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PubMed1997

Comparison of the effects of oral versus intravenous methylprednisolone regimens on peripheral blood T lymphocyte adhesion molecule expression, T cell subsets distribution and TNF alpha concentrations in multiple sclerosis.

We investigated in multiple sclerosis the difference between two commonly used oral and intravenous steroid regimens on the level of adhesion molecule expression on blood T lymphocytes, the distribution of circulating T cell subsets, and the concentration of serum tumour necrosis factor alpha. Venous blood samples were collected from a cohort of 22 patients with acute relapses who were participating in a randomised trial comparing intravenous methylprednisolone 1000 mg daily for 3 days with oral methylprednisolone 48 mg daily for one week, 24 mg daily for one week, and finally 12 mg daily for one week. There was a similar significant reduction of T cell LFA-1 surface expression and serum TNF alpha concentrations after 4 days of treatment with each regimen. There was no change in other lymphocyte adhesion molecules expression (ICAM-1, LFA-3 or CD2) at day 4, although LFA-3 and CD2 expression was moderately decreased at day 28 and day 90 respectively; nor was there any change in the distribution of lymphocyte subsets (CD4, CD8, and CD45RA, CD45RO), although a small decrease in CD45RO circulatory T cells was noted at day 28. This study suggests that some of the beneficial effects of glucocorticosteroids may be related to the inhibition of lymphocyte adhesion as well as the modulation of proinflammatory cytokines.

Administration, Oral↗

PubMed2004

Distribution and quantification of human herpesvirus 6 in multiple sclerosis and control brains.

Multiple sclerosis (MS) is thought to be precipitated by environmental factors, potentially including viruses, in genetically susceptible individuals and recently human herpesvirus 6 (HHV-6) has been associated with the disease. We have analysed post mortem brain for the presence, variant type and quantity of HHV-6 by PCR. A total of 124 samples from seven anatomically defined regions of brain were tested from MS cases and controls. HHV-6 DNA was detected in 41% and 44% of MS case and control samples. The median viral loads were 11 and 9 genome copies/microg DNA in cases and controls respectively and the viral load was not increased in lesions. Except in one instance, the HHV-6 DNA detected was variant B. There was no apparent difference in the distribution of HHV-6 DNA in the brains of MS cases versus controls, nor between normal appearing and lesional tissue in MS cases. Periventricular regions of the brain were more frequently positive for HHV-6 DNA in both MS cases and controls, although this difference was not statistically significant. These studies confirm the neurotropism of HHV-6 but do not demonstrate differences in the distribution, variant type or quantity of HHV-6 in brains from patients with MS versus controls.

Aged↗

PubMed2003

Depression-like changes of the sleep-EEG during high dose corticosteroid treatment in patients with multiple sclerosis.

Acute exacerbations of multiple sclerosis (MS) are commonly treated with high doses of corticosteroids that can influence sleep regulation and hypothalamo-pituitary-adrenal (HPA) activity. We examined the sleep-EEG (including conventional and spectral EEG analysis) in 9 female patients with relapsing-remitting MS (and no psychiatric disorder) just prior to and on days 2 and 10 of high dose corticosteroid treatment (500 mg/day methylprednisolone given IV for 5 days, then PO taper down) and age-matched healthy female controls. Before treatment with corticosteroids, MS patients compared to controls showed few changes of the sleep EEG, namely a significant increase in slow wave sleep (SWS) and a decrease in stage 2 sleep. In contrast, on day 10, but not day 2 of treatment, MS patients showed a number of sleep-EEG changes typically observed in patients with depression, including a reduction in REM latency, an increase in REM density, a decrease in the SWS and delta sleep ratio and a decrease in sigma EEG activity. However, no concomitant effect of treatment on mood was noted. In summary, unlike acute treatment with methylprednisolone, prolonged treatment induces several changes of the sleep-EEG in MS patients, that are also observed in patients with an acute depressive episode. Further prospective studies with longer-term follow-up are needed to examine the clinical relevance of our preliminary data.

Adult↗

PubMed1996

Impact of aerobic training on fitness and quality of life in multiple sclerosis.

Fifty-four multiple sclerosis (MS) patients were randomly assigned to exercise (EX) or nonexercise (NEX) groups. Before and after 15 weeks of aerobic training, aspects of fitness including maximal aerobic capacity (VO2max), isometric strength, body composition, and blood lipids were measured. Daily activities, mood, fatigue, and disease status were measured by the Profile of Mood States (POMS), Sickness Impact Profile (SIP), Fatigue Severity Scale (FSS), and neurological examination. Training consisted of 3 x 40-minute sessions per week of combined arm and leg ergometry. Expanded Disability Status Scale (EDSS) scores were unchanged, except for improved bowel and bladder function in the EX group. Compared with baseline, the EX group demonstrated significant increases in VO2max, upper and lower extremity strength, and significant decreases in skinfolds, triglyceride, and very-low-density lipoprotein (VLDL). For the EX group, POMS depression and anger scores were significantly reduced at weeks 5 and 10, and fatigue was reduced at week 10. The EX group improved significantly on all components of the physical dimension of the SIP and showed significant improvements for social interaction, emotional behavior, home management, total SIP score, and recreation and past times. No changes were observed for EX or NEX groups on the FSS. Exercise training resulted in improved fitness and had a positive impact on factors related to quality of life.

Adult↗

PubMed1995

Cobalt-57 SPET in relapsing-progressive multiple sclerosis: a pilot study.

Multiple sclerosis (MS) is predominantly a progressive immune-mediated disease of the white matter in the brain. We used single photon emission tomography (SPET) and cobalt-57 (57Co) as a calcium (Ca) analogue to visualize brain tissue damage, based on the fact that Ca influx occurs in both cell death and T-lymphocyte activation in MS. The aim of this study was to determine if 57Co-SPET detects MS lesions and, if so, to compare this with clinical data on the patient. Five MS patients underwent neurological examination including Expanded Disability Status Scale (EDSS) assessment and 57Co-SPET, using a single-headed camera. All available data were compared. The lesions were recognized as areas of increased signal intensity, although the poor count rate did not allow any statistical quantification. A relationship between one 57Co-SPET parameter (cobalt plaque load) and EDSS was demonstrated. In conclusion, this pilot study suggests that 57Co-SPET using a single-headed camera is not an appropriate imaging modality in MS. To obtain a more favourable signal-to-noise ratio, the use of a multi-headed camera, the administration of a higher activity of 57Co and a longer acquisition time are recommended. Validation of this method among a larger group of patients and a comparison with healthy volunteers is needed.

Brain↗

PubMed1995

Cardiac autonomic function during sleep and wakefulness in multiple sclerosis.

Some studies in multiple sclerosis (MS) patients have shown evidence of autonomic dysfunction involving the cardiovascular system. However, the findings in these studies have not been completely consistent. The discrepancy may be related to the limits of the traditional autonomic tests during wakefulness. In our study, after the investigation of the cardiovascular reflexes during wakefulness, heart rate (HR) variations were considered during sleep in order to avoid the limits of cooperation and the emotional state of the patient. We evaluated tonic (vagal activity) HR modifications in relation to the deepening of sleep, as well as phasic (sympathetic activity) HR modifications in relation to spontaneous body movements during sleep, in 25 MS patients and 25 age-matched controls. No difference was found between the two groups in autonomic function during wakefulness. A reduced parasympathetic activity was observed in MS subjects during both rapid eye movement (REM) and non-REM sleep, while no difference was found in sympathetic function between patients and controls. No significant correlation was found between cardiac autonomic data during sleep and MRI lesion load in the infratentorial areas and, in particular, of the brain stem. The findings of our study suggest that autonomic nervous system evaluation during sleep could show impairment earlier than the traditional autonomic tests during wakefulness.

Adult↗

PubMed2006

Long term safety of IVIg therapy in multiple sclerosis: 10 years experience.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. The majority of MS patients have a relapsing-remitting course with progressive neurological disability that accumulates over the years. Intravenous Immunoglobulin (IVIg) has demonstrated benefit in the treatment of some patients with relapsing-remitting MS. Concerns about adverse events of IVIg, mainly acute renal failure and thromboembolic events have been raised in the medical literature. We examined the adverse events profile of IVIg treatment in a large cohort of 293 relapsing-remitting MS patients treated with an initial loading dose of IVIg (0.4 g/Kg body weight/day, for 5 consecutive days) and additional booster dose infusions (0.4 g/Kg body weight/booster dose, every 6 weeks) as a maintenance treatment. A total of 9281 IVIg infusions were administered within a mean treatment period of 3.8 +/- 3.5 years (3 months-10 years). The main adverse event during the loading dose period was headache, occurring in 12.6% of the patients. The annual rate of any adverse event during the IVIg maintenance period was 4.4% during the first year and had a trend to decrease with every passing year of treatment. Adverse events during the loading dose did not predict adverse events during the maintenance phase. No severe adverse events were recorded. We conclude that IVIg is a safe therapy in MS either for short or for long-term periods.

Adult↗

PubMed2006

Growth-associated protein 43 in lesions and cerebrospinal fluid in multiple sclerosis.

Axonal damage in multiple sclerosis (MS) is correlated to disease progression. Early axonal damage may be compensated for by regenerative processes. Growth-associated protein 43 (GAP-43) is a marker for axonal growth and synaptogenesis in various neurodegenerative diseases. We investigated the expression of GAP-43 in 48 MS grey and white matter lesions of different stages. Decreased GAP-43 expression was found in 74% of the white matter lesions, independent of the lesion stage. In 19 out of 35 white matter lesions, areas of increased GAP-43 expression were present immediately adjacent to the lesions. Increased or unaltered expression was observed in remyelinated lesions. GAP-43 was expressed in neurofilament-positive structures. GAP-43 expression appeared unchanged in grey matter lesions. Macrophages were present in the areas of changed GAP-43 expression. cerebrospinal fluid GAP-43 levels were negatively correlated with magnetic resonance imaging measures of whole-brain atrophy (r = -0.30). In conclusion, these results indicate that decreased GAP-43 immunopositivity reflects axonal damage in MS lesions, which may again be reflected in decreased cerebrospinal fluid levels. The increased levels of GAP-43 in remyelinated or nondemyelinated white matter close to MS lesions may reflect regenerative attempts by damaged axons.

Adult↗

PubMed2006

An investigation of polymorphisms in the 17q11.2-12 CC chemokine gene cluster for association with multiple sclerosis in Australians.

BACKGROUND: Multiple sclerosis (MS) is a disorder of the central nervous system (CNS) characterised by inflammation and neuronal degeneration. It is believed to result from the complex interaction of a number of genes, each with modest effect. Chemokines are vital to the migration of cells to sites of inflammation, including the CNS, and many are implicated in MS pathogenesis. Most of the CC chemokine genes are encoded in a cluster on chromosome 17q11.2-12, which has been identified in a number of genome wide screens as being potentially associated with MS. METHODS: We conducted a two-stage analysis to investigate the chemokine gene cluster for association with MS. After sequencing the chemokine genes in several DNA pools to identify common polymorphisms, 12 candidate single-nucleotide polymorphisms (SNPs) were genotyped in a cohort of Australian MS trio families. RESULTS: Marginally significant (uncorrected) transmission distortion was identified for four of the SNPs after stratification for several factors. We also identified marginally significant (uncorrected) transmission distortion for haplotypes encompassing the CCL2 and CCL11 genes, using two independent cohorts, which was consistent with recent reports from another group. CONCLUSION: Our results implicate several chemokines as possibly being associated with MS susceptibility, and given that chemokines and their receptors are suitable targets for therapeutic agents, further investigation is warranted in this region.

Australia↗

PubMed2005

Co-localization of human herpes virus 6 and tissue plasminogen activator in multiple sclerosis brain tissue.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system of unknown etiology. Several viruses have been suggested as playing a role in the pathogenesis of MS. The aim of this study was to investigate the interrelationship of human herpesvirus 6 (HHV-6) and plasminogen activation at the cellular level in MS plaques. MATERIAL/METHODS: Brain tissue specimens obtained from autopsies of 15 patients with MS and 10 controls were studied immunohistochemically for HHV-6 and cytomegalovirus (CMV) antigen and tissue plasminogen activator (tPA) protein. The presence of Ebstein-Barr virus (EBV) EBER RNA was studied using RNA in situ hybridization. RESULTS: HHV-6 antigen was identified in the cells of 67% (10/15) of MS brain sections and 30% (3/10) of the control sections. All samples were negative for CMV antigen and all samples with intact RNA were negative for EBV EBER RNA as demonstrated by in situ hybridization. tPA expression was found to be increased in MS plaques compared with the control samples. Interestingly, in 5 MS samples both HHV-6 antigen and tPA stained clearly, compared with none in the controls, but HHV-6 and tPA only occasionally co-localized in the same cells. CONCLUSIONS: At the cellular level, HHV-6 and plasminogen activation seem to co-localize in MS.

Antigens, Viral↗

PubMedDate not supplied

[MSRV retrovirus and gliotoxin protein: potential biological markers in multiple sclerosis?].

The aetiopathogeny of multiple sclerosis, a neurological disease which prevalence and duration generate an important problem of public health in industrialized countries where it is most frequent, is not clearly understood. The keys for the diagnosis and therapeutic strategies of MS are nonetheless dependent upon the identification of a well-defined aetiology and upon the understanding of the mechanisms and pathogenic connexions which lead to the demyelinating lesions of the central nervous system and to the dysfunctions of the immune system (autoimmunity) characteristic for the disease. The recent identification of a retroviral agent (MSRV) which produces extracellular particles detectable in the plasma, the CSF, and in some cell cultures from patients with MS, as well as of a cytotoxic factor targeting glial cells (gliotoxin) detected in parallel, could help elucidating the aetiopathogeny of MS. The usefulness of biological markers and targets derived from MSRV retrovirus and this gliotoxin, in the diagnostic and therapeutic perspectives for MS, is discussed in the light of the different aetiopathogenic hypotheses for the disease. From our results it is conceivable that a retroviral agent and pathogenic molecules such as this gliotoxin and an eventual MSRV-associated retroviral superantigen might initiate and perpetuate the cascade of events leading to MS. However, similar data on different simple retroviruses were recently published concerning autoimmune diseases such as diabetes type 1, Sjögren's syndrome and systemic lupus erythematosis, which could prefigurate a broader concept for the role of such retroviruses in the aetiopathogenesis of autoimmune diseases.

Animals↗

PubMed2002

Proteolytic balance in patients with multiple sclerosis during interferon treatment.

Multiple sclerosis (MS) is a progressive, inflammatory, demyelinating disease. An altered cytokine network has been reported to occur during the disease, and its pathogenetic role has been hypothesized. To date, interferon-beta (IFN-beta) is the most effective and reliable therapy in the majority of MS patients, although the mechanisms underlying its therapeutic effects are not fully understood. Breakdown of the blood-brain barrier (BBB) with consequent extravasation of the T cells and their invasion of the brain parenchyma seems to be one of the most important steps in the pathogenesis of the disease. Matrix metalloproteinease-2 (MMP-2) and MMP-9 are enzymes with proteolytic activities toward extracellular matrix ECM components. They are physiologically balanced by the MMP tissue inhibitors TIMP-2 and TIMP-1, so that proteolysis occurs as the result of increased MMP or decreased TIMP levels. In 38 patients with MS, MMP-2 and TIMP-1 levels were similar before and after 9 months of IFN-beta therapy, whereas MMP-9 levels significantly decreased and TIMP-2 levels significantly increased in comparison to values obtained before treatment. These results suggest that IFN-beta modulates T cell activities, including MMP and TIMP production, thus contributing either to maintaining the integrity of the BBB or to slowing the progression of the disease.

Adolescent↗

PubMed1997

[A case-control study of multiple sclerosis in Alcoi].

INTRODUCTION: Multiple sclerosis (EM) is a neurological disorder of great epidemiological interest. Considerable variations have been described regarding the initial description of geographical distribution. In the Alcoi health district an epidemiological study showed more cases than would be expected from the latitude. Objective. To care out an analytical study to determine which factors influence this situation. MATERIAL AND METHODS: We carried out a case-control study, pairing one case with four controls from the population, as regards age, sex and place of residence. Only current cases were included, under the control of the only Neurology Unit in the area, and which fulfilled criteria defined by EM. The control group was randomly selected from the census. RESULTS: We analyzed 37 patients and 148 controls. There were no significant differences between the cases and the controls regarding socio-educational level, order of birth within the family, blood group, toxic habits and family history. We found a significantly greater frequency of urinary infections before the age of 15, and of cystitis and pneumonia after reaching the age of 15. Contact with textiles, their finished products and dogs reached significant values. In the patient group there was a significantly higher number of immigrants than in the control group. CONCLUSIONS: The correlation found between certain factors such as contact with textiles, their finished products and dogs should be evaluated in further studies in which the immigration factor is controlled.

Adult↗

PubMed2006

[Neuronal injury in multiple sclerosis].

The concept of multiple sclerosis (MS) as a demyelinating disease is deeply ingrained. Although the existence of a neurodegenerative component has always been apparent, it has only recently become emphasized. Thus, in recent years several studies have identified axonal degeneration as the major determinant of irreversible neurological disability in patients with MS. Axonal injury begins at disease onset and remains clinically silent for many years; irreversible neurological disability develops when a threshold of axonal loss is reached and CNS compensatory mechanisms are exhausted. The precise mechanisms of axonal loss are poorly understood, and three hypotheses have been proposed: 1) The damage is caused by an inflammatory process, 2) There is an excessive accumulation of intra-axonal Ca2+, 3) Demyelinated axons undergo degeneration due to lack of trophic support by myelin, or myelin forming cells. Although MS has traditionally been regarded as a disease of white matter, demyelination can also occur in the cerebral cortex. Cortical lesions exhibit neuronal injury represented by dendritic and axonal transection as well as neuronal apoptosis. Because conventional nuclear magnetic resonance (NMR) is limited in its ability to provide specific information about axonal pathology in MS, new techniques such as, diffusion-weighted MRI, proton magnetic resonance spectroscopy, functional MRI, as well as novel techniques designed to measure atrophy have been developed to monitor MS evolution. Recognition that MS is in part a neurodegenerative disease should trigger critical rethinking on the pathogenic mechanisms of this disease and provides new targets for a rational treatment.

Apoptosis↗

PubMed2004

Exercise and multiple sclerosis.

The pathophysiology of multiple sclerosis (MS) is characterised by fatigue, motor weakness, spasticity, poor balance, heat sensitivity and mental depression. Also, MS symptoms may lead to physical inactivity associated with the development of secondary diseases. Persons with MS are thus challenged by their disability when attempting to pursue an active lifestyle compatible with health-related fitness. Although exercise prescription is gaining favour as a therapeutic strategy to minimise the loss of functional capacity in chronic diseases, it remains under-utilised as an intervention strategy in the MS population. However, a growing number of studies indicate that exercise in patients with mild-to-moderate MS provides similar fitness and psychological benefits as it does in healthy controls. We reviewed numerous studies describing the responses of selected MS patients to acute and chronic exercise compared with healthy controls. All training studies reported positive outcomes that outweighed potential adverse effects of the exercise intervention. Based on our review, this article highlights the role of exercise prescription in the multidisciplinary approach to MS disease management for improving and maintaining functional capacity. Despite the often unpredictable clinical course of MS, exercise programmes designed to increase cardiorespiratory fitness, muscle strength and mobility provide benefits that enhance lifestyle activity and quality of life while reducing risk of secondary disorders. Recommendations for the evaluation of cardiorespiratory fitness, muscle performance and flexibility are presented as well as basic guidelines for individualised exercise testing and training in MS. Special considerations for exercise, including medical management concerns, programme modifications and supervision, in the MS population are discussed.

Exercise↗

PubMed2002

Sharing of a conserved haplotype suggests a susceptibility gene for multiple sclerosis at chromosome 17p11.

Multiple sclerosis (MS) is a chronic inflammatory disease resulting in demyelination in the central nervous system (CNS). Increasing evidence supports that genetic factors confer susceptibility to MS. One locus, the HLA complex (6p21), has been identified as important in MS, but no other loci have been clearly implicated, neither by a candidate gene approach, nor by a genomic screen strategy. Here, we studied a genetically isolated population in the northern-most part of Sweden, which demonstrates a high incidence of MS, using haplotype sharing analysis. Genealogical analysis demonstrated that 22 MS patients originate from a single common ancestral couple in the eighteenth century. Five affected individuals from four nuclear families were selected for an initial genomic screen with 390 microsatellite markers. Seven shared haplotypes in six different chromosomal regions were observed. After genotyping for these haplotypes with the same and additional markers in 15 MS patients and healthy relatives, some portion of a conserved haplotype spanning 10 cM at 17p11 was found to be shared by 12 of 15 affected individuals. The statistical analysis revealed a significant excess of transmission of alleles of three markers to affected individuals (P<0.05) by the transmission/disequilibrium test (TDT). An identical four-marker haplotype was shared by six of 15 patients (40%; P<0.01). Surprisingly, DR-typing revealed no significant sharing of the HLA region. In conclusion, our data suggests a novel susceptibility gene for MS in chromosome 17p11.

Chromosomes, Human, Pair 17↗

PubMed1985

Selective loss of a subset of T helper cells in active multiple sclerosis.

Patients with active multiple sclerosis (MS) have a selective loss of a subset of T helper cells (Th), detectable by two-color fluorescence-activated cell sorter analysis of peripheral blood lymphocytes. By using pairs of monoclonal antibodies to the T-cell subset markers CD4 (Th) and CD8 [T suppressor/cytotoxic cell (Ts)] and the common leukocyte markers Lp220 and Lp95-150, five phenotypically distinct T-cell subsets have been identified in peripheral blood: two CD4+ Th cell subsets and three CD8+ Ts cell subsets. The frequencies and absolute numbers of these five populations were measured in patients with active and inactive MS and were compared with those in healthy age-matched controls and in patients with other neurologic diseases. A high frequency of patients with active MS (80%) had a selective reduction of one Th subset (CD4+ Lp220+) compared with normal controls (P less than 0.001) or patients with inactive MS (P less than 0.001). Three patients examined sequentially had a further loss of the Lp220+ Th subset as disease activity progressed. The proportion of two Ts subsets was also abnormal in patients with active MS, but this defect was not restricted to that group. Total Th and Ts cell frequencies and Th/Ts ratios were not significantly different between patient and normal control groups. Thus, two-color analysis of T-cell subsets may be a more sensitive indicator than conventional single-marker assays of abnormal immune status in MS patients.

Adolescent↗

PubMed2005

Genomics, proteomics, metabolomics: what is in a word for multiple sclerosis?

PURPOSE OF REVIEW: Multiple sclerosis (MS) is the most common chronic inflammatory neurological disease. Despite major advances the aetiology of this disease it is still not completely understood. In the post-genome era, advances in global screening technologies offer an opportunity to accelerate the search of new pathological pathways and to identify new therapeutic targets. Some recent publications using novel global screening methods at the genome, transcriptome, proteome and metabolome levels are discussed. RECENT FINDINGS: The genetic association of susceptibility to MS with loci outside the MHC has been reconfirmed. Evidence of parent-of-origin and seasonal effects on disease susceptibility add further complexity to the genetics of MS. The search for MS susceptibility genes continues using the candidate-gene approach as well as large-scale single-nucleotide-polymorphism association studies and novel cross-species synteny analysis. Genome-wide expression profiling using microarrays produced numerous therapeutic targets and is progressing towards profiling of rare cells. Advances in classical proteomics methods paved the way to new initiatives aiming at determining the proteome of the nervous system in normal and diseased states. Although progress is still slow, array-based methods are making an impact on the MS field. SUMMARY: The complexity of MS is clearly reflected in the latest findings using global profiling methods. Nevertheless, these new technologies are confirming some of the basic aspects of the disease pathophysiology, i.e. its polygenicity, the central role of neuroinflammation and the emerging neurodegenerative processes. These data are primarily the results of genomic approaches, yet promising attempts are also made using proteomics and metabolomics.

Animals↗