Glycosylphosphatidylinositol (GPI) is a glycolipid, which anchors 150 or more types of proteins to the cell surface. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins (GPI-APs). Many inherited GPI deficiencies (IGDs) have been recently found using whole-exome sequencing. Patients with IGD have only a partial deficiency because complete GPI deficiency causes embryonic death. The major symptoms of IGDs include intellectual disability, epilepsy, coarse facial features, and multiple organ anomalies. These symptoms vary in severity depending upon the degree of the defect and/or position in the pathway of the affected gene. We clarified a mechanism of hyperphosphatasia, which is characterized by elevated release of tissue-nonspecific alkaline phosphatase. Hyperphosphatasia is observed in some patients with IGDs, such as hyperphosphatasia mental retardation syndrome or Mabry syndrome, caused by mutations in genes in the later stage of GPI biosynthesis. The possibility of IGD should be considered in patients with seizures and intellectual disability. The presence of hyperphosphatasia is strong evidence of IGD. Flow cytometric analysis of GPI-APs on granulocytes is also useful for the detection of IGD.

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  Objective: This study was undertaken to investigate the electroencephalographic (EEG) characteristics in patients with febrile status epilepticus. Methods: Medical records and EEG findings were retrospectively examined in 14 patients with febrile status epilepticus, who were transferred to the Shiga University Hospital between November, 2009 and March, 2012. Results: Mean time to the initial EEG examination from the cessation of febrile status epilepticus was 3.4 hours. δ waves were seen in 9 of 11 patients during awake or forced awake state, and these slow waves disappeared on or after the 2nd day. Slow waves were predominantly detected in the occipital and frontal leads in 4 and 2 patients, respectively, while diffuse slowing was seen in 4 patients. Spindle/hump waves were observed in 10 of 11 patients, but not detected in the 3 patients because only awake recordings were available. Conclusions: EEGs in the postictal state of febrile status epilepticus show slow waves, but improve early, then normal EEG sleep pattern such spindle/hump waves are commonly recognized thereafter.

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  Objectives: The purpose of the present study was to evaluate the efficacy and safety of topiramate (TPM) on inter-ictal headache in children with epilepsy. Methods: Patients were interviewed regarding whether they suffered from headaches. Data obtained from each patient included seizure frequency. Inter-ictal headache was defined as a headache beginning outside an hour before or after the seizure. The study group included 85 outpatients (42 valproate-treated, 34 carbamazepine-treated, 6 combination therapy, 3 other) between 5 and 15 years old. For children with headache, TPM was administered twice daily at a total initial dose of 0.5 mg/kg/day, up to 3.0 mg/kg/day in accordance with symptoms. Results: Of 85 patients, 18 (21.2%) patients (8 valproate-treated, 6 carbamazepine-treated, 3 combination therapy, and 1 other) complained of inter-ictal headache. Seizure frequency was significantly higher in children with headache (2.6 times/year) than in children without headache (0.9 times/year ; p<0.0001). The responder rate (rate of patients with a >50% reduction in headache frequency or degree) was 13/18 (72%). Six children (33.3%) achieved complete cessation for the entire 6 months. Mean dose of TPM was significantly lower in responders (1.1 mg/kg/day) than in non-responders (2.7 mg/kg/day ; p<0.001). Conclusions: Headache is encountered more frequently in patients with frequent seizures. In addition, TPM represents a useful addition to the treatments available for headache in children with epilepsy. The effective dose of TPM for headache may be lower than that for seizure.

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  Objective: We carried out a questionnaire survey to investigate the uses of melatonin and ramelteon in Japanese children. Methods: We sent a questionnaire to councilors of the Japanese Society of Child Neurology by e-mail, and sent the same questionnaire to members of the Japanese Society of Pediatric Psychiatry and Neurology by postal mail. Results: During the first phase of the survey, 220 responses were obtained, and 45% of the respondents prescribed melatonin. Imported supplements and chemical reagents were used by 64% and 29% of melatonin prescribers, respectively. Some prescribed melatonin without patient consent or institutional approval. In patients with pervasive developmental disorder, cerebral palsy, attention-deficit hyperactivity disorder, Rett syndrome, and visual disturbance, melatonin was prescribed by 37%, 29%, 10%, 6%, and 6% of the respondents, respectively. In terms of sleep disorders, melatonin was prescribed by 49% and 42% of respondents in patients with circadian rhythm disorders and insomnia, respectively. Ramelteon was prescribed by 52% of respondents. Regarding types of target diseases and sleep disorders, the use of ramelteon differed little from that of melatonin. In the second phase of the survey on the use of melatonin, 23 doctors prescribed the drug for 254 patients. The daily effective dose ranged from 0.2 mg to 8 mg in patients aged 2 months to 37 years. In more than 60% of the patients who took melatonin, PDD was diagnosed. In the patients with melatonin for insomnia, 90% and 25% had difficulty falling asleep and disorders in circadian rhythm, respectively. Conclusions: Both melatonin and ramelteon were widely prescribed in Japanese children. Melatonin tended to be used without sufficient ethical consideration in Japan, indicating the necessity of melatonin as medicine. Then, careful determination of an applicable dose are required in future studies.

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  Objective: Severe muscle hypertonia in patients with the mixed type of tetraplegia may be associated with significant deterioration in the quality of life of the patients. Intermittent use of oral muscle relaxant drugs, for example, Tizanidine (Ternelin^®), which is a fast-acting muscle relaxant, can provide relief from the severe hypertonia in these patients, but only for short durations. Methods: We conducted a retrospective study of the effect of continuous infusion of tizanidine via a feeding tube on the severe systemic muscle hypertonia in patients with the mixed type of tetraplegia. We mixed tizanidine with milk or other enteral nutrients and administered the mixture via a naso-duodenal tube at a constant infusion rate several hours to 5 patients with the mixed type of tetraplegia showing severe uncontrolled systemic hypertonia under intermittent treatment with oral muscle relaxant drugs. Results: Significant relief from the systemic muscle hypertonia was obtained in 4 of the 5 patients with improvement of the quality of life of the patients, e. g., they could get adequate sleep. There were no serious side effects in any of the cases. Conclusion: We consider that continuous infusion of tizanidine via a feeding tube would be useful for the treatment of severe systemic hypertonia in patients in whom the symptom cannot be adequately controlled by intermittent use of oral muscle relaxant drugs.

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  Objective: We performed high-dose erythropoietin therapy (hEPO) for acute encephalopathy or encephalitis (AE), and evaluated its safety and efficacy. Methods: We performed hEPO in AE patients with widespread lesions demonstrated by diffusion-weighted imaging, and prospectively investigated changes in hemoglobin levels, adverse events, changes in images, and developmental quotients. Results: All four patients showed neither an increase in the hemoglobin level nor adverse event possibly related to hEPO. One patient with acute encephalitis showed resolution of the lesion and normal developmental quotient. Two patients who had acute encephalopathy with febrile convulsive status epilepticus showed mild cerebral atrophy in the recovery phase; one had a normal developmental quotient. The patient with acute necrotizing encephalopathy including a brainstem lesion avoided acute-phase death. Conclusion: Two patients showed no sequelae despite images indicating widespread abnormality. hEPO could be performed safely in patients with AE, however further trials are necessary concerning its efficacy.

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  Objective: Reports of the prognosis of cerebrovascular disease (CVD) in children have not been common. We investigated the prognoses in 71 children with CVD, which were composed of 43 and 28 patients, suffering from hemorrhagic stroke (HS) and ischemic stroke (IS), respectively. They were followed for at least one year after the stroke event. Methods: The average age of onset was 9 years 8 months in HS and 6 years 8 months in IS, the present ages being 13 years 5 months and 12 years 5 months, respectively. The medical records were reviewed, and the clinical courses during the acute stage and the state of sequelae were investigated. Results: The etiologies were rupture of the arteriovenous malformation in 29 cases in HS, and traumatic brain damage, during rewarming from hypothermia therapy or during operations such as for heart diseases in IS. An age-related characteristic was seen in the heart diseases operation group. The main damaged regions were the frontal lobe, temporal lobe, parietal lobe, and cerebellum in HS, and the middle cerebral arterial area, basal ganglia, and frontal lobe in IS. The damage in the infra-tentorial area was more frequent in HS than in IS. The sequelae comprised physical disabilities in 39 cases with HS and 25 cases with IS, mental disabilities in 11/11, epilepsy in 4/7, and higher brain dysfunction such as attention deficit in 31/26. Severe disabilities were low as one case each. Conclusion: The etiology, region, and sequelae differed between HS and IS in children.

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  Objective: To propose an adequate rehabilitation program for children suffering from hypoxic-ischemic encephalopathy (HIE) based on estimated outcomes. Methods: Participants were 42 children, 28 boys and 14 girls, who suffered from HIE after neonatal period. We divided them into three groups; favorable (GMFCS level 1 or 2), moderate (level 3 or 4), and unfavorable (level 5), and compared the extent of brain lesions on MRI, age of onset, and complications among the groups. Results: The number of children in favorable, moderate, and unfavorable groups was 10, 10 and 22, respectively. All children in favorable and moderate groups showed focal cerebral lesions on MRI. In contrast, most children in unfavorable group (19/22) had diffuse brain damage and the rest were infantile onset with focal cerebral lesions. The etiology and situation of HIE did not differ among three groups. Three children in moderate group whose onsets were earlier than 5 months showed lesions similar to those in neonatal HIE; in bilateral basal ganglia, thalamus, and perirolandic cortex. In favorable group, 7 children were able to walk independently within 5 months after the insult, but 9 had moderate or severe mental retardation and 3 showed severe visual impairment. A majority of unfavorable group developed scoliosis or hip dislocation, and underwent tracheostomy or gastrostomy. Five children who had stayed acute hospitals for longer than 6 months developed irreversible complications such as joint contractures before discharge. Conclusions: Children with focal cerebral lesions need continual rehabilitation and education for mental retardation and visual impairment, even if they can walk within several months after HIE. Those with diffuse brain damage need sufficient rehabilitation as early as possible to avoid developing secondary complications. MR image, age of onset, and clinical course were of great prognostic value to make appropriate long-term rehabilitation and education programs.

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  Creatine transporter deficiency (CRTR-D) is an X-linked disorder characterized by hypotonia, developmental delay, and seizures. We report the third Japanese family with CRTR-D. The proband was an 8-year-old boy who presented with hypotonia, severe intellectual disability and two episodes of seizures associated with/without fever. Among 7 siblings (4 males, 3 females), the eldest brother had severe intellectual disability, epilepsy, and sudden death at 17 years of age, while 18-year-old third elder brother had severe intellectual disability, autism, and drug-resistant epilepsy. The proband's urinary creatine/creatinine ratio was increased. A reduced creatine peak on brain magnetic resonance spectroscopy and a known pathogenic mutation in the SLC6A8 gene (c.1661 C>T;p.Pro554Leu) confirmed the diagnosis of CRTR-D. The same mutation was found in the third elder brother. Their mother was a heterozygote. Symptoms of CRTR-D are non-specific. Urinary creatine/creatinine ratio should be measured in patients with hypotonia, developmental delay, seizure and autism whose family history indicates an X-linked inheritance.

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[in Japanese]

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[in Japanese]

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