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We report here two boys who presented with atrophy of the right calf muscle. The onset was insidious and the symptom was found in infancy in case 2. They were followed for more than 5 years and no progression was seen. No sensory disturbances or autonomic nervous system symptoms were observed. Although needle electric myograph and muscle biopsy findings showed a neurogenic pattern, no cause was confirmed. Recently, a new disease concept of "benign monomelic amyotrophy of lower limb" was established and this could be applied to these patients. This disorder is rare and it is seen in young adults. It is characterized by non-progressive unilateral calf muscle atrophy. There is almost no possibility that this disorder is a variant of spinal muscular atrophy. When a patient presents with unilateral calf muscle atrophy, the treatable causes of the atrophy, including spinal cord disorders or peripheral nerve disorders, should be excluded first. If a confirmed cause cannot be found, then there should be a careful follow-up of the patient, even if the symptoms are stable.

Here we report a 12-year-old boy with idiopathic neuralgic amyotrophy who had two episodes of shoulder pain followed by shoulder muscle atrophy and weakness at the age of 7 and 11 years, respectively. These symptoms were self-limited and disappeared within 9 months. During the second episode, electromyograph (EMG) revealed neurogenic changes in the deltoid muscle. Muscle imaging showed the right deltoid muscle atrophy with slightly high intensity areas on T1 and T2 weighted images in MRI. Muscle biopsy from the right deltoid muscle revealed neurogenic changes with denervating and reinnervating processes. Neuralgic amyotrophy is characterized by neuralgic pain followed by weakness and atrophy at a unilateral extremity and is usually self-limited. EMG and imaging studies showed focal neurogenic abnormalities, which were confirmed by muscle biopsy. Neuralgic amyotrophy usually occurs in young adults and it is very rare in children.

Chronic unilateral pleural effusion developed in three patients with severe motor and intellectual disabilities. All patients received 5-15 years of dantrolene administration for their spasticity. The cause of pleural effusion was indistinct, despite close investigations for etiologies such as infection or tumor. The pleural fluid consisted of sterile exudate in all patients. One patient had eosinophilia in his pleural fluid, while peripheral blood eosinophilia was seen in the other two. The pleural biopsy and autopsy specimens revealed only non-specific inflammatory findings. After dantrolene therapy was discontinued, pleural effusion almost disappeared in two patients in the following several months, but the other died of multi-organ failure from another underlying disease. It is important to take chemical pleurisy into consideration when dealing with pleural effusion of unknown etiology. Moreover, respiratory side effect should be examined in patients treated with chronic dantrolene administration.

We made a 3-dimensional, 99mTc-ECD brain perfusion single photon emission computed tomography (SPECT) database in children by a statistical analysis. We selected 52 individuals between 1 and 15 years of age whose brain SPECT and brain MRI findings were normal, and divided them into three age groups: 1-5, 6-10 and 11-15 years. By comparing databases obtained for each group, an age-dependent change of regional cerebral blood flow was investigated. The results showed that the relative blood flow increases in the frontal lobe and cerebeller hemisphere and decrease in the occipital lobe with increasing age, findings consistent with those of previous reports. This database enabled us to easily find 3-dimensional brain perfusion abnormality in individual patient by SPECT, and may help elucidate the pathophysiology of many brain disorders.

We examined efficacy of continuous midazolam (MDL) infusion in seven episodes of refractory nonconvulsive status epilepticus (NCSE) in five children. Diagnosis included Lennox-Gastaut syndrome (two cases), and symptomatic generalized epilepsy, ring chromosome 20 syndrome, and epilepsy with continuous spike-waves during slow-wave sleep (one case each). One patient with Lennox-Gastaut syndrome and another with ring chromosome 20 syndrome had two episodes of NCSE. MDL was given as an initial bolus of 0.15 to 0.3 mg/kg, followed by continuous intravenous infusion at 0.1 to 0.2 mg/kg/hr. The infusion rate was increased slowly by 0.1 mg/kg/hr every 0.5 to 1.0 hr, up to 0.4 mg/kg/hr or until NCSE was controlled. The electroencephalogram, vital signs, blood pressure, and oxygen saturation were monitored during therapy. Electrical status epilepticus was abolished within a few hours in five of the seven episodes, and two patients could maintain wakefulness, oral intake, and bowel and bladder control throughout the continuous infusion. In one patient in whom NCSE recurred, it then remained uncontrolled even at a maximum dose. Serious complications such as respiratory depression or hypotension were not observed. Continuous intravenous infusion of MDL was effective and safe for NCSE in children, and can be used as firstline therapy for this condition.

Objective: Microsomal epoxide hydrolase (mEH) is an enzyme that detoxifies reactive epoxides and catalyzes the biotransformation of carbamazepine-10,11-epoxide (CBZ-epoxide) to carbamazepine-10,11-diol (CBZ-diol). Utilizing single nucleotide polymorphisms (SNPs) of the EPHX1 gene encoding mEH, we identified the haplotypes of EPHX1 blocks and investigated the association between the block haplotypes and CBZ-epoxide metabolism., Methods: SNPs of EPHX1 were analyzed by means of polymerase chain reaction amplification and DNA sequencing using DNA extracted from the blood leukocytes of 96 Japanese epileptic patients, including 58 carbamazepine-administered patients. The plasma concentrations of CBZ and its four metabolites were determined using high-performance liquid chromatography., Results: From sequencing all 9 exons and their surrounding introns, 29 SNPs were found in EPHX1. The SNPs were separated into three blocks on the basis of linkage disequilibrium, and the block haplotype combinations (diplotypes) were assigned. Using plasma CBZ-diol/CBZ-epoxide ratios (diol/epoxide ratios) indicative of the mEH activity, the effects of the diplotypes in each EPHX1 block were analyzed on CBZ-epoxide metabolism. In block 2, the diol/epoxide ratios increased significantly depending on the number of haplotype *2 bearing Y113H (P=0.0241). In block 3, the ratios decreased depending on the number of haplotype *2 bearing H139R (P=0.0351). Also, an increasing effect of a *1 subtype, *1c, was observed on the ratio., Conclusion: These results show that some EPHX1 haplotypes are associated with altered CBZ-epoxide metabolism. This is the first report on the haplotype structures of EPHX1 and their potential in vivo effects.

In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A4 in a Japanese population, the distal enhancer and proximal promoter regions, all exons, and the surrounding introns were sequenced from genomic DNA of 416 Japanese subjects. We found 24 SNPs, including 17 novel ones: two in the distal enhancer, four in the proximal promoter, one in the 5'-untranslated region (UTR), seven in the introns, and three in the 3'-UTR. The most common SNP was c.1026+12G>A (IVS10+12G>A), with a 0.249 frequency. Four non-synonymous SNPs, c.554C>G (p.T185S, CYP3A4(*)16), c.830_831insA (p.E277fsX8, (*)6), c.878T>C (p.L293P, (*)18), and c.1088 C>T (p.T363M, (*)11) were found with frequencies of 0.014, 0.001, 0.028, and 0.002, respectively. No SNP was found in the known nuclear transcriptional factor-binding sites in the enhancer and promoter regions. Using these 24 SNPs, 16 haplotypes were unambiguously identified, and nine haplotypes were inferred by aid of an expectation-maximization-based program. In addition, using data from 186 subjects enabled a close linkage to be found between CYP3A4 and CYP3A5 SNPs, especially among the SNPs at c.1026+12 in CYP3A4 and c.219-237 (IVS3-237, a key SNP site for CYP3A5(*)3), c.865+77 (IVS9+77) and c.1523 in CYP3A5. This result suggested that CYP3A4 and CYP3A5 are within the same gene block. Haplotype analysis between CYP3A4 and CYP3A5 revealed several major haplotype combinations in the CYP3A4-CYP3A5 block. Our findings provide fundamental and useful information for genotyping CYP3A4 (and CYP3A5) in the Japanese, and probably Asian populations., (Copyright 2003 Wiley-Liss, Inc.)

Six novel nonsynonymous nucleotide alterations were found in the cytochrome P450 1A2 gene in a Japanese population, which resulted in the following amino acid substitutions: T83M, E168Q, F186L, S212C, G299A, and T438I. These individuals were heterozygous for the amino acid substitutions. The potential functional alterations caused by the amino acid substitutions were characterized by a cDNA-mediated expression system using Chinese hamster V79 cells. Among the six CYP1A2 variants, F186L showed the most profound and statistically significant reduction in O-deethylation of phenacetin and 7-ethoxyresorufin. Kinetic analyses performed for the ethoxyresorufin O-deethylation revealed that the Vmax of the F186L variant was approximately 5% of that of the CYP1A2 wild type, despite a 5-fold lower Km value of the variant, the consequence of which was reduced enzymatic activity toward the substrate. Thus, for the first time, phenylalanine at residue 186 is suggested to be a critical amino acid for catalytic activity.

We studied serial median nerve somatosensory evoked potentials (SEPs) and short latency somatosensory evoked potentials (SSEPs) in 17 patients with West syndrome. Four of the 7 patients with absent SEPs in the initial examination showed recognizable SEPs in the follow-up studies, associated with improvement of electroencephalogram (EEG). This indicated that SEPs were variable with condition of epilepsy and lack of initial SEPs was not always a poor prognostic factor for seizure control and developmental outcome. Persistent lack of SEPs, however, indicated poor outcome of seizures, EEG and development. Central conduction time in SSEPs did not correlate with seizure or developmental outcome.

We report here a 6-year-old boy with narcolepsy. The diagnostic criteria were met by the clinical symptoms including excessive daytime sleepiness and cataplexy, and by the results of overnight polysomnography (PSG), multiple sleep latency test (MSLT), and human leukocyte antigen (HLA). PSG showed increased ratio of sleep stages 1 and 2 due to frequent awakening. All the five test session of MSLT showed a sleep onset REM period. HLA typing was positive for DRB1* 1501 and DQB1* 0602. Though the present case had very early onset, all the clinical symptoms and results of sleep studies met the criteria of narcolepsy. The CSF orexin level was far below the lower limit of the control values. It is very useful to measure CSF orexin for the diagnosis of early onset narcolepsy.

Benign myoclonus of early infancy (BMEI) is a non-epileptic paroxysmal phenomenon. Some patients with BMEI were mistakenly treated as infantile spasms, because the fits resemble to tonic spasms in infantile spasms and they occur in cluster. However, the patients have normal development and no abnormal electroencephalograms (EEG), and the fits spontaneously subside without sequelae. There are only a few reports on BMEI, and it is not widely recognized in Japan. We report three cases of BMEI. All the cases were suspected to have infantile spasms from the characteristic features of paroxysmal events, and the parents had strong anxiety because of recurrent fits. However, the fits decreased dramatically in about three months, and spontaneously disappeared within one year without any sequelae. BMEI might be included in cases of suspected infantile spasms, and such patients should be followed by monthly EEG examinations and close observation for other seizure phenomena. To avoid unnecessary treatments, such patients should be observed without any therapeutic trials including antiepileptic drugs.

Parents' of patients with pediatric neurological disorders were sent a questionnaire, on their assessment and needs for home mechanical ventilation (HMV). Nine of 12 enrolled families responded. Respirator troubles were handled by a contracted HMV company. Decreased SpO2 levels and endotracheal bleeding were cared by family members under telephone instructions of doctors, though they felt anxious about dealing the problems. The mothers felt happy to live with their children by virtue of HMV, however, they had strong stress about the management of emergency care and medical care technique. They also felt very tired physically, but refreshed by being free from daily HMV care for a short time and enjoying their own time. The parents were not satisfied with the present house facilities and education system. They evaluated the induction of HMV positively but were most anxious for a better home care nursing system, doctors responding to a house call, more information on HMV, reduction of their anxieties and fatigue, and improvement of economical and educational environments.

We present the effects and adverse effects of dichloroacetate (DCA) in a girl with mitochondrial disorder. Oral administration of DCA 50 mg/kg per day, reduced the elevated levels of lactate to below the normal range. Treatment with DCA ameliorated electroencephalogram abnormalities, but caused the adverse effects with hepatomegaly and decreased activity, which were improved by reduction or withdrawal of DCA. The decreased activity may be an adverse effect on the central nervous system. The dosage of DCA should be adjusted for each patient.

Three patients with severe motor and intellectual disabilities presented deterioration of the activities of daily living, which was revealed to be caused by prolonged non-convulsive status epilepticus (NCSE). Their condition improved by the treatment with antiepileptics. Case 1, a 4-year-old girl with profound psychomotor retardation and past history of West syndrome of unknown etiology, became unable to sit and eat orally above age of two years. EEG showed continuous generalized slow spike and wave bursts indicating NCSE. Continuous intravenous infusion of midazolam abolished EEG abnormalities of NCSE, and she regained the ability of oral feeding. Case 2, a 3-year-old boy with Angelman syndrome and past history of West syndrome, presented decreased mental response, poor oral intake and somnolence. EEG showed continuous slow spike and wave bursts, indicating NCSE. High-dose phenobarbital therapy and continuous intravenous injection of vitamin B6 were effective, and remarkably improved his psychomotor activities. Case 3, a 3-year-old boy with Lennox-Gastaut syndrome, developed decreased psychomotor activity and loss of vocalization and walking. He could not sit by himself and became nearly bed-ridden. EEG showed very frequent generalized spike and wave bursts, showing NCSE. Continuous infusion of thiopental diminished NCSE, and he could walk again. Psychomotor deterioration in patients with severe motor and intellectual disabilities may be caused by NCSE, which should not be overlooked.

Five novel single nucleotide polymorphisms (SNPs) were found in the EPHX1 gene from 96 Japanese epileptic patients. The detected SNPs were as follows: 1) SNP, MPJ6_EX1009; GENE NAME, EPHX1 ACCESSION NUMBER, NT_004525.12; LENGTH, 25 bases; 5'-CCTCACTTCAGTG/ACTGGGCTTTGCC-3'. 2) SNP, MPJ6_EX1013; GENE NAME, EPHX1; ACCESSION NUMBER, NT_004525.12; LENGTH, 25 bases; 5'-TCCGCAGCCAGGG/CAGGACGACAGCA-3'. 3) SNP, MPJ6_EX1026; GENE NAME, EPHX1; ACCESSION NUMBER, NT_004525.12; LENGTH, 25 bases; 5'-GTTCTCCCTGGAC/TGACCTGCTGACC-3'. 4) SNP, MPJ6_EX1028; GENE NAME, EPHX1; ACCESSION NUMBER, NT_004525.12; LENGTH, 25 bases; 5'-AGGCAGGGGGACG/AGCCAGTCTTGGG-3'. 5) SNP, MPJ6_EX1030; GENE NAME, EPHX1; ACCESSION NUMBER, NT_004525.12; LENGTH, 25 bases; 5'-TGAAAAGTGGGTG/AAGGTTCAAGTAC-3'. The frequencies were 0.016 for MPJ6_EX1028 (IVS8+54G>A) and 0.005 for the other SNPs. The SNP MPJ6_EX1013 (130G>C) results in an amino acid alteration (E44Q). The other three SNPs in the coding region, MPJ6_EX1009 (30G>A), MPJ6_EX1026 (1056C>T), and MPJ6_EX1030 (1239G>A) result in synonymous changes (V10V, D352D, and V413V, respectively).

We report oral high-dose phenobarbital therapy for a patient with early infantile epileptic encephalopathy with suppression bursts (Ohtahara syndrome). At 1 month of age, many series of tonic spasms, with raising limbs and crying lasting for a few minutes, developed and increased up to approximately 300 times per day. Initially intravenous midazolam (0.5 mg/kg/hour) slightly decreased the seizures, although oral vitamin B6, valproic acid, clonazepam, and zonisamide had little effect. Oral high-dose phenobarbital therapy was begun at a dosage of 15 mg/kg/day, and the seizures markedly decreased to 5-10 times per day and the epileptic discharges on electroencephalogram greatly decreased. Serum phenobarbital levels ranged between 60 and 100 mg/dL. High-dose phenobarbital therapy should be considered for the treatment of early infantile epileptic encephalopathy with suppression bursts.

The management of refractory status epilepticus (RSE) is crucial in preventing neurologic impairment. Although a variety of treatments for RSE including continuous infusion of midazolam (MDL) or pentobarbital (PTB) have been carried out, they are not always effective. Intravenous very-high-dose phenobarbital (PB) has been recommended as having many advantages in the United States, but is not available in Japan. We treated 3 patients suffering from long term RSE with non-intravenous high-dose PB (NIHDPB). Their seizures were not controlled by continuous infusion of MDL and/or PTB. PB was initially given intramuscularly or rectally and then orally. Within a few or ten days, seizures were completely controlled, and consciousness level gradually improved in all cases. The serum levels of PB at seizure control ranged from 50 to 58 micrograms/ml. The epileptiform activities on EEG nearly disappeared in the absence of the burst suppression pattern. Hypotention and respiratory depression did not develop during NIHDPB. Elevated gamma-GTP levels with normal hepatic transaminases were seen in all cases, but it was not necessary to discontinue NIHDPB. NIHDPB may be one of the most effective and safe treatments in Japan for status epileptics refractory to continuous infusion of MDL or PTB.

Eleven novel single nucleotide polymorphisms (SNPs) were found in the NR1I2 (PXR/SXR) gene from 205 Japanese subjects. The detected SNPs were as follows: 1) SNP, MPJ6_1I2001; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-TTTCTACCTCTAC/TTATTGAAAGGGC-3'. 2) SNP, MPJ6_1I2004; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-AGGCCCAAATGTG/AAGTGATGCATAG-3'. 3) SNP, MPJ6_1I2007; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-TGCCAGGCCTGCC/TGCCTGCGCAAGT-3'. 4) SNP, MPJ6_1I2008; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GAGTGAGCAGTGG/CGCGCGCGGGCGG-3'. 5) SNP, MPJ6_1I2010; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-CAGAGGAGCAGCG/AGATGATGATCAG-3'. 6) SNP, MPJ6_1I2011; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-CTGGAAGTGGCCA/GGGAGGTTCAAAG-3'. 7) SNP, MPJ6_1I2013; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-TCTTCCTCTCGCC/TCCCAACTTCTGG-3'. 8) SNP, MPJ6_1I2017; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-ATTGAATGCAATC/TGGCCCCAGCCTG-3'. 9) SNP, MPJ6_1I2018; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GGTGAGCACAGCA/GGGGGGTGAGGAC-3'. 10) SNP, MPJ6_1I2019; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GAGCTCCGCAGCA/GTCAATGCTCAGC-3'. 11) SNP, MPJ6_1I2021; GENE NAME, NR1I2; ACCESSION NUMBER, AF364606; LENGTH, 25 bases; 5'-GGTGACACCTCCG/AAGAGGCAGCCAG-3'. The frequencies were 0.0293 for MPJ6_1I2021, 0.0073 for MPJ6_1I2011, and 0.0024 for the other 9 SNPs. All SNPs were found as heterozygous. Among these SNPs, MPJ6_1I2007, MPJ6_1I2010, MPJ6_1I2017 and MPJ6_1I2019 induce non-synonymous amino acid alterations (R98C, R148Q, R381W and I403V, respectively, in PAR1).