Discussion

This current meta-analysis, using new data for 230 prevalence points from 94 studies found in our present literature search, confirms the latitudinal gradient in MS prevalence. The overall global magnitude of this gradient has increased, the fully adjusted, age-standardised prevalence increasing significantly from 2.68/100 000 per degree latitude to 3.64/100 000. As previously,1 while the overall gradient was linear throughout much of the latitudinal range, there was a downturn in the higher latitudes above 55° encompassing the Scandinavian countries. While many of the general trends observed in the original study persisted here, some differed notably, including a marked attenuation in the inverse gradient in the Scandinavia/North Atlantic and an increase in the Atlantic Coast/Central Europe regional gradients.

Latitude’s association with MS prevalence was again evident in all the European-descent areas assessed, excepting Latin/South America. The significant positive gradients in Australasia, the UK/Ireland and North America found previously were again evident, as was the potent inverse gradient in the Italian region. Some gradients, however, were markedly altered, most notably the inverse gradient in the Scandinavia/North Atlantic region, which attenuated appreciably, while the weak positive gradient in the Atlantic Coast/Central Europe region found previously was now markedly enhanced, now on par with that seen in the UK/Ireland region. The Atlantic Coast/Central Europe change was influenced by the additional prevalence points in the 2016 Pivot study from France,30 since despite its covering a similar range to the 2007 Vukusic study31 included in the previous paper (roughly 42°–50°), the Pivot study prevalence estimates were on average twice as high (74.4/100 000 vs 150.5/100 000). These results, in combination with a number of studies conducted in the Iberian Peninsula, thus manifest in a markedly enhanced gradient in this region. On the other hand, in the Scandinavia/North Atlantic region, the 2011 Ahlgren study in Sweden11 and 2014 Berg-Hansen study in Norway,32 with their fairly consistently high prevalence across broad latitudinal ranges (56°–67.2° and 59.5°–66.4°, respectively), served to significantly attenuate the inverse gradient in that region. Indeed, in contrast to the potent inverse gradient above 60° in the original study, for the new studies, this gradient is completely flat, serving to dampen the inverse gradient for this region. Areas where the latitudinal gradient change, although of less dramatic extent, may instead be attributable to more classic methodological reasons, are those seen in the Middle East/Africa and Asia/Pacific regions, where influential prevalence points markedly impacted on the gradients in those regions, as described in the Results section. These results would seem to suggest that, while gradients are manifestly evident in most of the regions studied, there are some intraregional variations even over a relatively short timeframe. In some of these, like the Middle East/Africa and Asia/Pacific regions, these may simply reflect influential data points, and given as the gradients in these regions are of low magnitude, the general conclusions are likely to be consistent with the previous study.

The changes in the Atlantic Coast/Central Europe and Scandinavia/North Atlantic regions, however, may speak to more genuine change. While there is a notable difference in the study populations in the French studies—the Vukusic study utilising an insurance scheme of French farmers, while the Pivot study was more broadly based—there is nonetheless an appreciably greater increase in the prevalence of locations at the higher latitudes of this region. In the Scandinavia/North Atlantic region, on the other hand, we see a flattening of the inverse gradient we demonstrated in the previous study, the nationwide studies in Sweden and Norway conducted by Berg-Hansen and Ahlgren and their fairly even distribution of MS prevalence across a broad latitudinal range, potentially suggesting an attenuation in the protective dietary behaviours underlying the downturn in the prevalence gradient suggested previously.33 These changes are more likely to reflect the impact of changes in some modifiable lifestyle factors, of which sun exposure and/or vitamin D are prime candidates. The reasoning for this is twofold. First, the area is quite homogenous in terms of medical infrastructure, access to care and is not as affected by socioeconomic divides that may preclude seeking out medical care for chronic conditions. Thus, it is not expected that changes in these regions’ gradients would be attributable to changes in case ascertainment that would not be evident in other areas in the European region, or indeed in other European-descent nations, such as in North America or Australasia. In addition, since these areas had been comprehensively assessed across the regional latitudinal ranges and repeatedly over a long time course, they are less likely to be affected by large and influential data points that could have skewed the gradient trendline. The alternative interpretation, then, is that some aspect of the underlying risk structure has changed, leading to an increase in the frequency of disease commensurate with latitude. As previously, dietary intake of vitamin D has been suggested as a mode by which the latitudinal gradient in the far north of Scandinavia is attenuated,33 since dietary vitamin D intake would mitigate the latitudinal variation in winter ambient UV. This behaviour would have been a necessary element of survival for early migration into the far northern latitudes so as to avoid rickets and other hypovitaminosis D effects, but has in recent history has potentially had a beneficial effect on MS risk in this region. That we see in the Scandinavian region, the prevalence for serially measured sites in the south of the region (up to 60°N) is generally flat, while for mid-tier regions (60–65°N) and especially those in the north (≥65°N), prevalence increases much markedly over the period up to 2013, at that point prevalence estimates are largely overlapping. In the absence of concomitant rises in deleterious behaviours in the northern latitudes, such as smoking,34 35 or in differential rates of infection by EBV, these results suggest that some of the cultural practices, such as diet, which might previously have been protective against MS have become less common, leading to a rise in the vitamin D deficiency in this high latitude area. This is substantiated by work in the Inuit population of Greenland, where there was a marked increase in vitamin D deficiency alongside a decrease in traditional diet, overall36 and particularly among the younger age groups of the population.37 Similar results have been seen in the far north of Norway,38 where diet rich in vitamin D-containing foods was associated with vitamin D status, but this behaviour was less common among younger participants. While substantiation of this hypothesis would require a systematic longitudinal survey of diet behaviours across the Scandinavian region and across its latitudinal range, this would still seem to be the most plausible interpretation, as we suggested in our previous paper.1

On the other hand, the continued inverse gradient seen in the Italian region, which we previously suggested might be a function of regional variation in protective and deleterious HLA-DR variants, would provide some credence to this hypothesised explanation for the inverse gradient in this region. As in our previous analysis, we found that the inverse gradient in this region was solely a function of the regional variation in HLA-DRB1 allele frequencies, whereas other regional gradients in Europe were largely independent of this adjustment.

While there is some potential role for differential case ascertainment, this is not likely to be a potent driver of the changes in gradient observed in the European regions and European-descent populations, given as there have been relatively minor changes to the diagnostic criteria and use of paraclinical evidence over the duration of studies described here. Moreover, the fact that other regions in Western Europe, North America and Australasia were relatively consistent in their gradients, despite having similar medical infrastructure and access to care, would argue against improved case ascertainment being a driver of the changes seen in these regions.

Strengths of our study included consistent data collection and statistical analysis methodologies, which were well-defined and adjusted for variables that could introduce population bias. The data used in our updated meta-analysis were extracted independently and after analysis showed a clear latitudinal MS gradient, similar to our previous paper. Included studies were varied in geographical location and had clear inclusion criteria. Values obtained were age-/sex-standardised, as allowed by available data, and all prevalence estimates were time-corrected to allow comparability of prevalence studies conducted over time, as well as adjusting for diagnostic criteria and population inclusion.

Our study also had some weaknesses. A total of 94 studies that met our inclusion criteria were included, which is a much smaller number of studies compared with our previous analysis. This is, however, a comprehensive audit of the studies conducted over the years since our previous study. Indeed, reviews published since our previous meta-analysis drew our attention to studies in the Middle East and Asia/Pacific regions from prior to 2010 that we had not included previously.25–28 The fact that there are notable aggregations of prevalence studies in some regions of Western Europe and the Middle East, while other high prevalence regions, such as Australasia and North America, had comparatively few, may hinder our ability to definitely comment on the change, or lack thereof, of the latitudinal gradient in these regions. While publication bias is less a concern for studies of this sort, there being no ‘null’ finding in a prevalence study, this variability in studies conducted by region could be ascribed to a type of publication bias. We did not grade studies based on perceived study quality, instead endeavouring to constrain analyses to population-based and peer-reviewed epidemiological studies, as well as controlling for study methodological characteristics, such as diagnostic criteria used and inclusion of possible/probable cases in addition to definite MS.

Overall, these results are strongly supportive of the positive relationship of latitude with MS prevalence, though the regional idiosyncrasies, both in terms of local characteristics and the studies conducted, continue to manifest in markedly different regional gradients. While there are potential intraregional effects contributing to the latitudinal variation in MS prevalence, these results and the relative consistency across the whole of the globe continue to provide indirect evidence in support of the role of the sun and/or vitamin D in MS aetiology.