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Results for “SCLEROSIS, MULTIPLE”

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PubMed1999

The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis.

We report a natural history study of 216 patients with primary progressive (PP)- multiple sclerosis defined by at least 1 year of exacerbation-free progression at onset. This represents 19.8% of a largely population-based patient cohort having a mean longitudinal follow-up of 23 years. This subgroup of PP-multiple sclerosis patients had a mean age of onset of 38.5 years, with females predominating by a ratio of 1.3:1.0. The rate of deterioration from disease onset was substantially more rapid than for relapsing-remitting multiple sclerosis, with a median time to disability status score (DSS) 6 and DSS 8 of 8 and 18 years, respectively. Forty-nine percent of patients were followed through to death. Examination of the early disease course revealed two groups with adverse prognostic profiles. Firstly, a shorter time to reach DSS 3 from onset of PP-multiple sclerosis significantly adversely influenced time to DSS 8. Second, involvement of three or more neurological systems at onset resulted in a median time to DSS 10 of 13.5 years in contrast to PP-multiple sclerosis patients with one system involved at onset where median time to death from multiple sclerosis was 33.2 years. However, age, gender and type of neurological system involved at onset appeared to have little influence on prognosis. Life expectancy, cause of mortality and familial history profile were similar in PP-multiple sclerosis and non-PP-multiple sclerosis (all other multiple sclerosis patients from the total population). From clinical onset, rate of progression was faster in the PP-multiple sclerosis group than in the secondary progressive (SP)-multiple sclerosis group. When the rates of progression from onset of the progressive phase to DSS 6, 8 and 10 were compared, SP-multiple sclerosis had a more rapid progressive phase. A substantial minority (28%) of the PP-multiple sclerosis cohort had a distinct relapse even decades after onset of progressive deterioration. These studies establish natural history outcomes for the subgroup of multiple sclerosis patients with primary progressive disease.

Adult↗

PubMedDate not supplied

[Genetic and environmental factors in multiple sclerosis].

INTRODUCTION: Multiple sclerosis is expressed in genetically susceptible persons randomly affected by an unknown environmental factor, probably a virus, which sets off an abnormal immune process. DEVELOPMENT AND CONCLUSION: Race is an important predictive risk factor for multiple sclerosis, but genetics alone do not explain the occurrence of this disease. The genetic predisposition is complex, since several loci are involved in the susceptibility. Probably the immune process seen in multiple sclerosis is a consequence not a cause. The cause is possibly unique and due to infection. The causative agent may be rare or on the contrary may be frequent, but has different biological effects on susceptible persons. Epidemiology alone is not sufficient to find the cause. This requires collaboration from the basic sciences (genetics, microbiology, etc.). The results of epidemiological methods would be much improved if a biological marker for the disease was available.

Adolescent↗

PubMed2003

Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a genetic component. Until now, the more consistent association with the disease is found with the major histocompatibility complex, especially HLA-DRB1*1501-DQB1*0602 haplotype. In this report, we demonstrate the interaction of Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4 [CD152]) gene with DRB1*15 haplotype in multiple sclerosis genetic susceptibility. Our data were obtained from two European independent family-based studies including 610 multiple sclerosis family trios. Ann Neurol 2003;54:119-122

Abatacept↗

PubMed2005

A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility.

Multiple sclerosis is a common disease with proven heritability, but, despite large-scale attempts, no underlying risk genes have been identified. Traditional linkage scans have so far identified only one risk haplotype for multiple sclerosis (at HLA on chromosome 6), which explains only a fraction of the increased risk to siblings. Association scans such as admixture mapping have much more power, in principle, to find the weak factors that must explain most of the disease risk. We describe here the first high-powered admixture scan, focusing on 605 African American cases and 1,043 African American controls, and report a locus on chromosome 1 that is significantly associated with multiple sclerosis.

Black or African American↗

PubMed1992

Peripheral sensory abnormalities in patients with multiple sclerosis.

Although multiple sclerosis primarily affects myelin within the central nervous system, both pathologic and physiological studies suggest that mild deficits in peripheral nervous system myelin may be common. To evaluate this question further, we performed near nerve studies on sural nerves of 14 patients with multiple sclerosis. Peak-to-peak amplitude and maximum conduction velocity were normal in 9 of 14 patients, while minimum conduction velocity, or the velocity of the slowest-conducting component of the sensory action potential, was abnormally reduced in 9 patients. In addition, the supernormal period was evaluated for patients and compared with a control sample; multiple sclerosis patients showed a significant reduction in the amplitude of supernormality. Both the reduction in minimum conduction velocity and the alteration in the supernormal period are consistent with a mild defect in peripheral myelin.

Action Potentials↗

PubMed2004

Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis.

In multiple sclerosis, in which brain tissue becomes permeable to blood proteins, extravascular fibrin deposition correlates with sites of inflammatory demyelination and axonal damage. To examine the role of fibrin in neuroinflammatory demyelination, we depleted fibrin in two tumor necrosis factor transgenic mouse models of multiple sclerosis, transgenic lines TgK21 and Tg6074. In a genetic analysis, we crossed TgK21 mice into a fibrin-deficient background. TgK21fib(-/-) mice had decreased inflammation and expression of major histocompatibility complex class I antigens, reduced demyelination, and a lengthened lifespan compared with TgK21 mice. In a pharmacologic analysis, fibrin depletion, by using the snake venom ancrod, in Tg6074 mice also delayed the onset of inflammatory demyelination. Overall, these results indicate that fibrin regulates the inflammatory response in neuroinflammatory diseases. Design of therapeutic strategies based on fibrin depletion could potentially benefit the clinical course of demyelinating diseases such as multiple sclerosis.

Animals↗

PubMed1999

Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis.

BACKGROUND: Multiple sclerosis results from T-cell-dependent inflammatory demyelination of the central nervous system. Our objective was long-term suppression of inflammation with short-term monoclonal antibody treatment. METHODS: We depleted 95% of circulating lymphocytes in 27 patients with multiple sclerosis by means of a 5-day pulse of the humanised anti-CD52 monoclonal antibody, Campath-1H. Clinical and haematological consequences of T-cell depletion, and in-vitro responses of patients' peripheral-blood mononuclear cells were analysed serially for 18 months after treatment. FINDINGS: Radiological and clinical markers of disease activity were significantly decreased for at least 18 months after treatment. However, a third of patients developed antibodies against the thyrotropin receptor and carbimazole-responsive autoimmune hyperthyroidism. The depleted peripheral lymphocyte pool was reconstituted with cells that had decreased mitogen-induced proliferation and interferon gamma secretion in vitro. INTERPRETATION: Campath-1H causes the immune response to change from the Th1 phenotype, suppressing multiple sclerosis disease activity, but permitting the generation of antibody-mediated thyroid autoimmunity.

Adult↗

PubMed1999

Recent developments in the assessment of quality of life in multiple sclerosis (MS).

Multiple sclerosis (MS) and its treatment have broad-ranging effects on quality of life. This article reviews recent efforts to assess the impact of MS on activities of daily living (ADLs) and health-related quality of life (HRQL), and describes the development of the Multiple Sclerosis Quality of Life Inventory (MSQLI). The MSQLI is a modular MS-specific HRQL instrument consisting of a widely-used generic measure, the Health Status Questionnaire (SF-36), supplemented by nine symptom-specific measures (covering fatigue, pain, bladder function, bowel function, emotional status, perceived cognitive function, visual function, sexual satisfaction, and social relationships). Content validation consisted of evaluating its adherence to a conceptual model of the impact of MS, and review by MS specialists (neurologists and allied health professionals), HRQL experts, patients, and caregivers. The reliability and construct validity of the MSQLI were rigorously evaluated in a field test with 300 North American patients (198 female, 102 male) with definite MS (Poser criteria) and a broad range of physical impairment (EDSS=0. 0-8.5). This article concludes by comparing the MSQLI with two other MS-specific HRQL measures (MS Quality of Life-54 (QOL-54) and Functional Assessment of Multiple Sclerosis (FAMS)) and discussing key issues to consider in selecting an HRQL instrument for a collaborative database.

Activities of Daily Living↗

PubMed2006

Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response.

Multiple sclerosis (MS) is postulated to be a T cell-mediated autoimmune disease characterized clinically by a relapsing-remitting (RR) stage followed by a secondary progressive (SP) phase. The progressive phase is felt to be secondary to neuronal degenerative changes triggered by inflammation. The status of the innate immune system and its relationship to the stages of MS is not well understood. Dendritic cells (DCs) are professional APCs that are central cells of the innate immune system and have the unique capacity to induce primary immune responses. We investigated circulating myeloid DCs isolated directly from the blood to determine whether there were abnormalities in myeloid DCs in MS and whether they were related to disease stage. We found that SP-MS subjects had an increased percentage of DCs expressing CD80, a decreased percentage expressing PD-L1, and an increased percentage producing IL-12 and TNF-alpha compared with RR-MS or controls. A higher percentage of DCs from both RR and SP-MS patients expressed CD40 compared with controls. We then investigated the polarization effect of DCs from MS patients on naive T cells taken from cord blood using a MLR assay. Whereas DCs from RR-MS induced higher levels of Th1 (IFN-gamma, TNF-alpha) and Th2 (IL-4, IL-13) cytokines compared with controls, DCs from SP-MS only induced a polarized Th1 response. These results demonstrate abnormalities of DCs in MS and may explain the immunologic basis for the different stages and clinical patterns of MS.

Adult↗

PubMed1998

Case report: DNA fragmentation in glial cells in a cerebral biopsy from a multiple sclerosis patient.

Multiple sclerosis is characterized by myelin destruction and oligodendrocyte loss. The neuropathological hallmark of the disease is the presence of demyelinated plaques in the central nervous system. We have recently found a gliotoxic factor in MS cerebrospinal fluid which induces programmed cell death in vitro, in glial cells. Here we show DNA fragmentation and glial cell death in biopsy samples, obtained from a patient who underwent surgery with suspicion of tumor, and whose disease record, including brain autopsy, demonstrated an active multiple sclerosis. We used the in situ TUNEL technique, a method which sensitively detects the DNA fragmentation accompanying programmed cell death in tissue sections, and compatible with classical fixation techniques. We found intense DNA fragmentation in nuclei of glial cells at-or very near-to the site of demyelination. A double labeling technique showed that glial fibrillary associated protein positive astrocytes may undergo programmed cell death in multiple sclerosis.

Astrocytes↗

PubMed1998

Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology.

Multiple sclerosis is a chronic inflammatory disease characterized by perivenous inflammation and focal destruction of myelin. Many attempts have been undertaken previously to create animal models of chronic inflammatory demyelinating diseases through autoimmunity or virus infection. Recently, however, a new model of myelin oligodendrocyte glycoprotein (MOG) induced autoimmune encephalomyelitis became available, which, in a very standardized and predictable way, leads to chronic (relapsing or progressive) disease and widespread CNS demyelination. In the present study we actively induced MOG-experimental autoimmune encephalomyelitis (EAE) in different inbred rat strains using different immunization protocols. The pathology found in our models closely reflects the spectrum of multiple sclerosis (MS) pathology: Classical MS as well as variants such as optic neuritis, Devic's disease and Marburg's type of acute MS are mimicked in rats immunized with MOG antigen. Furthermore we demonstrate, that by using the proper strain/sensitization regime, subforms of MS such as for instance neuromyelitis optica can be reproducibly induced. Our study further supports the notion, that incidence and expression of the disease in this model, alike the situation in multiple sclerosis, is determined by genetic and environmental factors.

Animals↗

PubMedDate not supplied

Effect of immunosuppressive cladribine treatment on serum leucocytes system in two-year clinical trial in patients with chronic progressive multiple sclerosis.

BACKGROUND: Multiple sclerosis is presumably cell-mediated autoimmune disorder with immune abnormalities as presence of activated T-cells and increase interleukin 2 (IL-2) and soluble IL-2 receptor (sIL-2R) levels in central nervous system and peripheral blood of patients. The aim of immunosuppressive treatment is to diminish such activation. The aim of this study was to evaluate the influence of immunosuppressive cladribine treatment with total dose of 2.1 mg/kg b.w. administered in 7 cycles for 12 months, on serum leucocytes in 34 chronic progressive multiple sclerosis (CPMS) patients observed for 2 years as well as IL-2 and sIL-2R serum levels assessed before and right after the treatment. MATERIAL AND METHODS: The study was designed as a randomised, placebo-controlled, double-blind trial. The patients were divided in two groups: group I, cladribine-treated, n = 34; group II, placebo-treated, n = 35. Group III were healthy controls, n = 20. Leucocyte levels were determined with flow-cytometry. IL-2 and sIL-2R levels were assessed with enzyme-linked immunosorbent assay. RESULTS: Statistically significant gradual decrease of lymphocyte level was observed from 7th week to 12th month after the beginning of treatment. During the following 12 months, lymphocyte levels remained decreased in comparison to baseline. Mean values of IL-2 and sIL-2R levels measured 12 months after the treatment were found to be lowered by 20% (p. = 0.01) and by 24% (p. = 0.0005), respectively. CONCLUSION: The results obtained indicate fast and long-lasting decrease of serum leucocyte level and suppressive influence of cladribine treatment on immune processes in multiple sclerosis patients.

Adult↗

PubMed1977

[Pathogenesis of multiple sclerosis. Antibody dependent cytotoxicity of lymphocytes against myelin basic proteins in multiple sclerosis].

In 79 of 100 patients with multiple sclerosis, serum antibodies of the IgG type were demonstrated which render normal lymphocytes cytotoxic against basic protein of myelin. In 11 cerebrospinal fluids which were tested the antibody was also found. The method used was the release of 51Cr from chicken erythrocytes coated with antigen. The antibody-dependent lymphocyte cytotoxicity is related to the degree of activity of the disease and not to the evolution of the disease or its course. As the disease worsens, the frequency of positive reactions is higher than in inactive stages. The immunological reaction is very specific for multiple sclerosis, in patients with other neurological disorders only 5% had positive findings. The antibody-dependent cytotoxicity of lymphocytes against basic protein of myelin may be attributed with a certain diagnostic significance. The reaction seems suitable for the supervision of the course of multiple sclerosis and to check the effect of therapeutic measures. The antibody-dependent lymphocyte cytotoxicity against basic protein of myelin is considered to be significant in the pathogenesis of multiple sclerosis.

Antibody-Dependent Cell Cytotoxicity↗

PubMedDate not supplied

Neurologic disorders: amyotrophic lateral sclerosis, myasthenia gravis, multiple sclerosis, and poliomyelitis.

The patient who has multiple cranial neuropathies may pose a diagnostic dilemma. The neurologic disorders of amyotrophic lateral sclerosis, multiple sclerosis, myasthenia gravis, and poliomyelitis often cause bulbar dysfunctions such as diplopia, facial weakness, slurred or hypernasal speech, dysphagia, and hoarseness. In general, treatment is supportive and is directed toward restoring or aiding lost function (i.e., tracheostomy, esophagostomy, and cricopharyngeal myotomy). The relative infrequency of these disorders can lead to delays in diagnosis and rehabilitative therapy.

Adult↗

PubMed1999

The natural history of multiple sclerosis: a geographically based study. 6. Applications to planning and interpretation of clinical therapeutic trials in primary progressive multiple sclerosis.

The natural history of primary progressive multiple sclerosis (PP-multiple sclerosis) recently has been defined in a geographically based multiple sclerosis population. For a series of prognostically defined hypothetical entry criteria based upon current trends in presentation to the London Multiple Sclerosis Clinic, we determined the number of patients who would have been trial eligible. Using 23 year mean longitudinal natural history data, we identified the observed rate of deterioration for frequently used trial endpoints. Hypothetical entry criteria were based on the practical considerations which would attend the execution of clinical trials in progressive multiple sclerosis. We then developed a series of sample size tables giving the number of patients with PP-multiple sclerosis and the length of observation that would be required to detect a significant result (P = 0.05) for a 25, 50 and 75% decrease in the median time to progression with 80 or 90% power, with treatment efficacy based upon the ability to slow progression on the disability status score. It is expected that the considerations outlined here will prove useful for both trial design and interpretation of trials in PP-multiple sclerosis which will require multi-centre collaborative efforts.

Adult↗

PubMed2000

Morphometric analysis of axons in the minute multiple sclerosis lesions and shadow plaques in patients with multiple sclerosis.

The objective of the present study was to quantitatively detect axons in the minute multiple sclerosis (MS) lesions and in shadow plaques, taking into consideration the relapsing-remitting(R-R) and secondary progressive(SP) stages of MS. The brain tissue of 12 patients deceased due to MS was investigated. An image-computerized analysis was made for measurements of axons. Based on the findings we concluded that damage to axons appears in both the minute MS lesions and in shadow plaques. Demyelination and ineffective (too late or too slow) remyelination seemed to be very important factors in axonal damage. Irreversible damage to axons may appear in both the secondary progressive and relapsing-remitting stages of MS, causing permanent neurological deficits, irrespective of the duration of the disease.

Adult↗

PubMedDate not supplied

[Actual status of multiple sclerosis in Cuba. National cooperative group for the clinical trial "Recombinant interferon alpha-2b in multiple sclerosis"].

INTRODUCTION: Multiple sclerosis (MS) has been considered to be an uncommon disorder in Cuba. In recent years many Cuban investigators have worked hard studying MS in Cuba. DEVELOPMENT: We review the history, epidemiology, clinical characteristics, complementary investigations and clinical trials of recent studies published in national and international journals on the most important investigations done on MS in Cuba. There is an outstanding placebo-controlled, double blind, multicentric randomised clinical trial using recombinant alpha 2b-IFN in the relapsing-remitting clinical form in which the results obtained in the first 30 patients who completed 2 years treatment show a statistically significant reduction in the frequency of relapses and the number of patients free of relapses in patients who received alpha-IFN as compared with those given placebo treatment. CONCLUSIONS: There has been an increase in the number of studies made on MS in Cuba in the past two years. Numerous clinical, neuroepidemiological, neurophysiological, biochemical, immunological, imaging and neuropsychological investigations and clinical trials indicate a marked increase in understanding of MS. The results of all these studies indicated the need for the creation of a National Reference Centre for Patients with Multiple Sclerosis, due to the complexity of this type of patients and the need to offer improved medical attention from a specialist team and to integrate the investigations in Cuba and internationally so as to reach the level of more developed countries.

Adjuvants, Immunologic↗

PubMed1995

Geographic similarities between varicella and multiple sclerosis: an hypothesis on the environmental factor of multiple sclerosis.

The environmental factor causing multiple sclerosis (MS) is unknown. Kurtzke et al. (Neurology 1979; 29: 1228-1235) depicted a north to south diminishing gradient in the case/control ratios for MS among American veterans in the United States. A similar, but less precise, gradient emerged when the incidence rates of varicella from 37 states during 1978-91 were compared. A loose correlation appears to exist between the mean incidence of varicella and the MS risk ratio (n = 0.344 Spearman rank correlation coefficient, p = 0.037). Further, the data on the fat of migrants moving from a high risk MS country to a low risk country and the reverse, plus the great importance of the age at migration, raise the question of a possible connection between the two diseases. Because of these epidemiological and other similarities between the two diseases a further comparative study was suggested.

Adolescent↗