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PubMed2000

Interleukin 1 receptor antagonist (IL-1ra) in multiple sclerosis.

The autoimmune nature of multiple sclerosis introduces cytokine genes as logical candidates for the loci determining susceptibility to the disease, and/or influencing disease progression. Working on this principle, several groups have investigated the relevance of polymorphism in the interleukin 1 receptor antagonist gene (IL1RN) but with conflicting results. In an effort to clarify this situation, we typed the functionally significant variable number of tandem repeat (VNTR) polymorphism from intron 2 of IL1RN in 536 simplex families with multiple sclerosis. In order to improve the information extracted from these families, we also typed a closely mapped single nucleotide polymorphism (SNP) from the promoter of IL1B (the gene for IL-1beta). Disease associations were assessed by transmission disequilibrium testing (TDT), alone and after haplotype construction. There was highly significant (P</=2.48.10(-16)) linkage disequilibrium (LD) between the two polymorphisms studied, illustrating that LD adjacent to an SNP can be considerably more extensive than has recently been suggested. None of the alleles from the VNTR, the SNP or their haplotype showed statistically significant evidence for association. We stratified patients for current disability status but using this manoeuvre found no evidence that either of the polymorphisms influences disease severity. Combining the available data on the IL1RN VNTR suggests that any effect of this gene on susceptibility to multiple sclerosis, or its progression is, at best, small.

Adult↗

PubMed2005

[Application of the Multiple Sclerosis Functional Composite in Debrecen].

INTRODUCTION: The Multiple Sclerosis Functional Composite (MSFC) has been recommended by the National Multiple Sclerosis Society as a new clinical outcome measure. It is based on measurements in three clinical dimensions: leg function/ambulation (timed 25-foot walk), arm function (9-hole peg test), and cognitive function (paced auditory serial addition test). Scores on component measures are converted to standard scores (Z-scores) that reflect patient performance. This method has not yet been introduced into routine clinical practice. PATIENTS AND METHOD: MSFC calculation was applied to 17 patients with relapsing-remitting multiple sclerosis (age mean: 37.4+/-10.8 years; duration of the disease: 5.5+/-4.9 years, EDSS: 2.7+/-1.4) seen at the neuroimmunological outpatient clinic to evaluate its usefulness and its correlation with the traditionally applied Expanded Disability Status Scale (EDSS) and with patient-reported quality of life. Fifteen patients received immunomodulatory treatment (interferon beta and glatiramer acetate). MSFC and EDSS were measured at 0, 3, 6, 9, 12, 18 months, and questionnaires on quality of life were filled in by the patients at 0, 6, 12, 18 months of follow-up. RESULTS: The prospective study confirmed a strong correlation between EDSS and MSFC (Spearman correlation test, p=0.03, 0.004, 0.002, 0.004, 0.0008, 0.002; R=-0.54, -0.66, 0.68, -0.65, -0.73, -0.69) in multiple sclerosis. The MSFC was more sensitive to clinical changes than EDSS. The extent of changes on the two scales correlated only after 18 months (p<0.005, R=-0.65). The arm/hand function was the most sensitive measure for disease progression. There was no correlation between the quality of life and either of the two other clinical parameters. CONCLUSION: MSFC is a simple method, suitable for follow-up of multiple sclerosis patients in everyday clinical practice.

Adult↗

PubMed1988

Immunotherapy of multiple sclerosis.

Based on the assumption that multiple sclerosis is an autoimmune disease, a number of clinical trials designed to suppress the immune system or to restore immune balance in multiple sclerosis have been attempted. Depending on the disease category, the clinical goals of immunotherapy differ. Therapeutic goals include improving recovery from acute attacks, preventing or decreasing the number of relapses, and halting the disease in its progressive stage. The ultimate goal of multiple sclerosis therapy is the early treatment of patients in an attempt to halt the onset of progression. Specific strategies of immunotherapy include generation of a suppressor influence, removal of helper/inducer cells, manipulation of activated T cells, manipulation of class II major histocompatibility complex-bearing cells, alteration of lymphocyte traffic, extracorporeal removal of serum factors or cells, and manipulation of antigen-specific cells. Present treatment modalities are beginning to show some efficacy of nonspecific immunosuppression, but these treatments are limited by their toxicities. As the immunotherapy of multiple sclerosis moves to the next stage in the coming years, patients at an earlier stage of their disease will have to be treated, nontoxic forms of therapy developed, clinical trials lengthened, and a laboratory monitor of the disease developed. Given the positive effects of immunotherapy seen thus far in the disease, it is possible that appropriate immunotherapeutic intervention may provide effective treatment for the disease in the future.

Autoantibodies↗

PubMed1994

Multiple sclerosis in black South Africans and Zimbabweans.

Multiple sclerosis is rare among the indigenous black people of Africa. The first account of a black patient with multiple sclerosis in South Africa was published as late as 1987. Since then a search to find black patients with multiple sclerosis in Southern Africa has continued. Seven black patients have now been traced in South Africa and five in Zimbabwe in whom a diagnosis of multiple sclerosis can be accepted. Six of the 12 patients became blind, or nearly so, from severe optic neuritis. Multiple sclerosis in these few black patients more often resembled the disorder as it occurs in oriental people than among white people in southern Africa or the black people of North America or the Caribbean.

Adolescent↗

PubMed2002

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis.

Genetic factors influence susceptibility to multiple sclerosis but the responsible genes remain largely undefined, association with MHC class II alleles being the only established genetic feature of the disease. The Nordic countries have a high prevalence of multiple sclerosis, and to further explore the genetic background of the disease, we have carried out a genome-wide screen for linkage in 136 sibling-pairs with multiple sclerosis from Denmark, Finland, Norway and Sweden by typing 399 microsatellite markers. Seventeen regions where the lod score exceeds the nominal 5% significance threshold (0.7) were identified-1q11-24, 2q24-32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21-22, 6q21, 9q34.3, 10p15, 10p12-13, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12-13 and Xp22.3. Although none of these regions reaches the level of genome-wide significance, the number observed exceeds the 10 that would be expected by chance alone. Our results significantly add to the growing body of linkage data relating to multiple sclerosis.

Denmark↗

PubMed2006

Epidemiology and natural history of multiple sclerosis: new insights.

PURPOSE OF REVIEW: The cause of multiple sclerosis remains elusive. We review recent epidemiological studies of genetic and environmental factors that influence susceptibility to the disease and its clinical course. RECENT FINDINGS: Genetic advances strengthen the association of multiple sclerosis with the human leukocyte antigen (HLA)-DRB1 allele and interferon-gamma polymorphisms and suggest that apolipoprotein E alleles play an important role. In the environmental realm, nested case-control studies show that prior Epstein-Barr virus exposure is overrepresented in multiple sclerosis. Smoking has been associated with both risk of multiple sclerosis and progressive disease. Vitamin D deficiency might tie together environmental clues with higher multiple sclerosis prevalence rates; dietary vitamin supplementation is also associated with reduced multiple sclerosis risk. Natural history studies demonstrated dissociation between relapses and disease progression, facilitated the ability to distinguish neuromyelitis optica and related syndromes from typical multiple sclerosis, and spawned the exploration of large datasets to model long-term disease activity. SUMMARY: Our understanding of the contributions of specific genetic and environmental factors that contribute to multiple sclerosis has improved. Further refinements will eventually allow powerful longitudinal studies to assess genetic and environmental interactions with implications for prediction of individual disease susceptibility, clinical course, and response to therapy.

Disease Susceptibility↗

PubMed1996

Prevalence of multiple sclerosis in Rochdale.

The prevalence of multiple sclerosis in the Rochdale Metropolitan Borough in the north east of Greater Manchester has been established. Case ascertainment was partly prospective via a neurological register from 1979 and by contact with general practitioners, therapists, and social services. On prevalence day, 1 January 1989, 254 patients with multiple sclerosis were living in Rochdale. The overall prevalence was 122/100,000 population and 96/100,000 population for probable cases only. The peak rate for women aged 35 to 44 years was 437/100,000 population and for men aged 45 to 54 years 221/100,000. Familial multiple sclerosis was present in 10.8% of families. In this, the first study in north west England, the prevalence of multiple sclerosis in Rochdale is similar to that in southern England and Wales but lower than that in Scotland.

Adult↗

PubMed2003

Glatiramer acetate treatment in patients with childhood and juvenile onset multiple sclerosis.

BACKGROUND: Recent data indicate that in multiple sclerosis disease onset before the age of 16 is more common than previously assumed. However, current therapeutic options are limited to the treatment of acute attacks in these patients. Glatiramer acetate has been successfully applied in adults with relapsing-remitting multiple sclerosis, but there are no data available about the use of glatiramer acetate in childhood and juvenile onset multiple sclerosis. METHODS: Seven patients with relapsing-remitting multiple sclerosis and disease onset between 9 and 16 years of age were treated with daily subcutaneous injection of 20 mg glatiramer acetate (Copaxone). Patients were followed for 24 months. Treatment was initiated in all patients before the age of 18. RESULTS: The use of glatiramer acetate in our cohort of early onset multiple sclerosis patients was safe and well tolerated. Two out of seven patients remained relapse-free during the two year period. Clinical disability as measured by the EDSS remained stable in three out of seven patients. CONCLUSION: Due to the small number of patients the efficacy of the treatment has to be interpreted with caution. However, there might be a more pronounced treatment benefit in patients with low disability at treatment initiation and early treatment onset.

Adjuvants, Immunologic↗

PubMed2004

Multiple sclerosis: etiological mechanisms and future directions.

Multiple sclerosis (MS) is a complex human autoimmune-type disease with a predominantly unknown etiology. Immunologic destruction of myelin basic protein (MBP) throughout the nervous system is the major pathology of multiple sclerosis. This review will attempt to update new information about basic mechanisms and therapeutic management of the disease. The significance of the structure of MBP is discussed with respect to the contribution of such structures to the disease process. A number of MBP peptides that serve as the immunodominant antigens in MS patients have been identified. These peptides have been studied in animal models for their antigenic characteristics and ability to induce disease. Evidence for genetic contributions is reviewed with multigenerational twin studies providing the best evidence for susceptible haplotypes. The role of microorganisms/viruses and environmental agents are discussed as potential etiological factors but are now thought to be of minor importance to the primary causal development of the disease. Of major consideration are immunological mechanisms that contribute to the development of autoimmunity. In particular, antigen expression, cytokine and leukocyte interactions, and regulatory T-cells are discussed. Particular attention is given to regulatory T-cells (Treg), which help balance/modulate other T-cells such as Th1 and Th2 cells, and how such Treg regulate autoimmunity is addressed. The importance of the role of Tregs is exemplified by the demonstration that administration of oral antigens can induce specific Tregs that counteract experimental autoimmune encephalomyelitis in animal models. The significance of animal studies to human multiple sclerosis is discussed. A potential role for natural antibodies and innate immune mechanisms to help provide resistance to disease development is also reviewed. Finally, a variety of therapeutic agents that have been and continue to be utilized for multiple sclerosis is reviewed. Trials with oral antigens, such as glatirmer acetate (copolymer 1) especially in combination with interferon-beta, have shown promise. Antibody therapy and bone marrow transplantation are also briefly discussed.

Animals↗

PubMed1998

Attention impairment in recently diagnosed multiple sclerosis.

Patients with multiple sclerosis (MS) experience cognitive disorders which can occur early in the course of the disease. The present study tried to investigate attention abilities of MS patients at the early stage of the disease. Three attention modalities (sustained, simple and complex focused attention) were evaluated. The results show that MS patients at the early stage of the disease presented attentional dysfunction only when the cognitive load of the attention task was high and when controlled information processing was required. This suggests that MS patients probably suffer from a processing resources deficit without modification of the attentional mechanisms.

Journal Article↗

PubMed2005

Co-occurrence of autoimmune thyroid disease in a multiple sclerosis cohort.

BACKGROUND: Multiple sclerosis (MS), Hashimoto's disease and Graves' disease are autoimmune diseases that may share similar pathogenic mechanisms. The co-occurrence rates and demographic characteristics of Graves' disease and Hashimoto's disease (HT) in our MS population are compared with the general population. METHODS: The prevalence of thyroid disease in our MS patients was determined by chart review and survey. Previous diagnosis of thyroid disease, age at diagnosis, treatment used, and about the use of disease modifying medications used to treat their MS were asked. Chart reviews were used to estimate the population prevalence of Graves' disease and Hashimoto's disease and to estimate the demographics of patients with thyroid disease. RESULTS: A significant co-occurrence of Graves' disease with MS (p = 0.002), and a non-significant co-occurrence of Hashimoto's disease were noted (p = 0.097). No difference in the age of onset or gender of thyroid disease in MS patients compared to the general population was found. CONCLUSION: There is a significant co-occurrence in patients with MS and Graves' disease, and a trend to co-occurrence in patients with MS and Hashimoto's disease. There are no differences in the demographics of patients with thyroid disease in our MS patients compared to the general population.

Journal Article↗

PubMed2006

Production of IL-16 correlates with CD4+ Th1 inflammation and phosphorylation of axonal cytoskeleton in multiple sclerosis lesions.

BACKGROUND: Multiple sclerosis (MS) is a central nervous system-specific autoimmune, demyelinating and neurodegenerative disease. Infiltration of lesions by autoaggressive, myelin-specific CD4+Th1 cells correlates with clinical manifestations of disease. The cytokine IL-16 is a CD4+ T cell-specific chemoattractant that is biased towards CD4+ Th1 cells. IL-16 precursor is constitutively expressed in lymphocytes and during CD4+ T cell activation; active caspase-3 cleaves and releases C-terminal bioactive IL-16. Previously, we used an animal model of MS to demonstrate an important role for IL-16 in regulation of autoimmune inflammation and subsequent axonal damage. This role of IL-16 in MS is largely unexplored. Here we examine the regulation of IL-16 in relation to CD4+ Th1 infiltration and inflammation-related changes of axonal cytoskeleton in MS lesions. METHODS: We measured relative levels of IL-16, active caspase-3, T-bet, Stat-1 (Tyr 701), and phosphorylated NF(M+H), in brain and spinal cord lesions from MS autopsies, using western blot analysis. We examined samples from 39 MS cases, which included acute, subacute and chronic lesions, as well as adjacent, normal-appearing white and grey matter. All samples were taken from patients with relapsing remitting clinical disease. We employed two-color immunostaining and confocal microscopy to identify phenotypes of IL-16-containing cells in frozen tissue sections from MS lesions. RESULTS: We found markedly increased levels of pro- and secreted IL-16 (80 kD and 22 kD, respectively) in MS lesions compared to controls. Levels of IL-16 peaked in acute, diminished in subacute, and were elevated again in chronic active lesions. Compared to lesions, lower but still appreciable IL-6 levels were measured in normal-appearing white matter adjacent to active lesions. Levels of IL-16 corresponded to increases in active-caspase-3, T-bet and phosphorylated Stat-1. In MS lesions, we readily observed IL-16 immunoreactivity confined to infiltrating CD3+, T-bet+ and active caspase-3+ mononuclear cells. CONCLUSION: We present evidence suggesting that IL-16 production occurs in MS lesions. We show correlations between increased levels of secreted IL-16, CD4+ Th1 cell inflammation, and phosphorylation of axonal cytoskeleton in MS lesions. Overall, the data suggest a possible role for IL-16 in regulation of inflammation and of subsequent changes in the axonal cytoskeleton in MS.

Journal Article↗

PubMed2001

Limited pattern of TCR delta chain gene rearrangement on the RNA level in multiple sclerosis.

Susceptibility to multiple sclerosis (MS) is most likely affected by a number of genes, including HLA and T-cell receptor (TCR) genes. T cells expressing gamma/delta receptors seem to contribute to autoagression in MS, as evidenced by their localization in the MS plaques in the brain. The aim of this study was to analyse the TCRdelta chain gene rearrangement at the RNA (cDNA) level and compare to the DNA pattern rearrangement. TCRdelta gene rearrangement was analysed in MS patients and healthy individuals with the use of primers specific for Vdelta1-6 and Jdelta1 genes (at the DNA level) and specific for Vdelta1-6 and Cdelta1 genes (at the cDNA level). The size of PCR products was analysed on agarose gel and by ALF-Express (Pharmacia). Additionally, the lymphocyte surface immunophenotype was studied with specific monoclonal antibodies. At the DNA level a restricted pattern of Vdelta3-Jdelta1 and Vdelta5-Jdelta1 was found only in MS patients. Contrary to DNA, mono-, oligoclonal RNA (cDNA) rearrangements were limited to Vdelta1-Cdelta1, Vdelta2-Cdelta1 and Vdelta3-Cdelta1 only in MS patients as well. Surface immunophenotype analysis revealed in MS a much higher frequency of activated gamma/delta T lymphocytes, i.e. expressing HLA-DR and CD25. An elevated level of CD56 positive cells in MS was recorded. Mono-oligoclonal pattern of TCRdelta gene rearrangement at the RNA level, along with increase in activated gamma/delta T cells, strongly argue for a significant role of gamma/delta T lymphocytes in the pathogenesis of MS.

Journal Article↗

PubMed1995

Brain magnetic resonance imaging and multimodal evoked potentials in benign and secondary progressive multiple sclerosis.

Brain MRI and multimodal evoked potentials (EPs) were obtained for 13 patients with benign multiple sclerosis and 13 patients with secondary progressive multiple sclerosis, matched for age and duration of the disease, to investigate the nature of the disability in multiple sclerosis. Patients with secondary progressive multiple sclerosis had significantly greater lesion loads for five of seven periventricular regions and for three of nine regions separate from the ventricles. Patients with secondary progressive multiple sclerosis also had more severe infratentorial atrophy scores (p = 0.04), whereas there were no differences between the two groups in number and extent of enhancing lesions. The frequencies were significantly higher and severities greater for multimodal EP abnormalities of all the modalities in patients with secondary progressive multiple sclerosis. At least one EP component was absent in 12 (92%) patients with secondary progressive multiple sclerosis but in only one patient (8%) with benign multiple sclerosis (p < 0.001). There was neurophysiological evidence for cervical cord involvement in eight (61%) patients with secondary progressive multiple sclerosis and in one with benign multiple sclerosis (p < 0.01). These data indicate that the total amount of lesions, the distribution, and the nature of the pathological process might all account for the development of disability in multiple sclerosis.

Age of Onset↗

PubMedDate not supplied

[A study of various scales of fatigue and impact on the quality of life among patients with multiple sclerosis].

OBJECTIVES: To explore fatigue in multiple sclerosis and evaluate the specificity of three fatigue scales in this condition: the fatigue severity scale, the specific fatigue scale and the fatigue impact scale. MATERIAL AND METHODS: We sent out 60 questionnaires with the three scales and the quality of life scale, the Nottingham Health Profile, to patients with multiple sclerosis as clinically defined by Poser's criteria. Answers were received to 58 questionnaires and the data correlated by Sperman's correlation and the Student t test, with demographic variables (age, age of onset and sex) and clinical variables (clinical form, time the disease was present, period of time since the previous episode and Kurtzke scale (EDSS). RESULTS: Fatigue was present in 78% of the patients. There was correlation between fatigue severity scale and EDSS, pyramidal function, cerebellar function, the period of time the illness was present and the clinical form. We found that the specific fatigue scale is independent of EDSS. The fatigue impact scale was correlated with the EDSS apart from the questions concerning cognitive function. CONCLUSIONS: Fatigue is a common symptom of multiple sclerosis which has an independent effect on cognitive function. It is also related to involvement of the pyramidal and cerebellar systems, and depends on the degree of disability and time the disease has been present. The specific fatigue scale is a good tool for exploration of this symptom of multiple sclerosis.

Cognition Disorders↗

PubMed1997

Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis.

We compared MRI criteria used to predict conversion of suspected multiple sclerosis to clinically definite multiple sclerosis. Seventy-four patients with clinically isolated neurological symptoms suggestive of multiple sclerosis were studied with MRI. Logistic regression analysis was used to remove redundant information, and a diagnostic model was built after each MRI parameter was dichotomized according to maximum accuracy using receiver operating characteristic analysis. Clinically definite multiple sclerosis developed in 33 patients (prevalence 45%). The optimum cut-off point (number of lesions) was one for most MRI criteria (including gadolinium-enhancement and juxta-cortical lesions), but three for periventricular lesions, and nine for the total number of T2-lesions. Only gadolinium-enhancement and juxta-cortical lesions provided independent information. A final model which, in addition, included infratentorial and periventricular lesions, had an accuracy of 80%, and having more abnormal criteria, predicted conversion to clinically definite multiple sclerosis strongly. The model performed better than the criteria of Paty et al. (Neurology 1988; 38: 180-5) and of Fazekas et al. (Neurology 1988; 38: 1822-5). We concluded that a four-parameter dichotomized MRI model including gadolinium-enhancement, juxtacortical, infratentorial and periventricular lesions best predicts conversion to clinically definite multiple sclerosis.

False Negative Reactions↗

PubMed2004

Multiple sclerosis in women having children by multiple partners. A population-based study in Denmark.

We investigated whether having children with multiple men is a risk factor for being diagnosed with multiple sclerosis (MS). We studied a cohort of 151,328 women, of whom 64,704 had different men fathering their children and 86,624 the same partner for all births. Women were included if they had a second or higher parity child between 1973 and 1996. The follow-up for MS ended in 1997. There were a total of 213 cases of MS diagnosed during the study period. We analysed data through Poisson regression models. Women having children with different men were not at higher risk of being diagnosed with MS, with the possible exception of a short period after having a baby with a new partner. Women having children with more than one man may have a higher risk of a pregnancy accelerating the diagnosis of MS but are probably not at an overall higher risk of MS.

Adult↗

PubMed1995

Patients with multiple sclerosis presenting to psychiatric hospitals.

BACKGROUND: Although many neuropsychiatric syndromes are associated with multiple sclerosis, few recent studies have examined the clinical features of psychiatric illness in inpatients with multiple sclerosis. Florid psychopathology can obscure neurologic symptoms in multiple sclerosis. It is therefore important to consider the range of severe psychiatric states that can occur in multiple sclerosis and the frequency with which multiple sclerosis patients are seen in inpatient facilities. METHOD: We examined records for 2720 consecutive admissions to three psychiatric units and conducted a chart review comparing the DSM-III psychiatric diagnoses of patients with multiple sclerosis with those of the inpatient population as a whole. RESULTS: The 10 patients with multiple sclerosis were significantly more likely to present with histories of mania and manic psychosis than the inpatient population as a whole. Further, 7 of the 10 patients had psychiatric hospitalizations before the multiple sclerosis diagnosis. In 4 of these 7 patients, a review of the medical record documented neurologic symptoms that were not recognized as typical of multiple sclerosis. Three of these 4 patients were psychotic and the fourth was catatonic at the time of their admissions. CONCLUSION: While multiple sclerosis patients account for a small proportion of all psychiatric admissions, clinicians should consider the diagnosis of multiple sclerosis in patients exhibiting manic symptoms in tandem with unexplained neurologic findings.

Adult↗