Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype–phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype–phenotype correlations are unclear in NMOSD.

DOI： 10.1038/s41598-020-79833-7

researchmap

Other Link： http://www.nature.com/articles/s41598-020-79833-7

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.msard.2021.103427

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

PURPOSE: To assess the effect of maintenance therapy on visual outcomes in preventing recurrences one year after first onset in patients with aquaporin-4 antibody (AQP4Ab)-positive optic neuritis. STUDY DESIGN: Retrospective study. METHODS: The medical charts of 56 patients with optic neuritis (22 with AQP4Ab-positive and 34 with AQP4Ab-negative) at Niigata University Medical and Dental Hospital were retrospectively analyzed. Clinical characteristics, including visual acuity and number of recurrences one year after first onset, were compared among patients who were AQP4Ab-positivie with and those without maintenance therapy such as oral prednisolone and azathioprine, as well as those who were AQP4Ab-negative. RESULTS: The mean ages were 49.3 and 45.2 years in the AQP4Ab-positive and the AQP4Ab-negative groups. The female to male ratio was 21:1 and 18:16 in the two groups, respectively. Multiple between-group comparison showed a statistically significant difference in visual acuity one year after first onset between the AQP4Ab-positive without maintenance therapy group and the AQP4Ab-negative group (0.05 (median, same applies below) vs. 1.0, p < 0.01). There was also a statistically significant difference in the number of recurrences in the year after first onset between the AQP4Ab-positive with and without maintenance therapy groups (1 vs. 0, p < 0.01). CONCLUSION: This study demonstrates that patients with AQP4Ab-positive optic neuritis without maintenance therapy had the poorest visual acuity and the most recurrences one year after first onset. These results indicate that reducing the number of recurrences with maintenance therapy could improve the visual outcomes in patients with AQP4Ab-positive optic neuritis.

DOI： 10.1007/s10384-021-00858-0

PubMed

researchmap

Other Link： https://link.springer.com/article/10.1007/s10384-021-00858-0/fulltext.html

Language：English  

DOI： 10.1186/s40478-020-00945-2

PubMed

researchmap

Authorship：Lead author,　Corresponding author  

DOI： 10.1186/s12883-019-1534-9

PubMed

researchmap

Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

© 2019 Japanese Society for Neuroimmunology Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are the two main autoimmune demyelinating disorders of the central nervous system. MS is defined as autoimmune oligodendrocytopathy (unknown autoantigens), and NMOSD is defined as autoimmune astrocytopathy or aquaporin-4 channelopathy. Both diseases can occur throughout the central nervous system, and do often cause various “motor” and “non-motor” symptoms. “Non-motor” symptoms, including cognitive impairment, fatigue, pain and neuropsychological symptoms (e.g. depression, loneliness and anxiety), have gained renewed attention in MS and NMOSD since the past three decades, because they influence a patient&#039;s competence in daily life activities, including the participation in social activities and their employment status. Herein, we summarize the current concepts of the neuropathological processes of these “non-motor” symptoms in MS and NMOSD. These concepts help to define the novel disease-specific mechanisms of the two diseases, and to improve the quality of daily life of patients with MS and NMOSD.

DOI： 10.1111/cen3.12533

Scopus

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publisher：BMJ PUBLISHING GROUP  

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are autoimmune demyelinating diseases of the central nervous system (CNS), having distinct immunological and pathological features. They have two pathogenic components, 'inflammation' and 'neurodegeneration', with different degrees of severity and pathogenetic mechanisms. The target antigen of autoimmunity in NMO is the water channel aquaporin-4 (AQP4), and antibodies directed against this antigen result in astrocyte damage. MS is a disease primarily affecting myelin and oligodendrocytes, but thus far, no MS-specific autoantigen has been identified. The distinct inflammatory processes in these diseases may trigger cascades of events leading to disease-specific neurodegeneration. Damage of the CNS tissue appears to be amplified by mechanisms that are in part shared by the two conditions and involve oxidative burst activation in microglia/macrophages, mitochondrial damage and axonal energy failure, Wallerian degeneration and meningeal inflammation. However, they appear to differ regarding the nature of the inflammatory response, the type and extent of cortical injury, and the type of astrocyte reaction and damage. Here, we provide a detailed comparison of the pathology between MS and NMO, which may help to define shared and disease-specific mechanisms of neurodegeneration in these diseases.

DOI： 10.1136/jnnp-2016-313300

Web of Science

PubMed

researchmap

Language：English   Publisher：Wiley-Blackwell  

Autoimmune disorders of the central nervous system often involve autoimmune inflammation of the anterior visual pathways. Autoimmune optic neuritis can be categorized as: (i) isolated optic neuritis
(ii) relapsing isolated optic neuritis: (iii) chronic relapsing inflammatory optic neuropathy
(iv) neuromyelitis optica spectrum disorders-associated optic neuritis
or (v) multiple sclerosis-associated optic neuritis. Studies of serum-specific autoantibodies, such as aquaporin-4 and myelin oligodendrocyte glycoprotein, have revealed some underlying mechanisms of autoimmune optic neuritis. However, the etiology and pathogenesis of most cases of autoimmune optic neuritis remain unclear. The following clinical features of autoimmune optic neuritis are profoundly affected by the unique structure of the human anterior visual pathways: (i) vulnerability to swelling of the intracanalicular optic nerve as a result of the limited space within the bony canal
(ii) inflammatory cell infiltration through the subarachnoid space, pia and pial septa
(iii) compartmentalized dynamics of cerebrospinal fluid as a result of the cul-de-sac anatomy of the optic nerve
(iv) permeability of the prelaminar optic nerve head as a result of the lack of classical blood–brain barrier characteristics
and (v) retinal abnormalities, which are a diagnostic window of neurodegenerative processes of the optic nerves and/or brain. Future studies are required to configure a systemic nosology for optic neuritis with international consensus, elucidate specific diagnostic biomarkers, carry out clinical trials of the acute and chronic phases of the disease etiologies, and elucidate possible neuroprotective and remyelinating treatments.

DOI： 10.1111/cen3.12354

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare cause of demyelinating neuropathy, with multi-organ involvement characterised by plasma cell dyscrasia and VEGF overproduction. No treatments have been established for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide suppresses VEGF and plasma cell proliferation. We aimed to assess the safety and efficacy of thalidomide for the treatment of POEMS syndrome.
Methods We did a randomised, double-blind, placebo-controlled, phase 2/3 trial at 12 hospitals in Japan. Adults (age &gt;= 20 years) with POEMS syndrome who were ineligible for autotransplantation were randomly assigned (1:1) by a minimisation method to treatment with oral dexamethasone (12 mg/m(2) per day on the first 4 days of every 28-day cycle) plus either oral thalidomide (200 mg daily) or placebo for six cycles. All study personnel and patients were masked to treatment allocation. The primary endpoint was the reduction rate of serum VEGF concentrations at 24 weeks. Analysis was by intention to treat. This study is registered with the UMIN Clinical Trials Registry, UMIN000004179.
Findings Between Nov 11, 2010, and July 3, 2014, we randomly assigned 25 patients to receive either thalidomide (n=13) or placebo (n=12); one patient in the placebo group was excluded from analyses because of a protocol violation. The adjusted mean VEGF concentration reduction rate at 24 weeks was 0.39 (SD 0.34) in the thalidomide group compared with -0.02 (0.54) in the placebo group (adjusted mean difference 0.41, 95% CI 0.02-0.80; p=0.04). Mild sinus bradycardia was more frequent in the thalidomide group than in the placebo group (seven [54%] vs zero; p=0.006). Five patients had serious adverse events: three in the thalidomide group (transient cardiac arrest, heart failure, and dehydration) and two in the placebo group (ileus and fever). No deaths occurred during the randomised study. In the 48-week open-label study period (n=22), newly developed adverse events were sinus bradycardia (n=4), constipation (n=5), and mild sensory neuropathy (n=5). Two patients died in the open-label study; both patients were initially in the placebo group, and the cause of death was progression of the disease.
Interpretation Thalidomide reduces serum VEGF concentrations and represents a new treatment for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide treatment poses a risk of bradycardia; however, the benefits are likely to exceed the risk.

DOI： 10.1016/S1474-4422(16)30157-0

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective:To report a novel autoimmune encephalitis in which the antibodies target neurexin-3, a cell adhesion molecule involved in the development and function of synapses.Methods:Five patients with encephalitis and antibodies with a similar pattern of brain reactivity were selected. Antigen precipitation and determination of antibody effects on cultured rat embryonic neurons were performed with reported techniques.Results:Immunoprecipitation and cell-based assays identified neurexin-3 as the autoantigen of patients' antibodies. All 5 patients (median age 44 years, range 23-50; 4 female) presented with prodromal fever, headache, or gastrointestinal symptoms, followed by confusion, seizures, and decreased level of consciousness. Two developed mild orofacial dyskinesias, 3 needed respiratory support, and 4 had findings suggesting propensity to autoimmunity. CSF was abnormal in all patients (4 pleocytosis, 1 elevated immunoglobulin G [IgG] index), and brain MRI was abnormal in 1 (increased fluid-attenuated inversion recovery/T2 in temporal lobes). All received steroids, 1 IV immunoglobulin, and 1 cyclophosphamide; 3 partially recovered, 1 died of sepsis while recovering, and 1 had a rapid progression to death. At autopsy, edema but no inflammatory cells were identified. Cultures of neurons exposed during days in vitro (div) 7-17 to patients' IgG showed a decrease of neurexin-3 clusters as well as the total number of synapses. No reduction of synapses occurred in mature neurons (div 18) exposed for 48 hours to patients' IgG. Neuronal survival, dendritic morphology, and spine density were unaffected.Conclusion:Neurexin-3 autoantibodies associate with a severe but potentially treatable encephalitis in which the antibodies cause a decrease of neurexin-3 and alter synapse development.

DOI： 10.1212/WNL.0000000000002775

Web of Science

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

ObjectiveNeuromyelitis optica spectrum disorder (NMOsd) is an autoimmune disorder of the central nervous system characterized by aquaporin-4 (AQP4) autoantibodies. The aim of this study was to elucidate the characteristics of involvement of the anterior visual pathway (AVP) and neurodegeneration via glia-neuron interaction in NMOsd.
MethodsThirty Japanese patients with serologically verified NMOsd were assessed with a neuro-ophthalmological study. Using 27 tissue blocks from 13 other cases of NMOsd, we performed neuropathological analysis of glial and neuroaxonal involvement in the AVP.
ResultsThe AVP involvement in NMOsd was characterized by the following, compared to multiple sclerosis: (1) longitudinally extensive optic neuritis (ON); (2) more severe visual impairment and worse prognosis for ON; (3) unique AQP4 dynamics, including loss of AQP4 immunoreactivity on astrocytes with complement activation in ON lesions, loss of AQP4 immunoreactivity on Muller cells with no deposition of complement in the retinas, and densely packed AQP4 immunoreactivity on astrocytes in gliosis of secondary anterograde/retrograde degeneration in the optic nerves and retinal nerve fiber layer (RNFL); and (4) more severe neurodegeneration, including axonal accumulation of degenerative mitochondria and transient receptor potential melastatin 4 channel with complement-dependent astrocyte pathology in ON lesions, mild loss of horizontal cells, and RNFL thinning and loss of ganglion cells with abundance of AQP4(+) astrocytes, indicating secondary retrograde degeneration after ON.
InterpretationSevere and widespread neuroaxonal damage and unique dynamics of astrocytes/Muller cells with alterations of AQP4 were prominent in the AVP and may be associated with poor visual function and prognosis in NMOsd. Ann Neurol 2016;79:605-624

DOI： 10.1002/ana.24608

Web of Science

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting T(H)1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.

DOI： 10.1093/brain/awt314

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective: To describe the clinical features and outcome of anti-NMDA receptor (NMDAR) encephalitis in patients &gt;= 45 years old.
Method: Observational cohort study.
Results: In a cohort of 661 patients with anti-NMDAR encephalitis, we identified 31 patients &gt;= 45 years old. Compared with younger adults (18-44 years), older patients were more often male (45% vs 12%, p &lt; 0.0001), had lower frequency of tumors (23% vs 51%, p = 0.002; rarely teratomas), had longer median time to diagnosis (8 vs 4 weeks, p = 0.009) and treatment (7 vs 4 weeks, p = 0.039), and had less favorable outcome (modified Rankin Scale score 0-2 at 2 years, 60% vs 80%, p &lt; 0.026). In multivariable analysis, younger age (odds ratio [OR] 0.15, confidence interval [CI] 0.05-0.39, p = 0.0001), early treatment (OR 0.60, CI 0.47-0.78, p &lt; 0.0001), no need for intensive care (OR 0.09, CI 0.04-0.22, p &lt; 0.0001), and longer follow-up (p &lt; 0.0001) were associated with good outcome. Rituximab and cyclophosphamide were effective when first-line immunotherapies failed (OR 2.93, CI 1.10-7.76, p = 0.031). Overall, 60% of patients older than 45 years had full or substantial recovery at 24 months follow-up.
Conclusions: Anti-NMDAR encephalitis is less severe in patients &gt;= 45 years old than in young adults, but the outcome is poorer in older patients. In this age group, delays in diagnosis and treatment are more frequent than in younger patients. The frequency of underlying tumors is low, but if present they are usually carcinomas instead of teratomas in younger patients. Early and aggressive immunotherapy will likely improve the clinical outcome.

DOI： 10.1212/WNL.0b013e3182a4a49c

Web of Science

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS LTD  

Fingolimod acts as a functional antagonist of the sphingosine-1-phosphate receptor, and it traps lymphocytes in secondary lymphoid organs and precludes their migration into the central nervous system. We report the case of a patient who suffered a relatively severe relapse of multiple sclerosis (MS) during the initial 3 months of fingolimod therapy, with retention of CCR7 expression on CD4(+) T cells in the cerebrospinal fluid (CSF) despite decreased numbers of lymphocytes and decreased expression of CCR7 on CD4(+) T cells in the blood. These data suggest that fingolimod may cause differential effects on the CSF and blood lymphocytes of patients with MS during the initial months of therapy.

DOI： 10.1177/1352458513481395

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Background Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined. We aimed to assess the presentation of the disease, the spectrum of symptoms, immunotherapies used, timing of improvement, and long-term outcome.
Methods In this multi-institutional observational study, we tested for the presence of NMDAR antibodies in serum or C SF samples of patients with encephalitis between Jan 1,2007, and Jan 1, 2012. All patients who tested positive for NMDAR antibodies were included in the study; patients were assessed at symptom onset and at months 4,8,12,18, and 24, by use of the modified Rankin scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (ritincimab, cydophosphamide), and tumour removal. Predictors of outcome were determined at the Universities of Pennsylvania (PA, USA) and Barcelona (Spain) by use of a generalised linear mixed model with binary distribution.
Results We enrolled 577 patients (median age 21 years, range 8 months to 85 years), 211 of whom were children (&lt;18 years). Treatment effects and outcome were assessable in 501 (median follow-up 24 months, range 4-186): 472 (94%) underwent first-line immunotherapy or tumour removal, resulting in improvement within 4 weeks in 251 (53%). Of 221 patients who did not improve with first-line treatment, 125 (57%) received second-line immunotherapy that resulted in a better outcome (mRS 0-2) than those who did not (odds ratio [OR] 2.69, CI 1-24-5.80; p=0.012). During the first 24 months, 394 of 501 patients achieved a good outcome (mRS 0-2; median 6 months, IQR 2-12) and 30 died. At 24 months' follow-up, 203 (81%) of 252 patients had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (0.62,0.50-0.76; p&lt;0.0001) and no admission to an intensive care unit (0.12,0.06-0-22; p&lt;0.0001). 45 patients had one or multiple relapses (representing a 12% risk within 2 years); 46 (67%) of 69 relapses were less severe than initial episodes (p&lt;0.0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were similar to those of the entire cohort.
Interpretation Most patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line treatments fail. In this cohort, the recovery of some patients took up to 18 months.

DOI： 10.1016/S1474-4422(12)70310-1

Web of Science

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Objective: Neuromyelitis optica spectrum disorder (NMOsd) is an inflammatory and demyelinating syndrome characterized by optic neuritis and myelitis. Several magnetization transfer magnetic resonance imaging (MRI) studies have revealed abnormalities in normal-appearing gray matter in NMOsd. The aim of this study is to elucidate the characteristics and pathogenesis of cognitive impairment and neurodegeneration in NMOsd brains.
Methods: Fourteen Japanese patients with serologically verified NMOsd, 17 patients with multiple sclerosis (MS), and 37 healthy controls were assessed with the Rao's Brief Repeatable Battery of Neuropsychological Tests (BRBN). Using 128 tissue blocks from 6 other cases of NMOsd, 3 cases of MS, and 4 controls without central nervous system involvement, we performed quantitative analysis of cortical neuronal loss and layer-specific changes in NMOsd.
Results: In BRBN assessments, 57% of NMOsd patients and 47% of MS patients had impaired performance on at least 3 cognitive tests. Cognitive impairment in NMOsd was common even in the limited form of disease, indicating that NMOsd may progress insidiously from early stages of disease. Neuropathological assessments showed neuronal loss in cortical layers II, III, and IV, with nonlytic reaction of aquaporin-4 (AQP4)-negative astrocytes in layer I, massive activated microglia in layer II, and meningeal inflammation in NMOsd brains. All NMO cases showed no evidence of cortical demyelination.
Interpretation: We demonstrate cognitive impairment and substantial cortical neuronal loss with unique AQP4 dynamics in astrocytes in NMOsd. These data indicate pathological processes consisting not only of inflammatory demyelinating events characterized by pattern-specific loss of AQP4 immunoreactivity but also cortical neurodegeneration in NMOsd brains. ANN NEUROL 2013;73:65-76

DOI： 10.1002/ana.23721

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Proteasomes are multisubunit proteases that play a critical role in maintaining cellular function through the selective degradation of ubiquitinated proteins. When 3 additional β subunits, expression of which is induced by IFN-γ, are substituted for their constitutively expressed counterparts, the structure is converted to an immunoproteasome. However, the underlying roles of immunoproteasomes in human diseases are poorly understood. Using exome analysis, we found a homozygous missense mutation (G197V) in immunoproteasome subunit, β type 8 (PSMB8), which encodes one of the β subunits induced by IFN-γ in patients from 2 consanguineous families. Patients bearing this mutation suffered from autoinflammatory responses that included recurrent fever and nodular erythema together with lipodystrophy. This mutation increased assembly intermediates of immunoproteasomes, resulting in decreased proteasome function and ubiquitin-coupled protein accumulation in the patient's tissues. In the patient's skin and B cells, IL-6 was highly expressed, and there was reduced expression of PSMB8. Downregulation of PSMB8 inhibited the differentiation of murine and human adipocytes in vitro, and injection of siRNA against Psmb8 in mouse skin reduced adipocyte tissue volume. These findings identify PSMB8 as an essential component and regulator not only of inflammation, but also of adipocyte differentiation, and indicate that immunoproteasomes have pleiotropic functions in maintaining the homeostasis of a variety of cell types.

DOI： 10.1172/JCI58414

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1212/WNL.0b013e3181fc2788

Web of Science

researchmap

Authorship：Lead author   Language：English   Publisher：B M J PUBLISHING GROUP  

DOI： 10.1136/jnnp.2009.177261

Web of Science

Scopus

PubMed

researchmap

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background: Neuromyelitis optica (NMO) is a demyelinating syndrome characterized by myelitis and optic neuritis. Detection of anti-NMO immunoglobulin G antibody that binds to aquaporin-4 (AQP4) water channels allows the diagnosis of a limited form of NMO in the early stage with myelitis, but not optic neuritis. However, the detailed clinicopathologic features and long-term course of this limited form remain elusive.
Methods: We investigated 8 patients with the limited form of NMO with myelitis in comparison with 9 patients with the definite form.
Result: All patients with limited and definite form showed uniform relapsing-remitting courses, with no secondary progressive courses. Pathologic findings of biopsy specimens from the limited form were identical to those of autopsy from the definite form, demonstrating extremely active demyelination of plaques, extensive loss of AQP4 immunoreactivity in plaques, and diffuse infiltration by macrophages containing myelin basic proteins with thickened hyalinized blood vessels. Moreover, the definite form at the nadir of relapses displayed significantly higher amounts of the inflammatory cytokines interleukin (IL)-1 beta and IL-6 in CSF than the limited form and multiple sclerosis.
Conclusion: This consistency of pathologic findings and uniformity of courses indicates that aquaporin 4-specific autoantibodies as the initiator of the neuromyelitis optica (NMO) lesion consistently play an important common role in the pathogenicity through the entire course, consisting of both limited and definite forms, and NMO continuously displays homogeneity of pathogenic effector immune mechanisms through terminal stages, whereas multiple sclerosis should be recognized as the heterogeneous 2-stage disease that could switch from inflammatory to degenerative phase. This report is a significant description comparing the pathologic and immunologic data of limited NMO with those of definite NMO. Neurology (R) 2009; 73: 1628-1637

DOI： 10.1212/WNL.0b013e3181c1deb9

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (&lt; 5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10-20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule cells). The number of neurons displaying NCIs in each region was very small (1-3 per region, except the dentate gyrus). On the other hand, the occurrence of TDP-43-ir glial cytoplasmic inclusions (GCIs) was more widespread in the central nervous system, including the cerebral white matter. Again, however, the number of glial cells displaying GCIs in each region was very small (1-3 per region). In conclusion, compared to the usual form of SALS, TDP-43 pathology shown in SALS of long duration was apparently mild in degree and limited in distribution, corresponding to the relatively benign clinical courses observed. It is now apparent that SALS of long duration is actually part of a TDP-43 proteinopathy spectrum.

DOI： 10.1007/s00401-008-0443-6

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy ( DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 ( average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called 'senile chorea'. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3-q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (theta = 0.00). Haplotype analysis of both the families defined the candidate region as 21.5Mb interval flanked by M9267 and D8S1139. We named this adult- onset dominant inherited chorea 'benign hereditary chorea type 2 (BHC2)'.

DOI： 10.1093/brain/awm036

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Mucosal-associated invariant T (MAIT) cells reside primarily in the gut lamina propria and require commensal flora for selection/expansion. They are restricted by the highly conserved MHC class I-related molecule MR1 and, like most NK T cells, express an invariant TCR alpha chain. Although they probably contribute to gut immunity, MAIT cells have not been functionally characterized because they are so rare. To create a model in which they are more abundant, we generated transgenic mice expressing only the TCRa chain (V alpha 19i) that defines MAIT cells. By directly comparing V alpha 19i transgenic mice on MRI(+/+) and MRI(-/-) backgrounds, we were able to distinguish and characterize a population of V alpha 19i T cells dependent on MR1 for development. MR1-restricted V alpha 19i transgenic T cells recapitulate what is known about MAIT cell development. Furthermore, a relatively high proportion of transgenic MAIT cells express NK1.1, and most have a cell surface phenotype similar to that of V alpha 14i NK T cells. Finally, MR1-restricted V alpha 19i T cells secrete IFN-gamma, IL-4, IL-5, and IL-10 following TCR ligation, and we provide evidence for what may be two functionally distinct MAIT cell populations. These data strongly support the idea that MAIT cells contribute to the innate immune response in the gut mucosa.

DOI： 10.4049/jimmunol.176.3.1618

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BRITISH MED JOURNAL PUBL GROUP  

DOI： 10.1136/jnnp.72.5.676-a

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE AMERICA INC  

Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs(1-4). We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus(5). We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.

DOI： 10.1038/ng1001-184,

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Polymyositis (PM) is an inflammatory muscle disease caused by autoimmune dysfunction, considered to be caused by cytotoxic CD8 T cells. To date, no autoantigens have been identified. We attempted to induce an experimental allergic myositis (EAM) in BALB/c mice by inoculating syngeneic dendritic cells (DC) presenting peptides that are expected to match the binding anchor motif of H-2K(d) (BALB/c). We selected peptides that are highly expressed in skeletal muscle. Only when we inoculated syngeneic bone marrow-derived DC presenting pyruvate kinase M1/M2 peptide 464-472 in BALB/c mice, 41.7% of the mice (EAM) developed pathological changes in skeletal muscle compatible to human PM. Under other conditions (when we inoculated DC presenting no synthetic peptides into BALB/c or C57BL/6 mice and DC presenting pyruvate kinase M1/M2 peptide into C57BL/6 mice), there were no necrotizing and inflammatory lesions. Induction of EAM in the same manner as above also induced CTL activity against P815 cells with the same peptide and syngeneic differentiated cultured myotubes without peptides by the chromium release assay. Consistent with the similarity of the binding anchor motif of H-2Kd (BALB/c) and HLA A* 2402, we conclude that pyruvate kinase M1/M2 peptide is a candidate autoantigen not only in BALB/c-EAM but also in human-PM with the HLA A* 2402 allele. (C) 2001 Elsevier Science B.V, All rights reserved.

DOI： 10.1016/S0165-5728(01)00327-7

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1212/WNL.56.7.977

Web of Science

PubMed

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Wiley  

An 84‐year‐old man presented with somnolence, dysphagia, and right hemiplegia, all occurring within a month, approximately one year after initial admission due to subacute, transient cognitive decline suggestive of acute disseminated encephalomyelitis involving the cerebral white matter. Serial magnetic resonance imaging (MRI) studies over that period revealed three high‐intensity signal lesions on fluid‐attenuated inversion recovery images, appearing in chronological order in the left upper and left lower medulla oblongata and left pontine base. Despite some clinical improvement following methylprednisolone pulse therapy, the patient died of respiratory failure. Autopsy revealed four fresh, well‐defined lesions in the brainstem, three of which corresponded to the lesions detected radiologically. The remaining lesion was located in the dorsal medulla oblongata and involved the right solitary nucleus. This might have appeared at a later disease stage, eventually causing respiratory failure. Histologically, all four lesions showed loss of myelin, preservation of axons, and infiltration of lymphocytes, predominantly CD8‐positive T cells, consistent with the histological features of autoimmune demyelinating diseases, particularly the confluent demyelination observed in the early and acute phases of multiple sclerosis (MS). In the cerebral white matter, autoimmune demyelination appeared superimposed on ischemic changes, consistent with the cerebrospinal fluid (CSF) and MRI findings on initial admission. No anti‐AQP4 or MOG antibodies or those potentially causing autoimmune encephalitis/demyelination were detected in either the serum or CSF. Despite several similarities to MS, such as the relapsing–remitting disease course and lesion histology, the entire clinicopathological picture in the present patient, especially the advanced age at onset and development of brainstem lesions in close proximity within a short time frame, did not fit those of MS or other autoimmune diseases that are currently established. The present results suggest that exceptionally older individuals can be affected by an as yet unknown inflammatory demyelinating disease of the CNS.

DOI： 10.1111/neup.12976

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Objectives Chronic progressive neuro-Behcet's disease (CPNB) is characterized by progressive deterioration leading to disability. Methotrexate (MTX) has been shown to have beneficial effects on CPNB. However, while infliximab has been found to be effective for patients with inadequate responses to MTX, the appropriate timing for the introduction of infliximab remains unclear. We explored the effects of intervals before the introduction of infliximab on the functional outcome. Methods A retrospective analysis was performed for patients with CPNB who received infliximab and were followed up until October 2015. Functional disability was rated by the Steinbrocker functional classification as used in rheumatoid arthritis. Correlations between the outcomes and intervals before the introduction of infliximab were then analyzed by Spearman's rank correlation test. Patients Eleven patients with CPNB (8 men, 3 women, age 35.2±9.3 years old [mean±standard deviation]) who met the international classification criteria for Behcet's disease were included. Results All 11 patients had received MTX prior to infliximab. The intervals from the onset to the introduction of infliximab and the follow-up periods were 26.6±35.1 months and 65.2±43.6 months [mean±standard deviation], respectively. Among the 11 patients, 2 still showed progression after the introduction of infliximab. The functional disability grades after infliximab treatment were significantly correlated with the intervals from the onset of CPNB to the introduction of infliximab (r=0.6177, p=0.0476). Conclusion The results indicate that the delayed introduction of infliximab leads to irreversible functional disability in CPNB. Thus, it is recommended that infliximab be administered as soon as possible for CPNB patients with inadequate responses to MTX.

DOI： 10.2169/internalmedicine.1969-23

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Neurological disabilities, especially physical issues, can adversely affect the daily lives of people with multiple sclerosis (MS) and negatively impact their health-related quality of life (HRQOL). On the other hand, physical and psychiatric symptoms are variable in people with MS, and QOL can be influenced by cultural and educational background. This study aimed to evaluate the association of HRQOL with disabilities, fatigue, and depression in Japanese subjects with MS. METHODS: Evaluation of HRQOL, fatigue, and depression was performed in 184 Japanese individuals with MS, using the Functional Assessment of MS (FAMS), Fatigue Severity Scale (FSS), and Beck Depression Inventory-Second Edition (BDI-II), respectively. RESULTS: Multiple linear regression analysis demonstrated negative correlations of the Expanded Disability Status Scale (EDSS) with scores on the FAMS subscales of mobility, symptoms, thinking and fatigue, total FAMS, and additional concerns. The FSS score had negative correlations with mobility, symptoms, emotional well-being, thinking and fatigue, total FAMS, and additional concerns. There were negative correlations between BDI-II scores and all items of FAMS. CONCLUSIONS: HRQOL had relatively close correlations with disabilities and fatigue, and depression had an especially close relationship with HRQOL.

DOI： 10.1007/s00415-022-11453-9

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER HEIDELBERG  

Objectives Neurological disabilities, especially physical issues, can adversely affect the daily lives of people with multiple sclerosis (MS) and negatively impact their health-related quality of life (HRQOL). On the other hand, physical and psychiatric symptoms are variable in people with MS, and QOL can be influenced by cultural and educational background. This study aimed to evaluate the association of HRQOL with disabilities, fatigue, and depression in Japanese subjects with MS. Methods Evaluation of HRQOL, fatigue, and depression was performed in 184 Japanese individuals with MS, using the Functional Assessment of MS (FAMS), Fatigue Severity Scale (FSS), and Beck Depression Inventory-Second Edition (BDI-II), respectively. Results Multiple linear regression analysis demonstrated negative correlations of the Expanded Disability Status Scale (EDSS) with scores on the FAMS subscales of mobility, symptoms, thinking and fatigue, total FAMS, and additional concerns. The FSS score had negative correlations with mobility, symptoms, emotional well-being, thinking and fatigue, total FAMS, and additional concerns. There were negative correlations between BDI-II scores and all items of FAMS. Conclusions HRQOL had relatively close correlations with disabilities and fatigue, and depression had an especially close relationship with HRQOL.

DOI： 10.1007/s00415-022-11453-9

Web of Science

researchmap

Language：Japanese   Publisher：(一社)日本神経免疫学会  

researchmap

Authorship：Lead author,　Last author,　Corresponding author  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.clineuro.2021.106496

PubMed

researchmap

Authorship：Last author,　Corresponding author  

DOI： 10.11477/mf.1416201802.

researchmap

Authorship：Last author,　Corresponding author  

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.xjep.2020.100377

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

We report a 74-year-old man with a 2-year history of proximal limb pain, body weight loss of 15 kg, and muscle weakness. Muscle atrophy was evident in the limbs and trunk, as well as the tongue. He was admitted to our hospital with suspected amyotrophic lateral sclerosis (ALS). Although he had no physical manifestations of Basedow disease such as palpitations, hyperhidrosis, hand tremor, exophthalmos, and an enlarged thyroid, he was diagnosed as having thyrotoxic myopathy as laboratory examinations indicated hyperthyroidism and positivity for TSH receptor antibody. The serum level of soluble IL-2 receptor was also elevated. Despite the severe muscle atrophy, the serum CK level was normal. A biopsy from the left quadriceps muscle revealed Type 1 fibers atrophy. Administration of anti-thyroid drugs normalized his thyroid function and the level of soluble IL-2 receptor, leading to improvement of the generalized muscle atrophy.

DOI： 10.5692/clinicalneurol.cn-001365

PubMed

researchmap

Language：English   Publisher：WILEY  

Objective Brain parenchymal involvement in Behçet's disease (BD) (neuro-Behçet's disease, NB) can be classified into acute type (ANB) and chronic progressive type (CPNB) based on differences in the clinical course and responses to corticosteroid treatment. The present study developed evidence-based recommendations for the management of NB.Methods The task force of the research subcommittee consisted of seven board-certified rheumatologists (one was also a board-certified neurologist) and three board-certified neurologists. First, several clinical questions (CQs) were established. A systematic literature search was performed by The Japan Medical Library Association in order to develop recommendations. The final recommendations for each CQ developed from three blind Delphi rounds, for which the rate of agreement scores [range 1 (strongly disagree)-5(strongly agree)] was determined through voting by the task force.Results A flow chart of the algorithm was established for the management of ANB and CPNB. Thirteen recommendations were developed for NB (general 1, ANB 7, CPNB 5). The strength of each recommendation was established based on the evidence level as well as the rate of agreement.Conclusion The recommendations generated in this study are based on the results of uncontrolled evidence from open trials, retrospective cohort studies and expert opinions, due to the lack of randomized clinical trials. Nevertheless, these recommendations can be used for international studies, although verification by further properly designed controlled clinical trials is required.

DOI： 10.2169/internalmedicine.4705-20

Web of Science

PubMed

researchmap

Authorship：Lead author,　Corresponding author  

DOI： 10.11307/mededjapan.51.3_231

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Occurrence of basal ganglia involvement in neuromyelitis optica spectrum disorders (NMOSD) has rarely been reported and none documented pathologically.

Case presentation

A 73-year-old female was clinically diagnosed with a NMOSD based on the clinical and radiological features and positive serum autoantibodies to AQP4. One month before her death, she became acutely ill with disturbed consciousness and right hemiparesis, and was diagnosed and treated as having basal ganglia infarction based on the brain CT. She made a partial recovery but later died from heart failure. At autopsy, the corresponding basal ganglia process revealed a large fresh area of necrosis. Histologically, several pathological signatures of NMOSD could be recognized in the lesion, including inflammatory cell infiltrations by B and T lymphocytes, perivascular complement and fibrinogen deposition, and the appearance of numerous phagocytosed corpora amylacea within the infiltrating macrophages.

Conclusions

The present case illustrates that basal ganglia may be directly involved in the pathological processes of NMOSD, although the possibility of modification of the lesions by superimposed regional ischemia could not be excluded.

DOI： 10.1186/s12883-019-1580-3

PubMed

researchmap

Other Link： http://link.springer.com/article/10.1186/s12883-019-1580-3/fulltext.html

DOI： 10.5692/clinicalneurol.cn-001270

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

This report describes the autopsy case of a 4-year-old boy who died from hepatic hemorrhage and rupture caused by peliosis hepatis with X-linked myotubular myopathy. Peliosis hepatis is characterized by multiple blood-filled cavities of various sizes in the liver, which occurs in chronic wasting disease or with the use of specific drugs. X-linked myotubular myopathy is one of the most serious types of congenital myopathies, in which an affected male infant typically presents with severe hypotonia and respiratory distress immediately after birth. Although each disorder is rare, 12 cases of pediatric peliosis hepatis associated with X-linked myotubular myopathy have been reported, including our case. Peliosis hepatis should be considered as a cause of hepatic hemorrhage despite its low incidence, and it requires adequate gross and histological investigation for correct diagnosis.

DOI： 10.1016/j.legalmed.2019.04.005

Web of Science

PubMed

researchmap

DOI： 10.2217/nmt-2017-0047

Web of Science

PubMed

researchmap

Authorship：Lead author,　Last author,　Corresponding author  

DOI： 10.11477/mf.1416201006

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

Objective: To understand, through an analysis of health insurance claims data, the current treatment status and medical cost of multiple sclerosis (MS) in Japan. Methods: We analyzed claims data (January 2005–January 2016) from the Japan Medical Data Center Co., Ltd., identifying MS patients, except those with neuromyelitis optica, using an algorithm based on diagnosis codes. Prescription drug usage and medical costs for MS patients were analyzed. Results: A total of 713 MS patients were identified in the database. Between 2011 and 2015, the age-adjusted prevalence of MS in the database increased from 0.015% to 0.019%, and the female-to-male ratio increased from 1.70 to 2.03. The prescription rate for disease-modifying therapy drugs was higher in larger care settings. Prescriptions for fingolimod increased from 2011, with a concomitant decrease in prescriptions for interferon. The per patient per month cost for MS was \124 337 (US$1190 or €1084, as of October 2016). This was higher than the costs for Parkinson's disease (\84 410), myasthenia gravis (\82 944) and rheumatoid arthritis (\53 843). However, the total per member per month cost for MS, which represents the population-based economic impact, was \25.2, which was lower than the parallel costs for Parkinson's disease (\123.0) and rheumatoid arthritis (\311.6) because of the low prevalence of MS in Japan. Conclusions: Using real-world data, we obtained up-to-date prevalence, treatment status and medical cost information for MS in Japan. The present results showed the efficacy of a real-world database to obtain the latest national trends for rare diseases, such as MS
this could have important implications for clinicians and policymakers.

DOI： 10.1111/cen3.12411

Scopus

PubMed

researchmap

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jns.2017.08.3453

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS LTD  

Background: No large-scale studies have compared the efficacy of intravenous methylprednisolone pulse therapy (IVMP) for multiple sclerosis (MS) and neuromyelitis optica (NMO).
Objective: To explain differences in treatment responses of MS and NMO patients to IVMP.
Methods: Changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1week of IVMP completion were obtained in 2010 at 28 institutions, and retrospectively collated from 271 MS (478 courses) and 73 NMO (118 courses) cases.
Results: In MS patients, decreased EDSS score was significant after the first (-0.80.9), second (-0.7 +/- 0.9), and third (-0.7 +/- 0.8) courses (p&lt;0.05), but not after the fourth (-0.3 +/- 0.7) and fifth (-0.5 +/- 0.6). However, decreased EDSS score was only significant after the first course (-0.5 +/- 1.5, p&lt;0.05) in NMO patients. EDSS score was significantly decreased in MS compared with NMO patients at the first course (p&lt;0.05), but not thereafter. Model analysis for EDSS score improvement at the first course, adjusting for covariates, showed significantly greater decreases in MS compared with NMO patients (p&lt;0.05).
Conclusion: IVMP is effective in MS from the first to third courses, and in NMO at the first course. Additionally, IVMP is more efficacious in MS than NMO patients, even at the first course.

DOI： 10.1177/1352458515617248

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

DOI： 10.1111/cen3.12317

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

Objective To assist policymakers as they reflect on treatment protocols and approaches for the efficient delivery of medical care for multiple sclerosis (MS) patients in Japan. Methods We analyzed data from a large Japanese health insurance claims database. Using an algorithm based on diagnosis codes, all patients with a diagnosis of MS were identified
patients having a non-MS demyelinating disease were excluded from the population. MS patient data were used for cross-sectional analysis carried out on the data collected at a certain period. We identified a total of 1808 MS patients, and we analyzed data for 1133 patients with an observation period of ≥6 months from October 2013 to September 2014. Newly diagnosed MS patients were identified within the MS patients, and their data were used for longitudinal analysis, tracking each patient over a period of time. Results The total per patient per month cost for MS was \ 93 542 (US$781, €695 as of October 2015). Disease-modifying therapy drugs costs constituted half of the overall medical costs. For newly diagnosed MS patients, hospitalization costs were the largest component in the initial month, while drug costs were the largest component more than several months after the initial visit. There was a positive correlation between relapse frequency and medical cost. Conclusions These results provide up-to-date information on the demographics, medical treatment and cost status of MS in almost real-time by using a claims database. They suggest that claims data analysis can effectively support medical policymaking.

DOI： 10.1111/cen3.12299

Scopus

PubMed

researchmap

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 39-year-old woman with a 3-year history of a rounded face developed widespread myalgia. Detailed examinations revealed no disorders that could explain the pain other than concomitant Cushing's disease and central hypothyroidism. Both the hypercortisolemia and hypothyroidism completely resolved after the patient underwent surgery to treat Cushing's disease, but she continued to experience unresolved myalgia and met the diagnostic criteria for fibromyalgia. Few studies have so far investigated patients with fibromyalgia associated with Cushing's syndrome. In our case, the hypothyroidism caused by Cushing's disease probably played an important role in triggering and exacerbating fibromyalgia. This highlights the need to examine the endocrine function in patients with muscle pain.

DOI： 10.2169/internalmedicine.55.5926

Web of Science

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

We report a case of slowly progressive anti-Yo-associated paraneoplastic cerebellar degeneration (PCD) with breast cancer in a 54-year-old woman. The symptoms of limb and truncal ataxia, and dysarthria gradually progressed during the course of 1 year, and the modified Rankin scale (mRS) score was 2. A mastectomy with sentinel lymph node resection was performed for the breast cancer. No malignant cells were found on histopathological examination of the lymph node. Combination chemotherapy with adriamycin and cyclophosphamide (AC) prevented neurologic deterioration. However, subsequent treatment with trastuzumab and paclitaxel did not prevent progression of the symptoms (mRS score 3). Brain magnetic resonance imaging showed atrophy of the cerebellar hemispheres without brain stem atrophy. Anti-Yo antibody was detected in the serum, which led to a diagnosis of anti-Yo-associated PCD. We resected an enlarged axillary lymph node, which was found on computed tomography. The histopathological analysis of the lymph node revealed foreign body granuloma, which suggested an association with necrotic malignant tissue. Following additional tegafur-uracil therapy and two courses of intravenous immunoglobulin (IVIg), the cerebellar signs and symptoms gradually improved (mRS score 2). The clinical course shows that PCD can present as a slowly progressive cerebellar symptom. We propose an active treatment for anti-Yo-associated PCD consisting of tumor resection, combined chemotherapy, and IVIg.

DOI： 10.5692/clinicalneurol.cn-000872

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

Central nervous system (CNS) involvement, such as pachymeningitis and/or cerebrovascular events, is rare in patients with granulomatosis with polyangiitis (GPA). Furthermore, the details of pathological examinations of cases have rarely been described. We describe a case of GPA that manifested as an isolated paranasal sinus disease that invaded the subarachnoid space and caused a hemorrhagic venous infarction. We also describe the pathological characteristics of the biopsied brain material from the successful decompressive craniectomy. In particular, granulomatous inflammation with geographic necrosis and multinucleated giant cells were observed in the perivascular area of the thickened dura mater and leptomeninges. Small vessels in the meninges were involved in the granulomatous lesions, and the lumens of the veins were often occluded. In the cerebral cortices and white matter in these areas, hemorrhagic infarction was widely observed. We suggest that our findings represent a novel mechanism of CNS involvement in GPA. Moreover, we believe that the emergency decompressive craniectomy and partial lobectomy for the cerebral infarction in this patient with GPA likely contributed to his survival.

DOI： 10.1159/000381942

Scopus

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the two main autoimmune and inflammatory diseases of the central nervous system. MS is considered an 'oligodendrocytopathy' with undefined autoantibodies, whereas NMO is considered an 'astrocytopathy' with aquaporin-4 antibodies. Both have long been considered autoimmune diseases that primarily affect the white matter (WM). However, recent interest in gray matter (GM) pathology is emerging. Pathological evaluations reveal that substantial cortical demyelination is prominent at all stages or courses of MS. In addition, the neurodegeneration in MS is present not only in GM demyelination but also in normal-appearing GM. NMO involves cortical neurodegeneration and unique dynamics of astrocytes
however, no cortical demyelination is seen. Thus, MS and NMO are distinct diseases with unique pathological features in the brain WM and GM. Although the cause of GM and WM lesions in MS and NMO has not been fully determined, improved knowledge about the pathomechanisms in affected brains is desired. This would result in a more targeted pharmacotherapeutic approach to these diseases.

DOI： 10.11477/mf.1416200166

Scopus

PubMed

J-GLOBAL

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

We report the case of a 19-year-old woman who had been suffering from general fatigue and exercise intolerance since 15 years old. At 18 years old, she experienced muscle weakness and myalgia of the calves. Six months later, she was admitted to our hospital. She showed muscle weakness of the neck and proximal limbs, and myalgia of the calves was prominent. Serum levels of creatine kinase (CK) and lactic acid were elevated, as was the level of lactic acid in cerebrospinal fluid. T2-weighted and short-inversion-time inversion recovery (STIR) imaging of the lower limbs showed hyperintensity on bilateral gastrocnemius muscles, and the region revealed Gd enhancement. Based on histopathological findings from muscle and identification of a m.3271T&gt
C point mutation, mitochondrial myopathy was diagnosed. Rest and administration of vitamins B1, and B2, coenzyme Q10, and L-carnitine improved serum CK levels
however, exercise intolerance, myalgia, and lactic acidemia remained. Sodium pyruvate was then administered, and lactic acid levels, exercise intolerance, and findings on magnetic resonance imaging improved. Sodium pyruvate could prove effective in addressing both elevated serum lactic acid levels and exercise intolerance in mitochondrial disease.

DOI： 10.5692/clinicalneurol.cn-000652

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

Introduction: Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a fatal systemic disorder associated with plasma cell dyscrasia and the overproduction of the vascular endothelial growth factor (VEGF). Recently, the prognosis of POEMS was substantially improved by introduction of therapeutic intervention for myeloma. However, no randomised clinical trial has been performed because of the rarity and severity of the disease.
Methods and analysis: The Japanese POEMS syndrome with Thalidomide (J-POST) Trial is a phase II/III multicentre, double-blinded, randomised, controlled trial that aims to evaluate the efficacy and safety of a 24-week treatment with thalidomide in POEMS syndrome, with an additional 48-week open-label safety study. Adults with POEMS syndrome who have no indication for transplantation are assessed for eligibility at 12 tertiary neurology centres in Japan. Patients who satisfy the eligibility criteria are randomised (1:1) to receive thalidomide (100-300 mg daily) plus dexamethasone (12 mg/m(2) on days 1-4 of a 28-day cycle) or placebo plus dexamethasone. Both treatments were administered for 24 weeks (six cycles; randomised comparative study period). Patients who complete the randomised study period or show subacute deterioration during the randomised period participate in the subsequent 48-week open-label safety study (long-term safety period). The primary end point of the study is the reduction rate of serum VEGF levels at 24 weeks.
Ethics and dissemination: The protocol was approved by the Institutional Review Board of each hospital. The trial was notified and registered at the Pharmaceutical and Medical Devices Agency, Japan (No. 22-1716). The J-POST Trial is currently ongoing and is due to finish in August 2015. The findings of this trial will be disseminated through peer-reviewed publications and conference presentations and will also be disseminated to participants.

DOI： 10.1136/bmjopen-2014-007330

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

DOI： 10.1212/NXI.0000000000000108

Scopus

researchmap

Language：English   Publisher：BMJ PUBLISHING GROUP  

DOI： 10.1136/jnnp-2014-308221

Web of Science

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

DOI： 10.1111/cen3.12117

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

Objective The aim of the present study was to investigate the association of magnetic resonance imaging (MRI) findings and social activity with cognitive function in Japanese patients with multiple sclerosis (MS).
Methods The Brief Repeatable Battery of Neuropsychological tests (BRB-N) was carried out in 184 Japanese patients with MS, and 163 controls matched for age, sex and education. MRI findings of cerebral, brainstem, and cerebellar lesions and social activities of MS patients were further examined.
Results MS patients with higher numbers of cerebral lesions on MRI had lower scores in most BRB-N tests. BRB-N scores in the majority of tests were significantly lower in patients with brainstem and cerebellar lesions. Data from an analysis of variance model in which only the main effects of cerebral, brainstem and cerebellar lesions were hypothesized showed an association of cerebral lesions with decreased scores in all BRB-N tests, except symbol digit modalities test (SDMT) and paced auditory serial addition test (PASAT). In contrast, cerebellar lesions were associated with decreased SDMT and PASAT scores. Patients categorized as "unemployed because of MS" had lower BRB-N scores than other social activity groups. Lower SDMT scores had an effect on the "unemployed because of MS" group, whereas the Expanded Disability Status Scale had a significantly greater negative impact on patients in this social category.
Conclusions Higher numbers of brain lesions on MRI could have an impact on cognitive function in patients with MS, and impairment of information processing appears significantly associated with cerebellar lesions. Cognitive impairment affects the employment status of patients with MS.

DOI： 10.1111/cen3.12133

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Cognitive impairment could affect quality of life for patients with multiple sclerosis (MS), and cognitive function may be correlated with several factors such as depression and fatigue. This study aimed to evaluate cognitive function in Japanese patients with MS and the association between cognitive function and apathy, fatigue, and depression.
Methods: The Brief Repeatable Battery of Neuropsychological tests (BRB-N) was performed in 184 Japanese patients with MS and 163 healthy controls matched for age, gender, and education. The Apathy Scale (AS), Fatigue Questionnaire (FQ), and Beck Depression Inventory Second Edition (BDI-II) were used to evaluate apathy, fatigue, and depression, respectively. Student's t-test was used to compare MS patients and healthy controls. Correlations between two factors were assessed using the Pearson correlation test, and multiple regression analysis was used to evaluate how much each factor affected the BRB-N score.
Results: In all BRB-N tests, patients with MS scored significantly lower than controls, and the effect size of symbol digit modalities test was the highest among the 9 tests of the BRB-N. Patients with MS had higher AS (p &lt; 0.001), FQ (p &lt; 0.0001), and BDI-II (p &lt; 0.0001) scores than controls. In patients with MS, scores on most of the BRB-N tests correlated with scores on the AS and BDI-II; however, there was little correlation between scores on the BRB-N tests and those on the FQ.
Conclusions: Cognitive function was impaired, particularly information-processing speed, and decreased cognitive function was correlated with apathy and depression in Japanese patients with MS. Despite the association between cognitive variables and depression/apathy, cognitive function was impaired beyond the effect of depression and apathy. However, subjective fatigue is not related with cognitive impairment. Taken together, this suggests that different therapeutic approaches are needed to improve subjective fatigue and cognition, and thereby quality of life, in patients with MS.

DOI： 10.1186/1471-2377-14-3

Web of Science

researchmap

Language：Japanese   Publishing type：Research paper (international conference proceedings)   Publisher：Societas Neurologica Japonica  

Multiple sclerosis (MS) has long been considered to be the autoimmune disease that primarily affects oligodendrocyte and myelin in the white matter (WM) of the CNS. However, renewed interest in the gray matter (GM) pathology including cortical and deep GM of MS is emerging. Radiological and pathological assessments demonstrate that substantial cortical demyelination is prominent in all stages or courses of MS, and cortical neurodegeneration is also present in even normal-appearing GM in MS. Patients with MS have cognitive impairment as represented by the latent start of impairment from the very early stage of the disease course, and not only WM lesions but also GM lesions might be good predictors for cognitive impairment in MS. Although the cause of the GM lesions in MS has not been fully determined, an increase in knowledge of the structure of GM lesions in MS brains will result in more targeted therapeutic approaches to the disease.

DOI： 10.5692/clinicalneurol.54.1060

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background: Aquaporin 4 (AQP4) is a water-channel protein predominantly expressed in astrocyte end feet that make up the blood-brain barrier (BBB). Recently, anti-AQP4 antibody has been identified as a specific biomarker of neuromyelitis optica (NMO). However, whether anti-AQP4 antibodies damage the BBB is unclear. Methods: We evaluated BBB damage in patients with NMO and multiple sclerosis by measuring albumin leakage (AL) and studied its correlation with anti-AQP4 antibody. Results: No obvious difference in AL was observed between patients with and without anti-AQP4 antibodies. In the multivariate analysis, anti-AQP4 antibody was not associated with BBB damage. Of the anti-AQP4-positive patients, 58.0% had normal AL values, and the degree of BBB damage was unrelated to the anti-AQP4 antibody titer. In addition, 41.9% of anti-AQP4-positive patients showed no gadolinium enhancement of the MRI. Conclusion: These results indicate that the presence of anti-AQP4 antibody alone in plasma is insufficient to disrupt the BBB. (C) 2014 S. Karger AG, Basel

DOI： 10.1159/000360619

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Objectives There has been no large-scale study of methylprednisolone pulse therapy in Asian patients with multiple sclerosis (MS) or neuromyelitis optica (NMO), despite it being widely used for acute relapse. We aimed to clarify treatment response of MS and NMO patients to methylprednisolone pulse therapy and post-pulse oral corticosteroids in real clinical practice in a multicenter study in Japan. Methods Investigators at 28 institutions collected changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of completion of methylprednisolone pulse therapy carried out in 2010, and after post-pulse oral corticosteroids therapy, by retrospective review of medical records. Results In 345 patients (95.1% of all registered patients), 457 series of methylprednisolone pulse therapy were carried out for treatment of acute relapse. EDSS scores improved by 0.8 ± 1.1 (mean ± SD) after the first course. The second and third courses also produced sufficient improvements (by 0.7 and 0.6, respectively), but much smaller improvements were observed thereafter. The target neurological symptoms and signs improved in 79.5% of patients. Improvement rates were 5-20% lower after a course of pulse therapy than after a series of pulse therapy. A half dose (500 mg/day) produced less improvement than a standard dose (1000 mg/day
65.9 vs 79.5%). During post-pulse oral corticosteroid therapy, EDSS scores decreased by 0.6 ± 0.9. No significant adverse effects were observed. Conclusions Methylprednisolone pulse therapy is beneficial in nearly 80% of Japanese MS and NMO patients, and EDSS score improvements after therapy are compatible with those in Western MS patients. © 2013 Japanese Society for Neuroimmunology.

DOI： 10.1111/cen3.12071

Scopus

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3109/17482968.2012.727424

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Objectives To assess the association between serum aquaporin-4 (AQP4) autoantibodies and neuromyelitis optica spectrum disorders (NMOSDs) associated with systemic autoimmune diseases. Methods We retrospectively studied 626 hospitalized patients with systemic lupus erythematosus (SLE) or Sjö- gren's syndrome (SS). We collected serum samples from those patients with suspected NMOSDs (i.e., myelitis or optic neuritis) at the time of onset and thereafter. AQP4 antibodies were measured by a cell-based indirect immunofluorescence assay using AQP4-transfected HEK-293 cells in a semi-quantitative manner. Results Sera from 6 patients with suspected NMOSDs and SLE (n = 3) or SS (n = 3) were evaluated. Among these, 2 patients' sera samples, i.e., 1 with SLE and 1 with SS, were positive for AQP4 antibodies. There was an inverse relationship between disease amelioration and antibody titer in one NMOSD patient, whereas the antibody titer remained high in the other NMOSD patient, whose clinical manifestations of NMOSDs did not improve despite intensive immunosuppressive treatments. Conclusions These results indicate that serum AQP4 antibodies are present in some SLE/SS patients with myelitis/optic neuritis and might be associated with clinical outcomes. The semi-quantitative measurement of the AQP4 antibody might be a possible surrogate marker in patients with NMOSDs associated with systemic autoimmune diseases. © Japan College of Rheumatology 2012.

DOI： 10.1007/s10165-011-0572-y

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 60-year-old woman had frequent relapses of neuromyelitis optica (NMO) for 30 years despite receiving steroid and azathioprine therapy. She developed MGFA Class IIIb type of myasthenia gravis (MG) at the age of 23, and thymectomy resulted in complete remission of MG. The initial symptoms of NMO, including headache, high fever, retrobulbar optic neuritis, and neurogenic bladder, appeared at the age of 30. Two years later, paraplegia also developed. Although she received oral administration of steroids or azathioprine and intravenous steroid pulse therapy for treatment of NMO for over 30 years, she experienced frequent relapses. The examination at the ages of 58 and 60 years showed that anti-aquaporin-4 antibody was absent. Intravenous immunoglobulin therapy administered in January and June 2009 was effective, and she had 2 years of remission of NMO attack. Spinal MRI after frequent NMO attacks for 30 years revealed an extended spinal cord atrophy involving the lower cervical region and the entire thoracic region. We describe and discuss the prognosis of NMO and the effectiveness of therapies in an NMO patient who underwent thymectomy for MG.

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The case of an elderly patient who had chorea as an initial symptom of systemic lupus erythematosus (SLE) accompanied by antiphospholipid syndrome (APS) is reported. A 68-year-old woman suddenly developed chorea of her left arm and leg. Magnetic resonance imaging (MRI) of the brain demonstrated a focal lesion in the right caudate head, which showed hyperintensity on fluid-attenuated inversion recovery and diffusion-weighted imaging. This condition was thought to be a common form of vascular chorea, which is likely to occur in elderly individuals; however, the laboratory data of this patient finally fulfilled the diagnostic criteria of SLE and APS. Physicians should be careful in diagnosing elderly individuals simply as having a vascular chorea because this symptom can be the initial manifestation of SLE or APS.

DOI： 10.1155/2012/317082

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 66-year-old woman developed bilateral facial paralysis as well as sensory and motor disturbances of extremities. Two months after the onset of paralysis, she also developed sensory disturbance of her trunk and vesicorectal disturbance, and her symptoms worsened gradually. Because the interferon-γ level in the cerebrospinal fluid was elevated, we suspected that her symptoms were caused by polyneuropathy and myelitis associated with infection. Her serum IgM and IgG antibodies against Borrelia garinii and B. afzelli were positive. Therefore, we diagnosed her as having neuroborreliosis. Her symptoms gradually improved after the combined administration of antibiotics and steroids. The present case report showed that it might be better to consider the possibility of neuroborreliosis when there are increasing concentrations of cytokine and chemokine, and that combination treatment with antibiotics and steroids can be used for the treatment of this disease.

DOI： 10.5692/clinicalneurol.52.411

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 49-year old woman noticed her skin rash several days after taking supplements containing Spirulina, a planktonic blue-green alga. Her skin rash was spreading over large parts of her body, even after stop ingestion two months later. Five months later, she developed muscle weakness of neck flexor and left proximal upper extremity. On admission, creatine kinase (CK) was elevated to 1,268 IU/m/ in the serum. A muscle specimen revealed many necrotizing muscle fibers and the infiltration of mononuclear cells in the peri- and endomysium including a lot of eosinophils. Immunohistochemical staining showed the infiltration of CD4 positive cells in the periand endomysium and that of CD20 positive B cells in the perivascular regions. She was diagnosed as having inflammatory myopathy with widely skin rash. Therapy with administration of prednisolone and cyclophosphamide followed by methyl-prednisolone pulse improved her clinical symptoms. There is a similar report describing a case of dermatomyositis after ingestion of Spirulina, which is known to have immune-stimulating property such as accelerating tumor necrosis factor (TNF)-α production. Also, TNF-α single nucleotide polymorphisms (TNF-308A) was demonstrated to have strong association with onset of myositis in Caucasians. The use of Spirulina could result in inflammatory myopathy under some specific conditions.

DOI： 10.5692/clinicalneurol.51.330

Scopus

PubMed

researchmap

Language：Japanese  

Paraneoplastic neurological syndromes (PNS) are infrequent tumor-related disorders that are not caused by direct tumor invasion or metastases, metabolic and nutritional deficits, infections, coagulopathy, or the side effects of cancer treatment. PNS can affect any part of the central and peripheral nervous systems, the neuromuscular junction, or muscles. Because the onset of PNS often antedates the diagnosis of an underlying cancer, it is difficult to establish a definitive early diagnosis. Therefore, it is important for neurologists to consider the possibility of PNS when rapidly progressive neurological syndromes cannot be explained by other causes. Detection of onconeural antibodies is useful for diagnosing PNS, and detection of specific antibodies can aid the identification of the underlying tumor. However, not all patients with PNS have onconeural antibodies, and not all patients with onconeural antibodies have PNS. Although PNS are considered to be mediated by the immune system, various forms of immunotherapy have yielded disappointing results, with some exceptions (i.e., PNS cases with antibodies against neuronal cell-surface antigens such as N-methyl-D-aspartate receptors). The lack of clinical trials due to the rarity of patients with PNS makes it difficult to test the efficacy of immunomodulatory treatment. Rapid detection and immediate treatment of the underlying tumor is an important approach that offers the highest chances of improvilng or stabilizing the syndrome before irreversible neuronal damage occurs. In this review, we discuss the diagnostic criteria and management of PNS based on the PNS Euronetwork and other reports.

Scopus

PubMed

J-GLOBAL

researchmap

Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.99.1821

CiNii Article

CiNii Books

researchmap

Other Link： https://jlc.jst.go.jp/DN/JALC/00355107768?from=CiNii

Language：Japanese   Publishing type：Research paper (international conference proceedings)  

Neuromyelitis optica (NMO) is an inflammatory and demyelinating syndrome characterized by severe attacks of myelitis and optic neuritis. A crucial role for humoral immunity in the NMO pathogenesis has been suggested by the detection of a highly specific serum autoantibody NMO immunoglobulin G that binds to aquaporin4 (AQP4) water channels, and the pronounced deposition of immunoglobulins colocalizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels in NMO lesions. Moreover, we have recently demonstrated that levels of several cytokines such as interleukin (IL)-6 and IL-1β are increased in the cerebrospinal fluid of NMO patients, and the peripheral white matter-demyelinating cord lesions of NMO were accompanied by infiltration of lymphocytes in the leptomeningeal membrane. These cellular elements in patients with NMO might aid B cells and plasma cells in AQP4 antibody production, and break the blood-brain barrier due to the access of AQP4 antibodies to the extracellular domain of AQP4 at the astrocytic foot process.

DOI： 10.5692/clinicalneurol.50.873

Scopus

PubMed

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.5692/clinicalneurol.48.338

PubMed

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2008235962

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

DOI： 10.1002/mds.21523

Web of Science

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

To elucidate the etiology of chorea, we performed gene diagnoses of 79 consecutive cases of the disease (34 males, 45 females
age 15-79 years), which include 39 familial cases (37 pedigrees) and 40 sporadic cases, from 1997 to 2002, after their informed consent was obtained. We extracted genomic DNA from peripheral white blood cells, and performed genetic tests for Huntington disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), Huntington disease like 1 (HDL1), HDL2 and spinocerebellar ataxia type 17 (SCA17). We found 37 cases (36 pedigrees) of HD, seven cases (seven pedigrees) of DRPLA. No cases of HDL1, HDL2 and SCA17 were found. We also found three cases (two pedigrees) presenting an autosomal dominant trait with an unknown origin, and two cases whose parents were consanguineously related. Therefore, further genetic heterogeneity is expected in the cases of chorea in Japan.

Scopus

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

We report a 27-year-old man with Guillain-Barré syndrome (GBS) preceded by cytomegalovirus infection. He was admitted to our hospital because of distal dominant weakness and sensory disturbance 5 days after fever. Double filtration plasmapheresis (DFPP) was performed and clinical symptoms temporary but dramatically improved. However facial nerve palsy, difficulty in swallowing food, weakness, dysautonomia and respiratory failure rapidly progressed within 5 days áfter the onset. Repeated DFPP failed to improve his symptoms. Two months after the onset, he did not improve at all. On T1-weighted MRI, nerve roots were still enhanced with gadolinium, and CSF examination revealed 1,324 mg/dl of protein. These findings suggested us the existence of continuous inflammation on nerve roots. We gave steroid-pulse therapy. He dramatically improved after this treatment. We repeated steroid-pulse therapy for seven times. He was discharged without any major complication 6 months after the onset. Steroid-pulse therapy should be considered in GBS patients associated with CMV infection when other conventional treatments are ineffective.

Scopus

PubMed

researchmap

Language：Japanese   Publishing type：Doctoral thesis  

J-GLOBAL

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

J-GLOBAL

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

We monitored the cryptococcus count in the cerebrospinal fluid (CSF) using the filter technique in two cases of serious cryptococcal meningitis during the course of treatment with antifungal agents. Lumbar puncture was performed once a week, and 1 ml of CSF was filtered through a Millipore filter (5.0- μ m pore for cells), followed by staining of the filters with Alcian blue. All of the cryptococci on the filter were counted under a light microscope at a magnification of x 100. More than 500/ml and 2,000/ml Of cryptococci were still observed in the CFS in Cases 1 and 2, respectively, in whom CFS cultures for Cryptococcus neoformans became negative after 4 weeks of treatment. Even though the treatment with antifungal agents were continued in these cases, cryptococci could still be observed for 5 weeks and 60 weeks on the filter preparations of Cases 1 and 2, respectively, after the CSF cultures became negative. The cryptococcal antigen could also be detected in the CSF during the positive filter preparations in these cases. At autopsy in Case 2, patchy lepromeningeal inflammatory lesions with the characteristic capsules of cryptococci were observed in the subarachnoid space. These observations suggest that cryptococci, which persisted in the CSF despite the negαfive cultures, were responsible for the lesions in the subarachnoid space and protracted clinical course in the two cases of cryptococcal meningitis.

Scopus

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

Argyrophilic grain disease (AGD) is a progressive disorder producing dementia in elderly individuals characterized by the presence of numerous AGs in the limbic system. However, the occurrence of AGs has been reported in other neurodegenerative conditions including Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration, all of which show tau-positive cytoskeletal abnormalities. We examined the brains of 26 patients with multiple system atrophy(MSA), a neurodegenerative disorder fundamentally lacking tau pathology, histologically and immunocytochemically. Numerous AGs were found in the limbic system in 5 patients, of whom two had shown mild dementia. Immunocytochemically, these AGs were labeled with antibodies against phosphorylation-dependent and -independent tau protein, but not alpha-synuclein, whereas oligodendroglial cytoplasmic inclusions found exclusively in MSA were immunoreactive for alpha-synuclein and, less consistently, for phosphorylation-independent tau but not for phosphorylation-dependent tau protein. Furthermore, many phosphorylation- dependent tau-positive neurons and significant numbers of ballooned neurons (BNs) were found in the limbic system in all of the 5 patients with AGs. These findings suggest that AGs can occur with relatively high frequency in the limbic system of MSA patients, and that as in AGD, they may be accompanied by tau-positive neurons and BNs.

Scopus

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 33-year-old man underwent post-operative radiation therapy for the left testicular anaplastic seminoma. One year later, the patient developed muscle weakness and sensory disturbance in the left lower extremity, and muscle weakness in the right lower extremity. MRI demonstrated linear and focal gadolinium (Gd) enhancement of the anterior portion of the lumbosacral roots within the cauda equina. The neurological symptoms improved after administration of corticosteroid and warfarin. Radiation myelopathy of this type was classified as 'selective anterior horn cell injury or amyotrophy' by Reagan, and the site of the lesion was considered to be the lower motor neurons. However, based on the clinical and MRI findings, we proposed that the disease process was injury to the spinal nerve roots rather than the lower motor neurons. Recent neuropathological studies of this syndrome have demonstrated degeneration of the proximal spinal nerve roots. We consider that primary lesions of this syndrome occur in spinal nerve roots rather than in lower motor neurons, and 'lumbosacral radiculopathy' is a more appropriate term for this condition.

Scopus

PubMed

researchmap

researchmap

researchmap

researchmap

researchmap

Responsible for pages：30-39   Language：Japanese

researchmap

Total pages：xviii, 330p   Language：Japanese

CiNii Books

researchmap

Responsible for pages：164-172   Language：Japanese

researchmap

Responsible for pages：81-90   Language：Japanese

researchmap

Responsible for pages：331-337   Language：Japanese

researchmap

Responsible for pages：33-45   Language：Japanese

researchmap

Responsible for pages：256-270   Language：Japanese

researchmap

Authorship：Lead author,　Last author,　Corresponding author  

researchmap

Authorship：Last author,　Corresponding author   Publisher：Japanese Society of Spinal Surgery  

DOI： 10.2531/spinalsurg.34.25

researchmap

Authorship：Lead author,　Last author,　Corresponding author  

researchmap

Authorship：Lead author,　Last author,　Corresponding author  

researchmap

Authorship：Lead author,　Corresponding author  

researchmap

Authorship：Lead author,　Corresponding author  

researchmap

Authorship：Lead author,　Last author,　Corresponding author  

researchmap

Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：(株)中外医学社  

researchmap

Authorship：Lead author,　Last author,　Corresponding author  

DOI： 10.15082/jsnt.36.3_217

researchmap

Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：(有)科学評論社  

J-GLOBAL

researchmap

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese  

DOI： 10.11477/mf.5002200688

J-GLOBAL

researchmap

Authorship：Last author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese  

DOI： 10.15082/jsnt.33.3_475

J-GLOBAL

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Corresponding author   Language：Japanese  

CiNii Article

CiNii Books

J-GLOBAL

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese  

CiNii Article

CiNii Books

J-GLOBAL

researchmap

Language：Japanese   Publisher：医薬ジャーナル社  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2014354830

Language：Japanese   Publisher：医薬ジャーナル社  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2014311288

Authorship：Lead author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

CiNii Article

CiNii Books

J-GLOBAL

researchmap

Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.97.1823

CiNii Article

CiNii Books

researchmap

Other Link： http://hdl.handle.net/10191/17985

Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

researchmap

Authorship：Lead author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author   Language：Japanese   Publisher：Niigata University  

We reviewed recent advances of therapeutic apheresis in neuroimmunological diseases including Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), Miller Fisher syndrome (MFS), Bickerstaff brainstem encephalitis (BBE) and myasthenia gravis (MG). The etiology of GBS and its related disease (CIDP, MFS and BBE) still remains controversial, but important advances have been made in the delineation of the mechanisms that lead to nerve damages. The infecting organisms induce humoral (antiganglioside antibody et. al.) and cellular immune responses that, because of the sharing of homologous epitopes (molecular mimicry), cross-react with ganglioside on the surface of peripheral nerves. Plasma exchange (PE) that removes these pathogenic humoral factors improves the early outcome in GBS. Also, high-dose intra venous immunoglobulin (IVIG), but not steroid therapy, has been shown to be at least as effective as plasma exchange. PE and IVIG carry individual advantages and disadvantages compared with each other. We need establishment of a standard protocol for the therapy of GBS based on clinical and molecular parameters. While PE is a fundamental therapy for GBS, PE can be applied for MG for a rescue therapy to treat the crisis of MG. In MG, extended thymectomy and high-dose corticosteroids therapies, in which symptoms improve after several weeks or months, are essential. Therefore, in myasthenia crisis, when patients necessitate effective therapy immediately, PE can be a rescue treatment with improvement occurring within days of treatment. But the beneficial effect of PE are temporary, lasting only weeks. The purpose of therapeutic apheresis is different from various neuroimmunologic disorders, and in future, based on clinical and molecular mechanism, we should use various treatments (PE, IVIG, corticosteroids, immunosuppressive agents and specific immunotherapy).

CiNii Article

CiNii Books

J-GLOBAL

researchmap

Authorship：Lead author   Language：Japanese  

J-GLOBAL

researchmap

Authorship：Lead author   Language：Japanese  

CiNii Article

CiNii Books

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本医事新報社  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2000081514

Language：Japanese  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

Web of Science

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経治療学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：(一社)日本てんかん学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：(一社)日本てんかん学会  

researchmap

Language：English   Publisher：SAGE Publications  

DOI： 10.1177/2055217319864974

PubMed

researchmap

Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/2055217319864974

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

Web of Science

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本認知症学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本神経治療学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：BMJ PUBLISHING GROUP  

DOI： 10.1136/annrheumdis-2017-eular.1201

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：English   Publisher：Wiley-Blackwell  

DOI： 10.1111/cen3.12355

Scopus

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese  

CiNii Article

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2015374721

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：日本神経眼科学会  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.jneuroim.2014.08.169

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

CiNii Article

CiNii Books

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：Japanese   Publisher：新潟医学会  

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経眼科学会  

researchmap

Language：Japanese   Publisher：日本サルコイドーシス  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1111/cen3.12041

Scopus

researchmap

Language：Japanese   Publisher：新潟医学会  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

Web of Science

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE BV  

Web of Science

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：日本神経眼科学会  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：Japanese   Publisher：日本神経治療学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese  

J-GLOBAL

researchmap

Language：Japanese  

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：Japanese   Publisher：(一社)日本神経学会  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：SAGE PUBLICATIONS LTD  

Web of Science

researchmap

Language：Japanese   Publisher：(一社)日本神経治療学会  

researchmap

Language：Japanese   Publisher：日本神経免疫学会  

researchmap