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The changing course of multiple sclerosis

rising incidence, change in geographic distribution, disease course, and prognosis

Magyari, Melinda; Sorensen, Per Soelberg

Current Opinion in Neurology: June 2019 - Volume 32 - Issue 3 - p 320–326
doi: 10.1097/WCO.0000000000000695
DEMYELINATING DISEASES: Edited by Hans-Peter Hartung

Purpose of review This review provides a brief update of new research findings on the changing epidemiology, disease course, and prognosis of multiple sclerosis (MS).

Recent findings Evidence not only continues to support the female predominance in incidence and prevalence of the disease but also supports an increase in incidence of MS in geographic areas that were previously considered to be low incidence for the disease.

Summary An increased interest in population-based registries and databases will provide more valid epidemiological measures and observational studies conducted in well-defined study populations. Such studies are crucial for an accurate description of both changing prognosis of MS and differential characteristics of the various MS phenotypes.

Department of Neurology, Danish Multiple Sclerosis Center and the Danish Multiple Sclerosis Registry, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark

Correspondence to Per Soelberg Sorensen, MD, DMSc, Department of Neurology 2082, Danish Multiple Sclerosis Center, Rigshospitalet, DK-2100 Copenhagen, Denmark. Tel: +45 3545 2080; e-mail:

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Multiple sclerosis (MS) is now recognized as a global disease. There are more than 2.3 million persons with MS worldwide [1]. The occurrence of MS in Western Europe and North America is higher than in Asia, Africa, and Latin America, but new evidence reveals a changing landscape in the distribution of MS in terms of regional occurrence, sex, and age at onset [1].

The review summarizes the evolving epidemiological aspects of MS, including recent evidence as to global distribution, disease course, and prognosis.

Box 1

Box 1

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Epidemiological changes comprise temporal geographical and demographic alterations in the patterns of disease occurrence and age distribution and also alterations in mortality rates and causes of death (Table 1).

Table 1

Table 1

There is strong evidence of a pronounced change in the appearance of MS over last five to six decades where in particular the increase in incidence in women is conspicuous [2]. A steady trend of increasing incidence and prevalence for MS has been reported not only from countries with tradition and data sources for conducting incidence and prevalence studies with, for example, Norway [3], Denmark [4▪], Canada [5▪], and New Zealand [6], but also from countries traditionally regarded low-prevalence regions of the world such as India [7], Latin America [8,9], Iran [10▪], and Japan [11].

There is, however, a lack of studies providing incidence and prevalence data at the national level, and regions and populations that are underrepresented in addition to the considerable gaps in knowledge, which exists in larger countries such as the USA.

When it comes to temporal changes in MS, most incidence estimates do not include an entire country, which is why it is difficult to confirm the increases in incidence on a national level. When incidence increases, so does prevalence. Prevalence is a function of incidence and surviving time. An increasing number of studies report an increased prevalence of MS that, in surveys in which there is a lack of nationwide population-based measuring, can be partially attributed to an improvement in disease awareness and ascertainment. This could, for example, explain the modest increase of the incidence rate of MS from 6.1/100 000 in 2013 to 6.7/100 000 in 2016 in Puerto Rico [12]. A recent study using several registries and databases described that the nationwide prevalence rate in Croatia in 2015 was more than twice as high as the estimate from 2013 [13], far more than what could possibly be a true increase and must, at least partly, be ascribed to better case ascertainment. A substantial growth in the incidence rate of MS, with a trend of an increasing female/male ratio, was seen in Lithuania during the period of 2001–2015 [14]. Furthermore, a large German study using claim data found that the incidence of MS on a national level is higher than expected, suggesting a clear increasing tendency of MS incidence and prevalence in this country [15].

The consequence of a more pronounced incidence and prevalence increase in women is an increasing female/male ratio [2]. Figure 1 presents the sex distribution of the prevalent Danish population with MS and Fig. 2 the incident sex ratio based on current data from The Danish Multiple Sclerosis Registry. Currently, the highest increase has been reported from northern Japan where there is a female/male ratio of 3.57 compared with 2.63 in 2001 [16]. The sex ratio for MS prevalence was 2.2 in Austria in the first report of its kind on the basis of data of nationwide public health insurances [17], which is comparable with the sex ratio in most countries in Western Europe.





Longer follow-up times in population-based cohorts enable capture of a pattern of development in epidemiological outcomes in the same population. A recently published study from the nationwide population-based Danish Multiples Sclerosis Registry reported that the incidence of MS in women has more than doubled over 60 years, whereas in the same period, it had only moderately increased in men and the incidence increase was most pronounced in women older than 50 years [18]. The increasing occurrence of late-onset MS raises the mean age at disease onset during the last 50 years in the Danish MS population, as presented in Fig. 3. Although an age-period-cohort analysis in Denmark showed that effects of both period and birth cohort play a role in the increasing female incidence and thereby female-to-male ratio, a Swiss study carried out using mortality data from 1901 to 2010 concluded that the change in the sex ratio in MS is strongly driven by birth cohort effects [19▪▪,20].



There is still, however, a discussion over whether the recorded increasing incidence in women alone can be attributed to a true increase in incidence and not merely an increased ascertainment probability. A recent study from Canada, showing consistently increased incidence and prevalence of MS in women, reported equity of access to MRI across sex, region, and socioeconomic status [21], indicating that the increase is true.

Mortality is a fundamental factor in a population's dynamics. Improvement in MS survival has a substantial contribution to the increasing prevalence. In Norway, the survival of the population with MS improved considerably, but the overall MS mortality rate was still almost three-fold higher compared with the general population with a 7-year shorter life expectancy [22]. A higher mortality rate was found in women (standardized mortality rate [SMR] = 2.9) compared with men (SMR = 2.5, P = 0.009) when compared with the respective genders in the general population. The increased mortality among women in the last three decades, particularly in the older age groups, explains the increased female:male mortality ratio [23▪▪].

A decrease in excess mortality was also shown by The Danish Multiple Sclerosis Registry that comprises virtually all Danish patients with disease onset after 1950 followed until 2015. Excess death rate decreased from 11.29 to 2.56 and SMR defined as observed/expected number of death from 4.48 to 1.80 between the 1950–1959 and 1990–1999 onset cohort [18]. The age distribution of the prevalent Danish population with MS, presented in Fig. 4, reveals both increased survival and higher number of late-onset MS. A substantial decrease in mortality of the population with MS compared with individuals without MS was also supported by a study conducted in Sweden [24]. Contrary, MS-specific mortality rates appear to have steadily increased between 1999 and 2015 in the United States, especially with regards to racial/ethnic and sex differences, where a higher mortality was observed particularly in non-Hispanic whites and blacks [25▪]. A recent meta-analysis of mortality in patients with MS over time supported greater disadvantage in survival for women as compared with men but did not find changes in excess mortality in patients with MS relative to the general population over the past 50 years [26].



Interestingly, the decline in short-term excess mortality in patients with MS in Denmark started decades before disease-modifying treatment for MS became available, before use of MRI became widespread, and before the McDonald diagnostic criteria were introduced [4▪]. However, the role of early initiation of disease-modifying therapy (DMT) in the recently increased survival is supported by a recent study also from The Danish Multiple Sclerosis Registry, which presented that patients who started treatment with DMT on average 4 years clinical onset had an increased hazard rate for dying (38%) compared with patients who started DMT within 2 years of clinical onset [27▪].

Additionally, comorbidities are frequent in MS and have an adverse influence on outcome and mortality [28,29▪].

The increasing number of persons diagnosed with MS, the different aspects of gender inequity, and the increasing life expectancy also for patients with MS lead to an altered age distribution of the prevalent MS population. Comparing the 1950–1959 with the 2000–2009 onset-period cohorts, the increase of MS in Danish women was most prominent in persons with an onset of disease at an older age. With age at onset more or equal to 50 years, the incidence of MS increased with a factor 4.30 in women and 2.72 in men [4▪]. The uneven incidence increase in different age groups leads to changes in the age distribution of prevalent MS patients. The increasing proportion of the elderly in the population of people with MS and the shift in peak prevalence are attributed to an increase of occurrence of MS in persons over age 50, to increased longevity in the MS population, and also to improved ascertainment.

Another interesting aspect of epidemiology still preoccupying researchers is the changing geoepidemiology of MS related not only to the longitudinal gradient but also to geographical clustering, with some controversies existing. The well-accepted theory of a latitudinal gradient of incidence of MS was challenged in meta-regression analyses regarding Europe and North America, whereas this gradient was still apparent for Australia and New Zealand [2]. A recent study from Finland reported a higher prevalence of MS in southwest Finland compared with the easternmost area [30]. In France, a new digital epidemiological approach [31] supports the presence of an increasing southwest-to-northeast gradient of prevalence, as had been previously suggested [32], but was not confirmed by another French study [33]. The first study, prospectively assessing the incidence rate of MS in Ireland, found that there was a high incidence rate, comparable with the rest of the British Isles, with a persistent north–south gradient [34]. Small-scale geographical variations were found in the risk of MS according to residence at birth, age 15, and age at onset of disease in Denmark, although these differences were modest and without any north–south gradient [35].

As genetic factors impact the risk of developing MS, migration of populations with different ancestries has contributed to the epidemiological changes. Migration studies, however, also support the rapid effect of environmental factors, especially the exposure changes in childhood or early adolescence, thereby opening a possibility for prevention. The role of ethnicity is emphasized by a study conducted in Iran reporting that MS was unequally distributed between the ethnic groups and that the heterogeneity of parental ethnicity was found to be a significant risk factor for MS [36]. Studies on migration report an increased risk of MS in immigrants [37], which will remodel the worldwide epidemiological picture over the next few generations.

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Over recent decades, there have been changes in the many risk factors for MS, which will increasingly be expressed by a changing epidemiology of the disease. Several articles from various geographic areas provide compelling evidence of an increase of the female-to-male sex ratio in relapsing-remitting MS over the last decades. Gender-specific epigenetic interactions may be the driving forces behind the changing epidemiology of MS [38]. Differences in incidence and prevalence across populations can reveal spatial, temporal, and demographic patterns, which are important for identifying the genetic and environmental factors contributing to MS.

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Approval: The manuscript has been seen, reviewed, and approved by both contributing authors.

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Financial support and sponsorship

The author(s) received no financial support for the research, authorship, and/or publication of this article.

P.S.S. has received personal compensation for serving on advisory boards for Biogen, Merck, Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck, Teva, GSK, and Novartis; and has received speaker honoraria from Biogen, Merck Serono, Teva, Sanofi-Aventis, Genzyme, and Novartis. M.M. has served on scientific advisory board for Biogen, Sanofi, Teva, Roche, Novartis, Merck; has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme; and has received support for congress participation from Biogen, Genzyme, Teva, Roche.

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Conflicts of interest

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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multiple sclerosis disease course; multiple sclerosis epidemiology; multiple sclerosis geographic distribution; multiple sclerosis incidence; multiple sclerosis prevalence; multiple sclerosis

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