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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 differential diagnosis of FS and depend on the presence of seizures and a patient’s 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 fluid 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 defines 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 2–3 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. Ó 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 definite causative disease, such as central nervous system (CNS) infection, metabolic abnormality, intoxication etc. FS is almost always convulsive and generalized,

*

Tel.: +81 42 341 2711; fax: +81 42 346 1705. E-mail address: sugaik@ncnp.go.jp

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 5.5–8.3% [3]. One survey of all 10,391 children in all nursery schools in Kawasaki City, close to Tokyo,

0387-7604/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2009.09.019

CNS infection rather than FS should be suspected. midazolam. 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.0% in children under 1 year of age.3%. Among the differential diagnoses of FS. and Ichiyama et al. If i. and as high as 12. 1) [9]. treatment of convulsions. 1. In children without seizures but who have altered consciousness. treatment of high fever. 10. FS is the most commonly seen major neurological disorder. CNS infections. and vaccination. seizure. intravenous (i. MDL. including meningitis and encephalitis/encephalopathy. are particularly important. Acute management of febrile seizures on arrival in the emergency room. Nature of FS It is essential for the good chronic management of FS that the parents or guardians understand the nature of FS.4% in those under 4 years of age. Sz. If the child has no seizures and fully recovers consciousness. reported marked efficacy of a single dose of CBZ at 5 mg/kg in preventing clusters of seizures in patients with CwG [10]. with the exception of children who may develop convulsions with gastroenteritis (CwG) associated with fever. he/she can go home after a physical examination. with a gradual increase in cumulative prevalence with increasing age: 1.v. . In Japan. counseling parents or guardians. 2.0% in those under 3 years of age. 5 mg/kg.v. FS accounted for 60% of 267 patients with seizures in one emergency room [5]. 8. diazepam.2. because up to 80% of patients with CwG tend to have clusters of seizures. In terms of the pediatric emergency setting. Tx. 2. convulsions with gastroenteritis. For these cases. When seizures are ongoing. magnetic resonance imaging (MRI) and/or cerebrospinal fluid (CSF) examinations are recommended. CwG. Fig. DZP fails to stop the seizures. 70% of 167 patients admitted to hospital because of status epilepticus [6]. treatment. to reduce their anxiety or fear and to enable them to cope with episodes of FS. 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. the child should be hospitalized and receive treatment for status epilepticus [9]. if the child has one or more of the findings listed in Table 2. and 57% of 201 patients with prolonged (>15 min) or clustered (>3 seizures/24 h) seizures [7]. In these cases.0% in those under 5 years of age. 6. it is prudent to administer a single dose of carbamazepine (CBZ).1. DZP. Seizure characteristics and physical findings as listed in Table 2 should be evaluated and. guideline has been proposed for the chronic management of FS to prevent their recurrence [8]. close observation and some laboratory examinations are required. Acute management includes treatment of persistent seizures and the differential diagnosis of seizures.1% in children aged 5 and 6 years [4]. Sugai / Brain & Development 32 (2010) 64–70 65 reported a prevalence of FS of 9.) administration of diazepam (DZP) is mandatory. and investigation of the causes of the seizures and fever. computed tomography (CT). FS requires both acute and chronic management. 11. Differential diagnosis of FS Table 1 outlines the procedures for the differential diagnosis of FS upon arrival in a hospital or clinic.K. whereas chronic management includes prevention of recurrent FS. 3. Acute management of FS 2. Acute treatment for FS Acute management of FS in a hospital or clinic focuses on maintenance of cardiovascular/respiratory function.8% in those under 2 years of age.

cyanosis. staring. Electroencephalographic features Many electroencephalographic (EEG) features have been identified for FS by Japanese investigators. however.1. the risk of FS in siblings of patients with FS is 18–19%. headache. 3.4% and 9.6. presenting with atonia. For children with both parents having had FS. papilledema. Epileptiform discharges are detected in as many as 40–50% of affected children by the time they enter elementary school [17. Prognosis 3. 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 findings Signs of meningeal irritation: stiff neck. Epileptic discharges on the EEG of FS patients are not uncommon. Rolandic discharges are seen in 4% of FS patients [18]. The oldest child in whom FS .3% [2– 4]. compared with a rate of 29–55% (mean 34%) following a metaanalysis of the English literature [21]. no movement or no crying even after venipuncture) or prolonged for P 1 h If one or more of the above is positive. 3. eye deviation. in patients with complex or frequent FS.6. Seizure symptoms Over 90% of FS are generalized tonic or tonic-clonic.20]. Prevalence As noted above. 3. Epileptiform discharges are seen 6–11% more frequently in patients with complex FS than in patients with simple FS. CNS infection. bulging fontanelles.1. Febrile seizures CNS infections Meningitis Encephalitis/encephalopathy Influenza encephalitis/encephalopathy Reye’s encephalopathy AEFCSE (acute encephalitis with febrile convulsive status epilepticus) Acute encephalitis with biphasic seizures and late reduced diffusion AERRPS (acute encephalitis with refractory. Sugai / Brain & Development 32 (2010) 64–70 Table 1 Differential diagnosis for febrile seizures on arrival. Epileptiform discharges tend to appear at 3–5 years of age and disappear at 4–8 years of age [15. more than 50% will not experience recurrence. abnormal posture (opisthotonic posture etc. Recurrence of FS and associated risk factors Japanese studies have reported that the rate of recurrence of FS is approximately 45% [19.g. with generalized onset in two-thirds of cases and partial onset with secondary generalization in one-third of cases [14]. neurological disorders in infants and young children.3.4. The incidence of FS decreases markedly after 4 years of age and FS rarely occurs in children older than 6 years of age. Epileptiform discharges are more often detected in children aged 3 years or older. FS that occur before 6 months of age always raise the suspicion of CNS infection [11]. and parents or guardians should be made aware that FS is the most common. this compares with 20–24% for children with siblings who have FS. 3. 3.16]. 3. Family history and risk of FS Family history has an impact on the risk of FS. However.18] and in approximately 70% of children with FS by 9 years of age [17]. but not grave.13].66 K. epileptiform discharges are not correlated with the recurrence or disappearance of FS and cannot predict the later development of epilepsy. and by recurrent EEG examinations [17]. Age of onset and age at last FS FS first occurs most commonly in the second year of life (approximately 50%) and rarely before 6 months and after 3 years of age. Kernig’s sign. If neither parent has a history of FS. not febrile seizures. they are uncommon in children under 3 years of age and on EEG obtained within 1 week after the FS episode. should be suspected. or unconsciousness [1]. miosis Disturbed consciousness: severe (e. Brudzinski’s sign Signs of increased intracranial pressure: vomiting. 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.). compared with 23–31% if either parent had FS and 39– 67% if both parents had FS [12. Of patients who have had an episode of FS.5. the incidence of FS has been reported to be in the range 13–17%. Approximately 5% of FS are non-convulsive.2. 9% will experi- Table 2 Differential diagnosis between febrile seizures and central nervous system (CNS) infections. the prevalence of FS in Japan has been reported to ranging between 3.

Category 1: no medication and observation only If the patient has had only one or two episodes of FS and no warning factors. and 1–3% will experience nine or more further episodes. These two factors are associated with a 48% and 46% risk of recurrence.2. For children in whom DZP is contraindicated. The probability of developing epilepsy by 7 years of age is 1% in FS patients without any risk factors. partial seizures. The FS factors are defined as warning factors related to the recurrence of FS and include: (i) FS onset under 1 year of age. seizures lasting longer than 15 min. patients with GEFS+ have many recurrent episodes of FS and a positive family history of FS.2. Epileptic syndromes and FS Some epileptic syndromes often manifest as FS initially. On the occasion of differential diagnoses of FS and of explaining the prognosis to parents or guardians. the incidence of later epilepsy has been found to be 4. he/she should be followed up but not treated with antiepileptic medication. such as respiratory depression. excluding FS patients with prior brain dysfunction.2.K. Incidence of later epilepsy and associated risk factors The incidence of epilepsy in the general FS population ranges between 2% and 8. Recurrence occurs within 1 year after the first seizure in 70% of patients and within 2 years in 90% of patients [22]. mesial temporal lobe epilepsy (MTLE). (ii) atypical seizures (i. and 10% in patients with two or more risk factors [23]. . 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. Sugai / Brain & Development 32 (2010) 64–70 67 ence three or further episodes.5% of patients by 15 years of age. generalized epilepsy with febrile seizure plus (GEFS+).5% of patients by 10 years of age. From numerous studies on factors related to the recurrence of FS or the subsequent onset of epilepsy.2. Fukuyama) published a consensus statement and proposed practical guideline for physicians in the management of FS [8]. respectively [23]. the guideline divides patients with FS into three categories for treatment with either no medication.1. prolonged seizures for >15 min. the Committee introduced two types of warning factors. and lethargy. are very rare. 4. atypical seizures (partial seizures. Epilepsy develops in 2–3% of FS patients by 5–7 years of age.7% [26].6. 4.2. Of patients positive for either of these two factors. in 5. 2% in patients with one EP factor (=34% of the FS population). Table 3). but serious side effects. bradycardia. approximately 50% will have recurrent FS [21].26]. or recurrent seizures within a 24-h period). 6–8% will experience four or more further episodes.e. in 4. and childhood absence epilepsy. 3. and hypotension. 4. and (ii) a family history of FS in one or both parents.8% [18. These include severe myoclonic epilepsy in infancy (SMEI). Proposed guideline for the prevention of recurrent FS in Japan Depending on the presence of warning factors. 3. The risk factors for FS recurrence include onset of FS at age <1 year and a positive family history of FS in the parents. Prevention of recurrent FS The Task Committee of The Conference on Febrile Convulsions (Chair: Y.6. and in 7% of patients by 25 years of age [26].25]. namely those related to the onset of epilepsy (EP factors) and FS factors. occur often. DZP should be given intermittently. 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). or daily medication with phenobarbital (PB) or valproate (VPA. the term “warning factors” has been used instead of “risk factors” to designate useful parameters for selecting patients who should be monitored carefully. 4. a chloral hydrate suppository can be used as an alternative medication. epilepsy with grand mal seizures. or recurrent seizures within a 24-h period). intermittent DZP. However. and some frontal lobe epilepsy (FLE) presenting with tonic seizures. including benign childhood epilepsy with centrotemporal spike.24. 4.1. The EP factors consist of: (i) neurological abnormalities or developmental retardation before the onset of FS. though it is less effective than DZP suppository [27]. The risk factors for the development of later epilepsy include neurological abnormalities or developmental delay before the onset of FS. agitation. Category 2: intermittent prophylactic administration of DZP If the patient has any of the three conditions listed under Category 2 in Table 3. and patients with FLE tend to have clustered tonic seizures with febrile episodes. 2% in patients with one risk factor. and a positive history of epilepsy in parents or siblings [23. Warning factors In the guideline. this relationship between specific epileptic syndromes and FS should be kept in mind. and 10% in patients with two or more EP factors (=6% of the FS population) [23].3. such as mild ataxia. Transient side effects of DZP administration. Patients with SMEI and MTLE have recurrent FS status since early infancy. Other idiopathic epileptic syndromes also have a relatively frequent past history of FS.

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 3–5 mg/kg/day.g. During a mean follow-up of 1. however. or valproate 20–30 mg/kg/day. side effects of phenobarbital include hyperactivity.3. it may not be effective in preventing the development of later epilepsy.3. Use of antipyretic drugs The efficacy of administering antipyretic drugs during febrile episodes for the prevention of recurrent FS has not been demonstrated. or four over the course of 1 year) Treatment: When a child has a temperature of 37. The emergency preventive use of DZP during an acute febrile episode reduces the relative risk of FS recurrence by 44%. the dosage should be increased to the recommended dose from the third week. the rate of failure to prevent FS occurrence was 7. 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 (<38.5% [29]. Note that the prevention of recurrent FS is divided into three categories. The duration of treatment for the prevention of recurrent FS should be limited to 1–2 years.9 years. agitation. Longterm PB therapy appears to influence cognition and behavior and VPA may cause liver dysfunction.10 with DZP. in one or two divided doses. If the fever persists for >8 h after the first dose. and sedation or somnolence at high therapeutic concentrations. Side effects of intermittent diazepam (DZP) include transient ataxia. the same dose of DZP can be given again. A third dose may be given 24 h after the first dose if the fever persists. namely observation. depending on the warning factors.5 mg/kg per dose (maximum 10 mg) should be given rectally or orally. and side effects of valproate include liver dysfunction and thrombocytopenia or hyperammonemia at high therapeutic concentrations. Sugai / Brain & Development 32 (2010) 64–70 Table 3 Proposed guidelines for the prevention of recurrent febrile seizures (FS) in Japan. Category 3: daily anticonvulsant therapy When a child has any of the three conditions used to define Category 3 (Table 3). glaucoma. Daily anticonvulsant therapy is effective for the prevention of recurrent FS. When DZP was administered appropriately. the frequency of recurrent FS per person-years was 0. 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. three over a period of 6 months. When a DZP suppository is to be given concurrently with an antipyretic drug. irritability. in two divided doses Treatment period: Usually 1–2 years Parents or guardians should be fully informed of the side effects of the anticonvulsant drugs. 4. Adapted and tabulated from the consensus statement of The Task Committee of The Conference on Febrile Convulsions [8]. physicians should be cautious when making the decision to initiate daily anticonvulsant therapy and use an appropriate anticonvulsant at optimal dosage.2. 4. the antipyretic suppository should be given at least 30 min after the DZP suppository because concomitant rectal admin- . and lethargy. daily anticonvulsant therapy is preferable with PB or VPA. Treatment period: Usually 2 years or until 4–5 years of age Contraindications for DZP: Children with myasthenia gravis. 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. The anticonvulsants should be started initially with half the recommended dose and maintained for 2 weeks.19 for placebo [28]. compared with 0. then. 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. intermittent therapy with diazepam. DZP allergy DZP alternative: Chloral hydrate suppository (250 mg/dose for children <3 years of age. Thus. and daily medication.68 K.4–0. two episodes of FS in 12 h. Anticonvulsant levels should be monitored every 3–6 months and kept within the therapeutic range (15–30 lg/mL for PB and 50–100 lg/mL for VPA). DZP 0.5 °C or higher.

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