Multiple Sclerosis Journal

This review considers aspects of remyelination that require further clarification if successful strategies are to be devised to enhance remyelination in multiple sclerosis (MS). We speculate, based on our understanding of the rate with which oligodendrocyte progenitor cells (OPCs) repopulate OPC-depleted tissue in adult rats, that OPC depletion during the demyelination process could explain why remyelination fails in MS. We show that loss of OPCs in the context of large areas of demyelination would have serious consequences for remyelination as the rates of colonization of tissue by adult OPCs would lead to a situation where the cellular events associated with demyelination become uncoupled from the interaction of OPCs with demyelinated axons. Experimental studies indicate that transplanted neonatal OPCs would be able to repopulate large areas of demyelination with much greater efficiency than endogenous OPCs. This suggests that cell transplantation will have considerable potential to achieve remyelination in situations where the endogenous repair process is failing due to concurrent death of oligodendrocytes and OPCs. However, we suggest that for this approach to be effective, it will be critical that the environment is permissive for remyelination.

Multiple sclerosis (MS) is considered as an immune process influenced by genetic and environmental factors. HLA-DR2 and -DR4 have been documented to be associated with MS. The HLA-dependent differences of immune response to myelin and other antigens might point out some relevant mechanisms in MS development. The responses to myelin antigens and to PPD have been compared in 21 MS patients and 25 healthy controls (HCs) by primary proliferation and by short-term T-cell lines. There was a significantly higher response to MBP in DR2+ HCs compared to MS patients (SI: 5.9 versus 1.5, p=0.02). In short-term T-cell lines, we observed a higher response to PLP30-49 in both DR4+ HCs and MS patients. This response was significantly more frequent in DR4+ MS patients (34.6%) than both DR2+ MS patients (0%, p=0.0001) and DR4+ HCs (7.7%, p=0.001). The comparison between DR2+ and DR4+ MS patients has revealed that the response to MBP was also increased in DR4+ (p=0.02). Among DR4+ groups, an increased PPD response was detected in HCs compared to MS (65.2% versus 33.3%, p=0.01). These results may indicate that HLA-related differences to specific and recall antigens are detectable in MS and these differences may have implications in the disease pathogenesis.

Proinflammatory cytokines are deemed to play a pivotal role in the pathogenesis of multiple sclerosis (MS). They provide signals for T-cell activation and inflammatory cell recruitment in the brain and might directly alter neuroglial and neuronal cell survival and function. We found that peripheral blood mononuclear cells (PBMCs) from MS patients spontaneously produce high levels of TNFα, TNFβ, IFNγ, and oncostatin M (oncM), a proinflammatory cytokine acting on cells of neural, vascular, hematopoietic, and lymphoid origin. Spontaneous production of these cytokines was significantly higher (p<0.01) in PBMC short-term culture supernatants from MS patients than in blood donors (HC). On average, lectin-induced production of these cytokines by PBMC was higher in MS patients than in HC, significantly so only for TNFα (p=0.013). Determination of TNFα, TNFβ, IFNγ, and oncM in corresponding sera showed that, on average, oncM levels were higher in MS patients than in HC, though the results were not statistically significant, whereas levels of TNFα, TNFβ, and IFNγ were below the assay threshold in most patients. The finding that MS PBMCs are primed in vivo to produce and release high levels of proinflammatory cytokines suggests the presence of a basal activation of the immune system which, in turn, may play a role in the complex circuitry of molecular and cellular interactions responsible for neurologic damage in MS.

Cerebrospinal fluid samples from controls and patients with multiple sclerosis (MS) were split and sent to laboratories with different experiences for the detection of Chlamydia pneumoniae by polymerase chain reaction. Vanderbilt investigators identified C. pneumoniae in the majority of patients with MS and uncommonly in controls. Laboratories at Johns Hopkins University, University of Umea3, and the Centers for Disease Control and Prevention did not identify C. pneumoniae in any of the samples. Conflicting reports of C. pneumoniae detection in the same samples from patients with MS highlight the need to exchange detection techniques among laboratories involved in this controversy.

As the understanding of the autoimmune inflammatory response in multiple sclerosis (MS) expands, polymorphic genes involved in this process become possible candidates that may determine the severity of disease. Therefore, three candidate genes DRB1*1501, CCR5 and apolipoprotein E (APOE) were examined in a population-based patient sample (n=70) to assess an association between disease progression measured by clinical disability and MRI parameters. The total lesion area (TLA) on T2-weighted images was measured with a semi-automated threshold technique. Patients with the CCR5D32 allele showed a non-significant trend towards a smaller lesion burden (TLA/years duration), but were not associated to a milder EDSS/years duration. Our data support previous assumptions of a modulation of severity in MS by the CCR5D32 genotype, which may convey less inflammation and tissue destruction. Carriers of the DRB1*1501 and APOE-e4 alleles did not reveal more severe disease progression, neither by the EDSS/years of duration nor by the TLA/years duration. This study was performed on a population-based sample in a genetically homogeneous Danish population but, due to the limited number of patients examined, weak associations between candidate genes and disease variables cannot be excluded.

The efficacy of glatiramer acetate in multiple sclerosis (MS) is thought to involve the production of Th2 regulatory lymphocytes that secrete anti-inflammatory cytokines; however, other mechanisms cannot be excluded. Given that activated T lymphocytes infiltrate into the CNS and become in close proximity to microglia, we evaluated whether glatiramer acetate affects the potential interaction between T cells and microglia. We report that the co-culture of activated T lymphocytes with microglia led to the induction of several cytokines, and that these were reduced by glatiramer acetate treatment. Morphological transformation of bipolar/ramified microglia into an activated ameboid form was attenuated by glatiramer acetate. These results reveal a novel mechanism for glatiramer acetate: the impairment of activated T cells to effectively interact with microglia to produce cytokines. The net result of a non-inflammatory milieu within the CNS, in spite of T cell infiltration, may help account for the amelioration of disease activity in MS patients on glatiramer acetate therapy.

Glatiramer acetate (GA) interferes with antigen recognition and modulates cytokine secretion of T cells in an antigen-specific manner. Here we analysed the capacity of GA to modulate proliferative responses and cytokine secretion of peripheral blood mononuclear cells (PBMCs) in response to antigen-independent stimuli, i.e., phytohaemagglutinin (PHA) and staphylococcal enterotoxin B (SEB) stimulation in five healthy volunteers. A significant reduction of proliferative responses, as well as interferon-gamma (IFNγ) and tumour necrosis factor-alpha (TNFα) secretion, was observed at concentrations of 200 μmg/ml suggesting that GA may also exert immunomodulatory effects on mitogen- and superantigen-induced T-cell stimulation in vitro. However, since systemic GA concentrations of this magnitude are highly unlikely to occur in vivo the immunomodulatory effects observed here are not likely to contribute to the therapeutic mechanisms of action under physiological conditions.

The relationship between the cognitive and physical aspects of multiple sclerosis (MS) and health-related quality of life (HRQL) was examined with particular focus on illness intrusiveness as a mediator of this relationship. Disease severity, cognitive functioning, HRQL, depression, and illness intrusiveness were assessed in 90 patients with MS. Disease severity (Expanded Disability Status Scale [EDSS]) predicted physical aspects of HRQL (SF-36 Physical Component Summary [PCS], fatigue, and bladder control). Information-processing speed (Paced Auditory Serial Addition Test [PASAT]) predicted mental and emotional aspects of HRQL (SF-36 Mental Component Summary [MCS]). However, both the EDSS and the PASAT predicted depression. Illness intrusiveness was significantly correlated with all indicators of HRQL. Illness intrusiveness also mediated the manner in which disease severity predicted: physical health, fatigue, and depression. Results underscore the need to assess MS and its impact more broadly rather than relying on traditional mobility-centered assessments. While in most cases physical indices of disease predict physical quality of life and cognitive assessments predict mental and emotional quality of life, the individual’s perception of MS is also a major factor contributing to quality of life. MS clearly affects multiple aspects of life and activity, as illustrated by the broad and powerful network of relationships between illness intrusiveness and all aspects of HRQL. Perceptions of illness intrusiveness appear to be a central and essential measure of the impact of MS on HRQL.

Spasticity is a common disabling feature of multiple sclerosis. A variety of drugs are in regular use as oral treatment, including baclofen, dantrolene, tizanidine, and diazepam. Published evidence of effectiveness is limited. Most trials are of small size, of short duration, and have not reported on functional outcomes. Studies have been published which suggest that baclofen, tizanidine, and diazepam are all effective in reducing clinical measures of spasticity, but there is little evidence that they lead to an improvement in patient function. There is no evidence to suggest any difference in effectiveness between them. The evidence that dantrolene has any effect on spasticity is of poor quality. Diazepam and dantrolene are associated with more side effects than baclofen and tizanidine. There is evidence for the effectiveness of gabapentin in reducing spasticity and improving function in the short term, though longer-term studies are needed to establish its true value. One randomized controlled trial of threonine does not support its effectiveness.

The baseline MRI studies from the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial, a randomized, longitudinal, double-blind trial of 383 patients with a first acute clinical demyelinating event and evidence of prior subclinical demyelination on magnetic resonance imaging (MRI) of the brain, provides a large MRI database for patients likely in the earliest stages of multiple sclerosis (MS). High-resolution baseline MRIs revealed a median of 13 T2 lesions (maximum=103 lesions) and 2.05 cm³ of T2 lesion volume (maximum 35.04 cm³), with 30% of patients having one or more enhancing lesions despite receiving a standardized high-dose course of intravenous corticosteroids. Periventricular, discrete, and juxtacortical T2 lesions were present in 99%, 92% and 67% of the patients, respectively. Large (> 6 mm), T1-hypointense, infratentorial, and corpus callosum lesions were present in 69%, 50%, 55%, and 58%, respectively. Clinical presentation groups showed differences in T2 lesion volume, and enhancing lesion number and volume. At baseline, 97%, 81% and 72% of the patients met ‘Paty’, ‘Fazekas’, and ‘Barkhof’ research criteria for MS, respectively, with the percentages similar according to clinical presentation group. These results support and extend those of smaller and/or retrospective series, which have shown substantial subclinical injury, based on brain MRI, at the earliest identifiable stages of disease.

To investigate optic neuritis as a model for atrophy in multiple sclerosis (MS) lesions we performed serial magnetic resonance imaging (MRI) on 10 patients with a history of optic neuritis using a fat saturated short-echo fast fluid-attenuated inversion recovery (sTE fFLAIR) sequence. The first study was performed a median of 19.5 months after the onset of optic neuritis and the second 1 year later. Using a computer-assisted contouring technique, a blinded observer calculated the mean area of the intra-orbital optic nerves. The mean area of affected optic nerves decreased over 1 year by 0.9 mm² from 11.1 to 10.2 mm² (p=0.01). Poor visual acuity and decreased visual-evoked potential (VEP) amplitude were associated with atrophy. These findings suggest that atrophy is a feature of focal demyelinating lesions, it may evolve over several years, and may have functional significance. Optic neuritis provides a model to study the effect of inflammatory demyelination through the ability to accurately measure visual function and to visualize and measure the optic nerves using magnetic resonance imaging.

In order to define an activity profile in patients with multiple sclerosis (MS), T-cell subpopulations and proliferative responses to myelin basic protein (MBP) associated with anti-MBP antibodies, nitrotyrosine levels in serum and cerebrospinal fluid (CSF), and serum CD40L (sCD154) were simultaneously assessed in 29 consecutive and untreated MS patients. When compared to controls, patients in secondary progressive stable (SP/I), or in full remission (RR/I) stages, individuals with secondary progressive active disease (SP/A) or in acute relapse (RR/A) showed a significant decrease of CD4/CD45RA⁺ T cells associated with an increase of absolute numbers of CD4/45R0⁺ T cells (p<0.001). In addition, in vitro-specific T-cell proliferative responses against MBP (SP/A, RR/A, SP/I: p<0.001 versus controls) in association with augmented sCD154 serum levels (SP/A, RR/A, versus controls p<0.001) and a significant increase of both CSF and serum levels of anti-MBP antibodies and nitrotyrosine levels (p<0.001) were also found. Thus, the simultaneous evaluation of antibody and cell-mediated immunopathological parameters, along with the effector mediators of inflammation such as the nitric oxide products, offers a new integrative approach to characterize markers of clinical activity in MS patients, which may be used at the moment of the initial diagnosis and during an apparent recurrences of the disease to monitor therapeutic protocols and to determine whether immune-based nerve destruction mechanisms are still operating in patients with few clinical findings.

The long-term survival of multiple sclerosis (MS) was studied during 1964-1993 in a cohort of 1614 patients in Finland. Survival to death from the initial MS symptoms was analysed by the life-table method, separately for MS related and all causes of deaths. Survival at 40 years was 64% for MS deaths and 53% for all deaths. Higher proportions of violent deaths and neoplasms were observed among MS patients as compared to the general population, whereas the proportion of cardiovascular causes of death was low. MS-related causes accounted for 70% of the recorded 219 deaths. Favourable survival in MS was associated with relapsing-remitting disease course, age at onset below 30 years and optic neuritis or other sensory symptoms at presentation. We were unable to show any significant effect due to calendar time of diagnosis or gender, as the risk of men was similar (risk ratio [RR]=1.1, confidence interval [CI] 0.8-1.6) as compared to women.