Tridecylcyclohexane in incomplete Freund's adjuvant is a critical component in inducing experimental autoimmune diseases.

Incomplete Freund's adjuvant (IFA) has been used for many years to induce autoimmune diseases in animal models, including experimental autoimmune encephalitis and collagen-induced arthritis. However, it remains unclear why it is necessary to emulsify autoantigen and heat-killed Mycobacterium tuberculosis (HKMtb) with IFA to induce experimental autoimmune diseases. Here, we found that immunization with self-antigen and HKMtb was insufficient to induce autoimmune diseases in mice. Furthermore, IFA or one of its components, mineral oil, but not mannide monooleate, was required for the development of experimental autoimmune disease. Immunization with autoantigen and HKMtb emulsified in mineral oil facilitated innate immune activation and promoted the differentiation of pathogenic CD4+ T cells, followed by their accumulation in neuronal tissues. Several water-soluble hydrocarbon compounds were identified in mineral oil. Of these, immunization with HKMtb and autoantigen emulsified with the same amount of hexadecane or tridecylcyclohexane as mineral oil induced the development of experimental autoimmune encephalitis. In contrast, immunization with HKMtb and autoantigen emulsified with tridecylcyclohexane, but not hexadecane, at doses equivalent to those found in mineral oil, resulted in neuronal dysfunction. These data indicate that tridecylcyclohexane in mineral oil is a critical component in the induction of experimental autoimmune disease.

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.

Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study.

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.

Copy number variations in multiple sclerosis and neuromyelitis optica.

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.

Efficacy of intravenous methylprednisolone pulse therapy in patients with multiple sclerosis and neuromyelitis optica.

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.

Latitude and HLA-DRB1 alleles independently affect the emergence of cerebrospinal fluid IgG abnormality in multiple sclerosis.

BACKGROUND: It is unclear whether the prevalence of oligoclonal IgG bands (OCBs) in multiple sclerosis (MS) is different between northern and southern regions of Asia. OBJECTIVE: This study aimed to compare the prevalence of OCBs and positive cerebrospinal fluid (CSF) findings between northern and southern regions of Japan and to investigate the association of these CSF findings with HLA-DRB1 alleles. METHODS: The study included 180 MS patients from Hokkaido (northern Japan) and 184 patients from Kyushu (southern Japan). The IgG index was defined as increased if it was >0.658. Presence of CSF OCBs and/or increased IgG index was defined as positive CSF findings. RESULTS: Positive CSF findings and OCB positivity were significantly higher in MS patients from Hokkaido than in those from Kyushu (p < 0.0001 for both). Logistic regression analysis revealed that after adjusting for covariates that can be related to abnormal CSF IgG production, the geographic region (Hokkaido) showed odds ratios (ORs) of 4.08 and 2.57, whereas the HLA-DRB1*04:05 allele showed ORs of 0.36 and 0.30 for positive CSF findings and OCB positivity, respectively. CONCLUSIONS: The results indicate that latitude and HLA-DRB1 alleles independently affect the emergence of CSF IgG abnormalities in Japanese patients with MS.

Genetic polymorphisms related to vitamin D and the therapeutic potential of vitamin D in multiple sclerosis.

Vitamin D receptors (VDRs), which are responsible for most vitamin D functions, are expressed on various immune cells. Vitamin D is considered to be a potent immunomodulator. A variety of cells in the central nervous system (CNS) also express VDRs; thus, vitamin D may play a role in the regulation of neurodegeneration and repair processes within the CNS. Considered together with epidemiological studies, low vitamin D status is reckoned to be one of the risk factors for multiple sclerosis (MS). Further, vitamin D is considered to be a possible treatment for MS. However, previous clinical trials with small cohorts have not demonstrated significant effects of vitamin D in MS. Current ongoing clinical trials with large cohorts could provide answers with respect to the clinical effects of vitamin D in MS. However, genetic studies have suggested that genes associated with vitamin D, including VDRs, are susceptible genes for MS. Vitamin D needs to be considered from the perspective of the interaction between vitamin-D-related genetic factors and environmental factors affecting vitamin D levels.

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.

Apathy/depression, but not subjective fatigue, is related with cognitive dysfunction in patients with multiple sclerosis.

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

[Vitamin D and latitude as environmental factors in multiple sclerosis].

Multiple sclerosis (MS) shows a multifold increase in prevalence with an increase in latitudes, both north and south of the equator. One of the potential factors related to the difference of the prevalence is vitamin D, because the strength of ambient ultraviolet light, which is essential for vitamin D production, decreases with increasing latitude. It is known that vitamin D has immunomodulatory functions and suppresses an animal model of MS. It is also considered that vitamin D-related genes are critical susceptible genes for MS. An approach from environmental and genetic aspects is needed to investigate the association between vitamin D and MS.

Characterization of Japanese multiple sclerosis patients with progression independent of relapse activity: A 2-year multicenter cohort study.

Progression independent of relapse activity (PIRA) is prevalent among Caucasian patients with relapsing and remitting multiple sclerosis (RRMS). However, there is limited knowledge regarding the characteristics of PIRA in Asian patients with RRMS. Therefore, we retrospectively analyzed the clinical and radiological progression of 95 Japanese patients with RRMS during a 2-year observation period. PIRA was observed in three patients who were characterized by young age, large T2 lesion volume, and great reduction in brain volume. Despite having highly active disease, fewer patients with PIRA (33.3%) were treated with high-efficacy drugs compared with those without disease activity (60.7%).

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.

Structural equation modeling of factors contributing to quality of life in Japanese patients with multiple sclerosis.

BACKGROUND: To improve quality of life (QOL) in patients with multiple sclerosis (MS), it is important to decrease disability and prevent relapse. The aim of this study was to examine the causal and mutual relationships contributing to QOL in Japanese patients with MS, develop path diagrams, and explore interventions with the potential to improve patient QOL. METHODS: Data of 163 Japanese MS patients were obtained using the Functional Assessment of MS (FAMS) and Nottingham Adjustment Scale-Japanese version (NAS-J) tests, as well as four additional factors that affect QOL (employment status, change of income, availability of disease information, and communication with medical staff). Data were then used in structural equation modeling to develop path diagrams for factors contributing to QOL. RESULTS: The Expanded Disability Status Scale (EDSS) score had a significant effect on the total FAMS score. Although EDSS negatively affected the FAMS symptom score, NAS-J subscale scores of anxiety/depression and acceptance were positively related to the FAMS symptom score. Changes in employment status after MS onset negatively affected all NAS-J scores. Knowledge of disease information improved the total NAS-J score, which in turn improved many FAMS subscale scores. Communication with doctors and nurses directly and positively affected some FAMS subscale scores. CONCLUSIONS: Disability and change in employment status decrease patient QOL. However, the present findings suggest that other factors, such as acquiring information on MS and communicating with medical staff, can compensate for the worsening of QOL.

[Recent prognosis on etiology and pathophysiology of multiple sclerosis].

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. MS is characterized by axonal degeneration and glial scarring, and the formation of MS lesions is complex, involving cytokines, chemokines, and immunoglobulins. Environmental and genetic risk factors are clearly involved in the occurrence of MS although its etiology and pathophysiology are incompletely understood. In recent genetic studies on MS, approaches of genome-wide association study have been applied, and the several susceptibility genes of MS have been reported. Recent immunological studies have revealed the importance of IL-17 and Th17 cells in the pathogenesis of MS. This review discusses recent findings on etiology and pathophysiolosy of MS.

The prevalence and incidence of multiple sclerosis over the past 20 years in northern Japan.

OBJECTIVES: The prevalence of multiple sclerosis (MS) in East Asia is thought to be lower than in Western countries. Globally, there is a trend of increasing MS prevalence. We investigated the changes in the prevalence and clinical phenotype of MS in the Tokachi province of Hokkaido in northern Japan, from 2001 to 2021. METHODS: Data processing sheets were sent to all related institutions inside and outside the Tokachi area of Hokkaido island in Japan and were collected from April to May 2021. The prevalence according to the Poser's diagnostic criteria for MS was determined on March 31, 2021. RESULTS: In 2021, the crude MS prevalence in northern Japan was 22.4/100,000 (95% confidence interval, 17.6-28.0). The prevalences of MS standardized by the Japanese national population in 2001, 2006, 2011, 2016, and 2021 were 6.9, 11.5, 15.3, 18.5, and 23.3, respectively. The female/male ratio was 4.0 in 2021, increased from 2.6 in 2001. We checked the prevalence using the 2017 revised McDonald criteria, and found only additional male patient who had not fulfilled Poser's criteria. The age- and sex-adjusted incidence of MS per 100,000 individuals increased from 0.09 in 1980-1984 to 0.99 in 2005-2009; since then, it has remained stable. The proportions of primary-progressive, relapsing-remitting, and secondary-progressive MS types in 2021 were 3%, 82%, and 15%, respectively. CONCLUSION: Our results demonstrated a consistent increase in the prevalence of MS among the northern Japanese over 20 years, particularly in females, and consistently lower rates of progressive MS in northern Japan than elsewhere in the world.

[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.

Processing speed test: Results from a Japanese normative sample of healthy participants compared with a US normative sample.

BACKGROUND: The Processing Speed Test (PST), a validated iPad®-based cognitive screening test for MS, has been applied to the cognitive assessment of Japanese MS patients using US normative data. METHODS: To develop PST normative data from Japanese healthy volunteers and compare the PST score distribution between Japanese and US healthy volunteers, 254 healthy Japanese-speaking volunteers were enrolled and stratified by age (20-65 years). Potential participants with a Mini-Mental State Examination score < 27 were excluded. PST raw scores (total correct) were from the Japan cohort and compared with age-restricted US normative data and propensity score-matched data created by matching sex, age, and educational level from a published study of 428 healthy participants. PST score distributions and standardized z-scores were compared using t-test and Kolmogorov-Smirnov test statistics. RESULTS: The mean age of the Japan cohort was 44.1 years. The PST scores of Japanese volunteers were significantly different from those of the age-restricted (mean ± SD 61.8 ± 10.1 vs 53.7 ± 10.8; p < 0.001) and the propensity score-matched US cohort (62.1 ± 10.1 vs 53.3 ± 10.6; p < 0.001). CONCLUSION: Regression analyses centered on US normative data could underestimate disease severity in Japanese MS patients, suggesting that separate normative data should be considered for each population sample.

Health-related quality of life in Japanese patients with multiple sclerosis.

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.