Recent studies demonstrating that transcatheter occlusion of the patent foramen ovale (PFO) reduces the incidence of cryptogenic stroke versus drug treatment¹ have increased interest in the relationship between cryptogenic stroke and the presence of PFO.

Echocardiographic examinations and autopsies identified thrombi crossing the foramen ovale, confirming this mechanism as a cause of paradoxical embolism, i.e., a venous thrombus passing into the arterial circulation through a right-left shunt. However, this echocardiographic visualization is rare, with few studies published^2,3 (Figure 1).

Some clinical studies demonstrated a PFO predisposition to cause paradoxical embolism. Patients with diabetes, systemic arterial hypertension, and coronary artery disease present a low PFO predisposition to cause paradoxical embolism. On the other hand, a history of deep venous thrombosis, pulmonary embolism, pulmonary hypertension, prolonged travels, the Valsalva maneuver preceding the onset of stroke symptoms, migraine, and sleep apnea has been described as an independent risk factor for the association between PFO and cerebrovascular events.⁴

Although visualization of thrombi in the foramen ovale is uncommon, epidemiological observation leads to the belief that PFO is responsible for a considerable number of strokes.⁵

An autopsy study of 965 normal hearts showed a PFO prevalence of 27%, with similar distributions in men and women. This prevalence decreases with age, being 34% in people aged under 30 years, 25% between 30 and 80 years, and 20% over 80 years.⁶ However, cryptogenic stroke patients show a particularly high prevalence of up to 40% in patients aged under 55 years.⁷

It is important to note that the presence of PFO in cryptogenic stroke patients is not the only etiology for paradoxical embolism. Other mechanisms can cause it, such as undetected atrial fibrillation, cardiac tumors (myxoma and fibroelastoma), presence of spontaneous echocardiographic contrast in the left atrium, rheumatic mitral valve disease, mitral valve ring calcification, biological and mechanical heart prostheses, hypercoagulability states, and ascending aorta atheroma.⁸

An echocardiographic study is part of the routine PFO evaluation, mainly transesophageal echocardiography (TEE) with agitated saline solution (bubble). A small shunt is considered when three to 10 bubbles pass, a medium shunt when 10–30 bubbles pass, and a large shunt if more than 30 bubbles are counted in the first beats after the injection.⁹

In addition to shunt detection, TEE evaluates the anatomical characteristics of PFO and the differential diagnosis with atrial septal defect and pulmonary shunt.^10,11

Studies comparing TEE with bubbles and autopsy findings reported a sensitivity of 89% and a specificity of 92%, with autopsy being considered the gold standard.¹²

The performance of an efficient Valsalva maneuver associated with the use of bubble solution is extremely important. This aspect is often overlooked, especially when the test is performed under deep sedation, which can result in a false-negative result. The use of superficial sedation or local oropharyngeal anesthesia is recommended with bubble solution injection to diagnose PFO.¹³

Transcranial Doppler showed more sensitivity but less specificity than TEE in PFO diagnosis. This lower specificity is justified by insensitivity to a differential diagnosis between cardiac and pulmonary shunt in addition to the limited diagnosis of anatomical changes that favor the presence of PFO, such as the presence of an interatrial septum aneurysm and septal mobility.¹⁴

As for the best therapeutic option for cryptogenic stroke patients (drug therapy or percutaneous closure), the CLOSURE trial in 2012¹⁵ and the RESPECT¹⁶ and PC trials¹⁷ in 2013 showed no benefits of percutaneous therapy for PFO closure compared to drug therapy. However, the randomized CLOSE,¹⁸ REDUCE,¹⁹ and RESPECT²⁰ trials determined a therapeutic conduct change in 2017, as they demonstrated that percutaneous PFO closure is superior to drug treatment in preventing cryptogenic stroke in a specific population. After this conduct change, several studies have aimed to improve and more precisely determine which patients are most likely to benefit from interventional treatment.

The Risk of Paradoxical Embolism²¹ study evaluated the clinical characteristics of cryptogenic stroke patients with PFO and proposed a risk score to stratify patients by age and the presence or absence of vascular risk factors. Using clinical and radiological data from 3,000 patients, a multivariate regression model identified six variables associated with cryptogenic stroke, establishing a score with 10 points to stratify the probability of PFO being associated with stroke or being an incidental event. The variables analyzed included age, presence of cortical stroke on an imaging study, and presence or absence of diabetes, systemic arterial hypertension, stroke, or previous transient ischemic attack. The risk score was calculated using these 10 variables for a period of 2 years in each group (Table 1).

Young patients with superficial stroke and no vascular risk factors have a high score. The prevalence of PFO increases from 23% in patients with 0–3 points to 73% in patients with 9–10 points. High scores are seen in young patients with few or no traditional risk factors experiencing superficial cerebral infarctions. The presence of PFO in patients with low scores, whoa re older, and who have vascular risk factors suggests an incidental onset. The risk of stroke or transient ischemic attack is estimated for a period of 2 years in each group²² (Table 2).

A recent study showed that some anatomical characteristics of PFO predispose patients to the formation and passage of thrombi from the right to the left atrium, causingsystemic embolisms.²³ These characteristics are:

The multivariate analysis of these observations showed that cryptogenic stroke patients with PFO had wider (>2 mm) and more extensive (>10 mm) PFO (Figures 3A and 3B), more mobile interatrial septa, prominent Eustachian valves and Chiari network, and a PFO-IVC angle < 10° (Figure 3C). These factors are independent predictors of ischemic brain events²³ (Table 3). A risk score for PFO being responsible for paradoxical embolism in patients with stroke was developed based on the echocardiographic analysis of these anatomical data (Table 4).

High scores are seen in young patients undergoing superficial cerebral infarctions with few or no traditional risk factors. Since affected patients are more likely to have low scores, be older, and have vascular risk factors, PFO may have an incidental PFO onset not causally related to an ischemic event. The risk of stroke or transient ischemic attack is calculated for a period of 2 years.