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 . 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 , 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 . 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▪▪].
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 . A recent study from Finland reported a higher prevalence of MS in southwest Finland compared with the easternmost area . In France, a new digital epidemiological approach  supports the presence of an increasing southwest-to-northeast gradient of prevalence, as had been previously suggested , but was not confirmed by another French study . 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 . 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 .
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 . Studies on migration report an increased risk of MS in immigrants , which will remodel the worldwide epidemiological picture over the next few generations.
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 . 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.
Papers of particular interest, published within the annual period of review, have been highlighted as:
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A study using an interesting and important approach by investigating birth cohort effects in long-term trends of MS using Swiss mortality data from 1901 to 2010 providing evidence that birth cohort effects are strongly involved for the change in the sex ratios during the 20th century.
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This study based on mortality data from 1951 to 2015 from The Norwegian Cause of Death registry showed and increased female:male mortality ratio in MS associated mortality, driven by increased mortality among women in the last three decades, particularly in the older age groups.
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An important study performed in a racial/ethnic heterogenous population, emphasizing the importance of this factor when reporting MS-specific mortality. The study found that whites and women are more likely to die from MS, because of a higher occurrence of MS in these groups, but blacks dying at an earlier age.
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