PFOCUS study protocol: a prospective case-control study investigating genetic, haemodynamic, and platelet function in migraine with aura with or without patent foramen ovale

Migraine with aura (MA) is associated with an increased risk of ischemic stroke, particularly in young individuals without conventional vascular risk factors. A growing body of evidence indicates a strong association between MA and patent foramen ovale (PFO), the prevalence of which is up to three times higher in patients with MA than in the general population. The mechanisms underlying this association remain incompletely understood and are likely to extend beyond paradoxical embolism.

PFOCUS is a prospective, monocentric, observational case-control study designed to investigate the genetic, neurosonological, and hematological determinants linking MA and PFO. Specifically, the study evaluates whether genetic variants, particularly within the Notch signaling pathway, contribute to the coexistence of PFO and MA, and whether these patients display distinct cerebrovascular and prothrombotic profiles. As exploratory aims, the study will assess whether aura phenotypes and the distribution of MRI lesions are associated with different haemodynamic and prothrombotic profiles, potentially identifying clinically relevant subgroups within MA.A total of 240 patients with MA will be enrolled and classified as right-to-left shunt (RLS)-positive or RLS-negative on the basis of contrast-enhanced transcranial Doppler (TCD), used as a surrogate marker of PFO. Participants will undergo comprehensive phenotyping including genetic testing by whole-exome sequencing, neurosonological assessment of right-to-left shunt, cerebral microemboli detection, dynamic cerebral autoregulation and cerebral vasomotor reactivity (VMR), and platelet function testing. The primary endpoint is the difference in the frequency of NOTCH3 gene variants between groups. Secondary endpoints include associations with other panel genes, correlation with shunt size, and differences in haemodynamic and platelet function parameters. ClinicalTrials.gov: NCT07349004.

PFOCUS aims to identify a biologically distinct phenotype of MA associated with PFO, potentially driven by genetic predisposition and vascular dysfunction. Its findings may inform stroke risk stratification and open new avenues for personalized preventive strategies in patients with MA.

ClinicalTrials.gov, identifier NCT07349004 (https://clinicaltrials.gov/study/NCT07349004).