In a large cohort of Icelandic adults, we found that women who reported migraine with aura (MA) in middle age were at increased risk of late-life infarcts relative to those without migraine symptoms. The risk was primarily for cerebellar lesions; there was no increased risk for cortical or sub-cortical lesions or for those with migraine without aura or non-migraine headache.
This risk was independent of cardiovascular risk factors measured in mid- or late-life. Risk was not statistically different between subjects who were less than compared to older than 50 years of age when headache was ascertained or those with or without a history of diagnosed CAD or TIA/stroke.
Our study has substantial strengths. The large well-characterized cohort was established in 1967 when, at the time of headache assessment, subjects were aged 33 to 65. At those ages, many study subjects were still experiencing migraine attacks, so recall bias is likely reduced. Subjects were also at low risk for TIA or stroke, making the identification of migraine visual aura symptoms more robust. Measurement of late-life infarcts on MRI was performed by raters blinded to mid-life headache status. As subjects were followed as part of a cardiovascular disease study, we were also able to rigorously adjust for plausible confounding cardiovascular risk factors. Other strengths include the size of our cohort and broad age range, which gave us statistical power to consider sex, age and cardiovascular disease effects.
Some limitations of this study should be taken into account when interpreting the findings. Because migraine symptom questions were not asked of those reporting headache less than once per month, we are likely capturing only those with severe migraine with a higher attack frequency. Further, our assessment of migraine was based on pre-IHS diagnostic criteria although the questions touched on five symptoms included in the IHS guidelines. We note that our estimated prevalence of migraine overall (e.g., with or without aura) is highly consistent with prior studies.1
Our assessment of the migraine aura may include frequently occurring nonspecific visual symptoms such as blurring. Our prevalence of aura (as a proportion of the total migraine population) is higher than has been reported in other population studies. However, the effect of this misclassification would be to attenuate the relationship between MA and infarcts, unless, compared to aura, non-specific symptoms are differentially more strongly related to the risk for infarcts. Given the age of our study population, it is worth considering the extent to which overall or cardiovascular-related mortality may have affected our results presented herein. In particular, migraineurs with aura have been reported to be at increased risk of cardiovascular death compared to others.7
If the mid-life migraineurs with aura were more likely to die from cardiovascular disease before the late-life exam, and if these individuals were also more likely to have infarcts in the cerebellum or overall compared to others, then our results would have been attenuated. If however these lesions were somehow protective (e.g. migraineurs with aura and these lesions had lower all-cause mortality compared to migraineurs with aura without these lesions) then our results would have been exaggerated. The second scenario seems unlikely.
Our results are consistent with the cross-sectional CAMERA study,10
the only other study that measured infarcts on MRI, which also found the migraine-associated infarcts to be preferentially located in the cerebellum. Here we extend the findings of the CAMERA study to a longitudinal study with a long follow-up and an older cohort with a much higher background risk for brain lesions. Our results suggest that migraine with aura is a strong enough risk factor to be detected in older subjects, who typically have cardiovascular risk factors that lead to similar appearing lesions. Further, the study is based on a larger sample of men and women, so sex differences could be investigated. We found the relationship between MA and cerebellar infarcts may be specific to women. However, we cannot rule out a possible increased risk for men with MA due to the relatively small number of men with MA in our sample. The reason why migraine, particularly with aura, is a risk factor or marker for clinical and silent (presumed) ischemic stroke is uncertain and controversial; proposed mechanisms include atherosclerotic and non-atherosclerotic causes5,6,11
including traditional cardiovascular risk factors,11,18
shared genetic risk factors for migraine and stroke,11,22–24
vasoconstrictor medications taken to treat headache,11,21
cardiac abnormalities including patent foramen ovale,11,25
and diagnostic artifact,11,26
among other factors. These mechanisms do not obviously explain why migraine-related infarcts would be preferentially located in the cerebellum and in women. There are clinical reports suggesting that the cerebellum is vulnerable in migraineurs27–31
and in familial hemiplegic migraine, a rare Mendelian variant of migraine with aura.32
In population studies, no particular location pattern was evident for clinically evident ischemic stroke among women with aura.9,33
although, as mentioned earlier, silent infarcts (as per CAMERA) were preferentially located in the cerebellum.10
We also note that secondary analyses suggested the possibility of increased risk of cortical infarcts in some sub-groups (e.g. men with MO or MA or men and women who were older than 50 at the time of headache assessment).
In summary, this study suggests that a remote history of migraine with aura may be a strong risk factor for brain lesions commonly found in older populations. Results were unaffected by control for cardiovascular risk factors and history of cardiovascular disease, thus suggesting that the mechanism linking the migraine aura with these lesions is independent of the usual risk factors for ischemic vascular disease and may be specifically related to the effects of migraine. Additional longitudinal studies with repeat measures of MRI are needed to better establish the temporality, and dose-response relationship, between the migraine aura and brain lesions. Further, the late age functional consequences of migraine on cognition and motor function require investigation.