The genetic epidemiology of multiple sclerosis

Multiple sclerosis (MS) is a debilitating immunological and neurodegenerative disorder. Epidemiological studies have provided overwhelming evidence of complex genetic susceptibility to MS. However, with the exception of the human leukocyte antigen (HLA) locus, genetic studies have failed to consistently identify significant linkage or association with genes that modulate MS disease expression. Numerous functional candidate gene studies, linkage genomic screens, and locational candidate gene studies have been performed in an attempt to identify additional loci. However, these methods have demonstrated insufficient power to consistently identify genes or epigenetic factors for MS. More current approaches integrate information from a variety of sources (e.g. consistent linkage data, gene expression profiling, and functional characterization studies) and utilize high throughput methods (e.g. genotyping high density markers, utilizing pooling schemes and performing new statistical analyses) in an attempt to overcome power issues. The following article presents a review of MS genetics research and a brief overview of methods that are currently being developed and utilized for fine localization of MS loci, such as the method employed in the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) study that is presented elsewhere in this journal. It is the hope of researchers that these methods will lead to the identification of susceptibility genes for MS that aid in elucidating pathogenic mechanisms and potential therapeutic strategies for this debilitating disease.     

The epidemiology of multiple sclerosis in Europe

Multiple sclerosis (MS) is a chronic and potentially highly disabling disorder with considerable social impact and economic consequences. It is the major cause of non-traumatic disability in young adults. The social costs associated with MS are high because of its long duration, the early loss of productivity, the need for assistance in activities of daily living and the use of immunomodulatory treatments and multidisciplinary health care. Available MS epidemiological estimates are aimed at providing a measure of the disease burden in Europe. The total estimated prevalence rate of MS for the past three decades is 83 per 100 000 with higher rates in northern countries and a female:male ratio around 2.0. Prevalence rates are higher for women for all countries considered. The highest prevalence rates have been estimated for the age group 35–64 years for both sexes and for all countries. The estimated European mean annual MS incidence rate is 4.3 cases per 100 000. The mean distribution by disease course and by disability is also reported. Despite the wealth of epidemiological data on MS, comparing epidemiological indices among European countries is a hard task and often leads only to approximate estimates. This represents a major methodological concern when evaluating the MS burden in Europe and when implementing specific cost-of-illness studies.     

The epidemiology of multiple sclerosis in Finland: increase of prevalence and stability of foci in high-risk areas

ABSTRACT- Reliable data on the epidemiology of multiple sclerosis (MS) in Finland are available from 1964 and 1972. They show that the whole country is a high-risk area of MS with clustering in the western part. A reassessment of the prevalence data was carried out in the southern province of Uusimaa and in the western province of Vaasa, the prevalence day being January 1, 1979. The age-adjusted prevalence was 52.9 per 100,000 in Uusimaa and 92.9 per 100,000 in Vaasa, figures that were three times higher than those recorded for the same areas in 1964. The communities with the highest prevalence rates in the province of Vaasa were the same as those in the survey of 1972; some rates exceeded 200 per 100,000. The increase in the prevalence rates may be due to a better registration of MS cases, but it may also represent a true increase, a possibility that only can be answered by further incidence studies.     

Clinical trials in multiple sclerosis: methodological issues

PURPOSE OF REVIEW: The availability of partially effective immunomodulatory and immunosuppressive treatments for relapsing multiple sclerosis (MS) opens important ethical, methodological and practical issues in the design and conduct of new clinical trials in these patients. RECENT FINDINGS: The recommendation of the National Health Authorities to prioritize phase III clinical trials using placebo arm raises ethical questions. In addition, patients are reluctant to be involved in such trials. Alternative clinical trial designs will be discussed. Relapses and active lesions are accepted measures of disease activity; new/enlarging T2 lesions and/or enhancing lesions are accepted surrogate markers of disease activity in phase II clinical trials. On the contrary, there are no accepted magnetic resonance imaging (MRI) surrogate markers of disease progression and also the clinical measures to monitor the degenerative aspects of the disease are not without important limitations. New scales of impairment, disability and quality of life will be reviewed extensively. We will also focus on the value of modern and quantitative MRI techniques, which hold substantial promise as tools to estimate the extent of MS-related irreversible tissue loss. SUMMARY: The use of an active comparator in a superior clinical-trial design is becoming an attractive option for testing the efficacy of new drugs in relapsing MS. At present there are no fully reliable and sensitive clinical markers of the accumulation of irreversible tissue damage in MS. Although additional extensive application in longitudinal studies is needed, modern MRI techniques are promising tools to monitor the neurodegenerative aspects of MS.     

The incidence and prevalence of reported multiple sclerosis

A national survey, sponsored by the National Institute of Neurological and Communicative Disorders and Stroke, to determine the incidence, prevalence, and economic impact of multiple sclerosis has just been completed. These data are the first report of the results. Based on the data gathered, it is estimated that on Januaryuary 1, 1976, there were a reported 123,000 multiple sclerosis patients in the conterminous United States (a rate of 58 per 100,000). The annual incidence for the period 1970–1975 was estimated to be 8,800 (a rate of 4.2 per 100,000). The pattern of the disease being more common among females, whites, persons aged 30 to 50 years, and individuals living above the 37th parallel was also demonstrated. In addition to demographic characteristics, selected disease characteristics of the incidence and prevalence populations were also examined.     

The prevalence of multiple sclerosis in south east Wales.

A population-based survey of multiple sclerosis in the county of South Glamorgan has demonstrated a prevalence of 441/376718 (117/10(5)). Eighty six per cent of the patients (101/10(5)) had definite or probable disease and 14% (16/10(5)) had suspected multiple sclerosis on 1 January 1985. The estimated average incidence is 5.41/10(5)/year for the period 1947-84 and it has risen significantly over four decades. The prevalence is similar to that found in a recent survey from the south east of England but significantly lower than revised figures from Scotland.     

The prevalence of multiple sclerosis in the world: an update

The systematic study of multiple sclerosis (MS) in populations, started in 1929 by Sydney Allison, now consists of over 400 publications dealing with the prevalence of MS throughout the world. However, any attempt to redefine the pattern of geographical differences in MS frequency remains as difficult as ever. The comparison of prevalence studies carried out in different areas and times is made difficult by the variability in surveyed population sizes, age structures, ethnic origins and composition, and the difficult quantification of numerators, especially regarding the recognition of benign and very early cases. Additionally, complete case ascertainment depends on access to medical care, local medical expertise, number of neurologists, accessibility and availability of new diagnostic procedures, the degree of public awareness about MS, and the investigators' zeal and resources. Critical examination of the more recent data on MS prevalence leads to some revisions of previously held concepts, the most interesting of which is the appreciation of the greater influence of genetic factors on disease acquisition. The rarity of MS among Samis, Turkmen, Uzbeks, Kazakhs, Kyrgyzis, native Siberians, North and South Amerindians, Chinese, Japanese, African blacks and New Zealand Maoris, as well as the high risk among Sardinians, Parsis and Palestinians, clearly indicate that the different susceptibilities of distinct racial and ethnic groups are an important determinant of the uneven geographic distribution of the disease. The updated distribution of MS in Europe, showing many exceptions to the previously described north-south gradient, requires more explanation than simply a prevalence-latitude relationship. Prevalence data imply that racial and ethnic differences are important in influencing the worldwide distribution of MS and that its geography must be interpreted in terms of the probable discontinuous distribution of genetic susceptibility alleles, which can however be modified by environment. Because the environmental and genetic determinants of geographic gradients are by no means mutually exclusive, the race versus place controversy is, to some extent, a useless and sterile debate.     

Menopause in multiple sclerosis: therapeutic considerations

While the onset of multiple sclerosis (MS) typically occurs during the childbearing years, many women living with MS are of perimenopausal age. There is frequent overlap between menopausal and MS-related symptoms and co-morbidities (e.g. sexual dysfunction, mood disorders and bladder function). Furthermore, some MS symptoms may be exacerbated by perimenopausal changes such as hot flashes or sleep disturbance. The MS neurologist may frequently be the first to become aware of these symptoms and to play a role in monitoring and managing them. In this review, we describe immunological and neurologic changes at menopause as they may impact MS. We then review common symptoms, including fatigue, depression, sexual function, pain and insomnia, and provide both behavioral and pharmacological suggestions for their management. Next, we discuss the need for osteoporosis and cancer screening in perimenopausal women with MS. Finally, we highlight important research gaps, including what effect, if any, the menopausal transition may play on MS disease course as well as the potential modulatory role of hormone replacement therapies.     

The epidemiology of multiple sclerosis in Queensland, Australia

An epidemiological survey of multiple sclerosis (MS) in the State of Queensland was undertaken with its prevalence day being the national census day on June 30th, 1981, 20 years after a regional survey within the State. The relationship between increasing prevalence of MS and increasing south latitude within the State of Queensland which was suggested by the 1961 study was confirmed in the present study. The prevalence rate had increased significantly over the 20-year period between the studies but the State remained a medium frequency zone for MS (prevalence rate between 5 and 29 per 100 000 of population). Although a real increase in disease frequency could not be excluded as a contributing factor to the rise in prevalence, it was most likely due predominantly to an increase in life expectancy amongst the MS population and also in differential migration of a population at a greater risk of developing MS than the indigenous population. The proportions of Australian-born patients who had migrated to Queensland from the higher risk southern regions of Australia or travelled overseas to countries known to be high-risk for MS prior to disease onset, had fallen between the two surveys thus exerting, if anything, a negative influence on the change in prevalence. Analysis of MS prevalence rates amongst migrant populations in Queensland as compared to the more southerly city of Perth in Western Australia, suggested that the risk of acquisition of MS may extend over a wider age range than is generally accepted. Finally, there was an absence of MS cases amongst the Aboriginal population in Queensland but it can only cautiously be concluded from this study that the disease is rare in these peoples.