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Introduction Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is a non-catalytic component of the multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their correct tRNAs. Bi-allelic truncating variants in the AIMP1 gene have been associated with hypomyelinating leukodystrophy-3 (HLD3; MIM 260600), which is characterized by hypomyelination, microcephaly, seizures and decreased life expectancy. Although peripheral nerve involvement has been assumed for HLD3, no compelling evidence is available to date. Case report The case was a first-born Filipino male. He showed profound developmental delay, failure to thrive, and spasticity in his limbs. At three months of age he developed refractory epilepsy. Serial magnetic resonance imaging (MRIs) showed profound myelination delay and progressive cerebral atrophy. He showed abnormal nerve conduction studies. Genetic testing revealed a homozygous pathogenic variant in the AIMP1 gene (NM_004757.3: c.115C > T: p.Gln39*). The parents were heterozygous for the same variant. Conclusion Here, we report a patient with a homozygous nonsense AIMP1 variant showing peripheral neuropathy as well as HLD3. Our case suggests that AIMP1 plays a pivotal role in the peripheral nerve as well as the central nervous system.

We summarize the long-term motor outcome and disability level in a cluster of pediatric patients with acute flaccid myelitis (AFM) associated with the enterovirus D68 outbreak in 2015.This is a nationwide follow-up questionnaire analysis study. Clinical data including the motor function (manual muscle strength test) and other neurological symptoms were collected at the acute (nadir), recovery (six months), and chronic (three years) stages. We use the Barthel index, which measures 10 variables describing activity of daily living and mobility to assess the disability level.Clinical data of 33 patients with AFM (13 females, 20 males; median age = 4.1 years) were available. Among patients with tetraplegia or triplegia, paraplegia, and monoplegia at the acute stage, two of seven, four of thirteen, and two of thirteen exhibited complete recovery without paralysis; of those five of seven, eight of thirteen, and two of thirteen showed improvement with lesser limb involvement at the chronic stage, respectively. Nine patients (27%) demonstrated improvement at the recovery-to-chronic period. All six patients with positive isolation of enterovirus D68 from biological samples at the acute stage showed persistent motor deficits. Other neurological findings had better prognosis than motor weakness. Better Barthel index score at the chronic stage was observed (P 0.001; median difference [95% confidence interval], 53 [40 to 63]), implying an improved disability level even in patients with persistent motor deficits.AFM has a high rate of persistent motor deficits showing one- to two-limb paralysis. Disability level of patients with AFM, however, generally improved at the three-year time point.

Purpose To establish an objective method of [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) that can assist in the diagnosis of glucose transporter 1 deficiency syndrome (GLUT1-DS). Methods FDG-PET was performed in 8 patients with a mean age of 12.5 years (range, 2–22 years) with GLUT1-DS. Their PET findings were compared with those of 45 controls with a mean age of 11.2 years (range, 2–21 years) by statistical parametric mapping (SPM12, Welcome Neurological Institute). The controls had epilepsy of unknown etiology and normal MRI findings. The age-adjusted ratios of mean radioactivities in regions of interest (ROIs) of bilateral lenticular nuclei, thalami, and the whole cerebral cortex were also measured. The sensitivities and specificities of the ratios for the differential diagnosis of GLUT1-DS were also determined. Results SPM showed significantly decreased uptake in bilateral thalami and increased uptake in bilateral lenticular nuclei in patients with GLUT1-DS. There were no areas in the cerebral cortex with significant differences between patients and controls. On ROI analysis, by setting the cut-off value of the age-adjusted lenticular nuclei/thalami radioactivity ratio to 1.54, patients with GLUT1-DS were differentiated from controls with sensitivity of 1.00 and specificity of 0.98. Conclusion The age-adjusted lenticular nuclei/thalami radioactivity ratio on PET can distinguish patients with GLUT1-DS from patients with epilepsy of unknown etiology with high sensitivity and specificity. It is important to pay attention to the metabolism of the lenticular nuclei and thalami on PET for the diagnosis of GLUT1-DS.

Objective To investigate clinical risk factors for acute magnetic resonance imaging (MRI) abnormalities in patients with benign convulsions with mild gastroenteritis or benign infantile epilepsy. Study design We investigated clinical and diffusion-weighted imaging findings in 32 patients with benign convulsions with mild gastroenteritis and 22 patients with benign infantile epilepsy who underwent MRI within seven days of seizure onset between 2010 and 2015. Results Diffusion-weighted imaging showed signal hyperintensity in the splenium of the corpus callosum in seven patients with benign convulsions with mild gastroenteritis, but no abnormalities in patients with benign infantile epilepsy. Patients with benign convulsions with mild gastroenteritis with splenial lesions showed a higher rate of rotavirus detection from feces (P = 0.006), higher serum level of C-reactive protein (P = 0.04), and shorter interval between seizure onset and MRI (P = 0.002) than patients with benign convulsions with mild gastroenteritis without splenial lesions. Multivariate analysis revealed rotavirus infection as a significant risk factor for splenial lesions on diffusion-weighted imaging in patients with benign convulsions with mild gastroenteritis (P = 0.02). Conclusions Splenial lesions are often seen during acute period in patients with benign convulsions with mild gastroenteritis. Rotavirus infection is a risk factor for splenial lesions in patients with benign convulsions with mild gastroenteritis, suggesting the role of rotavirus to cause edema in the corpus callosum. From our observations, benign convulsions with mild gastroenteritis with a splenial lesion on diffusion-weighted imaging suggests good outcomes, and extensive evaluation of these patients may be unnecessary.

BackgroundVariants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear.MethodsWe examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.ResultsPathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.ConclusionsPrenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

Mucolipidosis type IV (MLIV) is a rare lysosomal storage disorder causing severe psychomotor developmental delay and progressive visual impairment. MLIV is an autosomal recessive disease caused by mutations in MCOLN1, which encodes for mucolipin-1. Here, we report a case of a 4-year-old Japanese girl with severe intellectual disability and motor deficits. Brain magnetic resonance imaging showed signal abnormalities in the white matter and thinning of the corpus callosum. Whole-exome sequencing was performed on the proband and her parents, and novel compound heterozygous mutations at c.936_938del (p.Phe313del) and c.1503dupC (p.Ile502Hisfs*106) in MCOLN1 (NM_020533.2) were identified in the proband. Additional biochemical examinations revealed elevated serum gastrin level and iron deficiency anemia, leading to the diagnosis of MLIV. More reports of such pathogenic mutations are expected to broaden the understanding of the channel function of mucolipin-1 and genotype-phenotype correlations.

Purpose This study was performed to clarify the clinical features of Japanese patients with PRRT2 mutations. Methods The PRRT2 gene was analyzed in 135 patients with benign infantile epilepsy (BIE) or paroxysmal kinesigenic dyskinesia (PKD) using a direct sequencing method: 92 patients had BIE alone, 25 had both BIE and PKD, and 18 had PKD alone. Of the cases, 105 were familial, and 30 were sporadic. Clinical information was collected using a structured questionnaire. Results PRRT2 mutations were identified in 104 patients. Among the familial cases, PRRT2 mutations were found in at least one individual in 21 of 28 families with BIE alone, in 26 of 27 families with infantile convulsions and choreoathetosis, and in 2 of 3 families with PKD alone. Among the sporadic cases, PRRT2 mutations were observed in 7 of 25 patients with BIE alone, in 1 of 1 patient with BIE and PKD, and in 3 of 4 patients with PKD alone. The c.649dupC mutation was the most frequent, followed by the c.981C > G mutation. Among the patients with epilepsy, the median age at BIE onset was 5 months, the median age at the last seizure was 6 months, and the median number of seizures was 5. Conclusion PRRT2 mutations were found in 68% of Japanese probands with BIE or PKD. The phenotypes of BIE associated with PRRT2 mutations were consistent with those of BIE diagnosed clinically.

We investigated the usefulness of segmental multifrequency bioelectrical impedance analyses (MBIA) for assessing muscle involvement in Duchenne muscular dystrophy (DMD) patients. Bioelectrical impedance data of the upper arm, thigh, and lower leg were obtained from 29 boys with DMD (ages 2–17 years old; mean 10.8 ± 3.9 years) at three institutions along with 41 healthy controls (ages 3–16; mean 9.8 ± 3.5 years). Then the muscle density index (MDI: 1- Z250/Z5) was calculated using segmental MBIA and compared between groups. The MDI was lower in boys with DMD, relative to controls, with older DMD patients exhibiting a significant decrease in MDI. The MDI of patient thighs was significantly correlated with the percent muscle volume index (%MVI), as measured using computed tomography (r = 0.79). MDI values for the upper arm, thigh, and lower leg were all significantly correlated with the Brooke and the Vignos scales, respectively, with correlation coefficients of 0.56–0.77. Finally, MDI was significantly greater in the glucocorticoid-treated group, relative to the untreated group in all regions. Taken together, these data show that segmental MBIA is feasible for evaluating muscle involvement and might serve as an outcome measure in DMD.

Epilepsy with myoclonic absences is a specific seizure type characterized by bilateral rhythmic clonic jerks with impairment of consciousness. Here, we report an individual with epilepsy with myoclonic absences, mild intellectual disabilities, language disorder, and autism spectrum disorder. His interictal electroencephalogram revealed a spike‐and‐slow wave complex dominant in the frontal area. His ictal polygraphic and video‐electroencephalogram showed a characteristic diffuse synchronous 3‐Hz spike‐and‐wave burst associated with bilateral upper limb myoclonic jerks with impairment of consciousness. Using whole‐exome sequencing, we found a novel de novo variant, c.386T>G, p.(Val129Gly), in SETD1B (SET domain containing 1B). We previously reported that two individuals with a de novo SETD1B variant showed intellectual disability, epilepsy, and autism. Of note, one of those individuals and the present case showed epilepsy with myoclonic absences. Therefore, this report supports the indication that SETD1B may be a causative gene for neurodevelopmental disorders and suggests that epilepsy with myoclonic absences may be a characteristic feature of SETD1B‐related disorders.

Background Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have a large impact on patients and their families. Improving intellectual ability outcomes using preventive vigabatrin (VGB) treatment has recently been reported. Aim The aim of this study was to investigate the severity of behavioral problems and degree of distress among families of patients with TSC with and without a history of VGB treatment. Method The study enrolled 21 children and adolescents who were patients with TSC from four hospitals: 14 in the VGB group and 7 in the no-VGB group. To evaluate patients' psychiatric and neurological symptoms, we used the TAND Checklist, Aberrant Behavior Checklist (ABC), Social Communication Questionnaire (SCQ), and Social Responsive Scale–2nd edition (SRS-2). Results All VGB-group patients were administered VGB after the onset of epileptic seizures. No obvious differences were observed between the VGB and no-VGB groups in behavioral problem scores on the TAND Checklist, or on the ABC, SCQ, and SRS-2 total scores. Behavioral problem scores were lower in patients with normal intelligence than in those with mild intellectual disability (ID; P = 0.042). Degrees of family distress assessed with the TAND Checklist were not correlated with the intelligence quotient/developmental quotient (IQ/DQ) or seizure frequency but were correlated with the total SRS-2 scores (P = 0.022). For several patients, there were large discrepancies between familial and physician ratings of the TAND impact score. Conclusion Children and adolescents with TSC may present with significant behavioral difficulties and family distress, regardless of whether they were treated with VGB or not after the onset of seizures. Difficulties in social communication may have the strongest “TAND impact” on families.

Objective To assess the success rate, procedure time, and adverse events of intrathecal administration of nusinersen via the paramedian approach in adolescents and adults with spinal muscular atrophy (SMA) associated with scoliosis. Methods Seven patients with genetically confirmed SMA (age, 12–40 years) were included. Intrathecal administration of nusinersen was performed via paramedian approach using fluoroscopy after determination of the largest interlaminal foramen among L2-L3, L3-L4, or L4-L5 by three-dimensional computed tomography. We measured the times for preparation, positioning, and puncture, and the total time of stay. Adverse effects of intrathecal administration were noted. Results Intrathecal administration via paramedian approach was successful for all 38 opportunities. The median total time of stay was 44.0 min (interquartile range, 37.3–50.0 min). The total time of stay was significantly longer in patients with SMA type 1 than in those with SMA type 2, but was not different according to the severity of scoliosis. Adverse effects included oxygen supplementation, headache, and back pain. Sedation was correlated with oxygen supplementation and headache. Conclusions Intrathecal administration of nusinersen via the paramedian approach had the advantages of a high success rate and short procedure time with fewer adverse events in SMA patients associated with scoliosis.

To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD)., info:eu-repo/semantics/published

An 11-year-old male was admitted to our hospital with the acute exacerbation of chronic heart failure. A peripherally inserted central catheter (PICC) was inserted from the left forearm. Ten days after its insertion, the withdrawal of PICC was attempted because of occlusion. However, it was not possible to remove PICC because a fibrin sheath had attached around its tip. A color Doppler and probe compression technique revealed the presence of a fibrin sheath, which could not be detected by gray-scale (real-time B-mode) ultrasonography. This case demonstrated that the color Doppler and probe compression technique is useful for detecting a fibrin sheath. Keywords: Peripherally inserted central catheter, Fibrin sheath, Ultrasonography, Probe compression technique

OBJECTIVE To clarify longitudinal changes in white matter microstructures from the onset of disease in patients with West syndrome (WS) of unknown etiology. METHODS Diffusion tensor imaging (DTI) was prospectively performed at onset and at 12 and 24 months old in 17 children with WS of unknown etiology. DTI was analyzed using tract-based spatial statistics (TBSS) and tract-specific analysis (TSA) of 13 fiber tracts, and fractional anisotropy (FA) and mean diffusivity (MD) were compared with those of 42 age-matched controls. Correlations of FA and MD with developmental quotient (DQ) at age 24 months were analyzed. Multiple comparisons were adjusted for using the false discovery rate (q-value). RESULTS TBSS analysis at onset showed higher FA and lower MD in the corpus callosum and brainstem in patients. TSA showed lower MD in bilateral uncinate fasciculi (UF) (right: q < 0.001; left: q = 0.03) at onset in patients. TBSS showed a negative correlation between FA at onset and DQ in the right frontal lobe, whereas FA at 24 months old exhibited a positive correlation with DQ in the diffuse white matter. MD for bilateral UF at 24 months old on TSA correlated positively with DQ (q = 0.04, both). SIGNIFICANCE These findings may indicate the existence of cytotoxic edema in the immature white matter and dorsal brainstem at onset, and subsequent alterations in the diffuse white matter in WS of unknown etiology. Microstructural development in the UF might play important roles in cognitive development in WS.

An m.10158T>C mutation in MT-ND3, encoding a subunit of respiratory complex I, causes early-onset Leigh syndrome (LS), mitochondrial encephalomyopathy with lactic acid and stroke-like episodes (MELAS) syndrome, and LS and MELAS overlapping syndrome, presumably dependent on the ratio of heteroplasmy. Herein, we report a 4-year-old girl with heteroplasmic m.10158T>C mutation, showing an evolving age-dependent phenotype from LS to MELAS syndromes. She showed mild developmental delay during infancy, which was associated with magnetic resonance imaging lesions in the brain stem and basal ganglia. At the age of 4 years, she developed rapid neurological deterioration and intractable seizures, which was associated with recurrent multiple cerebral lesions as well as basal ganglia lesions. Her cerebral lesions were located predominantly in white matter and appeared at multiple areas simultaneously, unique characteristics that are distinct from typical MELAS. Two patients with LS-MELAS overlapping syndrome with m.10158T>C have been previously reported, however, this is the first patient with m.10158T>C showing significant age-dependent changes in clinical features and neuro-images, implying an age-dependent role of complex I in the developing brain.

A loss of function mutation in SLC9A6 (Xq26.3) is responsible for Christianson syndrome in males. We identified a novel splicing mutation (NM_006359.2:c.1141-8C>A) of SLC9A6 in a seven-year-old boy with microcephaly, severe developmental delay, and intractable epilepsy. Functional analysis found multiple aberrant transcripts, none of which maintained the canonical open reading frame. Computer prediction tools, however, failed to detect all of the aberrant transcripts.

AIM We developed quality-of-life (QOL) scales for patients receiving home medical care. The objective of this study was to examine the agreement between the scores of the scales answered by patients and those answered by their proxy, as cognitive decline may interfere with one's ability to understand complex topics, such as the QOL. METHODS Participants were pairs of patients receiving home medical care and their proxy. The patients were asked to complete self-reported QOL scales (QOL-HC), and their proxies were asked to complete proxy-reported versions of the QOL scales (QOL-HC for caregivers). We then statistically examined the extent of agreement between the self- and proxy-reported QOL-HC scores using contingency tables and Spearman's rank correlation coefficient. The SPSS software program, version 24, was used for all statistical analyses. RESULTS The concordance rate between patients and caregivers for questions 1 ( "Do you have peace of mind?" ), 2 ( "Do you feel satisfied with your life when you reflect on it?" ), 3 ( "Do you have someone that you spend time talking with?" ), and 4 ( "Are you satisfied with the home care service system?" ) were 52.3%, 52.3%, 79.5%, and 81.8%, respectively. The total scores for the patients and caregivers were significantly correlated (Spearman's ρ=0.364*). CONCLUSIONS We created the first QOL scale for patients receiving home-based medical care and for caregivers. The findings of this study suggest that the QOL-HC can be used in clinical practice for the assessment of patients receiving professional home care.

Background Germline mutations of the PTEN gene are responsible for several PTEN hamartoma tumor syndromes. They are also implicated as a cause of macrocephaly and mild to severe developmental delay, regardless of the presence or absence of hamartomas in childhood. Nevertheless, because of limited information, the clinical features present during childhood in patients with a PTEN mutation are yet to be elucidated. Methods PTEN mutations were investigated by multiplex targeted sequencing of genomic DNA from 33 children with increased head circumference (>+2 SD) and developmental delay. The clinical features of all the patients with a PTEN mutation were abstracted by dysmorphologists. Results We have identified six children with a PTEN mutation. Clinical dissection of these six patients, in addition to patient reports in the literature, revealed distinctive facial features that included frontal bossing, dolichocephaly, horizontal eyebrows, and a depressed nasal bridge. Macrocephaly (+3.2 to +6.0 SD) was noticeable compared to their height (−0.8 to +2.1 SD), and the difference in the SD value of head circumference and height was more than 3 SD in all patients. Conclusion The presence of distinctive facies, extreme macrocephaly with normal to mildly high stature, and developmental delay may be useful for identifying patients with a PTEN mutation in childhood. Early identification of patients with a PTEN mutation would help uncover the natural course of tumor development in this group of individuals who have a possible predisposition to cancer, and be important for the development of an optimal surveillance strategy.

Introduction Filamin A (FLNA) is located in Xq28, and encodes the actin binding protein, filamin A. A mutation in FLNA is the most common cause of periventricular nodular heterotopia (PVNH), but a clear phenotype-genotype correlation has not been established. Indeed, some patients with a FLNA mutation have recently been shown to additionally have Ehlers-Danlos-like collagenopathy or macrothrombocytopenia. In an attempt to establish a clearer correlation between clinical symptoms and genotype, we have investigated a phenotype that involves thrombocytopenia in a patient with a truncation of the FLNA gene. Case report We present the case of a 4-year-old girl who, at birth, showed a ventral hernia. At 2 months of age, she was diagnosed with patent ductus arteriosus (PDA) and aortic valve regurgitation. At 11 months, she underwent ligation of the PDA. She was also diagnosed with diaphragmatic eventration by a preoperative test. At 19 months, motor developmental delay was noted, and brain MRI revealed bilateral PVNH with mega cisterna magna. Presently, there is no evidence of epilepsy, intellectual disability or motor developmental delay. She has chronic, mild thrombocytopenia, and a platelet count that transiently decreases after viral infection. Dilation of the ascending aorta is progressing gradually. Genetic testing revealed a de novo nonsense heterozygous mutation in FLNA (NM_001456.3: c.1621G > T; p.Glu541Ter). Immunofluorescence staining of a peripheral blood smear showed a lack of filamin A expression in 21.1% of her platelets. These filamin A-negative platelets were slightly larger than her normal platelets. Conclusion Our data suggests immunofluorescence staining of peripheral blood smears is a convenient diagnostic approach to identify patients with a FLNA mutation, which will facilitate further investigation of the correlation between FLNA mutations and patient phenotype.

Patients with a mutation at Arg756 in ATP1A3 have been known to exhibit a distinct phenotype, characterized by prolonged weakness and encephalopathy, triggered by febrile illness. With only eight reports published to date, more evidence is required to correlate clinical features with a mutation at Arg756. Here we report an additional case with an Arg756Cys mutation in ATP1A3. A four-year-old boy showed mild developmental delay with recurrent paroxysmal episodes of weakness and encephalopathy from nine months of age. Motor deficits, which included bilateral hypotonia, ataxia, dysmetria, limb incoordination, dysarthria, choreoathetosis, and dystonia, were observed from one year and three months. Whole-exome sequencing detected a heterozygous de novo variant at c.2266C>T (p.Arg756Cys) in ATP1A3. The episodic course and clinical features of this case were consistent with previously reported cases with mutations at Arg756. Furthermore, his phenotype of marked ataxia was more similar to that of an Arg756Cys patient with relapsing encephalopathy and cerebellar ataxia syndrome, than to those with Arg756His and Arg756Leu mutations. This report therefore provides evidence of genotype-phenotype correlations in ATP1A3-related disorders as well as in patients with mutations at Arg756 in ATP1A3.

Vici syndrome (VICIS) is a rare, autosomal recessive neurodevelopmental disorder with multisystem involvement characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Mutations in EPG5, a gene that encodes a key autophagy regulator, have been shown to cause VICIS, however, the precise pathomechanism underlying VICIS is yet to be clarified. Here, we describe detailed clinical (including brain MRI and muscle biopsy) and genetic features of nine Japanese patients with VICIS. Genetic dissection of these nine patients from seven families identified 14 causative mutations in EPG5. These included five nonsense, two frameshift, three splicing, one missense, and one multi-exon deletion mutations, and two initiation codon variants. Furthermore, cultured skin fibroblasts (SFs) from two affected patients demonstrated partial autophagic dysfunction. To investigate the function of EPG5, siRNA based EPG5 knock-down, and CRISPR/Cas9 mediated EPG5 knock-out HeLa cells were generated. EPG5-depleted cells exhibited a complete block of autophagic flux caused by defective autophagosome-lysosome fusion. Unexpectedly, endocytic degradation was normal in both VICIS SFs and EPG5 depleted cells, suggesting that EPG5 function is limited to the regulation of autophagosome-lysosome fusion.

We encountered two children with acute encephalopathy associated with unique clinical manifestations. Both the patients had status epilepticus at onset and neuroimaging studies revealed marked brain edema and bilateral thalamic lesions. Although they were treated with steroids and immunoglobulin, their outcomes were very poor. A thermolabile variant of carnitine palmitoyltransferase II and an elevated interleukin-6 level in cerebrospinal fluid were observed in one patient each. The constellation of clinical and neuroimaging findings in our patients is apparently not consistent with any established subtype of acute encephalopathy/encephalitis.

The purpose of this study was to examine the relationship between the volume and number of tubers and the age at seizure onset in patients with tuberous sclerosis complex. We also examined the relationship between the volume and number of cyst-like tubers and the age at seizure onset.We retrospectively studied 23 patients with TSC (16 males and 7 females, mean age 12.4 ± 9.5 years). Routine structural MR-imaging data analysis was performed using QBrain. Total brain volume, total tuber volume, and the number of tubers were measured semi-automatically. Additionally, the total volume and the number of only cyst-like tubers were measured. The tuber/brain proportion (TBP) and the cyst-like tuber/brain proportion (cTBP) were calculated, and these were compared with the age at seizure onset. The numbers of tubers and cyst-like tubers were also compared with the age at seizure onset.For both TBP and the number of tubers, a significant negative correlation with age at seizure onset was identified (ρ = -0.69, p0.01 and ρ = -0.56, p0.01). No significant correlation of cTBP or the number of cyst-like tubers with age at seizure onset was identified (ρ = -0.26, p = 0.37 and ρ = -0.048, p = 0.87).TBP may be associated with age at seizure onset.

Newborn males are more sensitive to brain injury than newborn females are. The aim of the present study was to find an explanation for this. We used the neuron-specific enolase (NSE) levels in the cerebrospinal fluid (CSF) for the classification of 32 newborns (19 males and 13 females) on their fifth postnatal day. The NSE levels were higher than normal (8.4 +/- 1.6 ng/mL) in 10 newborn males and 6 females and were, respectively, considered asphyxiated male and female groups. The remaining newborns, 9 males and 7 females, had normal CSF levels of NSE and were considered normal newborn male and female groups. The CSF samples were measured for 12 cytokines, using a cytokine array kit, and for total hydroperoxide and biological antioxidant potentials (BAPs), using the free radical analytic system. Among the 12 cytokines measured, only interleukin 8 (IL-8) was properly detected. The CSF levels of IL-8 were higher in the asphyxiated newborn females than in the other three groups. The mean CSF levels of BAPs in the asphyxiated newborn females were higher compared with the other three groups, but significance was detected only in comparison with the BAP levels in the CSF samples of the normal newborn males. There were no differences in total hydroperoxide levels among the groups. There are sex-related differences in the CSF levels of IL-8 and antioxidants in asphyxiated newborns, with higher levels in newborn females; this might contribute in the sexual dimorphism regarding the fact that females have better protection from brain injury than the males.

West syndrome (WS) is a generalized epileptic syndrome of infancy and early childhood with various etiologies, and consists of a triad of infantile spasm, arrest or regress of psychomotor development and specific electroencephalogram (EEG) pattern of hypsarrhythmia. WS had been believed to be refractory, but recent evidence supports effectiveness of adrenocorticotropic hormone (ACTH) treatment. The ACTH treatment, however, has a problem that it is often accompanied by adverse autonomic symptoms. We therefore examined heart rate variability (HRV) for assessing cardiac autonomic functions in WS and prospectively observed the changes during ACTH treatment. We studied 15 patients with WS and 9 age-matched controls during sleep (EEG stage 2). Compared with controls, the patients with WS were greater in the low-frequency component (LF) of HRV, an index reflecting sympatho-vagal interaction (p = 0.02), but were comparable for high-frequency component (HF) and LF-to-HF ratio (LF/HF), indices reflecting cardiac vagal activity and sympathetic predominance, respectively. During ACTH treatment, heart rate decreased (p < 0.01), LF and HF increased (p < 0.01), and LF/HF did not differ significantly. These results indicate that WS might be accompanied by autonomic changes and that ACTH treatment enhances parasympathetic function and causes bradycardia.

In this study, seven patients with cryptogenic West syndrome were subjected to short-duration adrenocorticotrophic hormone (ACTH) therapy. ACTH was administered daily for 7 to 12 days (mean 10 days), and then was withdrawn. Daily single dose was 0.022 to 0.027 mg/kg/day (0.024 mg/kg/day, 0.96 IU/kg), total dose was 0.17 to 0.28 mg/kg (0.23 mg/kg, 9.0 IU/kg), and treatment lag was 12 to 105 days (median 14 days). ACTH therapy controlled tonic spasms with no serious side effects in all patients, but two patients still had electroencephalographic abnormality. The intelligence quotients or developmental quotients of six patients with short treatment lag were 79 to 110 at the age of 2 to 6 years; only one patient with long treatment lag had a developmental quotient of 60. This new short-duration ACTH therapy could yield better cognitive outcomes for cryptogenic West syndrome.

Background Approximately 80% of cases of ischemic heart disease (IHD) occur in patients with nonstenotic coronary arteries, and few studies have systematically assessed exercise testing (TMT) as a predictor of risk in the elderly. Methods TMT was carried out using a protocol for the independent and active elderly ( n =176). After 4.1±0.5 years follow-up, logistic regression analysis was performed for each coronary risk factor such as diabetes mellitus (DM) and hypercholesterolemia (HC). According to the results, patients were divided into Gp HC, hypercholesterolemic patients; Gp DM, diabetics; Gp HC+DM, hypercholesterolemic diabetics; and Gp C, nonhyperlipidemic and nondiabetics. Sensitivity and specificity of TMT for IHD (significant stenosis or acute coronary syndrome) were analyzed. Results Odds ratios for each risk factors are as follows: DM, 4.167; HC, 4.485; and DM+HC, 8.652. Notably, TMT was 17.59. Age was a significant risk, but hypertension was not. Positive ischemic signs in TMT were observed in 52.7%, 28.6%, 33.3%, and 16.3% in the Gp HC+DM, HC, DM, and C groups, respectively. Only three participants complained of chest pain during the TMT. Significant stenosis was observed in 75.0%, 71.4%, 69.2%, and 60.0% of coronary angiography (CAG)-receiving patients of Gp HC, DM, HC+DM, and C. During the observation term, acute coronary syndromes occurred in 4.7%, 3.3%, 5.5%, and 0% of patients in the Gp HC, DM, HC+DM, and C groups, respectively. The sensitivity of TMT for IHD was higher than 66.7% and specificity was higher than 94.1% in each group. Conclusion An exercise tolerance test in the elderly, especially for diabetics and hypercholesterolemic patients, is useful for the diagnosis of IHD.

The current study was conducted to investigate the cognitive function in Japanese elderly with type 2 diabetes mellitus (DM). Participants included 69 diabetic and 27 nondiabetic subjects (60 to 85 years old). The cognitive functional tests conducted were the Mini-Mental State Examination (MMSE), Word Lists Recall (immediate, delayed), Digit Symbol Test (Wechsler Adult Intelligence Scale-Revised [WAIS-R]), and the Stroop Color Word Test. Hemoglobin A1c (HbA1c) was measured as the index of glycemic control, and information about recent hypoglycemic episodes was gathered by using questionnaires. Student's t test showed that DM subjects had significantly lower scores in the MMSE (P

Background: The rapidly aging society in Japan is putting demands on long-term care facilities for the elderly who require care. In Europe and the USA, there is ongoing reform of elderly care services, but the establishment of system based on social insurance is still being explored in Japan. Methods: Two studies were conducted, the first in 2000 and the second in 2001, involving 91 long-term care facilities located in or around the city of Nagoya. Questionnaires were sent to facility directors, chief administrators or head nurses to inquire about their admission policies for six major patient categories. Two educational lectures on methicillin-resistant Staphylococcus aureus (MRSA) and urinary incontinence were given between the distribution of the questionnaires. Results: For all six categories featured on the questionnaire, the acceptance rate in both studies was the highest in geriatric hospitals, and an improvement in acceptance rates was seen in the second study in all three types of care facilities. When the effect the lectures had on changes in admission policies at these facilities was examined, no correlation was found. Conclusions: Lectures should be given to facility management and personnel to raise their awareness of key issues and improve their efficiency.

Background: Several studies have shown cognitive functional impairment in elderly subjects with diabetic mellitus (DM). However, there have been few studies on the image of the brain in DM subjects. Methods: To assess brain atrophy in elderly DM subjects their brain images were evaluated using computed tomography (CT). Thirty-eight DM subjects and 17 non-DM subjects (60–80 years of age) were included. The mean age for DM subjects and control subjects were 71.2 ± 5.5 years and 71.6 ± 5.7 years, respectively. For assessment of brain CT images, five indices (Evan’s ratio, inverse cella media index, width of the third ventricle, the width of the temporal horns on both sides, and the maximal width of the Sylvian fissure at insula on both sides) were used. Results: Evan’s ratio and the temporal horns on both sides in DM subjects were significantly larger than those in control subjects. Further analysis within DM subjects, who were divided into three groups according to their therapy (insulin, medication, and diet therapy), showed that insulin-treated subjects had the widest temporal horns. Conclusions: The current study suggested that elderly DM subjects had brain atrophy compared with age-matched non-DM subjects. The insulin-treated group had the highest amount of brain atrophy of the DM subjects.

A 71-year-old man was referred to our department on January 30, 1998 with hard red papules that had developed on the philtrum in mid-January. On January 2, the patient had received high-dose steroid therapy (pulse therapy) for cluster asthma attacks and antibiotics at the Department of Internal Medicine of our hospital. Infiltrative, protruding reddish plaques were observed on the philtrum, which contained a number of small pustules at sites corresponding to hair follicles. There was partial opacity and slight irregularity of the nail plates on the first and second toes of the right foot. Fungal elements were detected from a lesion on the mustache and the nail. Histological examination of the lesion on the philtrum revealed infiltration of inflammatory cells comprising neutrophils, lymphocytes, and macrophages around the hair follicles. Beard hair and nail cultures revealed Candida albicans A, indicating that the patient had candidal sycosis and candidal onychia. He was treated with oral fluconazole (100 mg/day). The lesion was clinically improved within 50-days. Recently, extensive use of steroids and antibiotics has produced an increase in reports of patients with Folliculitis barbae Candidomycetica. We believe that the present case was also induced by high-dose steroid therapy and antibiotics.

The incidence of late-onset circulatory dysfunction (LCD) of premature infants, which is characterized by sudden hypotension and oliguria, has recently increased in Japan. This condition suddenly occurs after several days of age without obvious causes in preterm infants with stable respiration and circulation. Intravenous steroids frequently improve the hypotension. The main problem with LCD is the subsequent and frequent onset of periventricular leukomalacia (PVL), and neurological development appears to be worse in PVL patients with LCD than those without LCD. The aim of this study was to determine whether the severity of magnetic resonance imaging (MRI) findings and neurological outcomes differ between infants who developed PVL after LCD and those who developed PVL without LCD. We retrospectively studied preterm infants who were delivered at less than 33 weeks of gestation between the years 2000 and 2003. During the study period, 10 and 26 infants developed PVL with and without LCD, respectively. The incidence of severe or moderate MRI findings was significantly higher in PVL patients with LCD (100%) than those without LCD (50%; p < 0.05). The incidence of severe cerebral palsy was 88% in PVL infants with LCD and 43% in PVL infants without LCD (p < 0.05). Moreover, the incidence of visual disorders was significantly higher in PVL infants with LCD (63%) than those without LCD (9%; p < 0.01). In conclusion, neurological outcomes are worse in preterm infants who develop PVL with LCD than those without LCD, which is well correlated to the severity judged by MRI findings.

Migraine is the most common cause of recurrent headache among children and adolescents resulting in missing of school and disabling their daily life. The purpose of this study is to determine the prevalence and clinical features of headache in junior high school children in Japan. In December 2004, questionnaires were sent to 14 junior high schools. There were multiple-choice type questions on headache, mainly migraine. The questionnaires were given during school hours, and 6472 answers were obtained. One thousand four hundred seventy-eight (22.8%) students experienced severe headache and 476 (7.4%) had consulted physicians. Three hundred thirteen (4.8%) were identified as having migraine based on the ICHD-II criteria, consisting of 110/3346 boys (3.3%) and 203/3126 girls (6.5%): 91 (29.1%) with aura and 222 (70.9%) without aura. In about half of the children the migraine attacks were of short duration, ranging from 1 to 3 h. There were 36 boys (1.1%) and 45 girls (1.4%) who had shorter attacks of less than 1 h, whom we did not diagnose as having migraine according to the ICHD-II criteria. Although migraine is common among schoolchildren, it is often under- or miss-diagnosed since the clinical figure for childhood migraine differs from that for adults.

Context: A growing number of Japanese people have completed advance directives, especially living wills, even though there is no legislation recognising such documents and little empirical research on their impact on clinical care at the end of life in Japan. Objectives: To investigate physicians' attitudes about living wills and their experiences with patients who had completed a living will and later died. Design: Self administered survey and qualitative study using open question and content analysis. Setting: Japan. Participants: Physicians known to have cared for a patient who had presented a living will prior to death. Measurements: The physician's response to receiving a living will, communication about the living will, the impact of the living will on clinical care, demographics, and their opinion on advance directives, especially living wills. Main results: Fifty five per cent of respondents approved of advance directives in general, and 34% had more opportunities to communicate with a patient and his/her family after receiving the living will. Sixty nine per cent of the physicians who received a living will did not, however, change their course of therapy as a consequence of receiving the living wills. Based on the analysis, we identified three areas of concern in the comments on living wills: (1) concerns relative to patients, physicians, and families; (2) social context, and (3) clinical and administrative concerns. The physicians raised various topics for discussion; they tended to describe the issues from a clinical perspective. Conclusions: Our identified areas of concern should prove helpful in better understanding the clinical and ethical implications of living wills in Japan.

OBJECTIVES: To determine the contributors to elevating plasma brain natriuretic peptide (BNP) concentrations in older people with normal systolic function. To investigate the relationship between cyclic guanosine monophosphate (cGMP) and BNP in older people with and without ischemic heart disease (IHD). DESIGN: Observational study. SETTING: Hospitalized patients in Nagoya University Hospital from November 1997 to May 2000. PARTICIPANTS: Younger patients (

We reported a new index (muscle density index: MDI) to analyse muscle growth using bioelectrical impedance analysis (BIA). We investigated the MDI in patients with Fukuyama congenital muscular dystrophy (FCMD). Sixteen patients with FCMD homozygotes aged 0.9–15 were enrolled in our study, with the consent from parents. An impedance analyzer (BCA-100, Tanita Corp., Japan) and 10 mm wide stainless steel electrodes were used. The current used in the measurement was lower than 100 μA, and the 9 frequencies between 5 and 250 kHz. The impedance was measured at the middle part of the thigh, lower leg and upper arm. We measured the impedance index at 50 kHz (ZI50), which is generally used for estimating muscle volume in body composition analysis. We evaluated the ratio of ZI50 to the length between the electrodes, which we called net muscle volume by BIA (nMV_BIA), and MDI. The MDI is calculated by the subtraction of the division ration of the impedance at 5 kHz (Z5) by that at 250 kHz (Z250) from 1 (1 – Z5/Z250), that was considered to reflect the ratio of intracellular volume to whole muscle bundle of extremities. The results from nMV_BIA and MDI were analysed among the ages using Spearman rank-correlation analysis. The nMV_BIA of thighs, lower legs, and upper arm were measured as 0.138, 0.062, and 0.056 cm/Ω, respectively. The nMV_BIA of upper arm increased with ages ( r = 0.38, p = 0.04). The MDI of thighs, lower legs, and upper arm were measured as 0.091, 0.091, and 0.080, respectively ( p

In children, muscle volume and diameter of the muscle fibre generally increases, and the interstitial tissues among muscle decrease with their growth. We report a new method to analyse muscle development using bioelectrical impedance analysis (BIA). Ninety-two children aged 0 to 16 were enrolled to our study, with the consent from their parents. An impedance analyzer (BCA-100_CTanita Corp., Japan) and 10 mm wide stainless steel electrodes were used. The current used in the measurement was lower than 100 μA, and the 9 frequencies between 5 and 250 kHz. The impedance was measured at the middle part of the thigh, lower leg and upper arm. We measured the impedance index at 50 kHz (ZI50), which is generally used for estimating muscle volume in body composition analysis. We evaluated the ratio of ZI50 to the length between the electrodes, which we called as net muscle volume by BIA (nMV_BIA), and our new index: muscle density index (MDI). The MDI is calculated by the subtraction of the division ration of the impedance at 5 kHz (Z5) by that at 250 kHz (Z250) from 1 (1 – Z5/Z250), that was considered to reflect the ratio of intracellular volume to whole muscle bundle of extremities. The results from nMV_BIA and MDI were analysed among the ages using Spearman rank-correlation analysis. The nMV_BIA of thighs, lower legs, and upper arm were measured as 0.449, 0.191, and 0.127 cm/Ω, respectively. The MDI of thighs, lower legs, and upper arm were measured as 0.279, 0.290, and 0.202, respectively. These results significantly increased with the ages of the subjects ( p

Previous studies have suggested that type 2 diabetic mellitus could lead to learning and memory deficits. We studied cognitive function tests and brain computed tomography (CT) findings in elderly subjects with drug-treated type 2 diabetic patients (n = 9), diet-treated type 2 diabetic patients (n = 8) and nondiabetic subjects (CR, n = 21). A battery of cognitive function tests (Cog-T; WAIS-R's digit span test and symbol test, Stroop Test, ADAS's verbal memory test, and MMSE) was carried out on two occasions, separated by at least 6 months. Brain CT was analyzed by the following 5 variables; 1) Evan's Ratio, 2) Inverse Cella Media Index, 3) maximum width of the third ventricle, 4) maximum width of temporal horn tips on both sides and 5) maximum width of the Sylvian fissure at the insula, bilaterally. The scores of Cog-T did not differ significantly between the groups. On brain CT measurements, maximum width of the temporal horn tips on right side were significantly different in the three groups (ANOVA, P = 0.035). The drug-treated diabetics subjects had wider temporal horn tips on the right side than did the diet treated diabetics and nondiabetic subjects (Fisher's post hoc test, P = 0.030, P = 0.016).

This study examine whether around-the-clock medical support is a contributing factor to dying at home, and also tried to identify other such factors. Visiting nursing records of 81 elderly patients who died at home or in hospital after receiving home care at two facilities, one with and one without 24-hour medical support respectively were examined retrospectively. The subjects were divided into two groups: those who died at home and those who died in a hospital or nursing home. The two groups were compared in terms of clinical and sociodemographic characteristics and preferences for dying at home, expressed by patients, families and medical staff. Those who died at home showed a significantly higher rate of total dependence (84.6% vs. 48.1%) at month before death. Dying at home was significantly more preferred by all patients, families and medical staff. The major reason for hospitalization was rapid deterioration of the patients' condition. The facility with around-the-clock medical service had a higher rate of dying at home (42% vs. 27%, p = 0.18). Also, patients, families, and medical staff associated with their facility showed a higher preference for dying at home. We concluded from the above that the contributing factors for dying at home are: 1) total dependence level of ADL at one month before the death, and 2) preference for dying at home expressed by the patient, family and medical staff. This study suggests 24-hour medical support should be a requirement for in-home terminal care. Supporting advice from the staff to the family seems to be another contributing factor.

We examined the way medical students think about end-of-life care in the elderly by a questionnaire survey. The major variables of the evaluation instrument included the students' idea of the special nature of end-of-life care for the elderly, the necessity for disclosure of the name of disease, consideration for patient's age on disclosure, advance directives concerning their life-sustaining treatment, and communication concerning preferences for end-of-life care. The final items on the instrument asked for student comments about end-of-life care in the elderly. We analyzed this qualitative data using the process of immersion/crystallization. We received 95 responses, and of these 65 (68%) provided written commentaries that were analyzed using qualitative techniques. Fifty-nine (62%) students pointed out the special nature of end-of-life care in the elderly and most of them (96%) needed the disclosure of the name of disease. Fifty-two (55%) students agreed with advance directives for end-of-life care and 88 (93%) students pointed out the importance of communication with regard to patients' preferences. Medical students' concerns about end-of-life care in the elderly related to three major domains: 1) patient-physician relationship; 2) the procedures of end-of-life care; and 3) emotional and intuitive comments. These results suggest that in the education of geriatric medicine the patient-physician's relationship about end-of-life care is important and we may need to introduce systematic lectures and practical training.

It remains controversial whether or not a correlation exists between serum leptin levels and insulin resistance, and, if such a correlation does exist, whether it is independent of adiposity. To investigate the possible existence of an independent correlation, we have assessed serum leptin levels and insulin resistance in Japanese diabetic and non-diabetic subjects by means of Homeostatic Model Assessment (HOMA-R). Sixty-four Japanese patients with Type 2 diabetes mellitus (DM) (33 men and 31 women) and 53 sex-, age-, and body mass index (BMI)-matched non-diabetic adults (29 men and 24 women) were enrolled. The fasting plasma level of glucose (FPG) and the fasting serum levels of immunoreactive insulin (FIRI) and leptin were determined. Multiple linear regression analysis demonstrated that, in both male diabetic and male non-diabetic subjects, HOMA-R and BMI were independently correlated with serum leptin levels. In females, BMI, but not HOMA-R, was correlated to the serum levels of leptin in both groups. There was no statistically significant difference in the partial regression coefficients between male diabetic and male non-diabetic subjects. These results suggest that the correlation of HOMA-R to the serum levels of leptin in females is dependent on BMI. In males, the relationship between serum leptin levels and the insulin resistance was not affected by the extent of glucose intolerance.