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Abstracts from the fifth conference on febrile convulsions, Tokyo, December 18, 1982
A Study of the Clinical Classification of Febrile Convulsions
Abstracts from the Fifth Conference on Febrile Convulsions, Tokyo, December 18, 1982
Compiled by Yukio Fukuyama, MD Clinical Observation of Febrile Convulsions in Children over 6 Years Old
Kyoko Takizawa, MD, Kiyoomi Sumi, MD Pediatric Clinic, Ikeda City Hospital, Osaka (KT); Pediatric Clinic, Kohseinenkin Hospital, Osaka (KS)
Several studies on prophylactic treatment of febrile convulsions achieved significant success in the prevention of recurrence. We studied here the prophylactic efficacy in children over 6 with febrile convulsions, as compared with non-treated controls. Subjects and Methods: Seventy-six children aged over 6 who had had febrile convulsions were seen in the pediatric clinics of Kopseinenkin Hospital and Ikeda City Hospital for over one year. 38 were placed on prophylactic anticonvulsant medication and 38 had no medication. Six of the 38 children on prophylactic medication developed non-febrile convulsions. These three groups (A: control group n = 38, B: febrile convulsions on prophylactic medication n = 32 and C: non-febrile convulsions on prophylactic medication n =6) were investigated as to age of initial and most recent febrile convulsions; perinatal abnormalities and seizure recurrence rate were compared between the groups. Results: 27 of the 38 children (71%) in group A and 29 of the 32 children (91%) in group B experienced their last febrile convulsion before the age of 6 years. Children with perinatal abnormalities showed a high incidence of febrile convulsions. The recurrence rates of febrile convulsions in groups A and B were 18% and 13%, respectively. In recurrent cases of group B, the serum anticonVUlsant levels were low, but after serum levels were restored to the therapeutic range, recurrence of febrile convulsions was well-controlled. In group C, 5 of the 6 children (83%) who experienced their initial seizure before 2 years old, had EEG abnormalities and frequent febrile convulsions before they developed non-febrile convulsions. Their serum anticonvulsant levels were also low. Conclusion: Based on our observations, we advocate prophylactic treatment for children with perinatal abnormalities, high incidence of febrile convulsions and EEG abnormalities. The serum anticonvulsant level should be kept within the therapeutic range in order to prevent recurrent febrile convulsions and, later, non-febrile seizures.
338 Brain & Development, Vol 5, No 3,1983
Kazuko Kagawa, MD, Mitsutoshi Tsuchihashi, MD, Masako Okajima, MD Department of Pediatrics, Yokohama City Hospital, Yokohama, Kanagawa
The predictive ability of the prognOSIS In children with febrile convulsions (FC) classified by the clinical types proposed by Nelson [1], Fukuyama [2] and Ohtawara [3] was examined from the viewpoint of the frequency of development of afebrile seizures and an abnormal electroencephalogram (EEG). Materials and Methods: The children with FC who visited our clinic during 1980 were selected. Among them, 172 children, 95 boys and 77 girls, whose EEG had been examined, were followed to October, 1982. Results: The average age at the first examination was 4 years and at the final examination 7-2/12 years. The average period for observation was 3-4/12 years. Abnormal EEG were observed in·36 children (20.9%). EEG was examined 465 tinIes for 172 children. The frequency of abnormal EEG showed a tendency to increase with age, and that at 5 to 6 years old was over 30%. The frequency of development of afebrile seizures was 6.9% (12 children). 8 among them showed afebrile seizures after the age of 4 years and were considered to have epilepsy. There were no significant differences among the frequencies of abnormal EEG in the R1 (Risk factor 0), R2 (Risk factor 1) and R3 (Risk factor over 2) groups classified by Nelson. The frequency of development of afebrile seizures was 2.5% in the R1 group, 8.3% in the R2 group, and 16.7% in the R3 group, showing a sinIilar tendency to the data of Nelson et al. However, these differences were not significant (0.05 < p < 0.1). There were no significant differences among the frequencies of development of abnormal EEG and afebrile seizures in the sinIple and complicated types classified by Fukuyama, using the clinical data at the first FC and also during the observation period of 3-4/12 years. However, a significant difference (p < 0.01) was shbwn among the frequencies of development of abnormal EEG and afebrile seizures between the two types, using the clinical data of the observation period over 10 years. There were no significant differences among the frequencies of development of abnormal EEG and afebrile seizures in the sinIple and complicated types classified by Ohtawara using the clinical data at the first FC. However, the frequency of abnormal EEG during the total observation period of 3-4/12 years showed a significant difference (p < 0.025) between the two types. Conclusion: The classification of Nelson predicted the prognosis best when the clinical data at the first FC were used. The classifications of Fukuyama and Ohtawara predicted the prognosis only when the clinical data of the observation period over 3 years were used. References: 1. Nelson KB. et a1. Pediatrics 1978;61 :720. 2. Fukuyama Y. ClinPsychiatr (Tokyo) 1963;5:211. 3. Ohtawara S. et al. Jpn J Pediatr (Tokyo) 1979; 32:625.
Qualitative Analysis of Paroxysmal Discharges in Electroencephalograms of Febrile Convulsions Satoshi Kimiya, MD, Tohrn Seki, MD, Yasuo Tach ibana, MD, Tetsuya Yamada, MD, Mariko Maezawa, MD, Nobuyuki Suzuki, MD, Hidenori Yamawaki, MD, Makoto Hirose, MD Department of Pediatrics, School of Medicine, Keio University, Tokyo (SK, TS, YT, TY, MM, NS, HY); Yokosuka Kyosai Hospital, Yokosuka, Kanagawa (MH) The rate of paroxysmal discharges observed in EEG of febrile convulsions varies from 2% to 86% according to the previous reports. It is controversial as to whether paroxysmal discharges in febrile convulsions are one of the risk factors presaging afebrile convulsions. In this report we focused on qualitative analysis of the paroxysmal discharges in EEG of febrile convulsions.
Materials and Methods Thirty-eight children, 24 male and 14 female, were studied, who were followed up for longer than 4 years. As paroxysmal discharges, we included spike, sharp, spike and wave. We did not consider high voltage slow burst, 6-14 Hz positive spike, wave and spike phantom in this report. The follow-up period varied from 4 to 16 years. We divided the 38 cases into two groups depending on the presence (A) or absence (B) of the risk factors postulated by Nelson. Ages were divided into four groups: 0-2 years (Group 1), 3-5 years (Group 2), 6-9 years (Group 3) and older than 10 years (Group 4). Results (1) Paroxysmal discharges were not detected in Group 1. In Group 2, generalized paroxysmal discharges were prominent while in Group 3, focal paroxysmal discharges as well as generalized ones were observed. In Group 4, paroxysmal discharges had a tendency to disappear. No differences were observed between A and B. (2) We classified the localization of the focal paroxysmal discharges into (a) frontalantetemporal, (b) central-parietal-mid temporal, (c) occipital and (d) multiple foci. In 14 out of 31 cases, paroxysmal discharges existed in the central-parietal-midtemporal area. But no significant differences were found between A and B or among Groups 1, 2, 3 and 4. Conclusions We tried to determine whether there were qualitative differences in the localization of paroxysmal discharges in EEG of febrile convulsions which might presage afebrile convulsions. The number of cases in this research was too small to conclude that the localization of the paroxysmal discharges has nothing to do with the prognosis of febrile convulsions. We should continue to focus our attention on the quality of the paroxysmal discharges in EEG.
Follow-Up Study of Children with Simple Febrile Convulsions and Epileptiform EEG Activities without Chronic Anticonvulsant Medication Takashi Kajitani, MD Department of Pediatrics, Kawasaki Hospital, Kawasaki Medical School, Okayama In order to clarify the clinical significance of epileptiform EEG activities in febrile convulsions, I carried out a follow-up study of children with simple febrile convulsions and epileptiform EEG activities without chronic anticonvulsant medication.
Subjects and Method Febrile convulsions were defined as episodes of convulsions provoked by fever of over 38.0°C associated with an acute febrile illness of extracranial origin. The subjects were 126 cases of febrile convulsions (77 boys and 49 girls) who revealed diffuse spike-and-wave bursts and/or focal spikes and had neither an abnormal neurological or developmental status nor an atypical febrile seizure, such as a prolonged or focal seizure. The average age for showing epileptiform EEG activities was 4 years and 7 months of age (from 2 years and 4 months to 9 years and 3 months). The average observation period was three years and two months (from one year to twelve years and three months). Results During the follow-up observation, 113 cases (90%) experienced no convulsive seizures, 10 cases (8%) had one or more episodes of recurrent febrile seizures and only 3 cases (2%) developed subsequent recurrent afebrile seizures. Epileptiform EEG activities consisted of diffuse spike-and-wave bursts (83 cases, 66%), Rolandic spikes (28 cases, 22%), focal spikes other than Rolandic spikes (12 cases, 10%) and diffuse spike-and-wave bursts combined with focal spikes (3 cases, 2%). There was no significant difference of the type of epileptiform EEG activities between the recurrence group (13 cases) and the non-recurrence group (113 cases). Conclusion In children with simple febrile convulsions epileptiform EEG activities do not seem to be important predictors of the recurrence of febrile seizures or of developing epilepsy after febrile convulsions. There will be a few children with simple febrile convulsions and epileptiform EEG activities who have to receive chronic anticonvulsant medication with phenobarbital or valproic acid.
Brain & Development, Vol 5, No 3, 1983 339 J
Febrile Convulsions and Electroencephalographic Abnormalities; A Regional Population Study
Makoto Matsuo, MD, Touru Kurokawa, MD Department of Pediatrics, Faculty of Medicine Kyushu University, Fukuoka
We attempted field work on febrile convulsions and electroencephalography in infants and children. Electroencephalographic examination was performed in 760 - school children, aged from 6 to 12 years, in Hisayama Town (75.1% of the whole popUlation of equivalent age). Electrodes were arranged according to 10-20 international system with 8 monopolar and 4 bipolar leads. Hyperventilation was investigated in all children. A natural sleep record was taken in about 22.1% of the Ilxamined children. After completion of the questionnaires on behavior and history of illness by parents, physical and neurological examination was done of each child.
Results (1) The incidence of a history of febrile convulsions was 7.3% in school children (febrile convulsion; FC group) and there was no sexual difference. (2) Focal spikes were found on resting EEGs in about 1.0% of the control group (no history of febrile convulsions), 5.4% of the FC group and 7.1% in the group with a family history of FC but without FC in the children themselves. (3) A pseUdo-petit mal pattern was observed in natural sleep EEGs in 13.0% of the control group, 11.8% of the FC group and 7.8% of the group with a family history of FC. Conclusion This is the first report of field work revealing that the frequency of focal spike discharges was significantly higher in the FC group and the group with a positive family history than in the control group (P 0.01).
340 Brain & Development, Vol 5, No 3, 1983
Febrile Convulsions in Tamano City. Neuroepidemiologic Observations
Shunsuke Ohtahara, MD, Sumio Ishida, MD Department of Developmental Neuroscience and Child Neurology, Institute for Neurobiology, Okayama University Medical School, Okayama
Although febrile convulsions are a major medical and social problem, their incidence and prevalence remain uncertain. We studied, therefore, in detail, the epidemiology of febrile convulsions in children. The study was undertaken in Tamano City, Okayama Prefecture, Japan, on December 31,1978. All children under five years of age were studied. A list of those exhibiting febrile convulsions was compiled from medical records of hospitals and clinics in and around Tamano City. On the target day the population of children under five years was 6,591 of a total popUlation of 79,897. The criterion used for derming febrile convulsions in this study was "any seizures associated with high fever excepting seizures due to central nervous system infection". The results were as follows: 1) On December 31, 1978, 223 febrile convulsion cases were identified, the overall prevalence rate being 33.8/1,000. 2) The annual incidence rate for febrile convulsions was estimated to be 925.5/100.000 for 1978. 3) Simple febrile convulsions were found in 117 cases (58.5%), complex febrile conVUlsions in 28 cases (14.0%) and epileptic febrile convulsions in 55 cases (27.5%). 4) The age at onset of febrile convulsions was confirmed in 198 cases. As many as 112 cases (56.6%) had their initial attack between one and two years of age, 73 cases (36.9%) between 1 and 1.5 years of age, and 39 cases (19.7%) between 1.5 and 2 years of age. On the other hand, none had the Inst convulsion under 3 months of age, oilly 6 cases (3.0%) between 3 and 6 months, and only 8 cases (4.0%) after 3 years of age. 5) Regarding the presumed etiology, 56.3% of the cases had some genetic factors for convulsions. 6) The follow-up -study by questionnaire was performed for 150 cases who were over 6 years of age on March 31, 1982. Four (4.7%) of the 85 cases who answered had developed into afebrile seizures; two cases of complex and two cases of epileptic febrile convulsions but none of simple febrile convulsions.
Kawasaki Disease with Febrile Convulsions
Chronological Change of Serum Immunoglobulin A (IgA) Level in Febrile Convulsions
Chikaya Ohtsuka, MD, Kyoko Watanabe, MD, Toshi· hiro Honda, MD, Shigeaki Inoue, MD, Yoshio Kaneda, MD, Susumu Furnkawa, MD Department of Pediatrics, Juntendo University School of Medicine, Tokyo
Hiroaki Shiihara, MD, Shuichi Hibio, MD, Motomizu Ariizumi, MD Department of Pediatrics, Nihon University School of Medicine, Tokyo
It is known that Kawasaki disease (K-D.) complicates
It has already been reported that the serum IgA
cerebral angitis and pleocytosis. The purpose of this study was to determine the frequency and charac· teristics of febrile convulsions with K-D.
Subjects: The clinical subjects consisted of 155 children with K-D. who were seen at the Pediatric Department of Juntendo University from March 1973 to July 1982. Results: The age distribution of K.D. was nearly the same as that of febrile convulsions and was from one month to 9 years of age. 88% of the subjects were less than 4 years old and the largest number of K.D. cases were found in the one year old group of chilo dren. Only one case (0.65%) of febrile convulsions was found in the febrile period of K.D. This case was a boy aged 5 years. He was born with a normal delivery and had grown with normal development. He had had, however, 5 times of febrile convulsions in his past history and 2 cases of febrile convulsions (his mother and maternal sibling) were found in his pedigree. Three days after the onset, with a body temperature of 38AoC, he had a convulsive attack which was symmetrical and of the grand mal type. His EEG showed 14 Hz positive spike waves in the period of the drowsy state at 3 weeks after the convulsive attack. Two cases of febrile convulsions were found after K.D. One of them was a boy aged 11 months without a past febrile convulsion. About one month after a typical course of K.D., he had the simple type of febrile convulsion. Another case was a girl aged 1 year with a past febrile convulsion. She had a febrile convulsion again at about 8 months after K.D. These cases showed no abnormal EEG findings. Discussion and Conclusion: K-D. is a sort of febrile illness and its age distribution is nearly the same as that of febrile convulsions. Contrary to our expectation, only one case of febrile convulsions (0.65%) was found in 155 patients with K.D. We could not find any differences between K.D. and the other febrile illness in the characteristics of febrile convulsions.
concentration is at a low level in many cases of epilepsy and febrile convulsions. We studied the chronological change of the serum IgA level and its relation to the clinical course in children with febrile convulsions with low serum IgA.
Materials and Method The serum IgA concentration was followed up for 5 months to 4 years and a month in 19 children of 33 cases of febrile convulsions with a low serum IgA level at their first visit to hospital. There were 7 cases of the simple type and 12 cases of the complicated type. Nine children had family histories of febrile convulsions. Serum IgA was measured by the single radial immunodiffusion method or laser-nepherometry. The values were compared with normal IgA levels in Japanese children and a level under mean-2SD was regarded as low. Results The serum IgA concentration became within the normal range in 8 cases in the follow up period. The age of normalization ranged from 2 years and 4 months to 4 years and 5 months. An epileptic discharge on electroencephalography (EEG) was found only in one of these 8 cases. In other 11 cases the serum IgA concentration remained at a low level. Epileptic discharges on EEG were found in 4 cases who were aged from 5 to 9 years old. These cases with a continuous low serum IgA level and EEG abnormality were thought to have the tendency to become true epileptics. Conclusion Children with febrile convulsions with low serum IgA levels are divided into two groups. In one group, the serum IgA level becomes normal in infancy and they are thought to haye a benign prognosis. In the other, it remains at a low level even in childhood. These cases often have epileptic discharges on EEG and are thought to have the tendency to become true epileptics.
Brain & Development, Vol 5, No 3,1983 341
Allergy in Febrile Seizure Michiko Hara, MD, Fumie Uematsu, MD, Kazuko Kagawa, MD, Yukio Fukuyama, MD Department of Pediatrics, Tokyo Women's Medical College, Tokyo Close relationship between epilepsy and allergy has been pointed out by many authors. But the studies of allergy in febrile seizure (FS) are few. To detect the pathogenesis of FS, we examined the tendency of allergy in the children and their family members of this disorder.
Materials and Methods One hundred cases of FS, 54 of males and 46 of females, aged zero to ten, and their family members were examined about the incidence of allergic disorders such ~s bronchial asthma, atopic dermatitis, allergic rhinitis and urticaria. Results Allergies were detected in 72.0 per cent of FS patients. These consisted of bronchial asthma (36%), atopic dermatitis (31%), allergic rhinitis (32%), urticaria (16%) and others (3%). Serum immunoglobulin E levels (RIST, RAST) were examined in eleven cases. In ninety per cent of the cases examined, IgE exceeded over 100IVlm!. Family history of allergies was positive in 69.0 per cent of FS patients, and this figure was higher than that of family history of FS among the same material (58%). Conclusion We detected the high incidence of allergy in FS patients and their family members. This was thought to be the constitutional characteristics of FS patients and somewhat related to the pathogenesis of this disorder.
342 Brain & Development, Vol 5, No 3,1983
Study on the Number of Seizures and the Accompanying Abnormal Behavior in Febrile Seizures Hideki Horita, MD, Hideomi Ohta, MD, Yukikatsu Ochiai, MD, Komei Kumagai, MD, Kihei Maekawa, MD Department of Pediatrics, likei University School of Medicine, Tokyo Children with febrile seizures were followed for three years or more after the first examination, and investigated clinico-electroencephalographically as to the number of seizures and the accompanying abnormal behavior. Of 488 children who were examined first for febrile seizures from 1975 to 1978, 266 (183 males, 83 females) could be followed for over three years. Follow-up information was obtained through letters and medical records. The average age at the time of investigation was 7.7 years.
Results and Conclusion Children with more frequent febrile seizures indicated the tendencies of a lower age of the initial seizure, a higher percentage of males and a higher percentage of a family history of febrile seizures. There was no correlation between the number of seizures and an abnormal neurologic or developmental status, but children with only one seizure showed a high incidence of an abnormal neurologic or developmental status. As a reason for this finding, it is assumed that the children with only one febrile seizure visited more frequently when the neurologic or developmental status was abnormal. Forty-one children with abnormal behavior, consisting of restlessness, clumsiness, etc., exhibited the tendencies of a higher percentage of a history of probable brain damage, more frequent seizures, a higher incidence of subsequent epilepsy and a higher percentage of abnormal EEG findings than all the children with febrile seizures. The age at the initial seizure in the children with accompanying abnormal behavior tended to be higher than in all the children with febrile seizures, but there was no difference in the duration of febl'ile seizures. Since abnormal behavior was also observed in the children for whom anticonvulsants were not prescribed, it is presumable that the abnormal behavior is due not to anticonvulsants but to the febrile seizures themselves.
A Study on Blood Levels of Anticonvulsants in Prophylaxis of Febrile Convulsions
Pharmacokinetics of Rectal Administration of Diazepam in Infants with Febrile Convulsions
Michihito Nakazawa, MD, Soichi Kodama, MD, Tamotsu Matsuo, MD Department of Pediatrics, Kobe University School of Medicine, Kobe, Hyogo
Hisao Miura, MD, Kimio Minagawa, MD, Jiro Yagi, MD Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Kanagawa
In the prophylactic treatment of complicated febrile convulsions, blood levels of anticonvulsants were determined twice a day, Cmin and C2hrs, which was done before and 2 hours after administration on the same morning. The relationship between these blood levels and the recurrence rate was investigated.
The effectiveness of rectal administration of diazepam (DZP) suppositories or solutions for the prevention of febrile convulsions was studied clinically and pharmacologically.
Material and Methods Prophylaxis criteria were as follows: (1) early or late onset (before 6 months old or after 5 years old); (2) atypical seizure (over 15 min, asymmetry or postictal paralysis); (3) recurrence rate (more than two attacks during one febrile episode, more than three attacks before 3 years old or more than four attacks of febrile convulsions); (4) a neurological deficit or preexisting brain damage; (5) epileptic discharge on EEG. Seventeen children were studied as to blood levels of anticonvulsants, Cmin and C2hrs. Ten children were treated with phenobarbital (PB), five children with sodium valproate (VPA) and two children with polypharmacy. The mean duration of prophylactic treatment was 14 months. Blood levels were determined by the EMIT assay. Results and Conclusion The results were as follows. 1) Twelve children satisfied criterion(3) and none criterion (4). Electroencephalographic studies showed 5 cases with a normal record and 5 cases with epileptic discharge. 2) Dose, Cmin, C2hrs and 6. C/C2hrs for children treated with PB were 3.6 ± 1.3 mg/kg, 10.7 ± 4.5 ILg/ml, 12.2 ± 4.7 ILg/ml and 12.8 ± 6.4%, respectively. Those for children treated with VPA were 22.3 ± 2.7 mg/kg, 59.3 ± 32.0 ILg/ml, 109.5 ± 33.5 ILg/ml, respectively. 3) Four children out of 17 who had prophylactic treatment relapsed. Two of them were treated with PB and another two children were treated with VP A or CBZ. The blood levels of these children were not lower than mean values. Electroencephalographic studies of these children did not show specific abnormality, compared to the controlled group. Epileptic discharge was found in only one out of the four relapsed children. It was suggested that determination of blood levels twice a day is important for following up children with febrile convulsions.
Subjects and Methods A single dose of 0.5 mg/kg of DZP as a suppository or a solution was given rectally to 18 infants aged 4 to 23 months with febrile convulsions. Three types of preparations were used for the study; suppositories and solutions prepared for commercial use for 6 patients each, and solutions for parenteral injections for the other 6 patients. Another 6 patients of the same age were given DZP suppositories of 0.5 mg/kg/dose twice with an interval of 8 hours. Plasma concentrations of DZP and N-desmethyldiazepam (N-desmethyl-DZP) were followed closely for the first 48 hours after rectal administration of DZP preparations. Results Rectal administration of both types of DZP solutions resulted in a rapid increase in plasma concentrations of DZP. Therapeutic plasma levels (above 150 ng/ml) were attained within 5 minutes. DZP suppositories did not give the therapeutic level until 30 minutes after administration. However, the therapeutic plasma DZP levels were maintained for a longer period (about 8 hours) after administration of DZP suppositories. The value of the absorption rate constant determined using the equation for a two-compartment open model was significantly higher after administration of DZP solutions. There were no significant differences in such parameters as AVC, TI/2, Vd/F and Cl/F between the two dosage forms, suppositories and solutions. N-desmethyl-DZP, which has also been considered to have an anticonvulsant effect, appeared in the plasma around I hour after rectal administration of both dosage forms. Plasma levels of N-desmethyl-DZP continued to increase up to 48 hours. When DZP suppositories of 0.5 mg/kg/dose were given twice with an interval of 8 hours, plasma DZP levels increased again rapidly after the second dose and were maintained within the therapeutic range for 24 hours after the first dose. Plasma levels of N-desmethyl-DZP continued to increase and exceeded those of DZP at 24 hours after administration of the first dose. No serious side effects except for transient sedation were observed in any of the pa tien ts. Conclusion A single rectal administration of DZP solution (0.5 mg/kg) is effective for the acute treatment of convulsions as an alternative route to intravenous administration in infants. A DZP suppository (0.5 mg/kg/dose) may be given to a patient at home twice with an interval of 8 hours when the temperature remains elevated, for the prevention of recurrent febrile convulsions.
Brain & Development, Vol 5, No 3,1983 343
Abstracts from the Fifth Conference on Febrile Convulsions, Tokyo, December 18, 1982
Compiled by Yukio Fukuyama, MD Clinical Observation of Febrile Convulsions in Children over 6 Years Old
Kyoko Takizawa, MD, Kiyoomi Sumi, MD Pediatric Clinic, Ikeda City Hospital, Osaka (KT); Pediatric Clinic, Kohseinenkin Hospital, Osaka (KS)
Several studies on prophylactic treatment of febrile convulsions achieved significant success in the prevention of recurrence. We studied here the prophylactic efficacy in children over 6 with febrile convulsions, as compared with non-treated controls. Subjects and Methods: Seventy-six children aged over 6 who had had febrile convulsions were seen in the pediatric clinics of Kopseinenkin Hospital and Ikeda City Hospital for over one year. 38 were placed on prophylactic anticonvulsant medication and 38 had no medication. Six of the 38 children on prophylactic medication developed non-febrile convulsions. These three groups (A: control group n = 38, B: febrile convulsions on prophylactic medication n = 32 and C: non-febrile convulsions on prophylactic medication n =6) were investigated as to age of initial and most recent febrile convulsions; perinatal abnormalities and seizure recurrence rate were compared between the groups. Results: 27 of the 38 children (71%) in group A and 29 of the 32 children (91%) in group B experienced their last febrile convulsion before the age of 6 years. Children with perinatal abnormalities showed a high incidence of febrile convulsions. The recurrence rates of febrile convulsions in groups A and B were 18% and 13%, respectively. In recurrent cases of group B, the serum anticonVUlsant levels were low, but after serum levels were restored to the therapeutic range, recurrence of febrile convulsions was well-controlled. In group C, 5 of the 6 children (83%) who experienced their initial seizure before 2 years old, had EEG abnormalities and frequent febrile convulsions before they developed non-febrile convulsions. Their serum anticonvulsant levels were also low. Conclusion: Based on our observations, we advocate prophylactic treatment for children with perinatal abnormalities, high incidence of febrile convulsions and EEG abnormalities. The serum anticonvulsant level should be kept within the therapeutic range in order to prevent recurrent febrile convulsions and, later, non-febrile seizures.
338 Brain & Development, Vol 5, No 3,1983
Kazuko Kagawa, MD, Mitsutoshi Tsuchihashi, MD, Masako Okajima, MD Department of Pediatrics, Yokohama City Hospital, Yokohama, Kanagawa
The predictive ability of the prognOSIS In children with febrile convulsions (FC) classified by the clinical types proposed by Nelson [1], Fukuyama [2] and Ohtawara [3] was examined from the viewpoint of the frequency of development of afebrile seizures and an abnormal electroencephalogram (EEG). Materials and Methods: The children with FC who visited our clinic during 1980 were selected. Among them, 172 children, 95 boys and 77 girls, whose EEG had been examined, were followed to October, 1982. Results: The average age at the first examination was 4 years and at the final examination 7-2/12 years. The average period for observation was 3-4/12 years. Abnormal EEG were observed in·36 children (20.9%). EEG was examined 465 tinIes for 172 children. The frequency of abnormal EEG showed a tendency to increase with age, and that at 5 to 6 years old was over 30%. The frequency of development of afebrile seizures was 6.9% (12 children). 8 among them showed afebrile seizures after the age of 4 years and were considered to have epilepsy. There were no significant differences among the frequencies of abnormal EEG in the R1 (Risk factor 0), R2 (Risk factor 1) and R3 (Risk factor over 2) groups classified by Nelson. The frequency of development of afebrile seizures was 2.5% in the R1 group, 8.3% in the R2 group, and 16.7% in the R3 group, showing a sinIilar tendency to the data of Nelson et al. However, these differences were not significant (0.05 < p < 0.1). There were no significant differences among the frequencies of development of abnormal EEG and afebrile seizures in the sinIple and complicated types classified by Fukuyama, using the clinical data at the first FC and also during the observation period of 3-4/12 years. However, a significant difference (p < 0.01) was shbwn among the frequencies of development of abnormal EEG and afebrile seizures between the two types, using the clinical data of the observation period over 10 years. There were no significant differences among the frequencies of development of abnormal EEG and afebrile seizures in the sinIple and complicated types classified by Ohtawara using the clinical data at the first FC. However, the frequency of abnormal EEG during the total observation period of 3-4/12 years showed a significant difference (p < 0.025) between the two types. Conclusion: The classification of Nelson predicted the prognosis best when the clinical data at the first FC were used. The classifications of Fukuyama and Ohtawara predicted the prognosis only when the clinical data of the observation period over 3 years were used. References: 1. Nelson KB. et a1. Pediatrics 1978;61 :720. 2. Fukuyama Y. ClinPsychiatr (Tokyo) 1963;5:211. 3. Ohtawara S. et al. Jpn J Pediatr (Tokyo) 1979; 32:625.
Qualitative Analysis of Paroxysmal Discharges in Electroencephalograms of Febrile Convulsions Satoshi Kimiya, MD, Tohrn Seki, MD, Yasuo Tach ibana, MD, Tetsuya Yamada, MD, Mariko Maezawa, MD, Nobuyuki Suzuki, MD, Hidenori Yamawaki, MD, Makoto Hirose, MD Department of Pediatrics, School of Medicine, Keio University, Tokyo (SK, TS, YT, TY, MM, NS, HY); Yokosuka Kyosai Hospital, Yokosuka, Kanagawa (MH) The rate of paroxysmal discharges observed in EEG of febrile convulsions varies from 2% to 86% according to the previous reports. It is controversial as to whether paroxysmal discharges in febrile convulsions are one of the risk factors presaging afebrile convulsions. In this report we focused on qualitative analysis of the paroxysmal discharges in EEG of febrile convulsions.
Materials and Methods Thirty-eight children, 24 male and 14 female, were studied, who were followed up for longer than 4 years. As paroxysmal discharges, we included spike, sharp, spike and wave. We did not consider high voltage slow burst, 6-14 Hz positive spike, wave and spike phantom in this report. The follow-up period varied from 4 to 16 years. We divided the 38 cases into two groups depending on the presence (A) or absence (B) of the risk factors postulated by Nelson. Ages were divided into four groups: 0-2 years (Group 1), 3-5 years (Group 2), 6-9 years (Group 3) and older than 10 years (Group 4). Results (1) Paroxysmal discharges were not detected in Group 1. In Group 2, generalized paroxysmal discharges were prominent while in Group 3, focal paroxysmal discharges as well as generalized ones were observed. In Group 4, paroxysmal discharges had a tendency to disappear. No differences were observed between A and B. (2) We classified the localization of the focal paroxysmal discharges into (a) frontalantetemporal, (b) central-parietal-mid temporal, (c) occipital and (d) multiple foci. In 14 out of 31 cases, paroxysmal discharges existed in the central-parietal-midtemporal area. But no significant differences were found between A and B or among Groups 1, 2, 3 and 4. Conclusions We tried to determine whether there were qualitative differences in the localization of paroxysmal discharges in EEG of febrile convulsions which might presage afebrile convulsions. The number of cases in this research was too small to conclude that the localization of the paroxysmal discharges has nothing to do with the prognosis of febrile convulsions. We should continue to focus our attention on the quality of the paroxysmal discharges in EEG.
Follow-Up Study of Children with Simple Febrile Convulsions and Epileptiform EEG Activities without Chronic Anticonvulsant Medication Takashi Kajitani, MD Department of Pediatrics, Kawasaki Hospital, Kawasaki Medical School, Okayama In order to clarify the clinical significance of epileptiform EEG activities in febrile convulsions, I carried out a follow-up study of children with simple febrile convulsions and epileptiform EEG activities without chronic anticonvulsant medication.
Subjects and Method Febrile convulsions were defined as episodes of convulsions provoked by fever of over 38.0°C associated with an acute febrile illness of extracranial origin. The subjects were 126 cases of febrile convulsions (77 boys and 49 girls) who revealed diffuse spike-and-wave bursts and/or focal spikes and had neither an abnormal neurological or developmental status nor an atypical febrile seizure, such as a prolonged or focal seizure. The average age for showing epileptiform EEG activities was 4 years and 7 months of age (from 2 years and 4 months to 9 years and 3 months). The average observation period was three years and two months (from one year to twelve years and three months). Results During the follow-up observation, 113 cases (90%) experienced no convulsive seizures, 10 cases (8%) had one or more episodes of recurrent febrile seizures and only 3 cases (2%) developed subsequent recurrent afebrile seizures. Epileptiform EEG activities consisted of diffuse spike-and-wave bursts (83 cases, 66%), Rolandic spikes (28 cases, 22%), focal spikes other than Rolandic spikes (12 cases, 10%) and diffuse spike-and-wave bursts combined with focal spikes (3 cases, 2%). There was no significant difference of the type of epileptiform EEG activities between the recurrence group (13 cases) and the non-recurrence group (113 cases). Conclusion In children with simple febrile convulsions epileptiform EEG activities do not seem to be important predictors of the recurrence of febrile seizures or of developing epilepsy after febrile convulsions. There will be a few children with simple febrile convulsions and epileptiform EEG activities who have to receive chronic anticonvulsant medication with phenobarbital or valproic acid.
Brain & Development, Vol 5, No 3, 1983 339 J
Febrile Convulsions and Electroencephalographic Abnormalities; A Regional Population Study
Makoto Matsuo, MD, Touru Kurokawa, MD Department of Pediatrics, Faculty of Medicine Kyushu University, Fukuoka
We attempted field work on febrile convulsions and electroencephalography in infants and children. Electroencephalographic examination was performed in 760 - school children, aged from 6 to 12 years, in Hisayama Town (75.1% of the whole popUlation of equivalent age). Electrodes were arranged according to 10-20 international system with 8 monopolar and 4 bipolar leads. Hyperventilation was investigated in all children. A natural sleep record was taken in about 22.1% of the Ilxamined children. After completion of the questionnaires on behavior and history of illness by parents, physical and neurological examination was done of each child.
Results (1) The incidence of a history of febrile convulsions was 7.3% in school children (febrile convulsion; FC group) and there was no sexual difference. (2) Focal spikes were found on resting EEGs in about 1.0% of the control group (no history of febrile convulsions), 5.4% of the FC group and 7.1% in the group with a family history of FC but without FC in the children themselves. (3) A pseUdo-petit mal pattern was observed in natural sleep EEGs in 13.0% of the control group, 11.8% of the FC group and 7.8% of the group with a family history of FC. Conclusion This is the first report of field work revealing that the frequency of focal spike discharges was significantly higher in the FC group and the group with a positive family history than in the control group (P 0.01).
340 Brain & Development, Vol 5, No 3, 1983
Febrile Convulsions in Tamano City. Neuroepidemiologic Observations
Shunsuke Ohtahara, MD, Sumio Ishida, MD Department of Developmental Neuroscience and Child Neurology, Institute for Neurobiology, Okayama University Medical School, Okayama
Although febrile convulsions are a major medical and social problem, their incidence and prevalence remain uncertain. We studied, therefore, in detail, the epidemiology of febrile convulsions in children. The study was undertaken in Tamano City, Okayama Prefecture, Japan, on December 31,1978. All children under five years of age were studied. A list of those exhibiting febrile convulsions was compiled from medical records of hospitals and clinics in and around Tamano City. On the target day the population of children under five years was 6,591 of a total popUlation of 79,897. The criterion used for derming febrile convulsions in this study was "any seizures associated with high fever excepting seizures due to central nervous system infection". The results were as follows: 1) On December 31, 1978, 223 febrile convulsion cases were identified, the overall prevalence rate being 33.8/1,000. 2) The annual incidence rate for febrile convulsions was estimated to be 925.5/100.000 for 1978. 3) Simple febrile convulsions were found in 117 cases (58.5%), complex febrile conVUlsions in 28 cases (14.0%) and epileptic febrile convulsions in 55 cases (27.5%). 4) The age at onset of febrile convulsions was confirmed in 198 cases. As many as 112 cases (56.6%) had their initial attack between one and two years of age, 73 cases (36.9%) between 1 and 1.5 years of age, and 39 cases (19.7%) between 1.5 and 2 years of age. On the other hand, none had the Inst convulsion under 3 months of age, oilly 6 cases (3.0%) between 3 and 6 months, and only 8 cases (4.0%) after 3 years of age. 5) Regarding the presumed etiology, 56.3% of the cases had some genetic factors for convulsions. 6) The follow-up -study by questionnaire was performed for 150 cases who were over 6 years of age on March 31, 1982. Four (4.7%) of the 85 cases who answered had developed into afebrile seizures; two cases of complex and two cases of epileptic febrile convulsions but none of simple febrile convulsions.
Kawasaki Disease with Febrile Convulsions
Chronological Change of Serum Immunoglobulin A (IgA) Level in Febrile Convulsions
Chikaya Ohtsuka, MD, Kyoko Watanabe, MD, Toshi· hiro Honda, MD, Shigeaki Inoue, MD, Yoshio Kaneda, MD, Susumu Furnkawa, MD Department of Pediatrics, Juntendo University School of Medicine, Tokyo
Hiroaki Shiihara, MD, Shuichi Hibio, MD, Motomizu Ariizumi, MD Department of Pediatrics, Nihon University School of Medicine, Tokyo
It is known that Kawasaki disease (K-D.) complicates
It has already been reported that the serum IgA
cerebral angitis and pleocytosis. The purpose of this study was to determine the frequency and charac· teristics of febrile convulsions with K-D.
Subjects: The clinical subjects consisted of 155 children with K-D. who were seen at the Pediatric Department of Juntendo University from March 1973 to July 1982. Results: The age distribution of K.D. was nearly the same as that of febrile convulsions and was from one month to 9 years of age. 88% of the subjects were less than 4 years old and the largest number of K.D. cases were found in the one year old group of chilo dren. Only one case (0.65%) of febrile convulsions was found in the febrile period of K.D. This case was a boy aged 5 years. He was born with a normal delivery and had grown with normal development. He had had, however, 5 times of febrile convulsions in his past history and 2 cases of febrile convulsions (his mother and maternal sibling) were found in his pedigree. Three days after the onset, with a body temperature of 38AoC, he had a convulsive attack which was symmetrical and of the grand mal type. His EEG showed 14 Hz positive spike waves in the period of the drowsy state at 3 weeks after the convulsive attack. Two cases of febrile convulsions were found after K.D. One of them was a boy aged 11 months without a past febrile convulsion. About one month after a typical course of K.D., he had the simple type of febrile convulsion. Another case was a girl aged 1 year with a past febrile convulsion. She had a febrile convulsion again at about 8 months after K.D. These cases showed no abnormal EEG findings. Discussion and Conclusion: K-D. is a sort of febrile illness and its age distribution is nearly the same as that of febrile convulsions. Contrary to our expectation, only one case of febrile convulsions (0.65%) was found in 155 patients with K.D. We could not find any differences between K.D. and the other febrile illness in the characteristics of febrile convulsions.
concentration is at a low level in many cases of epilepsy and febrile convulsions. We studied the chronological change of the serum IgA level and its relation to the clinical course in children with febrile convulsions with low serum IgA.
Materials and Method The serum IgA concentration was followed up for 5 months to 4 years and a month in 19 children of 33 cases of febrile convulsions with a low serum IgA level at their first visit to hospital. There were 7 cases of the simple type and 12 cases of the complicated type. Nine children had family histories of febrile convulsions. Serum IgA was measured by the single radial immunodiffusion method or laser-nepherometry. The values were compared with normal IgA levels in Japanese children and a level under mean-2SD was regarded as low. Results The serum IgA concentration became within the normal range in 8 cases in the follow up period. The age of normalization ranged from 2 years and 4 months to 4 years and 5 months. An epileptic discharge on electroencephalography (EEG) was found only in one of these 8 cases. In other 11 cases the serum IgA concentration remained at a low level. Epileptic discharges on EEG were found in 4 cases who were aged from 5 to 9 years old. These cases with a continuous low serum IgA level and EEG abnormality were thought to have the tendency to become true epileptics. Conclusion Children with febrile convulsions with low serum IgA levels are divided into two groups. In one group, the serum IgA level becomes normal in infancy and they are thought to haye a benign prognosis. In the other, it remains at a low level even in childhood. These cases often have epileptic discharges on EEG and are thought to have the tendency to become true epileptics.
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Allergy in Febrile Seizure Michiko Hara, MD, Fumie Uematsu, MD, Kazuko Kagawa, MD, Yukio Fukuyama, MD Department of Pediatrics, Tokyo Women's Medical College, Tokyo Close relationship between epilepsy and allergy has been pointed out by many authors. But the studies of allergy in febrile seizure (FS) are few. To detect the pathogenesis of FS, we examined the tendency of allergy in the children and their family members of this disorder.
Materials and Methods One hundred cases of FS, 54 of males and 46 of females, aged zero to ten, and their family members were examined about the incidence of allergic disorders such ~s bronchial asthma, atopic dermatitis, allergic rhinitis and urticaria. Results Allergies were detected in 72.0 per cent of FS patients. These consisted of bronchial asthma (36%), atopic dermatitis (31%), allergic rhinitis (32%), urticaria (16%) and others (3%). Serum immunoglobulin E levels (RIST, RAST) were examined in eleven cases. In ninety per cent of the cases examined, IgE exceeded over 100IVlm!. Family history of allergies was positive in 69.0 per cent of FS patients, and this figure was higher than that of family history of FS among the same material (58%). Conclusion We detected the high incidence of allergy in FS patients and their family members. This was thought to be the constitutional characteristics of FS patients and somewhat related to the pathogenesis of this disorder.
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Study on the Number of Seizures and the Accompanying Abnormal Behavior in Febrile Seizures Hideki Horita, MD, Hideomi Ohta, MD, Yukikatsu Ochiai, MD, Komei Kumagai, MD, Kihei Maekawa, MD Department of Pediatrics, likei University School of Medicine, Tokyo Children with febrile seizures were followed for three years or more after the first examination, and investigated clinico-electroencephalographically as to the number of seizures and the accompanying abnormal behavior. Of 488 children who were examined first for febrile seizures from 1975 to 1978, 266 (183 males, 83 females) could be followed for over three years. Follow-up information was obtained through letters and medical records. The average age at the time of investigation was 7.7 years.
Results and Conclusion Children with more frequent febrile seizures indicated the tendencies of a lower age of the initial seizure, a higher percentage of males and a higher percentage of a family history of febrile seizures. There was no correlation between the number of seizures and an abnormal neurologic or developmental status, but children with only one seizure showed a high incidence of an abnormal neurologic or developmental status. As a reason for this finding, it is assumed that the children with only one febrile seizure visited more frequently when the neurologic or developmental status was abnormal. Forty-one children with abnormal behavior, consisting of restlessness, clumsiness, etc., exhibited the tendencies of a higher percentage of a history of probable brain damage, more frequent seizures, a higher incidence of subsequent epilepsy and a higher percentage of abnormal EEG findings than all the children with febrile seizures. The age at the initial seizure in the children with accompanying abnormal behavior tended to be higher than in all the children with febrile seizures, but there was no difference in the duration of febl'ile seizures. Since abnormal behavior was also observed in the children for whom anticonvulsants were not prescribed, it is presumable that the abnormal behavior is due not to anticonvulsants but to the febrile seizures themselves.
A Study on Blood Levels of Anticonvulsants in Prophylaxis of Febrile Convulsions
Pharmacokinetics of Rectal Administration of Diazepam in Infants with Febrile Convulsions
Michihito Nakazawa, MD, Soichi Kodama, MD, Tamotsu Matsuo, MD Department of Pediatrics, Kobe University School of Medicine, Kobe, Hyogo
Hisao Miura, MD, Kimio Minagawa, MD, Jiro Yagi, MD Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Kanagawa
In the prophylactic treatment of complicated febrile convulsions, blood levels of anticonvulsants were determined twice a day, Cmin and C2hrs, which was done before and 2 hours after administration on the same morning. The relationship between these blood levels and the recurrence rate was investigated.
The effectiveness of rectal administration of diazepam (DZP) suppositories or solutions for the prevention of febrile convulsions was studied clinically and pharmacologically.
Material and Methods Prophylaxis criteria were as follows: (1) early or late onset (before 6 months old or after 5 years old); (2) atypical seizure (over 15 min, asymmetry or postictal paralysis); (3) recurrence rate (more than two attacks during one febrile episode, more than three attacks before 3 years old or more than four attacks of febrile convulsions); (4) a neurological deficit or preexisting brain damage; (5) epileptic discharge on EEG. Seventeen children were studied as to blood levels of anticonvulsants, Cmin and C2hrs. Ten children were treated with phenobarbital (PB), five children with sodium valproate (VPA) and two children with polypharmacy. The mean duration of prophylactic treatment was 14 months. Blood levels were determined by the EMIT assay. Results and Conclusion The results were as follows. 1) Twelve children satisfied criterion(3) and none criterion (4). Electroencephalographic studies showed 5 cases with a normal record and 5 cases with epileptic discharge. 2) Dose, Cmin, C2hrs and 6. C/C2hrs for children treated with PB were 3.6 ± 1.3 mg/kg, 10.7 ± 4.5 ILg/ml, 12.2 ± 4.7 ILg/ml and 12.8 ± 6.4%, respectively. Those for children treated with VPA were 22.3 ± 2.7 mg/kg, 59.3 ± 32.0 ILg/ml, 109.5 ± 33.5 ILg/ml, respectively. 3) Four children out of 17 who had prophylactic treatment relapsed. Two of them were treated with PB and another two children were treated with VP A or CBZ. The blood levels of these children were not lower than mean values. Electroencephalographic studies of these children did not show specific abnormality, compared to the controlled group. Epileptic discharge was found in only one out of the four relapsed children. It was suggested that determination of blood levels twice a day is important for following up children with febrile convulsions.
Subjects and Methods A single dose of 0.5 mg/kg of DZP as a suppository or a solution was given rectally to 18 infants aged 4 to 23 months with febrile convulsions. Three types of preparations were used for the study; suppositories and solutions prepared for commercial use for 6 patients each, and solutions for parenteral injections for the other 6 patients. Another 6 patients of the same age were given DZP suppositories of 0.5 mg/kg/dose twice with an interval of 8 hours. Plasma concentrations of DZP and N-desmethyldiazepam (N-desmethyl-DZP) were followed closely for the first 48 hours after rectal administration of DZP preparations. Results Rectal administration of both types of DZP solutions resulted in a rapid increase in plasma concentrations of DZP. Therapeutic plasma levels (above 150 ng/ml) were attained within 5 minutes. DZP suppositories did not give the therapeutic level until 30 minutes after administration. However, the therapeutic plasma DZP levels were maintained for a longer period (about 8 hours) after administration of DZP suppositories. The value of the absorption rate constant determined using the equation for a two-compartment open model was significantly higher after administration of DZP solutions. There were no significant differences in such parameters as AVC, TI/2, Vd/F and Cl/F between the two dosage forms, suppositories and solutions. N-desmethyl-DZP, which has also been considered to have an anticonvulsant effect, appeared in the plasma around I hour after rectal administration of both dosage forms. Plasma levels of N-desmethyl-DZP continued to increase up to 48 hours. When DZP suppositories of 0.5 mg/kg/dose were given twice with an interval of 8 hours, plasma DZP levels increased again rapidly after the second dose and were maintained within the therapeutic range for 24 hours after the first dose. Plasma levels of N-desmethyl-DZP continued to increase and exceeded those of DZP at 24 hours after administration of the first dose. No serious side effects except for transient sedation were observed in any of the pa tien ts. Conclusion A single rectal administration of DZP solution (0.5 mg/kg) is effective for the acute treatment of convulsions as an alternative route to intravenous administration in infants. A DZP suppository (0.5 mg/kg/dose) may be given to a patient at home twice with an interval of 8 hours when the temperature remains elevated, for the prevention of recurrent febrile convulsions.
Brain & Development, Vol 5, No 3,1983 343