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BACKGROUND: Multiple sclerosis is an inflammatory disease of the central nervous system that destroys myelin, oligodendrocytes, and axons. Since most of the lesions of multiple sclerosis are not remyelinated, enhancement of remyelination is a possible therapeutic strategy that could perhaps be achieved with the transplantation of oligodendrocyte-producing cells into the lesions. We investigated the frequency distribution and configuration of oligodendrocytes in chronic lesions of multiple sclerosis to determine whether these factors limit remyelination. METHODS: Forty-eight chronic lesions obtained at autopsy from 10 patients with multiple sclerosis were examined immunocytochemically for oligodendrocytes and oligodendrocyte progenitor cells. Using confocal microscopy, we examined the three-dimensional relations between axons and the processes of premyelinating oligodendrocytes. RESULTS: Thirty-four of the 48 chronic lesions of multiple sclerosis contained oligodendrocytes with multiple extended processes that associated with demyelinated axons but failed to myelinate them. These axons were dystrophic and contained multiple swellings. In some regions, the densities of premyelinating oligodendrocytes (25 per square millimeter of tissue) were similar to those in the developing rodent brain (23 per square millimeter). In the patients with disease of long duration (more than 20 years), there were fewer lesions with premyelinating oligodendrocytes (P<0.001). CONCLUSIONS: Premyelinating oligodendrocytes are present in chronic lesions of multiple sclerosis, so remyelination is not limited by an absence of oligodendrocyte progenitors or their failure to generate oligodendrocytes. Our findings suggest that in the chronic lesions of multiple sclerosis, the axons are not receptive for remyelination. Understanding the cellular interactions between premyelinating oligodendrocytes, axons, and the microenvironment of lesions of multiple sclerosis may lead to effective strategies for enhancing remyelination.
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Multiple sclerosis is a chronic inflammatory demyelinating disease of the CNS. Although the aetiology of multiple sclerosis is still unknown, it is widely believed that T cells play a central role in its pathogenesis. To identify and characterize disease-relevant T cells, we analysed CD4+ and CD8+ T cells freshly isolated from the CSF and peripheral blood of 36 multiple sclerosis patients for their T-cell receptor variable beta (TCRBV) chain repertoire. In most patients, we found significant overexpression of individual TCRBV chains on CD8+ T cells from CSF compared with peripheral blood. In contrast, only a few multiple sclerosis patients showed differences between the two compartments in TCRBV expression on CD4+ T cells. The overexpression of specific TCRBV chains on CD8+ T cells was found to be stable over several months in selected patients and involved mainly T cells with a memory phenotype. In two patients studied, individual TCRBV chain overexpression was found to be caused by the expansion of T cell populations with identical or highly similar rearranged T-cell receptor beta- and alpha-chain sequences, which were not found among peripheral blood CD8+ T cells. Our findings demonstrate selective enrichment of memory CD8+ T cells in the CSF of multiple sclerosis patients, suggesting a role for these CD8+ T cells in the pathogenesis of multiple sclerosis. Our study provides a basis for future trials to identify disease-associated antigens and disease pathogenesis in multiple sclerosis.
The unexpectedly low rate of concordance in monozygotic (MZ) twins with multiple sclerosis (MS) suggests that they share a systemic condition called the multiple sclerosis trait. This trait constitutes the premorbid stage of the disease and is quite distinct from asymptomatic MS. It results from the action of an antigenic challenge to the immune system of a genetically susceptible person but is short of producing lesions of the central nervous system parenchyma; in fact, the disease may never develop in people with the trait. An environmental triggering event is required to transform the trait into the disease. The discordance of clinical involvement and magnetic resonance images in MZ twins reflects differences in the effect of environmental influences.
Multiple sclerosis [MS], a demyelinating disease of the central nervous system associated with inflammation and gliosis, may be an autoimmune disease with T lymphocytes and autoantibodies to myelin protein(s). This study deals exclusively with B cell autoimmunity to myelin basic protein (MBP). T lymphocytes and anti-MBP share a common MBP epitope located between P(85) and P(96) which contains the essential contact residues H(88)FFK(91) for the trimolecular complex. The purpose of this Phase I open label clinical study was to monitor CSF anti-MBP in patients with chronic progressive MS subsequent to IV administration of synthetic peptide (sp) MBP82-98 namely DEN(85)VVHFFKNIVTP(96)RT. Fifty-six patients who participated in this project were assigned to two groups: a 'control group' of 15 patients who received IV saline injections every 6 months for the first 2 years of the study and a 'peptide group' of 41 patients who received IV spMBP82-98 from the beginning of the study and then infrequently subsequent to a rise of their CSF anti-MBP. In the control group antibody levels remained persistently elevated during the 2 year period. Patients in the 'peptide group' segregated into four kinetic profiles: Cohort A (15 patients) illustrated prolonged anti-BMP suppression into the normal range. Cohort B (10 patients) illustrated significant anti-MBP suppression into the normal range for shorter durations. Cohort C (eight patients) showed significant CSF anti-MBP suppression after the initial injection but lost the ability to suppress the autoantibody titer following subsequent injections. Cohort D (eight patients) failed to show significant CSF anti-MBP suppression. In conclusion the B cell tolerizing effect of spMBP82-98 segregated into four kinetic profiles; this molecular variability should be considered in attempts to develop specific 'peptide therapies' for the broad range of clinical profiles currently diagnosed as 'multiple sclerosis'. Multiple Sclerosis (2000) 6 300 - 311
The Norwegian Multiple Sclerosis National Competence Centre was established at the Department of Neurology, Haukeland University Hospital, Bergen in 1996. Promotion of research, supervision and education of doctors and other health care professionals in Norway are the main responsibilities of the Centre. The centre has established national networks for MS care and research and has provided supervision and education of doctors and other health care professionals in Norway. Guidelines for diagnosis and treatment of MS have been established. The National Multiple Sclerosis Registry was established in 1998 and includes by January 2006 50-60% of all MS patients in Norway. Through a national collaboration, the registry aims for inclusion of a biobank unit for collection of cerebrospinal fluid and serum, DNA, and tissue samples.
OBJECTIVE: To evaluate the cost effectiveness of four disease modifying treatments (interferon betas and glatiramer acetate) for relapsing remitting and secondary progressive multiple sclerosis in the United Kingdom. DESIGN: Modelling cost effectiveness. SETTING: UK NHS. PARTICIPANTS: Patients with relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis. MAIN OUTCOME MEASURES: Cost per quality adjusted life year gained. RESULTS: The base case cost per quality adjusted life year gained by using any of the four treatments ranged from pound 42,000 (66,469 dollars; 61,630 euro) to pound 98,000 based on efficacy information in the public domain. Uncertainty analysis suggests that the probability of any of these treatments having a cost effectiveness better than pound 20,000 at 20 years is below 20%. The key determinants of cost effectiveness were the time horizon, the progression of patients after stopping treatment, differential discount rates, and the price of the treatments. CONCLUSIONS: Cost effectiveness varied markedly between the interventions. Uncertainty around point estimates was substantial. This uncertainty could be reduced by conducting research on the true magnitude of the effect of these drugs, the progression of patients after stopping treatment, the costs of care, and the quality of life of the patients. Price was the key modifiable determinant of the cost effectiveness of these treatments.
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INTRODUCTION: Multiple sclerosis is the most important disabling neurological disease in young adulthood in our environment. However, its etiology remains unknown. It has been proposed that multiple sclerosis is caused by an interaction of genetic and environmental factors. In particular, Epstein-Barr virus infection could play a fundamental role in the pathophysiology of multiple sclerosis. METHODS: We have reviewed the most recent and important bibliography, both from epidemiologic and basic research studies, dealing with the possible association between Epstein-Barr virus infection and multiple sclerosis. RESULTS: Retrospective and prospective epidemiologic studies suggest a direct association between Epstein-Barr virus infection and the risk of multiple sclerosis. Several physiopathologic mechanisms, including molecular mimicry and bystander activation, could be responsible for this association. CONCLUSIONS: Based on the published evidence, Epstein-Barr virus infection can be considered to have a causal role in the etiology of multiple sclerosis. Further research should be conducted to elucidate the mechanisms underlying this association and to assess its potential for multiple sclerosis prevention and treatment.
The remarkably low rate of concordance of multiple sclerosis (MS) in monozygotic twins has never been fully explained but it implies the possibility of a systemic condition called the multiple sclerosis trait (MST), which is quite different from asymptomatic MS. It results from the action of an antigenic challenge on the immune system of a genetically vulnerable person that does not cause damage to the nervous parenchyma; it may never evolve into the disease MS. A subsequent environmental viral-antigenic event in some MST-carriers can change the trait into the disease. This event could be an infection, which need not be symptomatic, or a vaccination. The MS may become symptomatic, remain asymptomatic, or manifested only by lesions visible by MRI. It is likely that the development of the MST, called activation, occurs early in life, while the transition from MST to MS, called acquisition, takes place at puberty in most patients. Differences in prevalence between pre-puberal migrants, and the locally born children of migrants, and their population of origin may also be explained by the MST.
AIMS: Multiple sclerosis is the most common cause of neurological disability in young adults. Mitoxantrone is a synthetic anthracenedione, recently approved for the treatment of worsening multiple sclerosis, which is known to induce cardiotoxicity. This study was designed to evaluate the early alterations in left ventricular function in patients with multiple sclerosis receiving mitoxantrone, by the use of the myocardial performance index, a new parameter of global (systolic and diastolic) ventricular function. METHODS AND RESULTS: The study included 29 Caucasian patients with multiple sclerosis (mean age 41.8+/-9.3 years, 12 males and 17 females) treated with mitoxantrone (mean cumulative dose 30.8+/-18.2 mg/m(2)) who were compared with 28 healthy subjects (mean age 37.8+/-11.8 years, 13 males and 15 females). Both groups underwent a complete two-dimensional and Doppler echocardiography including assessment of the mitral inflow and left ventricular outflow patterns for estimation of the Doppler-derived myocardial performance index. This parameter is defined as the sum of isovolumic contraction time and isovolumic relaxation time, divided by ventricular ejection time. No differences were observed in blood pressure, heart rate, left ventricular diameters, mass and ejection fraction in multiple sclerosis patients compared to the controls. The mitral flow pattern showed a significant decrease of E wave calculated as peak velocity (E(pv)) (63.3+/-13.4 vs. 77.2+/-17.2, P<0.002) and time velocity integral (E(tvi)) (8.8+/-1.9 vs. 10.3+/-2.4, P<0.02), with a significant decrease of E(pv)/A(pv) ratio and a non-significant decrease of E(tvi)/A(tvi) ratio in the patients. In addition, E-wave deceleration time was significantly increased in multiple sclerosis patients compared to controls (178.2+/-30.2 vs. 137.9+/-14.7, P<0.0001). The mean value of myocardial performance index was 0.55+/-0.1 in patients compared to 0.37+/-0.06 in the controls (P<0.0001). A significant correlation between the given cumulative dose of mitoxantrone and myocardial performance index (r=0.67, P<0.001) and E-wave deceleration time (r=0.45, P<0.001) respectively were demonstrated. CONCLUSION: The myocardial performance index represents a parameter of combined systolic and diastolic myocardial performance strongly correlated with the given cumulative dose of mitoxantrone. The myocardial performance index may be an adjunctive parameter to conventional echocardiography for detecting sub-clinical cardiotoxicity of mitoxantrone in the clinical management of the multiple sclerosis patients.
BACKGROUND: Because of their ability to increase nerve conduction in demyelinated nerve fibers, potassium channel blockers 4-aminopyridine (AP) and 3,4-diaminopyridine (DAP) have been proposed as a symptomatic therapy for people with multiple sclerosis (MS). OBJECTIVES: To determine the efficacy and safety of aminopyridines in improving neurological deficits in people with MS. SEARCH STRATEGY: Computerised general (MEDLINE, EMBASE) and specialised databases (Cochrane MS Group's trials register, CCTR). Hand search of bibliographic references from retrieved studies and recent MS symposia reports. Contact with principal investigators of known studies. SELECTION CRITERIA: Trials were included if they fulfilled all following criteria: randomised controlled trials (RCTs); adults with MS, out of exacerbation; AP or DAP treatment versus placebo; clinical endpoints. DATA COLLECTION AND ANALYSIS: We identified 26 potentially pertinent studies. Three reviewers independently extracted data and assessed trial quality from the 16 studies available as full papers. MAIN RESULTS: Five studies (six publications) and 144 participants were considered in this review. Two more abstracts are awaiting assessment. All five studies were single-centre, double-blind, crossover trials. Four studies assessed the efficacy of AP versus placebo, one compared DAP with active placebo. The duration of treatment ranged from hours to three months. The median quality score of the studies was 3 (range 2-5). The heterogeneity of outcome assessment and the absence of information on individual study periods, allowed quantitative pooling of results for few categorical variables. Of the 144 treated patients, there were six major side effects: one acute encephalopathy, three episodes of confusion, and two seizures. Manual muscle testing was assessed in three studies (54 patients), with 29 patients (54%) improving in at least one muscular district during study treatment versus four patients (7%) during placebo (odds ratio [OR] 14.5, 95% confidence interval [CI] 4.7-43.7). Ambulation was assessed in three studies (54 patients): 9 patients (17%) improved during study treatment versus none during placebo (p<0.001). An improvement in EDSS score was found in 13 of the 144 participants during study treatment (9%) versus none during placebo (p<0.001). No improvement in neuropsychological tests was found in the two trials that evaluated cognitive function. Finally, 47 of 136 people with MS (35%) felt improved when receiving the study drug, against 7(5%) on placebo (OR 9.7, 95% CI 4.3-22.0). REVIEWER'S CONCLUSIONS: Based on currently available information, no unbiased statement can be made about the safety or efficacy of aminopyridines for treating MS symptoms. Furthermore, we could not obtain any data on three unpublished RCTs involving more than 300 participants. We conclude that publication bias remains a pervasive problem in this area, and that until the results of these unpublished studies are available to the scientific community, no confident estimate of effectiveness of aminopyridines in the management of MS symptoms is possible.
The Clausen modification of the leukocyte migration test was used to test patients with multiple sclerosis, normal subjects, and patients with other neurologic diseases for cell-mediated immunity to 6/94 virus (a parainfluenza virus previously isolated from the brain tissue of a multiple sclerosis patient), c-RNA virus isolated from a tumor, and the nonviral antigens Candida and purified protein derivative. Leukocytes of multiple sclerosis patient showed significantly less mean inhibition of migration by the 6/94 virus (but not by the c-RNA virus, purified protein derivative, and Candida) than did the cells of normal controls and patients with other neurologic diseases. The relationship of these findings to previous observations in this area and to the pathogenesis of multiple sclerosis is discussed.
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BACKGROUND: Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. With a prevalence of 0.1-0.15% in Germany multiple sclerosis is the most common cause of severe disability in young adults. PATHOGENESIS: Epidemiological and family studies demonstrate the role of environmental and genetic factors in the pathogenesis of multiple sclerosis. Based on those observations and findings in experimental animal models, it is believed that multiple sclerosis is caused by an autoimmune process. However, target antigens and mechanisms leading to tissue destruction are largely unknown. THERAPY: Since the efficacy of current immunomodulatory and immunosuppressive therapies (beta-interferons, glatiramer acetate, mitoxantrone) is limited, it is necessary to develop new strategies for the treatment of multiple sclerosis. To reach this goal, a much better understanding of disease pathogenesis is necessary which takes into account the clinical, paraclincial and histopathological heterogeneity of the disease. CONCLUSION: Only further intensive research activity on basic mechanisms of disease pathogenesis and a consequent development of resulting therapeutic strategies--from animal models to phase III studies--will result in significant improvement of the long-term course of multiple sclerosis.
BACKGROUND: Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most patients have progressive neurologic deterioration that may reflect axonal loss. We conducted pathological studies of brain tissues to define the changes in axons in patients with multiple sclerosis. METHODS: Brain tissue was obtained at autopsy from 11 patients with multiple sclerosis and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions. RESULTS: Transected axons were a consistent feature of the lesions of multiple sclerosis, and their frequency was related to the degree of inflammation within the lesion. The number of transected axons per cubic millimeter of tissue averaged 11,236 in active lesions, 3138 at the hypocellular edges of chronic active lesions, 875 in the hypocellular centers of chronic active lesions, and less than 1 in normal-appearing white matter from the control brains. CONCLUSIONS: Transected axons are common in the lesions of multiple sclerosis, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.
After an open labelled pilot study of ginkgolide B, a potent inhibitor of platelet activating factor, in the treatment of acute exacerbations of multiple sclerosis, a randomised double blind placebo controlled study was undertaken. One hundred and four patients were enrolled in the study: for seven days 43 received placebo, 29 received 240 mg/day ginkgolide B and 32 received 360 mg/day ginkgolide B. There was no statistical difference between the three groups for changes in Rankin, Kurtzke expanded disability status scale (EDSS), and Hauser ambulation index (AI) scores. Although there was a trend in favour of groups treated with ginkgolide for a change of Rankin and AI scores, it is concluded that ginkgolide B is not an effective treatment of exacerbations of multiple sclerosis.