The relationship of age with the clinical phenotype in multiple sclerosis.

BACKGROUND: The multiple sclerosis (MS) clinical course and relapses frequency before progression vary widely. OBJECTIVE: To investigate the influence of age on the MS phenotype. METHODS: Among 751 primary progressive (PP = 217) and secondary progressive (SP = 534) MS patients from the London Ontario database, we assessed the relationship of age on the relapse frequency and on the progressive phase evolution, and the impact of relapses on the age at onset of progression. RESULTS: Age at onset did not influence the early attacks frequency, but patients younger at onset had larger number of total attacks before progression (age = 27.4, 31.0 and 32.8 mean years; ⩾4, 2-3 and 1 relapses, respectively) and longer latency to SP. Although frequent early relapses predicted younger age at SP onset, patients with no attacks (primary progressive multiple sclerosis (PPMS)), or 1, 2-3 and ⩾4 relapses during the relapsing-remitting phase started progressing at similar age (38.6, 41.3, 41.4 and 39.2 mean years, respectively). The age at onset of progressive phase did not affect its evolution. CONCLUSIONS: Age strongly influences the phenotype before progression. Relapsing-remitting patients younger at onset are more likely to display a predominantly inflammatory course, yet relapses number does not affect the age at onset of progression.

A web-based tool for personalized prediction of long-term disease course in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: The Evidence-Based Decision Support Tool in Multiple Sclerosis (EBDiMS) is the first web-based prognostic calculator in multiple sclerosis (MS) capable of delivering individualized estimates of disease progression. It has recently been extended to provide long-term predictions based on the data from a large natural history cohort. METHODS: We compared the predictive accuracy and consistency of EBDiMS with that of 17 neurologists highly specialized in MS. RESULTS: We show that whilst the predictive accuracy was similar, neurologists showed a significant intra-rater and inter-rater variability. CONCLUSIONS: Because EBDiMS was consistent, it is of superior utility in a specialist setting. Further field testing of EBDiMS in non-specialist settings, and investigation of its usefulness for counselling patients in treatment decisions, is warranted.

Review: the role of vitamin D in nervous system health and disease.

Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for multiple sclerosis.

fMRI and corpus callosum relationships in monozygotic twins discordant for handedness.

To further investigate brain structure and function in 26 handedness discordant monozygotic twin pairs (MzHd), MRI and behavioural assessments were carried out. These showed significant correlation between language-specific functional laterality in inferior and middle frontal gyri, and anterior corpus callosum. Previous studies of handedness discordant monozygotic twins failed to resolve the issue concerning handedness and hemispheric laterality for language due to methodological disparities. The results would be relevant to genetic theories as well as to brain structure:function explanations. MzHd twins underwent MRI and fMRI scanning as well as behavioural assessment of motor performance and cognition. There were significant differences on MRI and fMRI laterality measures, as well as a significant correlation between anterior callosal widths and functional laterality. LH twins showed higher frequencies of atypical functional laterality. There was no significant within-twin pair correlation on fMRI verbal laterality, nor did results show within-twin pair differences on verbal fluency or IQ. Implications for the field of laterality research pertain to frontal hemispheric equipotentiality for verbal processes in healthy individuals. In particular, there can be an apparent lack of cognitive 'cost' to atypical laterality. An fMRI verbal laterality index correlated significantly with corpus callosum widths near Broca's area.

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNß-1b trial.

OBJECTIVE: To examine the effects of interferon beta (IFNß)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. METHODS: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNß-1b 250 µg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary. RESULTS: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNß-1b 250 µg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNß-1b 250 µg-treated patients (46.0% among IFNß-1b 50 µg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. CONCLUSIONS: There was a significant survival advantage in this cohort of patients receiving early IFNß-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNß-1b benefit on all-cause mortality. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that early treatment with IFNß-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.

Age and disability accumulation in multiple sclerosis.

OBJECTIVES: We tested the hypothesis that age is a prognostic factor with respect to long-term accumulation of disability in multiple sclerosis (MS). METHODS: Kaplan-Meier analysis and binary logistic regression models determined the effect of age at disease onset, age at onset of progression, and current age on attainment of severe disability levels (Disability Status Scale [DSS] 6-8-10) from the London, Ontario, database (n = 1,023). RESULTS: Older age at relapsing-remitting (RR) phase onset was associated with higher risk of reaching advanced DSS scores. This was independent of disease duration and early relapse frequency but secondary to increased risk of conversion to secondary progressive (SP) MS. Onset at age 40 (odds ratio [OR] = 4.22) and at age 50 (OR = 6.04) doubled and tripled risks of developing SP, compared to age 20 (OR = 2.05). Younger age at conversion to SPMS was associated with shorter times to high DSS scores from disease onset. The progressive course, unaffected by age at RR onset, was only modestly affected by age at SP onset. Among primary progressive and RR/SP patients, median ages at attainment of DSS scores were strikingly similar: DSS = 6, 49 vs 48 years; DSS = 8, 58 vs 58 years; and DSS = 10, 78 years for both (p = NS for all comparisons). CONCLUSIONS: Development of SP is the dominant determinant of long-term prognosis, independent of disease duration and early relapse frequency. Age independently affects disability development primarily by changing probability and latency of SP onset, with little effect on the progressive course.

Relationship of UV exposure to prevalence of multiple sclerosis in England.

OBJECTIVE: To assess the potential relationship of ultraviolet B radiation (UVB) and Epstein-Barr virus (EBV) exposure in explaining the period prevalence of multiple sclerosis (MS) in England. METHODS: English national Hospital Episode Statistics covering all admissions to National Health Service hospitals in England in the 7 years from 1998 to 2005 were used to obtain the period prevalences of MS and infectious mononucleosis (IM) in England. The United States National Aeronautics and Space Administration's data on UVB intensity for England from the Nimbus 7 satellite was collected. The relationships among the 3 variables (MS prevalence, IM prevalence, and UVB intensity) were investigated. RESULTS: The regression of MS against UVB intensity for all seasons had an r(2) of 0.61; when including the interaction of IM with seasonal UVB, the r(2) rose to 0.72. CONCLUSIONS: UVB exposure and IM together can explain a substantial proportion of the variance of MS. The effect of UVB on generating vitamin D seems the most likely candidate for explaining its relationship with MS. There is a pressing need to investigate the role of vitamin D and EBV and how they might interact to influence MS risk to identify potential prevention strategies.

HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination.

BACKGROUND: Multiple sclerosis (MS) in the pediatric age group is being increasingly recognized. In adults, complex interactions between genetic and environmental factors contribute to risk and the major genetic component of MS susceptibility localizes to the major histocompatibility complex (human leukocyte antigen [HLA]). Whether HLA alleles predict MS in at-risk children presenting with acquired demyelinating syndromes (ADS) of the CNS is unknown. METHODS: HLA-DRB1 alleles were typed using an allele-specific PCR amplification method on samples from 266 children presenting with ADS enrolled in the prospective Canadian Pediatric Demyelinating Disease Study and from 196 healthy controls. RESULTS: Sixty-four of 266 children with ADS met established criteria for a diagnosis of MS during a mean follow-up of 3.2 ± 1.5 years. Children harboring DRB1*15 alleles were more likely to be diagnosed with MS (χ(2) = 12.2, p < 0.001; OR = 2.7), an observation strengthened by children of European ancestry (χ(2) = 10.5, p = 0.001; OR = 3.3). DRB1*15 allele frequencies in children with ADS of European ancestry subsequently diagnosed with MS were greater than in children with monophasic ADS (χ(2) = 10.7, p = 0.001) or healthy controls (χ(2) = 12.5, p < 0.001). The proportion of children with non-European ancestry diagnosed with MS was not influenced by DRB1*15 status. CONCLUSION: DRB1*15 alleles confer increased susceptibility to pediatric-onset MS, supporting a fundamental similarity in genetic contribution to MS risk in both pediatric- and adult-onset disease. The specificity of the DRB1*15 risk allele for children with subsequent MS diagnosis, but not for all children with ADS, indicates that the risk conveyed by DRB1*15 relates to chronic CNS disease (MS), rather than acquired demyelination in general.

Association of UV radiation with multiple sclerosis prevalence and sex ratio in France.

BACKGROUND: French farmers and their families constitute an informative population to study multiple sclerosis (MS) prevalence and related epidemiology. We carried out an ecological study to evaluate the association of MS prevalence and ultraviolet (UV) radiation, a candidate climatologic risk factor. METHODS: Mean annual and winter (December-March) UVB irradiation values were systematically compared to MS prevalence rates in corresponding regions of France. UVB data were obtained from the solar radiation database (SoDa) service and prevalence rates from previously published data on 2,667 MS cases registered with the national farmer health insurance system, Mutualité Sociale Agricole (MSA). Pearson correlation was used to examine the relationship of annual and winter UVB values with MS prevalence. Male and female prevalence were also analyzed separately. Linear regression was used to test for interaction of annual and winter UVB with sex in predicting MS prevalence. RESULTS: There was a strong association between MS prevalence and annual mean UVB irradiation (r = -0.80, p < 0.001) and average winter UVB (r = -0.87, p < 0.001). Both female (r = -0.76, p < 0.001) and male (r = -0.46, p = 0.032) prevalence rates were correlated with annual UVB. Regression modeling showed that the effect of UVB on prevalence rates differed by sex; the interaction effect was significant for both annual UVB (p = 0.003) and winter UVB (p = 0.002). CONCLUSIONS: The findings suggest that regional UVB radiation is predictive of corresponding MS prevalence rates and supports the hypothesis that sunlight exposure influences MS risk. The evidence also supports a potential role for gender-specific effects of UVB exposure.

Revisiting the T-cell receptor alpha/delta locus and possible associations with multiple sclerosis.

A role for T cells in the pathogenesis of multiple sclerosis (MS) is well supported, evidenced by myriad immunological studies, as well as the unequivocal genetic influence of the major histocompatibility complex (MHC). Despite many attempts, no convincing genetic associations have been made between T-cell receptor (TCR) gene loci and MS. However, these studies may not be definitive because of small sample sizes and under-representative marker coverage of the chromosomal regions being investigated. To explore potential roles between the TCR alpha locus and MS, we have genotyped a large family-based cohort, including 1360 affected individuals and 1659 of their unaffected first-degree relatives, at 40 single-nucleotide polymorphism (SNP) markers within the TCR alpha/delta locus. This represents the largest TCR alpha-MS study to date. From this screen, we identified three potential loci of interest in TCR alpha variable and constant gene regions using the transmission disequilibrium test. Although SNPs implicating each of these regions of interest will require genotyping in independent replication cohorts, these findings suggest a role for TCR gene polymorphisms in MS susceptibility. In the context of these findings we review the evidence.

MHC transmission: insights into gender bias in MS susceptibility.

OBJECTIVE: Major histocompatibility complex (MHC) genes dominate genetic susceptibility factors in multiple sclerosis (MS). Given the general consensus that incidence and prevalence of MS has been rising and specifically in women, we evaluated MHC-gender interactions. METHODS: In a large family-based cohort consisting of 7,093 individuals (2,127 affected individuals) from 1,055 MS families, we examined MHC transmission by family structure and gender stratified by genetic distance of affected relatives from the MS proband. RESULTS: We found that affected individuals with HLA-DRB1*15-positive genotypes have higher female-to-male ratios as compared with affected individuals with HLA-DRB1*15-negative genotypes (χ(2) = 9.97, p = 0.0015) with the exception of multiplex families with 3 or more affected across 2 generations. Transmission disequilibrium test results show that HLA-DRB1*15 transmission was more distorted in collateral families vs nuclear families (χ(2) = 8.030, p = 0.0046), exclusively in affected female-female pairs (χ(2) = 7.81, p = 0.0051), but not in mixed gender pairs (χ(2) = 1.58, p = 0.21) or matched male pairs (Fisher p = 0.21). CONCLUSIONS: These observations implicate the MHC as the site of interactions and modifications mediating the female-to-male gender ratio in MS and its progressive increase. They further suggest this occurs via gene-environment interactions and epigenetic modifications in this region. The difference between collateral and nuclear families provides some insight into the inheritance, decay, and gender specificity of putative epigenetic marks.

Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial.

BACKGROUND: Evidence for efficacy of disease-modifying drugs in multiple sclerosis (MS) comes from trials of short duration. We report results from a 16 y, retrospective follow-up of the pivotal interferon beta-1b (IFNB-1b) study. METHODS: The 372 trial patients were randomly assigned to placebo (n=123), IFNB-1b 50 microg (n=125) or IFNB-1b 250 microg (n=124) subcutaneously every other day for at least 2 y. Some remained randomised for up to 5 y but, subsequently, patients received treatment according to physicians' discretion. Patients were re-contacted and asked to participate. Efficacy related measures included MRI parameters, relapse rate, the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite Measure and conversion to secondary progressive MS. RESULTS: Of the 88.2% (328/372) of patients who were identified, 69.9% (260/372) had available case report forms. No differences in outcome between original randomisation groups could be discerned using standard disability and MRI measures. However, mortality rates among patients originally treated with IFNB-1b were lower than in the original placebo group (18.3% (20/109) for placebo versus 8.3% (9/108) for IFNB-1b 50 microg and 5.4% (6/111) for IFNB-1b 250 microg). CONCLUSIONS: The original treatment assignment could not be shown to influence standard assessments of long-term efficacy. On-study behaviour of patients was influenced by factors that could not be controlled with the sacrifice of randomisation and blinding. Mortality was higher in patients originally assigned to placebo than those who had received IFNB-1b 50 microg or 250 microg. The dataset provides important resources to explore early predictors of long-term outcome.

Cross-sectional study assessing long-term safety of interferon-beta-1b for relapsing-remitting MS.

OBJECTIVE: The 16-Year Long-Term Follow-Up (LTF) to the pivotal interferon-beta-1b (IFNbeta-1b) trial explored clinical, MRI, cognitive, and patient-reported outcomes. Here, we report the safety assessments. METHODS: In the pivotal study, 372 patients were randomized to placebo (n = 123), IFNbeta-1b 50 microg (n = 125), or IFNbeta-1b 250 microg (n = 124) subcutaneously every other day for up to 5 years. Sixteen years later, patients were asked to participate in this cross-sectional follow-up study. No particular therapy was stipulated during follow-up. Adverse events experienced since the pivotal trial were recorded. Neutralizing antibodies (NAbs) to IFNbeta-1b were measured using the myxovirus protein A induction assay. Statistical analyses were descriptive. RESULTS: In total, 88.2% of patients (328/372) were identified. Some centers achieved 100% ascertainment, obviating selection bias. Treatment-related adverse events (e.g., leukopenia and liver and thyroid dysfunction) reported by LTF participants were in keeping with those previously established. Based on a follow-up period that includes 2,000 patient-years of IFNbeta-1b treatment, no new adverse events were observed that were associated with long-term IFNbeta-1b exposure. By LTF, NAbs to IFNbeta-1b disappeared in the majority (76%) of NAb-positive patients. NAb status during the pivotal study appeared to have no impact on long-term clinical and MRI outcomes. There were more deaths among patients assigned to placebo in the pivotal study (20/109 [18.3%]) compared with patients who received IFNbeta-1b 50 microg (9/108 [8.3%]) or IFNbeta-1b 250 microg (6/111 [5.4%]). CONCLUSION: The results from the 16-Year Long-Term Follow-Up study support the long-term safety of interferon-beta-1b therapy in multiple sclerosis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that patients with relapsing-remitting MS taking IFNbeta-1b 50 microg or 250 microg subcutaneously every other day for up to 5 years, with subsequent unspecified treatment, have fewer deaths after 16 years of follow-up than similar patients on placebo for up to 5 years, with subsequent unspecified treatment (risk difference 11.5%, 95% confidence interval 4-19).

Genetic and environmental factors and the distribution of multiple sclerosis in Europe.

BACKGROUND: The observation that the incidence of multiple sclerosis (MS) increases further from the equator has prompted considerable interest in the factors that might underlie this latitude gradient. Potential candidates include population frequencies of disease-associated Human Leukocyte Antigen (HLA) alleles which are the major genetic component of MS susceptibility. Ultraviolet (UV) exposure and smoking have also been implicated as key environmental risk factors. METHODS: We used multiple sources of published data on MS prevalence, HLA allele frequencies, UV index and cigarette smoking to assess the contributions of both nature and nurture to the distribution of MS within Europe. RESULTS: We observed that HLA alleles unequivocally interact with a population-wide level to determine disease risk. The UV index and smoking behaviour was also shown to correlate with disease distribution in Europe. For countries with HLA, UV and smoking data, these three factors were shown to account for 75% of the variance in MS prevalence. CONCLUSIONS: Genetic (HLA) and environmental (UV and smoking) risk factors thus interact in a complex manner with each other to determine a large proportion of MS susceptibility within Europe.

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease.

Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of self-tolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotype-specific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter- and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

Sex ratio of multiple sclerosis and clinical phenotype.

BACKGROUND AND PURPOSE: In a longitudinal population-based dataset of patients with multiple sclerosis (MS), we have previously observed a substantial increase in the female to male sex ratio in Canada over the last 50 years. Here, we aimed to determine whether this change in sex ratio is related to the clinical course of MS. METHODS: We calculated sex ratios by birth year in 11 868 patients with relapsing-remitting (RR) MS and 2825 patients with primary progressive (PP) MS identified as part of the Canadian Collaborative Project on the Genetic Susceptibility to MS. RESULTS: Year of birth was a significant predictor for sex ratio in RR MS (P < 0.0001, chi(2) = 21.2; Spearman's rank correlation r = 0.67), but not for PP MS (P = 0.44, chi(2) = 0.6; Spearman's rank correlation r = 0.11). CONCLUSIONS: An increase in the number of female RR MS patients over time accounts for the increasing sex ratio of MS. This has implications for pathogenesis, for assessment of clinical trial results and for disease prevention. The factors underlying the selective increase in MS in females need to be uncovered.