Nontraditional risk factors, especially migraine with aura, significantly contribute to the risk of cryptogenic ischemic stroke in adults under 50 years of age rather than traditional risks such as high blood pressure, according to research published in the journal Stroke.¹

The Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome (SECRETO) study, which was conducted across 19 centers in Europe between November 2013 and January 2022. Researchers enrolled 523 patients, aged 18-49 years, who had recently suffered a cryptogenic ischemic. A total of 523 age- and sex-matched stroke-free individuals were also included in the study as controls. Women comprised nearly half of the study group.

A clinically significant patent foramen ovale (PFO), defined by the presence of high-risk features such as an atrial septal aneurysm or a large right-to-left shunt, was identified in 37.5% of participants. Researchers examined 12 traditional, 10 nontraditional (such as venous thromboembolism, migraine with aura, chronic kidney disease, chronic liver disease or cancer), and five female-specific risk factors (such as gestational diabetes, gestational HT, various pregnancy complications, estrogen use, current pregnancy or puerperium), as stratified by PFO status. More than one-third of the participants (37.5%) had a clinically relevant PFO.

Stroke patients without PFO had a higher number of traditional risk factors. In these patients, the probability of cryptogenic ischemic stroke increased with each additional traditional risk factor (OR 1.42), nontraditional risk factor (OR 1.70), and female sex-specific risk factor (OR 1.70).

In patients with a PFO, each additional traditional risk factor modestly increased stroke risk (OR 1.18), but only nontraditional risk factors and female sex-specific risk factors remained significant in fully adjusted models with ORs of 2.66 and 1.94 respectively.

Population-attributable risk analysis showed that in patients without a PFO, traditional risk factors accounted for 64.7% of cryptogenic ischemic stroke cases, nontraditional factors for 26.5%, and female-specific factors for 18.9%. Among patients with a PFO, traditional factors contributed to 33.8% of cases, nontraditional factors to 49.4%, and female-specific factors to 21.8%, highlighting the greater impact of nontraditional factors in this group.

Migraine with aura had the highest individual population-attributable risk for cryptogenic stroke in both groups, 45.8% in patients with a PFO and 22.7% in those without, which the authors note aligns with previous research linking migraine to cryptogenic stroke.

PFOs can raise the risk of stroke. These findings show that traditional risk factors were more strongly associated with cryptogenic ischemic stroke in patients without a PFO, whereas nontraditional factors played a greater role in those with a PFO. Migraine with aura was a significant factor in the development of young-onset cryptogenic ischemic stroke, especially in women. Hence, due to the overlap of symptoms, patients with migraine with aura should be vigilant about stroke signs and seek medical attention immediately if they experience any sudden neurological changes.

A major takeaway from this study therefore is the necessity to recognize and consider the impact of nontraditional risk factors including female-specific factors, as they also significantly increase stroke risk. Careful assessment of both traditional and nontraditional risk factors is essential for developing effective prevention and evaluation strategies in young adults, including those who may appear to be at low risk for stroke.

References

1.   Jukka Putaala, et al. Burden of modifiable risk factors in young-onset cryptogenic ischemic stroke by high-risk patent foramen ovale. Stroke. 2025 Apr 17. doi: 10.1161/STROKEAHA.124.049855.

2.   Todd Neale. TCTMD News. Available at: https://www.tctmd.com/news/pfo-risk-factors-both-exert-influence-younger-cryptogenic-stroke-patients. Dated April 23, 2025. Accessed on May 3, 2025.