be subtle in this age group, so lumber puncture should be considered. c. In children over the age of 18 months the decisions to perform lumbar puncture or not are according to the presence of meningeal signs and to the general conditions of the patients. Polymerase chain reaction (PCR) testing may identify a primary, human herpes virus-6 (HHV- 6), HHV-7 and influenzae virus infections of febrile children when an appropriate combination of clinical specimens is used (9,10). The levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) alpha and IL-6 as pro-

3 inflammatory cytokines in the cerebrospinal fluid (CSF) may facilitate differentiation between acute encephalitis/encephalopathy and prolonged FC (11,12). Elevated concentration of the CSF proinflammatory cytokines, TNF-alpha, IL-1 beta, and IL-6, indicate acute encephalitis/encephalopathy rather than FC (10-12). Computed tomography (CT) nor magnetic resonance imaging (MRI) are not indicated in patients with simple FC. Brain CT may be justifiable, but may not be clinically useful, in the management of patient with FC who have prior neuro-developmental deficits (13). Electroencephalogram (EEG) is not indicated in children with simple FC. Published studies demonstrate that the vast majority of these children have a normal EEG. In addition, some of those with an abnormal EEG have remained free of seizure for the duration of their follow up. On the other hand, some of the children with a normal initial EEG have experienced one or more a FC subsequent to the EEG. An EEG performed within one week of the FC will show an abnormal result in one third of cases. Posterior slow wave activity, which may be bilateral or unilateral, is not predictive of subsequent epilepsy. An EEG is indicated for atypical FC and for the child at risk for developing epilepsy. An abnormal EEG will not identify those children who will subsequently develop epilepsy, and should not be used as a basis for deciding which children need anticonvulsant medications (1-3). Vaccination is not contraindicated, but advice should be sought from a pediatrician in case any monitoring is needed. Vaccination is rarely followed by a FC on the first or second day of vaccination with a whole cell pertussis vaccine and 1-2 weeks after measles, mumps, rubella (MMR) vaccination (14). Genetics FCs tend to occur in families, although the exact mode of inheritance is not known and varies between families. In large families, the FC susceptibility trait is inherited by autosomal dominant pattern with reduced penetrance (15). It has long been recognized that there is a significant genetic component for susceptibility to this type of seizure and this may be caused by a mutation in several genes as detailed in Table 1 (15-21). The risk of another child having FC is one in five with one affected sibling and one in three if both parents and a previous child have had FC. The seizure incidence in offspring of individuals with a history of FC was 10% (only FC in 64% of the affected offspring). Offspring of females with affected parents were not at increased risk; and abnormal EEG findings of the probands were not related to an increased risk in offspring (21). Etiology The exact role of fever in the etiology of FC is not clear but there is a positive family history in 7-31% of cases (1). The definitive degree of fever is uncertain. In one series it was shown that at the time of convulsions, 75% of patients had a temperature over 39 C (22). Viruses are the most common cause of illnesses in children admitted to hospital with a first FC with reported correlations to specific viruses like herpes and infleunzae (9,10,23). Seizures that occur after immunizations are likely to be febrile, occurring in response to temperature elevation, particularly those occurring within 48 hours of diphtheria, pertussis, tetanus (DPT) and 7 to 14 day after measles immunization (14). Infants and young children are subject to frequent infections mainly upper respiratory tracts infections accompanied with high fever, which in combination with a relatively low seizure threshold, allows for the common occurrence of FC. Serum and CSF zinc levels are decreased in children with FC, and zinc deprivation may play a role in the pathogenesis of FC (24). Iron deficiency anemia has been found to be commoner in children with FC than controls and may also be related to FC (25). Çaksen et al. (26) have reported an immunoglobulin deficiency in FC, which may be of significance in causing of FC or the fever. Others have reported a possible immunological derangement in the cytokines and interferon axis in FC that may correlate with the pathogenesis of FC or at the fever (10-12). Epilepsy Most studies have shown that single FC do not increase the risk of epilepsy (27). Types of epilepsy that may develop after FC are variable. It is presumed that patients with generalized FC develop generalized epilepsy, whereas patients with focal one develop focal epilepsy. It has been suggested that FCs are an age specific expression of seizure susceptibility in patients with underlying seizure diathesis (16,27). Most evidence suggests no causal relation between FC and subsequent epilepsy (3). Risk factors for the development of epilepsy following FCs are neurodevelopmental abnormality before the attack of FC, family history of epilepsy, and complex FC (27). In one study analysis of a large family and a review of the literature led to the concept of a genetic epilepsy syndrome termed generalized epilepsy with FC plus (GEFS+). GEFS has a spectrum of phenotypes including FC, and FC plus (18,28). The syndrome comprised a childhood onset (median 1 year) of multiple FC, but unlike the typical FC syndrome, 11

4 12 Table 1. Details the different mutation reported and their clinical correlations Mutations Chromosomes Clinical Comments syndromes FEB1 8q13-q21 FEB2 19p13.3 FEB4 5q14-q15 The most common linkage locus in febrile convulsion families SCN1B 19p13.1 Generalized Mutation in the voltage-gated sodium epilepsy with channel beta 1 subunit gene febrile convulsion plus (GEFS+) SCN1A 2q24 Simple febrile Mutation in alpha 1 subunit gene convulsion AKAP18 6q22-q24 Simple febrile convulsion GABRG2 gene, encoding the GABA (A) receptor gamma 2 subunit either with or without absence epilepsy 1 beta (-511) Increase frequency Interleukin-1 beta polymorphism of febrile convulsion attacks with fever continuining beyond 6 years of age, or the recurrence of a FC and the less common myoclonic-astatic epilepsy. Molecular genetic study of such large families should allow identification of genes relevant to FC and generalized epilepsies (28,29). One of the most controversial issues in epilepsy is the relationship between FC and mesial temporal sclerosis. A recent prospective case control study on the occurrence of mesial temporal sclerosis and for a mean follow-up duration of 12.3 years after FC using MRI volumetry of amygdale and hippocampal formation and qualitative analysis of mesial temporal structure show no association to FC (30). Although prolonged FC may in some cases produce mesial temporal sclerosis the epidemiological data do not suggest that FCs are likely to account for the majority of the cases of mesial temporal sclerosis (30). Recent clinicopathological studies have provided evidence for a multiple etiology and the frequent presence of pathology like subtle migration defects (16). The long term prognosis in term of subsequent epilepsy, neurological, motor, intellectual, cognitive, and scholastic ability was not influenced by the type of treatment given in early childhood (31). There is a preferential association of FC with temporal lobe foci and a weaker association between FC and generalized epilepsy. FC do not appear to be a clear risk factor for extra temporal epilepsy (32). The relationship between FC and later epilepsy is a frequently genetic, recent clinical and molecular genetic studies suggesting that there are a number of syndrome specific genes for FC (33). Intellectual function There is no evidence that FC causes a decrease in intellectual function. In the British National Child Development study, there were no significant behavioral differences between children with a history of FC and the rest of the population (2). Children with FC did not show any deficits in school performance. In children with prolonged FC non-verbal intelligence was found to be significantly lower compared with children with simple FC and controls. Children with multiple recurrences of FC performed poorly in all intelligence tests when compared with children with only one FC or with control (34). Prevention of recurrences Prolonged anticonvulsant prophylaxis for the prevention of recurrent FC is no longer recommended (1,35). Phenobarbital has fallen into disfavor because of the high incidence (30-50%) of behavioral and cognitive side effects (1). Sodium valproate is effective in preventing recurrences of FC, but can be dangerous in

5 infants because of serious hepatotoxicity (Reye s encephalopathy) and close monitoring is required, other impotant side effect includes weight gain, hair loss, thrombocytopenia and tremor (16). Neither phenobarbital nor valproate is effective in reducing the risk of epilepsy in children with FC. Intermittent diazepam prophylaxis is effective in preventing FC, both orally and rectally (28,36). A potential drawback is that the seizure could occur before fever is noticed. However, the use of diazepam suppositories or oral solution given at the start of fever may prevent the recurrence of convulsion. It has been reported to reduce the convulsion rate from 27% to 12% of cases (1). Diazepam in a dose of 0.3 mg/kg/8 hours administered orally for the duration of the febrile illness (2-3 days) is recommended to prevent recurrence (16,28). Side effects are usually minimal, but adjusting the dose may reduce symptoms of lethargy, irritability and ataxia (2). Carbamazepine and phenytoin are ineffective in FC, and there is no published data on the effectiveness of the newer antiepileptic drugs like lamotrigine, topiramate and others on FC (16). There is no evidence that treatment to prevent recurrences can prevent the subsequent development of epilepsy (27). Febrile status epilepticus This account for 25% of status epilepticus in children. When status epilepticus occurs in relation to a FC, it is the first seizure 40% of the time and, therefore, is not preventable. There is no evidence that febrile status epilepticus causes any damage to the child s brain. A neurologically normal child who has a prolonged first FC (even if lasted longer than 30 minutes) has only a 3% risk of having a second episode of status epilepticus, and the same 25-30% risk of having more FC as the child whose first FC was brief. About two third of children who are neurologically abnormal at the time of the first episode of status will have further FC, and about one third risk another episode of status. Most physicians will consider placing such child on prophylactic anticonvulsant medicine. Parent s education The parents should be counselled about, the benign nature of the FC, that FC do not lead to neurological problems or developmental delay or intellectual deficit, and have no relation to future epilepsy, and that FC generally have an excellent prognosis, however, a risk of further FC during the current or subsequent febrile illnesses. A written handout answering all parents queries and information on home management is usually helpful (3,6). If another seizure occurs, stay calm, place the child on his or here side or abdomen with the face downward; do not force anything between the teeth and observe the child carefully. If the seizure does not stop after 5 minutes, they could use rectal diazepam and if does not stop after 10 minutes, the child should be brought to the nearest medical center. The handout should contain information on the procedures to control fever and dosing of antipyretics. Conclusion FC now are recognized as a benign syndrome with increasing reports on the molecular genetics factors. Long term management should be focused on parent education to decrease their anxiety and to teach them about home management of FC. Treatment to prevent recurrences has not been shown to prevent the later development of epilepsy. Potential risks of anticonvulsant therapy should be weighed against benefits. The majority of children with FC requires no treatment, and has an excellent prognosis. No currently available treatment that has been shown to be safe, effective and will change the outcome of FC. References 1. Campbell A, McIntosh C. Forfar and Arneil s Textbook of Pediatrics (4 th ed). Edinburgh: Churchill Livingstone, Royal College of Physician and British Pediatric Association. Guidelines for the management of convulsions with fever. BMJ 1991; 303: Commission on Epidemiology and Prognosis. International League against Epilepsy-Guidelines for epidemiologic studies on epilepsy. Epilepsia 1993; 34: Stenklyft PH, Carmona M.. Emerg Med Clin North Am 1994; 12: Annegers JF, Blakley SA, Hauser WA, Kurland LT. Recurrence of febrile convulsion in a populationbased cohort. Epilepsy Res 1990; 5: Knudsen FU. -treatment and outcome. Brain Dev 1996; 18: Berg AT, Shinnar S, Hauser WA, Leventhal JM. Predictors of recurrent febrile convulsion: a metaanalysis review. J Pediatr 1990; 116: American Academy of Pediatrics. Committee on Quality Improvement. Subcommittee on Febrile Convulsion Practice Parameter: long-term treatment of the child with simple febrile convulsion. Pediatrics 1999; 103: Clark DA, Kidd IM, Collingham KE, et al. Diagnosis of primary human herpes virus 6 and 7 infections in febrile infants by polymerase chain reaction. Arch Dis Child 1997; 77: 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:

6 Virta M, Hurme M, Helminen M. Increased plasma level of pro-and anti-inflammatory cytokines in patients with febrile convulsion. Epilepsia 2002; 43: Tilgen N, Pfeiffer H, Cobilanschi J, et al. Association analysis between the human interlukin 1 beta (-511) gene polymorphism and susceptibility to febrile convulsion. Neurosci Lett 2002; 334: Al-Qudah AA. Value of brain CT scan in children with febrile convulsions. J Neurol Sci 1995; 128: Hirtz DG, Nelson KB, Ellenberg JH. Seizures following childhood immunizations. J Pediatr 1983; 102: Iwasaki N, Nakayama J, Hamano K, Matsui A, Arinami T. Molecular genetics of febrile convulsion. Epilepsia 2002; 43 Suppl 9: Mukherjee A, Mukherjee A. -an overview. J Indian Med Assoc 2002; 100: Johnson EW, Dubovsky J, Rich SS, et al. Evidence for a novel gene for familial febrile convulsions, FEB2, linked to chromosome 19p in an extended family from the Midwest. Hum Mol Genet 1998; 7: Gerard F, Pereira S, Robaglia-Schlupp A, Genton P, Szepetowski P. Clinical and genetic analysis of a new mutigenerational pedigree with GEFS+. Epilepsia 2002; 43: Nabbout R, Prud homme JF, Herman A, et al. A locus for simple pure febrile convulsion maps to chromosome 6q22-q24. Brain 2002; 125: Kananura C, Haug K, Sander T, et al. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch Neurol 2002; 59: Doose H, Maurer A. Seizure risk in offspring of individuals with a history of febrile convulsion. Eur J Pediatr 1997; 156: Shinnar S, Glauser TA.. J Child Neurol 2002; 17 Suppl 1: S Lewis HM, Parry JV, Parry RP, et al. Role of viruses in febrile convulsion. Arch Dis Child 1979; 54: Burhanoğlu M, Tütüncüoğlu S, Coker C, Tekgül H, Özgür T. Hypozincaemia in febrile convulsion. Eur J Pediatr 1996; 155: 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: Çaksen H, Öner AF, Arslan Ş, Kan MC, Cesur Y, Üner A. Immunoglobulin subgroup in children with febrile convulsion. Pediatr Int 2001; 43: Verity CM, Golding J. Risk of epilepsy after febrile convulsion: a national cohort study. BMJ 1991; 303: Fukuyama Y, Seki T, Ohtsuka C, Miura H, Hara M. Practical guidelines for physicians in the management of febrile convulsion. Brain Dev 1996; 18: Scheffer IE, Berkovic SF. Generalized epilepsy with febrile convulsion plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 1997; 120: Tarkka R, Paakko E, Pyhitinen J, Uhari M, Rantala H. and mesial temporal sclerosis: No association in a long-term follow-up study. Neurology 2003; 60: Knudsen FU, Paerrgaard A, Andersen R, Andresen J. Long-term prognosis in febrile convulsion with and without prophylaxis. Ugeskr Laeger 1997; 159: (in Danish). 32. Hamati-Haddad A, Abou-Khalil B. Epilepsy diagnosis and localization in patients with antecedent childhood febrile convulsions. Neurology 1998; 50: Berkovic SF, Scheffer IE. : Genetics and relationship to other epilepsy syndrome. Curr Opin Neurol 1998; 11: Kolfen W, Pehle K, Konig S. Is the long-term outcome of children following febrile convulsion favorable? Dev Med Child Neurol 1998; 40: Gordon KE, Dooley JM, Camfield PR, Camfield CS, MacSween S. Treatment of febrile convulsion: the influence of treatment efficacy and side-effect profile on value to parents. Pediatrics 2001; 108: Visudtibhan A, Chiemchanya S, Visudhiphan P, Kanjanarungsichai A, Kaojarern S, Pichaipat V. Serum diazepam level after oral administration in children. J Med Assoc Thai 2002; 85 Suppl 4: S