, 2025-04-21 11:37:00
Migraine with aura is the most prominent individual risk factor for unexplained stroke in adults younger than 50 years, particularly in women and in those with patent foramen ovale (PFO), a new study showed.
While investigators found that both traditional and nontraditional risk factors contributed significantly to cryptogenic ischemic stroke (CIS) risk in young adults, there were notable differences depending on the presence of a clinically relevant PFO.
Traditional risk factors — such as hypertension, smoking, obesity, high cholesterol, and diabetes — were strongly associated with CIS without PFO, whereas nontraditional risk factors — such as migraine with aura, cancer, or kidney or liver disease — played a more prominent role in adults without PFO, the study team found.
“We were aware of the important role of migraine with aura in this patient population based on earlier knowledge but were surprised that it was so profound, especially when its prevalence and strength of association were put in perspective with traditional stroke risk factors,” lead investigator Jukka Putaala, MD, PhD, MSc, head of the Stroke Unit at the Neurocenter, Helsinki University Hospital, Helsinki, Finland, told Medscape Medical News.
“Healthcare providers should consider migraine with aura, particularly in young females, as a clinical clue prompting further cardiovascular evaluation and individualized stroke prevention strategies,” Putaala said.
The study was published online on April 17 in the journal Stroke.
Strokes of Unknown Cause Increasing
The occurrence of young-onset ischemic stroke is on the rise, driven by CIS and patients without traditional vascular risk factors.
Putaala and colleagues assessed the association of 12 traditional, 10 nontraditional, and five female sex-specific risk factors (together and alone) with young-onset CIS (age, 18-49 years), stratified by PFO.
Traditional risk factors included hypertension, diabetes, hypercholesterolemia, smoking, abdominal obesity, cardiovascular disease, alcohol consumption, psychosocial stress, and depression.
Nontraditional risk factors that have been increasingly recognized as relevant contributors to ischemic stroke, particularly in the younger population, include a history of venous thrombosis, malignancy, and any chronic multisystem disorder, such as autoimmune disease, inflammatory bowel disease, chronic kidney disease, chronic liver disease, or hematologic disease/thrombophilia; the presence of migraine with aura; and current use of illicit drugs.
The cohort included 523 adults with CIS (median age, 41 years; 47% women; 37.5% with PFO) and 523 matched stroke-free control individuals.
Adults with CIS with and without PFO had higher counts of traditional and nontraditional risk factors than stroke-free control individuals.
Traditional stroke risk factors were more strongly associated with CIS in men and women without PFO. In contrast, nontraditional risk factors were more strongly associated with CIS in those with PFO.
In the absence of PFO, each additional traditional risk factor increased stroke risk by 41%, while each nontraditional risk factor increased stroke risk by 70%, the study team reported.
With PFO, each traditional risk factor increased the risk for stroke by 18%. While nontraditional risk factors more than doubled the odds of ischemic stroke (odds ratio, 2.6) after considering individual demographic factors, such as age, sex, and level of education.
Female-specific risk factors, such as gestational diabetes or pregnancy complications, increased stroke risk by 70%, independent of traditional and nontraditional risk factors.
Cumulative Impact
The researchers also calculated the population-attributable risk by analyzing each risk factor and its contribution to the increased risk separately.
Without PFO, traditional risk factors accounted for about 65% of CIS cases, nontraditional risk factors contributed 27%, and female-specific risk factors made up nearly 19% of the cases.
For CIS with PFO, traditional risk factors contributed about 34%, nontraditional risk factors accounted for 49%, and female-specific risk factors represented about 22%.
Migraine with aura was the leading nontraditional risk factor associated with CIS, with a population-attributable risk of about 46% with PFO and about 23% without PFO, with a stronger impact in women.
“Why migraine carries a high risk of cryptogenic stroke in the young is a complex question and warrants further research,” Putaala said.
“Migraine onset peaks at adolescence and early adulthood, which may in part explain its high prevalence among young stroke patients. Migraine with aura may increase stroke risk through mechanisms such as endothelial dysfunction, cortical spreading depression, and a prothrombotic tendency,” he explained.
Migraine also frequently coexists with right-to-left cardiac shunts like PFO, which are more common in young patients with stroke. Migraine may also be more active and symptomatic in younger adults, which may further heighten stroke susceptibility, Putaala noted.
Clear Clinical Implications
Putaala said it’s important for healthcare providers to realize that traditional risk factors like hypertension, atherosclerosis, and diabetes may be “absent or less prominent” in young adults with CIS. This underscores the need to systematically assess nontraditional risk factors, including migraine with aura and sex-specific factors, “which often receive too little attention,” rather than focusing solely on conventional risks, investigators wrote.
In a statement, Tracy E. Madsen, MD, PhD, chair of the American Heart Association Clinical Cardiology/Stroke Women’s Health Science Committee and director of the EpiCenter for Epidemiology and Clinical Research at the Larner College of Medicine at the University of Vermont in Burlington, Vermont, said this study is helpful because the authors present data by sex and age group.
“We know that stroke risk changes based on sex and age. For instance, recent data shows that younger women may have a higher risk of stroke than younger men. However, during middle age, men usually have a higher risk,” said Madsen.
“Recognizing specific risks that affect women and those not commonly seen, such as migraine with aura and pregnancy complications, as significant contributors to stroke risk in younger women could change our approach to screening for these risks and educating our patients throughout their lives,” said Madsen, who was not involved in the study.
The study had no commercial funding. Putaala and Madsen had no relevant conflicts of interest.
