Abstracts from the 11th conference on febrile convulsions, Tokyo, December 17, 1988

PROCEEDINGS

Abstracts from the 11th Conference on Febrile Convulsions, Tokyo, December 17, 1988 Compiled by Yukio FukuYama, MD Department of Pediatrics, Tokyo Women's Medical College, Tokyo

INVITED SPECIAL LECTURE Physiological Problems in Fever Research AtD Department of Physiology, Yamanashi Atedical College, Yamanashi

AtasamiIrik~

Exogenous pyrogens, such as endotoxin, activate immupeactive cells, such as leukocytes and macrophages, which produce an endogenous pyrogen (EP). EP act on the thermoregulatory center via a mediator. As a result, heat loss is decreased, e.g., through cutaneous vasoconstriction, and heat production is increased, through shivering or nonshivering thermogenesis. Consequently, the body temperature rises. Recently it was found that interleukin 1 (IL-l), interferon and tumor necrosis factor act as EP. The most likely mediator is prostaglandin E2 (PGE 2), as suggested by the finding that antipyretics, such as indom~thacin, prevent the fever. However, it is not known whether or not IL-l passes through the bloodbrain-barrier (BBB) and directly causes glia cells in the brain to produce PGE 2. The orgasum vasculosum laminae terminalis (OVLT) is located within the rostral wall of the third ventricle in close connection, to either side, with the median septal and preoptic areas. Within the OVLT, IL-l can pass through the BBB or IL-l can induce the production of PGE 2. The core temperature rarely rises above 41.5°C because of the effects of endogenous antipyretics. Arginine vasopressin (AVP), adreno-cortico-stimulating hormone (ACTH) and a-melanocyte stimulating hormone (a-MSH) act as endogenous antipyretics. The concentrations of these substances in the blood and brain increase during fever. The body temperature is increased by injection of these substances into the ventral septal area (VSA). In addition, the administration of an endotoxin, EP,

All correspondence and reprint requests should be addressed to: Prof. Yukio Fukuyama, Department of Pediatrics, Tokyo Women's Medical College, 8-1 Kawadacho, Shinjuku-ku, Tokyo 162, Japan.

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or IL-l, induces various physiological responses, such as neurohumoral responses, acute phase reactions, immune responses, behavioral responses, prostaglandin synthesis and collagenase synthesis. Therefore, fever research is no longer concerned primarily with the changes in temperature regulation responsible for the febrile alteration of temperature regulation, but also aims at elucidation of the contributions made by both thermal and non-thermal components of the physiological responses to the defence of the host against the microbial intruders responsible for these responses with fever.

Reference Iriki M. Fever and fever syndrome - Current problems. Jpn J Physiol (Tokyo) 1988;38:122-50. Key words: Fever, pyrogens, PGE2 , interleukin 1.

FREE COAtAtUNICATIONS

1 Epidemiologic Study of Febrile Convulsions Based on Screening at the Fukagawa Health Center Hiroko Ataeda, AtD, Kihei Ataekawa, AtD, Koumei Kumagai, AtD, Yukiko Hiraizumi and Ichiro Shimamura, AtD Department of Pediatrics, Jikei University School of Atedicine, Tokyo (HAt, KAt); Department of Pediatrics, General Rehabilitation Center of Kanagawa Prefecture, Kanagawa (KK); Fukagawa Health Center, Koto-ku, Tokyo (YH, IS) There are no common ideas as to how we, as physicians, should treat children who have had febrile seizures. Therefore we examined the actual condition of our patients.

Materials and Atethods The study involved children born in Fukagawa, Koto-ku, Tokyo, between August 1 and November 30, 1981. According to their 3-year-old screening records, we sent them each a question by mail when they became 6 years old. Results The collection rate was 75.3% (355/471), ignoring the children who were transferred. Of the 355 remaining children, 33 (9.30%) had a history of febrile seizures. The prevalence rate of boys was 8.12% (16/197) and that of girls was 10.76% (17/158). Regarding the number of seizures, 53.6% of the chil-

dren with FC did not have subsequent seizures. 53.6% of the FC children didn't have a family history. There's no distinct relationship between a family history of FC and the risk of recurrence. A family history of afebrile convulsions was a relative risk factor for subsequent seizures. Most children had seizures in two minutes of duration and temperatures above 39°C. Long time seizures and low grade fever increase the risk of recurrence. The most likely age of onset is one to two years old. An early onset increases the recurrent risk. None of the children had focal seizures in our study. 46.4% of them were subjected to EEG examination. 39.2% of them were given anticonvulsant agents, but they were not always effective.

Conclusion It is suggested that the prognostic factors are a family history of epilepsy, an early onset, long time seizures and a low grade fever. Key words: Febrile convulsions, prevalance, risk factor for subsequent seizures.

was no difference in the developmental course or physical development. The incidence of a family history of FS was high in the FS group (33.9% vs 3.3%; p < 0.01).

Comments To discuss the occurrence of FS, a population-based study is necessary to determine the correct incidence. In this study, we examined 94.4% of the children in a part of Bunkyo-ku, Tokyo. Then, the occurrence rate of FS (6.5% in males and 5.3% in females) must be reliable. Compared to previous studies, the rate did not show significant changes. The recurrence of FC in our study (35.6%) was examined at 3 years old and FCs thereafter were not included. The recurrence was low compared to previous studies, including on the whole childhood. The ratio of the simple/complex types, according to Fukuyama's criteria, was higher than previously reported by two folds. At present, the reason is not known. Anyway, a population-based study is expected with a large population and a long observation period. We will continue this line of study among a larger population with a longer observation. Key words: Febrile seizures, prevalence, population-based study.

2 Febrile Seizures at Age 3 Years Mikio Hiraiwa, MD, Noriaki Funamoto, MD, Hisashi Yamada, MD, Mikiko Mishima, MD, Chizuru Nonaka, MD, Kazuhiko Ohmi, MD, Toshiaki Abe, MD, Masaaki Kobayashi, MD, Kuniko Hayashi and Akiko Sasaki, MD Department of Pediatrics, Teikyo University School of Medicine, Tokyo (MH, NF, HY, MM, CN, KO, TA, MK); Koishikawa Health Center (KH, AS), Tokyo To determine the incidence of febrile seizures (FS) at age 3 years, a population-based study was performed for a part of Bunkyo-ku, Tokyo. The subjects were 1,052 children born between May 1984 and August 1986 within the area. Among the 1,052 children, 993 (94.4%) answered the questionnaires concerning seizure disorders. The questions concerned the following items: the occurrence of seizures before 3 years of age, body temperature at the time of seizures, a family history of seizures and neurological illness, perinatal problems, developmental problems and so on. Out of the 993 children, 67 (6.7%) had seizures before 3 years old. Fifty-nine children (5.9%) were judged as having FS. Epilepsy was identified in 4. A mild difference in sex was noted in the occurrence of FS. The rates of occurrence were 6.5% in males and 5.3% in females. The first FSs were observed most frequently between 12 and 24 months. The rate of recurrent FSs before age 3 years was 35.6%. The frequency of seizures was between one and thirteen times. According to Fukuyam a's criteria, the 59 children were divided into two groups; simple and complex types. Two thirds of the children with FS were classified as simple type. The recurrence of FS was significantly high in the complex type (p < 0.05). Between children with FC and controls, there

3 A Clinical Study of Exanthema Subitum with Frequent Convulsive Attacks Hiroshi Takahashi, MD, Kenichiro Kaneko, MD, Masafumi Kaneko, MD, Shoko Urata, MD, Yasuko Sato, MD, Hisakuni Yoshida, MD, Mariko Ohkubo, MD, Chikako Kanazawa, MD and Chikaya Ohtsuka, MD Department of Pediatrics, luntendo Urayasu Hospital, luntendo University, Urayasu, Chiba Exanthema subitum (ES) is known as a common febrile disease with a good outcome. When ES has been complicated by febrile convulsions (FC), the FC have been considered to be of a simple type. We experienced 2 cases of ES with frequent convulsive attacks, which were not considered to be a simple type of FC, and 3 cases of ES with other neurological complications. We think that ES with FC might not always have a good outcome.

Subjects The clinical subjects consisted of 5 children aged from 7 to 10 months (1 female and 4 males). The family and past histories were not contributory. Results The neurological findings in each case were as follows: hyperirritability (case 1), apathetic state and chill (case 2), bulging of the anterior fontanel (case 3) and frequent convulsions (7 times) (cases 4 and 5), respectively. The neurological complications appeared 4 days (case 1) and 2 days (cases 2 and 3) after onset. In case 4, 4 GTCs lasting 30 seconds to a few minutes occurred at 38-39°C, one

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GTC lasting one minute occurred at 37.2°C 2 days after onset, and 2 myoclonic attacks lasting 2 minutes 30 seconds and 3 minutes 30 seconds, respectively occurred at 37.3°C 3 days after onset. In case 5, a tonic convulsion lasting 3 minutes occurred at 39°C 2 days after onset. Three tonic convulsions lasting 3 minutes at 36.5°C, a left sided clonic convulsion lasting 30 seconds at 36.4°C, and a right sided tonic convulsion, developing generally, lasting 5 minutes at 36.5°C occurred 6 days after onset. CSF examination revealed high pressure (200, 300, 320, 300 and 210 mm H2 0) in each case. The CSF cell count was 20/mm 3 in case 1.

was slightly retarded before the convulsion. She had a generalized clonic convulsion continuing for 30 minutes during the period of high fever in exanthema subitum. She also had frequent convulsions after her temperature decreased. She showed ankle clonus but no menigeal sign, and was stuporous on admission. Excessive slow waves were observed on EEG. The convulsion stopped with the administration of DZP. PB was also administered. The next day her consciousness was clear. Convulsions accompanied by exanthema subitum should be followed up carefully with regard to the possibility of development into the status convulsivus.

Discussion and Conclusion ES complicates several neurological symptoms, i.e., irritability, a bulging fontanel, increased CSF pressure, slight pleocytosis and/or increased protein content in CSF, etc, on occasions. Convulsions associated with ES occurred with a lower grade fever and a longer interval after onset than usual in our cases. The mechanism of convulsions associated with ES night be different from that in the case of a simple type of FC.

Key words: Exanthema subitum, febrile convulsion, status convulsivus.

Key words: Exanthema subitum, febrile convulsion.

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Three Cases of Exanthema Subitum Accompanying Prolonged Seizures Fumihiko Hamada, MD, Shinji Kido, Kayoko Kawai, Mikiya Fujieda, MD and Takanobu Kurashige, MD Department of Pediatrics, Kochi Medical School, Nankoku, Kochi It is k~own that exanthema subitum commonly accompanies febrile convulsions. But the prognosis is generally thought to be good. Three cases of exanthema subitum accompanying the status convulsivus were presented.

Case 1 The patient was a 10-month-old girl who had generalized clonic convulsions three times during the period of high fever in exanthema subitum. The last convulsion lasted 26 minutes. Neurological findings and cerebrospinal fluid on admission were normal. Spiking activity in the right posterior lead was observed on EEG one month after the convulsions. Case 2 The patient was a 11-month-old boy who had a generalized clonic convulsion during the period of high fever in exanthema subitum. The convulsion continued for 30 minutes and stopped with the administration of DZP. He showed nuchal rigidity, but cerebrospinal fluid was normal. From 6 days after the convulsion, VP A was administered. No seizure discharge was observed on EEG. Case 3 The patient was a 9-month-01d girl whose development

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Absence Seizures following Febrile Seizures Kiyoshi Hashimoto, MD, Takehisa Fujita, MD, Masanobu Furuya, MD, Hisashi Enokido, MD, Hiroko Shibui, MD, Yohsuke Koizumi, MD, Osamu Fujino, MD, Satoshi Kamayachi, MD, Yasuko Takaishi, MD, Hideki Komatsuzaki, MD and Toshisada Morita, MD Department of Pediatrics, The Second Hospital of Nippon Medical School, Kawasaki (KH, TF, MF, HE, HS, YK); Department of Pediatrics, Nippon Medical School Hospital, Tokyo (OF, SK, YT, HK); Department of Pediatrics, Tohsei National Hospital, Shizuoka (TM) Among 59 cases of absence seizures (ABS), in 14 they followed febrile seizures (FS). The follow-up period ranged from ly7m to 15y7m (mean 6y7m). The sex ratio (M:F) was 1: 6. The age of onset of ABS ranged from 4y to Ily (6.2 ± 1.9 SD). A family history of FS was observed in 8 cases (57.1%). The cases with FS consisted of 9 of simple FS and 5 of complicated FS (2 of multiple seizures within 24 hours, I of prolonged seizures, I with family history of epilepsy, I with early FS onset). The numbers of seizures were I in 2 cases, 2 in 4 cases and more than 3 in 8 cases. The age of onset of FS was younger than I year in 1 case, 1-2 years in 9 cases, and 3 years in 4 cases. Thus 10 cases (71.4%) had their first FS in the first 3 years. The age at the time of tne last FS was 2 to 4 years in 11 cases (78.5%). The interval between the last FS and the onset of ABS was less than 1 year in 2 cases, 1 to 3 years in 10 cases, and more than 4 years in 2 cases. That is, in most cases (85.7%), ABS occurred less than 3 years after the last FS. Non-febrile seizures occurred in 4 cases, all prior to appearance of ABS. As to antiepileptic drugs, phenobarbital was used in 2 cases and phenobarbital combined with carbamazepine in I case and valproic acid in I case. In the case treated with VPA, the drug was stopped by parents and ABS appeared 14 months later.

Key words: Absence seizures, febrile seizures, VPA.

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Severe Myoclonic Epilepsy and Related Epilepsy Kiyoomi Sumi, MD, Tomoaki Nagaura, MD and Toshisaburo Nagai, MD Department of Pediatrics, Osaka Koseinenkin Hospital, Osaka (KS, TN); Hyogo Prefectural Nishinomiya Hospital, Hyogo (TN). Severe myoclonic epilepsy in infants (SME) is an extremely intractable epileptic syndrome which should be diagnosed and treated at early stage. However, it is difficult to diagnose before the myoclonic epilepsy appears. In the present study, cases of SME and related epileptic syndromes were examined both clinically and electroencephalographically. Thirty-one patients, 11 males and 20 females, were enrolled in this study. All of them had mental retardation, and a history of febrile convulsions, frequent convulsive seizures and normal development before the onset of the seizures. The patients were divided into three groups: A, Band C; group A consists of 10 SME patients, group B of 11 SME-like patients with no myoclonic seizures and C of 10 SME-like patients with onset later than 1 year old. There were more females in groups A and C, and equal number of females and males in group B. The average observation period, and average ages of the patients at the times of first admission and the present investigation were almost the same in the three groups. Mental retardation and transient paralysis were found in all groups. The incidence of a family history of febrile convulsions and epilepsy was found to be similar in the three groups. There were one pair of twins and one pair of siblings in both groups A and B. The first seizure occurred within the first 6 months after birth in half the patients in groups A and B, but within 1 to 2 years in group C. Most of the first seizures were generalized, but various other types, such as focal, lateral and complex partial seizures, were also seen. Many patients in groups A and B experienced more than 10 febrile convulsions episodes, including seizures, while bathing, whereas those in group C experienced less than 4. Electroencephalographically, focal spike discharges were observed in many of group C, but not in half of groups A and B. The seizure pattern after the second one was variable. Over half the seizures observed in groups A and B were partial types, such as versive, unilateral and alternative. Convulsive seizures occurred every day in half the patients in groups A and B, however they occurred at least once a month in half of group C. A number of periods of a convulsive status or bursts of convulsions were documented in all groups. The convulsive seizures in groups A and B were frequently induced by fever and easily developed into the status. The febrile convulsions in group C were thought to have occurred only by chance and rarely developed into status. Groups A and B showed similar clinical and electroencephalographical courses, and their convulsions easily developed into the convulsive status with fever, and so these 2 groups, A and B, should be regarded as severe convulsive epileptic syndrome induced by having a fever, whch includes SME.

Key words: Epilepsy, myoclonic, febrile convulsion, mental retardation, SME.

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Interrelationship of Risk Factors in Patients with Febrile Convulsions Tohru Konishi, MD, Yoshihiro Naganuma, MD, Kazuhisa Hongo, MD, Miyako Murakami, MD, Miwa Yamatani, MD and Toshio Okada, MD Department of Pediatrics, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Toyama We evaluated the interrelationship of individual risk factors and the relationship to clinical developmental features in patients with febrile convulsions.

Materials and Methods Three hundred and seventy-three patients with FC and 38 epileptic patients who had had prior FC were studied. The 10 risk factors selected were: a neurological deficit before onset, 5 types of complex seizure patterns, age at onset, a family history of epilepsy and EEG abnormalities. Results The incidence of developing epilepsy was 8.8 percent. The patients developing epilepsy had significant number of risk factors. The factors of a neurological deficit before onset, focal seizures, prolonged seizures and postictal neurological signs were frequently found in the same patients. For children with any two of the factors, the incidence of developing epilepsy was 1.4 to 9.4 fold higher. The respective risk factors were related to seizure types and the prognosis of late developing epilepsy. Conclusion The risk factors may be related to each other, and may influence the clinical prognosis as well as developing epilepsy. Key words: Febrile convulsion, risk factor.

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A Study of Perinatal Factors for Febrile Convulsions Kazumasa Otani, MD, liro Abe, MD, Yasuyuki Futagi, MD, Hyakuji Yabuuchi, MD, Hiroko Tanabe, PhD and Nobuhiko Okamoto, MD Division of Pediatric Neurology, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka We performed a follow-up study on children born in our hospital to determine the influence of perinatal risk factors on subsequent febrile convulsions (FC).

Subjects and Methods One thousand six hundred and twenty-six children born in

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our hospital between October 1981 and December 1983 were investigated by sending the parents questionnaires concerning the history of convulsions, family history of convulsions, psychomotor development, etc. Further information was obtained from the parents of the children with convulsions by telephone. Differences in perinatal factors between the FC and non-FC (control) groups were analyzed statistically by means of the chi-square test. Children with congenital brain anomalies, chromosomal aberrations, neonatal convulsions, meningitis, hypoxic brain damage caused by heart disease, mental retardation, cerebral palsy and epilepsy were excluded.

Results We obtained the information for 818 children. FC were found in 79 (9.7%). Out of the 818, 620 had had more than one risk factor and/or involvement during pregnancy and delivery. There were significant differences between the FC and non-FC groups in sex (FC: male 59%, nonFC: male 47%; p < 0.05), the incidence of less than 30 weeks of gestational age (FC: .13%, non-FC: 5%; p < 0.01), a family history of FC and epilepsy (FC: 43%, non-FC: 10%; p < 0.00 I), resuscitation by means of an endotracheal tube (FC: 16%, non-FC: 8%; p
Conclu~ion The incidence of FC in a perinatal center was 9.7%. This was almost equal to that reported previously for the general population. The FC group, however, had significantly more extreme premature deliveries (less than 30 weeks of gestational age) than the non-FC group.

Key words: Febrile convulsions, perinatal risk factors, incidence.

9 A Clinical Study on the Effectiveness of Intermittent Therapy with Rectal Diazepam Suppositories for the Prevention of Recurrent Febrile Convulsions and the Risk Factors Prognostic Developing Epilepsy during the Study Period Hiroyuki Shirai, MD, Hisao Miura, MD and Wataru Sunaoshi, MD Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Kanagawa

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The clinical efficacy of intermittent therapy with rectal diazepam (DZP) suppositories for the prevention of recurrent febrile convulsions was studied, and the risk of developing epilepsy during the study period and the risk factors prognostic of it were evaluated.

Subjects and Methods Two hundred and sixty-nine children aged 5 months to 4 years with two or more previous febrile convulsions were treated intermittently with rectal DZP suppositories 0 when their temperatures were elevated above 38.0 C. The patients were followed closely for 6 to 50 months (mean, 21.7 months) at our pediatric seizure clinic for recurrences of febrile convulsions and the development of epilepsy. Results Of the total 2,032 febrile episodes of above 38.0°C in all the patients during the follow-up period, DZP suppositories were administered to the patients on 1,835 occasions (90.3%). Eighty-six of the 269 patients (32.0%) had a total of 133 recurrences of febrile convulsions (6.5% of the total 2,032 febrile episodes), of which only 9 were observed after the administration of DZP suppositories. In 81 out of the remaining 124 recurrences, the patients were noted to have fever first after the occurrence of seizures. However, in the other 43 recurrences, DZP suppositories were not administered to the patients arbitrarily, even if fever was noticed by the parents before the occurrence of seizures. Ten of the 269 patients (3.7%) developed epilepsy during the study period. Nine of these 10 patients had identified clinical risk factors or paroxysmal discharges on EEG or both, and all of the 10 developed partial seizures: 2 had complex partial seizures and the other 8 secondarily generalized partial seizures. When a multivariate model that included all the prognostic risk factors under consideration was fitted, a past history of brain damage of various causes, preexisting neurological or developmental abnormalities and focal paroxysmal discharges on EEG were each an important prognostic risk factor for the development of epilepsy. Conclusion Intermittent therapy by means of rectal administration of DZP suppositories at home seems to be safe and remarkably effective for the prevention of recurrent febrile convulsions, unless the timing of the rectal administration of DZP suppositories is delayed in cases of febrile episodes. A few patients with the risk factors developed epilepsy during the period of intermittent therapy with rectal DZP suppositories for the prevention of recurrent febrile convulsions. Key words: Diazepam, epilepsy, febrile convulsion, rectal administration, suppository.

10 Prophylactic Administration of Diazepam in a Small Dosage for Prevention of the Recurrence of Febrile Convulsions Fumio Hayakawa, MD, Kuniyoshi Kuno, MD, Izumi Takahashi, MD, Tamiko Negoro, MD and Kazuyoshi Watanabe, MD Department of Pediatrics, Anjo Kosei Hospital, Anjo, Aichi (FH, KK); Department of Pediatrics, Nagoya University School of Medicine, Nagoya, Aichi (IT, TN, KW)

Conclusion Intermittent therapy by means of rectal administration of bromazepam suppositories seems to be safe and remarkably effective for the prevention of recurrent febrile convulsions. Our study suggests that the appropriate dose is 0.15 to 0.2 mg/kg.

Although the effectiveness of diazepam suppositories is generally known, the dosages. presently prescribed lead to sedation as a side effect. In this study, the effectiveness of diazepam as to prevention of the recurrence of febrile convulsions and the occurrence of sedation were examined with a dosage of 0.2 mg/kg, orally administered, once a day. The results were: one recurrent case out of 19 cases who had experienced an attack of febrile convulsions (5.3%), and 10 recurrent cases out of 44 who had experienced such an attack more than once (22.7%). The recurrence rate in all cases was 17.5%. Sedation was observed in only 3 cases (4.8%). From these results, we conclude that diazepam in a small dosage is effective for prevention of the recurrence of febrile convulsions and is safe to administer, as adverse effects such as sedation are few.

12 Clinical Effects of Bromazepam Suppositories for Preventing Febrile Convulsions in Children Keiko Koterazawa, MD, Shinichi Nakayama, MD, Hirohide Nakasako, MD, Jiro Yagi, MD, Kazuhiro Tanaka, MD, Tadataka Matsui, MD, Tetsuya Yamada, MD, Shinichi Miyake, MD, Sumiyoshi Yokoyama, MD, Mikio Komatsu, MD and Soichi Kodama, MD Department of Pediatrics, Kobe University School of Medicine, Kobe, Hyogo (KK, SN, HN, JY); Hyogo Prefectural A waji Hospital, Sumoto, Hyogo (KT); Ono Municipal Hospital, Ono, Hyogo (TM); Suma Red Cross Hospital, Kobe, Hyogo (TY); National Kakogawa Hospital, Kakogawa, Hyogo (SM); Konan Hospital, Kobe, Hyogo (SY); Himeji Red Cross Hospital, Himeji, Hyogo (MK, SK)

Key words: Febrile convulsion, diazepam.

Bromazepam, one of the derivatives of benzoziazepin, is generally used as a premedication for general anesthesia, while the anticonvulsive effect of bromazepam is strong compared to that of diazepam. Bromazepam was administered in suppositories to children with febrile convulsions to prevent seizures and the clinical effects of bromazepam were evaluated in this study.

11 Clinical Trial of Intermittent Rectal Bromazepam Suppositories for the Prevention of Recurrent Febrile Convulsions Shoko Tsunoda, MD, Kazunori Araki, MD, Satoru Ueda, MD and Ryoji Umezu, MD Department of Pediatrics, Tokyo Women's Medical College Daini Hospital, Tokyo Materials and Methods Twenty-eight children aged 1 year 3 months to 5 years 11 months, who had had two or more previous febrile convulsions, were studied. They were treated intermittently with rectal bromazepam suppositories when their 0 temperatures went above 38.0 C. The dose of bromazepam used ranged from 0.08 to 0.3 mg/kg (mean dose: 0.17 mg/kg). A bromazepam suppository of the same dose was administered again 6 hours later, when the temperature remained above 38.0°C. Results In the total twenty-eight patients, bromazepam suppositories were administered 40 times. In one case (3.6%), the convulsion was ~ot prevented. Mild side effects including transient ataxia and an increase in secretion were observed, and in 4 cases (14.3%), a decrease in the dose was suggested. No serious side effect was observed.

Key words: Bromazepam, febrile convulsion, suppository.

Patients and Methods Forty children aged 9 months to 7 years with febrile convulsions were studied. Sixteen of the forty patients had one or two risk factors mentioned in the NIH consensus statement of 1980 and all of them had seizures more than twice. The patients had not previously received any kinds of anticonvulsants. Bromazepam was given in suppositories to the patients when their body temperature was above 38°C. The dose of bromazepam used depended on the patient's weight; patients with body weights of less than 7.5 kg, between 7.5 to 10 kg and over 10 kg received 1.5 mg, 2.0 mg and 3.0 mg of bromazepam, respectively. When the body temperature on the increase persisted for over six hours after administration of bromazepam, the same dose was administered to the patients. None of the patients received other anticonvulsants during this study. Results Thirty-nine of forty patients had no seizures after administration of bromazepam, while the other patient had generalized tonic clonic seizures even if the same dose of bromazepam was administered again. After the administration of bromazepam 2 slept very

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well, 12 slept well, 18 slept moderately well and 7 slept ligh t1y. The average sleeping time for the first 24 hours after administration was 11.87 ± 0.52 hours. Thirty-two of the forty patients had no side effects, while the other 8 had side effects, including dizziness, sleepiness and dullness.

Summary The results indicate that the administration of bromazepam in suppositories is effective for preventing febrile convulsions. Key words: Bromazepam suppository, febrile convulsion, prevention.

13 Evolution of the Epileptic EEG Foci in Children with Febrile Convulsions - The Second Report Yasuo Tachibana, MD, Tohru Seki, MD, Nobuyuki Suzuki, MD, Mariko Maezawa, MD, Tetsuya Yamada, MD, Mitsuhiro Hara, MD and Yuichi Takuma, MD Department of Pedidtrics, Shimada Rehabilitation Hospital for the Severely Handicapped, Tokyo (YT); Department of PediatriCS, Keio University School of Medicine, Tokyo (TS, NS, MM, TY, MH, YT) In order to determine the electroencephalographic characteristics of febrile convulsions (FC) in epilepsy, we compared the long-term follow-up EEG findings for FC with those for epileptic seizures such as afebrile generalized convulsions (AGC), absence seizures and Rolandic seizures.

Subjects and Methods This ;tudy was performed on 62 cases of FC, 61 cases of AGC, 45 cases of absence seizures and 22 cases of Rolandic seizures. They were followed for more than five years and examined electroencephalographically not less than five times. We analyzed the evolution of epileptic EEG foci. Results 1) FC: We found many patterns. Epileptic discharges were more often observed from 5 to 7.5 years of age. Diffuse epileptic discharges and C-P-mT foci were often observed at younger ages, and anterior or posterior foci were often observed at older ages. 2) AGC: We found similar patterns to in the case of FC. 3) Absence seizures: In many cases, diffuse epileptic discharges 'were found at the first visits, but disappeared soon after the control of seizures. 4) Rolandic seizures: In many cases, C-P-mT foci were observed on the first visit, which disappeared between the ages of 12.5 and 15.

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Conclusion FC and AGC have similar backgrounds. Key words: Febrile convulsions, EEG findings, evolution of epileptic EEG foci.

14 A Clinical and Electroencephalographic Study on Children with Febrile Convulsions Who Showed Epileptiform EEG Discharges after Seven Years of Age Takashi Kajitani, MD, Takafumi Kimura, MD, Nobuhiko Sengoku, MD, Yoshio Fujii, MD and Shoko Yamasaki, MD Department of Pediatrics, Kawasaki Hospital, Kawasaki Medical School, Okayama A febrile convulsion (FC) is a seizure in infancy and childhood, usually not occurring after the age of 7 years. During the first and second years of life, in which FCs occur frequently, hardly any epileptiform EEG activity is seen. Subsequently, on repeated EEG examinations between the ages of 3 and 6, epileptiform discharges are observed. But, sometimes they are found after the age of 7. We compared children with FC who showed epileptiform EEG discharges after 7 years of age (the study group) with ones with FC who showed them between the ages of 3 and 6, but not after the age of 7 (the control group). The following results were obtained: 1) Most of the epileptiform discharges were 3-4 cps generalized spike-wave bursts, centro-temporal spikes (Rolandic discharges) or a combination of these discharges in both groups. 2) The age at onset of FCs was between 1 and 2 in most cases. Onset after the age of 7 was seen in 5 cases (6%) in the study group. 3) FCs after the age of 7 were found in 26 cases (29%) in the study group, but in only 3 cases (5%) in the control group. 4) Thirty-two cases (35%) in the study group and 11 (19%) in the control group had a total number of recurrences of FCs of more than 6 times. 5) In the study group, 22 cases (24%) had only one episode of FC, 3 cases (3%) had two episodes and one had three episodes after 7 years of age, while in the control group, 3 cases (5%) had only one episode. 6) In the study group, 57 cases (63%) received continuous antiepileptic medication, but in 37 (41%) antiepileptic therapy was discontinued successfully when epileptiform EEG discharges were observed. 7) In most cases in the study group, there was a time lag of several years between the last FC and the last appearance of epileptiform EEG discharges. Although 65 cases (71 %) in the study group had FCs before 7 years of age, epileptiform activities persisted between 7 and 16 years. 8) We presented a case with a past history of FC who had been treated with continuous antiepileptic drugs unreasonably for 7 years and we stress that epileptiform

EEG discharges should not be an indicator of continuous antiepileptic medication.

FO-FC (85%) and AC-FC (64%), than in FC (59%) and non-Epi (41%).

Key words: Febrile convulsion, epileptiform EEG disdharge, age, antiepileptic medication.

Comment Our criteria for 4 resembling patterns may be valuable for differentiating irr sp & w from other 3 benign nonepileptic patterns.

15 Clinico-EEG Study of the Pseudo-Petit-Mal Pattern in Children with Febrile Convulsions (III) Shota Miyake, MD, Kiyoshi Matsui, MD, Takuya Kobayashi, MD, Noriyuki Ootsuki, MD, Tazuko Miyagawa, MD, Michiko Yamada, MD and Hiroko Iwamoto, MD Division of Neurology, Kanagawa Children's Medical Center, Yokohama, Ka1Ulgawa

Key words: Febrile convulsions, pseudo-petit-mal pattern, epileptiform EEGs, irregular spikes & waves.

The purpose of this study was to determine the frequencies of 4 abnormal EEG patterns in children with febrile convulsions (FC), epilepsY and non-epileptic disorders according to new criteria proposed at the 10th Conference on FC. The pseudo-petit-mal pattern (PPP) isn't thought to be an epileptiform EEG pattern, but it is difficult to distinguish from hypnagogic hypersynchronous 8 bursts with spiky notching (hypna), phantom spikes & waves (phantom) and irregular spike & wave bursts (irr sp & w). Only the last is an epileptiform EEG pattern. PPP comprises 3-4 Hz HVS bursts with spikes in the first 30-50% of the bursts, which are prominent in the centroparietal area. Hypna comprises paroxysmal 3-4 Hz HVS bursts with notching, which are hardly judged as being spikes. Phantom comprises positive spike bursts prior to the aboveu{entioned two patterns. Lastly, irr sp & w comprises 3-4 Hz diffuse irr sp & w complexes, of which the spike component continues clearly over half of a burst, contrary to in the case of PPP. Materials and Methods Three hundred and seventy cases were followed for more than 2 years and divided into 5 groups: FC group (231 cases), AC-FC group (11 cases; who had aFC accompanied by FC), FO-FC group (27 cases; who had FC following aFC), Epi group (50 cases; who had epilepsy without FC or other handicaps) and non-Epi group (51 cases; who had mild non-organic symptoms: headache, tics and so on). We performed longitudinal analysis of 1,269 EEG recordings which were obtained at rest and in sleep, including the drowsy state. Results Hypna, PPP and phantom were observed more frequently in FC (39%), AC-FC (27%) and FO-FC (22%), than in Epi (18%) and non-Epi (12%). But irr sp & w was observed more frequently in AC-FC (55%), FO-FC (37%) and Epi (36%), than in FC (10%) and non-Epi (4%). Benign 3 patterns and irr sp & w were both observed more frequently in AC-FC (18%) and FO-FC (17%), than in FC (9%), Epi (8%) and non-Epi (2%). Other epileptic discharges were observed more frequently in Epi (88%),

16 Monoamine Metabolism in Cerebrospinal Fluid in Febrile Convulsions Satoshi Kimiya, MD, Tohru Seki, MD and Mitsuhiro Hara, MD Kawakita General Hospital, Tokyo (SK); Department of Pediatrics, School of Medicine, Keio University, Tokyo (TS); Yokosuka Kyosai Hospital, Kanagawa (MH) We measured the concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) in cerebrospinal fluid in febrile convulsions to investigate monoamine metabolism in the brain. We have already reported that in normal controls there are significant inverse correlations between age and the concentrations of HV A and 5HIAA. As to concentration gradients, the concentration in the last 0.5 ml portion of CSF was higher than that in the first 0.5 ml portion for both HV A and 5HIAA. Subjects and Methods We selected 21 cases of febrile convulsions in which spinal taps were performed for differential diagnosis from meningitis. Their ages ranged from 8 months to 7 years. We could not fix the time of the spinal taps because of the nature of the febrile convulsions. High performance liquid chromatograph with an electrochemical detector, with dihydroxyhydrocinnamic acid as an internal standard, was used. As controls, we selected 46 patients with no evidence of CNS involvement. Patients with aseptic meningitis were included in the controls after they had been completely cured. Spinal taps were performed between 8 AM and lOAM. For comparison with febrile convulsions, 42 cases of non-organic epilepsy were selected. We defined non-organic epilepsy as epilepsY without psychomotor retardation or X-ray cranial CT abnormalities or abnormal neurological signs. The nature and purpose of the investigation were explained to the parents of each child in the non-organic epilepsy group and consent was obtained. Results and Discussion As to age-concentration correlations, no significant differences were noted in 5HIAA between the febrile convulsion and control groups, while in HV A, marked concentration variations, especially around the age of one, were observed in the febrile convulsion group, compared

Proceedings 273

to in the control group,. For 5HIAA, similar patterns were observed between febrile convulsions and non-organic epilepsy, while for HVA, the marked concentration variations seen in the febrile convulsion group were not observed in the non-organic epilepsy group. Marked HVA concentration variations, especially around the age of one, are unique to febrile convulsions. On the other hand, there was no such unique pattern in 5HIAA for febrile convulsions, which seems to indicate that there is little, if any, connection between serotonin metabolism and febrile convulsions.

Key words: Monoamine metabolism, febrile convulsion, non-organic epilepsy, cerebrospinal fluid.

17 Secretory Kinetics of the Hypophysis during Attacks of Febrile Convulsions - Especially the Role of Prolactin Mitsuhiro Hara, MD, Toru Seki, MD, Katsuaki Hirai, MD, Akira Shimazu, MD, Kenji Oyama, MD and Makoto Hirose, MD Department of Pediatrics, School of Medicine, Keio University, Tokyo (MH, TS, KH); Department of Pediatrics, Yamanashi Medical College, Yamanashi (AS, KO); Department of Pediatrics, Yokosuka Kyosai Hospital, Kanagawa (MH) During attacks of febrile convulsions (FC) and primary generalized epilepsy (PGE, generalized tonic epilepsy), we measured the levels of serum prolactin (PRL), thyroidstimulating hormone (TSH) and growth hormone (GH), in order to determine endocrinologic differences in the two conditions.

Subjects and Methods The subjects were 24 cases of FC (14 males, 10 females, age: 7 months - 6 years) with a total of the two conditions. Twenty-five attacks, each attack of less 15minutes in duration. No organic encephalic disturbance was observed. In cases with generalized tonic epilepsy, DZP was intravenously administered in 8 attacks. Eight cases of PGE (5 males, 3 females, age: 1-14 years) had a total of 9 attacks; females at puberty were excluded. DZP was administered intravenously in 4 attacks and antiepileptic drugs in 2 attacks. Basic levels were determined with an empty stomach in the early morning after 24 hours had elapsed following an attack. After each attack, measurements' were conducted at least twice within 15, 20 and 60 minutes. PRL, TSH and GH were determined by means of RIA in order to compare the two conditions. Moreover, because the FC and PGE groups exhibited clinical differences with respect to (1) age, (2) the presence or absence of fever and (3) whether or not the patients received DZP, we studied the effects of these differences on the kinetics of prolactin secretion. Thus, comparative studies as to the basic level of PRL for each age group were carried out and the results were as follows; 3-11 months: 17 cases, 6-9 years: 16 cases,

274 Brain & Development, Vol 11, No 4,1989

and 15 years: 9 cases, between 18 cases attended with fever due to respiratory infection and 29 cases without fever, and there were between 8 attacks in the DZP and FC groups, and 17 attacks in the non-administered group.

Results 1) The FC and PGE groups showed significant increases in serum PRL during attacks. However, variation in the FC group appeared to be less than in the PGE group. 2) Significant elevation of the levels of TSH and GH was not recognized in either group. 3) No significant difference was observed with respect to the PRL level within each group as to age, the presence or absence of fever, and whether or not DZP was intravenously administered. These results indicated that the effects of age, fever and intravenous DZP administration were minimal. Conclusion Since a significant difference in the serum PRL level at the times of attacks between the FC and PGE groups was recognized, a possible association with dopamine and the kinetics of GAB A on PRL inhibition was indicated. Key words: Febrile convulsion, primary generalized epilepsy, prolaction.

18 Complement-like Immunoreactivity in Cerebrospinal Fluid of Children with Febrile Convulsions Kazuo Hiyoshi, MD, Yasufumi Utsumi, MD, Osami Okubo, MD, Tatsuo Fuchigami, MD, Yukihiko Fujita, MD and Hitoe Okubo, MD Department of Pediatrics, Nihon University School of Medicine, Tokyo We examined cerebrospinal fluid and serum from 8 children with simple febrile convulsions, 12 children with the complex type and 23 normal control subjects for variation in complement (C 3,C4)-like immunoreactivity. The quantity of complements was determined with a Laser Nephelometer. The purpose of this study was to determine if intrathecal complement plays a role in the early immunoresponse of febrile convulsions. The C3,C4 Index and Ratio were calculated using the formulas proposed by Y Sano. C3,C4 Index = C3,4CSFj(C 3,4Serum x T.P.CSF) C3,C4 Ratio = C 3 CSFjC 4 CSF The CSF C3 and C4 values ranged from 60 to 370 Ilgjdl with a mean (± SD) of 193 ± 106llgjdl, and from 50 to 410 Ilg/dl, with a mean of 203 ± 110 Ilgjd1, in normal subjects, respectively. In febrile convulsions, the CSF C3 and C4 values ranged from 70 to 410 Ilgjdl (208 ± 98Ilg/dl) and from 90 to 450 Jlg/dl (245 ± 125 Ilgjdl), respectively. The mean absolute concentrations of CSF C3 and C4,

compared to in normal controls, were not significantly different for the simple and complex types. No correlation was found between simple febrile convulsions and the complex type or normal controls in the C3,C 4 Ratio. However, there was a tendency for higher C4 Index values in the complex type compared to the simple type. The children with long-term seizures (more than 15 minutes) had elevated C3, C4 Index values. The index was regarded as an indicator of complement activity in CSF. These data suggest that variations in complements in CSF are associated with diffusion across the blood-brain barrier and the local immunoresponse.

Key words: Cerebrospinal fluid, C3 and C4 complements, Laser Nephelometer, febrile convulsion.

19 Cerebral Blood Perfusion in Febrile Convulsions with N-Isopropyl-p-[ 123 1] lodoamphetamine and Single Photon Emission CT Narumi Michihiro, MD, Yumiko Kurosawa, MD, Tomoko Suemitsu, MD, Hiroaki Shiihara, MD and Motomizu Ariizumi, MD Department of Pediatrics, Dokkyo University School of Medicine, Koshigaya Hospital, Koshigaya, Saitama The relationship between febrile convulsions and epilepsy has been discussed previously by many authorities. Recently, single photon emission CT (SPECT) has been employed to disclose the epileptic focus in the brain. In this study, cerebral blood perfusion in febrile convulsions was investigated by means of SPECT, with N-isopropylp-[ 1231] iodoamphetamine 23 I-IMP) and the correlation of the SPECT pictures to the risk factors for epilepsy was examined.

e

Subjects and Methods The subjects were 16 patients (9 males and 7 females) with febrile convulsions, aged 6 months to 11 years. The age at onset of the seizures ranged from 6 months to 5 years. Each scan was started 20 minutes after intravenous injection of 123I_IMP 1-2 mCi. Results Seizure discharges on EEG were detected in 6 of the 16 patients. They comprised focal epileptic discharges in 2 patients and diffuse spike and wave complexes in 4. CT scans were normal in all patients. In 5 of the 16 patients, SPECT pictures revealed normal cerebral blood perfusion, despite that 3 of them showed seizure discharges on EEG (focal sharp wave: 1, and diffuse spike and wave complexes: 2). The other 11 patients showed focal hypoperfusion areas (frontal region: 1, fronto-temporal region: 1, parieto-temporal region: 4, temporal region: 5), but only 3 of them showed abnormal EEG (focal spike waves: 1, diffuse spike and wave complexes: 2). The patients with normal SPECT pictures had few risk factors for epilepsy. On the other hand, the patients with abnormal

SPECT pictures possessed a number of risk factors.

Conclusion It has been reported that the epileptic focus displays hypoperfusion on SPECT in the interictal stage. The present results indicate that there are many cases of focal hypoperfusion areas in the brain in febrile convulsions. Risk factors for epilepsy were observed in the majority of patients with focal hypoperfusion. These findings suggest that the brain pathology in febrile convulsions is similar to that in epilepsy. In this study, however, it could not be determined whether febrile convulsions accompanied by a focal hypoperfusion area would progress into epilepsy or not.

Key words: Febrile convulsion, 123I_IMP SPECT, cerebral blood perfusion, epilepsy.

20 Changes in Brain Peptide and Gamma-Amino-Butyric Acid (GABA) Contents in Febrile Convulsion Model Rats Sachiko Nagaki, MD, Shigeru Nagaki, MD, Yukio Fukuyama, MD, Kiyohisa Takahashi, MD, Nobumasa Kato, MD and Yukiko Minatogawa, PhD Department of Pediatrics, Tokyo Women's Medical College, Tokyo (SN, SN, YF); Division of Psychobiology, National Center of Neurology and Psychiatry, Tokyo (KT); Department of Psychiatry, Shiga University of Medical Science, Shiga (NK); Department of Psychiatry, Saitama Medical College, Saitama (YM) To further elucidate the roles of some peptides and GAB A in the pathogenesis of febrile convulsions (FC). In this study the effect of FC on the contents of brain immunoreactive arginine-vasopressin (IR-A VP), immunoreactive somatostatin (IR-SRIF) and GAB A were studied in rats after convulsions induced by ultrared light (UR).

Materials and Methods Male Wistar rats of 16 days of age were irradiated with UR and 29 developed generalized seizures. The rats were killed by microwave irradiation 3 min after the UR irradiation, or 0 min, 2 h, 6 h, 24 h or 48 h after the seizures. Non-irradiated rats served as controls. The brain was dissected into 4 regions: amygdala, hypothalamus, cortex and hippocampus. Then each tissue was sonicated in 0.1 N acetic acid, and AVP and SRIF were measured by radioimmunoassay. GABA was measured by an enzymeassay. Results 1) IR-SRIF was increased in the cortex and hippocampus at 3 min after UR irradiation, and 0 min after the seizures. 2) IR-AVP in the hypothalamus was increased 3 min after UR, and decreased 2 h and 6 h after the seizures. 3) The GABA content was increased in all regions at 2 hand 6 h after the seizures.

Proceedings 275

Conclusion These results suggest that the substances mentioned above are, if not directly, involved in the pathogenesis of FC. Key words: Febrile convulsion, GABA, brain peptide, IR-AVP.

21

Study on Rat Hyperthermic Seizures Takehiko Morimoto, MD, Hideo Nagao, MD, Nozomi Sano, MD, Mitsugi Takahashi, MD and Hiroshi Matsuda, MD Department of Pediatrics, Ehime University School of Medicine, Ehime Electroenceph~ographic

In the present study, we investigated the behavior and EEG during hyperthermic convulsions in rats, which had not been examined in detail, and compared them with those in the case of human febrile convulsions.

276 Brain & Development, Vol 11, No 4, 1989

Materials and Methods Eight Wistar albino rats aged 26 to 29 days were used. EEG, with epidural and intracorticalleads, and behavior were recorded with a vide'O-monitor system during hyperthermia induced by an increased ambient temperature (47°C). Results A slight increase (0.38 ± 0.15) in body temperature indu~ed diffuse 4-5 Hz theta bursts (hyperthermia-induced theta bursts: HITB). At 44.0 ± 0.25°C, continuous high voltage slow waves, intermittent diffuse spikes with myoclonus and rapid spike & wave bursts with generalized clonic convulsions occurred sequentially. Discussion In both human and rat febrile convulsions, the predoI)1inant seizure type was generalized clonic conVUlsions and EEG suggested the centrencephalic origin of the seizure discharges, which supports the usefulness of the rat model for studies on human febrile convulsions. Key words: Hyperthermia, rat, EEG.