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Balance impairment is frequent in people with multiple sclerosis (pwMS) and affects risk of falls and quality of life. By using inertial measurement units (IMUs) on the Single Leg Stance Test (SLS) we aimed to discriminate healthy controls (HC) from pwMS and detect differences in balance endurance and quality. Thirdly, we wanted to test the correlation between instrumented SLS parameters and selfreported measures of gait and balance. Fifty-five pwMS with mild (EDSS<4) and moderate disability (EDSS≥4) and 20 HC performed the SLS with 3 IMUs placed on the feet and sacrum and filled the Twelve Item Multiple Sclerosis Walking Scale (MSWS-12) questionnaire. A linear mixed model was used to compare differences in the automated balance measures. Balance duration was significantly longer in HC compared to pwMS (p  <  0.001) and between the two disability groups (p  <  0.001). Instrumented measures identified that trunk stability (normalized mediolateral and antero-posterior center of mass stability) had the strongest association with disability (R² marginal 0.30, p  <  0.001) and correlated well with MSWS-12 (R  =  0.650, p  <  0.001). PwMS tended to overestimate own balance compared to measured balance duration. The use of both self-reported and objective assessments from IMUs can secure the follow-up of balance in pwMS. [ABSTRACT FROM AUTHOR]

The aim of this work was to determine whether wearable inertial measurement units (IMUs) could detect gait improvements across different disability groups of people with Multiple Sclerosis (pwMS) by the six-minute walk test (6MWT) during a rehabilitation stay in a specialized rehabilitation center. Forty-six pwMS and 20 healthy controls (HC) were included in the study. They performed the 6MWT with two inertial measurement units (IMUs) placed on the feet. Thirty-two of the pwMS were retested at the end of the stay. PwMS were divided in a mild-disability and a moderate-disability group. The 6MWT was divided in six sections of 1 min each for technical analysis, and linear mixed models were used for statistical analyses. The comparison between the two disability groups and HC highlighted significant differences for each gait parameter (all p < 0.001). The crossing effect between the test–retest and the two disability groups showed greater improvement for the moderate-disability group. Finally, the gait parameter with the higher effect size, allowing the best differentiation between the disability groups, was the foot flat ratio (R2 = 0.53). Gait analyses from wearable sensors identified different evolutions of gait patterns during the 6MWT in pwMS with different physical disability. The measured effect of a short-time rehabilitation on gait with 6MWT was higher for pwMS with higher degree of disability. Using IMUs in a clinical setting allowed to identify significant changes in inter-stride gait patterns. Wearable sensors and key parameters have the potential as useful clinical tools for focusing on gait in pwMS. [ABSTRACT FROM AUTHOR]

Background: Moderate and high efficacy disease modifying therapies (DMTs) have a profound effect on disease activity. The current treatment guidelines only recommend high efficacy DMTs for patients with highly active MS. The objective was to examine the impact of initial treatment choice in achieving no evidence of disease activity (NEDA) at year 1 and 2. Methods: Using a real-world population-based registry with limited selection bias from the southeast of Norway, we determined how many patients achieved NEDA on moderate and high efficacy DMTs. Results: 68.0% of patients who started a high efficacy DMT as the first drug achieved NEDA at year 1 and 52.4% at year 2 as compared to 36.0 and 19.4% of patients who started a moderate efficacy DMT as a first drug. The odds ratio (OR) of achieving NEDA on high efficacy drugs compared to moderate efficacy drugs as a first drug at year 1 was 3.9 (95% CI 2.4–6.1, p < 0.001). The OR for high efficacy DMT as the second drug was 2.5 (95% CI 1.7–3.9, p < 0.001), and was not significant for the third drug. Patients with a medium or high risk of disease activity were significantly more likely to achieve NEDA on a high efficacy therapy as a first drug compared to moderate efficacy therapy as a first drug. Conclusions: Achieving NEDA at year 1 and 2 is significantly more likely in patients on high-efficacy disease modifying therapies than on moderate efficacy therapies, and the first choice of treatment is the most important. The immunomodulatory treatment guidelines should be updated to ensure early, high efficacy therapy for the majority of patients diagnosed with MS. [ABSTRACT FROM AUTHOR]

Objectives: Over the past few decades, there has been an improvement in the rate of disability progression in multiple sclerosis (MS) patients, and most studies relate this evolvement to the introduction of disease-modifying therapies. However, several other factors have changed over this period, including access to MRI and newer diagnostic criteria. The aim of this study is to investigate changes in the natural course of MS over time in a near-complete and geographically well-defined population from the south-east of Norway. Methods: We examined disease progression and demographics over two decades and assessed the effect of disease-modifying therapies using linear mixed-effect models. Results: In a cohort of 2097 patients, we found a significant improvement in disability as measured by the Expanded Disability Status Scale (EDSS) stratified by age, and the improvement remained significant after adjusting for time on disease-modifying medications, gender and progressive MS at onset. The time from disease onset to EDSS 6 in the total cohort was 29.8 years (95% CI 28.5–31.1) and was significantly longer in patients diagnosed after 2006 compared to patients diagnosed before. There are significant differences between patient demographics, as well as time to EDSS 6, in the near-complete, geographically well-defined population compared to an additional cohort from the capital Oslo and its suburbs. Conclusion: The natural course of MS is improving, but the improvement seen in disease progression has multifaceted explanations. Our study underlines the importance of completeness of data, relevant timeframes and demographics when comparing different MS populations. Studies on incomplete populations should be interpreted with caution. [ABSTRACT FROM AUTHOR]

DNA methylation is an epigenetic mark that is influenced by environmental factors and is associated with changes to gene expression and phenotypes. It may link environmental exposures to disease etiology or indicate important gene pathways involved in disease pathogenesis. We identified genomic regions that are differentially methylated in T cells of patients with relapsing remitting multiple sclerosis (MS) compared to healthy controls. DNA methylation was assessed at 450,000 genomic sites in CD4+ and CD8+ T cells purified from peripheral blood of 94 women with MS and 94 healthy women, and differentially methylated regions were identified using bumphunter. Differential DNA methylation was observed near four loci: MOG/ZFP57, HLA-DRB1, NINJ2/LOC100049716, and SLFN12. Increased methylation of the first exon of the SLFN12 gene was observed in both T cell subtypes and remained present after restricting analyses to samples from patients who had never been on treatment or had been off treatment for more than 2.5 years. Genes near the regions of differential methylation in T cells were assessed for differential expression in whole blood samples from a separate population of 1,329 women with MS and 97 healthy women. Gene expression of HLA-DRB1, NINJ2, and SLFN12 was observed to be decreased in whole blood in MS patients compared to controls. We conclude that T cells from MS patients display regions of differential DNA methylation compared to controls, and corresponding gene expression differences are observed in whole blood. Two of the genes that showed both methylation and expression differences, NINJ2 and SLFN12, have not previously been implicated in MS. SLFN12 is a particularly compelling target of further research, as this gene is known to be down-regulated during T cell activation and up-regulated by type I interferons (IFNs), which are used to treat MS. [ABSTRACT FROM AUTHOR]

Background: Although disability is considered the main cause of low bone mineral density (BMD) in multiple sclerosis (MS), other factors related to the disease process or treatment could also be involved. The aim of this study was to assess whether patients with MS are more likely to develop low BMD (osteopenia or osteoporosis) than patients with the non-inflammatory neurological diseases Hereditary Spastic Paraplegia (HSP) and Hereditary Ataxia (HA). Methods: We performed a case control study comparing BMD (spine, hip and total body) and biochemical measures of bone metabolism in 91 MS patients and 77 patients with HSP or HA, matched for age, gender and disability. Both patient groups had lived with the disease for at least 10 years. Results: In total 74.7% of the patients with MS and 75.3% of the patients with HSP or HA had osteopenia (-2.5 < T- score < -1.0) or osteoporosis (T- score≤-2.5) in one or more sites. Osteoporosis was more common in patients with MS than with HSP/HA (44.0 vs 20.8%, p =0.001). This difference was not significant after correction for confounders (p = 0.07), nor were any of the biochemical markers. Conclusion: Most patients with disabling neurological diseases like MS and HSP/HA develop osteopenia or osteoporosis. MS patients had osteoporosis more frequently than HA/HSP patients, though the difference was not significant after adjusting for confounders. Osteoporosis and bone health should be considered in all patients with both inflammatory and degenerative chronic neurological diseases. [ABSTRACT FROM AUTHOR]

Background Several environmental exposures, including infection with Epstein-Barr virus, low levels of vitamin D and smoking are established risk factors for multiple sclerosis (MS). Also, high hygienic standard and infection with parasites have been proposed to influence MS risk. The aim of this study was to investigate the influence of various environmental exposures on MS risk in a Norwegian cohort, focusing on factors during childhood related to the hygiene hypothesis. Methods A questionnaire concerning environmental exposures, lifestyle, demographics and comorbidity was administrated to 756 Norwegian MS patients and 1090 healthy controls. Logistic regression was used to calculate odds ratio (OR) with 95% confidence interval (CI) for the risk of MS associated with the variables infectious mononucleosis, severe infection during childhood, vaccination and animals in the household during childhood. Age, gender, HLA-DRB1*15:01, smoking and infectious mononucleosis were included as covariates. General environmental exposures, including tobacco use, were also evaluated. Results Infectious mononucleosis was confirmed to be significantly associated with increased MS risk, also after adjusting for the covariates (OR = 1.79, 95% CI: 1.12-2.87, p = 0.016). The controls more often reported growing up with a cat and/or a dog in the household, and this was significant for ownership of cat also after adjusting for the covariates (OR = 0.56, 95% CI: 0.40-0.78, p = 0.001). More patients than controls reported smoking and fewer patients reported snuff use. Conclusions In this Norwegian MS case-control study of environmental exposures, we replicate that infectious mononucleosis and smoking are associated with increased MS risk. Our data also indicate a protective effect on MS of exposure to cats during childhood, in accordance with the hypothesis that risk of autoimmune diseases like MS may increase with high hygienic standard. [ABSTRACT FROM AUTHOR]

Background: Low bone mass is prevalent in ambulatory multiple sclerosis (MS) patients even shortly after clinical onset. The mechanism is not known, but could involve shared etiological risk factors between MS and low bone mass such as hypovitaminosis D operating before disease onset, or increased bone loss after disease onset. The aim of this study was to explore the mechanism of the low bone mass in early-stage MS patients. Methodology/Principal Findings: We performed a population-based case-control study comparing bone turnover (cross-linked N-terminal telopeptide of type 1 collagen; NTX, bone alkaline phosphatase; bALP), metabolism (25-hydroxy- and 1, 25-dihydroxyvitamin D, calcium, phosphate, and parathyroid hormone), and relevant lifestyle factors in 99 patients newly diagnosed with clinically isolated syndrome (CIS) or MS, and in 159 age, sex, and ethnicity matched controls. After adjustment for possible confounders, there were no significant differences in NTX (mean 3.3; 95% CI -6.9, 13.5; p = 0.519), bALP (mean 1.6; 95% CI -0.2, 3.5; p = 0.081), or in any of the parameters related to bone metabolism in patients compared to controls. The markers of bone turnover and metabolism were not significantly correlated with bone mass density, or associated with the presence of osteoporosis or osteopenia within or between the patient and control groups. Intake of vitamin D and calcium, reported UV exposure, and physical activity did not differ significantly. Conclusions/Significance: Bone turnover and metabolism did not differ significantly in CIS and MS patients with prevalent low bone mass compared to controls. These findings indicate that the bone deficit in patients newly diagnosed with MS and CIS is not caused by recent acceleration of bone loss, and are compatible with shared etiological factors between MS and low bone mass. [ABSTRACT FROM AUTHOR]

Hypovitaminosis D may play a role in multiple sclerosis (MS), but little is known about intrathecal vitamin D. 25-Hydroxyvitamin D was measured in cerebrospinal fluid and sera from 36 patients with relapsing-remitting MS, 20 patients with other inflammatory neurological diseases and 18 patients with non-inflammatory neurological diseases with liquid chromatography-mass spectrometry. There were no significant differences in cerebrospinal fluid concentrations of 25-hydroxyvitamin D, but the cerebrospinal fluid : serum ratio was significantly lower in MS compared with other inflammatory neurological diseases (p = 0.0012) and non-inflammatory neurological diseases (p = 0.041) patients. The concentrations of 25-hydroxyvitamin D in cerebrospinal fluid and serum were positively correlated and their ratio was similar to that of albumin. Neither the concentrations of 25-hydroxyvitamin D in cerebrospinal fluid or serum nor their ratio were associated with the presence of relapses or gadolinium-enhanced lesions. These results do not support that 25-hydroxyvitamin D is actively transported to the cerebrospinal fluid, or that the cerebrospinal fluid or serum levels or their ratio exert a major impact on MS activity. [ABSTRACT FROM AUTHOR]

Background: Diagnostic criteria for multiple sclerosis have been developed to guide the diagnostic process. In the latest revision of the McDonald criteria, the presence of oligoclonal bands may replace the need for dissemination in time. The aim of this study is to investigate if the less time-consuming analysis of immunoglobulin G index in cerebrospinal fluid can safely predict the findings of oligoclonal bands. Methods: This is a retrospective study of patients with multiple sclerosis at three hospitals in South-East Norway where lumbar puncture is performed routinely. We included patients diagnosed with multiple sclerosis after 2005 with known oligoclonal band status and an immunoglobulin G index score. Results: Of 1295 patients diagnosed during or after 2005, 93.8% were oligoclonal band positive at diagnosis. Of 842 multiple sclerosis patients with known immunoglobulin G index and oligoclonal band status, 93.3% were oligoclonal band positive and 76.7% had an elevated immunoglobulin G index. The positive predictive value of a high immunoglobulin G index when oligoclonal bands are positive was 99.4% (95% confidence interval 98.4–99.8%). The negative predictive value of a normal immunoglobulin G index when oligoclonal bands are negative was 26.5% (95% confidence interval 23.5–29.9%). Conclusion: An immunoglobulin G index >0.7 has a positive predictive value >99% for oligoclonal bands. An elevated immunoglobulin G index adds diagnostic value versus oligoclonal bands and saves time in the diagnostic process. [ABSTRACT FROM AUTHOR]

Background: Although disability is considered the main cause of low bone mineral density (BMD) in multiple sclerosis (MS), other factors related to the disease process or treatment could also be involved. The aim of this study was to assess whether patients with MS are more likely to develop low BMD (osteopenia or osteoporosis) than patients with the non-inflammatory neurological diseases Hereditary Spastic Paraplegia (HSP) and Hereditary Ataxia (HA). Methods: We performed a case control study comparing BMD (spine, hip and total body) and biochemical measures of bone metabolism in 91 MS patients and 77 patients with HSP or HA, matched for age, gender and disability. Both patient groups had lived with the disease for at least 10 years. Results: In total 74.7% of the patients with MS and 75.3% of the patients with HSP or HA had osteopenia (-2.5 < T- score < -1.0) or osteoporosis (T- score ≤ -2.5) in one or more sites. Osteoporosis was more common in patients with MS than with HSP/HA (44.0 vs 20.8%, p =0.001). This difference was not significant after correction for confounders (p = 0.07), nor were any of the biochemical markers. Conclusion: Most patients with disabling neurological diseases like MS and HSP/HA develop osteopenia or osteoporosis. MS patients had osteoporosis more frequently than HA/HSP patients, though the difference was not significant after adjusting for confounders. Osteoporosis and bone health should be considered in all patients with both inflammatory and degenerative chronic neurological diseases. [ABSTRACT FROM AUTHOR]

Background: Several environmental exposures, including infection with Epstein-Barr virus, low levels of vitamin D and smoking are established risk factors for multiple sclerosis (MS). Also, high hygienic standard and infection with parasites have been proposed to influence MS risk. The aim of this study was to investigate the influence of various environmental exposures on MS risk in a Norwegian cohort, focusing on factors during childhood related to the hygiene hypothesis.Methods: A questionnaire concerning environmental exposures, lifestyle, demographics and comorbidity was administrated to 756 Norwegian MS patients and 1090 healthy controls. Logistic regression was used to calculate odds ratio (OR) with 95% confidence interval (CI) for the risk of MS associated with the variables infectious mononucleosis, severe infection during childhood, vaccination and animals in the household during childhood. Age, gender, HLA-DRB1*15:01, smoking and infectious mononucleosis were included as covariates. General environmental exposures, including tobacco use, were also evaluated.Results: Infectious mononucleosis was confirmed to be significantly associated with increased MS risk, also after adjusting for the covariates (OR = 1.79, 95% CI: 1.12-2.87, p = 0.016). The controls more often reported growing up with a cat and/or a dog in the household, and this was significant for ownership of cat also after adjusting for the covariates (OR = 0.56, 95% CI: 0.40-0.78, p = 0.001). More patients than controls reported smoking and fewer patients reported snuff use.Conclusions: In this Norwegian MS case-control study of environmental exposures, we replicate that infectious mononucleosis and smoking are associated with increased MS risk. Our data also indicate a protective effect on MS of exposure to cats during childhood, in accordance with the hypothesis that risk of autoimmune diseases like MS may increase with high hygienic standard. [ABSTRACT FROM AUTHOR]