ELSEVIER

Brain & Development

1996; 18: 479-484

Consensus Statement

Practical guidelines for physicians in the management seizures

a Child
Neurology Institute, c/o Sanbancho TY Plaza 5F, 24 Sanbancho, Chiyoda-ku.

of febrile
e

Yukio Fukuyama aY*,Tohru Seki b, Chikaya Ohtsuka Hisao Miura d, Michiko Hara ,
b Deparhnent Juntendo d Department e Department of Pediatrics, School

of Medicine,

Tokyo 102, Japan

Keio University, Tohyo. Japan Sagamihara. Kanagawa, Japan Japan

University School of Medicine,

Urayasu Hospital, Uravasu, Chiba, Japan

Fault?, of Education. Gunma University. Maebashi.

of Pediatrics,

Kitasato University School of Medicine,

of Special Education for the Handicapped,

Received 5 May 1996; accepted 5 June 1996

Recent studies have shown that adequate medication can prevent the recurrence of febrile seizures (FS). It has also been clarified that the vast majority of, though not all, FS patients follow a benign course. Then, questions arise as to whether or not FS should be prevented, particularly in light of the risks of side effects from drugs. Which kinds of FS can be prevented, if necessary ? The guidelines presented here are aimed primarily at helping general practitioners in considering how to manage FS most appropriately. The guidelines stress that judgements should be individualized, while referring to a few specific warning factors The guidelines follow a . laissez-faire principle for the majority of FS cases, whereas intermittent therapy with diazepam and continuous medication with either phenobarbital or valproate are indicated in other limited cases meeting respective definite criteria.

Keywords;

Febrile seizure: Diazepam

suppository;

Intermittent

therapy;

Physician s

guideline;

Prophylaxis;

Risk factor: Warning

factor

1. INTRODUCTION
In 1988, the Conference on Febrile Convulsions (Chairman: Yukio Fukuyama) published Guidelines for the treatment of febrile seizures in Japanese (Shonika Rinsho (Japanese Journal of Pediatrics) 1988; 41: 16-35). The Task Committee of the Conference here proposes a newly revised version of these guidelines based on the results of subsequent investigations conducted in Japan and overseas. These measures for dealing with febrile seizures (FS) are roughly divided into primary care, understanding the nature of FS, prevention of recurrences, propriety of vaccinations, and so on. The Committee proposes the following guidelines in the hope that they will be of service to physicians as a reference in

providing the most appropriate to best counsel their families.

treatment for FS patients and how

2. DEFINITION AND INCIDENCE

FS is a seizure disorder (most commonly convulsive, but occasionally non-convulsive) occurring in infants and young children, in association with a fever of 38.OC or higher but without evidence of any definite causative disease (abnormality), such as a central nervous system (CNS) infection, metabolic abnormality, intoxication, etc. The prevalence of this disorder in Japan has been reported, almost unanimously, to be 7-8% based on data obtained in several studies [l]. Most of these investigations were, however, carried out retrospectively on the occasions of obligatory child health examinations at public health centers or primary schools. The only exception is an epidemiological study carried out by Ohtahara et al. [2] in Tamano city, Okayama prefecture, which showed a much lower figure of about 3.4% for children under the

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author. Fax: +81 Copyright

3 3238-1502.

0 1996 Elsevier Science B.V. All rights reserved

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et al. /Brain

& Deuelopment 1996; 18: 479-484

age of 5 years. In the USA and European countries, the incidence of FS is 2-5% [3] for the entire pediatric population.

3. PRIMARY

CARE when a seizure has occurred

headache, vomiting, stiff neck) around the seizure period. In cases in whom a CNS infection is suspected, confirmation should be obtained by performing a lumbar puncture. However, caution must be exercised regarding the possible presence of space-occupying lesions in the cranial cavity.

3.1. Home first-aid

4. PROGNOSIS
1. Do not panic, remain calm. 2. Loosen the subject clothing, particularly around the neck. s 3. If unconscious, place the subject in the supine position, keeping the head lower than the body, and turn the head so as to face side ways while tilted upward. Wipe off any vomit or discharge in the perioral region or nasal cavity with gauze. Although the teeth may be clenched, do not attempt to insert anything into the mouth. 4. Take the subject temperature, and observe and record the s duration (length) and features of the seizure (any differences between the right and left sides, eye deviation, etc.). 5. Do not give any drugs or fluid orally. 6. Stay near the patient until the seizure has subsided. 1. More than half of all FS patients never have a repeat seizure after the first episode, remaining seizure free for the rest of their lives. 2. The recurrence rate for FS in patients who have experienced one FS is 25-50% (average, approximately 3Os%) [4]. Cases in whom seizures recur three times or more account for 9% of the total FS population [4]. Recurrences are most common within 1 year following the first seizure, being seen in about 70% of cases, and 90% of recurrences are within 2 years [5]. 3. The incidence of epilepsy in FS patients is 2-3% [4,6] before 5-7 years of age, 4.5% [6] before the 10 years of age, and 7% [6] before the 25 years of age. 4. The estimated recurrence rate for FS, or the likelihood of developing non-febrile seizures (epilepsy), in individual cases may differ according to the presence or absence of certain warning factors as described in Section 5 below. 5. In cases in whom no neurological abnormality or developmental disturbance is immediately evident, the likelihood of major neurological abnormalities emerging later is very low. The claim raised by some investigators that the incidence of cognitive/behavioral and learning disorders in children with FS, or a history of FS, is higher than for controls, has not been generally supported by the majority [7,8], although room remains for further investigation. 6. The incidence of FS among the siblings of FS patients both of whose parents have a history of this disorder is variable, ranging from 40 to SO%, according to different sources. The occurrence risk in siblings is reportedly 20-30% for those with one FS positive parent, and about 20% for those whose parents are both FS negative [l].

3.2. Circumstances under which the patient should be immediately taken to a physician (any one of the following is applicable)
1. Cases with a seizure duration of 10 min or longer. 2. Cases with frequently repeating short-term seizures with continued disturbance of consciousness in between. 3. Cases in which seizure either occurs locally (involving only one part of the body) or is focused in one part of the body although the entire body appears to be involved (indicated as partial seizures). 4. Cases of first seizure at any age, particularly those of infants under the age of 6 months. 5. Cases in which neurological symptoms (prolonged disturbance of consciousness, postictal paralysis, and so on), in addition to fever and seizure, are present.

3.3. Emergency

treatment

in cases of prolonged

seizure
5. WARNING

1. Maintenance of respiratory/circulatory competence. 2. Inhibition of convulsion: implement immediate potential anticonvulsive treatment. The procedure for this is shown in Supplement 1. 3. Treatment for high fever. 4. Investigation of cause. Measures for dealing with the cause of fever: the most common causes of fever are viral upper respiratory tract infections, and occasionally, urinary tract infections. Other bacterial infections may also contribute at times. However, CNS infections (encephalitis/meningitis) and/or encephalopathy can induce clinical features similar to those of FS, and it is therefore important to differentiate FS from these diseases. Close attention should be paid, in particular, to cases with the first seizure occurring before the age of 6 months, cases with seizures occurring 24 h or more after the onset of fever, and those with atypical seizures as defined below (Section 5.1.21, always keeping in mind the presence or absence of any prolonged disturbance of consciousness or meningeal signs (such as

FACTORS

Numerous studies have focused on factors related to recurrent FS, and factors correlated with the subsequent onset of epilepsy. Although views differ in detail, it is important to emphasize that each case should be carefully observed and evaluated bearing these factors in mind when establishing management principles and estimating the prognosis for individual patients. It merits emphasis that, in these guidelines, the use of the term risk factors has been avoided, and the term warning factors used instead (for an explanation, refer to Supplement 21.

5.1. Warning (EP factors)

factors

related

to the onset of epilepsy

of neurological abnormalities or developmental retardation before the onset of FS. 2. Atypical seizures (i. partial seizures; ii. long-lasting seizures

1. Apparent manifestations

Y. Fukuyama et al./Brain

& DeLaelopment1996; 18: 479-484

481

of more than 15-20 min duration; iii. clustering (two or more) seizures within 24 h). 3. Family history of epilepsy in parents/siblings. The probability of manifesting epilepsy before 7 years of age is 1% in cases in whom the above factors are absent (60% of the total FS population), 2% in cases with only one positive factor (34% of the total FS population), and 10% in cases with 2-3 positive factors (6% of the total FS population) [4] (see Supplement 3).

either continuous or intermittent, and simply monitor the natural course of the seizure without treatment.

6.4. Cases for whom rectal or oral administration of diazepam as an emergency measure when feverish, that is, intermittent therapy, is recommended
For patients with any one of the following three indications, it is advisable to administer diazepam early in the event of febrile episodes.

5.2. Warning (FS factors)

factors

related

to the recurrence

of FS

6.4.1. Indications
1. FS onset under the age of 6 months. 2. Family history of FS in one or both parents. In cases in whom either one of the above factors obtains, the recurrence rate may reach approximately 50% [3] (see Supplement 4). (a) Cases in whom there is a history of long-lasting seizures, exceeding 15-20 min in duration. (bl Cases in whom two or more warning factors are present nnd who have a history of two or more FS. (cl Cases with frequent seizures occurring over a short period of time (e.g., twice in half-a-day; three or more times in 6 months; four or more times in a year).

6. PROPHYLAXIS SEIZURES

FOR

RECURRENT

FEBRILE 6.4.2. Procedures

See Supplement 5.

6.1. Health care guidance 6.4.3. Effectiveness

To reduce the frequency of febrile episodes, patients and their parents/guardians should be encouraged to pay appropriate attention to physical hygiene and, whenever necessary, remove any chronic focus of infection, and to avoid contact with infective sources. Furthermore, appropriate treatment should be administered prophylactically in cases in which the subject is suffering from a cold, and so on.

and side effects

6.2. Prevention

by anticonvulsant

medication

Several investigations have demonstrated that the continuous administration of an anticonvulsant, such as phenobarbital, primidone or valproate, is effective in preventing recurrent FS, so long as the serum concentration is kept within a therapeutic range. There are, however, a number of drawbacks to this method, such as non-compliance, economic as well as psychological burdens, and particularly, potential side effects which may far outweigh the benefits of seizure prevention. Intermittent therapy with diazepam is also effective in preventing recurrent FS, provided that it is given at the onset of febrile episodes. However, mild side effects are inevitable here, also. Thus, the decision to implement anticonvulsant therapy should be made only after due consideration of both the merits and demerits of such treatment, and with full regard to the opinion of the patient guardians. s On such occasions, the following guidelines are recommended for the physician.

It has been reported that the emergency preventive use of diazepam during acute febrile episodes decreases the FS recurrence rate by l/3. Over a study period of 2 years, the recurrence rate was 12- 14% for the intermittent therapy group in contrast to 38-45% for the control group with no treatment [9]. Furthermore, recurrent FS in the intermittent therapy group took place mostly in patients to whom diazepam had not been appropriately administered for various reasons. The actual prevention failure rate was found to be 7.5% for the total number of FS recurrences, when only recurrences in cases to whom diazepam had been appropriately administered were taken into consideration [ 101. Although it is rare to observe serious side effects under the above regimen, it is still important to give parents adequate information on any potential side effects, even if usually mild and transient, which tend to occur rather often (see Supplement 5).

6.4.4. Utility
Usage and portability of the preparation are uncomplicated, and there is also an advantage in that it can be immediately administered by the guardian. whether at home, or elsewhere. The parents/guardian may feel more at ease and obtain a sense of satisfaction from being able to contribute to the prevention of seizure recurrence by themselves, and from having appropriate means of coping with the emergency at hand. On the other hand, rigorous cautions to the user are mandatory. As this individual is most likely to be a layperson, a full explanation of the potential risks of diazepam overdosage, precipitated by panic, is essential.

6.3. Cases in which the laissez-faire principle is preferable

or wait and see

6.5. Cases in which therapy is preferable

daily

continuous

anticonvulsant

In cases without warning factors (either EP or FS factors), and in whom the total number of FS episodes remains at two or less. it is advisable to refrain from active anticonvulsant medication.

It is advisable to recommend daily oral administration of an anticonvulsant, in cases corresponding to any of the following three indications.

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6.51.

Indications

8. VACCINATIONS
None of the current standard vaccinations are contraindicated. However, all vaccinations should be given individually under the personal supervision of the patient family doctor who is respons sible for providing the necessary information regarding their utility and potential side effects. The doctor should also obtain the parents /guardian s consent beforehand and give guidance on measures for coping with fever/convulsion. Particularly, when giving a measles vaccination to a FS patient who has a family history of convulsions, including FS, or has complications such as neurological abnormalities or mental or developmental retardation, it is recommended that either of the following measures be applied; that is, (1) Oral phenobarbital is prophylactically administered daily for 22 days extending from 10 days prior to vaccination to 12 days after [12], with the aim of achieving and maintaining serum phenobarbital at a therapeutic level during the highest risk period for fever development after the vaccination, or (2) while keeping the patient under close observation with no active intervention after the vaccination, parents/physician stand ready to immediately administer a suppository or oral dosage of diazepam in the event of a fever developing, especially during aforementioned high risk period.

(a) Cases with a previous history of two or more seizure episodes occurring in conjunction with a low fever (< 38.OC). (b) Cases with a previous history of prolonged FS lasting more than 15-20 min, and, in addition, in whom there is the possibility that the diazepam may not be given in time, as previous experience has shown that parents may fail to notice the onset of fever prior to a seizure. (c) Cases with a previous history of prolonged FS lasting more than 15-20 min, and, in addition, a history of failed prevention in which prolonged FS have occurred despite the timely administration of diazepam.

6.5.2. Procedure See Supplement 6.5.3. Effectiveness

6.

and side effects

Daily continuous anticonvulsant therapy is as effective for the prevention of recurrent FS as is emergency therapy with diazepam during febrile episodes. However, such therapy would not be effective for the prevention of evolving afebrile seizures (meaning epileptic seizures). which can subsequently occur. However, the use of a single appropriate drug at the optimum dosage would decrease side effects to a minimum, making significant adverse reactions rather more rare. Therefore, it is strongly recommended that the physician be circumspect and applies caution in reaching a decision.

9. ESSENTIAL

POINTS

OF

GUIDANCE

FOR

PAR-

ENTS / GUARDIAN (il. Explanation of the characteristics of FS (incidence, age dependency, recurrence rate, incidence in siblings, difference between epilepsy and this disorder, prognosis for onset of epilepsy, prognosis for mental/behavioral development). (ii). Measures for coping with fever as well as seizure episodes. (iii). Explanation of why over-reliance on drug therapy should be avoided and of the side effects of drugs. In giving guidance, it is advisable to provide an explanatory booklet or leaflet along with a verbal explanation. The authors are deeply grateful to every member of the Conference on Febrile Convulsion for their active participation in consensus development and for their expert review and critique
ACKNOWLEDGEMENTS of the manuscript. Special thanks are addressed to the following colleagues who made enormous contribution to this work and kindly agreed to publicize their names as collaborators: Dr A Abe (Teikyo University, Tokyo), Dr Y Awaya (Seibo Hospital, Tokyo), Dr H Horita (Jikei University 3rd Hospital, Komae). Dr T Ishikawa (Nagoya City University, Nagoya), Dr H Koide (Saitama Medical School, Higashimoro). Dr K Komiya (Tokyo Metropolitan Neurological Hospital, Fuchu), Dr T Konishi (Toyama Medical & Pharmaceutical University, Toyama), Dr K Maekawa (Jikei University, Tokyo). Dr T Matsumoto (Matsumoto Clinic for Children, Fukuoka), Dr S Miyake (Yokohama Ryoikuen, Yokohama), Dr T Nagai (Osaka University, Osaka), Dr M Osawa (Tokyo Women Medical College, Tokyo), Dr K s Sumi (Osaka Kohsei Nenkin Hospital. Osaka), Dr H Wada (Kenwakai Hospital, Iida).

6.5.4. Utility
The utility trust between economic and family, should of this therapy depends significantly on mutual physician and parents. Compliance, along with practical burdens for the patient and his/her not be overlooked.

6.6. Cases in which recommended therapy remains unspecified and it is advisable that therapy be decided on an individual basis
If a case does not come under any of the aforementioned indications (6.3., 6.4., and 6.5.1, the selection of treatment should be based on decisions made jointly by the patients guardian(s) and the attending physician.

7. USAGE OF ANTIPYRETIC

DRUGS

The effectiveness of administering antipyretic drugs during febrile episodes for the prevention of recurrent FS has not been demonstrated. Although antipyretic drugs may be necessary for the relief of discomfort associated with high temperatures, overuse should be avoided and only minimum requisite doses administered. In cases in which a diazepam suppository is to be given concurrently with an antipyretic drug, it is advisable that the antipyretic drug be given either orally or as a suppository 30 min or more after the administration of a diazepam suppository. The concomitant rectal administration of an antipyretic suppository may interfere with early absorption of the diazepam, if the above procedure is not followed [l 11.

Appendix

Papers presented at the 17 consecutive Conferences on Febrile Convulsions, held annually in Tokyo since 1978, were published

Y. Fukuyama et al./Brain & Development 1996; 18: 479-484

Table 1 Publications from the Conference on Febrile Conuulsions, Tokyo, 1978- I995

483 resuscita-

Care-givers should be ready to apply cardiopulmonary tion measures whenever indicated.

Annual conference

English proceedings (abstracts) published

in Brain & Development

Selected original papers published in Japanese

in special issues of Shonika Rinsho (Jpn J Pediatr) (Tokyo) 1979; 32: 577-87,599-681 _

1st (1978) 2nd (1979) 3rd (1980) 4th (1981) 5th (1982) 6th (1983) 7th (1984) 8th ( 1985) 9th (1986) 10th (1987) llth(1988) 12th 13th 14th 15th 16th 17th 18th (1989) (1990) (1991) (1992) (1993) (1994) (1995)

1981; 1982; 1983; 1984; 1985;

3: 4: 5: 6: 7:

103-9 305-I 1 338-43 66-73 253-60

1986: 8: 557-66 1988; 10: 197-205 1988: 10: 333-41 1989: 11: 266-76 1990; 1991; 1992; 1993; 1994; 1995: 1996; 12: 13: 14: 15: 16: 17: 18: 538-46 203-11 188-96 390-7 339-46 383-9 471-8

1984; 1985; 1987; 1987; 1988; 1988; 1989; 1989; 1990: 1991; 1992; 1993; 1994; 1995; 1996; 1996;

37: 38: 40: 40: 41: 41: 42: 42: 43: 44: 45: 46: 47: 48: 49: 50:

2223-328 2225-82 53-8 7-45 16-68 1983-2010 1013-8 2368-442 863-7 7-52 6-44 214-71 231-74 7-28 197-280

Supplement 2. Risk factors and warning factors Currently, the term risk factors is widely used in the medical literature to designate factors pertaining to the prognosis of recurrent FS or the onset of epilepsy. The expression risk may be scientifically proper, but it carries a connotation which engenders an unnecessary sense of crisis in laypersons and is deemed unsuitable for use in consultation with families. In this document, therefore, the term warning factors has been adopted to designate useful parameters for selecting those patients who should be carefully monitored. Supplement 3. Significance of EP factors The implications of the three EP factors differ according to the type of evolving epileptic seizure. Partial seizure is strongly related to atypical seizures (EP factor 2). In cases in which all of the subitems (i-iii) of EP factor 2 concerning atypical seizures are applicable, the incidence of partial epilepsy is anticipated to reach 50% before adulthood (in this circumstance, the duration of subitem ii would be 30 minutes or more) [6]. However, such cases account for only 1% of the total FS population. On the other hand, generalized seizures are strongly related to EP factor 3, that is, a family history of epilepsy, and recurrent FS numbering 3 or more episodes [6]. However, the presence of a single factor, such as frequently recurring FS, onset under the age of 6 months, or gender, bears little relation to the onset of epilepsy. Paroxysmal discharges seen on an electroencephalogram (EEG) are generally considered to be a significant EP factor in Japan, although it is also stressed that it is necessary to take into consideration the characteristic features of paroxysmal discharges (e.g.. benign Rolandic discharges are disregarded in most cases> [13]. In the USA and European countries, however, many hold the view that EEG findings are not useful in predicting either recurrent FS or the onset of epilepsy, although data contradicting this view have been reported. Supplement 4. Significance of FS factors The effect of a positive FS history in siblings on the likelihood of FS recurring is controversial [3]. Although none of the above described EP factors has a significant effect on the recurrence of FS, one view holds that the recurrence rate increases in cases with a combination of FS factors pertaining to items 1 and 2 [Sl. Supplement 5. Procedure for the emergency administration of diazepam during febrile episodes (1) Drug: the drug of first choice should be a diazepam solution for rectal use, which has a property of quick and reliable absorption. In Japan, however, it is not available, and as an alternative, a rectal diazepam suppository (products: 4 mg, 6 mg, 10 mg of DiappR suppository, Wakodo Co, Tokyo), or an oral dosage of diazepam (products: powder, tablets, syrup of CercineR or HorizonR1 is used. (2) Dosage: a 0.4-0.5 mg/kg/dose should be given by suppository or orally. (3) Usage: (i) The patient physician should determine the s appropriate dosage, and provide an appropriately adjusted diazepam preparation for the parent/guardian. (ii) In cases in

either as English abstracts or original articles in Japanese or both, as shown in Table 1.

Supplement 1. Emergency drug therapy for convulsions (status epilepticus) (a) First-step procedure: Intravenous diazepam (products: CercineR (Takeda Pharmaceut Co, Osaka), HorizonR (Yamanouchi Pharmaceut Co, Tokyo)) 0.3 mg/kg (or 1 mg X years of age + 1 mgl should be administered slowly over 2-3 min while closely monitoring respiratory conditions. If this protocol is effective, the seizure should subside during the course of the injection. If the seizure is refractory, the same dosage may be repeated, either consecutively or after a lo-mm interval of observation, again with full attention being paid to respiration/pulse. (b) Second-step procedure: Patient should be hospitalized for treatment and given an intravenous administration of phenytoin (product: AleviatinR, Dainippon Pharmaceut Co, Osaka) when: (1) the aforementioned first-step treatment is ineffective in controlling seizures; and (2) seizure relapse occurs one to several hours after the administration of diazepam, owing to its characteristically rapid but short duration of action. Therefore, in cases of serious status epilepticus, long-acting phenytoin should be given intravenously subsequent to the aforementioned first-step treatment. 15-20 mg/kg of phenytoin should be given slowly by intravenous drip infusion over 20-30 min while monitoring closely for arrhythmia or any decrease in blood pressure. cc) Other procedures: In cases of status epilepticus, treatment is best given by securing a venous line and vital signs and intracranial pressure should be carefully monitored. When seizures are intractable despite the above measures (diazepam, phenytoin). more potent drugs such as general anesthetics can be used.

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which there has been a febrile episode at a temperature exceeding 375C the parent/guardian should promptly administer either a rectal suppository or an oral product. If the fever continues for up to 8 h after the first dose, the same dosage of diazepam may be repeated. Usually, the administration of diazepam is limited to two doses [lo]. A third dose may be given if the situation demands, but only if 24 h have elapsed since the first dose [14]. (4) Side effects: Mild ataxia, agitation or lethargy often occur transiently, but serious side effects, such as respiratory depression, bradycardia or hypotension, are rare. (5) Treatment period: Usually, a period of 2 years or until the age of 4-5 years, is the landmark for this therapy. (6) In cases in whom it is difficult to use diazepam (myasthenia gravis, glaucoma, diazepam allergy, etc.), a chloral hydrate suppository may be used alternatively (products: EscreR suppository, SS Pharmaceut Co, Tokyo; 250 mg/dose, under 3 years of age; 500 mg/dose, 3 years of age or over). Supplement 6. Procedure for daily continuous anticonvulsant therapy (1) Drugs, dosage, usage: Phenobarbital (products: PhenobalR (Fujinaga Pharmaceut Co, Tokyo) or PhenobarbitalR in bulkpowder, powder or elixir form) 3-5 mg/kg once or twice a day, or sodium valproate (products: DepakeneR (Kyowa Hakko Kogyo Co, Tokyo), HyserenineR (Kanebo Co, Tokyo) or ValerinR (Dainippon Pharmaceut Co, Osaka) in fine granule or syrup form) lo-15 mg/kg bid, should be administered orally on a daily basis. However, over the first two weeks, this dosage should be half of that stated above, and from the third week onward, the dosage is increased so as to reach the amount described above. (2) Blood concentration: This should be monitored every 3-6 months, and kept within therapeutic ranges (phenobarbital 15-30 p,g/ml, valproic acid 50-100 kg/ml). (3) Side effects: Phenobarbital may cause lethargy, short attention span, and hyperkinesis. Valproate may cause thrombocytopenia, and particularly in young infants, liver dysfunction, hyperammonemia, or Reye-like syndrome. (4) Duration of treatment: For the prevention of recurrent FS, the duration of therapy should be limited to l-2 years. Supplement 7. Books on febrile seizures published after 1980 1. Nelson KB, Ellenberg JH, eds. Febrile seizures. New York: Raven Press, 1981. 2. Wallace SJ. The child with febrile seizures. London: Wright, 1988.

3. Fukuyama Y, ed. Febrile seizures: recent aduances (in Japanese). Tokyo: Nihon Shoni Iji Pub1 Co, 1991. 4. Nihei K, ed. Febrile seizures (in Japanese), New mook of pediatrics series No 2. Tokyo: Kanehara Pub1 Co, 1992.

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1. Kagawa K, Fukuyama Y. Prevalence and genetics of febrile seizures. In: Nihei K, ed. Febrile seizures (in Japanese), New mook of pediatrics series No 2. Tokyo: Kanehara Pub1 Co, 1992: 23-35. 2. Ohtahara S. Ishida S, Yamatogi Y, Oka E, Yoshida H, Matsuda M. Studies on febrile convulsions: 1. A neuroepidemiologic investigation on febrile convulsions in Tamano City, Okayama Prefecture (in Japanese). No Kenkyukai Kaishi (Jpn J Neurosci Res Assoc) (Tohyo) 1984; 6: 365-72. 3. Berg AT, Shinnar S. Hauser WA, Leventhal JM. Predictors of recurrent febrile seizures: a metaanalytic review. J Pediatr 1990; 116: 329-37. 4. Nelson KB, Ellenberg JH. Predictors of epilepsy in children who have experienced febrile seizures. N Engl JMed 1976; 295: 1029-33. In: Dam, M.. Gram, L., eds. 5. Knudsen FU. Febrile convulsions. Comprehensirle epileptology. New York; Raven Press, 1990: 133-43. 6. Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 1987; 316: 493-8. I. Ellenberg JH, Nelson KB. Febrile seizures and later intellectual performance. Arch Neural 1978; 35: 17-21. 8. Ross EM, Peckham CS. West PB, Butler NR. Epilepsy in childhood: findings from the national child development study. Br Med J 1980; 280: 207- 10. 9. Rosman NP. Febrile seizures. In: Resor SR, Kutt H. eds. The medical treatment of epilepsy. New York. Base1 Hong Kong: Marcel Dekker, 1992: 133-43. 10. Miura H. Prevention of recurrent febrile convulsions. In: Nihei K, ed. Febrile seizures (in Japanese). New mook of pediatrics series No 2. Tokyo: Kanehara Pub1 Co, 1992: 88-104. 11. Takei K, Miura H, Takanashi S. et al. The effects of concurrent rectal administration of an antipyretic on the rectal aborption of diazepam suppositories: a pharmacokinetic study in children with febrile convulsions (in Japanese). Shonika Rinsho (Tokyo) 1996; 49: 245-52. 12. Matsumoto T. Vaccinations in children with febrile seizures: measures taken by clinicians with respect to contraindications tin Japanese). Nihon rji Shinpo (Tokyo) 1986: 3241: 43-9. 13. Yamatogi Y, Ohtahara S. EEG in febrile convulsions. Am J EEG Technol 1990: 33: 267-80. 14. Minagawa K. Miura H, Mizuno S, Shirai H. Pharmacokinetics of rectal diazepam in the prevention of recurrent febrile convulsions. Brain Dee(Tokyo) 1986; 8: 53-9.