PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “MULTIPLE SCLEROSIS”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cerebrospinal fluid abnormalities in a phase III trial of Avonex (IFNbeta-1a) for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group.

BACKGROUND AND OBJECTIVE: This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNbeta-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex , Biogen). The clinical trial demonstrated that IFNbeta-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNbeta-1a therapy on these CSF abnormalities. METHODS: CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. RESULTS: (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNbeta-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. CONCLUSIONS: The current study documents significant reductions in CSF WBC counts in patients treated with IFNbeta-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

Adjuvants, Immunologic↗
PubMed2004

The regulatory role of natural killer cells in multiple sclerosis.

Multiple sclerosis is a chronic demyelinating disease of presumed autoimmune pathogenesis. The patients with multiple sclerosis typically shows alternating relapse and remission in the early stage of illness. We previously found that in the majority of multiple sclerosis patients in a state of remission, natural killer (NK) cells contain unusually high frequencies of the cells expressing CD95 (Fas) on their surface (>36.0%). Here we report that in such 'CD95+ NK-high' patients, NK cells may actively suppress potentially pathogenic autoimmune T cells that can mediate the inflammatory responses in the CNS. Using peripheral blood mononuclear cells (PBMCs) derived from 'CD95+ NK-high' or 'CD95+ NK-low' multiple sclerosis in a state of remission, we studied the effect of NK cell depletion on the memory T cell response to myelin basic protein (MBP), a major target antigen of multiple sclerosis. When we stimulated PBMCs of the 'CD95+ NK-high' multiple sclerosis after depleting CD56+ NK cells, a significant proportion of CD4+ T cells (1/2000 to 1/200) responded rapidly to MBP by secreting interferon (IFN)-gamma, whereas such a rapid T cell response to MBP could not be detected in the presence of NK cells. Nor did we detect the memory response to MBP in the 'CD95+ NK-low' multiple sclerosis patients in remission or healthy subjects, regardless of whether NK cells were depleted or not. Depletion of cells expressing CD16, another NK cell marker, also caused IFN-gamma secretion from MBP-reactive CD4+ T cells in the PBMCs from 'CD95+ NK-high' multiple sclerosis. Moreover, we showed that NK cells from 'CD95+ NK-high' multiple sclerosis could inhibit the antigen-driven secretion of IFN-gamma by autologous MBP-specific T cell clones in vitro. These results indicate that NK cells may regulate activation of autoimmune memory T cells in an antigen non-specific fashion to maintain the clinical remission in 'CD95(+) NK-high' multiple sclerosis patients.

Adult↗
PubMed1998

Characterization of the mitochondrial genome in childhood multiple sclerosis. III. Multiple sclerosis without optic neuritis and the non-LHON-associated genes.

The higher maternal transmission of multiple sclerosis in familial cases and the coincidence of a MS-like phenotype with mitochondrial point mutations in patients with Leber's hereditary optic neuropathy has inspired a detailed assessment of the mitochondrial genome as an etiological factor in the pathogenesis of MS. To further elucidate the contribution of maternally transmitted mutations to MS susceptibility, we sequenced five protein- and all RNA-coding genes of the mtDNA from thirteen children with MS and twenty unaffected individuals. After excluding several synonymous mutations and common polymorphisms, a total of ten ambiguous missense or protein synthesis mutations were selected and analysed. By defining minimal criteria for pathogenity--incidence, location and degree of evolutionary conservation--we conclude that sequence variations in COII, ATPase6 and 8, ND3, or ND4L subunits of oxidative phosphorylation as well as in rRNA and tRNA genes are unlikely to increase susceptibility for the development of MS.

Adolescent↗
PubMed2002

Genetic basis for clinical expression in multiple sclerosis.

Multiple sclerosis is a clinically heterogeneous demyelinating disease and an important cause of acquired neurological disability. An underlying complex genetic susceptibility plays an important role in multiple sclerosis aetiology; however, the role of genetic factors in determining clinical features of multiple sclerosis is unknown. We studied 184 stringently ascertained Caucasian multiple sclerosis families with multiple affected cases. A detailed evaluation of patient histories identified clinical variables including age of onset, initial clinical manifestations and disease severity. The concordance within families for continuous and categorical clinical variables was investigated using an intraclass correlation or Cohen's kappa coefficient, respectively. Genetic analyses included model-dependent, model-independent and association methodology. Linear and logistic regression models were used to evaluate the effect of human leucocyte antigen (HLA)-DR2 (DRB1*1501, DQB1*0602) on clinical outcome, taking account of correlation within families. Significant concordance for early clinical manifestations within families was observed for individuals with exclusive optic neuritis and/or spinal cord involvement as first and second multiple sclerosis attacks (P < 10(-6)). Linkage (LOD = 3.80, theta = 0.20) and association (P = 0.0002) to HLA-DR were present in the dataset; however, linkage was restricted to families in which the DR2 haplotype was present in at least one nuclear member. No evidence for linkage to HLA-DR in DR2-negative families was observed. When families were stratified by concordance of early clinical manifestations, a significant DR2 association was present in all subgroups. Concordance for early manifestations of multiple sclerosis was present in this familial dataset, but was not associated with HLA-DR2. The association of DR2 in families with different clinical presentations suggests that a common basis exists for susceptibility in multiple sclerosis. However, non-HLA genes or other epigenetic factors must modulate disease expression. Locus heterogeneity at the HLA region suggests a distinct immunopathogenesis in DR2 negative patients.

Adolescent↗
PubMed2002

The proteasome is a major autoantigen in multiple sclerosis.

Multiple sclerosis seems to be an autoimmune disease of unknown aetiology affecting the white matter of the CNS. It is generally accepted that the autoimmune response is directed against specific components of myelin. We show here that proteasome, a ubiquitous protease complex composed of 14 different subunits, is a target for autoantibodies (IgG and IgM classes) present in the serum (66%, 73 out of 110) and in the CSF (61%, 16 out of 26) of patients with multiple sclerosis. Using recombinant proteasomal subunits we demonstrate the presence of specific autoantibodies against subunits C2, C8, C9 and C5 in multiple sclerosis patients. Recombinant C2 constructs allow us to localize an immunodominant autoepitope recognized by the sera of multiple sclerosis patients within the C-terminal of C2 proteasomal subunit (251-DEPAEKADEPMEH-263). In addition, two constructs of the recombinant proteasomal subunits C2 and C8 were also used to study the proliferation of peripheral blood mononuclear cells from multiple sclerosis patients; 12 out of 30 (40%) multiple sclerosis patients show positive proliferation with one or both of these recombinant subunits. The high prevalence of anti-proteasome autoantibodies in multiple sclerosis sera compared with sera from patients with other chronic inflammatory conditions: systemic lupus erythematosus (35%, 35 out of 100), primary Sjogren's syndrome (16%, 5 out of 31), vasculitis (0 out of 20), sarcoidosis (7%, 1 out of 13) and Behcet's disease (19%, 4 out of 21) suggest that humoral autoreactivity to proteasome could be a useful test in multiple sclerosis patients that may be of help in the diagnosis and/or progression of this chronic inflammatory disease. Finally, these results suggest that some global abnormality in B and/or T cell function is also involved in the chronic inflammatory response observed in multiple sclerosis patients, as it is frequently observed in other human organ-specific autoimmune diseases.

Adult↗
PubMed2005

Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis.

Multiple sclerosis is a chronic inflammatory and demyelinating disorder of the CNS with an unknown aetiology. Although intrathecal immunoglobulin G (IgG) synthesis is a key feature of the disease, little is still known about the B cell response in the CNS of multiple sclerosis patients. We analysed the phenotype and kinetics of different B cell subsets in patients with multiple sclerosis, infectious disease (IND) and non-inflammatory neurological disease (NIND). B cells were detected in the CSF of multiple sclerosis and IND patients, but were largely absent in NIND patients. In the CSF, the majority of B cells had a phenotype of memory B cells and short-lived plasma blasts (PB); plasma cells were absent from the compartment. The proportion of PB was highest in multiple sclerosis patients and patients with acute CNS infection. While PB disappeared rapidly from the CSF after resolution of infection in IND patients, these cells were present at high numbers throughout the disease course in multiple sclerosis patients. CSF PB numbers in multiple sclerosis patients strongly correlated with intrathecal IgG synthesis and inflammatory parenchymal disease activity as disclosed by MRI. This study identifies short-lived plasma blasts as the main effector B cell population involved in ongoing active inflammation in multiple sclerosis patients.

B-Lymphocytes↗
PubMed2004

Towards cannabis and cannabinoid treatment of multiple sclerosis.

Multiple sclerosis is a common human demyelinating disease of the central nervous system (CNS), and it is thought to involve autoimmune responses to CNS myelin antigens. Current symptomatic therapies for multiple sclerosis are in some cases ineffective and may have a high risk of serious side effects. This has led some multiple sclerosis patients to self-medicate with cannabis, which anecdotal evidence suggests may be beneficial in controlling symptoms such as spasticity, pain, tremor and bladder dysfunction. In support of these claims, results from experimental studies have suggested that cannabinoid-based treatments may be beneficial in a wide number of diseases. Furthermore, recent research in animal models of multiple sclerosis has demonstrated the efficacy of cannabinoids in controlling disease-induced symptoms such as spasticity and tremor, as well as in ameliorating the severity of clinical disease. However, these initially promising results have not yet been fully translated into the clinic. Although cannabinoid treatment of multiple sclerosis symptoms has been shown to be both well tolerated and effective in a number of subjective tests in several small-scale clinical trials, objective measures demonstrating the efficacy of cannabinoids are still lacking. Currently, a number of large-scale phase III clinical trials are under way to further elucidate the use of cannabinoids in the symptomatic treatment of multiple sclerosis. This review highlights the recent advances in our understanding of the endocannabinoid system, discusses both the experimental and clinical evidence for the use of cannabinoids to treat multiple sclerosis and explores possible future strategies of cannabinoid therapy in multiple sclerosis.

Animals↗
PubMed2004

Childhood infections and risk of multiple sclerosis.

Multiple sclerosis has been hypothesized to be the result from an aberrant immune response possibly triggered by delayed exposure to a common childhood infection. Because the vast majority of previous studies testing this hypothesis have been based on a history of childhood infections recalled years to decades later in adulthood, we investigated whether age at six common childhood infections was associated with risk of multiple sclerosis, using information recalled in the childhood of a historical cohort of school children in Denmark. Cases included all individuals with multiple sclerosis in the country born between 1940 and 1975, who had attended school in the capital, Copenhagen. Controls were age- and sex-matched peers. School health records were obtained for all subjects. The records contained information on measles, pertussis, scarlet fever, birth order, sibship size, social class of the father, school years, and name of school and attended school classes for children born since 1940 (n(cases) = 455, n(controls) = 1801). For children born since 1950, the records also contained information on rubella, varicella and mumps (n(cases) = 182, n(controls) = 690). Neither age at infection with measles, rubella, varicella, mumps, pertussis and scarlet fever (upper age limit, 14 years) nor the cumulative number of these infections between the ages of 10 and 14 years was associated with the risk of multiple sclerosis. In addition, the risk of multiple sclerosis was not associated with birth order or social class. No clustering of multiple sclerosis in school classes was observed. Our findings suggest that measles, rubella, mumps, varicella, pertussis and scarlet fever, even if acquired late in childhood, are not associated with increased risk of multiple sclerosis later in life.

Adolescent↗
PubMed1990

T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis.

Multiple sclerosis is thought to be an autoimmune disease of the central nervous system mediated by T cells specific for a myelin antigen. Myelin basic protein has been studied as a potential autoantigen in the disease because of its role as an encephalitogen in experimental autoimmune encephalomyelitis and post-viral encephalomyelitis and because of the presence in the blood of multiple sclerosis patients of in vivo-activated T cells reactive to myelin basic protein. Immune involvement in multiple sclerosis has been further suggested by the association with the major histocompatibility complex class II phenotype DR2, DQw1. To define the T-cell specificity toward myelin basic protein, 15,824 short-term T-cell lines were established from multiple sclerosis subjects, subjects with other neurological diseases, and normal controls. Here we report a higher frequency of T-cell lines reactive with a DR2-associated region of myelin basic protein between residues 84-102 in patients with multiple sclerosis compared with controls. A second region, identified between residues 143-168, was recognized equally in multiple sclerosis patients and controls and was associated with the DRw11 phenotype. These DR2 and DRw11 associations were also observed among T-cell lines generated from family members of a multiple sclerosis patient. The immunodominant 84-102 peptide from myelin basic protein was both DR2- and DQw1-restricted among different T-cell lines. These results raise the possibility that this immunodominant region may be encephalitogenic in some DR2+ individuals.

Amino Acid Sequence↗
PubMed1998

Characterization of the mitochondrial genome in childhood multiple sclerosis. II. Multiple sclerosis without optic neuritis and LHON-associated genes.

The occurrence of mitochondrial mutations with primary pathogenic significance for Leber's hereditary optic neuropathy in patients with a multiple sclerosis-like phenotype and the preferential maternal transmission points to an involvement of the mitochondrial genome in conferring increased susceptibility to MS. To evaluate the link between MS and mtDNA variations we investigated a total of thirteen children with MS as well as twenty controls by sequencing eight mitochondrial encoded genes which are known to be the loci for LHON-associated mutations. Numerous synonymous nucleotide substitutions and common polymorphisms were excluded from comparative analyses. No primary LHON mutations were found. Secondary LHON mutations were identified more frequently in control subjects than in the children with MS. The remaining eight discrete missense mutations were chosen for further characterization. Only two of them were found in more than one patient. Our results suggest that nucleotide substitutions within the ND1, ND2, ND4, ND5, ND6, COI, COIII or cytochrome b genes of mtDNA do not contribute to the etiology of typical MS. However, the association of LHON mutations with visual impairment in MS as well as the relationship between phenotypic diversity in certain subgroups of patients with individual mtDNA genotypes merits further investigations.

Adolescent↗
PubMedDate not supplied

[Use of magnetic resonance imaging in the diagnosis and prognosis of multiple sclerosis].

Multiple sclerosis is an autoimmune disease characterized by demyelination and axonal loss. Conventional magnetic resonance imaging allows the demonstration of spatial and temporal dissemination of multiple sclerosis lesions earlier than is possible from clinical assessments. A variety of conventional magnetic resonance imaging protocols, in conjunction with clinical assessment, are now routinely used to increase the accuracy of diagnosis and long-term prognosis of multiple sclerosis. T2-weighted hyperintense lesions are related primarily to increased water content and thus cannot distinguish between inflammation, edema, demyelination, Wallerian degeneration, and axonal loss, whereas the contrast gadolinium-enhanced lesions on T1-weighted images reflect increased blood-brain barrier permeability associated with active inflammatory activity. Conventional magnetic resonance imaging metrics are not sufficiently sensitive to detect invisible brain damage in the normal appearing brain tissue, and they do not show a reliable correlation with clinical measures of disability. However, numerous studies showed that they can improve accuracy in the diagnosis and prognosis of multiple sclerosis. Recently, non-conventional magnetic resonance imaging techniques have been introduced to increase the accuracy of diagnosis and prognosis of multiple sclerosis. Several studies have used brain atrophy, T1-hypointense lesion volume, magnetization transfer imaging, diffusion-weighted imaging and magnetic resonance spectroscopy to test whether the extent and severity of tissue loss in lesions and in normal appearing gray and white matter at the time of clinically isolated syndrome may have diagnostic and prognostic value. These magnetic resonance imaging techniques represent a powerful tool to non-invasively study different pathological substrates of lesions and microscopic tissue changes. Additional short- and long-term prospective studies are requested to establish their value in the diagnosis and prognosis of multiple sclerosis.

Brain↗
PubMed1982

Colonic dysfunction in multiple sclerosis.

Multiple sclerosis is a central nervous system disease frequently accompanied by urinary symptoms and severe constipation. In order to investigate the pathophysiology of these symptoms, we studied colonic motor and myoelectrical activity, as well as colonic volume-pressure relationships (colonometrograms) and have correlated these data with cystometry and electrophysiologic studies of the central and peripheral somatosensory nervous system. The study group consisted of 7 patients with advanced multiple sclerosis marked by symptoms and signs of somatic and visceral nervous system dysfunction including severe constipation. Ten normal volunteers served as control subjects. The multiple sclerosis group demonstrated electrophysiologic evidence of lesions in the somatosensory neuroaxis central to the lumbosacral spinal cord. Abnormal cystometrograms suggested visceral central nervous system dysfunction. Colonometrograms in the multiple sclerosis group demonstrated a more rapid pressure rise than in the control group (p less than 0.01). The multiple sclerosis group failed to demonstrate the postprandial increase in colonic motor and myoelectrical activity observed in the control group (p less than 0.01). Abnormal colonometrograms and absent postprandial colonic motor and myoelectric responses may be features of visceral neuropathy in patients with advanced multiple sclerosis and severe constipation.

Colon↗
PubMed2005

Immunopathogenesis and immunotherapeutic approaches in multiple sclerosis.

Multiple sclerosis is an organ-specific autoimmune disease, characterized pathologically by cell-mediated inflammation, demyelination and variable degrees of axonal loss. Although inflammation is considered central to the pathogenesis of multiple sclerosis, to date, the only licensed and hence widely used multiple sclerosis immunotherapies are interferon-beta, glatiramer acetate and mitoxantrone. This review discusses the immunopathogenesis of multiple sclerosis, focusing on a number of emerging immunotherapies. A number of new approaches likely to manipulate the immunopathogenesis of multiple sclerosis and which may ultimately allow for the development of more effective immunotherapy are also highlighted.

Humans↗
PubMed1995

Noninvasive assessment of mitoxantrone cardiotoxicity in relapsing remitting multiple sclerosis.

Multiple sclerosis is the most common cause of neurologic disability in young adults. Recent reports have suggested that Mitoxantrone might be a candidate for clinical trials in multiple sclerosis patients. The authors studied 20 patients with relapsing remitting multiple sclerosis to evaluate cardiac toxicity during a one-year follow-up period. Patients were divided into 2 groups: group A, mitoxantrone treated patients (cumulative dose of 96 mg/m2); group B, placebo patients. The clinical course of multiple sclerosis was assessed using the Expanded Disability Status Scale and the number of relapses during the follow-up. Each patient had an electrocardiogram and a spectral and color flow Doppler echocardiographic examination at enrollment, and 6 and 12 months later, to investigate cardiac toxicity. The mean exacerbation rate was reduced significantly in group A patients. No significant differences in the electrocardiograms or the echocardiographic parameters of systolic and diastolic function were noted between the two groups or in group A during the follow-up. Mitoxantrone treatment seems able to improve the clinical course of relapsing remitting multiple sclerosis patients. It does not show any cardiac toxicity in selected patients at this dosage.

Adolescent↗
PubMed1997

Does immunosuppressive ultraviolet radiation explain the latitude gradient for multiple sclerosis?

Multiple sclerosis is regarded as an autoimmune disease. The autoimmune process is thought to be triggered by early-life exposure to viral/bacterial antigens that share key peptide sequences with myelin protein (the target of autoimmune attack in multiple sclerosis). It has long been known that the incidence of multiple sclerosis is positively correlated with latitude, particularly in Caucasian populations. There is no agreed explanation for this latitude gradient, however. Ultraviolet radiation level is negatively correlated with latitude. Recent evidence suggests that ultraviolet-B is immunosuppressive, affecting particularly T-cell activity and delayed-type hypersensitivity. We hypothesize here that the latitude gradient of multiple sclerosis may reflect differential ultraviolet-induced suppression of autoimmune activity, particularly since the autoimmune profile of multiple sclerosis is characterized by disturbances of those T-cell-related activities that are specifically affected by ultraviolet-B. We propose some specific tests of this hypothesis.

Autoimmunity↗