Patent foramen ovale and cryptogenic stroke: Many unanswered questions

Your patient has had an ischemic stroke, and so far you have found no obvious cause such as atrial fibrillation or carotid disease. Should you look for a patent foramen ovale (PFO)? And if you find it, what should you do?

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This scenario continues to challenge primary care physicians and subspecialists and requires an understanding of the relationship between PFO and cryptogenic stroke, as well as familiarity with current data on the safety and effectiveness of the management options. PFO is known to be associated with cryptogenic stroke, but many questions remain, including:

• How can we tell if PFO is a culprit (“pathologic”) or an innocent bystander (“incidental”) in a patient who has had a cryptogenic stroke?
• Should stroke patients receive different medical therapy if they have a PFO? In particular, should they receive warfarin in addition to aspirin? And what about the novel oral anticoagulants?
• Which patients should undergo percutaneous closure of the PFO?
• Should we even be looking for PFO in stroke patients at this point, if we cannot say with certainty what we should do if we find it?

WHY IS THIS IMPORTANT?

Cerebrovascular disease is common and costly. The estimated yearly incidence of stroke in the United States is 795,000 events, at a cost of nearly $30 billion.¹ The incidence of stroke in Europe is more than 1 million annually.²

During the diagnostic evaluation of stroke or transient ischemic attack (TIA), PFO is occasionally discovered incidentally by echocardiography. The management decisions that follow often fall to the primary care physician, who must decipher the conflicting data currently available and explain the options to the patient.

Although reviews have been published on this subject,³ several newer key trials and data on risk stratification warrant consideration.

DEFINITIONS

PFO is the failure of the septum primum to fuse with the septum secundum, so that a communication remains between the atria (Figure 1). The diagnosis is commonly made by echocardiography, when agitated saline is injected into the venous system and bubbles can be seen in the left atrium within three to five cardiac cycles (see video).

Atrial septal aneurysm is loosely defined as a septal excursion or bulging of at least 10 to 15 mm into the left and right atria during the cardiac cycle (Figure 2). The combination of PFO and atrial septal aneurysm may be more of a risk factor for stroke than PFO alone (see discussion below).

Cryptogenic stroke. The diagnostic workup of stroke fails to elucidate a clear cause in up to 40% of cases, which are thus called cryptogenic.⁴ The workup varies, but typically includes a search for a cardioembolic source and for atherosclerotic disease. Embolic sources are evaluated for by electrocardiography, transthoracic echocardiography, and possibly imaging of the aortic arch. Evaluation for atherosclerotic disease of the intracranial and extracranial arteries includes magnetic resonance angiography or, if that is unavailable, computed tomographic angiography or carotid Doppler ultrasonography. If no source is found, long-term cardiac monitoring may be used to detect paroxysmal atrial fibrillation, which may be more common than previously thought.

PFO AND CRYPTOGENIC STROKE ARE COMMON

As noted, there are approximately 800,000 strokes every year in the United States. If 25% to 40% of them are cryptogenic (the true prevalence warrants more evaluation),^4,5 then 200,000 to 320,000 strokes are cryptogenic.

Autopsy studies indicate that 25% of the general population have a PFO, and if the prevalence is the same in people with cryptogenic stroke, that would equal 80,000 people with both cryptogenic stroke and PFO every year. However, the prevalence of PFO in patients with cryptogenic stroke appears to be significantly higher than in the general population.⁶ Although these numbers are crude estimates, they provide some insight into the prevalence of this clinical presentation.

HOW ARE CRYPTOGENIC STROKE AND PFO RELATED?

The exact relationship between PFO and cryptogenic stroke is unknown, although cases have been reported of thrombus in transit through a PFO, supporting paradoxical embolism as the plausible cause in stroke patients with PFO.^7–9

There is clear evidence that the two conditions are associated by more than chance. Homma and Sacco⁶ reported that, in several studies, 93 (46%) of 202 patients under age 55 with cryptogenic stroke had PFOs, compared with 29 (11%) of 271 controls (P < .05 in all studies).⁶

In their evaluation of 23 case-control studies, Alsheikh-Ali et al¹⁰ found that the summary odds ratio (OR) for PFO in cryptogenic stroke vs PFO in control patients was 2.9 (95% confidence interval [CI] 2.1–4), largely driven by an OR of 5.1 (3.3–7.8) in those under age 55. Through Bayesian probability theory, this correlated with only a 33% probability that PFO in a patient with cryptogenic stroke was an innocent bystander rather than the culprit.¹⁰