Migraine headaches are a heterogeneous and recurrent condition with multiple potential phenotypes, making long-term management and preventive treatment extremely challenging on clinicians. In the general population, the prevalence of migraine headaches is approximately 15% with a female-to-male ratio of 3:1. Once diagnosed, simple analgesics should be used in mild to moderate cases, while triptans, -ditans, or -gepants should be used in the treatment of severe migraines. Emerging evidence has suggested that patent foramen ovale (PFO) may be associated with the development of migraines. Surprisingly, at least half of people who suffer from migraines, particularly those with aura, have a PFO.[1, 2] It is important to consider that the prevalence in the general population is quite high, with an estimated prevalence of 20-25%. Indeed, most individuals with a PFO do not develop related health issues and remain generally asymptomatic. My theory is that the pathogenesis of refractory migraines, particularly those with an associated aura, is multifactorial including activation of neurons in the central or peripheral nervous system, hormonal dysregulation, structural changes (e.g., PFO), and genetic heterogeneity. Echo screening for PFO in severe and refractory migraines may be useful.
There is emerging evidence regarding PFO closure in patients with severe, refractory migraines based on several recent clinical trials (MIST, MIST II, ESCAPE, EASTFORM, PRIMA, and PREMIUM trials). These RCTs assessed the effect of PFO closure on preventing migraines. Although they did not demonstrate a significant benefit of PFO closure (e.g., a significant reduction in migraine attacks at 6, 9 months or 1 year), these RCTS shed some light on the potential benefits of PFO closure (e.g., migraine improvement) in this population, compared to medical therapy alone. Interestingly, in a recent study published in JACC: Cardiovascular Interventions with a median follow up 3.2 [2.1 to 4.9] years, investigators found that PFO closure was associated with a significant improvement in migraine burden (headaches both with and without aura) and, notably, the absence of residual right-to-left shunt was a predictor of a significant reduction in migraine burden. Emerging evidence suggests that both presence of PFO and migraine headaches have a genetic predisposition. I believe that migraines and PFOs are primarily heterogeneous polygenic disorders (except familial hemiplegic migraine – monogenic) and that the triage and algorithmic approach should be similar to that taken for patients with hypertrophic cardiomyopathy (HCM). HCM is a monogenic disorder with an autosomal dominant pattern of inheritance, and a recent study showed that PFO and Migraine may be inherited in an autosomal dominant pattern as well. Overall, there are still many lessons to be learned from the HCM in order to adapt this methodology to the treatment of patients with PFO and migraines. A good place to start might be to determine whether PFO closure in migraines using the -omic approach (e.g., GWAS and PheWAS) to identify markers (e.g., SNP, metabolites associated with atrial stunning) is needed. Ideally, testing common genetic mutations in individuals (e.g., endocardial and neuronal alteration-related genes) with both PFO and migraine may a good start before a genome-driven clinical trial of prophylactic PFO closure. I proposed the algorithm to use genetic-guided PFO-migraine management. (Figure)
In the future, PFO screening in Migraine patients with high-risk features (e.g., genetic mutations and deep-sea divers) may be needed and PFO closure in these populations may be beneficial. Currently, there is a significant lack of genetic data in this area, and future clinical trials are needed to determine the potential benefit from PFO closure in patients who suffer from migraine headaches.
- Niessen, K. and A. Karsan, Notch signaling in the developing cardiovascular system. Am J Physiol Cell Physiol, 2007. 293(1): p. C1-11.
- Sadrameli, S.S., et al., Patent Foramen Ovale in Cryptogenic Stroke and Migraine with Aura: Does Size Matter? Cureus, 2018. 10(8): p. e3213.
- Ben-Assa, E., et al., Effect of Residual Interatrial Shunt on Migraine Burden After Transcatheter Closure of Patent Foramen Ovale. JACC: Cardiovascular Interventions, 2020. 13(3): p. 293-302.
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