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Background: Epstein-Barr virus (EBV) infection and vitamin D insufficiency are potentially interacting risk factors for multiple sclerosis (MS)., Objectives: To investigate the effect of high-dose vitamin D 3 supplements on antibody levels against the EBV nuclear antigen-1 (EBNA-1) in patients with relapsing-remitting multiple sclerosis (RRMS) and to explore any underlying mechanism affecting anti-EBNA-1 antibody levels., Methods: This study utilized blood samples from a randomized controlled trial in RRMS patients receiving either vitamin D 3 (14,000 IU/day; n = 30) or placebo ( n = 23) over 48 weeks. Circulating levels of 25-hydroxyvitamin-D, and anti-EBNA-1, anti-EBV viral capsid antigen (VCA), and anti-cytomegalovirus (CMV) antibodies were measured. EBV load in leukocytes, EBV-specific cytotoxic T-cell responses, and anti-EBNA-1 antibody production in vitro were also explored., Results: The median antibody levels against EBNA-1, but not VCA and CMV, significantly reduced in the vitamin D 3 group (526 (368-1683) to 455 (380-1148) U/mL) compared to the placebo group (432 (351-1280) to 429 (297-1290) U/mL; p = 0.023). EBV load and cytotoxic T-cell responses were unaffected. Anti-EBNA-1 antibody levels remained below detection limits in B-cell cultures., Conclusion: High-dose vitamin D 3 supplementation selectively reduces anti-EBNA-1 antibody levels in RRMS patients. Our exploratory studies do not implicate a promoted immune response against EBV as the underlying mechanism.

Background: There is a well-documented increase in the risk of multiple sclerosis (MS) when migrating from a region of low prevalence to one of high prevalence., Objective: We present here an investigation of MS prevalence and candidate environmental and genetic risk factors among Iranian immigrants to British Columbia (BC), Canada., Methods: MS cases of Iranian ancestry were ascertained from a population-based Canadian study. We collected blood samples for genetic and serological analyses, and administered a personal history questionnaire to the cases., Results: The crude prevalence of MS in this population of Iranian ancestry was 287/100,000 (95% CI: 229 - 356/100,000). MS cases were more likely to have a history of infectious mononucleosis (odds ratio (OR) = 7.5; p = 0.005) and smoking (OR = 17.0; p < 0.0001), as compared to healthy controls from previous studies in Iran. Cases were also more likely than controls to have been born between April and September (OR = 2.1; p = 0.019)., Conclusion: The prevalence of MS among Iranian immigrants to Canada is greater than the overall prevalence of MS in Iran by a factor of at least four, and is similar to that recently observed among Iranian immigrants in other western nations. No major genetic susceptibility variants were identified, suggesting the environment in Canada may be what is increasing the risk of MS in this population., (© The Author(s) 2014.)

Late Epstein-Barr virus infection and hypovitaminosis-D as environmental risk factors in the pathogenesis of multiple sclerosis are gaining great interest. We, therefore, tested for in-vivo interdependence between Epstein-Barr-virus (EBV)-status and 25-hydroxyvitamin D3 (25(OH)D3) -level in healthy young individuals from a United Kingdom (UK) autumn cohort. EBV-load was measured by quantitative polymerase chain reaction and 25(OH)D3 levels by isotope-dilution liquid chromatography-tandem mass spectrometry. This young, healthy UK autumn cohort showed surprisingly low levels of 25(OH)D3 (mean value: 40.5 nmol/L ± 5.02). Furthermore, we found that low 25(OH)D3 levels did not impact on EBV load and anti-EBV nuclear antigen-1 (EBNA-1) titers. However, we observed a correlation between EBV load and EBNA-1 titers. These observations should be of value in the study of the potential relationship between hypovitaminosis-D and EBV-status in the pathophysiology of multiple sclerosis.

Background: Progenitor cells from the subventricular zone (SVZ) of the lateral ventricles are assumed to contribute to remyelination and resolution of black holes (BHs) in multiple sclerosis (MS). This process may depend on the distance between the lesion and the SVZ., Objective: The objective of this paper is to investigate the relationship between lesion-to-ventricle (LV) distance and persistence of new BHs., Methods: We analysed the magnetic resonance images (MRIs) of 289 relapsing-remitting (RR) MS patients, obtained during a multi-centre, placebo-controlled phase II trial over one year., Results: Overall, 112/289 patients showed 367 new BHs at the beginning of the trial. Of these, 225 were located in 94/112 patients at the level of the lateral ventricles on axial MRIs and included in this analysis. In total, 86/225 (38%) BHs persisted at month 12. LV distance in persistent BHs (PBHs) was not longer than in transient BHs. In fact PBHs tended to be closer to the SVZ than transient BHs. A generalised linear mixed multivariate model adjusted for BHs clustered within a patient and including patient- as well as lesion-specific factors revealed size, ring contrast enhancement, and shorter LV distance as independent predictors for BH persistence., Conclusion: Location of BHs close to the lateral ventricles does not appear to favourably influence the resolution of new BHs in RRMS.

Background: Vitamin D deficiency is widely prevalent in India. The association between vitamin D status and multiple sclerosis (MS) has not been previously studied in Indians., Objective: The objective of this paper is to determine whether vitamin D status is associated with MS in India., Methods: In this study 110 MS patients and 108 matched controls were included. Serum 25-hydroxyvitamin D (25(OH)D) was measured in 63 patients in relapse, 77 patients in remission and all controls. Quantity of sun exposure in childhood and body mass index (BMI) were calculated. Patients and controls were genotyped for HLA-DRB1*1501., Results: Patients had significantly lower 25(OH)D levels than matched controls (p = 0.003), and patients in relapse had a significantly lower vitamin D level as compared to those in remission (p = 0.001). Vitamin D deficiency (< 50 nmol/l) was seen in a higher proportion of cases (71.8%) than controls (53.7%) (p = 0.01). Higher quartiles of vitamin D (> 58 nmol/l) showed an inverse relationship with MS (OR = 0.28, CI = 0.11-0.68, p= 0.005). This effect persisted after adjusting for sun exposure., Conclusion: The results of our study indicated that serum 25(OH)D shows an inverse relationship with MS in the Indian population. Reverse causality cannot be excluded.

Background: There is a lack of reliable biomarkers of axonal degeneration. Neurofilaments are promising candidates to fulfil this task. We compared two highly sensitive assays to measure two subunits of the neurofilament protein (neurofilament light (NfL) and neurofilament heavy chain (NfH))., Methods: We evaluated the analytical and clinical performance of the UmanDiagnostics NF-light(®) enzyme-linked immunosorbent assay (ELISA) in the cerebrospinal fluid (CSF) of a group of 148 patients with clinically isolated syndrome (CIS) or multiple sclerosis (MS), and 72 controls. We compared our results with referring levels of our previously-developed CSF NfH(SMI35) assay., Results: Exposure to room temperature (up to 8 days) or repetitive thawing (up to 4 thaws) did not influence measurement of NfL concentrations. Values of NfL were higher in all disease stages of CIS/MS, in comparison to controls (p ≤ 0.001). NfL levels correlated with the Expanded Disability Status Scale (EDSS) score in patients with relapsing disease (r(s) = 0.31; p = 0.002), spinal cord relapses and with CSF markers of acute inflammation. The ability of NfL to distinguish patients from controls was greater than that of NfH(SMI35) in both CIS patients (p = 0.001) and all MS stages grouped together (p = 0.035)., Conclusions: NfL proved to be a stable protein, an important prerequisite for a reliable biomarker, and the NF-light(®) ELISA performed better in discriminating patients from controls, compared with the ECL-NfH(SMI35) immunoassay. We confirmed and expanded upon previous findings regarding neurofilaments as quantitative markers of neurodegeneration. Our results further support the role of neurofilaments as a potential surrogate measure for neuroprotective treatment in MS studies.

Observational studies have shown an association between lower vitamin D levels and higher risk of relapse among people with multiple sclerosis (MS). This has raised interest in potential clinical benefits of vitamin D supplementation in the management of MS. The objectives were to examine the effect of vitamin D based interventions on the relative risk of relapse in MS. Any randomised controlled trial assessing the effect on the relative risk of relapse of any formulation or dose of vitamin D, in participants with MS, was eligible. The inverse variance with random effects model in Review Manager 5.1 was used to calculate the odds ratio of relapses in high dose vitamin D treated patients vs. controls. Five studies were published as of September 2012, yielding a total of 129 high-dose vitamin D-treated patients and 125 controls. We found no significant association between high-dose vitamin D treatment and risk of MS relapse (OR 0.98, 95% CI 0.45-2.16). In conclusion, although no significant association between high-dose vitamin D treatment and risk of MS relapses was found, the studies were limited by several methodological limitations. Further larger, more prolonged studies are merited.

Gene-environment interactions may shed light on the mechanisms underlying multiple sclerosis (MS). We pooled data from two case-control studies on incident demyelination and used different methods to assess interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). Individuals exposed to both factors were at substantially increased risk of disease (OR=7.32, 95% CI=4.92-10.90). In logistic regression models, DRB1-15 and IM status were independent predictors of disease while their interaction term was not (DRB1-15*IM: OR=1.35, 95% CI=0.79-2.23). However, interaction on an additive scale was evident (Synergy index=2.09, 95% CI=1.59-2.59; excess risk due to interaction=3.30, 95%CI=0.47-6.12; attributable proportion due to interaction=45%, 95% CI=22-68%). This suggests, if the additive model is appropriate, the DRB1-15 and IM may be involved in the same causal process leading to MS and highlights the benefit of reporting gene-environment interactions on both a multiplicative and additive scale.

Several lines of evidence support a role for Epstein-Barr virus (EBV) in the aetiology of multiple sclerosis (MS). This includes the observation that nearly all MS patients show serological markers of past EBV infection. Given the well-known association between MS prevalence and latitude, we investigated whether EBV seropositivity also increases with distance from the equator. We found that the proportion of EBV positive individuals is positively associated with latitude independently of MS status (odds ratio = 1.06, 95% CI = 1.02-1.09, p = 0.002). Latitude-related factors may be implicated in the immune response to EBV and its role in MS aetiology.

Infectious mononucleosis (IM) is associated with the risk of developing multiple sclerosis (MS). Using databases of hospital admissions for England (1999-2005), we investigated the female-to-male ratios (FMRs) for admission to hospital for IM and MS stratified by age. Males were more frequently admitted for IM for all age groups apart from ages 10-14 (FMR 1.50; 95% confidence interval (CI) 1.36-1.64) and, borderline significantly, at ages 15-19 (FMR 1.03, 95% CI 0.99-1.08). This intriguing aspect of IM epidemiology in adolescence, the atypical female excess, may be linked to the sex ratio of MS, where females predominate from adolescence.

Background: Epstein-Barr virus (EBV) infection is widely considered to be a risk factor for multiple sclerosis (MS). A previous meta-analysis estimated an odds ratio (OR) for MS in individuals seronegative for EBV of 0.06. Given the potential importance of this finding, we aimed to establish a more precise OR for adult and paediatric onset MS in EBV seronegative individuals., Methods: PubMed and EMBASE searches were undertaken to identify studies investigating the association between MS and EBV. Twenty-two adult and three paediatric studies were included. ORs were calculated using a fixed effects model. A sub-group analysis based on the method of EBV detection was performed., Results: The OR for developing adult MS in EBV seronegatives was 0.18 (95% confidence interval (CI) 0.13-0.26)) and for paediatric MS was 0.18 (95% CI 0.11-0.30). Sub-group analysis on EBV detection method showed that studies which used immunofluoresence generated an OR=0.07 (95% CI 0.03-0.16); for those that used enzyme-linked immunosorbent assay (ELISA) OR=0.33 (95% CI 0.22-0.50) and for studies which used ELISA and immunofluoresence OR=0.00 (95% CI 0-0.43)., Conclusion: The sensitivity and specificity of the assay used to measure EBV antibody titres have an influence on the association between MS and EBV. Looking at studies where two independent methods are used and therefore are likely to be the most robust, EBV appears to be present in 100% of MS patients. This has implications for future studies of EBV in MS. MS patients without EBV infection, if they truly exist, should be studied in more detail.

People with multiple sclerosis (MS) have many reasons to have low bone mineral density and an increased fracture risk. Osteoporosis is a major cause of morbidity and mortality, and is more common in people with MS than the general population. A number of studies have examined the relationship between multiple sclerosis and reduced bone mineral density. In this topical review we seek to address the risk of low bone mineral density, osteoporosis and fractures associated with MS, and make practical suggestions as to how this pertinent issue may be approached in clinical practice.

Background/objective: A clinically isolated syndrome compatible with demyelination (CIS) is the initial presentation for the majority of people that go on to develop multiple sclerosis (MS). There has previously been little work examining the effect of gender on the development and progression of CIS., Methods: Data from observational studies of CIS were used. In total, 33 suitable studies with 4732 subjects were identified., Results: The overall relative risk (RR) of CIS in females compared with males was 2.12 (95% CI 1.94-2.32). The RR of females developing MS following CIS was 1.20 (95% CI 0.98-1.46) compared with males., Conclusions: These data imply that the gender bias seen in MS is caused by factors acting early in the disease process.