Japanese translation and validation of the 12-item Multiple Sclerosis Walking Scale version 2.

BACKGROUND: Disability in ambulation has a critical impact on activities of daily living in patients with multiple sclerosis (MS). The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a self-reported instrument developed to assess the impact of MS on walking. The scale's 12 items assess various aspects of walking-related tasks during the past 2 weeks. MSWS-12 has been used in multiple clinical studies and translated into several languages. In the present study, we translated the MSWS-12 into Japanese and evaluated its psychometric properties in a cross-sectional study. METHODS: The original English MSWS-12 version 2 (v2) was translated into Japanese through a standard procedure. Sixty consecutive Japanese MS patients completed the newly prepared Japanese MSWS-12v2 questionnaire and repeated the test 14 days later. Physical disability was assessed by the Expanded Disability Status Scale (EDSS), Timed 25-foot Walk (T25FW), and 9-hole Peg Test (9HPT). Cognitive performance was evaluated using the Processing Speed Test (PST). Fatigue and health-related quality of life were assessed using the Japanese versions of the Fatigue Severity Scale (FSS) and the Functional Assessment of MS (FAMS). RESULTS: The mean age of the patients was 42.5 years, with median disease duration of 10 years, and median EDSS of 2.0 (range 0, 6.5). Forty-seven patients (78.3 %) had relapsing-remitting, 9 (15.0 %) had secondary-progressive, and 4 (6.7 %) had primary-progressive phenotypes. The median score of the MSWS-12v2 was 5.95 (interquartile range 0, 50.6). Twenty-seven patients (45 %) scored the lowest possible score (0 points), while one (1.7 %) scored the highest possible score (100 points). Cronbach's alpha was 0.98 (95 % confidence interval [CI] 0.97, 0.98), and the test-retest intraclass correlation was 0.95 (95%CI 0.94, 0.96). MSWS-12v2 score was strongly correlated with EDSS (Spearman's ρ = 0.73 [95%CI 0.58, 0.83]), T25FW (ρ = 0.70 [95%CI 0.55, 0.81]), and total FAMS score (ρ = -0.80 [95%CI -0.88, -0.69]), and moderately correlated with 9HPT (ρ = 0.65 [95%CI 0.47, 0.77] for the dominant hand; ρ = 0.62 [95%CI 0.43, 0.75] for the non-dominant hand), PST (ρ = -0.65 [95%CI -0.78, -0.47]), and FSS (ρ = 0.68 [95%CI 0.52, 0.80]). Among the subcomponents of FAMS, the mobility subcomponent showed the most robust correlation with MSWS-12v2 score (ρ = -0.91 [95%CI -0.94, -0.81]). In patients with minimal or no objective disability (EDSS < 3.0, n = 40), only the mobility subcomponent of FAMS was strongly correlated with MSWS-12v2 score (ρ = -0.76 [95% CI -0.87, -0.58]). In contrast, correlations of MSWS-12v2 score with EDSS and T25FW were weak in this subgroup (ρ = 0.28 [95%CI -0.03, 0.55] for EDSS; ρ = 0.25 [95%CI -0.06, 0.52] for T25FW). Response patterns for the single items showed that 32.5 % of the patients with EDSS below 3.0 reported having problems with balance, followed by climbing stairs and standing while doing things (both 25 %). CONCLUSION: The Japanese version of the MSWS-12v2 developed in this study is reliable, valid, and helpful for screening walking disability in Japanese MS patients, including those with minimal objective disability.

[Thymoma-associated generalized myasthenia gravis complicated with anti-VGKC complex antibody-associated limbic encephalitis: a case report].

We present a case of a 54-year-old woman. She was attending our department for thymoma-associated generalized myasthenia gravis. While she was treated with intravenous immunoglobulins for the exacerbation of myasthenic symptoms, she suddenly lost her consciousness for the first time and continued to have mild disorientation along with anterograde and retrograde amnesia afterwards. The symptoms improved after steroid pulse therapy. After searching for autoantibodies, she was diagnosed with anti-VGKC complex antibody-associated limbic encephalitis. As one-third of cases are complicated by thymoma, anti-VGKC complex antibody-positive limbic encephalitis has the aspect of a paraneoplastic neurological syndrome. In this case, masses suspected to be a recurrence of thymoma were found. In cases of thymoma, involvement of anti-VGKC complex antibodies should be considered when central nervous system symptoms appear, and when anti-VGKC complex antibodies are positive, recurrence or exacerbation of thymoma should be considered.

Smoking and younger age at onset in anti-acetylcholine receptor antibody-positive myasthenia gravis.

Smoking is a known risk factor for the development and progression of several autoimmune diseases. Previous studies have pointed out the association of smoking with the development and worsening of symptoms in myasthenia gravis (MG), but further investigation is necessary to confirm this association. Smoking history was investigated in a cross-sectional study of 139 patients with anti-acetylcholine receptor antibody-positive MG, and the association of smoking history with the age at the onset of MG was analyzed. Patients who had been smoking at the onset of MG were significantly younger compared with those who had never smoked or had quit before the onset of MG. A linear regression analysis adjusting for sex and the presence/absence of thymoma showed a significant association between smoking at onset and younger age at onset (regression coefficient -9.05; 95% confidence interval, -17.6, -0.51; p = 0.039). Among patients with smoking exposure within 10 years prior to or at the onset of MG, women were significantly younger at the onset of MG compared with men. Our results suggest that smoking is an independent risk factor for the earlier development of anti-acetylcholine receptor antibody-positive MG and further support the putative link between smoking and MG.

Stages of brain volume loss and performance in the Brief International Cognitive Assessment for Multiple Sclerosis.

BACKGROUND: Cognitive dysfunction occurs in a substantial proportion of patients with multiple sclerosis (MS), negatively affects their daily activities, and is associated with poor prognosis. Cognitive dysfunction in MS can extend across multiple cognitive domains, depending on the patterns and extent of the brain regions affected. Therefore, a combination of tests, including the Brief International Cognitive Assessment for MS (BICAMS), that assess different aspects of cognition is recommended to capture the full picture of cognitive impairment in each patient. However, the temporal relationships between the progression of the MS brain pathology and the performances in different cognitive tests remain unclear. METHODS: Global and regional brain volume data were obtained based on T1-weighted magnetic resonance imaging from 61 patients with MS, and hierarchical cluster analysis was performed using these brain volume data. Cognitive function was assessed using the three subcomponents of the BICAMS: the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test Second Edition (CVLT2), and Brief Visuospatial Memory Test-Revised (BVMTR). Clinical characteristics, patterns of regional brain volume loss, and cognitive test scores were compared among clusters. RESULTS: Cluster analysis of the global and regional brain volume data classified patients into three clusters (Clusters 1, 2, and 3) in order of decreasing global brain volume. A comparison of the clinical profiles of the patients suggested that those in Clusters 1, 2, and 3 are in the early, intermediate, and advanced stages of MS, respectively. Pair-wise analysis of regional brain volume among the three clusters suggested brain regions where volume loss starts early and continues throughout the disease course, occurs preferentially at the early phase, or evolves relatively slowly. SDMT scores differed significantly among the three clusters, with a decrease from Clusters 1 to 3. BVMTR scores also declined in this order, whereas the CVLT2 was significantly impaired only in Cluster 3. CONCLUSION: Our results suggest that SDMT performance declines in conjunction with brain volume loss throughout the disease course of MS. Performance in the BVMTR also declines in line with the brain volume loss, but impairment in the CVLT2 becomes particularly apparent at the late phase of MS.

Association of Smoking and Generalized Manifestations of Myasthenia Gravis.

Objective Smoking is a known risk factor for the development and progression of autoimmune diseases. Previous studies in ocular myasthenia gravis (MG) patients showed that smoking is associated with the severity of symptoms and progression to generalized MG. However, whether smoking affects MG symptoms in patients with a broader clinical spectrum of presentations is unknown. Therefore, in this study, the associations of smoking with the clinical characteristics of MG were analyzed in a cohort of patients including those with generalized, seronegative, and thymoma-associated MG. Methods The smoking history was investigated in a cross-sectional study of 187 patients with MG followed in a referral hospital for neurology. The association of smoking with MG-activities of daily living score at survey, the presence of generalized manifestations, and the age of onset was assessed using multiple regression models. Results Neither current nor prior smoking habit was associated with the MG-activities of daily living score at survey. However, smoking exposure after MG onset was significantly associated with the presence of generalized manifestations during the disease course (odds ratio, 3.57; 95% confidence interval, 1.04, 12.3). The smoking history before or at onset of MG was not associated with the age of onset. Conclusion Smoking exposure after the onset is associated with generalized manifestations of MG in our cohort of patients with a broad clinical spectrum of presentations.

Seasonal fluctuations in serum levels of vitamin D in Japanese patients with multiple sclerosis.

We explored the presence of seasonal fluctuations in serum vitamin D levels and potential relationship between vitamin D levels and disease severity or prognosis in patients with multiple sclerosis (MS) in northern Japan. Serum levels of 25(OH)D in spring were significantly lower than in summer and autumn, whereas no differences in 1,25(OH)2D levels were demonstrated among four seasons. Seasonal fluctuations in 25(OH)D were demonstrated in patients with EDSS ≤3.5, but not in those with EDSS≥4.0. Negative correlations between 25(OH)D and EDSS or MSSS were found in each season. Seasonal fluctuations in 25(OH)D levels may be affected by physical disabilities.

Progressive Multifocal Leukoencephalopathy during Tocilizumab Treatment for Rheumatoid Arthritis.

A 61-year-old woman was diagnosed with rheumatoid arthritis 12 years ago and received multiple treatment regimens before achieving symptomatic stability with methotrexate plus tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, about 2 years prior to the current presentation. Sixteen months after tocilizumab initiation, she exhibited dysarthria and disorientation; five months later, she was hospitalized with movement difficulties. Her neurological symptoms deteriorated thereafter, accompanied by enlarged cerebral white matter lesions on magnetic resonance imaging. A biopsy of the right frontal lesion confirmed progressive multifocal leukoencephalopathy (PML). While several therapeutic monoclonal antibodies have been linked to PML, this is the first case associated with tocilizumab.

Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis.

Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease.

Fingolimod suppresses bone resorption in female patients with multiple sclerosis.

Fingolimod is a sphingosine-1-phosphate receptor agonist used to inhibit the inflammatory activity of multiple sclerosis (MS), and has been shown to suppress osteoporosis in mouse models. In this study, levels of bone turnover markers were quantified in serum and urine samples from MS patients treated with fingolimod. Compared with untreated MS patients and healthy controls, fingolimod-treated MS patients had a significantly lower level of the bone resorption marker type I collagen cross-linked N-telopeptide in urine. This finding was prominent in female but was not seen in male subjects. Our results suggest that fingolimod may have a beneficial effect on bone mass loss in female MS patients.

Suppression of IL-10 production by calcitriol in patients with multiple sclerosis.

We investigated whether calcitriol (1,25-dihydroxyvitamin D) differentially modulates cytokine production by peripheral blood mononuclear cells from multiple sclerosis (MS) patients compared with that from healthy controls. In response to phytohemagglutinin (PHA) or lipopolysaccharide (LPS), cytokine level in a calcitriol-added sample was normalized to that in a calcitriol-absent sample, and this relative unit was compared. The relative unit of IL-12/23(p40) in LPS-stimulation was higher in MS patients. Moreover, the relative unit of IL-10 in PHA-stimulation was lower in MS patients, and negatively correlated with the Expanded Disability Status Scale. The anti-inflammatory response to vitamin D may be reduced in MS.

Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations.

The chief therapeutic mechanism of fingolimod in multiple sclerosis (MS) is considered to be sequestration of pathogenic lymphocytes into secondary lymphoid tissues. B cells have recently been recognized as important immune regulators in MS. In this study, the effects of fingolimod on B cells in MS patients were analyzed. MS patients treated with fingolimod (MS-F) had a significantly lower number of B cells in the circulation. The remaining B cells in the blood of MS-F had a reduced proportion of memory B cells and an increased proportion of naïve B cells, expressed lower levels of the costimulatory molecule CD80, and produced less tumor necrosis factor-α and more interleukin-10. These observations in MS-F were based on an increased proportion of the transitional B-cell subpopulation within the naïve B-cell compartment. The observed findings in B cells of MS-F might be related to the therapeutic effect of this drug in MS.

CD5-positive B cell subsets in secondary progressive multiple sclerosis.

Previous studies have demonstrated that CD5(+) B cells produce more interleukin (IL)-10 than CD5(-) B cells and that CD5(+) B cells confer significant protection against experimental autoimmune encephalomyelitis (EAE). The objective of the present study was to determine whether CD5-positive B cell populations are associated with secondary progressive multiple sclerosis (SPMS) and to explore which subsets on CD5(+) B cells are associated with SPMS. A total of 26 patients with SPMS, of whom 11 were treated with IFNß (IFN-SPMS) and 15 were not treated (non-IFN-SPMS), and 19 healthy control (HC) subjects were included in the study. Expression levels of CD11a, CD23, CD25, CD38, CD49d, CD80, CD86, CD138, CCR5, and CXCR5 on CD5(+) B cells in blood samples were examined by flow cytometry. The percentage of CD5(+) B cells in the SPMS group was significantly lower than in the HC group. Within the subsets of CD5(+) B cells, the expression of CD11a in the non-IFN-SPMS group was significantly decreased compared to the HC subjects. Patients with SPMS showed lower CCR5, CD25, and CD138 positivity on CD5(+) B cells than HC subjects. Our results indicate that CD5(+) B cell subsets might be associated with pathogenesis of SPMS.