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PubMedDate not supplied

[Pharmacologic treatment of multiple sclerosis].

INTRODUCTION: Multiple sclerosis (MS) is probably caused by many pathological factors, both intrinsic and extrinsic. DEVELOPMENT: When we consider the aetiology of MS, we have to take three basic factors into account: 1. Immunological factors: evidence of involvement of the immune system has been found in plasma, tissues and CSF; 2. Viral factors: epidemiological studies suggest that MS may be a result of contact with environmental factors during childhood or adolescence, and 3. Genetic factors although there is no evidence that MS is inherited directly, there is between 12 and 15 times more involvement of persons from affected families than from the general population. Regarding treatment, since this is a polysymptomatic disorder, the specialist should choose the most suitable drug or intervention in each case, according to the alterations which affect quality of life or the severity of the presenting symptom. Three pharmacological treatments are emphasized: steroids, immunomodulation and immunosuppression. CONCLUSION: In this article we review the aetiology of MS and its pharmacological treatment.

Adrenal Cortex Hormones↗

PubMed2004

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis.

In multiple sclerosis (MS), long-term disability is primarily caused by axonal and neuronal damage. We demonstrated in a previous study that neuronal apoptosis occurs early during experimental autoimmune encephalomyelitis, a common animal model of MS. In the present study, we show that, in rats suffering from myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis, systemic application of erythropoietin (Epo) significantly increased survival and function of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. We identified three independent intracellular signaling pathways involved in Epo-induced neuroprotection in vivo: Protein levels of phospho-Akt, phospho-MAPK 1 and 2, and Bcl-2 were increased under Epo application. Using a combined treatment of Epo together with a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K) prevented upregulation of phospho-Akt and consecutive RGC rescue. We conclude that in MOG-EAE the PI3-K/Akt pathway has an important influence on RGC survival under systemic treatment with Epo.

Animals↗

PubMed2000

Immunological time-course of gadolinium-enhancing MRI lesions in patients with multiple sclerosis.

In multiple sclerosis (MS) gadolinium (Gd)-enhanced MRI activity correlates weakly with immunological markers of disease activity. We, therefore, tested the hypothesis that the poor correlation could be partly explained by the temporal profile of Gd enhancement. We measured urinary neopterin:creatinine ratios (neopt.:creat.(urine)) in 5 patients with active MS undergoing weekly Gd-enhanced MRI studies of the brain. The neopt.:creat.(urine) associated with new Gd-enhancing lesions (<8 days) was significantly higher than the ratio not associated with new Gd-enhancing lesions [mean(geometric) neopt.: creat.(urine) = 413 micromol/mol (range = 207-521) vs. 250 micromol/mol (range = 132-492), p = 0.03]. Pro-inflammatory immunological markers, which are probably produced early on in the life cycle of an active MS lesion, should preferably be correlated with newly enhancing lesions (<8 days). Failure to do this may explain the poor and unpredictable correlations between immunological markers and Gd-enhanced MRI activity, which cannot be accurately aged in cross-sectional and serial monthly MRI studies.

Adrenal Cortex Hormones↗

PubMed2005

[Future possibilities of the multiple sclerosis treatment].

Multiple sclerosis is an autoimmune disease of the central nervous system. Pathogenetic mechanisms involve inflammation and neurodegeneration leading to myelin sheaths destruction and irreversible nerve fibre loss. At present mainly the inflammatory part can be influenced and undoubtedly only the earliest beginning of the treatment can effectively postpone irreversible disability. High-dose corticosteroids remain the "gold standard" in MS attack treatment. Interferon beta and glatiramer acetate represent disease modifying drugs. Both of these medicaments decrease the number of attacks for about 30 %, however each patient responds differently. In many cases new attacks appear and it is necessary to intensify the treatment--to add immunosuppresives, to use combinations of steroid and cytostatic treatment. Intravenous immunoglobulins represent second line treatment. In the case of rapid disease progression immunoablation and stem cells transplantation is available. From recently tested drugs the most successful was the monoclonal antibody natalizumab. Unfortunately because of serious adverse effects in patients treated by combination of interferon beta + natalizumab, the application has been stopped. Monoclonal antibody against inteleukin 12 and chemokine receptor CCR2, cytostatics fumarate, laquinimod and cladribine are also tested in the clinical studies. DNA vaccination represents revolutionary opportunity of inducing tolerance against myelin autoantigens.

Humans↗

PubMed2002

A functional and structural basis for TCR cross-reactivity in multiple sclerosis.

The multiple sclerosis (MS)-associated HLA major histocompatibility complex (MHC) class II alleles DRB1*1501, DRB5*0101 and DQB1*0602 are in strong linkage disequilibrium, making it difficult to determine which is the principal MS risk gene. Here we show that together the DRB1 and DRB5 loci may influence susceptibility to MS. We demonstrate that a T cell receptor (TCR) from an MS patient recognized both a DRB1*1501-restricted myelin basic protein (MBP) and DRB5*0101-restricted Epstein-Barr virus (EBV) peptide. Crystal structure determination of the DRB5*0101-EBV peptide complex revealed a marked degree of structural equivalence to the DRB1*1501-MBP peptide complex at the surface presented for TCR recognition. This provides structural evidence for molecular mimicry involving HLA molecules. The structural details suggest an explanation for the preponderance of MHC class II associations in HLA-associated diseases.

Animals↗

PubMed1995

Screening for major depression in the early stages of multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is associated with a high risk of developing major depression, but depression in MS patients frequently goes undetected and untreated. The current study examined the clinical utility of the Beck Depression Inventory (BDI) as a screening measure for major depression in newly diagnosed MS patients. METHODS: Forty-six new referrals to an MS clinic completed the BDI and participated in a structured interview for major depression, within 2 months of the diagnosis of MS. RESULTS: According to DSM-III-R criteria, 40% of patients were diagnosed with major depression, 22% had adjustment disorder with depressed mood, and 37% showed no evidence of mood disorder. Sensitivity and specificity values, and positive and negative predictive values are reported for every BDI cut-off score between 9 and 21. CONCLUSIONS: A BDI cut-off score of 13 (sensitivity = .71, specificity = .79) is recommended as optimal for use in screening for major depression in newly diagnosed MS patients. The use of the BDI as a screening measure for major depression must proceed with caution given that a cut-off score of 13 still yielded a false-negative rate of 30%.

Adult↗

PubMed1991

Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions.

Multiple sclerosis (MS) brain tissue, spleen, and PBMC were studied using immunocytochemistry and FACS for immunoreactivity for lymphotoxin (LT) and TNF. Both cytokines were identified in acute and chronic active MS lesions but were absent from chronic silent lesions. LT was associated with CD3+ lymphocytes and Leu-M5+ microglia cells at the lesion edge and to a lesser extent, in adjacent white matter. TNF was associated with astrocytes in all areas of the lesion, and with foamy macrophages in the center of the active lesion. In acute lesions, immunoreactivity for TNF in endothelial cells was noted at the lesion edge. No LT or TNF reactivity was detected in Alzheimer's or Parkinson's disease brain tissues but was present at lower levels in central nervous system (CNS) tissue from other inflammatory conditions, except for adrenoleucodystrophy which displayed high levels of LT in microglia. No increase in LT and TNF reactivity was detected in spleen and PBMC of MS patients suggesting specific reactivity within the CNS. These results indicate that LT and TNF may be involved in the immunopathogenesis of MS, and can be detected in both inflammatory cells and cells endogenous to the CNS.

Acute Disease↗

PubMed2006

Grey matter pathology in multiple sclerosis.

Although multiple sclerosis (MS) has been considered a white matter disease, MS lesions are known to occur in grey matter. Recent immunohistochemical studies have demonstrated extensive grey matter demyelination in chronic MS. The most common lesion type consists of purely cortical lesions extending inward from the surface of the brain, this lesion subgroup is grossly underestimated by standard histochemical myelin staining methods. Some MS patients have subpial demyelination in all cortical areas of the brain; this pattern has been termed ''general cortical subpial demyelination''. Extensive cortical demyelination is associated with the progressive phases of disease, as less cortical demyelination has been detected in relapsing-remitting MS. The pathology of grey matter lesions differs from that of white matter lesions; grey matter lesions are less inflammatory, with less macrophage and lymphocyte infiltration. In purely cortical lesions there is no significant increase in lymphocytes compared with non-demyelinated adjacent cortical areas in MS patients or cerebral cortex in control patients. Significant axonal transection and neuronal loss have been demonstrated in grey matter MS lesions. Current magnetic resonance imaging (MRI) methods are not sensitive for purely cortical MS lesions. The clinical significance of cortical MS lesions may not be characterised until more sensitive MRI methods are developed.

Cerebral Cortex↗

PubMed2005

P wave duration and dispersion in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) has been reported to be associated with extensive autonomic dysfunction as well as to involve the cardiovascular system. In this study we compared P wave duration and dispersion (PWD) of MS patients to healthy control subjects. METHOD: Thirty-one MS patients (mean age 35 +/- 9 years) and 33 healthy control subjects (mean age 34+/-7 years) were included in the study. Twelve-lead surface ECG recording (paper speed of 50 mm/s) was obtained from all participants. The change in maximum and minimum P wave duration was measured manually and the difference between the two values was defined as PWD. RESULTS: There was no difference between the two groups in terms of baseline demographic characteristics. Maximum P wave duration was higher in MS patients than controls (126 +/- 6 vs. 122 +/- 5 ms, p = 0.004). Minimum P wave duration was found to be similar in MS patients and healthy controls (72 +/- 8 vs. 75 +/- 8 ms, p = 0.2). Mean PWD value of MS patients was also found to be higher than those of controls (53 +/- 10 vs. 47 +/- 10 ms, p = 0.01). CONCLUSION: P wave duration and PWD was found to be statistically different in patients with MS and control subjects.

Adult↗

PubMed1998

[Blood levels of soluble ICAM-1 in patients with multiple sclerosis].

INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The Intercellular Adhesion Molecule plays a fundamental part in the migration of T cells to the inflammed tissues. It is known that there is an increase in the expression of endothelial cells and other cells found in lesions of the central nervous system of MS patients. ICAM-I may be detected in its soluble form in serum and it is of interest to understand its behaviour in this liquid since it is easily accessible. MATERIAL AND METHODS: We studied the concentration of soluble ICAM-I in the serum of patients with MS: one group which had clinical attacks were studied whilst in remission; another had the chronic progressive clinical form and a third group had optic neuritis as the probable initial sign of the disorder. Within the different clinical forms, some patients received treatment with beta-interferon or azathioprine and others did not. RESULTS AND CONCLUSIONS: We found a significant increase in the levels of soluble ICAM-I in patients with inactive, untreated MS as compared with normal persons, with no difference found between the different clinical types.

Autoimmune Diseases↗

PubMed2006

Novel image processing techniques to better understand white matter disruption in multiple sclerosis.

In Multiple Sclerosis (MS) patients, conventional magnetic resonance imaging (MRI) shows a pattern of white matter (WM) disruption but may also overlook some WM damage. Diffusion tensor MRI (DT-MRI) can provide important in-vivo information about fiber direction that is not provided by conventional MRI. The geometry of diffusion tensors can quantitatively characterize the local structure in tissues. The integration of both conventional MRI and DT-MRI measures together with connectivity-based regional assessment provide a better understanding of the nature and the location of WM abnormalities. Image processing and visualization techniques have been developed and applied to study conventional MRI and DT-MRI of MS patients. These include methods of: Image Segmentation for identifying the different areas of the brain as well as to discriminate normal from abnormal WM, Computerized Atlases, which include structural information obtained from a set of subjects, and Tractographies which can aid in the delineation of WM fiber tracts by tracking connected diffusion tensors. These new techniques hold out the promise of improving our understanding of WM architecture and its disruption in diseases such as MS. In the present study, we review the work that has been done in the development of these techniques and illustrate their applications.

Brain↗

PubMedDate not supplied

[Intercellular adhesion molecules and chemotaxic factors in the pathogenesis of multiple sclerosis].

INTRODUCTION: Multiple sclerosis (MS) is an inflammatory immune disorder of the central nervous system characterized by the destruction of myelin sheaths and the cells which make them, the oligodendrocytes. Experimental allergic encephalitis (EAE) is an autoimmune condition mainly induced by the myelin basic protein (MBP) that is a very useful model for the study of demyelinating inflammatory diseases, particularly MS. METHOD: Cellular adhesion molecules are a wide group of membrane receptors which mediate adhesion processes, both cell to cell and between cells and the extracellular matrix. These molecules play an essential role in inflammatory phenomena, including EAE/MS. Integrins of the b1 subfamily (mainly a4b1), as well as leukocyte integrins and adhesion receptors of the immunoglobulin superfamily (ICAM 1, VCAM 1) are the main molecules involved. Chemokines also have an important role in MS, since they are able to attract and activate leukocytes, essential phenomena in the inflammatory reaction. An increased expression of chemokines CC or beta (e.g., RANTES, MIP 1a and b, MCP 1, etc.) has been found in EAE/MS, and it is very likely that they are involved in the migration of lymphocytes and monocytes towards the MS inflammatory lesions. CONCLUSION: The pharmacological blockade of adhesion molecules and chemokines is a promising and novel therapeutic approach in MS.

Adjuvants, Immunologic↗

PubMed2001

Effect of corticosteroid therapy on serum and CSF malondialdehyde and antioxidant proteins in multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is a disease characterised by perivascular infiltrates and demyelination of the white matter in the central nervous system. Although the precise cause of MS remains unknown, some investigations have been carried out on antioxidant mechanisms in these patients. METHODS: In this study, malondialdehyde (MDA), as a lipid peroxidation marker, and ceruloplasmin (Cp) and transferrin (Trf), as antioxidant proteins, levels were determined in cerebrospinal fluid (CSF) and serum of 30 MS patients before and after corticosteroid therapy and in 20 control subjects. Transferrin and Cp levels were measured by the nephelometric method and MDA was measured spectrophotometrically. RESULTS: Mean MDA(serum) and MDA(CSF) levels were found to be highest in the pretreatment group and lowest in the control group. Although there was no significant difference in terms of serum Trf level, serum Cp was found higher in pre- and posttreatment groups than in the control groups. Ceruloplasmin and Trf levels of CSF were not detectable using the nephelometric method. A significant correlation was found between MDA(CSF) and MDA(serum) in the pretreatment group (r=0.58). CONCLUSIONS: These data revealed that lipid peroxidation was increased in serum and particulary in CSF of MS patients and was reduced with corticosteroid therapy.

Adolescent↗

PubMed1996

Power spectrum analysis contribution to the detection of cardiovascular dysautonomia in multiple sclerosis.

In multiple sclerosis (MS) autonomic cardiovascular dysfunction is an uncommon, but potentially dangerous event, to which studies of spectral analysis of heart rate variability have not been applied, yet. MATERIAL AND METHODS--We studied 16 patients with definite MS (11 women and 5 men, mean age 30.3 +/- 7.4 yrs., mean EDSS 2.06 +/- 1.42) and 16 sex- and age-matched healthy controls. Besides cardiovascular reflex tests (valsalva manoeuvre, deep breathing, lying to standing, Blood Pressure response to standing and sustained handgrip), each underwent spectral analysis of the R-R interval short-term variability at rest and after tilting, to detect three components: very low frequency (VLF), low frequency (LF) and high frequency (HF). A recent brain MRI was obtained from patients, to compare plaque characteristics with spectral parameters. RESULTS--At cardiovascular reflexes, only four patients (25%) showed an impairment, mostly of a mild degree. VLF and LF at rest were lower in MS subjects than in controls (p < 0.01). No significant correlation was found between spectral parameters and lesion area or localization as detected on MRI. CONCLUSIONS--Spectral analysis could usefully flank reflex tests to detect autonomic subclinical cardiovascular abnormalities.

Adult↗

PubMed1980

Analysis of visual evoked responses in multiple sclerosis.

In Multiple Sclerosis (MS) the modification of the latency of visual evoked responses (VER's) shows sequels of the involvement of anterior optic tracts manifested by a retro-bulbar optic neuritis (RBON). This study was made on 102 patients with MS. The stimulus used the pattern reversal of a checkboard. The influence of the size and squares 8' and 20' chosen as stimulus has been first studied in patients with antecedents of RBON. Using the 8' squares, all eyes with a history of RBON had pathological VER's. When there is no clinical antecedent of RBON, this means of stimulation enabled us to detect sequels of RBON. In "definitive" and "probable" MS, 100% of patients had pathological VER's either for both eyes of a single eyes. In "possible" MS a sequel of RBON was demonstrated in 57% of this population without clinical antecedent of RBON. A correlation between VER's result and the ophthalmological examination (visual acuity, fundoscopic examination and acquired dyschromatopsie) was made. Although VER's are an excellent method for detecting the sequels of RBON in MS. VER's abnormalities have no etiological significance, they are observed in other neurological involvements of anterior optic tracts. These different points are discussed and a physiological interpretation of VER's abnormalities is proposed.

Color Perception↗

PubMed1997

[Clinical-epidemiological characteristics of late onset multiple sclerosis].

INTRODUCTION: Multiple sclerosis (MS) is the most frequent demyelinating disorder of the central nervous system. It mainly affects young adults and it has been calculated that between 20% and 30% are of late onset (after the age of 40), presenting clinical features, a clinical course and prognosis which are specific to this disorder. MATERIAL AND METHODS: Between 1985 and 1994 we studied 297 cases of MS (diagnosed according to the criteria of Poser) and found that in 20.5% the illness had started when the patients were over the age the 40. RESULTS AND CONCLUSIONS: Certain aspects of the clinical features and course of the disorder were compared, taking the group of late onset cases and a randomized sample of 100 cases of early onset, showing that the symptoms and pyramidal signs were more frequent in the late onset group, whilst sensory and visual signs were commoner in the early onset group. In both groups there were more females. MS was defined according to Poser's criteria in 78.7% and 77% respectively. Chronic, primary and secondary progressive forms predominated in tire late onset group, whilst in the group with onset before the age of 40 there was a predominance of the exacerbating-remitting form.

Adolescent↗

PubMedDate not supplied

Different antiganglioside antibody pattern between relapsing-remitting and progressive multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disorder, but an unique antigen has not been found. Antiganglioside antibodies (AGA) have been reported in MS, nevertheless, a clinical significance of AGA in MS has not been established. The aims of this study were to study AGA in sera of MS patients and to investigate relationships between AGA and clinical course of MS. MATERIAL AND METHODS: 42 patients with MS who fulfilled the criteria of clinically definite disease (59% RRMS, 21% SPMS, 20% PPMS), 89 patients with systemic lupus erythematosus and 36 healthy controls were studied. A modification of previously described ELISA techniques was used to estimate serum IgG and IgM anti-GM1, asialoGM1 and anti-GD1a antibodies. RESULTS: 47.6% of the patients showed AGA reactivity. Anti-GM1 was found in 38% of MS patients, anti-asialoGM1 in 23.8% and anti-GD1a in 33.3%. IgG was the isotype more commonly found. A correlation between presence of AGA and progressive disease and between anti-GD1a and PPMS was found. CONCLUSIONS: The presence of AGA in MS patients is elevated. In contrast with the results of others authors, a strong correlation between AGA and progressive disease is showed in our study.

Adult↗

PubMed2005

Predictors of dyadic adjustment in multiple sclerosis.

Because multiple sclerosis (MS) is usually diagnosed between the ages of 20 and 50, a time during which most people begin serious relationships, dyadic adjustment for MS patients is a salient issue. However, little is known about factors that might contribute to dyadic adjustment problems in MS. In the present study, we predicted that MS patients showing evidence of three common sequelae of MS--depression symptoms, fatigue and cognitive dysfunction--would be most likely to display problems with dyadic adjustment. Sixty-four MS patients and 49 significant others were assessed. Patient-reported dyadic adjustment was significantly (P at least <0.05) associated with depression (r = -0.48) and fatigue (r = -0.31), but not cognitive functioning. Significant other-reported dyadic adjustment was significantly associated with patients' depression (r = -0.38), fatigue (r = -0.30) and executive functioning impairments (r = 0.37). Stepwise regression analyses revealed that depression was the only significant predictor of dyadic adjustment, regardless of whether significant other (r2 change = 0.16) or patient-reported (r2 change = 0.22) dyadic adjustment was used as the criterion variable. If depression leads to dyadic problems in MS patients, treatment of depression may result in improved dyadic adjustment. Conversely, if dyadic problems contribute to depression in MS, then treatment of dyadic problems may lead to relief from depression in these patients.

Adaptation, Psychological↗