Brain & Development 32 (2010) 6470 www.elsevier.

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Review article

Current management of febrile seizures in Japan: An overview

Kenji Sugai *
Department of Child Neurology, National Center Hospital of Neurology and Psychiatry, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8551, Japan Received 7 April 2009; received in revised form 14 June 2009; accepted 9 September 2009

Abstract Febrile seizures (FS) require both acute and chronic management. Acute management includes the treatment and dierential diagnosis of FS and depend on the presence of seizures and a patients level of consciousness upon arrival at hospital: a patient may be discharged after physical examination if there are no seizures and no alteration of consciousness; close observation and laboratory examinations may be indicated in cases when there are no seizures but the patient exhibits altered consciousness; and intravenous diazepam (DZP) is indicated if seizures persist. Central nervous system infections should be ruled out: if the patient has signs of meningeal irritation or increased intracranial pressure, disturbed consciousness for >1 h, atypical seizures (partial seizures, seizures for >15 min, or recurrent seizures within 24 h), cerebrospinal uid examinations and/or computed tomography/magnetic resonance imaging are warranted. Chronic management includes the prevention of recurrent FS, counseling parents, and vaccination. Japanese guideline for the prevention of recurrent FS denes two types of warning factors (WF) for selecting patients who should be monitored carefully: factors related to the onset of epilepsy (EP factors) and recurrence of FS (FS factors). The EP factors consist of neurological or developmental abnormalities prior to the onset of FS, atypical seizures, and history of epilepsy in parents or siblings. The FS factors include the onset of FS before 1 year of age and a history of FS in one or both parents. The guideline recommends no medication for children with two or fewer past episodes of FS without WF; prophylactic DZP for children with prolonged FS exceeding 15 min, or two or more episodes of FS with two or more WF; and daily administration of phenobarbital or valproate for children in whom FS occur under 38 C or who have prolonged FS despite prophylactic DZP. To reduce parents anxiety, the natural history of FS should be explained. A child can be given all current vaccinations 23 months after the last episode of FS by his/her family doctor with information provided to the parents as to how to cope with fever and convulsions. 2009 Elsevier B.V. All rights reserved.
Keywords: Febrile seizure; Acute management; Chronic management; Warning factors; Guideline; Prevention; Vaccination

1. Introduction Febrile seizure (FS) is an age-related seizure disorder in infants and young children that are associated with a fever of 38.0 C or higher without evidence of any denite causative disease, such as central nervous system (CNS) infection, metabolic abnormality, intoxication etc. FS is almost always convulsive and generalized,

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but 5% are non-convulsive, presenting with unconsciousness, staring, eye deviation, atonia, or cyanosis [1]. FS is a common neurological disorder in young children, with the reported prevalence in Japan ranging between 3.4% and 9.3%. A community survey of all children under 5 years of age in Tamano City, Okayama Prefecture, reported a prevalence of FS of 3.4% [2], whereas a retrospective survey at the mandatory health screening examination of infants aged 3 years in Tokyo metropolitan districts found the prevalence of FS to be 5.58.3% [3]. One survey of all 10,391 children in all nursery schools in Kawasaki City, close to Tokyo,

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reported a prevalence of FS of 9.3%, with a gradual increase in cumulative prevalence with increasing age: 1.0% in children under 1 year of age, 6.8% in those under 2 years of age, 8.0% in those under 3 years of age, 10.4% in those under 4 years of age, 11.0% in those under 5 years of age, and as high as 12.1% in children aged 5 and 6 years [4]. In terms of the pediatric emergency setting, FS is the most commonly seen major neurological disorder. FS accounted for 60% of 267 patients with seizures in one emergency room [5], 70% of 167 patients admitted to hospital because of status epilepticus [6], and 57% of 201 patients with prolonged (>15 min) or clustered (>3 seizures/24 h) seizures [7]. FS requires both acute and chronic management. Acute management includes treatment of persistent seizures and the dierential diagnosis of seizures, whereas chronic management includes prevention of recurrent FS, counseling parents or guardians, and vaccination. In Japan, guideline has been proposed for the chronic management of FS to prevent their recurrence [8]. 2. Acute management of FS 2.1. Acute treatment for FS Acute management of FS in a hospital or clinic focuses on maintenance of cardiovascular/respiratory function, treatment of convulsions, treatment of high fever, and investigation of the causes of the seizures and fever. The acute management of FS depends on seizure status and the level of consciousness of the patient upon arrival at the hospital or clinic (Fig. 1) [9]. If the child has no seizures and fully recovers consciousness, he/she can go home after a physical examination, with the exception of children who may develop convulsions with gastroenteritis (CwG) associated with fever. For

these cases, it is prudent to administer a single dose of carbamazepine (CBZ), 5 mg/kg, because up to 80% of patients with CwG tend to have clusters of seizures, and Ichiyama et al. reported marked ecacy of a single dose of CBZ at 5 mg/kg in preventing clusters of seizures in patients with CwG [10]. In children without seizures but who have altered consciousness, close observation and some laboratory examinations are required. When seizures are ongoing, intravenous (i.v.) administration of diazepam (DZP) is mandatory. If i.v. DZP fails to stop the seizures, the child should be hospitalized and receive treatment for status epilepticus [9]. 2.2. Dierential diagnosis of FS Table 1 outlines the procedures for the dierential diagnosis of FS upon arrival in a hospital or clinic. Among the dierential diagnoses of FS, CNS infections, including meningitis and encephalitis/encephalopathy, are particularly important. Seizure characteristics and physical ndings as listed in Table 2 should be evaluated and, if the child has one or more of the ndings listed in Table 2, CNS infection rather than FS should be suspected. In these cases, computed tomography (CT), magnetic resonance imaging (MRI) and/or cerebrospinal uid (CSF) examinations are recommended. A spinal tap should be performed after the possibility of increased intracranial pressure has been excluded on the basis of clinical signs and/or CT or MRI. 3. Nature of FS It is essential for the good chronic management of FS that the parents or guardians understand the nature of FS, to reduce their anxiety or fear and to enable them to cope with episodes of FS.

Fig. 1. Acute management of febrile seizures on arrival in the emergency room. DZP, diazepam; MDL, midazolam; Tx, treatment; Sz, seizure; CwG, convulsions with gastroenteritis.

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Table 1 Dierential diagnosis for febrile seizures on arrival. Febrile seizures CNS infections Meningitis Encephalitis/encephalopathy Inuenza encephalitis/encephalopathy Reyes encephalopathy AEFCSE (acute encephalitis with febrile convulsive status epilepticus) Acute encephalitis with biphasic seizures and late reduced diusion AERRPS (acute encephalitis with refractory, repetitive partial seizures) Others Epilepsy Severe myoclonic epilepsy in infancy Generalized epilepsy with febrile seizure plus Frontal lobe epilepsy presenting with tonic seizures Others Heat stroke Dehydration Convulsions with gastroenteritis

was reported was 9 years of age [2]. In the US, FS that occur before 6 months of age always raise the suspicion of CNS infection [11]. 3.3. Family history and risk of FS Family history has an impact on the risk of FS. For children with both parents having had FS, the incidence of FS has been reported to be in the range 1317%; this compares with 2024% for children with siblings who have FS. If neither parent has a history of FS, the risk of FS in siblings of patients with FS is 1819%, compared with 2331% if either parent had FS and 39 67% if both parents had FS [12,13]. 3.4. Seizure symptoms Over 90% of FS are generalized tonic or tonic-clonic, with generalized onset in two-thirds of cases and partial onset with secondary generalization in one-third of cases [14]. Approximately 5% of FS are non-convulsive, presenting with atonia, staring, eye deviation, cyanosis, or unconsciousness [1]. 3.5. Electroencephalographic features Many electroencephalographic (EEG) features have been identied for FS by Japanese investigators. Epileptic discharges on the EEG of FS patients are not uncommon; however, they are uncommon in children under 3 years of age and on EEG obtained within 1 week after the FS episode. Epileptiform discharges tend to appear at 35 years of age and disappear at 48 years of age [15,16]. Epileptiform discharges are detected in as many as 4050% of aected children by the time they enter elementary school [17,18] and in approximately 70% of children with FS by 9 years of age [17]. Epileptiform discharges are more often detected in children aged 3 years or older, in patients with complex or frequent FS, and by recurrent EEG examinations [17]. Epileptiform discharges are seen 611% more frequently in patients with complex FS than in patients with simple FS. Rolandic discharges are seen in 4% of FS patients [18]. However, epileptiform discharges are not correlated with the recurrence or disappearance of FS and cannot predict the later development of epilepsy. 3.6. Prognosis 3.6.1. Recurrence of FS and associated risk factors Japanese studies have reported that the rate of recurrence of FS is approximately 45% [19,20], compared with a rate of 2955% (mean 34%) following a metaanalysis of the English literature [21]. Of patients who have had an episode of FS, more than 50% will not experience recurrence, 9% will experi-

Table 2 Dierential diagnosis between febrile seizures and central nervous system (CNS) infections. Seizure characteristics First seizure before 6 months of age Late seizures occurring 24 h or more after the onset of fever Atypical seizures Partial seizures Seizures longer than 15 min More than one seizure within 24 h Physical ndings Signs of meningeal irritation: sti neck, Kernigs sign, Brudzinskis sign Signs of increased intracranial pressure: vomiting, headache, bulging fontanelles, abnormal posture (opisthotonic posture etc.), papilledema, miosis Disturbed consciousness: severe (e.g. no movement or no crying even after venipuncture) or prolonged for P 1 h If one or more of the above is positive, CNS infection, not febrile seizures, should be suspected.

3.1. Prevalence As noted above, the prevalence of FS in Japan has been reported to ranging between 3.4% and 9.3% [2 4], and parents or guardians should be made aware that FS is the most common, but not grave, neurological disorders in infants and young children. 3.2. Age of onset and age at last FS FS rst occurs most commonly in the second year of life (approximately 50%) and rarely before 6 months and after 3 years of age. The incidence of FS decreases markedly after 4 years of age and FS rarely occurs in children older than 6 years of age. The oldest child in whom FS

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ence three or further episodes, 68% will experience four or more further episodes, and 13% will experience nine or more further episodes. Recurrence occurs within 1 year after the rst seizure in 70% of patients and within 2 years in 90% of patients [22]. The risk factors for FS recurrence include onset of FS at age <1 year and a positive family history of FS in the parents. These two factors are associated with a 48% and 46% risk of recurrence, respectively [23]. 3.6.2. Incidence of later epilepsy and associated risk factors The incidence of epilepsy in the general FS population ranges between 2% and 8.8% [18,24,25]. However, excluding FS patients with prior brain dysfunction, the incidence of later epilepsy has been found to be 4.7% [26]. Epilepsy develops in 23% of FS patients by 57 years of age, in 4.5% of patients by 10 years of age, in 5.5% of patients by 15 years of age, and in 7% of patients by 25 years of age [26]. The risk factors for the development of later epilepsy include neurological abnormalities or developmental delay before the onset of FS, atypical seizures (partial seizures, prolonged seizures for >15 min, or recurrent seizures within a 24-h period), and a positive history of epilepsy in parents or siblings [23,26]. The probability of developing epilepsy by 7 years of age is 1% in FS patients without any risk factors, 2% in patients with one risk factor, and 10% in patients with two or more risk factors [23]. 3.6.3. Epileptic syndromes and FS Some epileptic syndromes often manifest as FS initially. These include severe myoclonic epilepsy in infancy (SMEI), generalized epilepsy with febrile seizure plus (GEFS+), mesial temporal lobe epilepsy (MTLE), and some frontal lobe epilepsy (FLE) presenting with tonic seizures. Patients with SMEI and MTLE have recurrent FS status since early infancy, patients with GEFS+ have many recurrent episodes of FS and a positive family history of FS, and patients with FLE tend to have clustered tonic seizures with febrile episodes. Other idiopathic epileptic syndromes also have a relatively frequent past history of FS, including benign childhood epilepsy with centrotemporal spike, epilepsy with grand mal seizures, and childhood absence epilepsy. On the occasion of dierential diagnoses of FS and of explaining the prognosis to parents or guardians, this relationship between specic epileptic syndromes and FS should be kept in mind. 4. Prevention of recurrent FS The Task Committee of The Conference on Febrile Convulsions (Chair: Y. Fukuyama) published a consensus statement and proposed practical guideline for physicians in the management of FS [8].

4.1. Warning factors In the guideline, the term warning factors has been used instead of risk factors to designate useful parameters for selecting patients who should be monitored carefully, because the Committee deemed that the term risk may bring about unnecessary anxiety or fear in families and is unsuitable for use in counseling families. From numerous studies on factors related to the recurrence of FS or the subsequent onset of epilepsy, the Committee introduced two types of warning factors, namely those related to the onset of epilepsy (EP factors) and FS factors. The EP factors consist of: (i) neurological abnormalities or developmental retardation before the onset of FS; (ii) atypical seizures (i.e. partial seizures, seizures lasting longer than 15 min, or recurrent seizures within a 24-h period); and (iii) a family history of epilepsy in parents or siblings. The probability of developing epilepsy under 7 years of age is 1% in FS patients without any EP factors (=60% of the FS population), 2% in patients with one EP factor (=34% of the FS population), and 10% in patients with two or more EP factors (=6% of the FS population) [23]. The FS factors are dened as warning factors related to the recurrence of FS and include: (i) FS onset under 1 year of age; and (ii) a family history of FS in one or both parents. Of patients positive for either of these two factors, approximately 50% will have recurrent FS [21]. 4.2. Proposed guideline for the prevention of recurrent FS in Japan Depending on the presence of warning factors, the guideline divides patients with FS into three categories for treatment with either no medication, intermittent DZP, or daily medication with phenobarbital (PB) or valproate (VPA; Table 3). 4.2.1. Category 1: no medication and observation only If the patient has had only one or two episodes of FS and no warning factors, he/she should be followed up but not treated with antiepileptic medication. 4.2.2. Category 2: intermittent prophylactic administration of DZP If the patient has any of the three conditions listed under Category 2 in Table 3, DZP should be given intermittently. For children in whom DZP is contraindicated, a chloral hydrate suppository can be used as an alternative medication, though it is less eective than DZP suppository [27]. Transient side eects of DZP administration, such as mild ataxia, agitation, and lethargy, occur often, but serious side eects, such as respiratory depression, bradycardia, and hypotension, are very rare.

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Table 3 Proposed guidelines for the prevention of recurrent febrile seizures (FS) in Japan. Note that the prevention of recurrent FS is divided into three categories, namely observation, intermittent therapy with diazepam, and daily medication, depending on the warning factors. Warning factors EP factors (risk factors related to the onset of epilepsy) Neurological abnormalities or developmental retardation before the onset of FS Atypical seizures (one or more of the following) Partial seizures Seizures lasting longer than 15 min Recurrent seizures within a 24-h period Family history of epilepsy in parents or siblings FS factors (risk factors related to the recurrence of FS) FS onset under the age of 1 year Family history of FS in one or both parents Prophylactic procedures for recurrent FS Category 1: No antiepileptic medication and observation only is preferable if the child has one or two episodes of FS and no warning factors, irrespective of EP or FS factors Category 2: Intermittent prophylactic administration of DZP is recommended if the child has any of the following: History of long-lasting FS (>15 min duration) Two or more warning factors and a history of two or more episodes of FS Frequent FS over a short period of time (e.g. two episodes of FS in 12 h, three over a period of 6 months, or four over the course of 1 year) Treatment: When a child has a temperature of 37.5 C or higher, DZP 0.40.5 mg/kg per dose (maximum 10 mg) should be given rectally or orally. If the fever persists for >8 h after the rst dose, the same dose of DZP can be given again. A third dose may be given 24 h after the rst dose if the fever persists. Treatment period: Usually 2 years or until 45 years of age Contraindications for DZP: Children with myasthenia gravis, glaucoma, DZP allergy DZP alternative: Chloral hydrate suppository (250 mg/dose for children <3 years of age; 500 mg/dose for children >3 years of age) Category 3: Daily anticonvulsant therapy is preferable if the child has any of the following: History of two or more episodes of FS with a low fever (<38.0 C) History of prolonged FS lasting >15 min with the possibility that DZP may not be given in time (experience indicates that parents may fail to notice the onset of a fever prior to a seizure) History of prolonged FS lasting >15 min with a history of failed prevention in which prolonged FS have occurred despite the timely administration of DZP Treatment: Phenobarbital 35 mg/kg/day, in one or two divided doses, or valproate 2030 mg/kg/day, in two divided doses Treatment period: Usually 12 years Parents or guardians should be fully informed of the side eects of the anticonvulsant drugs. Side eects of intermittent diazepam (DZP) include transient ataxia, agitation, and lethargy; side eects of phenobarbital include hyperactivity, irritability, and sedation or somnolence at high therapeutic concentrations; and side eects of valproate include liver dysfunction and thrombocytopenia or hyperammonemia at high therapeutic concentrations. Adapted and tabulated from the consensus statement of The Task Committee of The Conference on Febrile Convulsions [8].

The emergency preventive use of DZP during an acute febrile episode reduces the relative risk of FS recurrence by 44%. During a mean follow-up of 1.9 years, the frequency of recurrent FS per person-years was 0.10 with DZP, compared with 0.19 for placebo [28]. Failure to prevent FS recurrence in the intermittent therapy group occurred mostly in patients in whom DZP had not been administered appropriately for various reasons. When DZP was administered appropriately, the rate of failure to prevent FS occurrence was 7.5% [29]. 4.2.3. Category 3: daily anticonvulsant therapy When a child has any of the three conditions used to dene Category 3 (Table 3), daily anticonvulsant therapy is preferable with PB or VPA. The anticonvulsants should be started initially with half the recommended dose and maintained for 2 weeks; then, the dosage should be increased to the recommended dose from the third week. Anticonvulsant levels should be monitored every 36 months and kept within the therapeutic

range (1530 lg/mL for PB and 50100 lg/mL for VPA). The duration of treatment for the prevention of recurrent FS should be limited to 12 years. Daily anticonvulsant therapy is eective for the prevention of recurrent FS; however, it may not be eective in preventing the development of later epilepsy. Longterm PB therapy appears to inuence cognition and behavior and VPA may cause liver dysfunction. Thus, physicians should be cautious when making the decision to initiate daily anticonvulsant therapy and use an appropriate anticonvulsant at optimal dosage. 4.3. Use of antipyretic drugs The ecacy of administering antipyretic drugs during febrile episodes for the prevention of recurrent FS has not been demonstrated. When a DZP suppository is to be given concurrently with an antipyretic drug, the antipyretic suppository should be given at least 30 min after the DZP suppository because concomitant rectal admin-

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istration of an antipyretic suppository will interfere with the early and full absorption of DZP [30]. Oral antipyretics can be given concomitantly with a DZP suppository. 5. Vaccinations 5.1. Principles of vaccination for children with FS None of the current standard vaccinations is contraindicated in children with FS. All vaccinations should be given individually under the supervision of the patients family doctor, who is responsible for providing information regarding the usefulness and potential side eects of any vaccination. The doctor should obtain consent from a childs parents or guardian before administering the vaccination and provide advice on practical measures to cope with fever and convulsions. 5.2. Criteria for vaccination Children can be given a vaccination 23 months after the last episode of FS. This period may be shortened by the family doctor depending on the childs condition and the type of vaccine to be administered. A child with a history of prolonged FS lasting >15 min should be given vaccinations under the supervision of a pediatrician or child neurologist. 5.3. Prevention of vaccination-related FS When a temperature of 37.5 C or higher develops during the risk period for fever after vaccination, a DZP suppository or oral DZP should be administered prophylactically. For example, the risk period for the development of fever after a measles vaccination is 1 12 days after the vaccination, with a particularly high risk on Days 710, compared with 16 days after diphtheria tetanus (DPT) vaccination, with a particularly high risk on Days 12. The dose and dosing regimen for prophylactic DZP after vaccination are as the same with that for FS [31]. 6. Information for parents/guardians To reduce anxiety and/or fear and to enable parents/ guardians to cope with FS, the following explanations are essential: (i) the natural history of FS, including incidence, age dependency, natural course, recurrence rate, incidence in siblings, dierences between epilepsy and FS, the probability of onset of later epilepsy, and prognosis for mental/behavioral development; (ii) measures for coping with fever and seizure episodes; and (iii) avoidance of an over-reliance on drug therapy, as well as a full explanation of appropriate choice of antiepileptic drugs and potential side eects [8].

Acknowledgement This work was supported, in part, by a Research Grant (20A-14) for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare. References
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