Correspondence *Cardiovascular Research, Swedish Medical Center, 801 Broadway, Suite 927, Seattle, WA 98104, USA

Email amish.desai@swedish.org

Introduction

Stroke is the third leading cause of death in developed countries, after heart disease and cancer, and is the most important cause of serious, long-term adult disability and hospitalization. Of the 700,000 strokes that occur annually in the US, approximately 88% are classified as ischemic.¹ Despite extensive evaluation, more than 40% of all ischemic strokes have no clearly identifiable cause and are classified as cryptogenic. The occurrence of cryptogenic strokes is associated with young age, the presence of a superficial infarct, prior transient ischemic attack, and lack of clinically significant weakness in the face and extremities.²

Patent foramen ovale (PFO), a hemodynamically silent interatrial communication present in more than 25% of the US population,³ is the most common cause of systemic right-to-left shunt (RLS). Large-diameter PFOs, which predispose patients to intermittent paradoxical emboli, have been implicated in cryptogenic stroke, platypnea–orthodeoxia syndrome, decompression illness in scuba divers, cerebral fat embolism syndrome and transient global amnesia.^{4, 5} Case–control series have reported increased prevalence of PFO in patients with cryptogenic stroke (40–56%) compared with those with no history of stroke (10–18%),^{6, 7, 8} and meta-analysis suggests a strong relation between PFO and cryptogenic stroke, especially in people aged younger than 55 years.⁹ Calculations based on these findings suggest that in the US, 98,000–139,000 strokes per year could be attributed to PFO.

The following review summarizes current knowledge regarding PFO as a potential source of cryptogenic stroke. Embryologic origins, diagnostic techniques and treatment options for prevention of paradoxical embolism thought to be related to PFO are discussed. Finally, the emerging and controversial association between PFO and migraine headaches is presented.

What is a patent foramen ovale?

The foramen ovale is an opening in the interatrial septum resulting from incomplete coverage of the ostium secundum—an opening within the septum primum—by the septum secundum. The foramen ovale serves as a one-way valve for physiologic right-to-left shunting of oxygenated blood in utero. Blood from the placenta enters the right atrium through the inferior vena cava and crosses the foramen ovale into the systemic circulation. Postnatal lung expansion and initiation of the pulmonary circulation reverses the atrial pressure gradient, causing functional closure of the foramen ovale. Fibrosis follows closure and complete fusion of the interatrial septae occurs by 2 years of age in most individuals.¹⁰ Lack of septal fusion results in a PFO, a potential hole that can be opened by reversal of the interatrial pressure gradient or by an intracardiac catheter (Figure 1).

Figure 1 Autopsy specimen illustrating patent foramen ovale, as viewed from the left atrium

The probe is holding up the septum primum. Photograph courtesy of and reproduced with permission from S Mackey, Jesse E Edwards Registry for Cardiovascular Disease, St Paul, MN, USA.

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The prevalence of PFO in families is consistent with autosomal dominant inheritance.¹¹ An autopsy study found the frequency of PFO to be 26–40% in normal adult hearts,³ and the mean PFO diameter to be 4.9 mm. Notably, PFO prevalence diminishes with age, from 34% during the first three decades of life, to 25% in individuals aged 30–80 years, and 20% in those aged more than 80 years. Meissner et al.¹² corroborated the autopsy study findings in a prospective, population-based study of 581 individuals aged more than 45 years by reporting a PFO prevalence of around 26%.

Detection of patent foramen ovale

PFO can be detected noninvasively by venous injection of agitated saline contrast during transthoracic echocardiography (TTE), transesophageal echocardiography (TEE) or transcranial Doppler imaging. The agitated saline injections are performed at rest and after a calibrated Valsalva maneuver (40 mmHg strain measured by spirometry and sustained for 10 s) or maximal Valsalva maneuver. For detection with TTE or TEE, visualization of an injected saline microbubble in the left atrium or ventricle within three cardiac cycles of right atrial opacification is consistent with the presence of an intracardiac shunt. Notably, introduction of the contrast medium via the inferior vena cava from a femoral vein injection is preferentially directed towards the fossa ovalis and crosses the PFO more readily than an injection from an antecubital vein (100% versus 75% during a Valsalva maneuver; P <0.01), thus allowing for increased detection of RLS.¹³

Shunt detection by transcranial Doppler imaging involves the recording of agitated saline bubbles mimicking microemboli, passing through the middle cerebral artery during normal respiration or, after a calibrated Valsalva maneuver, as a series of embolic tracks seen on ultrasonography through the temporal bones. By comparison with earlier single-gated technology, power motion-mode transcranial Doppler imaging employs 33 sample gates to enhance the detection of embolic tracks (Figure 2). Spencer et al.¹⁴ reported 98% sensitivity and 94% accuracy when detecting PFO with power motion-mode transcranial imaging, compared with 91% sensitivity and 99% accuracy with TEE. The 'shower' (more than 300 tracks) or 'curtain' (too many tracks to count) patterns of microemboli on transcranial Doppler imaging are consistent with a large RLS and are associated with a higher risk of cryptogenic stroke;¹⁵ however, the presence of microbubbles in the cerebral circulation is not exclusive to an interatrial communication. Any cause of RLS, including ventricular septal defect and pulmonary arteriovenous malformation, can lead to a positive transcranial Doppler reading for an RLS, thus lowering the specificity of this test.¹⁶

Figure 2 Power motion-mode transcranial Doppler imaging in a patient with a 12 mm diameter patent foramen ovale

This defect was first diagnosed by bilateral power motion-mode transcranial Doppler and subsequently closed with a CardioSEAL^® device (NMT Medical, Boston, MA). Note the embolic tracks, shown in white, sloping across the red and blue bands of the displays and the presence of some of these microembolic signals in the spectrograms. Reproduced with permission from Spencer Vascular Technologies, Seattle, WA, USA.

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TTE, the least sensitive diagnostic method, can fail to detect up to 53% of PFOs.¹⁷Although power motion-mode transcranial Doppler imaging is a highly sensitive and less invasive method for the detection of RLS, TEE is the accepted 'gold standard' method for PFO documentation. Additionally, PFO diameter can be measured by TEE or by intracardiac echocardiography, which is commonly performed at the time of percutaneous closure for selection of device type and size.

Patent foramen ovale and stroke

More than 40% of ischemic strokes that occur in people younger than 55 years are cryptogenic.² The prevalence of PFO is higher in patients with cryptogenic stroke than in those with known stroke etiology (45% versus 23%).¹⁷ Notably, this discrepancy is greater in young patients than in older patients, in whom the relative risk of PFO-related stroke decreases as the incidence of hypertension and hyperlipidemia increase.⁷ PFO might have a familial predilection, as reported by Arquizan et al.,¹⁸ who found that female siblings of stroke patients with PFO were themselves more likely to have PFO than were siblings of stroke patients without PFO (odds ratio 9.8, P <0.01). Interestingly, this finding was not seen in male siblings of stroke patients with PFO; however, the reason for the difference was not clear.

Multiple potential thromboembolic mechanisms have been proposed to explain the increased risk of recurrent stroke in young patients with PFO. Paradoxical embolism—the systemic passage of thrombi of venous origin through an interatrial conduit—is thought to be the mechanism of stroke in patients with PFO. Small blood clots and microaggregates could cross the PFO, thereby escaping lysis in the lungs and leading to clinically important sequelae in the brain.¹⁹ The shunting of these particles could occur after a Valsalva maneuver or in relation to a chronic condition causing increased pulmonary artery pressure; however, the clinical diagnosis of paradoxical embolism remains presumptive in the majority of cases. Although the discovery of an in situ PFO thrombus is rare, thrombi could form within the PFO tunnel (the 'lurking clot' theory) and enter the systemic circulation during an increase in right atrial pressure.²⁰ Transient atrial arrhythmias are also associated with thrombus formation and higher embolic risks, and could possibly lead to cryptogenic stroke. In addition, patients with cryptogenic stroke and atrial septal abnormalities have increased atrial vulnerability and, therefore, could have a greater potential for paroxysmal atrial fibrillation and thrombus formation.²¹

Risk factors for stroke in patients with patent foramen ovale

Risk factors for stroke in patients with PFO are presented in Table 1. Increase in PFO diameter has been linked to increased risk of paradoxical embolism. PFO diameter increases with age, from a mean of 3.4 mm in the first decade of life, to 5.8 mm in people aged more than 80 years, suggesting spontaneous late closure of smaller communications.³ Patients with postulated paradoxical embolization appear to have larger PFOs than those without paradoxical embolization, and MRI findings have implicated cerebrovascular emboli as a potential mechanism in stroke patients with a large PFO.²² The presence of spontaneous RLS at rest has also been associated with stroke.²³ In the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), large PFOs—defined as at least 2 mm separation of septa or at least 10 microbubbles in the left atrium—were seen significantly more frequently among patients with cryptogenic stroke than among those with known causes of stroke.²⁴ In addition, the magnitude of RLS through a PFO is a significant risk factor for recurrent cerebrovascular events (odds ratio 14.8 for large PFO [defined as >10 bubbles recorded in the cerebral vessels using single-gated transcranial Doppler and >100 embolic tracks using power motion-mode transcranial Doppler] versus small PFO, P = 0.01).^{13, 25}

Table 1 Factors associated with increased risk of cryptogenic stroke in patients with patent foramen ovale

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Atrial septal aneurysm is defined as a hypermobile septum primum with at least 10 mm of phasic excursion into either atrium from the septal plane. The prevalence of isolated atrial septal aneurysm in the general population is less than 1% as measured by TTE;²⁶ in patients with cryptogenic stroke, the prevalence is 4–25%.⁷ While atrial septal aneurysm per se confers no additional risk for cryptogenic stroke,²⁷ the frequent association of this condition with PFO appears to suggest that it has embolic potential.²⁷ A robust association exists between the combined presence of atrial septal aneurysm and PFO and the primary occurrence of stroke in people younger than 55 years, compared with older people (odds ratio 15.59).⁷Recurrent stroke, despite aspirin therapy, is also significantly increased in those with both PFO and atrial septal aneurysm, compared with persons with previous stroke without either abnormality or those with atrial septal aneurysm alone (P = 0.007).²⁷ Persistence of the eustachian valve, a remnant of fetal circulation, can preferentially direct flow through an interatrial communication preventing its spontaneous closure after birth, and indirectly predispose individuals to paradoxical embolism.²⁸

Although they represent the presumed source of embolized clots, less than 10% of all peripheral deep vein thromboses are discovered on diagnostic imaging, a finding that is consistent in patients with PFO and stroke.²⁹ Investigation for deep vein thrombosis typically involves imaging the femoral and popliteal veins; however, the pelvic veins should also be considered as a potential embolic source. Cramer et al.³⁰ found that the incidence of pelvic deep vein thrombosis was significantly higher in patients with cryptogenic stroke (20%) and patients with cryptogenic stroke and PFO (22%) than in patients with stroke of determined origin (4%; P <0.025). Patients with cryptogenic stroke were significantly younger and had fewer risk factors for atherosclerosis than those with stroke of known cause. The prevalence of PFO was 61% in the cryptogenic stroke group and 19% in those with a determined origin of stroke. The finding that most patients with cryptogenic stroke and pelvic deep vein thrombosis also had a PFO supports paradoxical embolism as the stroke mechanism.

Inherited prothrombotic disorders have been linked to an increased risk of venous thromboembolism. Elevated levels of factor VIII, decreased activity of protein C and protein S and antithrombin, and mutations in the factor V Leiden and prothrombin (G20210A mutation) genes have all been associated with ischemic strokes. Pezzini et al.³¹ reported that the prothrombin gene G20210A mutation and, to a lesser extent, the factor V Leiden gene mutation were more frequent in PFO patients than non-PFO patients with ischemic stroke. This finding was corroborated by the study of Karttunen et al.,³² in which they compared 58 patients with cryptogenic stroke and PFO with 104 matched control patients. They found that patients with PFO in combination with these gene mutations had a significantly increased risk of cryptogenic stroke (P = 0.022). By contrast, Lichy et al.³³ found only the prothrombin mutation to be more common in patients with stroke and PFO than in stroke patients without PFO and healthy individuals.

Treatment of patent foramen ovale

A lack of randomized trial data means that the optimum management of patients with PFO and cryptogenic stroke is yet to be determined. In the Lausanne Stroke Registry,³⁴ which involved 140 patients with PFO and cryptogenic stroke, 92 patients were treated with a daily regimen of 250 mg aspirin, 37 patients were treated with daily warfarin to an international normalized ratio (INR) of 3.5, and 11 underwent surgical PFO closure. During a follow-up period of 3 years, annual recurrence rates were 1.9% for ischemic stroke alone and 3.8% for ischemic stroke and transient ischemic attack, which were too low to allow comparisons between therapies. Mas et al.²⁷ retrospectively investigated the rate of recurrent stroke despite treatment with 250–500 mg aspirin or warfarin daily (target INR 2–3) during a 23-month follow-up. In 132 patients with cryptogenic stroke—69 of whom had an isolated PFO, 25 an isolated atrial septal aneurysm and 38 of whom had both—there was a 1.2% annual rate of recurrent ischemic stroke alone, and a 3.4% annual rate of ischemic stroke and transient ischemic attack. In the subgroup of patients with PFO and atrial septal aneurysm, the annual rates were 4.4% and 11.7%, respectively. The 4-year cumulative risk for recurrent stroke in this subgroup was 15.2%. In the PICSS trial²⁴ there was no difference in mortality or recurrent stroke rates at 2 years between patients who received 325 mg aspirin daily or warfarin therapy (target INR 1.4–2.8). In a secondary analysis of this trial, patients with PFO aged 65 years or older had an increased risk of death or recurrent ischemic stroke compared with age-matched patients without PFO (hazard ratio 2.92, P = 0.01).³⁵ A raised risk of adverse effects was not seen in PFO patients aged younger than 65 years.

Surgical closure of PFO, a procedure requiring general anesthesia and cardiopulmonary bypass, has been used to prevent recurrent cryptogenic stroke. The results of selected surgical PFO closure studies are presented in Table 2. Major perioperative complications of surgical PFO closure include postpericardiotomy syndrome (2.3%), tamponade (1.9%), exploratory reoperation (1.4%), and ventricular fibrillation (0.5%).^{36, 37, 38}

Table 2 Results of selected studies of surgical patent foramen ovale closure to treat recurrent stroke

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Transcatheter closure of PFO has been developed as a minimally invasive alternative to surgery. The procedure, which involves percutaneous implantation of a device to occlude the interatrial septum, allows patients to be discharged from hospital within 24 h. Although multiple PFO closure devices have been developed, only the CardioSEAL^® (NMT Medical, Boston, MA) and Amplatzer^® (AGA Medical, Golden Valley, MN) devices are approved by the FDA.³⁹ A 0–6% rate of recurrent stroke or transient ischemic attack is reported after transcatheter PFO closure, as shown in Table 3.^{40, 41, 42, 43, 44, 45, 46, 47, 48} High rates of recurrent cerebrovascular events were seen with the use of earlier closure devices, such as the Rashkind^® hook device (WJ Rashkind, Philadelphia, PA),^{40, 41, 48} and in patients with residual RLS.⁴¹ Early devices were also less effective in achieving total PFO closure than the currently available devices.⁴¹ The presence of a thrombophilic disorder with PFO did not affect the rate of recurrent cerebrovascular events after closure.⁴⁵ Notably, reported complications following PFO closure are infrequent and are associated with low morbidity and mortality. Long-term consequences of PFO closure are unknown. In a study of 276 patients with stroke and PFO closure, Hung et al.⁴⁰ found that adverse events included brief atrial fibrillation (0.8%), device dislodgement (0.4%), device arm fracture (3.6%) and surgical explantation (0.8%). Migraine headaches that occur after percutaneous closure of atrial septal defects have not been reported after transcatheter PFO closure.⁴⁹ In 1,000 patients who underwent PFO closure, deployment of the Amplatzer^® device resulted in lower rates of postprocedure thrombi than use of the CardioSEAL^®, STARFlex^® (NMT Medical, Boston, MA) and PFO-Star™ (Cardia Inc, Burnsville, MN) devices (0, 7.1%, 5.7%, and 6.6%, respectively; P <0.05).⁵⁰ Thrombus formation was not associated with clinical events, for example stroke, and has been shown to be reduced by aspirin and clopidogrel use until the device is endothelialized, which generally takes 2–4 months.

Table 3 Reports of recurrent stroke in patients following transcatheter patent foramen ovale closure

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Several nonrandomized studies have attempted to compare surgical or transcatheter PFO closure with medical PFO treatment. Bogousslavsky et al.³⁴ reported that stroke recurrence was not related to the method of treatment (i.e. surgical closure versus medication); however, Khairy et al.⁵¹ reviewed data from 10 PFO closure studies and 6 medical therapy studies and reported a 1-year recurrence rate of 3.8–12.0% for medical therapy compared with 0–4.9% for surgical or transcatheter closure. Patients who underwent PFO closure were more likely to have multiple cerebrovascular events, but this finding could be related to selection bias. Schuchlenz et al.⁴⁸ reported that the rate of recurrent cerebrovascular events in the patients treated with closure was 0.6% per year, significantly lower than that in patients receiving warfarin (5.6%) and aspirin (13%). Two randomized trials comparing medical therapy using aspirin, warfarin, or both, with closure are in progress: the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) study, sponsored by AGA, and Closure I, sponsored by NMT Medical. Despite the lack of randomized trials, the evidence indicates that transcatheter PFO closure is associated with better long-term outcome than medical treatment alone.

Migraine and patent foramen ovale

Migraine headache, categorized as either classic (with aura) or common (without aura), is a paroxysmal, often debilitating, condition affecting about 13% of the US adult population.⁵² Patients who have migraines with aura are more likely than those who have migraines without aura or those without migraines altogether to have a PFO.⁵³ Schwerzmann et al.⁵⁴ reported that PFO was more frequently seen among people who had migraine with aura than among controls matched for age and sex (47% versus 17%). A large RLS was seen in 57% of patients with migraines and 16% of control patients. The odds ratio of having migraine in the presence of PFO with a moderate or large RLS was 7.78 (95% CI 2.53–29.3, P <0.001), suggesting that interatrial communication might be associated with migraine pathogenesis.

Evidence indicates an association between migraine, stroke and PFO. Although the overall risk of stroke in patients with migraine headaches is low,⁵⁵ cryptogenic stroke patients with PFO are twice as likely to have a history of migraine headache as those without PFO (27% versus 14%).⁵⁶ Patients younger than 45 years with migraine and stroke had a higher prevalence of posterior circulation infarcts than stroke patients without migraine, matched for age and sex (55% versus 34%, P <0.01).⁵⁷ Patients who had classic migraine had an increased prevalence of subclinical posterior circulation infarcts compared with those with common migraine (8.1% versus 2.2%, P = 0.03).⁵⁸ The odds ratio for risk of ischemic stroke among patients with migraine in the Physicians' Health Study was 2.00 (95% CI 1.10–3.64).⁵⁹ The relative risk for stroke is 2.88 (95% CI 1.89–4.39) for migraine with aura and 1.56 (95% CI 1.03–2.36) for migraine without aura.⁶⁰ These data have led to the theory that interatrial transit of microemboli or vasoactive compounds through the PFO evades pulmonary filtration and results in cerebral vasoreactivity and migraine symptoms, ischemic stroke, or both.⁵⁴ Several small studies have suggested that PFO closure in patients with cryptogenic stroke or decompression illness could reduce migraine symptoms. The findings of these trials are listed in Table 4. Unfortunately, these studies were limited by nonrandomized design, small sample size and lack of a control group. The results must, therefore, be interpreted cautiously. Nevertheless, the migraine resolution rate (i.e. complete cessation of headache) following PFO closure was 29–60%, and 14–59% of patients saw improvement in severity or frequency of headaches. Our group found a net reduction in migraine episodes per month of 80% (6.8 9.6 before closure versus 1.4 3.4 after closure, P <0.001).⁶¹ Migraine relief was independent of closure status at 1-year follow-up.

Table 4 The major studies of migraine relief following transcatheter closure of patent foramen ovale

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The data presented here point to the need for large randomized trials designed to assess the efficacy of PFO closure in reducing the incidence of migraine headaches. An example of such a trial is the Migraine Intervention with STARFlex^® Technology (MIST) trial, sponsored by NMT Medical, a randomized UK-based trial designed to determine the effect of PFO closure on migraine frequency. A similar study is about to launch in the US.

Conclusions

PFO is a risk factor for cryptogenic stroke, independent of traditional risk factors, particularly in people younger than 55 years. The continued risk of recurrent neurologic events despite medical therapy warrants consideration of PFO closure as a treatment option. Prospective multicenter trials are needed to determine whether PFO closure can reduce the disability associated with recurrent stroke or migraine headaches.

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Subject areas under which this article appears: Intervention | Stroke