ARTICLE IN BRIEF
Researchers reported that migraine with visual aura was associated with a higher risk of atrial fibrillation, as well as a heightened risk of cardioembolic stroke.
Migraine with visual aura poses an elevated risk for incident atrial fibrillation, a large longitudinal population-based cohort study suggests.
The study, published in the November 14 online issue of Neurology, adds to previous epidemiological evidence demonstrating migraine with aura is associated with an increased risk of cardioembolic cerebrovascular events such as stroke and transient ischemic attack.
The current study highlighted that migraine with visual aura is independently linked to heightened risk of cardioembolic stroke in comparison to migraine without aura and controls without headaches.
“Since AF is a common source of cardioembolic stroke, the question that begs to be answered is if the association between migraine with visual aura and cardioembolic stroke may be explained by a higher rate of atrial fibrillation (AF) in this subgroup of the cohort,” the authors wrote.
“If migraine with aura is associated with AF,” they said, “the AF may lead to thromboembolism into the cerebral blood vessels leading to ischemic strokes.”
“A lot of other hypotheses have been put forward. But this opens up a new idea. People have always wondered why migraine with visual aura is a risk factor for stroke,” lead author Souvik Sen, MD, MS, MPH, professor and chair of neurology at the University of South Carolina School of Medicine, told Neurology Today.
The cohort study's findings support “a strong association” between migraine with visual aura and incident atrial fibrillation,” Dr. Sen said. The findings were not based on a randomized clinical trial, so they might be limited. Still, “this is the next best thing you can get,” he said.
To study the association, researchers reviewed data for 11,939 participants in the Atherosclerosis Risk in Communities (ARIC) study, which has been tracking residents of four different US communities in North Carolina, Mississippi, Minnesota, and Maryland since baseline visits in 1987-1989. Follow-up visits took place between 1990-1992, 1993-1995, 1996-1998, and 2011-2013.
Trained interviewers administered a headache questionnaire to participants during the 1993-1995 visits. Based on the responses, the researchers detected cases of migraine with visual aura. At the time, the participants had no known history of atrial fibrillation or ischemic stroke.
After the 1993-1995 visits, diagnoses of atrial fibrillation were obtained from electrocardiograms, hospital discharge codes, and death certificates.
The researchers examined vascular risk factors and acquired hospital medical records, looking specifically at hospitalizations and new diagnoses. In addition, the study team contacted the ARIC participants on an annual basis to determine their well-being and any adverse events, including stroke and atrial fibrillation.
Of the 1,516 participants identified with migraine, 426 had migraine with visual aura, and 1,090 had migraine without visual aura. Participants with migraine with visual aura had an increased risk of incident atrial fibrillation relative to participants without headache (hazard ratio, 1.30; 95% confidence interval, 1.03-1.62) and participants with migraine without visual aura (hazard ratio, 1.39; 95% confidence interval, 1.05-1.83).
The analysis showed that atrial fibrillation was a possible mediator of the increased stroke risk observed in patients with migraine with aura.
Several neurologists interviewed by Neurology Today commended the investigators for long follow-up and sound statistical analyses.
“By elegantly demonstrating that atrial fibrillation acts as a mediator in the causal pathway, this well-designed, highly impactful study deepens our understanding of the association between migraine with aura and stroke risk,” said Amytis Towfighi, MD, associate professor of neurology at the University of Southern California's Keck School of Medicine and director of neurological services at Los Angeles County Department of Health Services.
Although a prior Danish cohort study had shown an association between migraine with aura and atrial fibrillation as well as stroke, Dr. Towfighi pointed out that the nature of this link was not fully understood. “The current analysis helps to illuminate potential mechanisms for the association between migraine with aura and stroke risk,” she said.
It may be reasonable for neurologists to inform patients who have migraine with aura about the higher risk of atrial fibrillation and ischemic stroke. However, Dr. Towfighi said, no clinical trial evidence exists to suggest that these patients should be managed differently.
In patients with embolic stroke of undetermined origin, long-term cardiac monitoring for detection of paroxysmal atrial fibrillation is often indicated. If the patient also has a history of migraine with aura, Dr. Towfighi said it would heighten her index of suspicion for possible paroxysmal atrial fibrillation.
More studies are needed before it becomes standard practice to recommend additional screening for atrial fibrillation, Melissa Rayhill, MD, FAHS, clinical assistant professor in the department of neurology and School of Medical and Biomedical Sciences at the State University of New York at Buffalo.
Until more data materialize, Dr. Rayhill said she continues to advise “all of my patients with migraine — men and women, with or without aura — that they should optimize their cardiovascular health whenever possible, as we are still delineating the mechanism and extent of cardiovascular risk associated with migraine and its subtypes.” She recommends exercise, smoking cessation, and a healthy diet.
In addition, the current standard of care indicates that oral contraceptives are contraindicated in women with migraine with aura, but Dr. Rayhill encourages patients to discuss this issue with their primary care physicians and gynecologists.
Despite the study's solid epidemiological data, including strict definitions of atrial fibrillation and migraine and its subtypes, “we must keep in mind that the estimated risk is low and may be affected by unmeasured confounders,” said José G. Merino, MD, FAAN, FAHA, associate professor in the department of neurology at the University of Maryland School of Medicine.
The researchers adjusted well for relevant known confounders, Dr. Merino said. However, he added that “the issue of unknown confounders is a limitation of all observational studies.” In such studies, “there may be differences between the groups beyond the usual factors considered in the adjustment: these are the unmeasured confounders. Some may be known, others not, but they are not included in the analysis. When effect sizes are small, we must be cautious in interpreting the results.”
Furthermore, an observational cohort study does not allow for concluding causation from a detected association between migraine with aura and atrial fibrillation. But Dr. Merino is intrigued by the authors' analysis suggesting that the link between migraine with aura and stroke, noted in earlier studies, may be mediated by atrial fibrillation. He described the study's findings as “hypothesis-generating,” and encouraged neurologists to be on alert for any potential vascular risk factors in patients with migraine with aura, including atrial fibrillation.
“Looking at the vasculature would be useful in elucidating some of these connections,” said Gretchen E. Tietjen, MD, professor and chair of neurology and director of the Headache Treatment and Research Center at the University of Toledo College of Medicine and Life Sciences.
The study prompts reflection into whether migraine with aura causes cerebrovascular disease, or if it appears as a consequence of an abnormally functioning vasculature. The question: “Is migraine sometimes more of a systemic condition?” Dr. Tietjen said.
Research has shown that migraine with aura has been linked to endothelial dysfunction, which can induce a hypercoagulable state, Dr. Tietjen said. When the endothelium becomes activated, it may predispose an individual to clotting that leads to transient ischemic attacks, some with features of aura, and stroke, she pointed out.
“Is there some common factor — a shared pathogenesis, some common etiology — that in some people leads to symptomatic migraine with aura and in some people leads to atrial fibrillation, by way of atherosclerotic heart disease? In other words, do they have a shared basis?” Dr. Tietjen asked, noting that endothelium dysfunction has the potential to cause atherosclerosis later in life.
Dr. Tietjen pointed out that the majority of individuals who develop migraine with aura tend to be a subset of women younger than 45, which is not the cohort the researchers of the current study analyzed.
Before extrapolating the study's findings to other populations, the results should be validated in another cohort, perhaps in a different region of the world, said Luciano A. Sposato, MD, MBA, FRCPC, associate professor in the department of clinical neurological sciences and co-director of the London Health Sciences Centre-Western University Stroke Program in London, Ontario, Canada.
“One of the study's weaknesses stems from the fact that many patients with atrial fibrillation are asymptomatic. If they are not continuously monitored with a long-term Holter or other device, many short spells could be missed,” said Dr. Sposato, who is also the university's Kathleen and Dr. Henry Barnett Chair in Stroke Research.
As a result, some of the participants classified in the study as not having atrial fibrillation may have been unaware of its presence. “Atrial fibrillation remains undiagnosed in quite a significant proportion of stroke patients, making it difficult to determine which came first — migraine with aura or atrial fibrillation,” he said.
The study's greatest impact is in raising awareness of potentially novel pathophysiological correlations between migraines and strokes. “Perhaps the most intriguing aspect is the research implication,” Dr. Sposato said. “It really opens a whole new field about the relationship between strokes and migraines.”
Dr. Sen received research funding for the study from the National Institutes of Health.