The patent foramen ovale and neurologic events

The persistently patent foramen ovale has been implicated in a variety of neurologic and embolic events, including transient ischemic attacks and stroke, decompression illness in divers, platypnea-orthodeoxia syndrome, and systemic embolization in patients with acute pulmonary embolism.

It has also been linked to migraine headaches. Although there is no doubt that paradoxical embolism through a PFO can be implicated in the above problems, the most important questions involve the frequency with which paradoxical embolism occurs, the risk of recurrent episodes, and what therapy patients with ischemic TIAs or stroke with no apparent etiology, the so-called “cryptogenic stroke,” should receive. About 40% of all strokes fall into this category.

Anatomic considerations

The septum primum initially divides the two atria. As it advances toward the endocardial cushions, the gap preceding the septum is referred to as the ostium primum. If the septum primum does not fuse with the endocardial cushions, this gap persists and a primum atrial septal defect results. If the septum primum fuses properly with the endocardial cushions, single or multiple fenestrations or holes then appear in the middle of the septum primum forming the ostium secundum.

Thomas Bashore, MD

Melvin Cheitlin, MD

A second septum, the septum secundum, then advances over the ostium secundum from the right atrial side. If this second septum fails to cover the ostium secundum completely either due to inadequate formation of the septum secundum or too large a defect in the septum primum, an ostium secundum atrial septal defect results. In the developing fetus, this second septum completely covers the ostium secundum and reaches to the endocardial cushion, though a large ovale hole (foramen ovale) persists normally in the septum secundum. The persistence of this foramen allows fetal blood streaming from both the inferior vena cava and superior vena cava to cross the foramen and enter the left atrium, thus bypassing the fetal pulmonary circuit. In about 2% to 3% of the population, the septum primum is redundant and can be seen to flop back and forth across the foramen opening. This latter condition is referred to as an atrial septal aneurysm. By transesophageal echocardiography the atrial septum aneurysm involves only the foramen ovale area in about half of the cases and the entire septum in the remaining half. A high proportion of patients with an atrial septal aneurysm (more than 50%) will have an associated PFO and evidence for right-to-left shunting.

The prevalence of a PFO in the general population is known to be in the range of 20% to 30%, depending on whether the presence of a PFO is determined by autopsy studies, by transthoracic or transesophageal Doppler-echocardiography with or without bubble contrast, or by transcranial Doppler. The sensitivity in identifying a PFO is increased by imaging after release of a Valsalva maneuver. This maneuver transiently increases right atrium pressure while reducing flow to the left atrium. In general, the prevalence of a PFO decreases with age (fusion tends to occur with time), whereas the size of any PFO found increases with age (the smaller ones tend to close). The diagnosis of an atrial septal aneurysm is made by echocardiography when the base of the aneurysm is >15 mm and the maximal excursion exceeds 10 mm. Evidence for spontaneous or provoked right-to-left shunting with saline microcavitations is often graded 0=none, 1=minimal (1 to 5 bubbles), 2=moderate (6 to 20 bubbles) or 3=severe (>20 bubbles).

PFO relationships

The evidence that a PFO is causally related to cryptogenic TIA or stroke is mostly dependent on retrospective observational studies. Whether there is greater prevalence of a PFO in those patients with a cryptogenic stroke than in the control group depends on how the control group was chosen. In most studies, the controls are those patients referred for echocardiography for reasons other than cryptogenic stroke or TIA, but referred to evaluate a suspected cardiovascular problem. In most studies, usually in patients aged <55 years, patients with cryptogenic stroke or TIA have a higher PFO prevalence compared with a control group. Homma and Sacco reported that the average prevalence of PFO in cryptogenic stroke patients <55 was 46% compared with 11% for controls.

The majority of patients with TIAs or stroke are due to etiologies other than paradoxical embolism, even in patients where superficial evaluation reveals no other etiology and the patient is classified as a cryptogenic stroke. Other problems must be excluded before blaming the neurologic event on a paradoxical embolism through a PFO.

In many of the observational studies, transient AF and emboli from aortic atherosclerotic plaques were not ruled out and certainly our ability to define the hypercoagulable state is admittedly primitive.

The vast majority of strokes occur in the older population. Only 3% of cerebral infarction occurs in patients aged <40. Since atherosclerosis, AF and other causes of cerebral embolism are more frequent in the older population, the search for a PFO in the population aged <50 becomes more fruitful. Jones and colleagues reported 220 consecutive patients with cerebral ischemia, mean age 66 +13 years and 202 community-based control subjects, mean age 64 +11 years, all of whom had transesophageal echocardiography and carotid imaging. Of the patients with stroke, 16% had a PFO compared with 15% of the control subjects. Patients aged <50 years tended to have a higher incidence of PFO than control patients (27% vs. 11%, P=.33), but there were only 26 patients and 19 controls aged <50. Patients and controls >50 years had a similar prevalence of PFO. These results suggest that PFO is not likely a risk for cerebral ischemia in patients >50 years.

Recent studies have muddied the waters a bit. In the French PFO-Atrial Septal Aneurysm Study involving 581 young patients with cryptogenic stroke, 46% had a demonstrable PFO, though other features, such as a demonstrable shunt or deep vein thrombosis, were not more frequent in stroke patients with a PFO than in those with no neurologic events. Of interest, migraines were more common in PFO patients (27%) than those without a PFO (14%), especially if a septal aneurysm was present.

There are several anatomic factors that have been associated with an increased incidence of recurrent neurologic events, although not all studies agree. These include the size of the PFO, the presence of a resting right-to-left shunt through the PFO, an associated trial septal aneurysm, and either a large Eustachian valve or Chiari network, which may increase the chance of thrombus forming or directing a thrombus from the inferior vena cava to the PFO. Young patients with a PFO have been reported to have an ischemic stroke following air travel, the “economy class stroke syndrome” providing further evidence for possible paradoxical emboli.

The question of the risk of recurrence of another TIA or stroke is vitally important to determining the urgency of possible preventive treatment. What is the risk of a man who has had the first paradoxical embolism at age 45 having a recurrence? Since the PFO has been there all his life, if the embolism is a random event, the chances of a repeat embolism occurring within a short time are remote. Since no patient with a cryptogenic stroke goes without some attempt at preventive therapy, the recurrence rate must be assessed with the patient on medical or interventional therapy.

Medical therapy

Although a meta-analysis of five retrospective studies showed that direct surgical closure of the PFO was superior to medical management in preventing recurrence of neurologic events (OR=0.27), it was mainly due to its superiority over antiplatelet drugs. There was no difference of surgical closure over treatment with warfarin. There is currently no definitive study proving that closure, either surgical or catheter, is superior to medical management in preventing recurrence.

There are, however, several prospective studies that compare recurrence rates between antiplatelet drugs and warfarin. Bogousslavsky and colleagues studied recurrences of stroke in 140 consecutive patients with PFO, mean age 44+14, selected from 340 patients. The control group included 200 patients aged <60 years with acute stroke. One-fourth of the patients with a PFO had an associated atrial septal aneurysm. During a follow-up period of three years the stroke or death rate was 2.4%/year, but only eight patients had a recurrent cerebral infarct (1.9%/year). Multivariate analysis showed that the PFO, a history of recent migraine, posterior cerebral artery infarct and a coexisting cause of stroke were associated with recurrence, whereas treatment type (medical or surgical closure of the PFO) was not.

In the Warfarin-Aspirin in Recurrent Stroke Study (WARSS), 630 patients were assigned to warfarin or aspirin. Of these, 265 had experienced a cryptogenic stroke and were enrolled in the PFO in Cryptogenic Stroke Study (PICSS). Homma and colleagues reported the results of this randomized trial. There were no significant differences with or without PFO in time to primary endpoints (recurrent ischemic stroke or death), two-year event rates in the overall population (14.8% vs. 15.4%), or in the cryptogenic stroke group (14.3% vs. 12.7%). There were also no significant differences in the two-year event rate among those with no, a small or a large PFO (15.4%, 18.5%, 9.5%) and no differences in two-year event rates between patients with isolated PFO (14.5%) and those with associated atrial septal aneurysms (15.9%). Of interest, there was no significant difference in the two-year event rate in those on aspirin vs. those on warfarin (13.2% vs. 16.5%). On medical therapy, aspirin and warfarin, the presence of a PFO in stroke patients did not increase the chance of adverse events regardless of PFO size or the presence of an atrial septal aneurysm.

Mas and colleagues in a multi-hospital study reported 581 patients aged <55 with a cryptogenic stroke. All received aspirin 300 mg daily for secondary prevention. After four years, the risk of recurrent stroke was 2.3% (95% CI=0.3-4.3%) among patients with PFO alone, 15.2% (95% CI=1.8-8.6%) in those with both PFO and an atrial septal aneurysm, and 4.2% (95% CI=1.8-6.6%) among those with neither of these cardiac abnormalities. There were no recurrences in those with atrial septal aneurysm alone. The presence of both PFO and atrial septal aneurysm, compared with those without these abnormalities, presented a hazard ratio of 4.17 (95% CI=1.47-11.84). In this study, patients with PFO alone on aspirin did not have a substantial risk for recurrence compared with patients without PFO.

Surgical closure

In studies where the PFO has been surgically closed, the incidence of recurrent TIA, stroke or death varies from zero to 5.55/100 patient years. Most of the adverse events were TIAs. Within the last decade there have been a number of catheter occluder devices developed to percutaneously close the PFO. In these studies as well, the incidence of recurrent neurologic events or death varies from zero to 3/100 patient years. Studies randomizing surgical vs. catheter device closure of a PFO in patients with cryptogenic stroke are ongoing (see the RESPECT trial below).

Percutaneous device closure

A variety of devices have been investigated for the closure of PFOs using a percutaneous approach. The two most commonly used devices currently under investigation are the Amplatzer PFO occluder (AGA Medical Corp.) and the STARflex (NMT Medical) occluder.

The group in Bern, Switzerland, reported the first large experience with percutaneous PFO closure. The majority of their recent patients have had the Amplatzer device implanted based on their experience that fewer residual shunts resulted compared with the other available devices. Though their numbers remain small, the patients nonrandomized, and the follow-up still ongoing, the risk of TIA or peripheral embolism after PFO device closure was only 1.6% per year with no strokes and no deaths. Those with complete closure did better (1.0% recurrent events per year) than those with residual shunts (3.4% per year). The presence of an atrial septal aneurysm does not appear to affect the immediate or longer term outcome.

Braun and colleagues from Dresden, Germany, recently reported on 307 consecutive patients using a variety of devices for PFO closure. A 100% implantation rate was reported with nine major complications (five with ST-segment elevation, one with an AV fistula, two with TIAs and one with device dislodgement). During a follow-up of 24 months, the annual risk of recurrent thromboembolic events was 0.6% for TIA, 0% for stroke and 0.2% for peripheral embolism. Others have reported similarly favorable results.

Although several PFO closure devices are currently in use overseas, the FDA has yet to approve any PFO closure device in this country. In December 2001, limited approval under a Humanitarian Device Exemption was given to the Amplatzer PFO device. This HDE approval requires individual center Institutional Review Board monitoring, and the device use to be limited to patients with cryptogenic stroke who have a PFO and have had a recurrent event on any type of medical treatment (including aspirin or warfarin) as part of the Randomized Evaluation of recurrent Stroke comparing PFO closure to Established Current Standard of Care Treatment (RESPECT) trial. As of November 2005, 140 of the anticipated 500 patients have been randomized. The RESPECT involves a two-to-one randomization of device vs. surgical intervention.

Complications related to the device deployment are uncommon, but experience with the devices and long-term follow-up remains limited. Atrial arrhythmias and evidence of residual shunting appear to be the most common long-term complications. Chest pain has been shown to be a particular concern with the atrial septal occluder device due to possible erosion of the device, and it may be applicable to the PFO devices as well. Nickel allergy due to the device metal has also been reported. It may well be that the most sensitive detector of a residual right-to-left shunt after PFO closure is transcranial Doppler, with one study noting residual shunting of 22% at one month dropping to 9% at one year using this technique.

The efficacy of the PFO occluder device has also been shown in patients with platypnea-orthodeoxia (hypoxemia upon assuming the upright position) and in those with hypoxemia due to right-to-left shunting in a variety of situations, including sleep apnea or significant pulmonary disease, high altitude pulmonary edema, following a LVAD or other cardiac surgery. It may also be useful in decompression illness in underwater divers and high-altitude aviators if the size of the right-to-left shunt is large.

Nonrandomized trials evaluating the role of PFO closure in migraine patients is intriguing, with multiple studies suggesting a reduction in the severity or frequency of migraine symptoms following percutaneous closure of a PFO. This has led some to speculate that there is either a common genetic predisposition or some hypothetical vasoactive substance that enters the arterial system that would otherwise be deactivated by the pulmonary circulation. One review even suggests that closure of the PFO may reduce or eliminate migraine headaches in up to 75% of patients, especially if the migraines are associated with auras. Recently the results of MIST I (Migraine Intervention with STARflex Technology) were presented at the ACC 2006 meeting. This is a British trial in migraine patients who have undergone randomization to either the STARflex PFO occluder or to a sham procedure in the cardiac catheterization laboratory. The results suggested a 37% reduction in “migraine burden” — a product of the number of migraines headaches x headache length in hours. The results were encouraging enough to proceed to a U.S.-based MIST II trial that will begin in 2006, hoping to enroll 600 patients to the device vs. the sham procedure. MIST III is a planned extension of the original MIST I patients, offering those who received sham procedures to undergo PFO closure.

Conclusions

We would tend to agree with a recent editorial wherein percutaneous PFO closure was recommended in younger stroke survivors with no apparent source of emboli or evidence for hypercoagulability whenever cerebral ischemia occurs on medical therapy or if a contraindication to anticoagulant therapy exists. That is probably the best posture to take at this time until the results of properly designed randomized trials are reported.

Thomas M. Bashore, MD, is a professor of medicine at Duke University Medical Center. He is section editor of Cardiology Today’s Valvular and Congenital Heart Disease section. Melvin D. Cheitlin, MD, is a professor of medicine at the University of California San Francisco. He is on Cardiology Today’s Valvular and Congenital Heart Disease section.

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