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PubMed2001

Combination of cyclophosphamide and interferon-beta halts progression in patients with rapidly transitional multiple sclerosis.

The effects of combined treatment with cyclophosphamide (CTX) and interferon-beta (IFN-beta) are described in selected patients with "rapidly transitional" multiple sclerosis. This form of multiple sclerosis is extremely active with very frequent and severe attacks which produce a dramatic increase on the expanded disability status scale (EDSS). Ten patients with rapidly transitional multiple sclerosis were previously treated with interferon-beta, but none benefited by this treatment. Monthly treatment with intravenous CTX, from 500 mg/m(2) to 1500 mg/m(2) to obtain a chronic lymphocytopenia (600/mm(3) to 900/mm(3)) produced a marked and significant reduction in the number of relapses (p<0.0001), disability previously accumulated (p<0.0001), and a reduction of T2 MRI burden of lesion. This particular group of patients benefited by combining cyclophosphamide and IFN-beta. The possibility is considered of carrying out further studies to test the efficacy of the association between the two drugs for patients who are not responsive to IFN-beta or other active disease modifying therapies.

Adjuvants, Immunologic↗
PubMed1994

Benign and secondary progressive multiple sclerosis: a preliminary quantitative MRI study.

In a preliminary study, we compared by means of quantitative magnetic resonance imaging (MRI) methods (1) the T2 values and the decay characteristics of chronic brain lesions, (2) the T2 values of normal-appearing frontal white matter (NAWM) and (3) brain lesion volumes in patients with benign and secondary progressive multiple sclerosis (MS) in order to evaluate the mechanisms underlying the development of disability. Eleven clinically definite MS patients with either benign MS (n = 5) or secondary progressive MS (n = 6) were studied. Fifty-two chronic lesions (identified by comparison with MRI scans obtained at least 12 months previously) were identified. The mean T2 of large lesions (cross-sectional area greater than 41 mm2) and of the NAWM was similar in both clinical groups. However, small lesions had higher mean T2 values (P < 0.01) in the benign group, probably at least in part because of partial volume effects. Analysis of large lesions revealed biexponential T2 relaxation in 6 of 8 "secondary progressive" and in 2 of 16 "benign" lesions, perhaps indicating a greater degree of axonal loss in large lesions of patients with secondary progressive MS. Patients with secondary progressive MS had higher (although not significant) total and infratentorial lesion loads than those of the benign group. These preliminary findings suggest, but do not establish, that variations in the extent, site and pathological nature of lesions may all contribute to different patterns of disease evolution in MS.

Adolescent↗
PubMed1988

Determination of activated lymphocytes in peripheral blood of patients with multiple sclerosis.

Using monoclonal antibodies Ta1 and CD25 (interleukin-2 receptor: I-2R) and flow cytometry, the levels of activated lymphocytes in the peripheral blood of 50 patients with multiple sclerosis (16 relapsing inactive; 14 relapsing active; 20 chronic progressive) and 20 normal subjects were investigated. No significant differences were observed in the percentage or absolute numbers of Ta1 and IL-2R reactive lymphocytes between the normal and multiple sclerosis patient groups, irrespective of disease activity. Monitoring peripheral blood lymphocytes with respect to these markers would appear to have little value in the management of multiple sclerosis.

Humans↗
PubMed1996

Progressive systemic sclerosis associated with multiple mononeuropathy.

BACKGROUND: Progressive systemic sclerosis (PSS) is a chronic connective tissue inflammatory disease which commonly attacks the skin and the visceral organs, but rarely the peripheral nervous system. OBJECTIVE: The aim of this study was to investigate PSS accompanied by peripheral neuropathy clinically, electrophysiologically and pathologically from a sural nerve biopsy. METHODS: Two women suffering from PSS but without any other collagen disease were studied. Both patients developed peripheral neuropathy with multiple mononeuropathy of the limbs, and in one woman, in the trunk as well. RESULTS: A biopsy of the sural nerve revealed axonal and myelin segmental degeneration, loss of large myelinated fibers and an increase of collagen fibers, but there was no evidence of vasculitis. An electron microscopic examination revealed degenerated axons, disrupted myelin sheaths and multilayered basal lamina in the capillaries. CONCLUSION: Mononeuropathy in PSS suggests that ischemic neuropathy may be related to the immune-mediated vasculopathy.

Aged↗
PubMed1986

Neuropsychology of multiple sclerosis: a critical review.

Multiple sclerosis (MS) is a relatively common, chronic progressive neurological illness affecting individuals primarily in the third and fourth decades of life. Autopsy studies indicate that the disease preferentially attacks white matter throughout the CNS, including the cerebral hemispheres. This article reviews the current state of knowledge regarding cognitive dysfunction in MS and relates these findings to neuropathological changes. The view that affective disturbance may also result from cerebral demyelination is presented, along with a brief discussion of MS as a prototype "subcortical" dementia. Finally, methodological problems intrinsic to the study of MS are presented, and suggestions for future research are made.

Cognition Disorders↗
PubMedDate not supplied

[Lipid peroxides in the sera of patients with multiple sclerosis].

Serum lipid peroxides (LPX) were determined in 24 patients with multiple sclerosis and in 30 healthy controls. Patients with relapses or chronic progression had significantly higher serum LPX level than healthy controls: mean 3.09 +/- 0.15 nmol/ml versus 2.30 nmol/ml, p less than 0.01. Relapsing-remitting patients showed slightly higher LPX level than slowly progressive patients. It is supposed that lipid peroxides are unspecific mediators of the inflammatory reaction in multiple sclerosis.

Adult↗
PubMedDate not supplied

[Increased expression of aminopeptidase N on lymphocytes in multiple sclerosis].

Aminopeptidase N is an ectoenzyme. Its expression on lymphocytes is the effect of cell activation. We studied APN expression on peripheral blood lymphocytes of multiple sclerosis (MS) patients and in the control group of patients with other neurological diseases (OND). We observed increased APN expression on lymphocytes of MS patients during acute exacerbation and in the course of chronic progressive MS compared to MS remission and OND groups. No such differences were found in CD11a molecule of LFA-1 integrin expression on lymphocytes. We suppose that APN expression on lymphocyte surface can be a sensitive marker of these cell activation in the course of MS.

Acute Disease↗
PubMedDate not supplied

Macrophage populations associated with multiple sclerosis plaques.

The macrophage population within and outside plaques from eight cases of multiple sclerosis (MS) (two clinically acute, four chronic progressive and two chronic non-progressive) has been examined in fresh frozen sections with a panel of monoclonal antibodies of macrophage, monocyte and MHC class II specificity. The majority of cells in active, hypercellular plaques, and at active borders, reacted with macrophage- and class II MHC-specific antibodies, and such cells extended beyond the border between demyelinated and myelinated parenchyma. In inactive plaques such cells that reacted with macrophage-specific antibodies were sparse and reacted only inconstantly with class II MHC-specific antibodies. Macrophage heterogeneity was evident in as much as one macrophage antibody, RFD7, reacted only with perivascular and not parenchymal macrophages in most plaques, but reacted with a variable proportion of parenchymal macrophages in active plaques. It is suggested that the RFD7 antibody may identify a sub-population of acute plaques, and that its use may clarify interpretation of findings related to other inflammatory cell populations by providing greater precision of classification of active plaques.

Adult↗
PubMed1994

Improvement in word-fluency performance in patients with multiple sclerosis by electromagnetic fields.

Impairment of cognitive functions is well recognized in patients diagnosed with multiple sclerosis (MS), especially those with a chronic progressive course. In fact, MS has been considered a type of "subcortical dementia" in which cognitive and behavioral abnormalities resemble those observed in patients with frontal lobe syndrome. Patients with frontal lobe syndrome are known to exhibit diverse cognitive and behavioral abnormalities which include, among others, diminished spontaneity of speech with difficulties producing appropriate words and phrases. It has been reported recently that extracranial application of extremely weak electromagnetic fields (EMF) in the picotesla range produced improvement in motor and cognitive functions in patients with MS. The present report concerns three women with MS (mean age: 44.3 +/- 8.5 yrs; mean duration of illness: 18.3 +/- 3.5 yrs), two with chronic progressive course and the third with a relapsing-remitting course in whom the Thurstone Word-Fluency Test, a reputed test of frontal lobe function, was administered prior to and following a series of 4 to 5 treatment sessions with EMF. Prior to the initiation of treatment with EMF all patients demonstrated word fluency performance which was well below age and sex-matched normal controls of similar level of education (mean output of MS patients was 42.6 +/- 1.1 words vs. 79.0 +/- 6.2 words of the controls). A series of treatments with EMF produced a 100% increase in word output within a short period of time (mean: 83.3 +/- 14.0 words). These findings suggest that this treatment modality improves frontal lobe functions in patients with MS and corroborate previous reports indicating beneficial effects of EMF on cognitive functions in these patients.

Adult↗
PubMed2004

Hyperbaric oxygen therapy for multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a chronic, recurrent and progressive illness with no cure. On the basis of speculative pathophysiology, it has been suggested that Hyperbaric Oxygen Therapy (HBOT) may slow or reverse the progress of the disease. OBJECTIVES: The object of this review was to evaluate the efficacy and safety of HBOT in the treatment of MS. SEARCH STRATEGY: We searched the Cochrane MS Group trials register (July 2002), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2002), MEDLINE (January 1966 to October 2002) and the National Library of Medicine (NLM) database (July 2002), along with specialised hyperbaric resources and handsearching of relevant journals and proceedings. SELECTION CRITERIA: All randomised, controlled trials involving a comparison between HBOT and a sham therapy in MS were evaluated. DATA COLLECTION AND ANALYSIS: Two reviewers independently appraised all comparative trials identified, extracted data and scored them for methodological quality. MAIN RESULTS: We identified ten reports of nine trials that satisfied selection criteria (504 participants in total). Two trials produced generally positive results, while the remaining seven reported generally no evidence of a treatment effect. None of our three a priori subgroup analyses placed these two trials in the same group and were therefore unable to account for this difference. Three analyses (of 21) did indicate some benefit. For example, the mean Expanded Disability Status Scale (EDSS) at 12 months was improved in the HBOT group (group mean reduction in EDSS compared to sham -0.85 of a point, 95% confidence interval -1.28 to -0.42, P = 0.0001). Only the two generally positive trials reported on this outcome at this time (16% of the total participants in this review). REVIEWER'S CONCLUSIONS: We found no consistent evidence to confirm a beneficial effect of hyperbaric oxygen therapy for the treatment of multiple sclerosis and do not believe routine use is justified. The small number of analyses suggestive of benefit are isolated, difficult to ascribe with biological plausibility and would need to be confirmed in future well-designed trials. Such trials are not, in our view, justified by this review.

Humans↗
PubMed1988

Frequency of blood-retina and blood-brain barrier changes in multiple sclerosis.

The frequency of blood-retina barrier (BRB) and blood-brain barrier (BBB) alterations was studied in 20 cases of Multiple Sclerosis (MS) (12 relapsing and 8 chronic-progressive). BBB impairment was found in 7 out of 20 patients (35%), 3 of whom had the chronic-progressive form of the disease. Alterations to BRB were found in 9 out 20 cases (45%): 2 out 12 (17%) of the relapsing cases and 7 out 8 of the chronic-progressive cases (87.5%). BBB impairment was found in 3 of the 9 cases (33%) with BRB alterations. Our findings indicate that BRB and BBB alterations do not occur simultaneously. We propose that the higher frequency of BRB alterations in chronic-progressive MS may be a sign of persistent antigenic stimulation.

Blood-Brain Barrier↗
PubMed1986

Interferon induction, 2'-5' oligo A synthetase and lymphocyte subpopulations in out-patients with multiple sclerosis in a longitudinal study.

Nine patients with multiple sclerosis, four with relapsing-remitting disease, and five with chronic progressive disease, together with eight healthy control, were followed for nearly a year with monthly clinical and laboratory examinations. Alpha- and gamma-interferon was induced in lymphocytes with different viruses and PHA, no differences were found between healthy controls and multiple sclerosis patients. The alpha- and gamma-interferon induced enzyme 2'-5' oligo A synthetase in lymphocytes was found to have a tendency to be lower in multiple sclerosis patients than in healthy controls. When medians of ratios of helper/suppressor blood lymphocytes in multiple sclerosis patients were compared with healthy controls, the same results were found, although higher values of ratios were found among the patients and the highest value was found in a patient with chronic progressive disease. No correlation to disease activity could be found in interferon inductions, 2'-5' oligo A synthetase concentrations and ratios of OKT4/OKT8. In particular no change in ratio was found in relation to five exacerbations taking place in the four multiple sclerosis patients with acute relapses.

2',5'-Oligoadenylate Synthetase↗
PubMed2003

Multiple sclerosis: a study of chemokine receptors and regulatory T cells in relation to MRI variables.

Magnetic resonance imaging (MRI) remains the most valuable tool for monitoring disease activity and progression in patients with multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system (CNS) with presumably autoimmune etiology. Chemokine receptors have been implicated in MS as key molecules directing inflammatory cells into the CNS. Regulatory (CD4+CD25+) T cells (Tr cells) are important in suppressing autoimmunity, and their absolute or functional deficit could be expected in MS. In the present study, venous blood was obtained from MS patients concurrent with MRI examination of the brain, and expression of chemokine receptors CCR1, CCR2, CCR5, CXCR3 and CXCR4 by CD4 T cells and monocytes, proportions of Tr cells, as well as expression of CD45RO, CD95, CTLA-4, HLA-DR and interleukin (IL)-10 by Tr cells and non-Tr (CD25-) CD4 T cells was analyzed by flow cytometry. Surface expression of CXCR3 by CD4 T cells was downregulated in the group of patients with high lesion load (LL) on T2-weighted images and gadolinium (Gd)-enhancing lesions on T1-weighted images, compared to the group with high LL and no Gd-enhancing lesions, and to the group with low LL, suggesting internalization of CXCR3 due to the release of its chemokine ligand (IP-10/CXCL10) from active MS lesions. Proportions of Tr cells amongst all CD4 T cells, and expression of IL-10 by Tr cells were increased in the patients with high LL and Gd-enhancing lesions. These results suggest that there is correlation between MRI parameters, chemokine receptor expression and the status of circulating Tr cells in MS, but further studies need to discriminate between pathogenetically relevant and bystander phenomena.

Adult↗
PubMed1998

Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiple sclerosis.

Multiple sclerosis is an immune-mediated demyelinating disease of unknown etiology that presents with either a chronic-progressive or relapsing-remitting clinical course. Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) and relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) in the SJL/J mouse are both relevant murine CD4+ T cell-mediated demyelinating models that recapitulate the multiple sclerosis disease phenotypes. To determine the cellular and molecular basis for these observed differences in clinical course, we quantitatively analyzed the temporal expression of pro- and antiinflammatory cytokine mRNA expression in the central nervous system (CNS) and the phenotype of the inflammatory mononuclear infiltrates. TMEV-infected SJL/J mice expressed IFN-gamma, TNF-alpha, IL-10, and IL-4 mRNA during the preclinical phase, and their levels continued to increase throughout the duration of the chronic-progressive disease course. These data correlated with the continued presence of both CD4+ T cells and F4/80+ macrophages within the CNS infiltrates. In contrast, SJL/J mice with PLP(139-151)-induced R-EAE displayed a biphasic pattern of CNS expression for the proinflammatory cytokines, IFN-gamma and TNF-alpha, with expression peaking at the height of the acute phase and relapse(s). This pattern correlated with dynamic changes in the CD4+ T cell and F4/80+ macrophage populations during relapsing-remitting disease progression. Interestingly, IL-4 message was undetectable until disease remission(s), demonstrating its potential role in the intrinsic regulation of ongoing disease, whereas IL-10 was continuously expressed, arguing against a regulatory role in either disease. These data suggest that the kinetics of cytokine expression together with the nature of the persistent inflammatory infiltrates are major contributors to the differences in clinical course between TMEV-IDD and R-EAE.

Animals↗
PubMed2005

Inflammation stimulates remyelination in areas of chronic demyelination.

A major challenge in multiple sclerosis research is to understand the cause or causes of remyelination failure and to devise ways of ameliorating its consequences. This requires appropriate experimental models. Although there are many models of acute demyelination, at present there are few suitable models of chronic demyelination. The taiep rat is a myelin mutant that shows progressive myelin loss and, by 1 year of age, its CNS tissue has many features of chronic areas of demyelination in multiple sclerosis: chronically demyelinated axons present in an astrocytic environment in the absence of acute inflammation. Using the taiep rat and a combination of X-irradiation and cell transplantation, it has been possible to address a number of questions concerning remyelination failure in chronic multiple sclerosis lesions, such as whether chronically demyelinated axons have undergone changes that render them refractory to remyelination and why remyelination is absent when oligodendrocyte progenitor cells (OPCs) are present. Our experiments show that (i) transplanted OPCs will not populate OPC-containing areas of chronic demyelination; (ii) myelination competent OPCs can repopulate OPC-depleted chronically demyelinated astrocytosed tissue, but this repopulation does not result in remyelination--closely resembling the situation found in some multiple sclerosis plaques; and (iii) the induction of acute inflammation in this non-remyelinating situation results in remyelination. Thus, we can conclude that axonal changes induced by chronic demyelination are unlikely to contribute to remyelination failure in multiple sclerosis. Rather, remyelination fails either because OPCs fail to repopulate areas of demyelination or because if OPCs are present they are unable to generate remyelinating oligodendrocytes owing to the presence of inhibitory factors and/or a lack of the stimuli required to activate these cells to generate remyelinating oligodendrocytes. This non-remyelinating situation can be transformed to a remyelinating one by the induction of acute inflammation.

Acute Disease↗
PubMed1998

Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells.

In the past decade, considerable progress has been made in the understanding of the biology of rodent oligodendrocyte precursor cells and their role in the generation of oligodendrocytes in the developing and adult rodent CNS. Much less is known about human oligodendrocyte lineage cells and about the reasons for the failure of the regeneration of the oligodendrocyte population during chronic stages of multiple sclerosis (MS). In particular, the fate of the oligodendrocyte precursor population in MS has remained elusive. The present study examined the possibility that oligodendrocyte regeneration ultimately fails because of the local destruction of both oligodendrocytes and their precursor cells. Analysis of chronic stage MS tissue suggested that this is not the case, because all chronic MS lesions studied contained significant numbers of oligodendrocyte precursor cells, identified as process-bearing cells that bound the O4 antibody but not antibodies to GalC and GFAP. The oligodendrocyte precursor cells appeared, however, to be relatively quiescent, because none expressed the nuclear proliferation antigen recognized by the Ki-67 antibody, and because most lesions lacked myelinating oligodendrocytes in their centers. Thus, it appears that the regeneration of the oligodendrocyte population fails during chronic stages of MS because of the inability of oligodendrocyte precursor cells to proliferate and differentiate rather than because of the local destruction of all oligodendrocyte lineage cells. The identification of ways of stimulating the endogenous oligodendrocyte precursor population to expand and generate remyelinating cells may represent an alternative to transplantation of oligodendrocyte lineage cells to promote myelin repair in MS.

Adult↗
PubMed1984

Lymphocytapheresis therapy in multiple sclerosis, a preliminary study.

10 patients with definite multiple sclerosis (MS), most of them with the chronic progressive type, were treated with lymphocytapheresis during one year. The DSS (Disability Status Scale) improved in 4 patients during the intensive phase of treatment, remained stable in 5 patients and deteriorated in one. The NSS (Neurological Status Scale) showed a stabilisation for the majority of the neurologic functions. Using the ISS (Incapacity Status Scale), an improvement was measured in 6 patients, a stabilisation in one and a deterioration in 3. Exacerbations could not be prevented by lymphocytapheresis.

Adult↗