ObjectiveSeveral groups have reported apparent association between month of birth and multiple sclerosis. We sought to test the extent to which such studies might be confounded by extraneous variables such as year and place of birth.MethodsUsing national birth statistics from 2 continents, we assessed the evidence for seasonal variations in birth rate and tested the extent to which these are subject to regional and temporal variation. We then established the age and regional origin distribution for a typical multiple sclerosis case collection and determined the false-positive rate expected when comparing such a collection with birth rates estimated by averaging population-specific national statistics.ResultsWe confirm that seasonality in birth rate is ubiquitous and subject to highly significant regional and temporal variations. In the context of this variation we show that birth rates observed in typical case collections are highly likely to deviate significantly from those obtained by the simple unweighted averaging of national statistics. The significant correlations between birth rates and both place (latitude) and time (year of birth) that characterize the general population indicate that the apparent seasonal patterns for month of birth suggested to be specific for multiple sclerosis (increased in the spring and reduced in the winter) are expected by chance alone.InterpretationIn the absence of adequate control for confounding factors, such as year and place of birth, our analyses indicate that the previous claims for association of multiple sclerosis with month of birth are probably false positives. ANN NEUROL 2013;73:714–720

Increasing evidence implicates B cells in the pathogenesis of multiple sclerosis. Smets et al. report that the CD40 multiple sclerosis risk allele lowers CD40 expression, whereas the CD86 risk allele increases CD86 expression. B cells may have an important antigen presentation and immunoregulatory role in multiple sclerosis.

Association studies form the backbone of biomedical research, with almost every effort in the field ultimately boiling down to a comparison between groups, coupled with some form of statistical test intended to determine whether or not any observed difference is more or less than would be expected by chance. Unfortunately, although the paradigm is powerful and frequently effective, it is often forgotten that false positive association can easily arise if there is any bias or systematic difference in the way in which study subjects are selected into the considered groups. To protect against such confounding, researchers generally try to match cases and controls for extraneous variables thought to correlate with the exposures of interest. However, if seemingly homogenously distributed exposures are actually more heterogeneous than appreciated, then matching may be inadequate and false positive results can still arise. In this review, we will illustrate these fundamental issues by considering the previously proposed relationship between month of birth and multiple sclerosis. This much discussed but false positive association serves as a reminder of just how heterogeneous even easily measured environmental risk factors can be, and how easily case control studies can be confounded by seemingly minor differences in ascertainment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-014-7241-y) contains supplementary material, which is available to authorized users.

Coronavirus disease of 2019 (COVID-19) is associated with hypercoagulopathy, but haemorrhage, including spontaneous intracerebral parenchymal haemorrhage and diffuse petechial cerebral haemorrhage, has also been reported. We present two cases of nonaneurysmal subarachnoid haemorrhage (SAH) in patients with severe COVID-19. Careful review of neuroimaging for haemorrhagic complications of COVID-19 should be undertaken, particularly for those patients receiving enhanced prophylaxis for venous thromboembolism. Although likely to be a marker of severe disease, non-aneurysmal SAH can be associated with favourable outcome.