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Background Biallelic variants in POLR3A encoding the largest subunit of RNA polymerase III cause POLR3-related (or 4H) leukodystrophy characterized by neurologic dysfunction, abnormal dentition, endocrine abnormalities and ocular abnormality. Recently, whole-exome sequencing enabled the discovery of POLR3A variants in cases lacking diffuse hypomyelination, the principal MRI phenotype of POLR3-related leukodystrophy. Homozygous c.1771-6C > G variants in POLR3A were recently suggested to cause striatal and red nucleus involvement without white matter involvement. Case report: Here, we report three cases in two families with biallelic POLR3A variants. We identified two sets of compound heterozygous variants in POLR3A, c.1771-6C > G and c.791C > T, p.(Pro264Leu) for family 1 and c.1771-6C > G and c.2671C > T, p.(Arg891*) for family 2. Both families had the c.1771-6C > G variant, which led to aberrant mRNA splicing. Neuropsychiatric regression and severe intellectual disability were identified in three patients. Two cases showed dystonia and oligodontia. Notably, characteristic bilateral symmetric atrophy and abnormal signal of the striatum without diffuse white matter signal change were observed in brain MRI of all three individuals. Conclusions Striatum abnormalities may be another distinctive MRI finding associated with POLR3A variants, especially in cases including c.1771-6C > G variants and our cases can expand the phenotypic spectrum of POLR3A-related disorders.

Objective Limited data exist regarding the comparative detailed clinical characteristics of patients with ischemic stroke (IS)/transient ischemic attack (TIA) and intracerebral hemorrhage (ICH) receiving oral anticoagulants (OACs). Methods The prospective analysis of stroke patients taking oral anticoagulants (PASTA) registry, a multicenter registry of 1,043 stroke patients receiving OACs [vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulant (NOACs)] across 25 medical institutions throughout Japan, was used. Univariate and multivariable analyses were used to analyze differences in clinical characteristics between IS/TIA and ICH patients with atrial fibrillation (AF) who were registered in the PASTA registry. Results There was no significant differences in cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidemia, smoking, or alcohol consumption (all p0.05), between IS/TIA and ICH among both NOAC and VKA users. Cerebral microbleeds (CMBs) [odds ratio (OR), 4.77; p0.0001] were independently associated with ICH, and high brain natriuretic peptide/N-terminal pro B-type natriuretic peptide levels (OR, 1.89; p=0.0390) were independently associated with IS/TIA among NOAC users. A history of ICH (OR, 13.59; p=0.0279) and the high prothrombin time-international normalized ratio (PT-INR) (OR, 1.17; p0.0001) were independently associated with ICH, and a history of IS/TIA (OR, 3.37; 95% CI, 1.34-8.49; p=0.0101) and high D-dimer levels (OR, 2.47; 95% CI, 1.05-5.82; p=0.0377) were independently associated with IS/TIA among VKA users. Conclusion The presence of CMBs, a history of stroke, natriuretic peptide and D-dimer levels, and PT-INR may be useful for risk stratification of either IS/TIA or ICH development in patients with AF receiving OACs.

Controlling the oral microbial flora is putatively thought to prevent not only oral diseases, but also systemic diseases caused by oral diseases. This study establishes the antibacterial effect of the novel bioactive substance “S-PRG filler” on oral bacteria. We examined the state of oxidative stress caused by the six types of ions released in eluate from the S-PRG filler in oral bacterial cells. Moreover, we investigated the effects of these ions on the growth and pathogenicity of Gram-positive and Gram-negative bacteria. We found that the released ions affected SOD amount and hydrogen peroxide in bacterial cells insinuating oxidative stress occurrence. In bacterial culture, growth inhibition was observed depending on the ion concentration in the medium. Additionally, released ions suppressed Streptococcus mutans adhesion to hydroxyapatite, S. oralis neuraminidase activity, and Porphyromonas gingivalis hemagglutination and gingipain activity in a concentration-dependent manner. From these results, it was suggested that the ions released from the S-PRG filler may suppress the growth and pathogenicity of the oral bacterial flora. This bioactive material is potentially useful to prevent the onset of diseases inside and outside of the oral cavity, which in turn may have possible applications for oral care and QOL improvement.

Background and Purpose: The characteristics of direct oral anticoagulant (DOAC)-related intracerebral hemorrhage (ICH) have not been fully clarified. We planned to recruit patients prospectively and to investigate the characteristics and outcomes in patients with ICH receiving direct oral anticoagulant (DOAC) and warfarin treatment. Methods: The prospective analysis of stroke patients taking anticoagulants (PASTA) registry study is an observational, multicenter, prospective registry of stroke patients receiving OAC. Patient enrollment started in April 2016 at 25 tertiary centers across Japan. We compared imaging, clinical characteristics, and discharge modified Rankin Scale (mRS) between DOAC- and warfarin-related ICH patients with atrial fibrillation (AF). Results: A total of 154 patients (51 women; median age 77 [quartiles 69-87] years) were analyzed. Of these, 111 patients (72%) received prior DOAC treatment and the remaining 43 (28%) received prior warfarin treatment (Fig. A, B and C). There were no relevant differences in clinical and hematoma characteristics between DOAC- and warfarin-related ICH regarding baseline hematoma volume (median [quartiles]: DOAC, 11 [5-23] mL vs. warfarin, 12 [5-30] mL; P =0.95), rate of hematoma expansion (DOAC, 12/111 [11%] vs. warfarin, 4/43 [9%]; P =0.80), rate of subcortical hemorrhage (DOAC, 15/111 [11%] vs. warfarin, 10/43 [9%]; P =0.80) and the proportion of patients with unfavorable outcome (mRS, 4-6: DOAC 76/108 [70%] vs. warfarin 23/38 [61%]; P =0.26). Cerebral microbleeds (CMBs) were detected more frequently in DOAC group than in warfarin (47/76 [62%] vs. 11/32 [34%]; P Conclusions: Our results showed that there were no significant differences in hematoma characteristics and functional outcome among AF patients with DOAC- or warfarin-related ICH.

Background and Purpose: The characteristics of patients with stroke prior receiving direct oral anticoagulant (DOAC) have not been fully clarified. We planned to recruit patients prospectively and to investigate the characteristics and outcomes in stroke patients taking DOAC and warfarin treatment prior to the event. Methods: The prospective analysis of stroke patients taking anticoagulants (PASTA) registry study is an observational, multicenter, prospective registry of stroke patients receiving OAC. Patient enrollment started in April 2016 at 25 tertiary centers across Japan. We compared clinical characteristics and discharge modified Rankin Scale (mRS) between DOAC-and warfarin-treatment in patients with atrial fibrillation (AF). Results: A total of 580 patients (231 women; median age 80 [quartiles 73-84] years) were analyzed (Fig. A). Of these, 365 patients (63%) received prior DOAC treatment and the remaining 215 (37%) received prior warfarin treatment (Fig. B and C). There were significant differences in clinical characteristics and outcome between DOAC-and warfarin-treatment prior to the event regarding initial NIHSS score (median [quartiles]: DOAC, 4 [2-16] vs. warfarin, 9 [3-21]; P =0.0001), rate of medium-large size of infarct (DOAC, 202/340 [59%] versus warfarin, 152/203 [75%]; P =0.0003) and the proportion of patients with favorable outcome (mRS, 0-3: DOAC 218/354 [62%] vs. warfarin 108/212 [49%]; P =0.0036). Subclassification according to DOAC dosing revealed patients with low-dose (259/365; 71%) to be older and to have a higher NIHSS score compared with regular dose (low-dose, 5 [2-17] vs. regular-dose, 3 [1-11]; P =0.0023) (Fig. D). Type of DOAC agent did not result in relevant differences in clinical characteristics or outcome (Fig. E). Conclusions: Our results showed that patients with DOAC treatment before the event showed smaller infarct size, milder initial stroke severity, and favorable outcome compared to patients with warfarin.

Rapid decline of pulmonary function in acute respiratory distress syndrome (ARDS) can make ARDS a dangerous and potentially life-threatening condition. Gadolinium-based contrast agents are considered safe alternatives to iodine-based contrast agents, with comparatively fewer adverse effects and a lower incidence of serious adverse events, such as dyspnea or hypotension. There are five reported cases of gadolinium-induced ARDS.A 59-year-old woman with respiratory failure 30 min after gadolinium administration was diagnosed with ARDS; she was admitted to the intensive care unit. Her condition improved by artificial respiration management and adrenaline and steroids administration. She was discharged on day 13.Considering ARDS occurred 30 min after gadolinium administration and findings suggesting anaphylaxis, such as wheezing and failure in organs other than the lungs, were absent, the involvement of any immediate-onset reaction was excluded; thus, a diagnosis of gadolinium-induced ARDS was made. Keywords: Acute respiratory distress syndrome, Contrast agents, Dyspnea, Gadobutrol, Gadolinium

Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.

Foix-Chavany-Marie syndrome (FCMS) is a rare cortical type of pseudobulbar palsy characterized by the loss of voluntary control of the facial, pharyngeal, lingual, and masticatory muscles with preserved reflexive and autonomic functions. FCMS is generally associated with cerebrovascular diseases affecting the bilateral opercular regions. We herein report the clinical features of an 84-year-old right-handed Japanese man with FCMS due to a unilateral brain abscess. The patient's symptoms were resolved after treating the brain abscess. The present clinical results suggest that a unilateral brain abscess in the temporal operculum with a persistent old lesion in the contralateral insular cortex can induce FCMS.

A 77-year-old man with a right kidney stone was admitted to our hospital. A ureteroscope was introduced into the ureter without dilation under direct vision. We then performed flexible transurethral lithotripsy (f-TUL) using a ureteral access sheath and successfully fragmented the stone and extracted almost all the stone fragments without any complications. Just 3 hours after the operation, he suddenly developed right abdominal pain with a decrease in hemoglobin. A CT scan showed a retroperitoneal hemorrhage around the lower ureter. We herein describe a rare complication associated with flexible transurethral lithotripsy.

Mutations in small heat shock protein beta‐1 (HspB1) have been linked to Charcot‐Marie‐Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole‐exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1‐related disorders.

We recently showed using prepro-orexin knockout (ORX-KO) mice and orexin neuron-ablated (ORX-AB) mice that orexin neurons in the hypothalamus, but not orexin peptides per se, are indispensable for stress-induced thermogenesis. To examine whether orexin neurons are more generally involved in central thermoregulatory mechanisms, we applied other forms of thermogenic perturbations, including brain prostaglandin E2 (PGE2) injections which mimic inflammatory fever and environmental cold exposure, to ORX-KO mice, ORX-AB mice and their wild-type (WT) litter mates. ORX-AB mice, but not ORX-KO mice, exhibited a blunted PGE2-induced fever and intolerance to cold (5°C) exposure, and these findings were similar to the results previously obtained with stress-induced thermogenesis. PGE2-induced shivering was also attenuated in ORX-AB mice. Both mutants responded similarly to environmental heating (39°C). In WT and ORX-KO mice, the administration of PGE2 and cold exposure activated orexin neurons, as revealed by increased levels of expression of c-fos. Injection of retrograde tracer into the medullary raphe nucleus revealed direct and indirect projection from the orexin neurons, of which the latter seemed to be preserved in the ORX-AB mice. In addition, we found that glutamate receptor antagonists (D-(-)-2-amino-5-phosphonopentanoic acid and 6-cyano-7-nitroquinoxaline-2,3-dione) but not orexin receptor antagonists (SB334867 and OX2 29) successfully inhibited PGE2-induced fever in WT mice. These results suggest that orexin neurons are important in general thermogenic processes, and their importance is not restricted to stress-induced thermogenesis. In addition, these results indicate the possible involvement of glutamate in orexin neurons implicated in PGE2-induced fever.

A 54-year-old-woman with sarcoidosis presented with progressive symmetric, predominantly distal weakness and sensory dysfunction with areflexia in all four limbs. Nerve conduction studies showed multifocal conduction blocks in several nerves. Oral steroids were ineffective; however, intravenous immunoglobulin (IVIG) therapy rapidly and repeatedly improved the patient's neurologic symptoms with a resolution of the conduction blocks. Multifocal conduction blocks are not frequently reported in patients with sarcoid neuropathy, but they may respond to early treatment with IVIG.

Introduction: Cortical vessel signs (CVSs) on susceptibility-weighted MR imaging (SWI) are frequently observed in acute ischemic stroke patients. However, the clinical implications of this sign have not yet been clearly defined. We assumed the hypothesis that grade of CVSs on SWI predicts outcomes in acute stroke patients. Methods: We retrospectively enrolled stroke patients who presented with anterior circulation cerebral infarction within 24 hours after onset. We excluded patients with no SWI. CVSs was defined as more veins or lager veins with a greater signal loss on SWI than those in the opposite normal hemisphere. CVSs was graded as 1) absent, 2) subtle as presence of CVSs less than 1/3 of the anterior circulation perfusion lesion, or 3) prominent as presence of CVSs more than 1/3 of the perfusion lesion. Unfavorable outcome was defined as discharge modified Rankin scale score 4-6. Results: We included 114 patients from October 2012 to June 2014, 71% of patients were men, median age was 71 years, and the average initial NIHSS score was 7 (range 0-32). CVSs was seen in 53 (47%) of patients. There were 14 patients (13%) with subtle CVSs, and 39 patients (35%) with prominent CVSs. Unfavorable outcome was as follows: 15% of patients with none CVSs, 43% with subtle CVSs, and 59% with prominent CVSs (figure 1). As with grade of CVSs, proportional rate of unfavorable patients gradually increased (P < 0.01). Conclusions: Grade of CVSs on SWI can predict outcomes in acute stroke patients.

Purpose: Vertebral artery hypoplasia (VAH) is congenital anatomical variation, which is frequently observed in clinical situation. In previous reports, it was not unclear whether VAH was the independent risk factor for posterior circulation ischemia. The purpose of this study is to evaluate an impact of VAH on posterior circulation ischemia. Methods: Subjects were patients with acute ischemic stroke who underwent brain MRI and carotid ultrasonography. The diameter of vessel and flow velocities of extracranial vertebral artery (VA) was measured by carotid ultrasonography. Diagnostic criteria of VAH was as follows: 1) diameter of VA 0.75. We divided all patients into three groups by the location of the acute ischemic stroke evaluated by MRI: ischemic lesion on posterior circulation (P group), on anterior circulation (A group), and multiple lesions on both anterior and posterior circulation (AP group). Then, the prevalence rate of VAH was compared between P group and A+AP group. In order to evaluate independent factors of VA occlusion, we conducted multivariate regression analyses. Results: We evaluated a total of 129 consecutive patients (87 male, median age; 71 years). P group was 36 patients, and A+AP group was 93 patients. VAH was seen in 39 patients (31.5%), and VA occlusion was found in 15 patients. The prevalence rate of VAH in P group (44.4%) was significantly higher than in A+AP group (24.7%, p=0.034). In univariate analysis, the patients with VA occlusion were higher rates of hypertension (p=0.066), large artery atherosclerosis (p=0.095), posterior circulation ischemia (p=0.001), and the presence of VAH (p=0.038). Multivariate regression analysis demonstrated that large artery atherosclerosis (odds ratio, 6.3; 95% confidence interval, 1.3-30.1), posterior circulation ischemia (odds ratio, 12.0; 95% confidence interval, 2.8-51.2) and VAH (odds ratio, 4.2; 95% confidence interval, 1.2-15.0) were independently associated with the presence of VA occlusion. Conclusion: VAH was independent factor of VA occlusion, and should be associated with posterior circulation ischemia.

We report a case of generalized myasthenia gravis with obstructive sleep apnea in which myasthenia gravis symptoms improved dramatically after initiation of continuous positive airway pressure therapy. A 42-year-old man was admitted with generalized myasthenia gravis. He was found to snore loudly during sleep and was diagnosed with obstructive sleep apnea by polysomnography. Continuous positive airway pressure therapy contributed to immediate improvements in not only the apnea–hypopnea index (70.6–20.9), but also the myasthenia gravis-specific activities of daily living scale (10–1) and quantitative myasthenia gravis scale (21–8). We suggest that when a myasthenia gravis patient is obese and suspected to have sleep problems, examinations to detect obstructive sleep apnea should be carried out. If obstructive sleep apnea is diagnosed, continuous positive airway pressure therapy might also improve the patient's myasthenia gravis.

We recently showed using prepro-orexin knockout (ORX-KO) mice and orexin neuron-ablated (ORX-AB) mice that orexin neurons in the hypothalamus, but not orexin peptides per se, are indispensable for stress-induced thermogenesis. To examine whether orexin neurons are more generally involved in central thermoregulatory mechanisms, we applied other forms of thermogenic perturbations, including brain prostaglandin E2 (PGE2) injections which mimic inflammatory fever and environmental cold exposure, to ORX-KO mice, ORX-AB mice and their wild-type (WT) litter mates. ORX-AB mice, but not ORX-KO mice, exhibited a blunted PGE2-induced fever and intolerance to cold (5°C) exposure, and these findings were similar to the results previously obtained with stress-induced thermogenesis. PGE2-induced shivering was also attenuated in ORX-AB mice. Both mutants responded similarly to environmental heating (39°C). In WT and ORX-KO mice, the administration of PGE2 and cold exposure activated orexin neurons, as revealed by increased levels of expression of c-fos. Injection of retrograde tracer into the medullary raphe nucleus revealed direct and indirect projection from the orexin neurons, of which the latter seemed to be preserved in the ORX-AB mice. In addition, we found that glutamate receptor antagonists (d-(–)-2-amino-5-phosphonopentanoic acid and 6-cyano-7-nitroquinoxaline-2,3-dione) but not orexin receptor antagonists (SB334867 and OX2 29) successfully inhibited PGE2-induced fever in WT mice. These results suggest that orexin neurons are important in general thermogenic processes, and their importance is not restricted to stress-induced thermogenesis. In addition, these results indicate the possible involvement of glutamate in orexin neurons implicated in PGE2-induced fever.

Cerebral microbleeds (CMBs) are recognized as a manifestation of arteriolosclerosis in cerebral small vessels. However, little is known regarding whether stroke patients with CMBs often have systemic atherosclerosis. The aim of the present study was to elucidate this issue using the cardio-ankle vascular index (CAVI), a new index of systemic atherosclerosis, in acute ischemic stroke patients. We prospectively studied 105 patients (71 males, median age=70.0 years) with acute ischemic stroke. All of the patients were examined using T2*-weighted gradient echo magnetic resonance imaging (MRI) to look for and assess the CMBs and using fluid-attenuated inversion recovery to evaluate white matter hyperintensity (WMH). We assigned the patients into CMB and non-CMB groups and compared the clinical characteristics of these groups. The factors associated with CMBs were investigated using multivariate logistic regression analysis. T2*-weighted gradient echo MRI revealed CMBs in 47 patients (44.8%) and no CMBs in 58 patients (55.2%). The CAVI was significantly higher in the CMBs group (10.5 vs. 8.6, P

We report here in a 61-year-old woman in whom sensory disturbance predominantly affecting the distal portion of the limbs progressed over the course of 1 year. Blood tests showed IgM monoclonal gammopathy as well as the presence of anti-myelin-associated glycoprotein (MAG) antibody. Nerve conduction studies revealed significant prolongation of distal latency, and sural nerve biopsy showed IgM deposition on the myelin sheath. She was diagnosed as suffering anti-MAG neuropathy. High-dose intravenous immunoglobulin therapy proved to be ineffective and her symptoms progressed. Therefore, rituximab was administered and the sensory disturbance improved. Although no detailed studies on rituximab therapy for anti-MAG neuropathy have been reported in Japan, the present findings suggest that rituximab may be more effective than immunoglobulin therapy and other conventional therapies that have been used for autoimmune neuropathies.

Keywords: corticospinal tract; dying-back; magnetic resonance imaging; Waller degeneration; X-linked adrenoleukodystrophy