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PubMed1977

Cellular hypersensitivity in attacks of multiple sclerosis. I. A comparative study of migration inhibitory factor production and lymphoblastic transformation in response to myelin basic protein in multiple sclerosis.

Although cell-mediated hypersensitivity to basic myelin protein has been demonstrated in multiple sclerosis with use of cell migration assays, results with the lymphoblastic transformation technique have been inconclusive. However, prospective studies relating results of lymphoblastic transformation to the clinical course of multiple sclerosis have not been reported. In the present study, both lymphoblastic transformation and migration inhibitory factor assays were used, and results related to the temporal course of multiple sclerosis. Results of the present investigation show that cell-mediated hypersensitivity to myelin basic A1 protein is most significant during exacerbations of multiple sclerosis. Responses obtained employing either the lymphoblastic transformation or migration inhibitory factor assay were equally significant. The results support the hypothesis that a factor suppressing deoxyribonucleic acid synthesis is present in multiple sclerosis and is inhibited by the use of steroids.

Cell Migration Inhibition↗
PubMed2002

Baseline MRI characteristics of patients at high risk for multiple sclerosis: results from the CHAMPS trial. Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study.

The baseline MRI studies from the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial, a randomized, longitudinal, double-blind trial of 383 patients with a first acute clinical demyelinating event and evidence of prior subclinical demyelination on magnetic resonance imaging (MRI) of the brain, provides a large MRI database for patients likely in the earliest stages of multiple sclerosis (MS). High-resolution baseline MRIs revealed a median of 13 T2 lesions (maximum = 103 lesions) and 2.05 cm3 of T2 lesion volume (maximum 35.04 cm3), with 30% of patients having one or more enhancing lesions despite receiving a standardized high-dose course of intravenous corticosteroids. Periventricular, discrete, and juxtacortical T2 lesions were present in 99%, 92% and 67% of the patients, respectively. Large (> 6 mm), T1-hypointense, infratentorial, and corpus callosum lesions were present in 69%, 50%, 55% and 58%, respectively. Clinical presentation groups showed differences in T2 lesion volume, and enhancing lesion number and volume. At baseline, 97%, 81% and 72% of the patients met 'Paty', 'Fazekas', and 'Barkhof' research criteria for MS, respectively, with the percentages similar according to clinical presentation group. These results support and extend those of smaller and/or retrospective series, which have shown substantial subclinical injury, based on brain MRI, at the earliest identifiable stages of disease.

Adult↗
PubMed2026

Genome-wide association analyses highlight the neuronal contribution to multiple sclerosis susceptibility.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Previous genetic studies have identified susceptibility loci that primarily impact immune cells and microglia. Here we performed a multi-ancestry genome-wide association study of 20,831 MS cases and 729,220 controls and identified 236 susceptibility variants outside of the major histocompatibility complex, including four novel genomic loci. We also derived a polygenic score for MS; while optimized for European ancestry, it is informative for African American and Latino individuals. Integrating single-cell data from blood and brain tissue, we identified 76 candidate causal genes. Inhibitory neurons emerged as a key target cell type for MS-associated variants, with seven loci, including STAT3, displaying altered expression only in these cells. The STAT3 variant is also associated with cognition and white matter integrity in individuals with no MS and greater sNfL levels in individuals with MS, suggesting that MS susceptibility may reflect reduced central nervous system resilience to inflammatory challenges.

Humans↗
PubMed2006

Perspectives in multiple sclerosis health care: special focus on the costs of multiple sclerosis.

Brain disorders are amongst the leading causes of disease and disability worldwide, accounting for 35% of the burden of all diseases in Europe. Despite their enormous personal and national impact the knowledge of the financial and economic impression of brain disorders has been relatively little researched. Recently it has been estimated that there are nearly 400,000 multiple sclerosis (MS) patients in Europe, which is 0.003% of all brain disease patients in the continent. In MS economic consequences are predominantly the early loss of work capacity and the impact of physical and psychological disabilities in a population of young adults, hospitalization during severe disease exacerbations and the need for assistance in activities of daily living. In the last decade the introduction of new immunomodulatory treatments led to an increase in direct costs due to the cost of these drugs, but also led to a more intensive management of patients. However, most studies of MS costs were carried out prior to the widespread use of newer treatments. In the present study we estimated the economic impact of MS in Israel and compared the traditional-vertical management model with the integrated-multidisciplinary model of health service delivery following the introduction of immunomodulatory treatments. Mean direct health cost was 8,554 euros and 5,599 euros in the traditional and integrative models, respectively (p<0.01). After 1-year follow-up, full-time employment decreased by 10% in the traditional model and increased by 17% in the integrated model (p<0.05). Analysis of variance demonstrated that the model of service delivery explained most of the difference in cost between the two models. Compared to mean annual costs in Europe that are estimated at 23,695 euros per case the cost of health services in Israel by MS patients is significantly lower. MS represents a high economic burden to society. In line with the findings from 15 studies published in Europe, we can conclude that studies agree with the following findings: a) costs outside the healthcare system, non-medical costs and informal care dominate the costs of MS, b) costs increase with increasing severity of the disease and c) an integrated service delivery model that is satisfying to patients on the one hand and cost effective on the other is to be recommended.

Cost of Illness↗
PubMed1988

Epidemiology of multiple sclerosis: incidence and prevalence rates in Denmark 1948-64 based on the Danish Multiple Sclerosis Registry.

The Danish Multiple Sclerosis Registry (DMSR) is a national register based upon the ethnically homogeneous Danish population of about 5 millions. The DMSR was founded in 1956 following a nationwide Danish prevalence survey of MS in 1949 and a continuous registration of incident cases of MS since January 1, 1948. Included in DMSR are all Danish cases of MS (or suspicion of MS) diagnosed by a neurologist or a department of neurology. The sources of notification are the 22 neurological departments in Denmark, the National Patient Registry, the neuropathological departments, the Registry of Causes of Death, and, up to 1975, the Disablement Insurance Court. Notified cases which do not comply with the standardized diagnostic criteria of the DMSR are excluded. An estimate of the completeness of the DMSR is 90-95% and the validity is around 94%. Age- and sex-specific incidence rates of MS for the interval 1948-64 are presented. The crude annual incidence rate of MS in Denmark was in the year 1948-64 4.42 per 100,000 population, 22% higher in females than males. There was a significant geographical variation of incidence rates and a significant downward trend in incidence rates during the interval, whereas the prevalence rates showed a slight increase.

Adolescent↗
PubMed2001

Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.

The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

Humans↗
PubMed2001

[Sjögren's syndrome and multiple sclerosis].

INTRODUCTION: Multiple sclerosis (MS) usually follows a relapsing-remitting course and attacks multiple areas of the central nervous system (CNS). Certain rheumatic diseases, including Sjögren's syndrome (SS), can present with a similar clinical picture. RESULTS: Two patients out 67 of 100 with MS exhibited xerophthalmia and xerostomia and positive Ro antibodies, thus fulfilling 55 diagnostic criteria. Case 1. A 62-year-old woman developed several episodes of numbress and weakness in her left extremity and ataxia. MRI demonstrated a high-intensity areas in periventricular white matter. Initial laboratory studies failure to demonstrate antinuclear antibodies. Xerostomia and xerophthalmia were apparent. Follow-up laboratory examinations showed elevated ANA, Anti-SSA and anti-SSB. Case 2. A 58-year-old woman was diagnosed as having MS at the age of 53 years. Several high-signal foci on MRI were demonstrated in the white matter. Initial serum findings including autoantibodies were unremarkable. Sicca syndrome was present. Laboratory investigations included elevated anti-SSA, anti-SSARo52 and ANA while anti-SSB was within normal limits. DISCUSSION: Primary SS is a chronic autoimmune inflammatory disease of unknown etiology. The CNS symptoms are present in 20-25% of the patients with SS. Some patients have a relapsing-remitting course mimicking MS. Focal brain lesions in SS can occur in the cerebral white matter. The features of our patients sufficiently mimicked those of MS and this disorder was the diagnosis in each patient at the time of initial evaluation. SS should be considered in th

Antibodies, Antinuclear↗
PubMed1993

Epidemiology of multiple sclerosis in U.S. veterans: V. Ancestry and the risk of multiple sclerosis.

Self-reported ancestry data for the U.S. population from the 1980 decennial census and multiple sclerosis (MS) risk data derived from a large series of World War II white male veterans with MS and matched controls were aggregated on a state level and analyzed to determine the relationship between ancestry and MS risk. A significant portion of the state-by-state variation in MS risk is explainable statistically by differences in ancestry among state populations, even when geographic latitude is included in analyses. In the main, Swedish and other Scandinavian ancestry is most consistently associated with places with increased MS risk. In some analyses, Italian, French, and (to a lesser extent) Scottish ancestries are also associated with increased risk, whereas English and Dutch ancestries are each associated with decreased risk, but most of these non-Scandinavian correlations may reflect predominantly geography per se. These findings provide evidence that ancestry of the resident population, a confounded measure of genetic susceptibility and cultural environment, is part of the complicated picture of MS as a disease of place.

Analysis of Variance↗
PubMed2000

Immunogenicity of interferon-beta in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Danish Multiple Sclerosis Study Group.

A total of 754 consecutive patients with relapsing-remitting multiple sclerosis were investigated for interferon-beta (IFNbeta) antibodies by protein-G affinity chromatography and antiviral neutralization bioassay during 24 months on 6 MIU (22 microg) of subcutaneous IFNbeta-1a once weekly (n = 143) or three times weekly (n = 160), 6 MIU (30 microg) of intramuscular IFNbeta-1a once weekly (n = 140), or 8 MIU every other day of IFNbeta-1b (n = 311). The proportion of binding antibodies was higher in those receiving IFNbeta-1b compared with 6 MIU of IFNbeta-1a three times weekly (97 vs 89% at 12 months), and fewer became positive if 6 MIU of IFNbeta-1a was administered once weekly (58 vs 89%). Fewer patients on intramuscular than subcutaneous IFNbeta-1a became positive (33 vs 58%). The binding and neutralizing capacities were higher in the IFNbeta-1b group than in the IFNbeta-1a groups; these differences, however, were not significant after 12 months. The number of positive patients varied considerably and depended on the amount of IFN added to the bioassay; adding 10 LU/ml or more masked antibody detection. Antibodies induced by either preparation neutralized both IFNbeta species but not IFNalpha. In conclusion, IFNbeta-induced antibodies are frequently found in multiple sclerosis patients, and IFNbeta-1b is more immunogenic than IFNbeta-1a. The immunogenicity of IFNbeta-1a increases with the frequency of administration and if it is given subcutaneously.

Adolescent↗
PubMed2004

Outcome measures for multiple sclerosis clinical trials: relative measurement precision of the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite.

We compared the relative measurement precision (RMP) of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) for discriminating between groups of patients known to differ in their extent of multiple sclerosis (MS). A total of 133 patients were rated with the EDSS and MSFC and had magnetic resonance imaging (MRI) scans. Patients were grouped on the basis of MRI appearances (T1- and T2-weighted lesion loads, parenchymal and ventricular fractions--T1LL, T2LL, PF, VF, respectively) and RMP was determined using the method of group differences. For each MRI parameter, the total sample was arranged in ascending order of magnitude and divided into two, three, four and five similar sized groups. For each division (two, three, four or five groups), EDSS and MSFC scores for the groups were compared using parametric (paired samples t-tests, one-way ANOVA) and nonparametric (Wilcoxon's rank-sum test, Kruskal-Wallis analysis of variance) statistical methods and RMP was estimated. The EDSS and MSFC were correlated substantially (r = -0.64). Relative to the MSFC, the EDSS had inferior measurement precision regardless of the number of groups into which the total sample was divided, or the statistical method. However, the RMP of the EDSS compared with the MSFC varied from 2% to 86%. Results suggest the MSCF is better than the EDSS for detecting differences between groups of patients, defined by these MRI markers of MS. However, the finding that both scales correlated weakly with MRI markers, indicated that they are limited as predictors of MS pathology as defined by MRI. An explanation for this well-established clinical-MRI paradox is that rating scales and MRI measure fundamentally different manifestations of MS.

Adolescent↗
PubMed1993

Beta-arrestin and arrestin are recognized by autoantibodies in sera from multiple sclerosis patients.

Multiple sclerosis (MS), one of the most common chronic neurologic diseases, is characterized by the presence of multiple plaques of demyelination throughout the central nervous system. Although the etiology of the disease has not been established, it is believed to involve autoimmune mechanisms. We have examined sera from patients with MS for the presence of antibodies to antigens from brain and retina. Immunoblot analysis of soluble fraction of proteins from bovine brain revealed a prominent band at 45 kDa stained with sera of 8-14 patients with MS. In two patients with MS, serum antibody titers during relapse were higher compared with those when the patients were in remission. These antibodies were undetectable in cerebrospinal fluid of our MS patients and additionally were absent in sera of patients with other neurological diseases and normal control subjects. Furthermore, immunoblot analysis of the soluble fraction from bovine retinal rod outer segments revealed a prominent protein band at 48 kDa stained with MS sera. This antigen was purified to homogeneity from bovine retinal outer segments and identified as arrestin. Additionally, sera from MS patients reacted with purified beta-arrestin 1, a 45-kDa protein homologous to arrestin that is found in various tissues. Using limited proteolysis of arrestin and a competitive ELISA test with a synthetic peptide, we identified the recognition site(s) for antibodies in sera of MS patients at a dominant immunogenic site on arrestin located at the C-terminal region of the molecule. We suggest that the presence of circulating antibodies reactive with beta-arrestin or arrestin may be related to the course of MS progression.

Amino Acid Sequence↗
PubMed2005

Magnetization transfer histograms in clinically isolated syndromes suggestive of multiple sclerosis.

In established multiple sclerosis, magnetization transfer ratio (MTR) histograms reveal abnormalities of normal-appearing white matter (NAWM) and grey matter (NAGM). The aim of this study was to investigate for such abnormalities in a large cohort of patients presenting with clinically isolated syndromes suggestive of multiple sclerosis. Magnetization transfer imaging was performed on 100 patients (67 women, 33 men, median age 32 years) a mean of 19 weeks (SD 3.8, range 12-33 weeks) after symptom onset with a clinically isolated syndrome and in 50 healthy controls (34 women, 16 men, median age 32.5 years). SPM99 software was used to generate segmented NAWM and NAGM MTR maps. The volumes of T2 lesions, white matter and grey matter were calculated. Eighty-one patients were followed up clinically and with conventional MRI after 3 years (n = 61) or until they developed multiple sclerosis if this occurred sooner (n = 20). Multiple regression analysis was used to investigate differences between patients and controls with age, gender and volume measures as covariates to control for potential confounding effects. The MTR histograms for both NAWM and NAGM showed a reduction in the mean (NAWM, 38.14 versus 38.33, P = 0.001; NAGM 32.29 versus 32.50, P = 0.009; units in pu) and peak location, with a left shift in the histogram. Mean NAWM and NAGM MTR were also reduced in the patients who developed clinically definite multiple sclerosis and multiple sclerosis according to the McDonald criteria but not in the 24 patients with normal T2-weighted brain magnetic resonance imaging (MRI). MTR abnormalities occur in the NAWM and NAGM at the earliest clinical stages of multiple sclerosis.

Adult↗
PubMed2000

Benefits of glatiramer acetate on disability in relapsing-remitting multiple sclerosis. An analysis by area under disability/time curves. The Copolymer 1 Multiple Sclerosis Study Group.

New immunomodulatory therapies for relapsing-remitting multiple sclerosis (RRMS) have well-documented effects in reducing relapses, but it has been difficult to demonstrate their benefits on disability in relatively short treatment trials. Commonly utilised disability outcome measures are problematic both in usefulness and clinical interpretation when applied to MS subjects with fluctuating and variable disease courses. An alternative technique is to use the summary measure 'area under the disability/time curve' (AUC) to index the total in-trial morbidity experienced by patients. In this study, we applied AUC analyses to the serial Expanded Disability Status Scale (EDSS) scores from the U.S. multicentre, Phase III, two-year core study of glatiramer acetate in 251 RRMS patients. When all available EDSS evaluations were analysed with AUC(CHANGE) ('combined data', including relapse-related assessments), active treatment was significantly superior to placebo (P=0.018). The benefits of glatiramer acetate persisted when transient relapse effects were reduced by using 'scheduled visit data' only (P=0.021). With the more conservative AUC(SUM) measure, significant active treatment effects remained (P=0.029 and 0.046, for both 'combined' and 'scheduled visit' data, respectively). Subgroup calculations performed with baseline disability stratified at EDSS 3.5 also showed benefits of treatment over placebo, but statistical significance was not reached. This analysis of data from a Phase III treatment trial illustrates the AUC summary measure technique and provides further evidence of the efficacy of glatiramer acetate in RRMS.

Disability Evaluation↗