Multiple Sclerosis Current Status and Strategies for the Future (2001) / Chapter Skim
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8 Recommendations
8 Recommendations
Pages 347-368
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From page 347... ...
This chapter summarizes the recommendations that the committee believes have the greatest potential to facilitate broad advances in MS research. The committee was not asked to review specific programs of the National Multiple Sclerosis Society (the MS Society)
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From page 348... ...
ETIOLOGY AND PATHOGENESIS RECOMMENDATION 1: Research on the pathological changes underlying the natural course of MS should be emphasized, because it provides the key to predicting disease course in individual patients, understanding the physiological basis of MS, and a basis for developing improved therapeutic approaches. Unpredictability imposes a particularly acute burden on people with MS.
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From page 349... ...
· delineation of the relationship of axonal injury to demyelination and inflammation, to the role of cytokines, and to the role of cell and antibody-mediated immune mechanisms; delineation of the detailed nature of the secondary injury cascade that underlies calcium-mediated damage of axons within white matter; improved understanding of the molecular mechanisms underlying restoration of conduction in demyelinated axons, with particular attention to identification of the sodium channel subtypes involved in conduction in chronically demyelinated axons, and identification and characterization of the promoter regions of the sodium channels that support impulse conduction in myelinated and demyelinated axons; and identification of promoters and inhibitors of axon regeneration. Specific needs for research on oligodendroctyes include identification of: the role of oligodendrocytes in the trophic support of axons and neurons;
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From page 350... ...
. include: MULTIPLE SCLEROSIS the role of oligodendrocytes in maintaining the distribution of sodium channels in axons: the mechanisms that disable and destroy oligodendrocytes in MS; how and to what extent progenitor cells are induced to become oligodendrocytes that remyelinate axons; and the relationship between demyelination, injury to axons, and neuropathic pain in MS, and demyelination and axon injury in appropriate animal models.
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From page 351... ...
and is most likely related to the known function of these molecules in the normal immune response, antigen binding, and T-cell repertoire determination. The MHC region contains more than 250 genes, and despite the common assumption that DR2 is an MS susceptibility gene, because of marked linkage disequilibrium (or fixity of certain haplotypes)
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From page 352... ...
With the advances in deciphering the human genome code and sequences readily available in the public domain, future work should focus on the detailed analysis of candidate genes, in particular genes located in chromosomal segments linked to MS susceptibility or to susceptibility to demyelination in animal models. "Case-control" population-based studies with limited statistical power should be replaced with the analysis of large collections.
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From page 353... ...
Genomic, clinical, and endocrinologic information should be combined to investigate potential MS risk factors in large groups of female patients. Although sex differences in genetic susceptibility to MS have been well documented, rigorous studies assessing the potential role of sex-linked genetic factors in MS have not yet been performed.
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From page 354... ...
Although myelin basic protein (MB P) might trigger a particularly vigorous autoimmune response, it is not the only autoantigen, nor does it account for the full autoimmune response.
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From page 355... ...
identification of pathogenic T-cell clones using animal models that incorporate human-related genes and potential autoantigens and methods such as PCR, microarray assays, and phage display that do not rely on the ability of pathogens to grow in cell cultures; characterization of the disappearance, reappearance, and persistence of autoreactive T lymphocytes over time; identification of the blood-borne substances and cellular mediators that stimulate the migration of T cells and permit their passage across the blood-brain barrier and into the CNS; and elucidation of the involvement of B cells in immune-mediated attack on the central nervous system. Toots FOR RESEARCH AND DIAGNOSIS RECOMMENDATION 6: The power of neuroimaging as a tool for basic research and for clinical assessment should be taken advantage of more extensively.
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From page 356... ...
, which provides an index of neuronal destruction, to study the evolution of early changes in normalappearing white matter and to evaluate neurochemical change at various stages of the disease process; gadolinium enhancement and contrast intensification of MRI to probe the evolution of inflammatory and blood-brain barrier changes; diffusion tensor imaging, which can detect subtle pathological changes not apparent on conventional magnetic resonance imaging (MRI) and might thereby allow detection of pathological change in white matter tracts, including demyelination and loss of axons quantitative volumetric analyses of tissue destruction including the presence of "black holes" and atrophy; functional MRI (fMRI)
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From page 357... ...
Although the models that are presently available have yielded a tremendous amount of information relevant to MS, better animal models can be developed. Key advantages of current animal models include the fact that the initiating trigger is known, the exact time of the initiating event is known, a great deal is known about the genetics and the immune system in the case of rodents, and finally, the availability of animal mutants with "knockouts" of genes for particular arms of the immune system or those that carry a transgene perturbing a protein that is relevant to MS.
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From page 358... ...
. repair axona Injury; development of therapeutic approaches that will induce restoration of conduction in demyelinated axons, for example, by inducing expression of appropriate densities of the appropriate subtypes of sodium channels among them; development of approaches to stimulate re-growth of damaged axons; and development of systems for the delivery of neuroprotective and repair factors to the central nervous system.
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From page 359... ...
For example, newly formed myelin might be destroyed through the same immune response that destroyed the original myelin. RECOMMENDATION 9: New, more effective therapeutic approaches to symptom management should be pursued, including those directed at neuropathic pain and sensory disturbances.
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From page 360... ...
The committee noted that many of the pivotal MS clinical trials on diseasemodifying therapies were terminated early, usually because of predetermined stopping rules and, thereby, unique opportunities to obtain critical data were lost. The MS Trials Research and Resource Center that is being organized by the International Federation of MS Societies*
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From page 361... ...
Given the chronicity and uncertain course of MS, tracking its impact over time can assist with care of individual patients by suggesting near-term prognoses and the need for various interventions. Tabulating these findings across individuals offers insight into the burden of MS-related disability within populations, information increasingly used to set research, health, and social policy priorities.
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From page 362... ...
There is such a small body of empirical research on this topic that the committee was not able to specify the most appropriate research strategies. Rather, the committee recommends that the MS Society work in partnership with people with MS to guide the development of specific research strategies that will identify the most effective approaches toward improving their everyday lives.
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From page 363... ...
research to better understand the best approaches to making decisions about patient care in the face of uncertainty, with emphasis on addressing needs expressed by the patient; research on ways to help people with MS adapt to the illness and enhance ability to function; research to define the optimal models of care at different disease stagesthis should include the impact of managed health care and policies of national health care plans; and research to define protocols for appropriate health care referrals. These should be useful for all health care providers, but especially primary care physicians and nurses who are not MS specialists and who would benefit from guidance about when to refer patients to occupational or physical therapy or when to recommend assistive technology.
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From page 364... ...
Contemporary neuroscientists bring an appreciation of nervous system functioning across the breadth of cell and molecular biology, and the committee feels that specific efforts should be made to encourage greater integration of neuroscience researchers into the multidisciplinary MS research community. To bring new researchers into MS, it is not enough to rely on people who have already shown an interest in it.
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From page 365... ...
This has been tried successfully by a number of other private health foundations (for example, the Hereditary Disease Foundation, CaP CURE, and the Amyotrophic Lateral Sclerosis Association)
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From page 366... ...
Examples of such diseases include rheumatoid arthritis, diabetes, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS)
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From page 367... ...
It might also be possible to offer the possibility of confirming such path-breaking claims prior to their initial publication in order to increase the immediate impact of the discoveries or spare investigators embarrassment should their data be incorrect. The Amyotrophic Lateral Sclerosis Association has recently tried such an approach in response to a report of enteroviral RNA found in gray matter tissue of the spinal cord of patients with ALS.i The association provided funds to the author of that paper to replicate the study and expand it.
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From page 368... ...
Some information is important to deliver at the time of diagnosis (for example what to expect in the next few years, how to ensure health care) ; other information is only of interest to patients much later in the disease course (for example, how to obtain and choose a wheelchair)
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