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Introduction: Satralizumab, an anti-interleukin-6 receptor antibody, is approved in Japan for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and is undergoing post-marketing surveillance (PMS) of clinical use. We aimed to describe the real-world safety and effectiveness of satralizumab in Japanese patients with NMOSD. Methods: This is an ongoing PMS (planned completion: February 2027). This 6-month interim analysis assessed the safety and effectiveness of satralizumab in Japanese patients with NMOSD using data collected from August 2020 to July 2021. Results: Among 570 patients who participated, 523 (91.75%) were female and the mean ± standard deviation (SD) age was 52.4 ± 14.1 years. At baseline, NMOSD expanded disability status scale mean ± SD was 4.19 ± 2.19; 490 (85.96%) patients used glucocorticoids and 277 (48.59%) patients used immunosuppressants concomitantly. Of 570 satralizumab-treated patients, 85 (14.91%) had discontinued satralizumab treatment at 6 months. For the overall adverse drug reactions (ADRs), 76.22 (66.07–87.48) events/100 person-years occurred in 118 (20.70%) patients, and infections occurred in 28 (4.91%) patients. Serious infections occurred in 18 (3.15%) patients, with an event rate of 9.05 (5.80–13.47) events/100 person-years. Of the 24 events of serious infections, respiratory tract infections (29.17%; 7) and urinary tract infections (25.00%; 6) were the most common serious infection events. One fatal ADR (septic shock) suspected to be related to satralizumab was reported. The mean ± SD glucocorticoid dose reduced from 12.28 ± 10.17 mg/day at the index date to 8.11 ± 7.30 mg/day at 6 months. The Kaplan–Meier cumulative relapse-free rate (95% confidence interval) was 94.59% (92.25–96.23) at 6 months. Conclusion: In this study, satralizumab was found to be safe, well tolerated, and effective in patients with NMOSD in routine clinical practice. The results are consistent with those of previous clinical trials. The safety and effectiveness of satralizumab in Japanese patients with NMOSD will be analyzed over the 6-year surveillance period. Trial Registration: UMIN Clinical Trials Registry, UMIN000041047. [ABSTRACT FROM AUTHOR]

Glutamate and its receptors are involved in pleiotropic roles including experience‐dependent synaptic plasticity and brain development as the main fast excitatory neurotransmitters in the central nervous system. There are two main families of the glutamate receptors: (1) ionotropic glutamate receptors (iGluRs) that are ligand‐gated ion channel receptors accessible for fast synaptic transmission, and (2) metabotropic glutamate receptors (mGluRs) that are G‐protein‐coupled receptors modulating slow synaptic transmission through intracellular second messengers. Here, we summarize the current concepts of autoimmunity to these glutamate receptors in neurological disorders: anti‐GluN1 subunit of N‐methyl‐D‐aspartate receptor (NMDARs) for anti‐NMDAR encephalitis, anti‐GluA1 and GluA2 subunits of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPARs) for anti‐AMPAR encephalitis, and anti‐mGluR5 subunit for Ophelia syndrome. Most identified autoimmunity to glutamate receptors can lead to unique synaptopathies or neuronal antibody‐mediated encephalopathies. Evidence‐based optimal management guidelines and new disease‐modifying therapies need to be developed for patients with autoimmune encephalitis including anti‐glutamate receptor encephalitis. [ABSTRACT FROM AUTHOR]

This study investigated the effects of an online interprofessional education (IPE) program on nursing students at a university in Japan. It conducted a comparative analysis between traditional face-to-face and online interventions. All students who enrolled in the "Team Medical Practice" course in both 2019 and 2020 were invited to participate. After team-based learning with different healthcare professions, we quantitatively analyzed pre- and post-intervention outcomes using two measures: the Readiness for Interprofessional Learning Scale (RIPLS) and the IPE Questionnaire TSUKUBA model (IPET). We compared the results of 153 nursing students. The RIPLS results demonstrate significant pre- and post-intervention score differences in the teamwork and collaboration subscale for the online group only. The post-IPE score analysis revealed that scores were significantly higher in the online group in all subscales: Teamwork and collaboration, Opportunities for IPE, and Uniqueness of profession. Based on the IPET results, there were no significant differences in pre- and post-intervention scores. However, the online group showed a significant increase in post-intervention scores in participation in group work, thoughts about the team in health and welfare, and thoughts about interprofessional collaboration. These findings indicate that the online IPE program improved nursing students' readiness for interprofessional learning, demonstrating practical efficacy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: No head‐to‐head clinical trials have compared ofatumumab with other disease‐modifying therapies (DMTs) available in Japan for patients with relapsing multiple sclerosis (RMS). In this study, a network meta‐analysis (NMA) was conducted to compare the efficacy of ofatumumab to other DMTs currently available in Japan for the treatment of patients with RMS. Methods: Systematic searches were conducted in biomedical databases from inception to June 2020 to identify randomized controlled trials. Only English‐ and Japanese‐language publications describing studies conducted in Japan were included. Trials with sufficiently similar study and patient characteristics were included in a Bayesian NMA. A sensitivity analysis was conducted to explore the impact of potential sources of uncertainty. Results: Four trials, each comparing a DMT with placebo in a ≥50% Japanese population, were sufficiently similar that comparative efficacy could be assessed for annualized relapse rate (ARR). Ofatumumab numerically reduced ARR compared with fingolimod (rate ratio [RR]: 0.84, 95% credible interval [CrI]: 0.20–3.39), dimethyl fumarate (RR: 0.61, 95% CrI: 0.16–2.30), and placebo (RR: 0.41, 95% CrI: 0.12–1.39), but not natalizumab (RR: 1.33, 95% CrI: 0.33–5.45). In a subgroup analysis of Japanese patients only, ofatumumab reduced relapses compared with all other treatments including natalizumab. These results were limited by the lack of studies reporting direct comparisons between included treatments and by heterogenous reporting of outcome data. Conclusion: These findings, although limited by the paucity of evidence for Japanese patients, suggest that monoclonal antibody therapies (ie, natalizumab and ofatumumab) may provide improved efficacy compared with other DMTs available in Japan for patients with RMS. [ABSTRACT FROM AUTHOR]

Introduction: The healthcare situation of multiple sclerosis (MS) and its course are not being thoroughly investigated in Japan. We aimed to examine the current healthcare situation, including treatment and healthcare costs, of MS according to duration since its first diagnosis using Japanese real-world data to determine unidentified healthcare issues at each disease stage. Methods: This retrospective, non-comparative, non-interventional study used a Japanese nationwide claims database (April 2008–August 2018) comprising 20 million patients from 329 acute care hospitals (as of June 2018). Treatment patterns, comorbidities, healthcare resource utilization, and healthcare costs were analyzed using longitudinal analyses of patients with MS according to duration since the first diagnosis. The time from diagnosis to first treatment was examined using Kaplan–Meier analysis. Results: We identified 7067 patients with MS [mean (standard deviation) age at first diagnosis 45.0 (16.2) years]. About 70% of the patients did not receive disease-modifying therapy (DMT) within the first year of diagnosis. The frequency of DMT use decreased in patients with a longer duration since the first diagnosis. MS treatment costs tended to increase with a longer duration from the first diagnosis until 9 years, followed by a tendency to decrease; contrastingly, other healthcare costs tended to increase with duration after decreasing from the year of the first diagnosis to the next year. The frequencies of hospitalizations and hospital visits, healthcare costs—excluding those for MS treatment and tests—and prevalence of comorbidities tended to be higher in patients with a longer duration since the first diagnosis. Conclusion: A considerable proportion of patients did not receive DMT, suggesting that patients with early-stage MS may lose the opportunity to improve their prognosis through early intervention with DMT. Among patients with a longer duration since the first diagnosis, fewer treatment choices may be available despite the larger clinical and treatment burden. [ABSTRACT FROM AUTHOR]

Introduction: Claims databases are preferred for research on multiple sclerosis (MS) as this condition is characterized by low prevalence and long disease course. However, Japanese claims databases contain no information on disease severity or disability status of MS. Here, we aimed to explore the possibility of utilizing a principal component analysis (PCA) to estimate MS severity using a Japanese claims database. Methods: An MS severity score was developed using a PCA. Factors related to functional systems for Expanded Disability Status Scale (EDSS) and higher disease severity (74 diagnoses, 68 drug prescriptions, and 77 procedures) were extracted from the claims database (April 2008–August 2018). The score (PC1 score) was developed for each patient-year—each year from the first diagnosis (excluding the year of the first diagnosis), based on the first principal component of the included factors. Finally, the patient-years were classified into quartiles based on the PC1 score, and demographic information and medical status were analyzed. Results: The database contained 7067 patients with MS. The highest score group had a higher mean age (55.4 ± 0.2 [mean ± standard error] years), lower percentage of women (64.4 ± 0.7%), and longer mean disease duration from first diagnosis (8.1 ± 0.1 years) than the lowest score group (43.3 ± 0.2 years, 68.4 ± 0.8%, and 6.0 ± 0.1 years, respectively). In addition, the PC1 score of each patient positively correlated with disease duration from diagnosis. Conclusion: We developed a PC1 score to indicate MS severity using information from a Japanese claims database. Since changes in demographic features we observed are consistent with findings of previous research, this score might represent MS severity to some extent. Further research is necessary to validate this score with clinical measurement of disability such as the EDSS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Keywords: Oculopharyngodistal myopathy; Neuronal intranuclear inclusion disease; Oculopharyngeal myopathy with leukoencephalopathy; Noncoding CGG expansions; Neuropathology EN Oculopharyngodistal myopathy Neuronal intranuclear inclusion disease Oculopharyngeal myopathy with leukoencephalopathy Noncoding CGG expansions Neuropathology 1 5 5 06/05/20 20200603 NES 200603 Unstable tandem repeat expansions are important genetic motifs that underlie various neurological disorders. OPDM Oculopharyngodistal myopathy NIID Neuronal intranuclear inclusion disease OPML Oculopharyngeal myopathy with leukoencephalopathy RV Rimmed vacuole Supplementary information B Supplementary information b accompanies this paper at 10.1186/s40478-020-00945-2. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Background: In this study, we aimed to understand the trends in total and itemized medical expenses, especially of disease-modifying therapy (DMT), for multiple sclerosis (MS) in Japan through an analysis of health insurance claims data.Methods: We analyzed a database containing health insurance claims data from hospitals that have adopted the Diagnosis Procedure Combination/Per-Diem Payment System in Japan. According to an algorithm based on diagnosis codes, data for all patients diagnosed with MS from April 2008 to July 2016 were extracted. Medical costs, rate of each medical treatment, and rate of relapses were analyzed by calendar-year. Medical costs in the month of relapse were compared with average medical costs per month of all MS patients by a cross-sectional analysis.Results: Four thousand three hundred seventy-four MS patients were identified in the database. Total medical cost per patient per month (PPPM) increased from ¥87,640 (US$787.7 or €723.0 as of May 2017) to ¥102,846 (US$924.4 or €848.4) during the study period. This increment was mainly attributed to the growth in cost of outpatient DMT prescriptions, which increased from ¥23,039 (US$207.1 or €190.1) to ¥51,351 (US$461.5 or €423.6). In contrast, the rate of hospitalizations and relapses PPPM decreased during the study period (from 0.053 to 0.030, and 0.032 to 0.019, respectively). Medical costs in the month of relapse (¥424,661, US$3816.8 or €3503.1) were 3.57 times higher than the average monthly costs for all MS patients (¥119,021, US$1069.8 or €981.8), with the majority comprising hospitalization cost.Conclusion: Concomitant with the increased usage of DMT, the total medical cost for treating MS is increasing in Japan. However, rates of relapse and hospitalization have shown a decreasing trend. Although this study does not show the direct causality between DMT and reduction of relapse rates/fewer hospitalizations among MS patients, a reduction in hospital costs has been revealed concomitantly with the increasing prevalence of DMT. [ABSTRACT FROM AUTHOR]

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'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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article offers information on the Third Annual Meeting of the Multiple Sclerosis (MS) Summer College held at the Kobe Portpia Hotel in Kobe, Japan from August 6-7, 2016. Topics discussed include pathomechanisms of neuromyelitis optica (NMO), role of fingolimod in bone resorption in female patients with MS, and diagnosis and treatment strategies in pediatric MS patients. Associate Professor Monika Bradl of the Medical University of Vienna in Austria gave the opening lecture on NMO.

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 1 week 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 (−0.8 ± 0.9), second (−0.7 ± 0.9), and third (−0.7 ± 0.8) courses (p < 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 < 0.05) in NMO patients. EDSS score was significantly decreased in MS compared with NMO patients at the first course (p < 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 < 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Neuromyelitis 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.Methods: Thirty 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.Results: The 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 Müller 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.Interpretation: Severe and widespread neuroaxonal damage and unique dynamics of astrocytes/Müller cells with alterations of AQP4 were prominent in the AVP and may be associated with poor visual function and prognosis in NMOsd. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the two main autoimmune diseases of the CNS. In patients with NMO, the target antigen is aquaporin-4 (AQP4), the most abundant water channel protein in the CNS. AQP4 is mainly expressed on astrocytic endfoot processes at the blood-brain barrier and in subpial and subendymal regions. MS and NMO are distinct diseases, but they have some common clinical features: both have long been considered autoimmune diseases that primarily affect the white matter (WM). However, because WM demyelination by itself cannot explain the full extent of the clinical disabilities, including cognitive decline in patients with MS and NMO, renewed interest in gray matter (GM) pathology in MS and NMO is emerging. Important hallmarks of WM and GM lesions in MS and NMO may differentially influence neuronal degeneration and demyelination in the brain and spinal cord, given different detrimental effects, including cytokine diffusion, disruption of water homeostasis associated with or without AQP4 (the target antigen in NMO) dynamics, or other unidentified mechanisms. An increase in knowledge of the structure of GM and WM lesions in MS and NMO will result in more targeted therapeutic approaches to these two diseases. [ABSTRACT FROM AUTHOR]

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. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Hypertrophic pachymeningitis is an important cause of cranial polyneuropathy. Yokoseki et al. report 36 patients with hypertrophic pachymeningitis associated with myeloperoxidase anti-neutrophil cytoplasmic antibody, and argue that such patients most commonly have granulomatosis with polyangiitis (Wegener’s granulomatosis) confined to the CNS.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 TH1-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. [ABSTRACT FROM AUTHOR]

Multiple sclerosis ( MS) and neuomyelitis optica ( NMO) are the two main autoimmune and inflammatory diseases of the central nervous system. They have long been considered to be autoimmune diseases that primarily affect the white matter ( WM). However, renewed interest in gray matter ( GM) pathology is emerging. This review focuses on the current knowledge of the details of GM pathology, and its clinical aspects including cognitive impairment in MS and NMO. Patients with MS and NMO have similar cognitive profiles as represented by the latent start of impairment from a very early stage of the disease course. Pathological assessments show that substantial cortical demyelination is prominent in all stages or courses of MS, and cortical neurodegeneration is also present not only in cortical demyelination, but also in normal-appearing GM in MS. In contrast, cortical neurodegeneration is present in NMO and involves unique dynamics of astrocytes, but no cortical demyelination is seen in NMO. Thus, two distinct diseases, MS and NMO, each have unique characteristic features of pathological modalities in the brain. These important hallmarks of MS and NMO might influence neuronal and cognitive function in the brain, given different detrimental effects including cytokine diffusion, disruption of water homeostasis associated with aquaporin-4 dynamics, or other unidentified mechanisms. Although the cause of GM lesions in MS and NMO has not been fully determined, an increase in knowledge of the structure of GM lesions, and the pathomechanisms in MS and NMO brains will result in more targeted pharmacotherapeutic approaches to these diseases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

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 Sjögren'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. [ABSTRACT FROM AUTHOR]

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 (<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. [ABSTRACT FROM AUTHOR]

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. 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. 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. [ABSTRACT FROM AUTHOR]

The article discusses Immune-mediated hypertrophic pachymeningitis (HP) and presents the clinical significance of anti-neutrophil cytoplasmic antibody and Wegener's granulomatosis. Topics mentioned include autoimmune diseases, infections, syphilis and bacterial diseases such as tuberculosis and neoplasms like lymphoma. A study on patients with HP is presented with observations namely predominance in elderly females, presence of garnulomatosis with polyangiitis and lesions in dura mater.

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. [ABSTRACT FROM AUTHOR]

The article focuses on a study based on pathomechanism of Neuromyelitis optica spectrum disorder (NMOSD). Topics discussed include effector mechanisms of aquaporin-4 (AQP4) antibody binding to its cellular target astrocytes which include complement dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and internalization of AQP4 channels; pattern-specific loss of AQP4 immunoreactivity on astrocytes; and melastatin 4 in the optic nerves of NMOSD.

The article presents a study that investigates the incidence rates of dropped head syndrome (DHS) on patients with amyotrophic lateral sclerosis (ALS) in Okinawa, Japan. Researchers studied 105 ALS patients with DHS, where they obtained the age of DHS onset, muscular weakness distribution, initial symptoms and neurological finds. Moreover, they found that incidence rates in three patients with ALS was 2.9% and they were 56, 63 and 53 years old when ALS occurred.

Dropped head syndrome (DHS), which is characterized by severe neck flexion without thoracic or lumbar curvature, limits activities of daily living (ADL) because the patient can only look downward. Patients with amyotrophic lateral sclerosis (ALS) may develop DHS. In total, 105 consecutive ALS patients (65 males and 40 females) were studied, and all patients had sporadic ALS. [Extracted from the article]

The article focuses on the cortical degeneration as potential pathogenesis of cognitive impairment in neuromyelitis optica (NMO). It reports on a study during which 57 percent of the NMO spectrum disorder (NMOsd) patients and 47 percent of the multiple sclerosis (MS) patients showed impaired performance by an assessment through a neuropsychological test. It states that further research is needed to investigate the essential mechanisms of cognitive impairment and neurodegeneration.