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Background: Neoehrlichia mikurensis infections can cause symptomatic disease, particular among immunosuppressed persons. Long-lasting asymptomatic carriage of N. mikurensis may be common in endemic areas. This study explores possible associations between carriage of N. mikurensis DNA and persistent health complaints in persons who attribute their symptoms to a tick-borne disease., Methods: Eleven persons tested positive for N. mikurensis DNA by PCR in a study cohort of 285 persons reporting persistent health complaints. The 11 persons were tested again in a follow-up sample. Oral doxycycline treatment was given if the confirmatory PCR-test was positive. Treatment response was assessed by telephone interview. Demographics, clinical manifestations, tick exposure, physical health, somatic symptom burden and fatigue were compared to persons with negative N. mikurensis PCR (controls, N = 274)., Results: Six persons had detectable N. mikurensis DNA in a follow-up sample up to 9.5 months after the index sample. Seven persons (one without a positive confirmative test) received doxycycline treatment. Three reported symptom restitution after completed antibiotic treatment. However, their symptoms were not clearly attributed to infection by N. mikurensis. We did not find any significant differences between infected persons and non-infected controls regarding their clinical manifestations and health burdens., Conclusions: We corroborate previous evidence of long-term carriage of N. mikurensis, but cannot infer that to be causative of persistent health complaints., Competing Interests: Declaration of competing interest None, (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objective: To study the age at onset of relapsing-remitting multiple sclerosis (RRMS) during the past century., Methods: This is a population-based cohort study of persons diagnosed with RRMS in Hordaland, Møre, and Romsdal counties, Western Norway, from 1920 to 2022. Individual patient data were available and assessed from previously conducted prevalence and incidence studies in addition to hospital records up until October 31, 2022. Participants were categorized according to onset period and analyzed for temporal trends in age at onset, time from onset to diagnosis, and distribution of onset over time., Results: We identified 3364 persons with confirmed RRMS. The mean age at onset significantly increased (p < 0.001) throughout the study period, despite a decrease in time from symptom onset to diagnosis (p < 0.001). The proportion of persons with MS onset after 50 years of age increased from 2.6% before 1970 to 11.9% after 2010. We also found a trend toward a bimodal distribution of age at onset that peaked at around 30 years and 40-45 years of age in the latest period., Conclusion: Age at onset of MS significantly increased throughout the study period. This was mainly due to an increasing number of persons with MS, predominantly female, experiencing onset after 40-45 years of age. This bimodal distribution could indicate different susceptibility periods of MS or changes in exposure to risk factors during the observation period., (© 2023. The Author(s).)

Background: Cancer is a major cause of death, but how cancer influences mortality risk in Multiple Sclerosis (MS) is unclear., Objectives: Determine all-cause mortality and mortality following a cancer diagnosis among MS patients compared with matched population controls., Methods: Norwegian MS patients born 1930 - 1979 (n= 6950) followed-up 1953 - 2016, were matched with 37 922 controls. We compared incident cancer diagnosis from the Cancer Registry of Norway, date of death from the Cause of Death Registry, education from the National Education Database, by multivariate Cox proportional hazard regression., Results: Hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality among MS patients was 4.97 (4.64 - 5.33), and 2.61 (2.29 - 2.98) for mortality following a cancer diagnosis. Mortality in MS was highest following urinary- (2.53: 1.55 - 4.14), colorectal- (2.14: 1.47 - 3.11), hematological- (1.76: 1.08 - 2.88), ovarian - 2.30 (1.73-3.06) and breast cancer diagnosis (2.61: 1.85 - 3.68), compared to controls. High education was inversely associated with mortality among MS patients., Conclusions: All-cause mortality was five- fold and mortality following a cancer diagnosis was two- fold increased among MS patients. Mortality following specific cancers raises the possibility of diagnostic neglect., Competing Interests: Competing interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N.G., T.R., J.H.A., A.V., R.M., and E.B. reports no disclosures. K.M.M. reports grants or personal fees from Biogen, Novartis, Roche, Teva and Sanofi, outside the submitted work. E.G.C. reports grants or personal fees from Almirall, Biogen, Merck, Novartis, Roche, Sanofi Genzyme and Teva, outside the submitted work. Ø.T. reports personal fees from Biogen, Merck, Sanofi, Roche, and Teva, outside the submitted work., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Persons with multiple sclerosis (pwMS) have higher risk of mortality compared with the general population. Longitudinal studies are important for understanding the evolution of survival in pwMS., Objective: Examine changes in mortality among pwMS during the past seven decades., Methods: We followed pwMS from Hordaland and Møre and Romsdal in Western Norway, with disease onset from before 1950, identified from population-based epidemiological surveys and the Norwegian MS Registry and Biobank, until 1 January 2021. Data were linked to the Norwegian Cause of Death Registry to obtain underlying cause of death. We examined all-cause, and cause-specific mortality using standardised mortality ratios (SMR) and excess death rates (EDR). We calculated life expectancies and assessed survival stratified by sex, age and disease phenotype at onset. We compared hazard ratios (HRs) for mortality, in pwMS diagnosed before and after the era of disease-modifying treatment (DMT)., Results: Of 3624 pwMS, 964 (55.5% women) had died, predominantly of multiple sclerosis (49.0%). Median life expectancy for pwMS was 74.3 years (95% CI 73.3 to 75.3), compared with 83.1 years for the general population (p<0.001). From disease onset, pwMS survived 14.6 years shorter than the general population (p<0.001). Overall, SMR was 2.3 (95% CI 2.13 to 2.42) and EDR was 6.8 (95% CI 6.42 to 7.09) for pwMS. Treatment-eligible pwMS diagnosed in the DMT era had the lowest risk of mortality, HR 0.49 (95% CI 0.34 to 0.70,p<0.001)., Conclusion: Excess mortality among pwMS declined during the past seven decades, possibly due to improved diagnostics, better symptomatic treatment and access to DMTs., Competing Interests: Competing interests: JSW reports personal fees from Biogen Idec, NG, JHA, RM and TÅM report no disclosures. K-MM reports grants and personal fees from Biogen Idec and Novartis; personal fees from Genzyme, Roche, Almirall, and Merck; personal fees and nonfinancial support from Teva, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: The relationship between smoking, long-term brain atrophy, and clinical disability in patients with multiple sclerosis (MS) is unclear. Here, we assessed long-term effects of smoking by evaluating MRI and clinical outcome measures after 10 years in smoking and nonsmoking patients with relapsing-remitting MS (RRMS)., Methods: We included 85 treatment-naive patients with RRMS with recent inflammatory disease activity who participated in a 10-year follow-up visit after a multicenter clinical trial of 24 months. Smoking status was decided for each patient by 2 separate definitions: by serum cotinine levels measured regularly for the first 2 years of the follow-up (during the clinical trial) and by retrospective patient self-reporting. At the 10-year follow-up visit, clinical tests were repeated, and brain atrophy measures were obtained from MRI using FreeSurfer. Differences in clinical and MRI measurements at the 10-year follow-up between smokers and nonsmokers were investigated by 2-sample t tests or Mann-Whitney tests and linear mixed-effect regression models. All analyses were conducted separately for each definition of smoking status., Results: After 10 years, smoking (defined by serum cotinine levels) was associated with lower total white matter volume (β = -21.74, p = 0.039) and higher logT2 lesion volume (β = 0.22, p = 0.011). When defining smoking status by patient self-reporting, the repeated analyses found an additional association with lower deep gray matter volume (β = -2.35, p = 0.049), and smoking was also associated with a higher score (higher walking impairment) on the log timed 25-foot walk test (β = 0.050, p = 0.039) after 10 years and a larger decrease in paced auditory serial addition test (attention) scores (β = -3.58, p = 0.029)., Discussion: Smoking was associated with brain atrophy and disability progression 10 years later in patients with RRMS. The findings imply that patients should be advised and offered aid in smoking cessation shortly after diagnosis, to prevent long-term disability progression., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in multiple sclerosis (MS) is still unclear., Objective: Investigate the relation between sNfL levels over a 2-year period in patients with relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years., Methods: 85 patients, originally enrolled in a multicentre, randomised trial of ω-3 fatty acids, participated in a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24. The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained using FreeSurfer., Results: Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or recently present) predicted lower total (β=-0.399, p=0.040) and deep (β=-0.556, p=0.010) GM volume, lower mean cortical thickness (β=-0.581, p=0.010) and higher T2 lesion count (β=0.498, p=0.018). Of the clinical outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant hand Nine-Hole Peg Test (β=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions present or recently present) did not predict GM atrophy or disability progression., Conclusion: Higher sNfL levels during periods of active inflammation predicted more GM atrophy and specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM atrophy is mainly due to neuroaxonal degradation within new lesions., Competing Interests: Competing interests: The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. AB, SG, GK, YSS, KNV and CAV declares no disclosures relevant to the manuscript. IAL has received research grants from the Meltzer Research Fund, Gerda Meyer Nyquist Guldbrandson & Gert Meyer Nyquists Legat and the Independent Order of Odd Fellows. KW has received unrestricted research grants from Novartis and Biogen, research grant from the Independent Order of Odd Fellows and speaker honoraria from Biogen. IB has received research support from Merck KGaA, Novartis, and Teva. SW has received speaker honoraria from and served on scientific advisory boards for Biogen, Janssen-Cilag, Sanofi and Novartis. SSK received unrestricted research grants from Novartis, Biogen. TH has received speaker honoraria, research support/grants and participated in clinical trials for Biogen, Merck, Sanofi, Bristol Myers Squibb, Roche and Novartis, is member of the scientific board of the Norwegian MS society, and has received financial support from the Research Council of Norway (grant #250864). RM has served on scientific advisory boards for Novartis Norway and Merck and received travel funding and/or speaker honoraria from Biogen, Novartis and Sanofi Genzyme. AE has received speaker honoraria from Biogen, Merck, Sanofi and Novartis. RE has received speaker honoraria from Novartis. HFH has received speaker honoraria from Biogen, Sanofi-Aventis, Merck, Novartis, and Roche. NØ has received speaker honoraria from Biogen, participated in clinical trials for Biogen and Sanofi-Aventis, and has served on a scientific advisory board for Novartis. FB has received compensation for steering/safety committee, activities and consulting services from Roche, Biogen, Merck, Combinostics, Janssen and IXICO. He is co-founder and shareholder of Queen Square Analytics. CET has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, PeopleBio, Roche, Toyama, Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book Springer. LB has received unrestricted research grants to his institution and/or scientific advisory board or speaker honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Roche and Teva; and has participated in clinical trials organized by Biogen, Merck, Novartis, Roche, and Genzyme. ØT has received research grants and speaker honoraria from Biogen, Roche, Novartis, Merck and Sanofi. KMM has received unrestricted research grants to his institution; scientific advisory board, or speaker honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, and Teva; and has participated in clinical trials organized by Biogen, Merck, Novartis, and Roche. HV has received research grants from Pfizer, Merck Serono, Novartis and Teva; speaker honoraria from Novartis; and consulting fees from Merck Serono; all funds were paid directly to his institution., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Whether disease-modifying therapies (DMTs) influence cancer in multiple sclerosis (MS) is uncertain., Objectives: Assess incidence of cancer diagnosis among Norwegian MS patients compared to the general population in 1953 to 1995 and 1996 to 2017-reflecting era before and after introduction of DMTs., Methods: We performed a nationwide cohort study comprising 6949 MS patients and 37,922 controls, matched on age, sex and county. The cohort was linked to Norwegian Cancer Registry, Cause of Death Registry and National Educational database. We used Poisson regression to calculate incidence rate ratio (IRR) of cancer., Results: During 1953-1995 MS patients had similar cancer frequency compared to controls (IRR: 1.11 (95% Confidence Intervals (CI): 0.90-1.37)), although MS patients had increased frequency of cancer in endocrine glands (IRR: 2.51 (1.27-4.93). During 1996-2017 we identified significant increased frequency of cancer among MS patients compared to controls (IRR: 1.38 (95% CI: 1.28-1.52): in brain (IRR: 1.97 (1.41-2.78)), meninges (IRR: 2.44 (1.54-3.77)), respiratory organs (IRR: 1.96 (1.49-2.63)). The excess cancer diagnosis was most frequent among MS patients ≥ 60 years of age (HR 1.30 (1.15-1.47))., Conclusion: Incidence of cancer among MS patients compared to controls was higher in 1996 to 2017, corresponding in time to the introduction of DMT for MS. This was observed more frequently among MS patients older than 60 years of age., (Copyright © 2021. Published by Elsevier B.V.)

Background: Low vitamin D levels, tobacco use and high body mass index (BMI) have been linked to adverse disease outcomes in multiple sclerosis (MS), but their influence on long-term disability progression remains unclear. Therefore, we explored whether these modifiable lifestyle factors were associated with 10-year clinical disability progression in patients with MS., Methods: In this prospective study, a cohort of 88 patients with relapsing-remitting MS completed a randomized controlled study on ω-3 fatty acids between 2004 and 2008. During 24 months, serum 25-hydroxyvitamin D (25(OH)D), serum cotinine (nicotine metabolite), and BMI were repeatedly measured. In 2017, a follow-up study was conducted among 80 of the participants, including disability assessment by the Expanded Disability Status Scale (EDSS). Linear regression was used to explore associations between the lifestyle factors and the EDSS change over 10 years., Results: Higher seasonally adjusted 25(OH)D levels were associated with lower 10-year EDSS progression (change in EDSS per 1 SD increase in 25(OH)D in a model adjusted for sex, age and baseline EDSS: -0.45 point, 95% CI: -0.75 to -0.16, p=0.003). Further adjustments for potential confounders related to lifestyle and disease status gave similar results. The association was mainly driven by low 25(OH)D levels during spring, as well as seasonally adjusted levels below 80 nmol/L. No clear association was found for BMI and cotinine., Conclusion: Lower 25(OH)D levels, but apparently not tobacco use or higher BMI, were significantly associated with worse long-term disability progression in MS., (Copyright © 2021. Published by Elsevier B.V.)

Background: Risk of cancer in multiple sclerosis (MS) patients compared to their siblings is unknown., Objective: The objective was to prospectively investigate the risk of cancer among MS patients compared to siblings without MS and to population controls., Methods: We retrieved data on MS patients born between 1930 and 1979 from the Norwegian Multiple Sclerosis Registry and population studies and on cancer diagnosis from the Cancer Registry of Norway. We used adjusted Cox proportional hazard regression to estimate cancer risk among 6883 MS patients, 8918 siblings without MS, and 37,919 population controls., Results: During 65 years of follow-up, cancer risk among MS patients was higher than that among population controls (hazard ratio (HR) = 1.14, 95% confidence interval (CI): 1.05-1.23) in respiratory organs (HR = 1.66, 95% CI: 1.26-2.19), urinary organs (HR = 1.51, 95% CI: 1.12-2.04), and the central nervous system (HR = 1.52, 95% CI: 1.11-2. 09). Siblings had higher risk of hematological cancers compared with MS patients (HR = 1.82, 95% CI: 1.21-2.73) and population controls (HR = 1.72, 95% CI: 1.36-2.18)., Conclusion: MS patients were associated with increased risk of cancer compared to population controls. Siblings had increased risk of hematological cancer. This indicates that MS and hematological cancer could share a common etiology.

Aim: To study the effect of cognitive function, fatigue and emotional symptoms on employment after a minor ischemic stroke compared to non-ST-elevation myocardial infarction (NSTEMI)., Material and Methods: We included 217 patients with minor ischemic stroke and 133 NSTEMI patients employed at baseline aged 18-70 years. Minor stroke was defined as modified Rankin scale (mRS) 0-2 at day seven or at discharge if before. Included NSTEMI patients had the same functional mRS. We applied a selection of cognitive tests and the patients completed questionnaires measuring symptoms of anxiety, depression and fatigue at follow up. Stroke patients were tested at three and 12 months and NSTEMI at 12 months., Results: The patients still employed at 12 monthswere significantly younger than the unemployed patients and the NSTEMI patients employed were significantly older than the stroke patients (59 vs 55 years, p < .001). In total, 82 % of stroke patients and 90 % of the NSTEMI patients employed at baseline were still employed at 12 months (p = 06). Stroke patients at work after 12 months had higher education than unemployed patients. There were no difference between employed and unemployed patients in risk factors or location of cerebral ischemic lesions. Cognitive function did not change significantly in the stroke patients from three to 12 months. For stroke patients, we found a significant association between HADS-depression and unemployment at 12 months (p = 04), although this association was not present at three months. Lower age and higher educational level were associated with employment at 12 months for all patients., Discussion and Conclusion: Age and education are the main factors influencing the ability to stay in work after a minor stroke. Employed stroke patients were younger than the NSTEMI patients, but there was no difference in the frequencies in remaining employed. The employment rate at 12 months was high despite the relatively high prevalence of cognitive impairment in both groups., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020. Published by Elsevier Inc.)

Objective: To determine prevalence and longitudinal trends in incidence of MS in Møre and Romsdal County, Western Norway, from 1950 to 2018., Methods: Retrospective longitudinal population-based observational study. All patients diagnosed, or living, with MS in Møre and Romsdal were identified as incident or prevalent cases from local, regional, and national sources. We compiled the data in the Norwegian Multiple Sclerosis Registry and Biobank and used the aggregated data set to calculate incidence and prevalence rates using population measures obtained from Statistics Norway., Results: On January 1, 2018, the estimated prevalence was 335.8 (95% CI, 314.1-358.5) per 100,000 inhabitants, with a female:male ratio of 2.3. From 1950 through 2017, we observed a considerable ( p < 0.001) increase in average annual incidence rates from 2.1 (95% CI, 1.3-3.3) to 14.4 (95% CI, 11.9-17.3) per 100,000. From 2005 through 2017, the incidence among women increased from 17.1 (95% CI, 14.0-20.7) to 23.2 (95% CI, 18.7-28.5) per 100,000, whereas the incidence among men declined from 10.3 (95% CI, 7.9-13.2) to 5.9 (95% CI, 3.4-8.8) per 100,000., Conclusion: Møre and Romsdal County in Western Norway has the highest prevalence of MS reported in Norway. The incidence has steadily increased since 1950, and during the latest 15 years, we observed opposing trends in sex-specific incidence rates., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: More than 80% of people with multiple sclerosis (MS) are affected by spasticity. Spasticity is known to reduce quality of life and contribute to additional symptoms, such as pain and reduced mobility, but the association between spasticity, balance, and mobility has not yet been established. Our aim was to examine whether a relationship exists between spasticity in the lower limbs, balance, and gait, as well as to explore the involvement of different muscle groups., Methods: This study employed a cross-sectional design. Thirty patients with MS were included. The Modified Ashworth Scale (MAS) was used to examine spasticity in the ankle plantar flexors, knee extensors, and hip adductors. Balance was measured using the Mini-Balance Evaluation Systems Test, and gait with the 2-Minute Walk Test. The participants were tested once with no additional follow-up. Spearman's correlation, recursive partitioning, and linear regression analyses were used to explore the association., Results: A significant correlation between gait distance and spasticity in the ankle plantar flexors (ρ = -.69, p < .001) and knee extensors (ρ = -.45, p = .012) was observed. Balance significantly correlated with spasticity in ankle plantar flexors (ρ = -.69, p < .001), knee extensors (ρ = -.52, p = .003), and hip adductors (ρ = -.5, p = .005). The relationship between spasticity in ankle plantar flexors and hip adductors was significant, even from low levels of spasticity, whereas MAS score ≥ 2 was clinically correlated with a decrease in gait and balance function. Adjustments for sex, age, or years since diagnosis had only minor impact on the results., Conclusions: This study indicates that spasticity in the lower limbs is clinically significantly associated with mobility in people with MS., (© 2019 The Authors. Physiotherapy Research International Published by John Wiley & Sons Ltd.)

Introduction: Patients with multiple sclerosis may have a distinct gut microbiota profile. Delayed-release dimethyl fumarate is an orally administered drug for relapsing-remitting multiple sclerosis, which has been associated with gastrointestinal side-effects in some patients., Objectives: The purpose of this study was to determine if dimethyl fumarate alters the abundance and diversity of commensal gut bacteria, and if these changes are associated with gastrointestinal side-effects., Methods: Thirty-six patients with relapsing-remitting multiple sclerosis received either dimethyl fumarate ( n  = 27) or an injectable multiple sclerosis disease-modifying therapy (glatiramer acetate or interferons, n  = 9) for 12 weeks. Stool samples were collected at baseline, two and 12 weeks. We included 165 healthy individuals as controls., Results: At baseline, 16 microbial genera were altered in multiple sclerosis patients compared with healthy controls. In the dimethyl fumarate-treated patients ( n  = 21) we observed a trend of reduced Actinobacteria ( p  = 0.03, Q FDR  = 0.24) at two weeks, mainly driven by Bifidobacterium ( p  = 0.06, Q FDR  = 0.69). At 12 weeks, we observed an increased abundance of Firmicutes ( p  = 0.02, Q FDR  = 0.09), mostly driven by Faecalibacterium ( p  = 0.01, Q FDR  = 0.48)., Conclusions: This pilot study did not detect a major effect of dimethyl fumarate on the gut microbiota composition, but we observed a trend towards normalization of the low abundance of butyrate-producing Faecalibacterium after 12 weeks treatment. The study was underpowered to link microbiota to gastrointestinal symptoms., (© The Author(s) 2019.)

Objectives: To study the development of cognitive and emotional symptoms between 3 and 12 months after a minor stroke., Material and Methods: We included patients from stroke units at hospitals in the Central Norway Health Authority and from Haukeland University Hospital. We administered a selection of cognitive tests, and the patients completed a questionnaire 3 and 12 months post-stroke. Cognitive impairment was defined as impairment of ≥2 cognitive tests., Results: A total of 324 patients completed the 3-month testing, whereas 37 patients were lost to follow-up at 12 months. The results showed significant improvement of cognitive function defined as impairment of ≥2 cognitive tests (P = .03) from months 3 to 12. However, most patients still showed cognitive impairment at 12 months with a prevalence of 35.4%. There is significant association between several of the cognitive tests and hypertension and smoking (P = .002 and .05). The prevalence of depression, but not anxiety, increased from 3 to 12 months (P = .04). The prevalence of fatigue did not change and was thus still high with 29.5% after 12 months., Conclusions: This study shows that an improvement of cognitive function still occurs between 3 and 12 months. Despite this, the prevalence of mostly minor cognitive impairment still remains high 12 months after the stroke. The increasing prevalence of depressive symptoms highlights the importance of being vigilant of depressive symptoms throughout the rehabilitation period. Furthermore, high prevalence of fatigue persisted., (© 2019 The Authors. Acta Neurologica Scandinavica Published by John Wiley & Sons Ltd.)

Background: The plant-based ω-3 fatty acid α-linolenic acid (ALA) has been associated with lower MS risk. It is currently unknown whether ALA affects disease activity., Objective: To investigate the association between ALA levels and disease activity., Methods: We conducted a cohort study including 87 multiple sclerosis (MS)-patients who originally participated in a randomized trial of ω-3 fatty acids (the OFAMS study). We measured serum levels of ALA during follow-up and used random intercept logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association between ALA levels, new magnetic resonance imaging (MRI) lesions, Expanded Disability Status Scale (EDSS) progression and new relapses adjusting for age at inclusion, sex, and use of interferon beta-1a., Results: In continuous (per 1-SD increase) multivariable-adjusted analyses, higher ALA levels were significantly associated with lower odds of new T2-lesions (OR: 0.59, 95% CI: 0.37-0.95) during follow-up. The effect estimates were similar for new T1Gd + lesions (OR: 0.73, 95% CI: 0.48-1.11), EDSS-progression (OR: 0.62, 95% CI: 0.34-1.16) and new relapses (OR: 0.49, 95% CI: 0.22-1.10), but these estimates did not reach statistical significance. Further adjustment for vitamin D and tobacco use did not materially change the results., Conclusion: We found that higher levels of ALA were associated with lower disease activity in MS-patients.

Aim: To study the prevalence of cognitive and emotional impairment following a minor ischemic stroke compared to an age-matched group with non-ST-elevation myocardial infarction (NSTEMI)., Methods: We included patients aged 18-70 years with a minor ischemic stroke defined as modified Rankin Scale (mRS) 0-2 at day 7 or at discharge if before and age-matched NSTEMI patients with the same functional mRS. We applied a selection of cognitive tests and the patients completed a questionnaire comprising of Hospital Anxiety and Depression scale (HADS) and Fatigue Severity Scale (FSS) at follow-up 12 months after the vascular event. Results of cognitive tests were also compared to normative data., Results: 325 ischemic stroke and 144 NSTEMI patients were included. There was no significant difference in cognitive functioning between ischemic stroke and NSTEMI patients. Minor stroke patients and to a lesser extent NSTEMI patients scored worse on more complex cognitive functions including planning and implementation of activities compared to validated normative data. For the minor stroke patients the location of the ischemic lesion had no influence on the result. The prevalence of anxiety, depression, and fatigue was significantly higher in the stroke group compared to the NSTEMI group. Depression was independently associated with reduced cognitive function., Discussion and Conclusion: Minor ischemic stroke patients, and to lesser degree NSTEMI patients, had reduced cognitive function compared to normative data, especially executive functioning, on 12-month follow-up. The difference in cognitive function between stroke and NSTEMI patients was not significant. Depression was associated with low scores on cognitive tests highlighting the need to adequately address emotional sequelae when considering treatment options for cognitive disabilities.

Adipokines secreted by fatty tissue have inflammatory properties and are suggested biomarkers of MS disease activity. To assess this, 88 MS patients were followed with nine repeated measurements of leptin and adiponectin and 12 magnetic resonance imaging (MRI) scans for two years; six months without any immunomodulatory treatment followed by 18 months during interferon-beta (IFNB) treatment. Serum levels of leptin dropped and adiponectin increased upon initiation of IFNB-therapy, but were not associated with clinical or MRI disease activity or with treatment response. Our findings indicate that leptin and adiponectin are not useful as biomarkers of MS disease activity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The conflicting results from studies on socioeconomic status (SES) and multiple sclerosis (MS) risk might be due to a change in the distribution of environmental exposures over time or to methodological limitations in previous research., Objective: To examine the association between SES and MS risk during 50 years., Methods: We included patients registered in Norwegian MS registries and prevalence studies born between 1930 and 1979, and identified their siblings and parents using the Norwegian Population Registry. Information on education was retrieved from the National Education Registry, categorized into four levels (primary, secondary, undergraduate and graduate) and compared in patients and siblings using conditional logistic regression., Results: A total of 4494 MS patients and 9193 of their siblings were included in the analyses. Level of education was inversely associated with MS risk ( p trend < 0.001) with an odds ratio (OR) of 0.73 (95% confidence interval (CI): 0.59-0.90) when comparing the highest and lowest levels. The effect estimates did not vary markedly between participants born before or after the median year of birth (1958), but we observed a significant effect modification by parental education ( p = 0.047)., Conclusion: Level of education was inversely associated with MS risk, and the estimates were similar in the earliest and latest birth cohorts., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EG Celius has received funding for travel, advice and speaker’s fees from Sanofi-Aventis, Merck-Serono, Genzyme, Biogen Idec, Roche, Teva, Almirall and Novartis, and received unrestricted research support from Biogen Idec and Novartis. KM Myhr has participated on scientific advisory boards for Novartis Norway, Biogen Idec, Genzyme and Roche; received funding for travel from Allergan, Bayer, Novartis, Merck-Serono and Biogen; received speaker honoraria from Allergan, Almirall, Bayer, Biogen, Genzyme, Novartis, Merck-Serono and Teva; and received unrestricted research support from Bayer, Genzyme, Novartis, Merck-Serono, Biogen, Pronova Biocare and Bergen and Norwegian MS Society. Ø Torkildsen has served on scientific advisory boards for Biogen Idec, Genzyme and Merck-Serono and received speaker honoraria and travel grants from Genzyme, Merck-Serono, Novartis and Biogen Idec.

Study Design: A randomized, controlled, single-center pilot study., Objective: The aim of this study was to investigate the feasibility of running a trial to explore if early intervention in individuals with chronic low back pain (CLBP) would lead to an early return to work (RTW) and reduce sick leave during 12 months of follow-up compared with patients on a 3-month waiting list., Summary of Background Data: Back pain is the reason for numerous absent days from work. In Norway, the government initiated a priority program, Earlier Return to Work (ERTW), to reduce work absences through early intervention. However, no proper evaluation has been performed on populations with CLBP. There is no consensus on how RTW should be measured. Only a few studies have examined how waiting time affects RTW., Methods: Fifty-eight patients were included in the study. The group with early intervention was examined within 2 weeks, and the group on the waiting list was examined after 12 weeks. The intervention was identical in both groups and consisted of an outpatient, intensive back school. The data were obtained by questionnaire after 3, 6, and 12 months. The primary outcome was absence from work., Results: The sample size in a full-scale study must comprise at least 382 patients on the basis of the assumptions in the pilot. In the pilot study, early intervention directly compared with an ordinary waiting list did not significantly affect the number of sick leave days after 12 months of follow-up., Conclusion: A prerequisite for launching a full-scale clinical trial is a redesign of the intervention, an improvement of procedures concerning inclusion and randomization, and finally a more precise definition of RTW., Level of Evidence: 3.

Objective: To prospectively investigate potential signs of preclinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort., Methods: We linked the cognitive performance of all Norwegian men born 1950-1995 who underwent conscription examination at age 18 to 19 years to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database. In this nested case-control study, cognitive test scores were available for 924 male cases and 19,530 male controls. We estimated mean score differences among cases and controls (Student t test) and the risk of developing MS comparing lower to higher scores (Cox regression) in strata of years to clinical onset., Results: Men developing first clinical MS symptoms up to 2 years after the examination scored significantly lower than controls (Δ = 0.80, p = 0.0095), corresponding to a 6 intelligence quotient (IQ)-point difference. Those scoring lowest, that is, >1 standard deviation below the controls' mean, had an increased MS risk during the 2 following years (relative risk = 2.81, 95% confidence interval = 1.52-5.20). Whereas results were similar for relapsing-remitting MS cases (RRMS), those developing primary-progressive MS (PPMS) scored a significant 4.6 to 6.9 IQ points lower than controls up to 20 years prior to first progressive symptoms., Interpretation: RRMS may start years prior to clinical presentation, and disease processes in PPMS could start decades prior to first apparent progressive symptoms. Cognitive problems could be present in both MS forms before apparent symptoms. Apart from potential implications for clinical practice and research, these findings challenge our thinking about the disease. Ann Neurol 2016;80:616-624., (© 2016 American Neurological Association.)

Objective: To study whether tobacco use is associated with MRI and clinical disease activity in patients with multiple sclerosis (MS)., Methods: Prospective cohort study of 87 patients with relapsing-remitting MS originally included in a randomized placebo-controlled trial of omega-3 fatty acids in MS (the OFAMS Study). Serum levels of cotinine (biomarker of tobacco use) were analyzed at baseline and every 6 months for 2 years. MRI activity was assessed at baseline and monthly for 9 months and after 12 and 24 months., Results: Fifty-three patients (61%) had serum cotinine levels ≥85 nmol/L on ≥60% of the measurements and were considered tobacco users and 34 (39%) had cotinine levels <85 nmol/L, consistent with non-tobacco use. There was no association between tobacco use and the occurrence of new gadolinium-enhancing T1 lesions, new or enlarging T2 lesions, or their aggregate (combined unique activity). Furthermore, there was no association between cotinine levels and MRI activity for the tobacco users, and tobacco users did not have more relapses or Expanded Disability Status Scale progression., Conclusion: Our results indicate that tobacco use does not directly influence MRI activity or relapse rate in MS. This may implicate that the reported association between smoking and MS disease progression could be mediated through other mechanisms.

Background and Purpose: Our objective was to study the association between serum levels of anti Epstein-Barr virus nuclear antigen 1 (EBNA-1) antibody and 25-hydroxyvitamin D (25(OH)D) in a prospective cohort of patients with relapsing-remitting multiple sclerosis., Method: The study comprised 90 patients with relapsing-remitting multiple sclerosis, all participants in a randomized clinical trial of ω-3 fatty acids (the OFAMS study). Repeated, paired measurements of serum 25(OH)D and serum EBNA-1 immunoglobulin G (IgG) levels were obtained at baseline and every 6 months for 24 months. The association between serum EBNA-1 IgG and serum 25(OH)D levels was analysed using generalized linear models for hierarchical data., Results: There was a significant variation in EBNA-1 IgG antibody level between sampling months (Fdf 11 = 1.8, P = 0.043, one-way anova). There was a negative association between EBNA-1 IgG and 25(OH)D [B = -0.230, 95% confidence interval (CI) (-0.440, -0.023), P = 0.030] and a positive association between EBNA-1 IgG and HLA-DRB1*15 positive status [B = 94.7, 95% CI (2.423, 186.9), P = 0.044]. The association between 25(OH)D and EBNA-1 IgG remained significant after adjusting for the patient's age, gender, HLA-DRB1*15, retinol levels and interferon β-1a treatment., Conclusion: Our study demonstrates monthly differences in EBNA-1 IgG levels and an association between EBNA-1 IgG, 25(OH)D levels and HLA-DRB1*15. These results indicate that EBNA-1 IgG serum levels are affected by genetic and environmental factors that also modulate multiple sclerosis risk., (© 2016 EAN.)

Background: It has been suggested that polymorphisms in the WT1 gene modulate the effect of IFN-β treatment in multiple sclerosis (MS) through regulation of the relationship between IFN-β and vitamin D., Objective: To examine whether WT1 modulates the relationship between IFN-β and vitamin D in a longitudinal study with repeated assessment of vitamin D before and after initiation of IFN-β., Methods: In a prospective study of 85 patients with relapsing remitting MS, 25-hydroxyvitamin D was measured at month 0, 1, 3, 6, 7, 9, 12, 18 and 24. None of the patients used any immunomodulatory treatment at inclusion, and all started IFN-β treatment at month 6., Results: The mean concentrations of seasonally adjusted 25-hydroxyvitamin increased slightly (3.1 ± 1.2 nmol/l, P = 0.008) after initiation of IFN-β. The association between IFN-β treatment and 25-hydroxyvitamin D was similar in patients carrying any of the two alleles in the WT1 SNPs (rs10767935 and rs5030244) recently reported to modulate this relationship., Conclusions: In this prospective study with repeated measurements of 25-hydroxyvitamin D before and during treatment with IFN-β, we did not find that genetic variation in WT1 plays any role in regulating the relationship between IFN-β and serum 25-hydroxyvitamin D., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Obesity is a possible risk factor of multiple sclerosis (MS), but the association between obesity and MS disease activity has not been explored. In a cohort of 86 MS patients, 80% of overweight or obese patients (BMI≥25kg/m(2)) had MRI activity compared to 48% of the normal-weight patients (BMI<25kg/m(2)) (p=0.001) during interferon-beta treatment. NEDA-status (no evidence of disease activity) was defined as a composite that consisted of absence of any relapses, sustained disability-progression and MRI-activity. Among normal-weight patients 26% obtained NEDA-status compared to only 13% of patients with BMI >25 (p=0.05). This may indicate that BMI affects interferon-beta treatment response., (Copyright © 2015 Elsevier B.V. All rights reserved.)

To explore if vitamin D modulates interferon-β1a treatment effects in relapsing-remitting multiple sclerosis, we examined relationships between serum vitamin D and magnetic resonance imaging (MRI) activity and ten systemic inflammation markers in 88 patients, before and during treatment. Odds ratios for all MRI parameters were negatively associated with vitamin D levels before therapy, but converged to equally low values irrespective of vitamin D status during treatment. During therapy, similar alterations of MRI activity and inflammation markers were found across patients categorized by mean vitamin D values. This suggests that vitamin D status has no major influence on interferon-β1a treatment effects., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Previous reports indicate an association between Epstein-Barr virus (EBV) antibody levels and multiple sclerosis (MS) disease activity, but the results have been conflicting., Objectives: The objective of this paper is to study if EBV antibody levels reflect MRI disease activity in MS and examine the potential for EBV antibody levels as biomarkers for treatment response., Methods: A total of 87 MS patients were followed for two years prior to and during interferon beta (IFNB) treatment, with MRI examinations and serum measurement of IgM and IgG antibodies to viral capsid antigen (VCA), EBV nuclear antigen 1 (EBNA-1) and early antigen (EA). Associations between EBV antibody levels and MRI activity were assessed by a logistic regression model., Results: Higher anti-EBNA-1 IgG levels were associated with increased MRI activity, OR = 2.95 (95% CI 1.07-8.10; p = 0.036) for combined unique activity (CUA; the sum of T1Gd+ lesions and new or enlarging T2 lesions). Although most patients were anti-VCA IgM negative, there was an inverse association, OR = 0.32 (95% CI 0.12-0.84; p = 0.021) with CUA during IFNB treatment., Conclusions: This study supports an association between anti-EBNA-1 IgG levels and MS disease activity. We also found an inverse association with anti-VCA IgM levels during IFNB treatment not previously described, indicating anti-VCA IgM as a possible biomarker for IFNB treatment response., (© The Author(s), 2014.)

To explore the relationships between vitamin A, D and E and inflammation in relapsing remitting multiple sclerosis, we assessed their associations with 11 inflammation markers in 9 serial serum samples from 85 patients, before and during interferon-β1a treatment. A negative association was found between vitamin A and pentraxin 3 independent of interferon-β1a use, whereas positive associations between vitamin D and interleukin-1 receptor antagonist and secreted frizzled-related protein 3 were seen before, and between vitamin E and chemokine (C-X-C motif) ligand 16 during interferon-β1a treatment. These findings suggest associations with diverse inflammatory pathways, which may be differentially influenced by interferon-β1a treatment., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A month of birth effect on multiple sclerosis (MS) risk has been reported from different countries. Recent critics have suggested that this finding is caused by confounding and that adequately adjusting for year and place of birth would markedly reduce this effect. All inhabitants in Norway are registered in the Norwegian Population Registry (Statistics Norway), making this an ideal area for performing adjusted analyses. Using the entire Norwegian population born between 1930 and 1979 (n = 2,899,260), we calculated the excess between observed and expected number of births for each month for 6649 Norwegian MS patients, 5711 mothers, 5247 fathers, and 8956 unaffected siblings. The analyses were adjusted for year of birth and place of birth according to the 19 counties in Norway. An unadjusted analysis revealed 13% fewer MS births than expected in February (P = 0.0015; Bonferroni corrected P = 0.018), 10% more in April (P = 0.0083; Bonferroni corrected P = 0.0996) and 15% more in December (P = 0.00058; Bonferroni corrected P = 0.007). Adjustments for both year and place of birth significantly altered our results for February and December, but even after these adjustments there were still 10% more MS births than expected in April (P = 0.00796; Bonferroni corrected P = 0.096). MS patients had a higher incidence of April births than their siblings (Fisher-exact test; P = 0.011), mothers (Fisher-exact test; P = 0.004), and fathers (Fisher-exact test; P = 0.011) without MS. Adjustments for confounding significantly affected our results. However, even after adjustments, there appears to be a persistent higher than expected frequency of April births in the MS population.