Migraine With Aura Plays Most Prominent Role in Women With Young-Onset CIS

Risk factors that are considered “traditional” significantly contribute to cryptogenic ischemic stroke (CIS) without patent foramen ovale (PFO), whereas “nontraditional” factors appear more critical for CIS with PFO, suggested clinical data published in Stroke. The study authors urge that further research is needed to gain a deeper understanding of the complex physiological and molecular mechanisms that are involved within these associations.¹

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The incidence of young-onset ischemic stroke is rising, the authors explained, driven primarily by CIS and patients who do not have vascular risk factors. This study evaluated the burden and associations of both modifiable traditional (eg, high blood pressure, smoking history, obesity, high cholesterol, type 2 diabetes) and nontraditional risk factors (eg, chronic kidney disease, blood clots in the veins, migraine with aura, chronic liver disease or cancer), as well as risk factors specific to female patients (eg, gestational diabetes, complications related to pregnancy) with young-onset CIS. These were stratified by clinically relevant PFO, which is defined by high-risk features of atrial septal aneurysm or large right-to-left shunt.^1,2

The investigators enrolled consecutive patients aged 18 to 49 years with recent CIS as well as frequency-matched stroke-free controls of the same age and sex from 19 European medical sites. The logistic regression assessed the association of risk factor counts (12 traditional, 10 nontraditional, and 5 female sex–specific) and individual risk factors, stratified by PFO. Further, analyses were stratified by sex and age (18–39 and 40–49 years), with computation of population-attributable risk.

In this study, 523 patients with a median age of about 41 years were included. About 47.3% were women, and 37.5% (n = 196) had PFO. A total of 523 controls were also enrolled for comparison.¹

In patients with CIS who did not have PFO, each additional traditional (OR: 1.417 [95% CI, 1.282–1.568]), nontraditional (OR: 1.702 [95% CI, 1.338–2.164]), and female sex–specific risk factor (OR: 1.700 [95% CI, 1.107.1–2.611]) increased the risk of CIS. Conversely, for patients with CIS with PFO, each traditional risk factor increased the risk (OR: 1.185 [1.057–1.328]); however, only nontraditional risk factors remained significant when fully adjusted (OR: 2.656 [2.036–3.464]).¹

“Up to half of all ischemic strokes in younger adults are of unknown causes, and they are more common in women. For effective prevention, careful and routine assessment of both traditional and nontraditional risk factors in younger people is critical,” lead study author Jukka Putaala, MD, PhD, MSc, head of the stroke unit at the Neurocenter, Helsinki University Hospital in Helsinki, Finland, said in a new release. “We should also carefully screen people after they have a stroke to prevent future strokes.”²

Further, population-attributable risks for CIS without PFO were approximately 64.7%, 26.5%, and 18.9% for traditional, nontraditional, and female sex–specific risk factors, respectively. For CIS with PFO, population-attributable risks were 33.8%, 49.4%, and 21.8%, respectively. Interestingly, migraine with aura was the most significant contributor, with population-attributable risks of 45.8% for CIS with PFO and 22.7% for CIS without PFO, with a stronger impact in women compared with men.¹

“We were surprised by the role of nontraditional risk factors, especially migraine headaches, which seem to be one of the leading risk factors in the development of strokes in younger adults,” Putaala said in a news release. “Our results should inform the health professional community to develop a more tailored approach to risk factor assessment and management. We should be asking young women if they have a history of migraine headaches and about other nontraditional risk factors.”²

REFERENCES

1. Putaala J, Martinez-Majander N, Leppert M, et al. Burden of Modifiable Risk Factors in Young-Onset Cryptogenic Ischemic Stroke by High-Risk Patent Foramen Ovale. Stroke. 2025. doi:10.1161/STROKEAHA.124.049855

2. American Heart Association. Nontraditional risk factors shed light on unexplained strokes in adults younger than 50. News release. April 17, 2025. Accessed April 17, 2025. https://www.eurekalert.org/news-releases/1080238