Proper functioning of the nervous system relies on the precise formation of neural circuits during development. At birth, neurons have redundant synaptic connections not only to their proper targets but also to other neighboring cells. Then, functional neural circuits are formed during early postnatal development by the selective strengthening of necessary synapses and weakening of surplus connections. Synaptic connections are also modified so that projection fields of active afferents expand at the expense of lesser ones. We have studied the molecular mechanisms underlying these activity-dependent prunings and the plasticity of synaptic circuitry using gene-engineered mice defective in the glutamatergic signaling system. NMDA-type glutamate receptors are critically involved in the establishment of the somatosensory pathway ascending from the brainstem trigeminal nucleus to the somatosensory cortex. Without NMDA receptors, whisker-related patterning fails to develop, whereas lesion-induced plasticity occurs normally during the critical period. In contrast, mice lacking the glutamate transporters GLAST or GLT1 are selectively impaired in the lesion-induced critical plasticity of cortical barrels, although whisker-related patterning itself develops normally. In the developing cerebellum, multiple climbing fibers initially innervating given Purkinje cells are eliminated one by one until mono-innervation is achieved. In this pruning process, P/Q-type Ca²⁺ channels expressed on Purkinje cells are critically involved by the selective strengthening of single main climbing fibers against other lesser afferents. Therefore, the activation of glutamate receptors that leads to an activity-dependent increase in the intracellular Ca²⁺ concentration plays a key role in the pruning of immature synaptic circuits into functional circuits. On the other hand, glutamate transporters appear to control activity-dependent plasticity among afferent fields, presumably through adjusting extracellular glutamate concentrations to optimally reflect their different neural activities in postsynaptic target neurons. Thus, armed with both molecular mechanisms, functional neural circuits develop and mature during the early postnatal period.

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  Objective: The purpose of this study is to develop a computer training program of reading for the Japanese dyslexic children and to examine its short-term efficacy on their reading and writing abilities.
  Methods: Fifteen dyslexic children underwent two sets of training programs, one for single-hiragana and non-word reading, and the other for the reading of real words, in which each hiragana was followed by the correctly read sound. Subjects were required to use a given program for five minutes a day for three weeks, switching to the other program after a three-week interval. Four kinds of reading test and one writing test were done at the beginning and end of each program period.
  Results: The averages reading speeds increased, and the single-hiragana reading error average was lower after the training. Hiragana-writing errors also decreased, even though no writing procedure was involved in the programs.
  Conclusions: The results indicate the usefulness of these training programs as an early intervention of reading and writing for the Japanese dyslexic children.

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  Objective: We examined the effectiveness of repeated adrenocorticotropic hormone (ACTH) therapy in short-term and long-term seizure control in patients with intractable epileptic spasms.
  Methods: Twenty-five patients with intractable spasms, in whom epileptic seizures were not controlled or relapsed after the first ACTH therapy, were given repeated ACTH therapy. The short-term effect (seizure control longer than two months) of repeated ACTH therapy was analyzed, and the long-term effect was estimated by Kaplan-Meier method.
  Results: Short-term seizure control by repeated ACTH therapy was achieved in 13 of 25 patients (52.0%), and in 5 of 13 patients, seizures were controlled by ACTH therapy at higher doses compared with the first ACTH therapy. Short-term effectiveness was obtained in 76.5% of patients who had epileptic spasms alone at the time of the second ACTH therapy, but was ineffective in all 8 patients who had multiple types of seizures, with relapses within 2 months. Short-term effectiveness was not associated with clinical factors such as onset age, age of repeated ACTH treatment, and EEG findings.
  Regarding the long-term effect of repeated ACTH therapy, the period until seizure relapse was significantly longer in patients with epileptic spasms alone compared to patients with multiple seizure types. Spasms were controlled in 5 of 25 cases (20.0%) at the final observation. In patients with multiple seizure types and patients with onset age older than eight months, seizure control was not obtained. Long-term outcome was good in patients with treatment lag within 2 months.
  Conclusion: In repeated ACTH therapy, seizure type seems to be one of the major determinants for short-and long-term seizure outcome.

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  Objective: Ketogenic diets tend to cause trace mineral deficiencies. Ketonformula is a foumula for a ketogenic diet developed by Meiji Co Ltd in Japan. No reports are available on the trace mineral deficiencies associated with a use of Ketonformula.
  Methods: We monitored the serum levels of selenium, zinc and copper as well as the amount of the daily intake of these minerals before and at 6 months after the initiation of the ketogenic diet with Ketonformula in six patients with intractable epilepsy associated with severe motor and intellectual disabilities.
  Result: The median serum selenium concentration decreased from 7.0 (range, 6.5-12.3) μg/dl to 6.2 (5.4-10.9) μg/dl as a result of the 6-month-treatment with Ketonformula (p<0.05, Wilcoxon signed-rank test). The median daily selenium intake decreased from 17.8 (15.0-27.0) μg/day at the baseline to 5.5 (5.0-22.0) μg/day after 6 months on the diet (p<0.05). The median serum zinc concentration increased slightly (from 66.0 (46.0-84.0) μg/dl to 68.0 (46.0-71.0) μg/dl), but the difference was not significant. The median daily zinc intake, however, significantly decreased from 4.2 (3.7-6.0) mg/day to 2.2 (2.0-3.0) mg/day (p<0.05). The median serum copper concentration also showed no significant decrease (from 134.5 (119.0-168.0) μg/dl to 126.0 (86.0-183.0) μg/dl). The median daily copper intakes, however, decreased significantly from 0.80 (0.35-1.30) mg/day to 0.30 (0.26-0.40) mg/day (p<0.05).
  Conclusions: The decline of the serum selenium concentrations and daily enteral intakes of selenium, zinc, and copper after 6 months on Ketonformula suggested that patients on this ketogenic formula needs close monitoring as well as supplementation of these trace minerals.

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  Objective: The clinical characteristics of neurological sequelae in patients with acute encephalopathy with febrile convulsive status epilepticus (AEFCSE) was elucidated.
  Methods: We retrospectively reviewed 8 patients, which were admitted to our hospital from 2002 to 2011.
  Results: In the subacute phase, transient neurological symptoms, such as dystonia (n=3), choreoathetosis (n=2), oral tendency (n=5) and unilateral spatial neglect (n=6), appeared from 3 weeks after onset. Then, severe intellectual disability (n=7), attention deficit (n=7), disturbance of communication skill (n=7) and emotional disturbance (n=2), persisted from one month after onset. Although seven patients resumed ambulatory abilities, six exhibited unstable gait without ataxia or muscular weakness. The neuroradiological findings on MRI corresponded to the clinical course. In the subacute phase, reversible bilateral signal changes were noted in the subcortical white matter (n=8), caudate nuclei (n=2), putamen (n=1) and thalamus (n=1). In the chronic phase, diffuse cortical atrophy, predominantly in the fronto-temporal lobes. Diffuse cortical atrophy suggested that the persistent neurological sequelae of AEFCSE represent cortical dysfunction. Therefore, we propose that the unstable gait in our patients was gait ataxia, being related to the frontal lobe dysfunction.
  Conclusions: These neurological findings of AEFCSE showed characteristic temporal changes, which should be considered in the development of rehabilitation programs.

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  Objective: We investigated the visiospatial disturbance in 103 children with acute encephalopathy at more than one year from the onset.
  Methods: The patients were divided into two groups: group① with visiospacial disturbance (43 cases), group② without (60 cases). We checked the etiology, consciousness loss, complications and disabilities including higher cortical dysfunction in their medical charts.
  Results: The average age of onset was 3 years 5 months in group①, and that 2 years 8 months in group②. Regarding the etiology, influenza infection, was most common (36 cases), and there was no statistical difference between two groups. The duration of consciousness loss was 10.8 days in group① and 7.7 days in group②. The abnormal region on MRI brain and single photon emission computed tomography was mainly the occipital area in group① and the frontal area in group②. Prominent complicating disabilities comprised higher cortical dysfunction, such as visiospatial disturbance in group① and interpersonal skill disturbance in group②. The symptoms of visiospatial disturbance were difficulty in searching, writing, recognizing bumps, etc. After proper evaluation and rehabilitation programs, continuous performance of the programs was necessary in daily living.
  Conclusions: It is important for children with acute encephalopathy to be checked for visiospatial disturbance. An early rehabiitation approach should be taken for children with visiospatial disturbance.

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  Objective: The purpose of this study was to assess the characteristics of women with epilepsy who developed polycystic ovary syndrome (PCOS) owing to therapy with valproate sodium (VPA).
  Methods: Our study comprised 77 patients on therapy with VPA—20 patients with PCOS and 57 without PCOS (control group). We assessed their epilepsy type, status of seizure control, and mental and physical statuses as well as the starting age, administration period, total dosage, and the highest value of blood concentration of VPA.
  Results: As compared with the control group, the PCOS group showed significantly high rates of association with mental retardation, severe physical disabilities, and poor seizure control, and symptomatic generalized epilepsy. However, the starting age, administration period, total dosage, and the highest value of blood concentration of VPA were not significantly different between the 2 groups. Nineteen of the 20 patients with PCOS had characteristically high androstenedione levels.
  Conclusions: Our study demonstrated that refractory symptomatic generalized epilepsy, polypharmacy including VPA and severe motor and intellectual disabilities are risk factors of developing PCOS.

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  Brain hypoperfusion observed on single-photon emission computed tomography (SPECT) is a typical finding in the acute phase of human herpesvirus-6 (HHV-6) encephalopathy. However, from 2004 to 2010, we encountered three cases of HHV-6 encephalopathy in which hyperperfusion in the area of the brain lesion was observed on SPECT performed within 48 hours after disease onset. The hyperperfusion in the brain was followed by hypoperfusion in the recovery phase. These cases suggest that hyperperfusion may appear in damaged areas prior to the hypoperfusion that is normally associated with HHV-6 encephalopathy.

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  Febrile myoclonus is a benign neurological symptom induced by fever. The physiological mechanism is unknown. We herein report a 1 year and 7 months old male patient with intermittent jerks of the whole body during a high fever caused by acute otitis media. He experienced more than 50 jerks over a period of 2 days. The jerks appeared only during sleep. He showed no impairment of consciousness and no abnormalities in neurological examination, blood examination, electroencephalogram, or brain MRI findings. We diagnosed him with febrile myoclonus. The myoclonic jerks disappeared as the fever decreased without neurological sequelae. To the best of our knowledge, febrile myoclonus only during sleep has never been reported. To clarify the pathophysiology of febrile myoclonus, we should focus on the relationship between the myoclonus and the sleep/awake states.

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  We report two patients with latent general myasthenia gravis (MG) with refractory ocular symptoms who were successfully treated with pre-evening meal administration of tacrolimus. Patient 1 was a 4-year-old girl with persistent ocular symptoms despite high-dose steroid therapy and thymectomy. Oral tacrolimus was initiated at the age of 3 years, which was resulted in complete resolution of symptoms. After one year, hemilateral ptosis recurred. The plasma consentration of tacrolimus was very low, probably due to sudden weight gain. Increasing the dose and a change from post-to pre-evening meal administration of tacrolimus enabled maintenance of its concentration and complete control of ocular symptoms. Patient 2 was a 2-year-old boy whose symptoms were refractory to steroid therapy after his first relapse. Since post-meal administration of tacrolimus provided partial benefit, the closing schedule was changed to pre-evening meal administration, with good results. Neither patient had adverse effects of tacrolimus. It is difficult to maintain an effective tacrolimus concentration in children due to marked growth and rapid metabolic rates. Pre-evening meal administration of tacrolimus is an easy, safe and useful method of treatment in MG young children.

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[in Japanese]

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