Multiple sclerosis: postlinkage genetics

Because of the relative failure of linkage analysis in multiple sclerosis, despite the investigation of more than 700 affected relative pairs, we have applied four alternative strategies to identify genes that confer susceptibility to the disease. First, we have reported two clusters of MS patients from isolated populations where 19 and 13 patients, respectively, could be shown to have common ancestry tracing back several centuries. Three and five haplotypes, respectively, were shown to be shared by affected individuals, however, these haplotypes were extended and the statistical evidence modest. Second, we have recently reported the results of a two-stage candidate gene analysis of 66 selected genes, mostly of immune function. The IL-7 receptor alpha gene and LAG-3 both had three SNP markers associated with MS. Third, we recently identified the MHC class II transactivator gene in an animal model with inflammatory properties and later confirmed it to be of importance for MS, rheumatoid arthritis and acute myocardial infarction. Finally, in collaboration with the Serono Genetics Institute, we have completed a genome-wide screen with over 100,000 markers in three sets of 300 MS patients and 300 matched controls. Eighty genes showed evidence of importance in all three populations. These strategies appear to hold some promise of success where linkage analysis has proven less successful than anticipated.     

Multiple sclerosis: pseudotumoral forms

Neurological Sciences - The pseudotumoral forms of multiple sclerosis often represent a diagnostic problem. In this paper, the main clinical, radiological and pathological characteristics of these...     

Multiple sclerosis: infectious hypothesis

In the search for the etiology of multiple sclerosis (MS), consideration has been given in turn to infectious agents, to genetic markers, and more recently to a combination of genetic and environmental factors, but after over a century of research, a definite conclusion has not been reached. The hypothesis that an infectious agent is responsible for triggering MS is perhaps one of neurology's most enduring notions. Interest in an infectious etiology has waxed and waned over the last two centuries since Pierre Marie first proposed that MS often starts as an infectious process. The possible role of infectious agents has been suggested by: the different geographic gradients in frequency among Caucasians; changes in prevalence due to migration, and the effect of age at migration; the suggestion of epidemics and clusters of cases in some small communities; and the remarkably low degree of concordance in monozygotic twins. The infectious hypothesis is strongly supported by the different temporal patterns of the disease in different geographic areas. Incidence rates have remained stable in some areas, but have changed over time in other regions. On the other hand, the hypothesis is hampered by the lack of evidence for a specific agent, and the weakness of the results of analytical studies that have tested the association between MS and previous infections. Despite these drawbacks, recent studies of a few select pathogens suggest that viral or bacterial infections or reactivations may trigger clinical exacerbations in relapsing-remitting MS.     

Multiple sclerosis: therapeutic update

Therapy for multiple sclerosis (MS) is undergoing rapid changes. We discuss recent developments in the therapy of MS, failures as well as successes, and consider some newer approaches. Multiple sclerosis, a multifocal, initially remitting-relapsing, and in some cases primarily progressive, inflammatory central nervous system immune-mediated demyelinating disease, with some axonal involvement, is currently the most common disabling neurologic disease of young people in North America and Europe. Although much is known about the pathogenesis, there is no cure and the disease must be managed long-term. Recently, there have been a number of advances in the treatment of MS.     

Multiple sclerosis: Symptomatic treatment

Reports of new therapeutic agents designed to suppress inflammatory processes in multiple sclerosis have excited much interest but, thus far, have had little influence on symptoms, disability and handicap in patients. The clinical application of recent advances in physical, pharmacological and surgical approaches to management will, at least in the medium-term future, therefore offer significantly greater opportunities for improving the quality of life of patients with multiple sclerosis. Here, symptomatic treatment of the whole range of difficulties encountered by patients with multiple sclerosis is reviewed in the context of the multidisciplinary strategy crucial to an optimal outcome.     

Multiple sclerosis

Poster Session 3

Multiple sclerosis     

Multiple sclerosis

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that commonly leads to inflammatory and atrophic brain pathology, often causing cognitive impairment. MS-associated cognitive impairment was first described over a century ago. However, with the advent of standardized neuropsychological testing and quantitative brain imaging, the frequency, quality, and correlates of cognitive impairment are better understood. Dementia is rare in MS, although it is known to occur in 10 to 25% of patients. Our data suggest a frequency of 22% among clinic attendees. In addition to the cognitive impairments evident in MS dementia, changes in personality and social behavior also occur. For example, some patients develop euphoria sclerotica and marked deficiency in social empathy, conditions that in combination with executive dysfunction cause considerable hardship for patients and caregivers. These neuropsychiatric manifestations of MS dementia are correlated with magnetic resonance imaging indicators of brain atrophy, including ventricle enlargement, neocortical volume, and normalized whole brain volume. Recent developments in pharmacological treatment for disease progression and management of cognitive symptoms hold promise for patients suffering from the degenerative aspects of MS.     

Oral session XVII: Multiple sclerosis

Journal of Neurology -     

Multiple sclerosis: the present position

The advances of the past decade particularly in the application of evoked potential techniques and electrophoresis of CSF proteins have improved the accuracy of early diagnosis of multiple sclerosis. The geographical distribution of the disease, the effect of migration on prevalence, and the existence of clusters suggest that an environmental factor is involved in the aetiològy; it is probably infective. Family and twin studies provide evidence for a genetic contribution which is probably multifactorial and related to immune regulation. The pathogenesis is at least in part immunologically mediated. A rational approach to therapy is difficult. In the present state of knowledge we are unlikely to be able to modify the course of multiple sclerosis by tackling a putative environmental agent. We are more likely to be able to do so by manipulating the pathogenesis, although an effective means of doing so has yet to be defined.     

Multiple sclerosis imaging: recent advances

In this review, we summarize advances in knowledge derived from the application of magnetic resonance imaging (MRI)-based techniques to patients with multiple sclerosis (MS) published in the Journal of Neurology over the past year. We highlight the pivotal role played by conventional MRI techniques for a correct and early diagnosis of this condition and the exclusion of alternative disorders. Advanced MR methods have contributed to demonstrating how damage to selected brain structures is related to disease clinical manifestations, thus contributing to overcome the well-known “clinical-radiological” paradox of MS, and ameliorating the understanding of the mechanisms underlying the accumulation of irreversible disability. Finally, we discuss the use of MRI to assess treatment efficacy and optimize therapeutic approaches in this condition.