桑原 聡

Standardization of Electromyography (EMG) instrumentation is of particular importance to ensure high quality recordings. This consensus report on "Standards of Instrumentation of EMG" is an update and extension of the earlier IFCN Guidelines published in 1999. First, a panel of experts in different fields from different geographical distributions was invited to submit a section on their particular interest and expertise. Then, the merged document was circulated for comments and edits until a consensus emerged. The first sections in this document cover technical aspects such as instrumentation, EMG hardware and software including amplifiers and filters, digital signal analysis and instrumentation settings. Other sections cover the topics such as temporary storage, trigger and delay line, averaging, electrode types, stimulation techniques for optimal and standardised EMG examinations, and the artefacts electromyographers may face and safety rules they should follow. Finally, storage of data and databases, report generators and external communication are summarized.

Both cognitive function and striatal dopamine function decline by normal aging. However, the relationship among these three factors remains unclear. The aim of this study was to elucidate the association among age-related changes in the striatal dopamine transporter (DAT) and cognitive function in healthy subjects. The 30 healthy volunteers were enrolled in this research, the age ranged from 41 to 82 (64.5 ± 11.5, mean ± SD). All subjects were scanned with both T1-weighted magnetic resonance imaging (MRI) and 123I-FP-CIT single-photon emission computed tomography (SPECT) images. The Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) was used to evaluate cognitive function. Six spherical regions of interest (ROI) using 10 mm in diameter on the caudate nucleus, anterior putamen and posterior putamen were manually drawn on MRI image which was applied onto SPECT image. The relationship between striatal occipital ratio (SOR) values and WAIS-III subscore were analyzed by multiple regression analysis. Subscores which was significant were further analyzed by path analyses. Full intelligence quotient (IQ), verbal IQ, verbal comprehension were all positively correlated with age-adjusted striatal DAT binding (P < 0.01). Multiple regression analyses revealed that the coding digit symbol correlated with all striatal regions except for the left caudate (P < 0.04). Picture completion and right caudate, similarities and left caudate also showed a positive correlation (P < 0.04). Path analysis found that the right caudate and picture completion; the left caudate and similarities were correlated independently from age, whereas the models of coding digit symbol were not significant. These results suggest that age-based individual diversity of striatal DAT binding was associated with verbal function, and the caudate nucleus plays an important role in this association.

BACKGROUND: Neuropsychological tests, structural neuroimaging, and functional neuroimaging are employed as diagnostic and monitoring biomarkers of patients with Alzheimer's disease (AD)Objective:We aimed to elucidate the similarities and differences in neuropsychological tests and neuroimaging with the use of the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog), structural magnetic resonance image (MRI), and perfusion single photon emission computed tomography (SPECT), and parametric image analyses to understand its role in AD. METHODS: Clinically-diagnosed AD patients (n = 155) were scanned with three-dimensional T1-weighted MRI and N-isopropyl-p-[123I] iodoamphetamine SPECT. Statistical parametric mapping 12 was used for preprocessing images, statistical analyses, and voxel-based morphometry for gray matter volume analyses. Group comparison (AD versus healthy controls), multiple regression analyses with MMSE, ADAS-cog total score, and ADAS-cog subscores as variables, were performed. RESULTS: The AD group showed bilateral hippocampal volume reduction and hypoperfusion in the bilateral temporo-parietal lobe and posterior midline structures. Worse MMSE and ADAS-cog total score were associated with bilateral temporo-parietal volume loss and hypoperfusion. MMSE, but not ADAS-cog, was associated with the posterior midline structures. The ADAS-cog subscores were associated with the temporal volume, while perfusion analyses were linked to the left temporo-parietal region with the language function and right analogous region with the constructional praxis subscore. CONCLUSION: MMSE and ADAS-cog are associated with temporo-parietal regions, both in volume and perfusion. The MMSE score is associated with posterior midline structures and linked to an abnormal diagnostic AD pattern. Perfusion image analyses better represents the cognitive function in AD patients.

OBJECTIVE: To investigate the difference of fatigue and pain in patients with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). METHODS: Data from the Modified Fatigue Impact Scale (MFIS) and Pain Effects Scale (PES) were compared between 51 NMOSD and 85 MS patients. Each score was compared in each disease group with or without clinical abnormalities. Since almost no MS patients are without brain magnetic resonance imaging abnormalities, volumetry analysis by the Lesion Segmentation Tool and statistical parametric mapping 12 were added to obtain total lesion volume and intracranial volume in MS patients, and the correlations between total lesion volume/intracranial volume and each score were investigated. RESULTS: Compared to the MS group, the NMOSD group showed a higher PES score (median, 15.0 vs. 7.0, P = 0.045), no difference in MFIS, and an increased percentage of patients with extended spinal cord lesions (58.8% vs. 8.2%, P < 0.001). Moreover, NMOSD and MS patients with extended spinal cord lesions tended to demonstrate higher PES scores than those without. A positive correlation between MFIS and PES were found in patients with NMOSD and MS. On the other hand, MS patients showed a higher percentage of brain abnormalities (80.4% vs. 97.6%, P = 0.001) and a positive correlation between total lesion volume/intracranial volume and MFIS (Spearman's ρ = 0.50, P = 0.033). CONCLUSIONS: The origin of fatigue may be associated with spinal cord lesions causing pain in NMOSD patients, but with brain lesions in MS patients.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) is an established therapy for alleviating motor symptoms in advanced Parkinson's disease (PD) patients; however, a postoperative decline in cognitive and speech function has become problematic although its mechanism remains unclear. The aim of the present study was to elucidate the properties of language and drawing ability and cerebral perfusion in PD patients after bilateral STN DBS surgery. METHODS: Western aphasia battery, including drawing as a subcategory, and perfusion (N-isopropyl-p-[123I] iodoamphetamine) SPECT scan was conducted in 21 consecutive PD patients, before, and three to six months after, bilateral STN DBS surgery while on stimulation. Perfusion images were compared with those of 17 age- and gender-matched healthy volunteers. In the parametric image analysis, the statistical peak threshold was set at P < 0.001 uncorrected with a cluster threshold set at P < 0.05 uncorrected. RESULTS: Although motor symptoms were improved and general cognition was preserved in the patient group, 11 patients (52.4%) showed a decline in the drawing subcategory after surgery, which showed a reduction in Frontal Assessment Battery score in this group of patients. Statistical parametric analysis of the brain perfusion images showed a decrease of cerebral blood flow in the prefrontal and cingulate cortex after surgery. Patients whose drawing ability declined showed decreased perfusion in the middle cingulate cortex comparing before and after surgery. CONCLUSION: Present results show that some PD patients show a decline in drawing ability after bilateral STN DBS which may attributable by dysfunction in the cingulate network.

Aims: The patients with Parkinson's disease (PD) present with lower urinary tract symptoms (LUTS), but the efficacy of subthalamic nucleus deep brain stimulation (STN-DBS) on LUTS is unknown. The medial prefrontal cortex (mPFC) is a known higher micturition center which are modulated by STN-DBS. We aim to clarify STN-DBS-related changes in the neuronal activity of the mPFC in terms of bladder contraction, using normal and PD rats. Methods: Experiments in normal and 6-hydroxydopamine hemi-lesioned PD rats were conducted under urethane anesthesia. STN-DBS was applied to the left STN, with simultaneous monitoring of bladder contractions. The mPFC's local field potential (LFP) was recorded before, during, and after STN-DBS (n = 6: normal rats, n = 6: PD rats). Before, during and after STN-DBS (n = 5: normal rats, n = 6: PD rats), extracellular fluid was collected from mPFC. Results: STN-DBS significantly increased bladder inter-contraction interval. STN-DBS significantly decreased mPFC alpha power in normal rat and increased alpha power in PD rat. The mPFC levels of levodopa, dopamine, serotonin and their metabolites in PD rats decreased significantly during and after STN-DBS, whereas the serotonin and its metabolites and homovanillic acid (HVA) levels decreased significantly in normal rats following STN-DBS. Conclusion: STN-DBS increased intercontraction intervals for the bladder in both normal and PD rats, as assessed by alpha power and catecholamine levels in mPFC, probably due to changes in neural activity. The effect of STN-DBS on mPFC levels of catecholamine differentiated between the normal and PD rats.

Background: Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated damage at the neuromuscular junction. Recently, the REGAIN study showed that eculizumab was effective and well tolerated in patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG). However, there is no consensus regarding which kind of patients with gMG are selected to preferentially receive eculizumab. Methods: Between January and December 2018, we followed 1388 patients with MG at seven hospitals located in Tokyo and Chiba. We evaluated the clinical features of MG and the patients' quality of life. Clinical status and severity were determined by the recommendations of the Myasthenia Gravis Foundation of America. Results: Of 1388 patients with MG, 12 (0.9%) patients received eculizumab. A total of 11 patients who were anti-acetylcholine receptor antibody-positive with refractory gMG (M:F = 3:8) completed the 26-week treatment with eculizumab. The disease subtypes represented included five cases of early onset MG, one of late-onset MG, and five of thymoma-associated MG. Overall, seven patients had experienced myasthenic crisis. The mean quantitative MG score ranged from 18.6 at baseline to 9.1 at week 26 (p = 0.008). Similarly, the mean MG activities of daily living score ranged from 10.8 at baseline to 4.2 at week 26 (p = 0.002). There were marked improvements in all patients' quality of life status. Overall, seven patients were able to reduce the dose of prednisolone at week 26. All but one patient did not require additional rescue treatment. Overall, one patient with early onset MG could not continue the eculizumab treatment due to nausea and vertigo. Conclusion: We demonstrate that eculizumab provided remarkable benefits for refractory gMG in practical real-world experience as well as in the REGAIN study. Patients with refractory gMG with myasthenia crisis and thymoma-associated MG are suitable for eculizumab administration.

BACKGROUND: In Parkinson's disease (PD) patients, the factors related to weight loss remain unclear. OBJECTIVE: To investigate determinants of low body mass index (BMI) in PD patients. METHODS: We identified factors associated with low BMI in PD patients in a multicenter case-control study. A total of 435 PD patients and 401 controls were included. RESULTS: The mean BMI was significantly lower in PD patients than in controls (22.0±3.4 kg/m2 vs. 25.4±4.3 kg/m2), with an adjusted odds ratio (AOR) of 3.072 (95% CI, 2.103-4.488; p < 0.001) for low BMI (<22 kg/m2) in PD. Compared to the high-BMI PD group (>22 kg/m2), the low-BMI PD group (<22 kg/m2) had more women; a longer disease duration; higher revised Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) II and IV scores; an increased levodopa equivalent dose (LED); and increased constipation, visual hallucination, dysphagia, dyskinesia and wearing off rates. There were no between-group differences in depression, anhedonia, apathy, sleep problems and daytime sleepiness. Multivariable analysis showed that visual hallucination (AOR, 2.408; 95% CI, 1.074-5.399; p = 0.033) and the MDS-UPDRS IV (AOR, 1.155; 95% CI, 1.058-1.260; p = 0.001) contributed to low BMI after controlling for clinical factors. In a second model, visual hallucination (AOR, 2.481; 95% CI, 1.104-5.576; p = 0.028) and dyskinesia (sum of the MDS-UPDRS 4.3-4.6) (AOR, 1.319; 95% CI, 1.043-1.668; p = 0.021) significantly contributed to low BMI. CONCLUSION: PD patients were 3 times more likely than healthy controls to have a low BMI. Motor complications, particularly dyskinesia, and visual hallucination were significantly associated with low BMI in PD patients.

We used quantitative susceptibility mapping (QSM) to assess the brain iron deposition in 28 patients with the cerebellar subtype of multiple system atrophy (MSA-C), nine patients with spinocerebellar ataxia type 6 (SCA6), and 23 healthy controls. Two reviewers independently measured the mean QSM values in brain structures including the putamen, globus pallidus, caudate nucleus, red nucleus, substantia nigra, and cerebellar dentate nucleus. A receiver operating characteristics (ROC) analysis was performed to assess the diagnostic usefulness of the QSM measurements. The QSM values in the substantia nigra were significantly higher in the MSA-C group compared to the HC group (p = .007). The QSM values in the cerebellar dentate nucleus were significantly higher in MSA-C than those in the SCA6 and HC groups (p < .001), and significantly lower in the SCA6 patients compared to the HCs (p = .027). The QSM values in the cerebellar dentate nucleus were correlated with disease duration in MSA-C, but inversely correlated with disease duration in SCA6. In the ROC analysis, the QSM values in the cerebellar dentate nucleus showed excellent accuracy for differentiating MSA-C from SCA6 (area under curve [AUC], 0.925), and good accuracy for differentiating MSA-C from healthy controls (AUC 0.834). QSM can identify increased susceptibility of the substantia nigra and cerebellar dentate nucleus in MSA-C patients. These results suggest that an increase in iron accumulation in the cerebellar dentate nucleus may be secondary to the neurodegeneration associated with MSA-C.

POEMS syndrome is a rare paraneoplastic disease associated with monoclonal plasma cells; however, the pathogenic importance of plasma cells remains unclear. We performed comprehensive genetic analyses of plasma cells in 20 patients with POEMS syndrome. Whole exome sequencing was performed in 11 cases and found a total of 308 somatic mutations in 285 genes. Targeted sequencing was performed in all 20 cases and identified 20 mutations in 7 recurrently mutated genes, namely KLHL6, LTB, EHD1, EML4, HEPHL1, HIPK1, and PCDH10. None of the driver gene mutations frequently found in multiple myeloma (MM) such as NRAS, KRAS, BRAF, and TP53 was detected. Copy number analysis showed chromosomal abnormalities shared with monoclonal gammopathy of undetermined significance (MGUS), suggesting a partial overlap in the early development of MGUS and POEMS syndrome. RNA sequencing revealed a transcription profile specific to POEMS syndrome when compared with normal plasma cells, MGUS and MM. Unexpectedly, disease-specific VEGFA expression was not increased in POEMS syndrome. Our study illustrates that the genetic and transcriptional profiles of plasma cells in POEMS syndrome are distinct from MM and MGUS, indicating unique function of clonal plasma cells in its pathogenesis.

In amyotrophic lateral sclerosis (ALS), the "zebra sign" in the precentral gyrus on phase difference enhanced magnetic resonance imaging (PADRE) recently has been reported as a possible imaging biomarker for upper motor neuron (UMN) involvement. A previous study has shown that the "zebra sign" allowed us to differentiate patients with ALS from healthy subjects with excellent accuracy. We validated the usefulness of the sign for differentiating patients with ALS from healthy subjects and investigated whether the "zebra sign" can be observed other neurodegenerative disorders with UMN involvement. The "zebra sign" on PADRE was assessed in 26 patients with ALS, 26 with multiple system atrophy (MSA) and 26 healthy controls, and the sign was observed in 50%, 23%, and no subjects, respectively. ALS patients with the "zebra sign" demonstrated a higher UMN burden score than those without the sign. The "zebra sign" on PADRE is not specific to ALS, also present in MSA, but might reflect the degeneration of the UMN within the motor cortex in neurodegenerative disorders.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction mainly caused by anti-nicotinic acetylcholine receptor (AChR) antibodies. Complements are known to play a prominent role in the pathogenesis of MG. Long-term remission may not necessarily be achieved in MG patients with conventional therapies. Recently, complement inhibitor, the humanized monoclonal anti-C5 antibody eculizumab, complement inhibitor, was approved for patients with anti-AChR antibody-positive generalized refractory MG in Japan. In this review, we focus on the role of complements in the pathogenesis of MG and the action mechanism, efficacy, and future prospects of eculizumab.

OBJECTIVE: Although it is well known that patients with multiple system atrophy (MSA) cerebellar dominant type (MSA-C) show severe autonomic dysfunction, the relationship between autonomic and motor dysfunction remains uncertain. Previously we reported that severe urinary voiding dysfunction is useful in differential diagnosis of MSA and other diseases. Herein, we aimed to clarify the relationship between the severity of motor dysfunctions and urinary dysfunction. METHOD: This study is a retrospective review of 46 patients with MSA-C diagnosed according to Gilman's second consensus criteria. The severity of motor dysfunctions was evaluated using International Cooperative Ataxia Rating Scale (ICARS). Urinary voiding dysfunction was evaluated by measuring post-void residual (PVR). The mean duration of motor unit potentials in external anal sphincter muscles on electromyography, which represents the severity of neurodegeneration in Onuf's nucleus, was also examined. RESULTS: The mean age of patients was 63.8 ± 8.2 years and mean disease duration was 3.0 ± 1.9 years. The mean ICARS score was 40.1 ± 14.7. The mean PVR was 119.1 ± 102 ml and the mean duration of motor unit potentials (MUPs) in anal sphincter electromyography was 9.2 ± 2.2 ms. The correlation coefficient between ICARS and PVR was 0.093 (p = .539), and between ICARS and mean duration of MUPs was 0.105 (p = .811). A significant positive correlation (r = 0.296, p = .005) was noted between PVR and the mean duration of MUP. CONCLUSION: Motor and urinary dysfunctions were not correlated in MSA-C.

© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. Background: [11C]pyridinyl-butadienyl-benzothiazole 3 is a PET imaging agent designed for capturing pathological tau aggregates in diverse neurodegenerative disorders, and would be of clinical utility for neuropathological investigations of PSP. Objectives: To explore the usefulness of [11C]pyridinyl-butadienyl-benzothiazole 3/PET in assessing characteristic distributions of tau pathologies and their association with clinical symptoms in the brains of living PSP patients. Methods: We assessed 13 PSP patients and 13 age-matched healthy control subjects. Individuals negative for amyloid β PET with [11C]Pittsburgh compound B underwent clinical scoring, MR scans, and [11C]pyridinyl-butadienyl-benzothiazole 3/PET. Results: There were significant differences in binding potential for [11C]pyridinyl-butadienyl-benzothiazole 3 between PSP patients and healthy control subjects (P = 0.02). PSP patients exhibited greater radioligand retention than healthy control subjects in multiple brain regions, including frontoparietal white matter, parietal gray matter, globus pallidus, STN, red nucleus, and cerebellar dentate nucleus. [11C]pyridinyl-butadienyl-benzothiazole 3 deposition in frontoparietal white matter, but not gray matter, was correlated with general severity of parkinsonian and PSP symptoms, whereas both gray matter and white matter [11C]pyridinyl-butadienyl-benzothiazole 3 accumulations in the frontoparietal cortices were associated with nonverbal cognitive impairments. Autoradiographic and fluorescence labeling with pyridinyl-butadienyl-benzothiazole 3 was observed in gray matter and white matter of PSP motor cortex tissues. Conclusions: Our findings support the in vivo detectability of tau fibrils characteristic of PSP by [11C]pyridinyl-butadienyl-benzothiazole 3/PET, and imply distinct and synergistic contributions of gray matter and white matte tau pathologies to clinical symptoms. [11C]pyridinyl-butadienyl-benzothiazole 3/PET potentially provides a neuroimaging-based index for the evolution of PSP tau pathologies promoting the deterioration of motor and cognitive functions. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Myasthenia gravis (MG) is an inflammatory disorder caused by autoantibodies against the nicotinic acetylcholine receptor (AChR). New therapeutic options for MG are required because the conventional treatments cannot always achieve long-term remission in MG patients. We developed a fusion protein, AChR-Fc, as a novel therapeutic agent for patients with MG. It is composed of the extracellular domain of human AChR-α1 subunit and human IgG1. AChR-Fc exhibited dual activities: it neutralized anti-AChR antibodies and demonstrated an enhanced cytotoxicity against autoantibody-producing B cells. Therefore, AChR-Fc is a novel biomolecule that can be used in the treatment of patients with MG, and potentially overcomes the disorder.

Peripheral neuropathy is a common extracerebellar manifestation of spinocerebellar ataxia type 3 (SCA3). However, to date, only a few SCA3 case reports have described the development of neuropathy before the emergence of apparent cerebellar signs. We herein report a case of very late-onset SCA3 in which preceding peripheral neuropathy seemingly concealed cerebellar signs, with seven years lapsing from the onset to the diagnosis. Horizontal gaze-evoked nystagmus and brain magnetic resonance imaging (MRI) findings prompted genetic testing, which confirmed the diagnosis of SCA3. A careful follow-up of neurological findings, such as nystagmus, and brain MRI are imperative for such cases.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months. OBJECTIVE: This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. METHODS: The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period. RESULTS: This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020. CONCLUSIONS: This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/12046.