Free Papers: Pediatric Aspects


*Hiroki Hasumi, *Hisamitsu Tamaki, *Masahiro Ito, and *Ichiro Seki *Department of Pediatrics, Metropolitan Bokuto Hospital, Tokyo, Japan .

Background:“Tokyo ER-Bokuto” was opened in November 2001. It covers a part of the eastern district of Tokyo, and the targeted population is ∼1.4 million.

Purpose: The aim of this retrospective study was to assess the epidemiologic outline of first unprovoked afebrile seizures in children presenting at the ER during a 1-year period.

Methods: A total of 16,435 pediatric patients visited our pediatric ER between November 2001 and October 2002: 715 patients manifested seizures, and 96 patients had afebrile unprovoked seizures. Among them, 50 patients had no previous history of seizures. We studied these 50 patients and monitored them for 1–2 years.

Results: The mean age was 4.8 years; 44% of the patients were younger than 2 years. The number of male patients was 1.6 times higher than that of female; 20% of patients had identifiable underlying diseases antedating the visit; 6% were administered theophylline at the time of visit; 34% had recurrence of seizures during the follow-up period; 52% started antiepileptic drugs (AEDs), and 18% started AEDs after the first episode. The presumed clinical seizure types were partial seizures in 44%, generalized seizures in 22%, unclassified seizures in 2%, and unknown in 32%. Among those who were diagnosed as having epilepsy, the epilepsies were classified as localization-related epilepsies (LEs) in 50%, generalized epilepsies (GEs) in 35%, and special syndromes in 15%.

Conclusions: In the ER setting, unprovoked afebrile seizures were relatively rare in children compared with seizures with fever. Although many studies questioned the necessity to start AEDs for the first unprovoked afebrile seizures, 18% of patients started AEDs at the first unprovoked afebrile seizures in our study. Most of them demonstrated either status epileptics and/or severe underlying illnesses, such as tuberous sclerosis, at presentation. Theophylline is well known for its potency to provoke seizures. Although we cannot determine if theophylline was related to the seizures, 6% of the patients were administered theophylline at the time of the ER visit in our study. We noticed that LE was more common than GE, although it was sometimes difficult to distinguish the types of seizures in the ER setting.


*Mitsugu Kimura, †Nobutada Tachi, *Kimihira Seki, *Takako Furuya, *†Masahisa Hiraki, and ‡Katsunori Fujii *Takikawa City Hospital , †School of Health Sciences Sapporo Medical University , and ‡Chiba University Graduate School of Medicine, Japan .

Background: Gorlin syndrome is an autosomal dominant disorder with full penetrance and is characterized by multiple basal cell carcinomas, palmar and plantar pits, odontogenic keratocysts, and skeletal anomalies. It has been reported that germline mutations result in the human patched (PTC) gene, which is a human homologue (PTCH) of the Drosophila patched gene that encodes a membrane receptor and regulates signal transmission. This syndrome often involves neurologic disorders, such as medulloblastoma, meningioma, intracranial calcification, and mental retardation. Some cases of epilepsy have been associated with this syndrome, but West syndrome as a complication of this syndrome has never been reported. We present the first case of Gorlin syndrome complicated by West syndrome.

Case Report: The patient was born normally at term by vaginal delivery. Mental and developmental retardation was recognized when he was followed up at the clinic. West syndrome was diagnosed based on manifestation of spasms ∼3–5 times a day and modified hypsarrhythmia recorded on the electroencephalogram (EEG) at age 7 months. Vitamin B6 and valproate sodium (VPA) were not effective. Therefore, adrenocorticotropic hormone (ACTH) injection was started. He became spasm free, and EEG findings also improved. Vitamin B6 was discontinued at age 18 months. Spasms were controlled with VPA alone, although he seemed to be delayed mentally and developmentally. Some tanned maculae appeared on his face at age ∼3.5 years. From his facial features and cranial computed tomography, depicting intracranial calcification of falx cerebri and the brain, Gorlin syndrome was suspected clinically. At age 4 years, Gorlin syndrome was diagnosed from his skin biopsy, which showed nevoid basal cell carcinoma pathologically.

Conclusions: Several mutations of the PTCH gene, which is mapped to the long arm of chromosome 9, are known to cause Gorlin syndrome. This gene is a human homologue of Drosophila patched, which encodes membrane receptor protein (PTC). The gene expression is activated at the neural tube and around the zone of polarizing activity of the somite and the limbs. That is why the patients show central nervous system and skeletal anomalies in this syndrome. There are many reports on the association of Gorlin syndrome with mental retardation as well as some abnormalities of the central nervous system, but only five reports exist of epilepsy associated with this syndrome. Although many reports have described various types and complicated patterns of seizure as well as diverse manifestations of Gorlin syndrome, Gorlin syndrome complicated by West syndrome has not been reported. In our patient, epilepsy was well controlled with medication and injection of antiepileptic drugs, as have been other cases of epilepsy in this syndrome. Although spasms were not controlled initially with only VPA and vitamin B6, control was achieved by the addition of ACTH injections. No recurrence of spasms was observed even though he was treated with only VPA.


*Yoko Ohtsuka, *Iori Ohmori, *Tatsuya Ogino, *Katsuhiro Kobayashi, and *Eiji Oka *Department of Child Neurology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan .

Purpose: Certain patients with epilepsy manifest some of the typical characteristics of severe myoclonic epilepsy in infancy (SME), but have no distinct epileptic myoclonic seizures or atypical absences. We previously reported that these borderline cases (BSME) shared the same genetic abnormality with typical SME (TSME) cases. However, the relation between TSME and BSME has not yet been fully clarified.

Patients and Methods: We performed an electroclinical investigation and genetic analyses on 56 cases that we had diagnosed and followed up. All cases had prolonged generalized or alternating hemiconvulsions beginning in the first year of life, often associated with fever and hot baths. We divided them into three groups. Group 1 (TSME) (22 cases) had myoclonic seizures associated with ictal EEG changes and/or atypical absences. Group 2 (BSME) (21 cases) lacked these two types of seizures and massive myoclonias, but most of them had erratic myoclonias. Group 3 (13 cases) had massive myoclonias, but ictal EEGs were not recorded or did not show any epileptic discharges. We reviewed all EEG records in each patient. Each case was classified as diffuse epileptic discharge–dominant type (D-type), focal epileptic discharge–dominant type (F-type), or equivalent diffuse and focal discharges (E-type), according to the ratio of EEG records with diffuse discharges versus those with only focal discharges. When the ratio was between 1.0 and 1.5, the case was classified as E-type.

Results: The mean ages at seizure onset were 4.6, 5.8, and 5.1 months in groups 1, 2, and 3, respectively. All cases had generalized seizures. Alternating hemiconvulsions occurred in 91%, 86%, and 85%, respectively, of cases in the three groups. Seizure precipitation by light and/or pattern in daily life was observed in 41% of cases in group 1 and 15% in group 3. The proportions of female patients were 73%, 43%, and 54%, respectively, in the three groups. Photoparoxysmal response and/or pattern-sensitivity on EEG were observed in 86%, 14%, and 23%, respectively, in the three groups. In group 1, 64%, 32%, and 5% of cases were classified as E-type, D-type, and F-type, respectively. In contrast, in group 2, 71%, 19%, and 5% of cases were classified as F-type, E-type, and D-type, with no spikes in 5% of cases. In group 3, 61%, 23%, and 15% of cases were classified as F-type, E-type, and D-type. Gene analyses revealed SCN1A gene mutation in 10 (77%) of 13 patients in group 1, 12 (92%) of 13 patients in group 2, and six (86%) of seven patients in group 3.

Conclusions: Patients with TSME and BSME often display erratic myoclonias without ictal EEG changes. Some TSME cases have subtle epileptic myoclonic seizures that are difficult to differentiate from erratic myoclonias without ictal EEG analyses. Accordingly, some cases cannot be diagnosed clearly as either TSME or BSME. In this study, we separated these cases as group 3 to minimize the diagnostic bias between TSME and BSME. Even with this strict classification, we confirmed our previous results about the common characteristics and differences (presence of myoclonic seizures and/or atypical absences, female predominance, and significantly higher rate of photo and/or pattern sensitivity in TSME) between TSME and BSME. Gene analyses were performed in 54–62% of cases in all groups and revealed a high rate of SCN1A mutations in all three groups, with the highest in BSME. These findings suggest that TSME and BSME are closely related from electroclinical and genetic points of view, and their differences might be caused by some as-yet-undiscovered molecular genetic difference(s).


*†Tetsuo Kubota, *Akihisa Okumura, *Toru Kato, *Hiroko Kakizawa, *Yoko Kondo, *Tamiko Negoro, ‡Nobuhiko Ochi, and *§Kazuyoshi Watanabe *Department of Pediatrics, Nagoya University School of Medicine, Nagoya ; †Department of Pediatrics, Anjo Kosei Hospital, Anjo ; ‡Aichi Daini Aoitori Gakuen, Okazaki ; and §Aichi Shukutoku University, Nagoya, Aichi, Japan .

Purpose: It is well known that periventricular leukomalacia (PVL) is sometimes associated with West syndrome (WS). However, other types of epilepsy related to PVL have not sufficiently been documented. The aim of this study was to clarify the clinical features of symptomatic localized-related epilepsy (LRE) in patients with PVL.

Methods: We retrospectively studied 96 patients who fulfilled the following conditions: (a) spastic diplegia requiring rehabilitation; (b) PVL diagnosed by magnetic resonance imaging (MRI); and (c) aged 3 years or older at the last follow-up. The definition of PVL on MRI is ventriculomegaly with an irregular margin and periventricular high-intensity areas on the T2-weighted image. The severity of PVL was classified as mild, moderate, or severe according to the extent of the brain lesions. Mild PVL was defined as lesions localized to the trigonal zone; moderate PVL, as those around the bodies and trigones of the lateral ventricles; and severe PVL, as those extending around the anterior horn of the lateral ventricles. Among these patients, seven had additional MRI findings, such as posthemorrhagic porencephaly and parasagittal infarction, and were excluded from the study.

Results: Among the 89 eligible patients, 12 had WS, 16 had epilepsies other than WS, and 61 had no epileptic seizures. All 16 patients with epilepsies other than WS had partial seizures with motor symptoms and were diagnosed as having LRE. No significant differences were found in gestational age and birth weight between patients with WS and LRE. The mean age atf onset of LRE was 5 years 5 months (range, 1 year to 12 years 10 months). The age at onset was within 2 years in three patients, 3 or 4 years in seven, 5–10 years in four, and older than 10 years in two. The mean follow-up period from the first seizure was 7 years 4 months. Nine patients had a history of febrile convulsions. One patient had only simple partial seizures, and the others had complex partial seizures. Five patients had autonomic symptoms such as ictal vomiting and nausea. Seven had secondarily generalized seizures. Interictal electroencephalography commonly revealed spikes and/or spike–waves in the parietal, temporal, and occipital areas, although frontal-dominant spikes, multifocal spikes, and diffuse irregular spike–waves were observed in some patients. PVL was moderate in two patients and severe in 10 among patients with WS; whereas it was mild in four patients, moderate in seven, and severe in five among those with LRE. Severe PVL was more frequent in patients with WS than in those with LRE (p < 0.01). At the last follow-up, seven patients were not taking antiepileptic drugs (AEDs), four had one drug, and five had two drugs. Five patients had never received AED treatment. Among them, three patients had only one seizure, one had two seizures, and two had three seizures. The number of seizures after AED treatment was 0 in two patients, one in three patients, and more than five in only two patients.

Conclusions: Our results showed that LRE associated with PVL was characterized by infrequent seizures and relatively favorable seizure outcome. The severity of PVL was milder in patients with LRE than in those with WS. Interictal paroxysmal discharges were posterior dominant and may be related to MRI abnormalities. Intensive AED treatment is necessary for patients with LRE associated with PVL.


*Akihisa Okumura, *Tamiko Negoro, *Toru Kato, *Tetsuo Kubota, *Yoko Kondo, *Yuko Kakizawa, †Kazuyoshi Watanabe, ‡Tatsuya Ishikawa, §Yoshiko Ishiguro, and ∥Hiroyuki Takada *Department of Pediatrics, Nagoya University Graduate School of Medicine ; †Faculty of Medical Welfare, Aichi Shukutoku University ; ‡Department of Pediatrics, Neonatology and Congenital Disorders, Nagoya City University Graduate School of Medical Sciences ; §Department of Pediatrics, Aichi Aoitori Medical Center for Disabled, Nagoya ; and ∥Department of Pediatrics, Tsushima City Hospital, Tsushima, Japan .

Purpose: Five years have passed since the “Pocket Monster” incident, in which the animated cartoon induced an epileptic seizure in ∼700 Japanese children. We conducted a 5-year follow-up study in patients with a Pocket Monster seizure. The aims of this study were to elucidate (a) the rate of seizure recurrence; (b) factors associated with seizure recurrence; and (c) characteristics of patients with seizure recurrence.

Methods: In December 2002, we sent questionnaires to all the physicians who had responded to the previous questionnaire survey. In the previous survey, 103 patients were reported to have a “Pocket Monster” seizure. In this study, responses to questionnaires were obtained for 91 cases. The patients were divided into two groups: 24 patients with a history of epilepsy (epilepsy group) and 67 patients without a history of epilepsy (nonepilepsy group). Photoparoxysmal response was defined as generalized spike–wave complex induced by intermittent photic stimulation. First, the relation between clinical variables and seizure recurrence in each group was investigated. Second, the patients with seizure recurrence in epilepsy and nonepilepsy groups were compared.

Results: Twenty-five (27%) patients had seizure recurrence. A recurrence of seizures was observed in 13 (19%) of 67 patients in the nonepilepsy group and in 12 (50%) of 24 patients in the epilepsy group, with a higher recurrence rate in the epilepsy group than in the nonepilepsy group (p = 0.007). In the nonepilepsy group, a history of febrile convulsion was more often observed in patients with seizure recurrence than in those without recurrence (42 vs. 13%; p = 0.046). Ninety-two percent of patients with seizure recurrence were younger than 12 years, whereas 59% of those without recurrence were younger than 12 years (p = 0.026). Multiple regression analysis showed that age younger than 12 years was associated with seizure recurrence. In the epilepsy group, photoparoxysmal response at the incident occurred more often in patients without seizure recurrence than in those with recurrence (90 vs. 18%; p = 0.002). A history of seizures within a year before the incident was more commonly found in patients with seizure recurrence than in those without recurrence (67% vs. 0; p = 0.001). Among patients with seizure recurrence, more patients in the nonepilepsy group than in the epilepsy group were younger than 12 years at the Pocket Monster incident (92 vs. 42%; p = 0.011). The interval between the incident and recurrence was shorter in the epilepsy group (median, 6 months; range, 0–40 months) than in the nonepilepsy group (median, 37 months; range, 0–58 months; p = 0.02). The rate of generalized epilepsies was higher in the nonepilepsy group than in the epilepsy group (85 vs. 17%; p = 0.001). Our study showed that the rate of seizure recurrence was 27% in patients who had a Pocket Monster–related seizure. However, 12% of the patients were lost to follow-up. We consider that the true rate of seizure recurrence was lower than the results of our study.

Conclusions: In the nonepilepsy group, the rate of seizure recurrence was 19%. Age younger than 12 years was associated with seizure recurrence. The interval between the incident and seizure recurrence was long, photoparoxysmal response was frequent, and generalized epilepsy was common among those with seizure recurrence. In the epilepsy group, the rate of seizure recurrence was 50%. Negative photoparoxysmal response at the incident and seizures within a year before the incident correlated with seizure recurrence. Moreover, the interval between the incident and seizure recurrence was short, photoparoxysmal response was less frequent, and localization-related epilepsy was common among those with seizure recurrence.


*Etsuko Yamazaki, †Takashi Sugawara, †Emi Mazaki, *Tateki Fujiwara, *Kazuichi Yagi, †Kazuhiro Yamakawa, and *Yushi Inoue *Shizuoka Medical Institute of Neurological Disorders. Shizuoka ; and †Laboratory for Neurogenetics, Brain Science Institute, RIKEN, Saitama, Japan .

Purpose: Various missense mutations of the SCN1A gene have been reported in GEFS+ families. We found a novel missense mutation in one family with GEFS+. The proband was a 9-year-old girl with a history of febrile convulsion (FC) at ages 7 months and 1 year, the latter being a left hemiconvulsive status. At age 4 years, she started to have complex partial seizures, manifesting staring arrest and facial pallor, as well as afebrile convulsions. Both of her sisters, aged 20 and 18 years, had a history of complex FCs, and the younger still has afebrile convulsions. Their mother had a history of FCs until age 5 years. The father has no relevant medical history.

Methods: All family members were screened for the SCN1A gene mutation according to the methods of our previous study (Sugawara et al., 2001). All gave written informed consent, and the study protocol was approved by the Ethical Committees of Shizuoka Medical Institute of Neurological Disorders and RIKEN.

Results: A SCN1A missense mutation (c.3980T>C, L1327S) was found in the proband, her two sisters, and their mother (all who had seizures), but not in the father (who had no seizures). This mutation was not found in the control and is thus considered to relate to these epileptic conditions.

Conclusions: All female members of the family share the same gene mutation and a history of FCs, suggesting a major role of the SCN1A gene mutation in FCs. Furthermore, a spectrum of clinical symptoms was seen among them. One sister and the mother had only FCs, the other sister has ongoing afebrile convulsions, and the proband has afebrile convulsions and complex partial seizures, implying severer symptoms in younger family members. This variation in clinical manifestations is difficult to explain by a single gene mutation. Previous reports of GEFS+ in the literature also indicated a wide spectrum of clinical manifestations, although some common features might be extracted from a detailed clinical analysis of more cases in the future. A complex relation to other genes or other undetected mutations also may be involved.


*Kiyokuni Miura, *Toshiyuki Kumagai, *Yoshiko Suzuki, †Seiji Mizuno, ‡Akiko Matsumoto, ‡Syuji Miyazaki, ‡Chiemi Hayakawa, §Junji Kato, ∥Naoko Ishihara, ¶Yasukazu Yamada, ¶Shinichi Sonta, ¶Nobuaki Wakamatsu, #Tsutomu Yamanaka, and §Masahiro Nagaya *Departments of Pediatric Neurology , †Pediatrics and §Pediatric Surgery, Central Hospital, Aichi Welfare Center for Persons with Developmental Disabilities, Kasugai ; ‡Kobato Gakuen, Aichi Welfare Center for Persons with Developmental Disabilities, Kasugai ; ∥Department of Pediatrics, Nagoya University, School of Medicine, Nagoya ; ¶Department of Genetics, Institute for Developmental Research, Aichi Welfare Center for Persons with Developmental Disabilities, Kasugai ; and #Okazaki Women's Junior College, Okazaki, Japan .

Background: Mowat–Wilson syndrome is a multiple congenital anomaly syndrome associated with deletions or mutations of the ZFHX1B gene on chromosome 2q22, which encodes Smad-interacting protein 1 (SIP1). All patients have specific facial features, severe mental retardation, and delayed motor development, often associated with microcephaly, epilepsy, congenital heart diseases, Hirschsprung disease, and midline defects such as agenesis or hypoplasia of the corpus callosum and hypospadias. We report the follow-up examinations of 14 patients with Mowat–Wilson syndrome, to clarify the electroclinical manifestation of epilepsy and the evolutionary EEG changes in this syndrome.

Subjects and Methods: We examined the clinical data and the EEGs of 14 (nine male and five female) patients with Mowat–Wilson syndrome, who had been followed up in our hospital for Hirschsprung disease or psychomotor delay. All patients had characteristic facial features, severe mental retardation, and ZFHX1B gene abnormalities (Ishihara et al., J Med Genet 2004; in press). The ages at the last follow-up were 2–30 years, with eight patients older than 20 years. Seizures associated with fever >37.5°C were defined as febrile convulsion regardless of the EEG findings. We define the onset of epilepsy as the time when the first afebrile seizure occurred.

Results: (a) Febrile convulsion and epilepsy: Febrile convulsions were observed in 12 patients spanning ages 6 months to 3 years. In two patients, seizures associated with fever repeated after the onset of epilepsy. Epileptic seizures were seen in 12 patients, and the ages at seizure onset ranged from 11 months to 4 years 9 months. The seizures occurred monthly on average in most patients. One patient without epilepsy had a history of febrile convulsions, and another patient had neither febrile convulsion nor epilepsy. (b) Prognosis of epilepsy: Six patients older than 20 years were seizure free for >3 years, and the age at the last seizure ranged from 10 years 8 months to 22 years. In one patient, antiepileptic drugs (AEDs) were discontinued at age 24 years. (c) Seizure types: Complex partial seizures and secondarily generalized seizures were observed in all cases. (d) Status epilepticus: In six patients, convulsive status epilepticus with fever was observed, and three of them had status epilepticus without fever. Another patient had only status epilepticus without fever. (e) EEG evolutional changes: The typical course of EEG findings of these patients was normal at first, followed by focal spikes, and finally continuous bilateral frontal dominant diffuse high-voltage slow waves or spike and waves from age 1 year 9 months to 9 years. Continuous bilateral frontal dominant diffuse high-voltage slow waves or spike–waves were seen in all patients. In three patients, these findings disappeared at ages 15, 19, and 22 years.

Conclusions: We believe that Mowat–Wilson syndrome is one of the main etiologic underlying diseases of epilepsy in childhood. When we see a patient with characteristic facial features, mental retardation, complex partial seizures, and specific EEG findings, we seriously consider a diagnosis of Mowat–Wilson syndrome and monitor the case carefully, bearing in mind the possibility of status epilepticus with or without fever.