Language：English   Publisher：Dialogues in Clinical Neuroscience  

Introduction: Depression includes different phenotypes. Modern-type depression (MTD) is a gateway disorder to pathological social withdrawal, known as hikikomori. Adverse childhood experiences (ACEs) are also important aetiologies of depression. Recently, immune imbalance has been proposed as a biological basis of depression. We hypothesised that peripheral immunological characteristics may be involved in subtyping of depression. Methods: 21 patients with major depressive disorder (MDD) and 24 healthy controls (HC) were recruited. Peripheral blood mononuclear cells (PBMCs) were examined for surface antigens by flow cytometry. Participants were administered psychological scales such as Patient Health Questionnaire (PHQ)-9, Modern-Type Depression Trait Scale (TACS-22), Hikikomori Questionnaire (HQ-25), Child Abuse and Trauma Scale (CATS). Results: MDD group showed significantly higher percentage of B cells than HC group (p = 0.032). MDD group presented a negative correlation between: PHQ-9 and CD8 T effector memory cells (r= –0.639, p = 0.002), TACS-22 and monocytes (r= –0.459, p = 0.036), HQ-25 and NK T cells (r= –0.638, p = 0.004), CATS and Intermediate monocytes (r= –0.594, p = 0.009). Conclusions: MTD traits, hikikomori tendencies, and ACEs were correlated with specific characteristics of peripheral immune cells. Our results suggest that immune imbalance influences the diverse presentations of depression. Further validation is warranted by large-scale prospective studies.

DOI： 10.1080/19585969.2025.2452842

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Language：English   Publisher：Journal of Neuroimmunology  

Neuromyelitis optica spectrum disorders (NMOSD) are characterized by severe inflammation-mediated astrocytopathy in the central nervous system. Neuropathic pain (NP) is highly prevalent among patients with NMOSD, and significantly impairs their quality of life. Alpha-calcitonin gene-related peptide (α-CGRP) is a neuropeptide related to pain and neuroinflammation in the central and peripheral nerves; however, the involvement of α-CGRP in NMOSD pathophysiology remains unexplored. Here, we measured serum levels of α-CGRP in 33 patients with NMOSD and 36 healthy controls by enzyme-linked immunosorbent assay to clarify associations between serum α-CGRP levels and clinical NMOSD features, including NP. The NMOSD patients showed significantly higher serum α-CGRP levels than healthy controls [median (interquartile range), ng/mL; 1.89 (1.66–2.39) vs 1.54 (1.34–1.87), p = 0.008]. NMOSD patients with sensory or bowel and bladder dysfunction had elevated serum α-CGRP levels compared with those without [2.02 (1.76–2.80) vs 1.76 (1.44–1.95), p = 0.049; 2.19 (1.96–2.86) vs 1.71 (1.40–1.90), p < 0.001, respectively]. Serum α-CGRP levels were higher in NMOSD patients with neuropathic pain than in those without [2.00 (1.71–2.76) vs 1.78 (1.51–1.97), p = 0.120]. NMOSD patients with spinal cord lesions on magnetic resonance imaging showed significantly higher serum α-CGRP levels compared with those without [2.02 (1.73–2.83) vs 1.73 (1.36–1.87), p = 0.044]. These findings indicate an association between α-CGRP and NMOSD pathophysiological status, especially sensory and bowel and bladder dysfunction derived from spinal cord lesions.

DOI： 10.1016/j.jneuroim.2025.578615

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DOI： 10.1038/s41409-025-02616-z

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Language：English   Publisher：Cell Genomics  

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by optic neuritis and transverse myelitis, with an unclear genetic background. A genome-wide meta-analysis of NMOSD in Japanese individuals (240 patients and 50,578 controls) identified significant associations with the major histocompatibility complex region and a common variant close to CCR6 (rs12193698; p = 1.8 × 10−8, odds ratio [OR] = 1.73). In single-cell RNA sequencing (scRNA-seq) analysis (25 patients and 101 controls), the CCR6 risk variant showed disease-specific expression quantitative trait loci effects in CD4+ T (CD4T) cell subsets. Furthermore, we detected somatic mosaic chromosomal alterations (mCAs) in various autoimmune diseases and found that mCAs increase the risk of NMOSD (OR = 3.37 for copy number alteration). In scRNA-seq data, CD4T cells with 21q loss, a recurrently observed somatic event in NMOSD, showed dysregulation of type I interferon-related genes. Our integrated study identified novel germline and somatic mutations associated with NMOSD pathogenesis.

DOI： 10.1016/j.xgen.2025.100776

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Language：English   Publisher：Annals of Clinical and Translational Neurology  

Objectives: To assess blood exosome (Ex)-connexin (Cx)43 (encoded by GJA1) and its truncated isoforms in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), which show distinct alterations in astroglial Cx43. Methods: Serum Exs from 48 patients with MS (34 relapsing–remitting, 14 secondary-progressive), 35 with NMOSD, 20 with other inflammatory neurologic diseases (OIND), and 17 healthy controls (HC) were subjected to quantitative Western blotting for Cx43, single-molecule array for neurofilament-L, and quantitative polymerase chain reaction for non-coding RNAs detected by RNA sequencing. Sera from control and astroglia-specific Cx43 inducible conditional knockout (Cx43-icKO) mice with experimental autoimmune encephalomyelitis (EAE) were also tested. Results: Ex-GJA1-29k was markedly higher in MS than in NMOSD, OIND, and HC; it successively increased at relapse, remission, and secondary progression, and positively correlated with disability scores. Ex-hsa-miR-133b and other hsa-miRs that bind to full-length Cx43 were significantly lower in secondary-progressive MS than in HC, and Ex-hsa-miR-133b was negatively correlated with disability scores. Ex-GJA1-11k expression was lower in NMOSD at relapse than in HC and OIND, and was negatively correlated with disability score worsening and Ex-neurofilament-L levels. NMOSD at relapse had significantly higher expression of small nucleolar RNA (SNORD37, SNORD95, and SNORD97) than HC, and SNORD37 and SNORD95 showed strong negative correlations with disability scores. Control mice showed increased Ex-GJA1-43k and -29k during EAE; this effect was markedly reduced in Cx43-icKO mice with attenuated EAE. Interpretation: Blood Ex-Cx43-truncated isoforms and small non-coding RNAs, which partially come from brain astroglia, are distinctly dysregulated in MS and NMSOD.

DOI： 10.1002/acn3.52307

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Language：English   Publisher：Neurology  

BACKGROUND AND OBJECTIVES: All 4 previous nationwide surveys of multiple sclerosis (MS) in Japan were conducted before the discovery of anti-aquaporin-4 (AQP4) antibodies; thus, neuromyelitis optica spectrum disorder (NMOSD) was included in MS, as optic-spinal MS. We aimed to clarify the epidemiologic features and trends of MS and NMOSD in Japan separately using a fifth nationwide survey. METHODS: The primary survey, in which a questionnaire was sent to 3,799 selected departments (including neurology/internal medicine, pediatrics, and ophthalmology), explored the estimated number and prevalence of patients with MS or NMOSD in 2017, and the secondary survey collected detailed characteristics of the patients using a second questionnaire. RESULTS: The response rates for the primary and secondary surveys were 60.1% and 53.9%, respectively. The estimated total number of patients with MS or NMOSD was 24,800, 2.5-fold higher than that in the fourth survey in 2003. The crude prevalence was 19.6 per 100,000 patients (14.2 for MS and 5.4 for NMOSD), compared with 7.7 per 100,000 patients in the fourth survey. Patients with MS showed milder disability (median Expanded Disability Status Scale [EDSS] score: 2.0 [interquartile range 1.0-4.5] vs 2.5 [1.0-6.0]), decreased secondary progression (8.5% vs 15.2%), and increased usage of disease-modifying drugs (63.7% vs 37.2%) compared with those with conventional MS in the fourth survey. The proportions of oligoclonal bands and Barkhof criteria fulfillment on MRI, which are features of classical MS, increased with advancing year of birth. Patients with NMOSD also showed less disability and shorter disease duration than patients with optic-spinal MS in the fourth survey (EDSS score: 3.5 [2.0-5.5] vs 3.8 [2.0-6.0]; disease duration: 8.0 [3.9-14.8] vs 10.0 [5.0-16.0]). Among patients with NMOSD, disability was exacerbated by a history of longitudinally extensive spinal cord lesions and anti-AQP4 antibody positivity, which both decreased with advancing year of birth. DISCUSSION: The prevalences of MS (particularly with classical features) and NMOSD have been increasing in Japan, suggesting the contribution of environmental factors. However, disabilities in patients with MS and NMOSD have been mitigated. Extensive usage of various disease-modifying drugs could be a factor contributing to this disability mitigation in MS.

DOI： 10.1212/WNL.0000000000209992

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Language：English  

DOI： 10.7759/cureus.73205

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Language：English   Publisher：Multiple Sclerosis and Related Disorders  

Background: The previous Japanese clinical practice guidelines for multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) were published in 2017. Recently, for the first time in 6 years, the MS and NMOSD guideline development committee revised the Japanese guidelines for MS, NMOSD, and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Methods: The committee utilized the Grading of Recommendations Assessment, Development, and Evaluation system based on the “Minds Handbook for Clinical Practice Guideline Development 2020 Ver. 3.0″ with a focus on clinical questions (CQs). The committee also discussed clinical issues other than CQs, categorizing them as a question-and-answer (Q&A) section, including “issues on which experts’ opinions agree to a certain extent” and “issues that are important but not included in the CQ”. Results: The committee identified 3, 1, and 1 key CQs related to MS, NMOSD, and MOGAD, respectively, and presented recommendations. A Q&A session regarding disease-modifying therapies and relapse prevention therapies for MS, NMOSD, and MOGAD was conducted. The revised guidelines were published in September 2023. Conclusions: The Japanese guidelines for clinical practice on MS, NMOSD, and MOGAD were updated. Treatment strategies for MS, NMOSD, and MOGAD are changing, and these updated guidelines may assist with treatment decisions for these diseases in clinical practice.

DOI： 10.1016/j.msard.2024.105829

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Publisher：Neurology and Clinical Neuroscience  

DOI： 10.1111/ncn3.12852

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Language：English   Publisher：Journal of the Neurological Sciences  

Background: Recent developments in the retinal hyperspectral imaging method have indicated its potential in addressing challenges posed by neurodegenerative disorders, such as Alzheimer's disease. This human clinical study is the first to assess reflectance spectra obtained from this imaging as a tool for diagnosing patients with Parkinson's disease (PD). Methods: Retinal hyperspectral imaging was conducted on a total of 40 participants, including 20 patients with PD and 20 controls. Following preprocessing, retinal reflectance spectra were computed for the macular retina defined by four rectangular regions. Linear discriminant analysis classifiers underwent training to discern patients with PD from control participants. To assess the performance of the selected features, nested leave-one-out cross-validation was employed using machine learning. The indicated values include the area under the curve (AUC) and the corresponding 95% confidence interval (CI). Results: Retinal reflectance spectra of PD patients exhibited variations in the spectral regions, particularly at shorter wavelengths (superonasal retina, wavelength < 490 nm; inferonasal retina, wavelength < 510 nm) when compared to those of controls. Retinal reflectance spectra yielded an AUC of 0.60 (95% CI: 0.43–0.78) and 0.60 (95% CI: 0.43–0.78) for the superonasal and inferonasal retina, respectively, distinguishing individuals with and without PD. Conclusion: Reflectance spectra obtained from retinal hyperspectral imaging tended to decrease at shorter wavelengths across a broad spectral range in PD patients. Further investigations building upon these preliminary findings are imperative to focus on the retinal spectral signatures associated with PD pathological hallmarks, including α-synuclein.

DOI： 10.1016/j.jns.2024.123061

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Language：English   Publisher：Scientific Reports  

In chronic stages of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalitis (EAE), connexin (Cx)43 gap junction channel proteins are overexpressed because of astrogliosis. To elucidate the role of increased Cx43, the central nervous system (CNS)-permeable Cx blocker INI-0602 was therapeutically administered. C57BL6 mice with chronic EAE initiated by MOG35-55 received INI-0602 (40 mg/kg) or saline intraperitoneally every other day from days post-immunization (dpi) 17–50. Primary astroglia were employed to observe calcein efflux responses. In INI-0602-treated mice, EAE clinical signs improved significantly in the chronic phase, with reduced demyelination and decreased CD3+ T cells, Iba-1+ and F4/80+ microglia/macrophages, and C3+GFAP+ reactive astroglia infiltration in spinal cord lesions. Flow cytometry analysis of CD4+ T cells from CNS tissues revealed significantly reduced Th17 and Th17/Th1 cells (dpi 24) and Th1 cells (dpi 50). Multiplex array of cerebrospinal fluid showed significantly suppressed IL-6 and significantly increased IL-10 on dpi 24 in INI-0602-treated mice, and significantly suppressed IFN-γ and MCP-1 on dpi 50 in the same group. In vitro INI-0602 treatment inhibited ATP-induced calcium propagations of Cx43+/+ astroglial cells to similar levels of those of Cx43−/− cells. Astroglial Cx43 hemichannels represent a novel therapeutic target for chronic EAE and MS.

DOI： 10.1038/s41598-024-61508-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of the Neurological Sciences  

The epidemiology and etiology of facial onset sensory and motor neuronopathy (FOSMN), a rare syndrome that initiates with facial sensory disturbances followed by bulbar symptoms, remain unknown. To estimate the prevalence of FOSMN in Japan and establish the characteristics of this disease, we conducted a nationwide epidemiological survey. In the primary survey, we received answers from 604 facilities (49.8%), leading to an estimated number of 35.8 (95% confidential interval: 21.5–50.2) FOSMN cases in Japan. The secondary survey collected detailed clinical and laboratory data from 21 cases. Decreased or absent corneal and pharyngeal reflexes were present in over 85% of the cases. Electrophysiological analyses detected blink reflex test abnormalities in 94.1% of the examined cases. Immunotherapy was administered in 81% of cases and all patients received intravenous immunoglobulin. Among them, 35.3% were judged to have temporary beneficial effects evaluated by the physicians in charge. Immunotherapy tended to be effective in the early stage of disease. The spreading pattern of motor and sensory symptoms differed between cases and the characteristics of the motor-dominant and sensory-dominant cases were distinct. Cases with motor-dominant progression appeared to mimic amyotrophic lateral sclerosis. This is the first nationwide epidemiological survey of FOSMN in Japan. The clinical course of FOSMN is highly variable and motor-dominant cases developed a more severe condition than other types of cases. Because clinical interventions tend to be effective in the early phase of the disease, an early diagnosis is desirable.

DOI： 10.1016/j.jns.2024.122957

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DOI： 10.3390/biology12091217.

Language：English   Publisher：Biology  

We previously reported a novel secondary progressive multiple sclerosis (SPMS) model, progressive experimental autoimmune encephalomyelitis (pEAE), in oligodendroglia-specific Cx47-inducible conditional knockout (Cx47 icKO) mice. Based on our prior study showing the efficacy of iguratimod (IGU), an antirheumatic drug, for acute EAE treatment, we aimed to elucidate the effect of IGU on the SPMS animal model. We induced pEAE by immunizing Cx47 icKO mice with myelin oligodendrocyte glycoprotein peptide 35–55. IGU was orally administered from 17 to 50 days post-immunization. We also prepared a primary mixed glial cell culture and measured cytokine levels in the culture supernatant after stimulation with designated cytokines (IL-1α, C1q, TNF-α) and lipopolysaccharide. A migration assay was performed to evaluate the effect of IGU on the migration ability of T cells toward mixed glial cell cultures. IGU treatment ameliorated the clinical signs of pEAE, decreased the demyelinated area, and attenuated glial inflammation on immunohistochemical analysis. Additionally, IGU decreased the intrathecal IL-6 level and infiltrating Th17 cells. The migration assay revealed reduced Th17 cell migration and IL-6 levels in the culture supernatant after IGU treatment. Collectively, IGU successfully mitigated the clinical signs of pEAE by suppressing Th17 migration through inhibition of IL-6 production by proinflammatory-activated glial cells.

DOI： 10.3390/biology12091217

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

The pathological hallmark of multiple system atrophy (MSA) is aberrant accumulation of phosphorylated α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions (GCIs). Extensive demyelination occurs particularly in the olivopontocerebellar and striatonigral pathways, but its precise mechanism remains elusive. Glial connexins (Cxs), which form gap junction channels between astrocytes and oligodendrocytes, play critical roles in myelin maintenance, and have not been studied in MSA. Therefore, we immunohistochemically investigated glial Cx changes in the cerebellar afferent fibers in 15 autopsied patients with MSA. We classified demyelinating lesions into three stages based on Klüver–Barrera staining: early (Stage I), intermediate (Stage II), and late (Stage III) stages showing subtle, moderate, and severe myelin reduction, respectively. Myelin-associated glycoprotein, but not myelin oligodendrocyte glycoprotein, was preferentially decreased in Stage I, suggesting distal oligodendrogliopathy type demyelination. Accumulation of phosphorylated α-synuclein in oligodendrocytes was frequently seen in Stage I but less frequently observed in Stages II and III. Tubulin polymerization-promoting protein (TPPP/p25α)-positive oligodendrocytes were preserved in Stage I but successively decreased in Stages II and III. Even at Stage I, Cx32 was nearly absent from myelin, despite the relative preservation of other nodal proteins, such as neurofascin, claudin-11/oligodendrocyte-specific protein, and contactin-associated protein 1, which successively decreased in the later stages. Cx32 was re-distributed in the oligodendrocyte cytoplasm and co-localized with GCIs. Cx47 gradually decreased at the oligodendrocyte surface in a stage-dependent manner but was not co-localized with GCIs. Astrocytic Cx43 was down-regulated in Stage I but up-regulated in Stages II and III, reflecting astrogliosis. Cx43/Cx47 gap junctions significantly decreased from Stage I to III. Activated microglia/macrophages and T cells infiltrated in Stage I rather than Stages II and III. Therefore, early and extensive alterations of glial Cxs, particularly Cx32 loss, occur in MSA and may accelerate distal oligodendrogliopathy type demyelination and nodal/paranodal dysfunction through disruption of inter-glial communication.

DOI： 10.1111/bpa.13131

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Neurology, Neurosurgery and Psychiatry  

Background Granulocyte invasion into the brain is a pathoanatomical feature differentiating neuromyelitis optica spectrum disorder (NMOSD) from multiple sclerosis (MS). We aimed to determine whether granulocyte activation markers (GAM) in cerebrospinal fluid (CSF) can be used as a biomarker to distinguish NMOSD from MS, and whether levels associate with neurological impairment. Methods We quantified CSF levels of five GAM (neutrophil elastase, myeloperoxidase, neutrophil gelatinase-associated lipocalin, matrixmetalloproteinase-8, tissue inhibitor of metalloproteinase-1), as well as a set of inflammatory and tissue-destruction markers, known to be upregulated in NMOSD and MS (neurofilament light chain, glial fibrillary acidic protein, S100B, matrix metalloproteinase-9, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1), in two cohorts of patients with mixed NMOSD and relapsing-remitting multiple sclerosis (RRMS). Results In acute NMOSD, GAM and adhesion molecules, but not the other markers, were higher than in RRMS and correlated with actual clinical disability scores. Peak GAM levels occurred at the onset of NMOSD attacks, while they were stably low in MS, allowing to differentiate the two diseases for ≤21 days from onset of clinical exacerbation. Composites of GAM provided area under the curve values of 0.90-0.98 (specificity of 0.76-1.0, sensitivity of 0.87-1.0) to differentiate NMOSD from MS, including all anti-aquaporin-4 protein (aAQP4)-antibody-negative patients who were untreated. Conclusions GAM composites represent a novel biomarker to reliably differentiate NMOSD from MS, including in aAQP4 - NMOSD. The association of GAM with the degree of concurrent neurological impairment provides evidence for their pathogenic role, in turn suggesting them as potential drug targets in acute NMOSD.

DOI： 10.1136/jnnp-2022-330796

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：European Journal of Pediatrics  

Myelin oligodendrocyte glycoprotein antibody (MOG-Ab) is an autoantibody associated with acquired demyelinating syndrome (ADS) in childhood and adults. The pathogenic roles of MOG-Ab and long-term outcomes of children with MOG-Ab-associated disease (MOGAD) remain elusive. We investigated the clinical features of children with ADS during follow-up in our institute. Clinical data were retrospectively analyzed using medical charts of patients managed in Kyushu University Hospital from January 1st, 2001, to March 31st, 2022. Participants were children of < 18 years of age when they received a diagnosis of ADS in our hospital. Cell-based assays were used to detect MOG-Ab in serum or cerebrospinal fluid at the onset or recurrence of ADS. The clinical and neuroimaging data of MOG-Ab-positive and MOG-Ab-negative patients were statistically analyzed. Among 31 patients enrolled in this study, 22 (13 females, 59%) received tests for MOG antibodies. Thirteen cases (59%) were MOG-Ab-positive and were therefore defined as MOGAD; 9 (41%) were MOG-Ab-negative. There were no differences between MOGAD and MOG-Ab-negative patients in age at onset, sex, diagnostic subcategories, or duration of follow-up. MOGAD patients experienced headache and/or somatosensory symptoms more frequently than MOG-Ab-negative patients (12/13 (92%) vs. 3/9 (22%); p = 0.0066). Somatosensory problems included persistent pain with hyperesthesia in the left toe, perineal dysesthesia, and facial hypesthesia. No specific neuroimaging findings were associated with MOGAD or the presence of somatosensory symptoms. Conclusions: Long-lasting somatosensory disturbances are prominent comorbidities in children with MOGAD. Prospective cohorts are required to identify molecular and immunogenetic profiles associated with somatosensory problems in MOGAD. What is Known: • Recurrence of demyelinating events occurs in a group of children with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). What is New: • Long-lasting headache and somatosensory problems are frequent comorbidities with pediatric MOGAD. Pain and somatosensory problems may persist for more than 5 years. • Neuroimaging data do not indicate specific findings in children with somatic disturbances.

DOI： 10.1007/s00431-023-04989-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Multiple Sclerosis and Related Disorders  

Background: In relapsing-remitting multiple sclerosis (RRMS), smoking is a known risk factor for disease susceptibility and disability progression. However, its impact on the efficacy of oral disease-modifying drugs (DMDs) is unclear. Therefore, we initiated a single-center, retrospective, observational study to investigate the relationship between smoking and disease activity in RRMS patients under oral DMDs. Methods: We retrospectively enrolled RRMS patients who initiated oral DMDs (fingolimod or dimethyl fumarate) at our hospital between January 2012 and December 2019. Clinical data and smoking status at oral DMD initiation were collected up to December 2020. We conducted survival analyses for relapse and any disease activity, defined as relapse or MRI disease activity, among patients with distinct smoking statuses. Results: We enrolled 103 RRMS patients under oral DMDs including 19 (18.4%) current smokers at baseline. Proportions of relapses and any disease activity during follow-up were higher in current smokers (relapse: p = 0.040, any disease activity: p = 0.004) and time from initiating oral DMDs to relapse was shorter in current smokers (log-rank test: p = 0.011; Cox proportional hazard analysis: hazard ratio (HR) 2.72 [95% confidence interval (CI) 1.22–6.09], p = 0.015) than in non-smokers. Time from initiating oral DMDs to any disease activity was also shorter in current smokers (log-rank test: p = 0.016; Cox proportional hazard analysis: HR 2.18 [95% CI 1.14–4.19], p = 0.019) than in non-smokers. The survival curves for relapse and any disease activity were not different between the former smoker and never-smoker groups. Multivariate survival analysis showed current smoking was an independent risk factor for relapse or any disease activity after adjusting for covariates (relapse: HR 2.54 [95% CI 1.06–6.10], p = 0.037; any disease activity: HR 3.47 [95% CI 1.27–9.50], p = 0.015). Conclusion: Smoking was a risk factor for disease activity in RRMS patients under oral DMD treatment. RRMS patients should be advised to stop smoking even after the initiation of DMDs.

DOI： 10.1016/j.msard.2023.104513

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Publisher：Neurology and Clinical Neuroscience  

Chromosomally integrated human herpesvirus 6 (ciHHV6) is a condition where HHV6-DNA is integrated into the host germline genome. ciHHV6 can be misdiagnosed as active HHV6 infection. We report a 30-year-old woman presenting with psychological symptoms without a history of immunodeficiency. She had an ovarian teratoma and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in the cerebrospinal fluid (CSF) with HHV6-DNA in the serum and CSF. The final diagnosis was anti-NMDAR encephalitis and ciHHV6 because laparoscopic oophorectomy and immunotherapy ameliorated her symptoms and HHV6-DNA was detected in her oral mucosa cells. This case suggests the need to assess whether HHV6-DNA is related to infection or ciHHV6 when HHV6-DNA is detected in the CSF of patients with encephalitis.

DOI： 10.1111/ncn3.12681

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

脳脊髄液(CSF)で抗NMDA受容体(NMDAR)抗体とヒトヘルペスウイルス6(HHV6)-DNA陽性を示し、抗NMDAR脳炎および染色体に組み込まれたHHV6(ciHHV6)と最終診断された1例について報告した。症例は30歳女性で、Day0に亜急性の情動不安と錯乱状態を呈し頭痛を伴い、Day39に自宅の二階から飛び降りた。救急搬送されたが妄想が認められたため精神病院に移送され、移送先の医療施設で自己免疫性脳炎が疑われたことから、Day67に見当識障害、幻視、被害妄想、妄想気分、情緒不安定、激越を伴った状態で当院に移送された。CSFには軽度の髄液細胞増加、高タンパク血症、抗NMDAR抗体が検出され、血清とCSFからはHHV6-DNA陽性が示されたが、他のヘルペスウイルスDNAは陰性であった。脳波では突発活動を伴わないdiffuse background slowingが検出され、脳MRI検査では正常所見であったが、HHV6脳炎と抗NMDAR脳炎を疑い、抗ウイルス薬投与とメチルプレドニゾロン静注後に、静注免疫グロブリンが投与された。Day82に左卵巣腫瘍に対し腹腔鏡下卵巣摘出術を行い、血漿交換を行ったところ症状は改善され、CSF中細胞数とタンパク質も正常値に低下し、脳波も正常化した。しかし、6週間のガンシクロビル投与後も血清/CSFともにHHV6-DNA陽性、口腔粘膜細胞もHHV6-DNA陽性で、ガンシクロビル投与を中止したが、症状の増悪はみられなかった。以上の所見から、本例は抗NMDAR脳炎とciHHV6と最終診断された。

Language：English   Publisher：Wiley  

Chromosomally integrated human herpesvirus 6 (ciHHV6) is a condition where HHV6- DNA is integrated into the host germline genome. ciHHV6 can be misdiagnosed as active HHV6 infection. We report a 30-year-old woman presenting with psychological symptoms without a history of immunodeficiency. She had an ovarian teratoma and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in the cerebrospinal fluid (CSF) with HHV6-DNA in the serum and CSF. The final diagnosis was anti-NMDAR encephalitis and ciHHV6 because laparoscopic oophorectomy and immunotherapy ameliorated her symptoms and HHV6-DNA was detected in her oral mucosa cells. This case suggests the need to assess whether HHV6-DNA is related to infection or ciHHV6 when HHV6-DNA is detected in the CSF of patients with encephalitis.

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neurology: Neuroimmunology and NeuroInflammation  

Background and ObjectivesThe choroid plexus has been shown to play a crucial role in CNS inflammation. Previous studies found larger choroid plexus in multiple sclerosis (MS) compared with healthy controls. However, it is not clear whether the choroid plexus is similarly involved in MS and in neuromyelitis optica spectrum disorder (NMOSD). Thus, the aim of this study was to compare the choroid plexus volume in MS and NMOSD.MethodsIn this retrospective, cross-sectional study, patients were included by convenience sampling from 4 international MS centers. The choroid plexus of the lateral ventricles was segmented fully automatically on T1-weighted MRI sequences using a deep learning algorithm (Multi-Dimensional Gated Recurrent Units). Uni- and multivariable linear models were applied to investigate associations between the choroid plexus volume, clinically meaningful disease characteristics, and MRI parameters.ResultsWe studied 180 patients with MS and 98 patients with NMOSD. In total, 94 healthy individuals and 47 patients with migraine served as controls. The choroid plexus volume was larger in MS (median 1,690 µL, interquartile range [IQR] 648 µL) than in NMOSD (median 1,403 µL, IQR 510 µL), healthy individuals (median 1,533 µL, IQR 570 µL), and patients with migraine (median 1,404 µL, IQR 524 µL; all p < 0.001), whereas there was no difference between NMOSD, migraine, and healthy controls. This was also true when adjusted for age, sex, and the intracranial volume. In contrast to NMOSD, the choroid plexus volume in MS was associated with the number of T2-weighted lesions in a linear model adjusted for age, sex, total intracranial volume, disease duration, relapses in the year before MRI, disease course, Expanded Disability Status Scale score, disease-modifying treatment, and treatment duration (beta 4.4; 95% CI 0.78-8.1; p = 0.018).DiscussionThis study supports an involvement of the choroid plexus in MS in contrast to NMOSD and provides clues to better understand the respective pathogenesis.

DOI： 10.1212/NXI.0000000000001147

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PubMed

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

DOI： 10.1002/acn3.51264

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

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

DOI： 10.1111/bpa.12898

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

Background: Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) is a rare but serious complication of some disease-modifying drugs used to treat multiple sclerosis (MS). Japanese MS patients treated with fingolimod were reported to be 10 times more likely to develop PML than equivalent patients in other countries. The strongest susceptibility human leukocyte antigen (HLA) class II alleles for MS are distinct between races (DRB1*15:01 for Caucasians and DRB1*04:05 and DRB1*15:01 for Japanese); therefore, we investigated whether HLA class II alleles modulate anti-JCV antibody serostatus in Japanese MS patients with and without fingolimod. Methods: We enrolled 128 Japanese patients with MS, in whom 64 (50%) were under fingolimod treatment at sampling, and examined the relationship between HLA class II alleles and anti-JCV antibody serostatus. Serum anti-JCV antibody positivity and index were measured using a second-generation two-step assay and HLA-DRB1 and -DPB1 alleles were genotyped. Results: HLA-DRB1*15 carriers had a lower frequency of anti-JCV antibody positivity (57% vs 78%, p = 0.015), and lower antibody index (median 0.42 vs 1.97, p = 0.037) than non-carriers. Among patients without HLA-DRB1*15, DRB1*04 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB1*04:02 carriers had a higher anti-JCV antibody index than non-carriers (3.20 vs 1.34, p = 0.008) although anti-JCV antibody-positivity rates did not differ. Patients treated with fingolimod had a higher antibody index than other patients (1.46 vs 0.64, p = 0.039) and treatment period had a positive correlation with antibody index (p = 0.018). Multivariate logistic regression analysis revealed that age was positively associated, and HLA-DRB1*15 was negatively associated with anti-JCV antibody positivity (odds ratio [OR] = 1.06, p = 0.006, and OR = 0.37, p = 0.028, respectively). Excluding HLA-DRB1*15-carriers, DRB1*04 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023). Conclusions: HLA-DRB1*15 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB1*15, DRB1*04 carriers are associated with a high antibody positive rate in Japanese, suggesting the effects of two susceptible HLA-DRB1 alleles on anti-JCV antibody serostatus differ.

DOI： 10.1186/s12974-020-01865-7

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

Background: The effects of distinct HLA alleles on the brain and lesion volumes remain to be established, particularly in non-Caucasian populations. Two distinct susceptibility alleles, DRB1*15:01 and DRB1*04:05, are prevalent in the Japanese population; we therefore aimed to clarify the effects of HLA-DRB1 alleles on brain and lesion volumes in multiple sclerosis (MS). Methods: A total of 66 patients with MS (50 relapsing remitting, 16 progressive) underwent brain MRI volumetry measuring fluid-attenuated inversion recovery (FLAIR) and T1 lesion volumes, and normalized whole-brain (NWBV), white matter (NWMV), gray matter (NGMV), cortical gray matter (NCGMV), deep gray matter (NDGMV) and thalamus (NTV) volumes, and HLA-DRB1 genotyping. Results: Carriers of HLA-DRB1*15:01(+)*04:05(−) and HLA-DRB1*15:01(−)*04:05(+) comprised 25.8% and 31.8% of patients, respectively. HLA-DRB1*15:01 carriers showed negative correlations between disease duration and NWBV (r_s = −0.484, p = .036), NWMV (r_s = −0.593, p = .008), and NTV (r_s = −0.572, p = .011), and positive correlations between disease duration and FLAIR (r_s = 0.539, p = .017) and T1 lesion volumes (r_s = 0.545, p = .016). By contrast, no significant correlation of any MRI parameters with disease duration was found in HLA-DRB1*04:05 carriers. HLA-DRB1*15:01 carriers had a significantly faster reduction in NWBV and NWMV by disease duration and smaller NDGMV than DRB1*15:01 non-carriers, whereas HLA-DRB1*04:05 carriers had a significantly slower increase in FLAIR and T1 lesion volumes than HLA-DRB1*04:05 non-carriers. Conclusions: Our study suggests that distinct HLA-DRB1 alleles could differentially influence brain and lesion volumes over the disease course of MS.

DOI： 10.1016/j.jns.2020.116768

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

The patient was a 40-year-old woman who was previously diagnosed with systemic lupus erythematosus and myasthenia gravis and had received prednisolone and tacrolimus for more than 7 years. In February 2017, she noticed pain in her lower back and weakness of the lower limbs, and was referred to our hospital on day 5. She had shingles in the right lower thoracic dermatomes and Brown-Séquard syndrome with right-sided dominant weakness in her lower limbs and left-sided superficial sensory disturbance below the L1 level. Varicella zoster virus (VZV)-associated myelopathy was suspected because of her symptoms and clinical findings. Despite the immediate administration of intravenous acyclovir after hospitalization, she lost consciousness and experienced a seizure related to cerebral hemorrhage in the left temporal lobe on the night of day 5. MRI showed enhanced lesions along the spinal cord and leptomeninges of the brainstem and temporal lobe. VZV-IgG and VZV-DNA were positive in the cerebrospinal fluid. Based on these clinical features and laboratory findings, she was diagnosed as VZV-associated vasculopathy and myelopathy. She subsequently had multiple cerebral infractions and hemorrhage, and developed sudden cardiopulmonary arrest on day 6, culminating in death on day 17. Autopsy showed that inflammatory mononuclear cells had infiltrated the vascular walls of the spinal cord. Immunohistochemistry revealed that some neurons and macrophages in the white matter of the spinal cord were positive for VZV. In addition, atrophic neurons, satellite cells surrounding these neurons, and infiltrating macrophages were immune-positive for VZV at the L2 dorsal root ganglia. These findings were consistent with VZV-associated vasculopathy and myelitis. Under immunosuppressive conditions, VZV can cause shingles and neuronal complications such as vasculopathy and myelitis, which are sometimes fatal despite the immediate administration of intravenous acyclovir. New treatment drugs or drugs to prevent VZV activation are desired.

DOI： 10.5692/clinicalneurol.cn-001413

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

Background: The prevalence of multiple sclerosis (MS) has been increasing worldwide in recent years, especially among females. The same increasing trends are even observed in East Asian countries, where the prevalence of MS is relatively low compared with Northern European ancestries. Whether the environmental risk factors for MS are shared between Asian and North European ancestries, and the types of environmental factors that contribute to the low and recent increase in MS prevalence in Asian countries remain unknown. This study provides the first comprehensive survey of environmental risks for MS in East Asia. Methods: Patients with MS were recruited from the Department of Neurology at Kyushu University Hospital, Japan between 01 April 2017 and 31 March 2018. Healthy controls (HCs) were recruited by public notification. All participants were residents of Kyushu Island and were required to complete medical history and lifestyle questionnaires. Dietary data were collected using a Food Frequency Questionnaire comprising intake of approximately 140 food and beverage items in the past 1 year. One hundred and three patients with MS and 124 healthy controls (HCs) completed the questionnaires. Age at onset and disability score measured by the Kurtzke Expanded Disability Status Scale (EDSS) were obtained from medical records. Results: Frequency of obesity (body mass index ≥25 kg/m²) at present time was higher in MS patients than in HCs (19.4% vs. 7.4%, p = 0.009), while body mass index at age 18–20 years did not differ between the two groups. Frequency of current or ex-smokers was higher in MS patients than in HCs (50.5% vs. 22.8%, p < 0.0001) and disability measured by the EDSS was more severe in MS patients with active smoking history than in patients without such history (p = 0.006 after adjusting for sex). Passive smoking after age 16 years was also a risk factor for MS (odds ratio: 1.31, 95% confidence interval: 1.05–1.63, p = 0.015). Longer sunlight exposure in early childhood was a protective factor for MS (odds ratio: 0.65 during summer and 0.71 during winter at age 6–10 years; 0.71 during summer and 0.72 during winter at age 11–15 years). MS patients had earlier age of menarche than HCs (mean: 12.4 years vs. 12.9 years, p = 0.031). Intake of grains was lower in MS patients than in HCs, with intake of rice in particular being significantly lower in MS patients than in HCs (mean: 235.2 g/day vs. 280.6 g/day, p = 0.006). Previously reported foods associated with MS in Northern European ancestries were not replicated in Japanese people. Conclusion: Smoking and earlier age of menarche are positively associated and sunlight exposure in early childhood is negatively associated with MS in Japanese people as shown in Caucasians. Intake of steamed short-grain white rice, a staple food in Japan, is newly found to be negatively associated with MS in Japanese people. Although the causality is unclear because the participants were prevalent cases, these environmental factors may be involved in the rising prevalence of MS in Japanese females.

DOI： 10.1016/j.msard.2019.101872

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

In multiple sclerosis plaques, oligodendroglial connexin (Cx) 47 constituting main gap junction channels with astroglial Cx43 is persistently lost. As mice with Cx47 single knockout exhibit no demyelination, the roles of Cx47 remain undefined. We aimed to clarify the effects of oligodendroglia-specific Cx47 inducible conditional knockout (icKO) on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein peptide (MOG35-55) in PLP/CreERT;Cx47fl/fl mice at 14 d after tamoxifen injection. Cx47 icKO mice demonstrated exacerbation of acute and chronic relapsing EAE with more pronounced demyelination than Cx47 flox (fl)/fl littermates. CD3+ T cells more abundantly infiltrated the spinal cord in Cx47 icKO than in Cx47 fl/fl mice throughout the acute to chronic phases. CXCR3-CCR6+CD4+ and IL17+IFNγ-CD4+ helper T (Th) 17 cells isolated from spinal cord and brain tissues were significantly increased in Cx47 icKO mice compared with Cx47 fl/fl mice, while MOG35-55-specific proliferation and proinflammatory cytokine production of splenocytes were unaltered. Microarray analysis of isolated microglia revealed stronger microglial activation toward proinflammatory and injuryresponse phenotypes with increased expressions of chemokines that can attract Th17 cells, including Ccl2, Ccl3, Ccl4, Ccl7, and Ccl8, in Cx47 icKO mice compared with Cx47 fl/fl mice. In Cx47 icKO mice, NOS2+ and MHC class II+ microglia were more enriched immunohistochemically, and A1-specific astroglial gene expressions and astroglia immunostained for C3, a representative A1 astrocyte marker, were significantly increased at the acute phase, compared with Cx47 fl/fl mice. These findings suggest that oligodendroglia-specific Cx47 ablation induces severe inflammation upon autoimmune demyelination, underscoring a critical role for Cx47 in regulating neuroinflammation.

DOI： 10.1073/pnas.1901294117

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

Background and purpose: The cervical and thoracic cross-sectional spinal cord area (CS-SCA) in multiple sclerosis (MS) correlates with disability, whilst such a correlation remains to be established in neuromyelitis optica spectrum disorder (NMOSD). Our aim was to clarify differences between MS and NMOSD in spinal cord segments where CS-SCA is associated with disability. Methods: The CS-SCA at C2/C3, C3/C4, T8/T9 and T9/T10 vertebral disc levels was measured in 140 MS patients (111 with relapsing–remitting MS and 29 with progressive MS) and 42 NMOSD patients with anti-aquaporin-4 immunoglobulin G. Disability was evaluated by Expanded Disability Status Scale (EDSS) scores. Multivariate associations between CS-SCA and disability were assessed by stepwise forward multiple linear regression. Results: Thoracic CS-SCA was significantly smaller in NMOSD patients than in MS patients even after adjusting for age, sex and disease duration (P = 0.002 at T8/T9), whilst there was no difference in cervical CS-SCA between the two diseases. Cervical and thoracic CS-SCA had a negative correlation with EDSS scores in MS patients (P < 0.0001 at C3/C4 and P = 0.0002 at T8/T9) whereas only thoracic CS-SCA correlated with EDSS scores in NMOSD patients (P = 0.0006 at T8/T9). By multiple regression analyses, predictive factors for disability in MS were smaller cervical CS-SCA, progressive course, older age and a higher number of relapses, whilst those in NMOSD were smaller thoracic CS-SCA and older age. Conclusions: Thoracic CS-SCA is a useful predictive marker for disability in patients with NMOSD whilst cervical CS-SCA is associated with disability in patients with MS.

DOI： 10.1111/ene.14038

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

We report a patient with neuromyelitis optica spectrum disorders (NMOSD) with anti-aquaporin 4 (AQP4) antibodies, who developed intractable axonal neuropathy presenting with multifocal peripheral nerve swelling by magnetic resonance (MR) neurography. A 52-year-old woman with a 12-year history of polymyositis and rheumatoid arthritis had been treated with prednisolone, tacrolimus, and abatacept (CTLA-4-Ig). She developed progressive numbness and tingling sensations in the distal parts of all limbs at the age of 50 years, followed by weakness of both upper limbs 6 months later. Neurological examination revealed severe muscle weakness and atrophy of the right upper limb with proximal dominance, diffuse moderate weakness of the left upper limb, severe sensory impairment of all modalities of four limbs in glove and stocking distribution, wide-based gait with positive Romberg's sign, and absence of all tendon reflexes. She was diagnosed with NMOSD due to positive serum anti-AQP4 antibodies and a longitudinally extensive cervical spinal cord lesion on MR images. Intravenous methylprednisolone pulse therapy, plasma exchange and intravenous immunoglobulin administration were performed, which improved the spinal cord lesion on MRI, but did not ameliorate her symptoms. Notably, she also had axonal neuropathy characterized by asymmetrical, multifocal swelling of peripheral nerves by MR neurography. Histopathological examination of the biopsied sural nerve revealed axonal degeneration and endoneurial edema but no inflammatory cell infiltration. Although she was treated with intravenous methylprednisolone, intravenous immunoglobulin, oral prednisolone, tacrolimus and tocilizumab, her symptoms gradually progressed. Neurologists should be aware of co-existing intractable axonal neuropathy in NMOSD cases presenting as immunotherapy-resistant sensorimotor disturbances.

DOI： 10.1016/j.msard.2019.06.033

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

BACKGROUND: We previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies (untreated MS) and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells. Interferon-β (IFN-β) is one of the first-line disease-modifying drugs for MS. However, no previous studies have reported changes in γδ T cell subsets under IFN-β treatment. Therefore, we aimed to clarify the effects of the long-term usage of IFN-β on γδ T cell subsets in MS patients. METHODS: Comprehensive flow cytometric immunophenotyping was performed in 35 untreated MS and 21 MS patients on IFN-β for more than 2 years (IFN-β-treated MS) including eight super-responders fulfilling no evidence of disease activity criteria, and 44 healthy controls (HCs). RESULTS: The percentages of Vδ2+Vγ9+ cells in γδ T cells were significantly lower in untreated and IFN-β-treated MS patients than in HCs. By contrast, the percentages of Vδ1-Vδ2-Vγ9- cells in γδ T cells were markedly higher in IFN-β-treated MS patients than in HCs and untreated MS patients (both p < 0.001). A significant negative correlation between the percentages of Vδ2+Vγ9+ cells in γδ T cells and EDSS scores was confirmed in untreated MS but not evident in IFN-β-treated MS. Moreover, class-switched memory B cells were decreased in IFN-β-treated MS compared with HCs (p < 0.001) and untreated MS patients (p = 0.006). Interestingly, the percentages of Vδ1-Vδ2-Vγ9- cells in γδ T cells were negatively correlated with class-switched memory B cell percentages in all MS patients (r = - 0.369, p = 0.005), and the percentages of Vδ1-Vδ2-Vγ9- cells in Vδ1-Vδ2- γδ T cells were negatively correlated with EDSS scores only in IFN-β super-responders (r = - 0.976, p < 0.001). CONCLUSIONS: The present study suggests that long-term usage of IFN-β increases Vδ1-Vδ2-Vγ9- γδ T cells, which are associated with a better outcome, especially in IFN-β super-responders. Thus, increased Vδ1-Vδ2-Vγ9- cells together with decreased class-switched memory B cells may contribute to the suppression of disease activity in MS patients under IFN-β treatment.

DOI： 10.1186/s12974-019-1574-5

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

We report a 60-year-old male with anti-myelin oligodendrocyte glycoprotein (MOG) antibody who developed progressive cognitive deterioration and behavioral changes, with no other focal signs, over 9 months. MRI showed numerous T2-hyperintense lesions with partial contrast enhancement in white and grey matter of cerebrum, cerebellum and spinal cord. A brain biopsy revealed perivascular inflammatory cell infiltration, disturbed vascular continuity and no demyelination, indicative of a lymphocytic pattern of primary CNS vasculitis (PCNSV). Contrast enhancement disappeared after immunotherapy; however, cognitive impairment was not improved. Neurologists should note that MOG antibody disease can present as immunotherapy-resistant progressive cognitive impairment with PCNSV-like histopathology.

DOI： 10.1016/j.msard.2019.01.053

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

Background: During pregnancy, dynamic changes occur not only in coagulation, but also in immune responses. We report a case of a patient who developed an inflammatory disease in the central nervous system during late pregnancy and was challenging to diagnose. Case presentation: A 27-year-old woman experienced dysarthria during pregnancy at approximately 33 gestational weeks. From the 38th week of pregnancy, she developed general fatigue, clumsiness of the left hand and numbness of the right side of the body. After delivery of her child at 41 weeks’ gestation, she was moved to the neurology ward for further investigation. She showed limb ataxia of the left extremities and sensory disturbance on the right side of the body, including the face. Magnetic resonance imaging detected multiple gadolinium-enhanced lesions at the brainstem and cerebrum. High-dose intravenous methylprednisolone pulse therapy was effective, but her symptoms still remained, including palatal myoclonus. Diagnosing this patient was challenging, but clinically isolated syndrome or multiple sclerosis and neuro-Behҫet's disease were the main candidates. Conclusions: We present a case of a pregnant woman who developed brain inflammatory lesions with unknown etiology. Longitudinal follow up is mandatory for diagnosis with careful tapering of oral prednisolone.

DOI： 10.1111/cen3.12503

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

Objectives: Studies of longitudinally extensive spinal cord lesions (LESCLs) in neuromyelitis optica (NMO) have focused on gray matter, where the relevant antigen, aquaporin-4 (AQP4), is abundant. Because spinal white matter pathology in NMO is not well characterized, we aimed to clarify spinal white matter pathology of LESCLs in NMO. Methods: We analyzed 50 spinal cord lesions from eleven autopsied NMO/NMO spectrum disorder (NMOSD) cases. We also evaluated LESCLs with three or fewer spinal cord attacks by 3-tesla MRI in 15 AQP4 antibody-positive NMO/NMOSD patients and in 15 AQP4 antibody-negative multiple sclerosis (MS) patients. Results: Pathological analysis revealed seven cases of AQP4 loss and four predominantly demyelinating cases. Forty-four lesions from AQP4 loss cases involved significantly more frequently posterior columns (PC) and lateral columns (LC) than anterior columns (AC) (59.1%, 63.6%, and 34.1%, respectively). The posterior horn (PH), central portion (CP), and anterior horn (AH) were similarly affected (38.6%, 36.4% and 31.8%, respectively). Isolated perivascular inflammatory lesions with selective loss of astrocyte endfoot proteins, AQP4 and connexin 43, were present only in white matter and were more frequent in PC and LC than in AC (22.7%, 29.5% and 2.3%, P^corr = 0.020, and P^corr = 0.004, respectively). MRI indicated LESCLs more frequently affected PC and LC than AC in anti-AQP4 antibody-seropositive NMO/NMOSD (86.7%, 60.0% and 20.0%, P^corr = 0.005, and P^corr = 0.043, respectively) and AQP4 antibody-seronegative MS patients (86.7%, 73.3% and 33.3%, P^corr = 0.063, and P^corr = 0.043, respectively). PH, CP and AH were involved in 93.3%, 86.7% and 73.3% of seropositive patients, respectively, and in 53.3%, 60.0% and 40.0% of seronegative patients, respectively. Conclusions: NMO frequently and extensively affects spinal white matter in addition to central gray matter, especially in PC and LC, where isolated perivascular lesions with astrocyte endfoot protein loss may emerge. Spinal white matter involvement may also appear in early NMO, similar to cerebral white matter lesions.

DOI： 10.1111/bpa.12386

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

Background: Higher latitude and human leukocyte antigen (HLA)-DRB1*04:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown. We aimed to clarify the effects of latitude and the HLA-DRB1 and HLA-DPB1 genes on disease severity in Japanese patients with MS. Methods: We enrolled 247 MS patients and 159 healthy controls (HCs) from the northernmost main island of Japan, Hokkaido Island (42-45° north), and 187 MS patients and 235 HCs from the southern half (33-35° north) of the Japanese archipelago (33-45° north). We genotyped HLA-DRB1 and HLA-DPB1 alleles, compared demographic features, and analyzed factors contributing to differences in clinical and laboratory findings between MS patients from southern and northern Japan. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Kurtzke's Expanded Disability Status Scale score according to disease duration, was used to estimate disease severity. Results: The HLA-DRB1*04:05 and DRB1*15:01 alleles conferred susceptibility to MS in our Japanese population (p ^corr=0.0004 and p ^corr=0.0019, respectively). Southern patients had higher MSSS scores than northern patients (p=0.003). Northern patients had higher frequencies of brain lesions meeting the Barkhof criteria (Barkhof brain lesions) and cerebrospinal fluid (CSF) IgG abnormalities than southern patients (p=0.0012 and p<0.0001, respectively). DRB1*04:05-positive MS patients had lower MSSS scores and lower frequencies of Barkhof brain lesions and CSF IgG abnormalities than DRB1*04:05-negative MS patients (p=0.0415, p=0.0026, and p<0.0001, respectively). Multivariate analyses revealed that latitude and DRB1*04:05 were independently associated with the lowest quartile of MSSS and that latitude was positively associated with Barkhof brain lesions and CSF IgG abnormalities. DRB1*04:05 was negatively associated with these parameters. MSSS was decreased by 0.57 per DRB1*04:05 allele (p=0.0198). Conclusions: Living at a higher latitude and carrying the DRB1*04:05 allele independently lessens MS symptom severity as defined by MSSS. However, these factors influence the frequency of Barkhof brain lesions and CSF IgG abnormalities in opposite ways; higher latitude increases the frequency of Barkhof brain lesions and CSF IgG abnormalities, whereas DRB1*04:05 decreases them.

DOI： 10.1186/s12974-016-0695-3

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

DOI： 10.1111/cen3.12274

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

Objective To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. Methods Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. Results A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti-aquaporin-4 antibody or had significantly lower titers than those without CNV. Interpretation Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility.

DOI： 10.1002/ana.24511

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

DOI： 10.1111/cen3.12029

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

Lymphomatosis cerebri (LC) is a rare form of primary central nervous system lymphoma characterized by subacute progressive dementia and unsteady gait MRI study of LC typically reveals diffuse leukoencephalopathy without contrast enhancement. The clinical presentation and MRI features of LC can resemble infectious, inflammatory, toxic or vascular leukoencephalopathy. Hence diagnosis of LC is easily mistaken for other, more common diseases. In this report, we present a case of a 55-year-old man presenting with subacute progressive dementia and ataxic gait. Brain MRI showed diffuse hyperintense lesions in the cerebral white matter of both hemispheres, left amygdala, brainstem and cerebellar peduncles on FLAIR image. No contrast-enhanced lesion was observed. Cerebrospinal fluid analysis showed elevated levels of soluble interleukin-2 receptor and β2-microglobulin. Based on MRI findings and ¹²³I-IMP SPECT, stereotactic biopsy targeting white matter of the left medial temporal lobe was performed (day 0). On the day after the brain biopsy, corticosteroid therapy was initiated and improved the patient's cognitive function and gait disturbance. Pathological diagnosis of large B-cell lymphoma was obtained on day 9. High-dose intravenous methotrexate chemotherapy was started on day 14 and led to complete remission by day 52. This case highlighted the importance of brain biopsy for diagnosis of LC. This report raises a possibility that timely and proper treatment leads to a favorable outcome of LC that has been regarded as an intractable disease with poor prognosis.

DOI： 10.5692/clinicalneurol.52.486

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

Introduction: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by monogenic mutations in the autoimmune regulator (AIRE) gene. No attention has been paid to muscle manifestations in this disorder. We aimed to uncover whether progressive myopathy is a component of this disorder. Methods: A case description and literature search for APECED cases presenting with myopathy and analysis of AIRE gene expression in biopsied muscles from 4 healthy volunteers and the patient by reverse transcriptase polymerase chain reaction. Results: A 52-year-old woman with APECED caused by AIRE gene mutations developed progressive myopathy involving proximal limb and paraspinal muscles. Muscle biopsy specimens showed myopathic changes without inflammatory cell infiltrate. We detected AIRE gene expression in all muscle tissues examined. An extensive literature search uncovered 5 cases of APECED with myopathy, all of whom had similar features. Conclusions: Progressive myopathy involvement could be a hitherto unknown manifestation of APECED.

DOI： 10.1002/mus.23321

Event date： 2018.12

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2018.12

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Venue：Sydney   Country：Australia  

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Venue：東京   Country：Japan  

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Venue：Berlin   Country：Germany  

Event date： 2023.11

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Venue：Perth   Country：Australia  

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Venue：Milan   Country：Italy  

Event date： 2022.10

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Venue：長崎   Country：Japan  

Event date： 2021.10

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Venue：佐賀（web）   Country：Japan  

Event date： 2019.9

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Venue：千葉（幕張）   Country：Japan  

Event date： 2019.9

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Venue：Stockholm   Country：Sweden  

Event date： 2018.12

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Venue：福島県郡山市   Country：Japan  

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Language：English  

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Language：Japanese  

Language：English  

Language：English  

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Language：Japanese   Publisher：(株)日本臨床社  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

DOI： 10.1111/cen3.12384

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

The relationship between central nervous system demyelinating disorders (CNSDDs) and anti-neural antibodies (Abs), with the exception of anti-aquaporin 4 (AQP4) Abs, is not well understood. We previously screened for a variety of anti-neural Abs in the sera of Japanese patients with CNSDDs and found three patients with anti-N-methyl-d-aspartate receptor (NMDAR) Abs and three patients with anti-contactin-associated protein 2 (CASPR2) Abs. These Abs have not yet been considered as causing CNSDDs. Here, we describe CNSDD patients with these autoantibodies and discuss whether these Abs are pathogenic or not, based on the clinical presentation and literature documentation. Moreover, we propose points to which attention should be paid when dealing with patients with CNSDDs in a clinical setting.

DOI： 10.4172/0975-9042.000108

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：5

Number of peer-reviewed articles in Japanese journals：1

学部5年生：ベッドサイド実習のPOMR担当

学部5年生：ベッドサイド実習のPOMR担当

学部4年生：ベッドサイド実習のPOMR担当

学部5年生：ベッドサイド実習のPOMR担当

学部5年生：ベッドサイド実習のPOMR担当

学部5年生：ベッドサイド実習のPOMR担当

学部5年生：ベッドサイド実習のPOMR担当

学部5年生：ベッドサイド実習のPOMR担当

学部5年生：ベッドサイド実習のPOMR担当

学部6年生：クリニカルクラークシップ実習Web講義

学部6年生：クリニカルクラークシップ実習Web講義

学部5年生：ベッドサイド実習のPOMR担当

学部5年生：ベッドサイド実習のPOMR担当

学部4年生：シミュレーション実習指導

学部5年生：ベッドサイド実習のWeb講義

学部5年生：ベッドサイド実習のWeb講義

学部5年生：ベッドサイド実習のWeb講義

学部5年生：ベッドサイド実習のWeb講義

学部4年生：OSCE試験監督

学部5年生：ベッドサイド実習のPOMR担当

学部5年生：ベッドサイド実習のPOMR担当

学部5年生：ベッドサイド実習のPOMR担当

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Seminar, workshop

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Other

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

前年度に引き続き多発性硬化症・視神経脊髄炎診療ガイドラインの作成に、システマティックレビュー委員として参加し、2023年9月に発刊された。

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Seminar, workshop

前年度に引き続き多発性硬化症・視神経脊髄炎診療ガイドラインの作成に、システマティックレビュー委員として参加した。

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Seminar, workshop

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture

多発性硬化症・視神経脊髄炎診療ガイドラインの作成に、システマティックレビュー委員として参加している。

Audience：General,　Scientific,　Company,　Civic organization,　Governmental agency

Type：Lecture