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PubMed2000

Reduction of both pro- and anti-inflammatory cytokines after 6 months of interferon beta-1a treatment of multiple sclerosis.

Treatment of multiple sclerosis (MS) with interferon beta (IFNbeta) reduces relapse rate, magnetic resonance imaging (MRI) activity and progression of disability. It has been suggested that this beneficial effect is paralleled by an inhibition of proinflammatory cytokines such as interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) and an induction of anti-inflammatory cytokines such as interleukin-4 (IL-4) and interleukin-10 (IL-10). In this study, we record a reduced number of spontaneously IFNgamma mRNA-expressing cerebrospinal fluid mononuclear cells (CSF-MC) and IFNgamma, TNFalpha and IL-10 mRNA-expressing peripheral blood mononuclear cells (PBMC) after 6 months of IFNbeta-1a treatment, paralleled by a decreased purified protein derivate (PPD)-stimulated and unstimulated IFNgamma secretion by PBMC. These effects were not apparent after 2 weeks of treatment, and IFNbeta-1a induced IFNgamma production by naive PBMC in vitro. We did not record increased numbers of IL-4 mRNA-expressing CSF-MC or PBMC, increased plasma IL-10 levels, increased numbers of IgG, A or M secreting plasma cells or in vitro induction of IL-10 production by IFNbeta-1a. We conclude that long-term cytokine modulation by IFNbeta-1a differs from acute effects and that downregulation of both pro- and anti-inflammatory cytokines, rather than a shift in the cytokine profile, is apparent after 6 months of IFNbeta-1a treatment of MS patients.

Adjuvants, Immunologic↗
PubMed2003

Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes.

In multiple sclerosis (MS), matrix metalloproteinase (MMP) activity in tissues is the result of a balance between MMPs and their tissue inhibitors (TIMPs). MMP-9 predominates in acute MS lesions and is inhibited by TIMP-1, while MMP-2 may participate in the remodeling of the extracellular matrix (ECM) such as in chronic disease and is inhibited by TIMP-2. These differences may be reflected in serum and cerebrospinal fluid (CSF). We have tried to characterize MMP-2 and MMP-9 activities, in relation to their respective TIMPs, 2 and 1, as a factor of different types of the disease, as this information was not previously clearly stated. We found the MMP-2/TIMP-2 ratio in serum to show higher values in secondary progressive (SP, p=0.02) and primary progressive (PP, p=0.01) MS than short disease duration (SDD) relapsing-remitting (RR) MS, but not different from the healthy control (HC) group. Whereas the MMP-9/TIMP-1 ratio in serum showed higher (p=0.04) values in SDD RR MS than PP but also in active patients, evaluated either clinically (p=0.006) or from the magnetic resonance imaging (MRI, p<0.05), compared to inactive disease. CSF MMP to TIMP ratios did not differ between MS subtypes, suggesting systemic rather CNS-restricted changes. These results show that an increase in MMP-2/TIMP-2 ratio marks chronic progression in MS, but it is as high as in HC, and also confirm that high MMP-9 activity characterizes short duration relapsing and active forms of the disease.

Adult↗
PubMed1988

Fluctuations of CD4+ T-cell subsets in remitting-relapsing multiple sclerosis.

Patients with multiple sclerosis (MS) frequently have selective depletion of the CD45R+CD4+ T-cell subset during active phases of disease. To study the relationship between changes in this subset and the onset of objective clinical exacerbations of disease, a longitudinal study was undertaken. Two CD4+ T-cell subsets and two CD8+ T-cell subsets were monitored by two-color immunofluorescence using a fluorescence-activated cell sorter. These subsets of peripheral blood lymphocytes were monitored monthly for one year in a group of 9 patients with remitting-relapsing MS and in 11 healthy age-matched control subjects. Significant changes in the ratio of two CD4+ T-cell subsets (CD45R-/CD45R+) were detected in 7 of 9 patients with MS, but not in any of the control subjects. Of those 7 persons, 4 suffered major clinical relapses substantiated by alterations in the neurological examination. The other 3 suffered minor relapses with subjective clinical abnormalities. All 7 had increased CD4+ T-cell subset ratios (%CD4+CD45R-/%CD4+CD45R+) within the month that new symptoms were reported. Most such increases resulted from a simultaneous depletion in the number of CD45R+CD4+ T cells and an increase in the number of CD45R-CD4+ T cells. One patient suffered a major relapse with no change in the ratio of CD4+ subsets but had a depletion of all CD4+ T cells. There were no consistent changes in any of the other subsets measured. These results indicate that a subgroup of patients with MS have abnormal fluctuations of two CD4+ T-cell subsets, which may correlate with increased disease activity.

Adult↗
PubMed2002

The relationship between lesion and normal appearing brain tissue abnormalities in early relapsing remitting multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), pathological changes have been found both in macroscopic lesions and normal appearing tissue. Magnetisation transfer ratio (MTR) and T1 relaxation time are abnormal in normal appearing tissues in established MS. This study used these MR techniques in early MS to study normal appearing tissues and lesions. The purpose was to determine whether abnormalities are already detectable in normal appearing tissues in early MS, and if so how they correlate with lesion characteristics. METHODS: Twenty two patients with early relapsing remitting (RR) MS (median disease duration 2 years, range 7 months-3 years) and 11 age-matched controls were studied. MTR and T1 relaxation times were measured in 9 regions of normal appearing white matter (NAWM) and 7 of normal appearing grey matter (NAGM). Gadolinium enhancing, T1-hypointense and T2 lesion loads were measured in all patients. RESULTS: When all regions were combined, there was a significant difference between patient and control NAWM for both T1 and MTR; T1 was abnormal in 6/9 and MTR in 3/9 NAWM regions. Global assessment of NAGM revealed a significant difference between patients and controls for Ti but not for MTR; T1 was significantly abnormal only in frontal NAGM. There was no significant correlation between NAWM T1 or MTR and any of the lesion load measurements. CONCLUSIONS: This study reveals quantitative MR abnormalities in both NAWM and NAGM in early RR MS, with more extensive changes in the former. The lack of correlation between NAWM and lesion abnormalities suggests that they have developed by at least partly independent mechanisms. T1 may be more sensitive than MTR in detecting subtle pathological changes in NAWM and NAGM.

Adult↗
PubMed1997

Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke.

Multiple sclerosis (MS) and stroke pathology are characterized blood-brain barrier breakdown, leucocyte emigration, and tissue destruction. Each process is thought to involve the matrix metalloproteinases (MMP), but little is known of their expression. We undertook to investigate whether MMP expression is dependent on the nature of the CNS lesion and whether expression would coincide with the histopathology. MS or cerebral-infarct tissue was examined for the presence of gelatinase-A, gelatinase-B, matrilysin and stromelysin-1. Gelatinases A and B and matrilysin expression was found to be up-regulated in microglia/macrophages within acute MS lesions. In active-chronic MS lesions, matrilysin and gelatinase-A expression was pronounced in the active borders. In chronic MS lesions, the expression of matrilysin was confined to macrophages within perivascular cuffs. The pattern of MMP expression in infarct lesions differed considerably. Gelatinase-B was strongly expressed by neutrophils in tissue from patients up to 1 week after an infarct, whereas gelatinase-A and matrilysin staining was much less marked. From 1 week to 5 years, neutrophils were absent and the large number of macrophages present were expressing matrilysin and gelatinase A. Only a low level of gelatinase-A and matrilysin expression was observed in normal brain controls. Thus, MMPs are expressed in inflammatory lesions in the CNS, but their individual expression is dependent on the nature and chronicity of the lesion. However, the general pattern of expression, in perivascular cuffs and in active lesions, supports a role for these enzymes as mediators of blood-brain barrier breakdown and tissue destruction, both in MS and in cerebral ischaemia.

Acute Disease↗
PubMed2002

Genetic dissection of the human leukocyte antigen region by use of haplotypes of Tasmanians with multiple sclerosis.

Association of multiple sclerosis (MS) with the human leukocyte antigen (HLA) class II haplotype DRB1*1501-DQB1*0602 is the most consistently replicated finding of genetic studies of the disease. However, the high level of linkage disequilibrium (LD) in the HLA region has hindered the identification of other loci that single-marker tests for association are unlikely to resolve. In order to address this issue, we generated haplotypes spanning 14.754 Mb (5 cM) across the entire HLA region. The haplotypes, which were inferred by genotyping relatives of 152 patients with MS and 105 unaffected control subjects of Tasmanian ancestry, define a genomic segment from D6S276 to D6S291, including 13 microsatellite markers integrated with allele-typing data for DRB1 and DQB1. Association to the DRB1*1501-DQB1*0602 haplotype was replicated. In addition, we found that the class I/extended class I region, defined by a genomic segment of approximately 400 kb between MOGCA and D6S265, harbors genes that independently increase risk of, or provide protection from, MS. Log-linear modeling analysis of constituent haplotypes that represent genomic regions containing class I (MOGCA-D6S265), class III (TNFa-TNFd-D6S273), and class II (DRB1-DQB1) genes indicated that having class I and class II susceptibility variants on the same haplotype provides an additive effect on risk. Moreover, we found no evidence for a disease locus in the class III region defined by a 150-kb genomic segment containing the TNF locus and 14 other genes. A global overview of LD performed using GOLD identified two discrete blocks of LD in the HLA region that correspond well with previous findings. We propose that the analysis of haplotypes, by use of the types of approaches outlined in the present article, should make it possible to more accurately define the contribution of the HLA to MS.

Alleles↗
PubMed1972

Lymphocyte sensitization to carcinoembryonic antigen (Gold) with special reference to multiple sclerosis.

Lymphocytes from patients with multiple sclerosis are sensitized to carcinoembryonic antigen (C.E.A.) in almost the same degree as are those from subjects with cancer. During pregnancy and the early puerperium there is an even higher degree of cellular sensitization to C.E.A. Patients with neurological diseases other than multiple sclerosis also show significant sensitization to C.E.A. though of less degree than do those with multiple sclerosis. Sensitization to C.E.A. is thus not specifically characteristic of cancer. The unexpected sensitization in multiple sclerosis may be associated with the pronounced degree of gliosis found in that condition.

Adolescent↗
PubMed2006

Italian Multiple Sclerosis Database Network.

The Multiple Sclerosis Database Network (MSDN) is the first Italian multiple sclerosis (MS) registry. The preliminary results on the MSDN cohort demonstrated that the risk of disability progression, in a sample of 2090 MS patients, was reduced by about four- to five-fold in patients exposed to IFNbeta for more than 4 years compared with patients exposed for up to 2 years. More recent results showed, in a subset of 1170 relapsing-remitting MS patients, of whom 918 were treated with IFNbeta and 252 were untreated, that IFNbeta-treated patients had a differential reduction in EDSS score change of -0.055 for each year of follow-up in comparison with the untreated group. These results provide significant information on the effectiveness of IFNbeta treatment on long-term disability progression in MS.

Computer Communication Networks↗
PubMed1975

Oligodendroglial toxicity by serum and lymphocytes from patients with multiple sclerosis.

The gliotoxic effect of multiple sclerosis serums and lymphocytes was investigated by the measurement of Cr51 release from prelabeled bovine oligodendroglia. There was no difference in glial toxicity between multiple sclerosis patients and normal controls except for a depression of Cr51 release from bovine oligodendroglia in the presence of autologous serum plus lymphocytes in the multiple sclerosis patients compared with the normal controls. This correlated with the phase of the disease and may be due to the presence of a lymphotoxic factor in the active multiple sclerosis serums.

Animals↗
PubMed2002

A prospective study of the incidence, prevalence and mortality of multiple sclerosis in Leeds.

OBJECTIVE: To establish the prospective incidence of multiple sclerosis and mortality rates of people with multiple sclerosis in Leeds Health Authority and an updated prevalence of multiple sclerosis on 31 October 1999. METHODS: A population based prevalence register established on 30 April 1996 was maintained by prospectively registering all new cases of multiple sclerosis, flagging all cases with the National Health Service Central Register for notification of deaths and by registering all new clinical events. General practitioners notified patients with multiple sclerosis moving into or out of the area. RESULTS: 136 incident cases were prospectively registered from 30 April 1996 living in Leeds Health Authority (with an estimated resident population of 728,840). 57 deaths were notified. 792 people with multiple sclerosis were identified living in Leeds on 31 October 1999. The mean annual incidence rate for the three-year period 1996-1998 was 6.1/10(5) (95% CI: 5.1-7.2). The sex ratio of incident cases was 2.3 to 1 women to men. On 31 October 1999 the prevalence of multiple sclerosis in the Leeds Health Authority was 108.7/10(5) (95% CI: 101.2-116.5). This compares with a prevalence of 97.3/10(5) (95% CI: 90.3-104.7) on 30 April 1996. The prevalence of definite and probable multiple sclerosis was 93.3/10(5) (95% CI: 86.4-100.6) and of suspected multiple sclerosis was 15.4/10(5) (95% CI 12.7-18.5). Crude annual mortality rates of people with multiple sclerosis for 1997 and 1998 were 1.9/10(5) (95% CI: 1.1 to 3.2) and 3.2/10(5) (95% CI: 2.0 to 4.7). Multiple sclerosis was noted as the underlying cause of death in 8 (14%) cases. CONCLUSION: The incidence of multiple sclerosis in the Leeds Health Authority is similar to that in the south of the United Kingdom. The difference in successive prevalence figures is less than that published in other serial studies. Multiple sclerosis was notified as the underlying cause of death in a minority of deaths in people with multiple sclerosis.

Adult↗
PubMedDate not supplied

Concurrence of multiple sclerosis and Hodgkin's disease.

Although multiple sclerosis and Hodgkin's disease are reported to have similar epidemiologic features, this is only the first case report in which there was concurrence of these diseases. Fourteen years after successful treatment of Hodgkin's disease, this 31-year-old white male developed multiple sclerosis. The diagnosis of multiple sclerosis was made on the basis of clinical and paraclinical findings that were characteristic of multiple sclerosis. In addition, specific tests were performed to rule out a variety of infectious, metabolic, and neoplastic diseases that simulate multiple sclerosis.

Adult↗
PubMed1973

Multiple cerebral gliomas in multiple sclerosis.

A patient with multiple sclerosis and a multicentric anaplastic astrocytoma is described. The evidence suggests that the relationship is not coincidental and that the astrocytomas originate in multiple sclerosis plaques.

Adult↗
PubMed1997

[Optic nerve neuritis after 50 years of age: symptom of a previously undiagnosed multiple sclerosis].

BACKGROUND: The onset of multiple sclerosis after the age of 50 years is rare. We report four patients with optic neuritis and oligoclonal bands or increased IgG production in the cerebrospinal fluid. Three of them subsequently developed clinically definite multiple sclerosis. PATIENTS: Four apparently healthy women, 62, 56, 50 and 50 years of age, presented with progressive visual loss, three patients in one eye and one patient in both eyes. The diagnostic work-up revealed no findings indicating an ischemic process, an infectious, systemic inflammatory, or neoplastic disease. Examination of the cerebrospinal fluid revealed oligoclonal bands and/or increased production of IgG. Visual acuity recovered during the following weeks to 8 months. Three of the 4 patients subsequently developed additional neurologic signs compatible with multiple sclerosis. CONCLUSION: Optic neuritis can be the presenting sign of multiple sclerosis even after the age of 50.

Diagnosis, Differential↗
PubMed2005

AANA Journal course: update for nurse anesthetists--an overview of multiple sclerosis and implications for anesthesia.

Multiple sclerosis is the most common demyelinating, chronic disease of the central nervous system diagnosed in and affecting young adults. This disease can significantly alter the life of affected people, and there is no known cure. It is important to understand and review this disease process because anesthesia providers are likely to encounter patients with multiple sclerosis in their practice. The purpose of this AANA Journal course is to present an overview of multiple sclerosis. The pathophysiologic features, symptoms, manifestations, diagnosis, and pharmacologic treatment are discussed, with a focus on the implications of multiple sclerosis for general and regional anesthesia.

Anesthesia↗
PubMed2002

Pathogenesis of multiple sclerosis: an update on immunology.

Multiple sclerosis is characterized by demyelination and chronic inflammation of the central nervous system. Extensive studies in the animal model experimental autoimmune encephalomyelitis have suggested that multiple sclerosis is an autoimmune disorder mediated by myelin-specific CD4 T cells secreting T helper type 1 cytokines and tumor necrosis factor alpha. This concept has been widely used to develop new experimental therapies. However, recent findings in both experimental autoimmune encephalomyelitis and multiple sclerosis question a simple CD4 T helper type 1 T cell paradigm and provide evidence for the role of various immune cells in the pathogenesis of experimental autoimmune encephalomyelitis and multiple sclerosis. In this paper we review recent progress and discuss the implications for new therapeutic strategies.

Animals↗
PubMed2006

The value of animal models for drug development in multiple sclerosis.

The rodent model for multiple sclerosis, experimental allergic (autoimmune) encephalomyelitis (EAE), has been used to dissect molecular mechanisms of the autoimmune inflammatory response, and hence to devise and test new therapies for multiple sclerosis. Clearly, artificial immunization against myelin may not necessarily reproduce all the pathogenetic mechanisms operating in the human disease, but most therapies tested in multiple sclerosis patients are nevertheless based on concepts derived from studies in EAE. Unfortunately, several treatments, though successful in pre-clinical EAE trials, were either less effective in patients, worsened disease or caused unexpected, severe adverse events, as we review here. These discrepancies must, at least in part, be due to genetic and environmental differences, but the precise underlying reasons are not yet clear. Our understanding of EAE pathogenesis is still incomplete and so, therefore, are any implications for drug development in these models. Here, we suggest some potential explanations based on new thinking about key pathogenic concepts and differences that may limit extrapolation from EAE to multiple sclerosis. To try to circumvent these rodent-human dissimilarities more systematically, we propose that pre-clinical trials should be started in humanized mouse models.

Animals↗
PubMed1984

A review of the etiology of multiple sclerosis.

The geographic distribution of multiple sclerosis and the influence of migration on the risk of contracting it point to an environmental factor as cause of the disease. This environmental factor might be a virus which might produce the demyelination process through an autoimmune reaction against components of the central nervous system. The other possible cause of multiple sclerosis is a genetic susceptibility, inferred from the higher risk for the disease found among relatives of patients with multiple sclerosis and on the association between the disease and some histocompatibility antigens of the HLA system. Both theories seem to be correct, with the environmental factors(s) causing multiple sclerosis only in the presence of a genetic susceptibility.

Age Factors↗
PubMedDate not supplied

Chronic recurrent transverse myelitis or multiple sclerosis.

The simultaneous occurrence of multiple sclerosis and transverse myelitis is known in the literature. Apart from the spinal symptoms, other neurological signs of brain involvement are usually found and magnetic resonance imaging (MRI) reveals disseminated foci in the brain. The positive evoked responses, the immunological abnormalities of the cerebrospinal fluid (CSF), and the oligoclonality together prove the presence of multiple sclerosis. In these cases the symptoms of transverse myelitis can separately precede other signs of multiple sclerosis, or appear as a relapse. Recurrent transverse myelitis as an independent entity, with negative MRI and CSF immunology, is an exciting topic in terms of the etiological factors and therapeutic considerations. The view in the literature is that the occurrence of transverse myelitis as an independent entity is rather rare. The present article reports the case of a female patient with recurrent spinal cord signs, and negative MRI and CSF immunology. During a ten-year follow-up observation period, symptoms of multiple sclerosis did not develop. Further studies of such cases are needed in order to clarify the etiological factors, the pathomechanism and the therapeutic considerations relating to this relatively new and probably independent clinical entity.

Adult↗