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.

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.

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.

Modelling and prediction of 25-hydroxyvitamin D levels in Norwegian relapsing-remitting multiple sclerosis patients.

BACKGROUND/AIM: 25-Hydroxyvitamin D (25(OH)D) levels are suggested to influence the susceptibility and risk of disease progression in multiple sclerosis (MS). Seasonal fluctuation of 25(OH)D levels may differ in magnitude between individuals. The purpose of this paper was to model the seasonal fluctuation of vitamin D in Norwegian MS patients and to examine to which extent one single 25(OH)D measurement predicts the level at other time points throughout the year. METHODS: During December 2004 and July 2008, 762 serum samples were collected from 92 Norwegian relapsing-remitting MS patients. Time series analysis and multivariate modelling techniques were used to model seasonal fluctuations and intra- and inter-individual variations in 25(OH)D values. RESULTS: Most patients reached their lowest 25(OH)D level in March/April and the highest in July/August. There were substantial intra-individual variations in the extent of seasonal fluctuation, with 36.6% of explainable variation in seasonally adjusted 25(OH)D levels (on a logarithmic scale) attributable to the patient level. The remaining 63.4% could be accounted for by sources of inter-individual variation. Both the total and inter-individual variabilities were lowest in February, and the prediction interval in this month was up to 26% narrower compared to other months. The prediction intervals would be at least 21% wider with only one observation available per patient. CONCLUSIONS: The seasonal fluctuations of 25(OH)D levels in Norwegian relapsing-remitting MS patients are subject to pronounced intra- and inter-individual variation. The most representative measurements of 25(OH)D levels are taken in February.

Incidence and clinical features of amyotrophic lateral sclerosis in Møre and Romsdal County, Norway.

BACKGROUND: To determine the annual incidence rate and clinical features of amyotrophic lateral sclerosis (ALS) in Møre and Romsdal County, Norway, in the 20-year period from 1988 to 2007. METHODS: We recruited ALS patients retrospectively from the patient database of the two neurological departments in Møre and Romsdal County, Norway. The patients were identified by use of the international classification code for diseases. We recorded gender, age, municipality, symptoms, clinical signs, time from onset to diagnosis and death. RESULTS: 105 patients met the inclusion criteria. The crude annual incidence was 2.17 per 100,000 for the period 1988-2007. Gender-specific incidence for men was 2.32 per 100,000, and for women 2.03 per 100,000. Mean age at symptom onset was 66.8 ± 10.5 years. Mean interval from onset of symptoms to diagnosis was 13.5 ± 11.0 months, and mean survival time from diagnosis was 18.0 ± 22.0 months. Prevalence rate estimated on December 31, 2007 was 4.06 per 100,000. CONCLUSION: The present study shows an annual incidence of ALS of similar magnitude to the previous studies from the Nordic countries during the past years. The short survival time corroborates prior studies, and is stable throughout the two studied decades.

Gut microbiota composition during a 12-week intervention with delayed-release dimethyl fumarate in multiple sclerosis - a pilot trial.

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, QFDR = 0.24) at two weeks, mainly driven by Bifidobacterium (p = 0.06, QFDR = 0.69). At 12 weeks, we observed an increased abundance of Firmicutes (p = 0.02, QFDR = 0.09), mostly driven by Faecalibacterium (p = 0.01, QFDR = 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.

Unusual manifestations of nervous system Borrelia burgdorferi infection.

Borrelia burgdorferi infection may show disease manifestations in different organ systems, including the skin, heart, central nervous system, peripheral nervous system, and joints. We report two hitherto unknown (to our knowledge) disease manifestations, an arteritis in the central nervous system, and a neuromyopathy of 11 years' duration. Diagnoses were made by demonstrating specific antibodies against B burgdorferi in the cerebrospinal fluid, and elevated specific antibody index. Both patients responded well to treatment, and intrathecal immunologic activity could not be demonstrated after treatment. Serologic analyses (enzyme-linked immunosorbent assay) in serum and cerebrospinal fluid should be performed widely in cases with inflammatory findings in cerebrospinal fluid combined with neurologic disease of unclear origins.

Epidemiologic trends in multiple sclerosis in Møre and Romsdal, Norway: a prevalence/incidence study in a stable population.

The western part of Norway has been a low-to medium-frequency area for multiple sclerosis (MS). The prevalence of definite/probable MS on January 1, 1961, was 24.3/100,000 in the county of Møre and Romsdal, western Norway. Based on the same diagnostic criteria, the prevalence of definite/probable MS increased to 75.4/100,000 on January 1, 1985. The average annual incidence rate increased from 1.94/100,000 in the period 1950-1954 to 3.78/100,000 from 1975-1979. Remitting MS in the younger age groups of both sexes increased the most. We consider this increase of MS to be due to alteration in exogenous factors as variation in genetic susceptibility cannot account for the increase in the stable western Norwegian population. The rise in prevalence/incidence over the last 20 to 25 years in western Norway supports the theory that MS is a disease influenced by exogenous factors that show variation over time.

Impairment, disability, and handicap in multiple sclerosis. A cross-sectional study in an incident cohort in Møre and Romsdal County, Norway.

We conducted a cross-sectional, geographically based study of functional status in an incident cohort of 124 multiple sclerosis (MS) patients with onset of disease from 1 January 1976 to 31 December 1986 in Møre and Romsdal County, Norway. The cohort comprised 58 men (46.8%) and 66 women (53.2%). One hundred and thirteen patients (91.1%) had a primary remitting course of disease and 11 (8.9%) had primary progressive MS. The mean age of onset was 33.3 years (range 14-64), and the mean duration of disease 7.8 years (range 1-23). The Minimal Record of Disability (MRD) of multiple sclerosis was applied to measure the degree of impairment, disability and handicap. The mean Kurtzke Expanded Disability Status Scale (EDSS) score was 3.76 (0-10), and the frequency distribution of the EDSS scores in the cohort was bimodal. Twenty-eight (22.6%) patients in the cohort had marked paraparesis, paraplegia of quadriplegia. Nineteen patients (15.3%) had frequent urinary incontinence, need for almost constant catheterization, or need for constant use of measures to evacuate stools. Five patients (4%) had a severe decrease in mentation or dementia. Forty-eight patients (38.7%) reported frequent problems with fatigue or fatigability preventing sustained physical function. Less than half of the cohort (42.7%) was working full-time, and 49.2% of the patients reported that they received external support to maintain their usual financial standard. Lack of ability to work full-time and accordingly the dependence upon external financial support were significantly associated with the primary progressive course of disease. Fatigue was statistically significantly related to lack of working ability. The estimated cost of MS in the county in 1991 was 48.2 million NOK (approximately 7.531.250 US $) based on the cost-of-illness methodology.

Corticosteroids or ACTH for acute exacerbations in multiple sclerosis.

BACKGROUND: Corticosteroids are often used to improve the rate of recovery from acute exacerbation in multiple sclerosis (MS) patients. However, it is still unclear just how relatively effective these agents are and the type of drug, optimal dose, frequency, duration of treatment and route of administration are unknown. OBJECTIVES: The object of this review was to determine the efficacy and safety of corticosteroids or ACTH in reducing the short and long term morbidity from MS. Moreover, we wished to examine from indirect comparisons if the effect of corticosteroids is different according to different doses and drugs, routes of administration, length of treatment. SEARCH STRATEGY: A search strategy developed for the Cochrane MS Group (last searched: June 1999) completed with handsearching and personal contacts with trialists and pharmaceutical companies was used. SELECTION CRITERIA: All randomised, double-blind, unconfounded trials comparing corticosteroids or ACTH to placebo in patients with MS, treated for acute exacerbations, without any age or severity restrictions, were evaluated. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected articles for inclusion, assessed trials' quality and extracted the data. A third reviewer cross-checked them and disagreements were resolved by a joint discussion. MAIN RESULTS: Six trials contributed to this review; a total of 377 participants (199 treatment, 178 placebo) were randomised. The drugs analysed were methylprednisolone (MP) (four trials, 140 patients) and ACTH (two trials, 237 patients). Overall, MP or ACTH showed a protective effect against the disease getting worse or stable within the first five weeks of treatment (odds ratio[OR]=0.37, 95% confidence interval [CI] 0.24-0.57) with some but non significant greater effect for MP and intravenous administration. Short (five days) or long (15 days) duration of treatment with MP did not show any significant difference. Only one study (with 51 patients) reported data after one year of follow-up: no difference between oral MP and placebo in the prevention of new exacerbations or improvement in long term disability was detected. No data are available beyond one year of follow-up to indicate whether steroids or ACTH have any effect on long-term progression. One study reported that a short term treatment with high dose intravenous MP was not attended by adverse events. On the contrary, gastrointestinal symptoms and psychic disorders were significantly more common in the oral, high-dose MP than in the placebo group. Weight gain and edema were significantly more frequent in the ACTH group than in controls. REVIEWER'S CONCLUSIONS: We found evidence favouring the corticosteroid MP for acute exacerbation in MS patients. Data are insufficient to reliably estimate effect of corticosteroids on prevention of new exacerbations and reduction of long-term disability. Studies assessing long term risk/benefit and adverse effects of corticosteroids in MS patients are urgently needed.

Incidence and prevalence of multiple sclerosis in Norway.

The incidence and prevalence of multiple sclerosis in several Norwegian counties have been assessed in a number of epidemiological studies since the first nationwide study covering the period from 1935 to 1948. Although the observations are not continuous, a large increase in incidence and prevalence is reported in these studies. The most remarkable incline has taken place in western and northern Norway. Parallel to the observed increase in occurrence of multiple sclerosis (MS), the Norwegian society has gone through notable changes from being a poor country immediately after World War II to an affluent, modern nation today. Thus, the healthcare system and neurological services have improved. Readily accessible services contribute to a quicker and better case ascertainment. Also, a lower threshold among the public to seek help for symptoms thought to originate in the CNS is probable. Environmental factors of possible biological importance in MS have also changed, for example diet, smoking habits and exposure to ultraviolet radiation, but the knowledge of change in these factors is so far mainly on the population level. To explore these questions, a comprehensive national MS registry combined with detailed information of assumed environmental risk factors operating in parallel in the society might be an important tool to further knowledge.

A 50-year follow-up of the incidence of multiple sclerosis in Hordaland County, Norway.

OBJECTIVE: To assess longitudinal follow-up of the incidence of multiple sclerosis (MS) through five decades and estimate the prevalence rate in Hordaland County, Norway, on January 1, 2003. METHODS: All patients with MS diagnosed from 1953 to 2003 were identified in the patient records of the Department of Neurology, Haukeland University Hospital, Bergen, Norway. The diagnostic criteria of Poser et al. were applied and only patients with definite and probable MS were included. The study comprises 912 patients, and 666 patients with MS were living in Hordaland on January 1, 2003. The annual incidence rates for the years 1953 to 2003 were calculated. RESULTS: The total crude prevalence rate on January 1, 2003, was 150.8 per 100,000 population: 191.3 per 100,000 among women and 109.8 per 100,000 among men. The annual incidence of MS increased from 1.8 per 100,000 in 1953 to 1957 to 6.0 per 100,000 in 1993 to 1997. CONCLUSIONS: Hordaland County, Norway, has changed from a low-risk to a high-risk area for multiple sclerosis (MS) during the last 50 years. During the last 25 years, the incidence of MS has been stable rather than increasing. Systematic longitudinal follow-up studies are essential to calculate reliable prevalence and incidence rates in MS. The results suggest that both methodologic and environmental factors are essential in determining the distribution of MS.

EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses.

Relapses, exacerbations or attacks of multiple sclerosis are the dominating feature of relapsing-remitting multiple sclerosis (MS), but are also observed in patients with secondary progressive MS. High-dose methylprednisolone is the routine therapy for relapses at present, but other treatments are also in current use. The objective of the task force was to review the literature on treatment of MS relapses to provide evidence-based treatment recommendations. Review was carried out on the literature with classification of evidence according to the EFNS guidelines for scientific task forces. Short-term, high-dose methylprednisolone treatment should be considered for the treatment of relapses of MS (level A recommendation). The optimal glucocorticoid treatment regimen, in terms of clinical efficacy and adverse events, remains to be established. A more intense, interdisciplinary rehabilitation programme should be considered as this probably further improves recovery after treatment with methylprednisolone (level B recommendation). Plasma exchange is probably efficacious in a subgroup of patients with severe relapses not responding to methylprednisolone therapy, and should be considered in this patient subgroup (level B recommendation). There is a need for further randomized, controlled trials in order to establish the optimal treatment regimen for relapses of MS.

[Lyme neuroborreliosis in More and Romsdal]. / Lyme-nevroborreliose i Møre og Romsdal.

BACKGROUND: The broad variations in the clinical manifestation in Lyme borreliosis underline the importance of laboratory investigations in serum and cerebrospinal fluid. MATERIAL AND METHODS: We have studied patients with neurological signs compatible with Lyme neuroborreliosis, pleocytosis in cerebrospinal fluid and positive Borrelia serology in serum/cerebrospinal fluid analysed by ELISA. We have evaluated clinical characteristics, laboratory parameters, treatment effects, and incidence variations. RESULTS: We included 25 patients in the study. Isolated facial palsy was often seen, but clinical manifestations showed huge variation. Fourteen of 25 (56%) patients had positive Borrelia burgdorferi-IgM and IgG titres in cerebrospinal fluid despite negative tests in serum. The mean annual incidence rate in the county judged by notified cases to the Norwegian Surveillance System for Communicable Diseases (MSIS) was 4.4/100,000 in the period 1989-99 as compared to the national rate of 4.3/100,000 in the same period. In 1998, however, the annual incidence rate in the county was 8.8/100,000 as compared to the national rate of 4.1/100,000. INTERPRETATION: The diversity of symptoms and signs suggests a liberal attitude towards serological testing including CSF analyses. Møre and Romsdal is a high incidence region for Lyme borreliosis in Norway. The annual variation in incidence might reflect a changing prevalence of the tick vector along the Norwegian coastline.

Multicystic syringomyelia treated with a single, non-valved syringoperitoneal shunt: fast and near-complete MRI normalization.

Four patients with multi-cystic syringomyelia were treated by a single, non-valved syringoperitoneal shunt. In all the patients, the cavitations were separated by a segment of apparently normal cord. In two of the patients, the cavitations also contained multiple transverse septa. In three patients the shunt was inserted in the most caudal cavitation, causing the shunted compartment to collapse, usually within a few weeks. The width of the more cranial cavitations normalized on postoperative MRI scans over several months. This was the case also in one patient where the most cranial cavitation was shunted. No complications or side effects were observed that could be attributed to the use of a non-valved shunt.

Oligoclonal bands in cerebrospinal fluid: a comparative study of isoelectric focusing, agarose gel electrophoresis and IgG index.

OBJECTIVE: To compare the sensitivity and specificity of isoelectric focusing (IEF) with immunofixation, agarose gel electrophoresis (AGE) and the IgG index in detecting intrathecally synthesized IgG in multiple sclerosis (MS) and in other nervous system disorders. MATERIALS AND METHODS: Cerebrospinal fluid (CSF) and serum from 147 patients with various nervous system diseases, 20 of whom had MS, were compared with IEF, AGE and the IgG index. RESULTS: CSF-restricted oligoclonal bands (OCB) were found in 20 of 20 patients with MS using IEF and in 9 of 20 using AGE. OCB were found in 12 patients with other nervous system disorders (OND) using IEF and 4 using AGE. The mean IgG index was 0.50 in OND and 0.96 in MS (P< 0.0001). Of 20 MS patients, 9 had an IgG index above the defined cut-off value of 0.72. CONCLUSIONS: IEF is about twice as sensitive as AGE in detecting OCB in MS. IEF is also far superior to the IgG index in determining intrathecal IgG synthesis.

Disability and mortality in multiple sclerosis in western Norway.

INTRODUCTION: Continued studies of frequency trends in carefully selected sites around the world can provide clues to the cause of multiple sclerosis (MS). MATERIAL AND METHODS: Based on information from three different, semi-independent sources of information, we have examined the temporal trends in the average annual age-adjusted rates of disability pension incidence, mortality, and incidence of MS from 1966 to 1991 in Møre and Romsdal County, Norway. RESULTS: The average annual age-adjusted disability pension incidence rates (1966-68 = 3.62/100,000; 1990-91 = 7.33/100,000), the mortality rates (1966-68 = 0.91/100,000; 1990-91 = 1.88/100,000), and the incidence rates (1966-68 = 4.22/100,000; 1990-91 = 5.02/100,000) all showed a statistically significant increase. The difference in the development of MS-specific disability pension prevalence rates in the county compared to the nation is notable. CONCLUSIONS: We consider that the increase in disability pension incidence, mortality, and incidence of MS is of biological significance. Thus three different sources of information corroborate corresponding trends indicating that better case ascertainment and improved diagnostic facilities only partially can explain the reported MS increase in western Norway.

Infections in childhood and adolescence in multiple sclerosis. A case-control study.

A case-control study on multiple sclerosis was conducted in Western Norway during the years 1986-1988. Included were 155 persons with multiple sclerosis and 200 controls, marginally matched according to age, sex and area of residence. The mean age at measles infection was for the cases 6.6 years and for the controls 5.7 years (p = 0.06). The cases had more frequently experienced bronchitis and/or pneumonia in the age group 11-15 years (OR = 3.20, 95% confidence interval 0.96-10.63). Tonsillectomies were reported more frequently by the cases. The odds ratio was especially high for those treated at age 0-6 years (OR = 3.44, 95% confidence interval 1.63-7.27). The results are consistent with the idea of MS as an age-dependent, host-immune response to infection during childhood or adolescence.

Multiple sclerosis in Nord-Trøndelag County, Norway: a prevalence and incidence study.

OBJECTIVE: To calculate the prevalence and incidence of multiple sclerosis (MS) in Nord-Trøndelag County, Norway. MATERIAL AND METHODS: The study comprised everyone diagnosed with MS according to the Poser criteria. On 1 January 2000 a total of 208 were identified: 130 women (62.5%) and 78 men (37.5%). We calculated the crude and age-adjusted annual incidence rates from 1974 to 1999. RESULTS: The prevalence on 1 January 2000 was 163.6 of 100,000, 204.8 of 100,000 for women and 122.6 of 100,000 for men. The age-adjusted annual incidence increased from 3.9 to 5.6 per 100,000 from 1974 to 1999; women from 4.6 to 6.3 and men from 2.2 to 4.4. After 1984, the incidence among women increased most, peaking at 10.2 per 100,000 in 1984-88. CONCLUSIONS: MS incidence is increasing in Nord-Trøndelag County. The prevalence is among the highest ever in Norway.