Increasing age of multiple sclerosis onset from 1920 to 2022: a population-based study.

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.

Vitamin D, HLA-DRB1 and Epstein-Barr virus antibody levels in a prospective cohort of multiple sclerosis patients.

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 ß-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.

Disease-modifying treatments for multiple sclerosis - a review of approved medications.

BACKGROUND AND PURPOSE: There is still no curative treatment for multiple sclerosis (MS), but during the last 20 years eight different disease-modifying compounds have been approved for relapsing-remitting MS (RRMS). METHODS: A literature search was conducted on published randomized controlled phase III trials indexed in PubMed on the approved medications until 21 May 2015. RESULTS: In this review the mode of action, documented treatment effects and side effects of the approved MS therapies are briefly discussed. CONCLUSIONS: Based on current knowledge of risk-benefit of the approved MS medications, including factors influencing adherence, it is suggested that oral treatment with dimethyl fumarate or teriflunomide should be preferred as a starting therapy amongst the first-line preparations for de novo RRMS. In the case of breakthrough disease on first-line therapy, or rapidly evolving severe RRMS, second-line therapy with natalizumab, fingolimod or alemtuzumab should be chosen based on careful risk-benefit stratification.

WT1 and interferon-ß-vitamin D association in MS: a longitudinal study.

BACKGROUND: It has been suggested that polymorphisms in the WT1 gene modulate the effect of IFN-ß treatment in multiple sclerosis (MS) through regulation of the relationship between IFN-ß and vitamin D. OBJECTIVE: To examine whether WT1 modulates the relationship between IFN-ß and vitamin D in a longitudinal study with repeated assessment of vitamin D before and after initiation of IFN-ß. 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-ß 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-ß. The association between IFN-ß 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-ß, we did not find that genetic variation in WT1 plays any role in regulating the relationship between IFN-ß and serum 25-hydroxyvitamin D.

The Norwegian Multiple Sclerosis Registry and Biobank.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with unknown cause and various benefits from disease modifying therapies. Systematic recording of data into national MS registries is therefore needed to optimize treatment and define the pathogenesis of the disease. The Norwegian MS Registry and Biobank was established for systematic collection of clinical and epidemiological data, as well as biological samples. Data collection is based on informed consent from the individual patients and recordings by treating neurologists. All researchers have, by application, access to data and biological samples from the Norwegian Multiple Sclerosis Registry and Biobank. By this combined effort from both patients and healthcare personnel, the Registry and Biobank aims to facilitate research for improved understanding of disease mechanisms and improved health care in MS.

Time trends in the incidence and prevalence of multiple sclerosis in Norway during eight decades.

Norway has been subjected to numerous epidemiological investigations on the prevalence and incidence of multiple sclerosis (MS), dating back to 1935. The objective of this study was to review the studies on the prevalence and incidence of MS in Norway, provide an update on the prevalence of MS in Norway, and describe the time trends in the prevalence and incidence of MS in relation to risk factors, case ascertainment, and data. We performed a systematic search on PubMed and MEDLINE up to November 2014 using the search string 'multiple sclerosis prevalence in Norway' or 'multiple sclerosis incidence in Norway'. In addition, we scrutinized the reference lists of the publications identified for relevant citations. We retrieved data on the distribution of MS in Norway on December 31, 2013 from the Norwegian Multiple Sclerosis Registry and Biobank and the Norwegian Patient Registry. We identified 29 articles. From 1961 to 2014, the reported prevalence of MS increased from 20 to 203 per 100,000 inhabitants, and the incidence increased from 1.9 to 8.0 per 100,000. The nationwide crude prevalence in Norway, based on the Norwegian Patient Registry, was 208 per 100,000 on December 31, 2013. The reported prevalence of MS in Norway has increased 10-fold, with several possible causes. During eight decades, neurological health services have generally become more accessible to the population, and transforming diagnostic criteria has made the diagnosis of MS more precise and valid. There have also been changes in lifestyle behavior and known risk factors, such as vitamin D and smoking, that might have contributed to the increased incidence of MS. A possible role of increased survival in MS needs to be examined further.

Fat-soluble vitamins as disease modulators in multiple sclerosis.

BACKGROUND: Fat-soluble vitamins (A, D, E and K) have properties that could be relevant as modulators of disease activity in multiple sclerosis (MS). METHODS: We performed a systematic search on PubMed and Medline up to May 2012, using the search strings 'vitamin A', 'retinol', 'retinal', 'carotenoids', 'vitamin D', 'vitamin E', 'alpha-tocopherol', 'vitamin K' in conjunction with 'multiple sclerosis', 'animal model' and 'experimental autoimmune encephalitis (EAE)'. In addition, the reference lists of the publications identified were examined for further citations of relevance. RESULTS: There is comprehensive evidence from epidemiological, observational, and experimental studies that vitamin D may be beneficial in MS. Results from small-scale clinical studies are inconclusive, and large-scale, adequately powered, randomized, controlled trials are still lacking. For vitamin D, Oxford Centre for Evidence-Based Medicine level 2c evidence exists for a positive therapeutic effect. Evidence from animal models indicates that all the examined fat-soluble vitamins could have potential as modulators of disease activity in MS. For vitamin A and E, level 4 and 5 evidence exists for a modulatory effect in MS; for vitamin K, too few studies have been conducted to indicate an effect in humans. CONCLUSION: Vitamin D is a promising candidate as modulator of disease activity in MS, and controlled studies are currently being conducted. All the fat-soluble vitamins have, however, been demonstrated to be effective in different animal models for the disease, and vitamin A and E have biological properties that could be relevant for MS pathogenesis. Thus, vitamin A and E seem to be promising candidates for future case-control and cohort studies.

A need for national registries and international collaborative research in multiple sclerosis.

OBJECTIVE: There is a growing need to identify biomarkers for early diagnosis and treatment in multiple sclerosis (MS). Such markers may also be involved in the cause and pathogenesis of the disease. METHODS: Established national MS registries have through several decades allowed data collection to facilitate MS research. The European MS Registry (EUReMS) is a recent international collaborative effort to ultimately promote MS research and quality in health care across European countries. International collaborations based on such initiatives can facilitate studies on new biomarkers in MS. RESULTS: Important studies on data from MS registries, as well as national- and international collaboration networks have been conducted. CONCLUSION: The symposium "National MS Registries--to improve health care and research in Multiple Sclerosis" held in Bergen, Norway, earlier this year aimed to highlight the need and benefit from national MS registries and promote international collaborative research in MS.

Month of birth as a risk factor for multiple sclerosis: an update.

BACKGROUND: Several studies have indicated month of birth as a risk factor for multiple sclerosis (MS) susceptibility and disease progression. METHODS: We performed a systematic search on PubMed and Medline up to May 2012 using the search string 'multiple sclerosis' and 'month of birth' or 'season of birth'. In addition, congress abstracts and the reference lists of the publications identified were examined for further citations of relevance. RESULTS: A total of fifteen published studies and two congress abstracts were found on the effect of month or season of birth on MS risk (sixteen in the northern and one in the southern hemisphere). Most studies in the northern hemisphere detected an excess of MS births in spring and a decrease in autumn. In the southern hemisphere, a reverse pattern was detected, with an excess in November and a decrease in April. Only three studies did not report any month of birth effect, all in low-risk areas for MS. Five studies have analysed a possible effect on disease course by month of birth. Of these, two studies reported an association between month of birth and age at onset of relapsing-remitting MS, with a younger disease onset for those born in the winter months. No consistent findings have been detected on the association between month of birth and disease progression. DISCUSSION: The month of birth effect is consistently found to influence the risk of MS, and the effect seems to be most prominent in high-risk areas of the disease, especially in areas with low sunlight exposure. There seems to be little or no month of birth effects in areas with high sunlight exposure. These findings indicate a possible role for vitamin D concentrations during pregnancy or early life of the newborn. A possible effect of vitamin D supplementation needs to be further investigated.

Vitamin D supplementation and monitoring in multiple sclerosis: who, when and wherefore.

OBJECTIVES: Observational studies suggest that increasing the serum concentration of 25-hydroxyvitamin D with 50 nm could halve the relapse risk in relapsing-remitting multiple sclerosis (MS). Assuming that the association between disease activity and vitamin D status is entirely causal may however exaggerate the potential benefit. The aim of this paper is to address whether and how vitamin D should be monitored in patients with MS. METHODS: Possible benefits of vitamin D supplementation were assessed from observational, experimental and clinical studies. Based on repeated measurements of 25-hydroxyvitamin D in Norwegian patients with MS , we estimate the effect of different supplementation regimes. RESULTS: Serum levels of 25-hydroxyvitamin in the upper physiological range are associated with lower risk of relapses and magnetic resonance imaging disease activity, but the causality is uncertain. Osteoporosis develops early in patients with MS , and 25-hydroxyvitamin vitamin should therefore at least be 50 nm throughout the year. Levels between 75 and 125 nmol may offer some additional benefit for bone health, are not toxic and are associated with low disease activity. Adding 400 IU (10 µg) vitamin D daily would only bring 56% of the patients >50 nm and 11% >75 nm throughout the year, whereas 800 IU (20 µg) would maintain 97% >50 nm and 67% >75 nm. CONCLUSION: We recommend that MS patients are supplemented with 800 IU of vitamin D at least from autumn to spring. Alternatively, 25-hydroxyvitamin D should be measured and the nadir level estimated and supplementation given to a target level between approximately 75 and 125 nm.

Polyunsaturated fatty acids in multiple sclerosis therapy.

BACKGROUND: Results from epidemiological and uncontrolled intervention studies in multiple sclerosis (MS) suggest a beneficial disease-modifying effect of increased intake of polyunsaturated fatty acids (PUFAs). OBJECTIVE: To review the current evidence from animal studies and randomised controlled trials on the therapeutic effect of PUFAs in MS. METHODS: We searched PubMed and Medline for articles using the terms 'polyunsaturated fatty acids', 'eicosapentaenoic acid', 'docosahexaenoic acid', 'linoleic acid', 'linolenic acid', 'omega-3' and 'omega-6' combined with 'multiple sclerosis', 'randomised controlled trials', 'animal models', 'experimental autoimmune encephalomyelitis' and 'cuprizone'. The abstracts of retrieved citations were reviewed and checked for relevant content. RESULTS: There was some evidence from animal model studies indicating an effect of ω-6 PUFAs, while the results from randomised controlled trials (RCTs) indicated that the ω-6 PUFAs linoleic acid or γ-linolenic acid have no beneficial effects on clinical disease activity in MS. However, the identified studies had several limitations in design with a mixture of relapsing-remitting and progressive MS patients. No studies investigated ω-6 efficacy on MRI disease activity. For ω-3 PUFAs, there was conflicting results from animal studies. RCTs show no beneficial treatment effect of the ω-3 PUFAs eicosapentaenoic acid and docosahexaenoic acid on MRI or clinical disease activity in MS. CONCLUSION: Randomised controlled trials of PUFA intervention provide no evidence of beneficial effects from ω-3 or ω-6 PUFAs on relapse rate, disability progression or MRI disease activity in MS.

Fcγ receptors in Norwegian multiple sclerosis patients and healthy controls.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system in genetically susceptible persons. Fcγ receptors (FcγR) are involved in autoimmune diseases. PATIENTS AND METHODS: Sixteen Norwegian patients with relapsing-remitting MS (RRMS) were studied to see whether treatment with either interferon-beta (INF-ß) or glatiramer acetate (GA) influenced the proportion of FcγR1a, FcγR2a, and FcγR3b positive monocytes, granulocytes, or lymphocytes or FcγR1a, FcγR2a, and FcγR2b mRNA levels in leukocytes. One hundred and twenty-seven patients with RRMS and 54 Norwegian healthy blood donors were also analyzed for FcγR2b polymorphisms. RESULTS: Interferon-beta or GA treatment initiated an increase in the proportion of FcγR positive lymphocytes, but did not cause major influence of the long-term proportion of FcγR positive leukocytes or their FcγR mRNA levels. No significant differences were observed between RRMS patients and healthy controls for the genotype and allele frequencies of FcγR2b polymorphisms. DISCUSSION: INF-ß or GA treatment probably has no major role in the regulation of FcγRs on immune cells in RRMS. Furthermore, polymorphisms of the inhibitory FcγR2b do not seem to influence the susceptibility for MS.

The cuprizone model for demyelination.

BACKGROUND: Important advances in multiple sclerosis (MS) research have been made as a direct or indirect result of experiments in animal models for the disease, although MS is a disease only affecting humans. The cuprizone model is a model for toxic demyelination. In this model, young mice are fed with the copper chelator cuprizone, leading to oligodendrocyte death and a subsequent reversible demyelination. Spontaneous remyelination can be seen as early as 4 days after withdrawal of cuprizone. MATERIALS AND METHODS: This article reviews previous research on this model and discusses the potential of the model for future application in MS research. DISCUSSION: The cuprizone model correlates with newer histopathological data in MS and is a valuable tool for studies on de- and remyelination. The use of the C57BL/6 strain offers the potential for future studies on transgene and knockout mice.

Epstein-Barr virus reactivation and multiple sclerosis.

Infection with Epstein-Barr virus (EBV) is considered one of the possible key environmental factors in the aetiology of multiple sclerosis (MS). Whether EBV plays an underlying role as an activator of MS remains, however, controversial. Sixty-one patients with definite relapsing-remitting multiple sclerosis (RRMS) according to the Poser criteria were followed for 1 year. Blood samples were drawn at baseline, months 3, 6 and 12, and in case of any clinical exacerbation. Twenty-three baseline-paired exacerbation samples in the same set were quantitatively analysed to examine whether exacerbations in MS were associated with a change in anti-diffuse component of the EBV-early antigen (EA-D) IgG ratio. All the 61 patients (100%) were anti-viral capsid antigen (VCA) IgG positive, one (2%) was anti-VCA IgM positive and 60 (98%) were anti-EBV nuclear antigen IgG positive. Mean anti-EA-D IgG at baseline was 0.57 (range 0.12-2.70) and at the time of exacerbations 0.61 (range 0.11-2.70). Wilcoxon signed rank test revealed no differences between the 23 baseline and paired exacerbation samples (P = 0.58). Our findings suggest that reactivation of latent EBV infection does not play a significant role for exacerbations in RRMS.

Immunomodulatory treatment of multiple sclerosis in Norway.

OBJECTIVES AND METHODS: National guidelines for immunomodulatory treatment in multiple sclerosis (MS) were established in Norway in 2001. However, the nation-wide treatment practice has not been evaluated since. We therefore obtained information of all patients who have received prescriptions for the approved immunomodulatory medications, interferon-beta (Betaferon, Avonex, Rebif) and glatiramer acetate (Copaxone) registered in the Norwegian Prescription Database (Reseptregisteret). We also made a survey of patients treated with mitoxantrone (Novantrone) as well as patients supplied with immunomodulatory drugs in treatment trials. To further calculate the treatment frequency, a nation-wide prevalence of MS in Norway was estimated, based on available prevalence studies. RESULTS: The estimated frequency of MS was approximately 150/100,000 in southern Norway and 100/100,000 in northern Norway. The treatment frequencies varied from 15% to 47% between the different counties with a frequency of 28% for the whole country. CONCLUSION: Substantial differences in treatment frequencies between counties were detected, reflecting major differences in clinical practice within the country. This calls for increased focus on clinical application of the established treatment guidelines.

FcgammaR and multiple sclerosis: an overview.

Receptors for the Fc domain of IgG (FcgammaR) play a key role in the immune system by linking the cellular and humoral immune systems. Despite extensive documentation of CNS-specific antibodies in cerebrospinal fluid and plaques in multiple sclerosis (MS) patients, the role of FcgammaR in this disease remains largely unexplored. Studies indicate however, that polymorphisms in some FcgammaR genes and treatment that induces FcgammaR on immune-competent cells could influence disease progression and treatment response.

Ethnic variations of IL-10 polymorphisms in a Sami and Norwegian population.

Interleukin-10 (IL-10) production is genetically determined and influenced by different polymorphisms in the promoter region of IL-10. These polymorphisms may contribute to the risk and clinical outcome of various infectious and immunological-related diseases. The Samis are the aboriginal inhabitants of Norway and Fennoscandinavia and are ethnically different from the Norwegians. Different distribution of various immune-related diseases among the Samis compared with Norwegians have been reported. This is the first study to evaluate the distribution of IL-10 polymorphisms in the Sami population. Two hundred healthy Samis were genotyped for polymorphisms in the promoter region of IL-10 at region -1082 (G/A), -819 (T/C) and -592 (A/C). The allele frequencies, genotypes and haplotypes were compared with 187 healthy Norwegians. A significantly higher number of the Samis than the Norwegians had the ATA/ATA genotype, whereas the Norwegians displayed a higher frequency of the GCC/GCC genotype (P=0.0057). There was a significant difference in haplotypes in the two populations with a P=0.0024. These findings may be important for the distribution and clinical outcome of various infectious and immune-related disorders in the two populations.

High dose methylprednisolone induces FcgammaRI on granulocytes in MS-patients.

Immune complexes impinge on receptors for the Fc domain of IgG (FcgammaR) and may thus influence the disease course in multiple sclerosis (MS). We analyzed FcgammaR distribution on monocytes and granulocytes in twenty relapsing-remitting MS patients at baseline, immediately after a five day course of high dose intravenous methylprednisolone (IVMP) treatment and after two months. After a five day course of IVMP the proportion of granulocytes with FcgammaRI was increased, P=0,002. There was no change in FcgammaRII and FcgammaRIII expression. The effect of IVMP on FcgammaRI expression could be important for the clearance of immune complexes in MS.