Patent foramen ovale: A new disease?

International Journal of Cardiology 122 (2007) 1 – 9 www.elsevier.com/locate/ijcard

Review

Patent foramen ovale: A new disease? Abdenasser Drighil ⁎, Hanane El Mosalami, Nadia Elbadaoui, Said Chraibi, Ahmed Bennis Ibn Rochd Hospital, Division of Cardiology, Quartier des Hopitaux 20200, Casablanca, Morocco Received 21 February 2006; received in revised form 12 August 2006; accepted 30 December 2006 Available online 28 March 2007

Abstract Patent foramen ovale is a frequent remnant of the fetal circulation. Affecting approximately 25% of the adult population. Its recognition, evaluation and treatment has attracted increasing interest as the importance and frequency of its implication in several pathologic processes, including ischemic stroke secondary to paradoxic embolism, the platypnea–orthodeoxia syndrome, decompression sickness (DCS) (an occupational hazard for underwater divers and high altitude aviators and astronauts) and migraine headache, has become better understood. Echocardiographic techniques have emerged as the principle means for diagnosis and assessment of PFO, in particular contrast echocardiography and transcranial Doppler. Its treatment remains controversial with a general tendency to propose a percutaneous closure among the symptomatic patients. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Patent foramen ovale; Interatrial shunt; Stroke; Migraine; Decompression sickness

1. Introduction

2. Clinical significance

Patent foramen ovale (PFO) is known since the time of Galien. It has been described at first in 1564 by Leonardi Botali. Its clinical significance remained poorly understood during numerous decades. Before the advent of echocardiography, the clinical diagnosis of the paradoxical embolism through the PFO was problematic and limited to some cases [1]. During the last fifteen years, the noninvasive detection of the right-to-left shunt (RLS) by contrast echocardiography, has been followed by many studies which have confirmed the implication of the PFO in several pathologic processes as the ischemic stroke by paradoxical embolism [2,3], the decompression sickness [4] (underwater divers, high altitude aviators and astronauts), the migraine [5], and platypnea– orthodeoxia syndrome [6]… etc. However, the majority of individuals with PFO will never present any complications [7]. This paper reviews current knowledge of this interesting lesion with particular emphasis on the clinical impact of PFO in a number of diseases.

The PFO occurs in about a quarter of the adult population. It's a residual, oblique, slit-shaped defect resembling a tunnel, which normally is closed by fibrous adhesions between the septum primum and secundum during the first months of life. It functions as a valve-like structure with the “door-jam” on the left atrium (LA) side of the atrial septum. Normally, there is a modest pressure gradient across the interatrial septum with left atrial pressure slightly higher than right atrial pressure. With conditions that determine an increase in pulmonary pressure (cough, Valsalva maneuver, sexual intercourse), this gradient is transiently reversed (i.e., right atrial pressure exceeds left atrial pressure) and when a PFO is present, there can be reversal of flow across the defect with a resultant right-to-left shunt (Figs. 1 and 2).

⁎ Corresponding author. Tel.: +21 264 237566. E-mail address: [email protected] (A. Drighil). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.12.028

2.1. Association with congenital heart disease The PFO is associated with several anatomic anomalies. A common association is the Ebstein's anomaly. It is probably in relation with the distension of the RA caused by the tricuspid regurgitation [8]. In pulmonary stenosis, the communication is assured in several cases by PFO [9]. And in

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In recent years, several publications have recognized the PFO as responsible for cerebrovascular accidents such as ischemic stroke [10], transient ischemic attacks [11], attack recurrence [12,13] and brain abscess [14–16]. But the relationship between paradoxical (right-to-left) embolism through a patent foramen ovale (PFO) and stroke remains still controversial because of the variability in reported stroke risk from PFO [3,7,17,18]. Also the evaluation of the role of

a PFO in patients with a neurologic event is complex because it may either be an innocent bystander or could be the etiologic mechanism involved in paradoxical embolus, especially in patients younger than 55 years [19]. The clinical diagnosis of paradoxical embolism is presumptive and based on: 1) the absence of a left-sided thromboembolic source; 2) a right-to-left shunt and 3) optionally the detection of thrombus in the venous system or right heart chambers. In subjects with ischemic stroke, prevalence of PFO is approximately 40–54% [10,20], reaching 47–77% [21,22] if only patients with cryptogenic ischemic stroke are studied. The mechanisms proposed as responsible for cerebrovascular accidents are: (1) paradoxical embolism, with passage of thrombi from the peripheral venous system to the left cardiac cavities through a septal defect after a Valsalva maneuver. (2) Thrombi formation in the atria as a consequence of possible atrial arrhythmias often associated with PFO [23]. (3) Thrombi formation within the tunnel of PFO secondary to blood stasis inside the tunnel [24]. (4) Hypercoagulable states often associated with PFO [25]. Atrial septal aneurysm (ASA) is another anomaly that is commonly associated with PFO (in 50% to 89% of cases) [26,27]. ASA consists of a congenital redundant atrial septal tissue at the region of the fossa ovalis bulging into the right or left atrium during respiration (Fig. 3). There is variation in the anatomical definition, but in general, the basal width of an atrial septal aneurysm should be more than 15 mm and the excursion of the aneurysm beyond the plane of the residual atrial septum should be at least 10 or 15 mm [28]. The prevalence of ASA in the general population ranges from 1% in autopsy [26] to 2.2% in transesophageal echocardiographic (TEE) series [27,29]. ASA is considered to harbor an increased risk for stroke and transient attack reccurence [30,31]. Pathological studies have emphasized the association between an ASA and stroke in up to 40% of cases [32], and patients with both ASA and PFO constitute a high-risk population with a three- to five-fold increased risk for recurrent events compared to patients with PFO alone [19]. Cabanes and associates [33], in a prospective study on a

Fig. 2. Longitudinal transesophageal echocardiographic imaging with color Doppler in the midupper esophagus at 45° showing a PFO.

Fig. 3. Transesophageal echocardiogram. Bicaval view of the interatrial septum showing an atrial septal aneurysm (ASA) involving the entire atrial septum bulging toward the right atrium (RA).

Fig. 1. Schematic representation of interatrial septum. After birth, there is functional closure of foramen ovale because left atrial (LA) pressure exceeds right atrial (RA) pressure (left). Usually a permanent seal develops. In patients with a patent foramen ovale, the seal does not fully develop, allowing blood to flow from RA to LA if RA pressure rises such as seen with Valsalva. LV, left ventricle; RV, right ventricle.

tricuspid atresia, PFO permits the passage of blood from right atrium to left atrium and left ventricle in 75% of cases [10]. A high left atrial pressure observed in mitral stenosis, mitral regurgitation, patent ductus arteriosus (PDA)… causes a dilation of PFO responsible for a left-to-right shunt. In tricuspid stenosis, right ventricle hypoplasia, pulmonary arterial hypertension, and developed Chiari network in the RA, the increase in right atrial pressure may facilitate the opening of the virtual interatrial valve and thus promoting shunting of blood to the left heart chambers which in turn might contribute to further desaturation of arterial blood. 2.2. PFO and cerebrovascular accident

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consecutive series of 100 patients less than 55 years of age found that both ASA (OR 4.3 — 95%; CI 1.3–14.6) and PFO (OR 3.9 — 95%; CI 1.5–10) were independently associated with the diagnosis of cryptogenic stroke, but the stroke odds of a patient with both abnormalities was 33.3 times (95% CI, 4.1–270) the stroke odds of a patient with neither of these cardiac disorders. ASA may act as facilitator for paradoxical embolism via the following mechanisms: 1) it may increase the PFO diameter due to the highly mobile atrial septal tissue, leading to a more frequent and wider opening of an otherwise small channel [34,35]; 2) it may promote right-to-left shunting by redirecting flow from the inferior vena cava toward the PFO [36]; 3) and it has been considered a nidus for local thrombus formation with subsequent embolization [26]. However the most important mechanism remains paradoxical embolism via the right-toleft shunting [37]. The repeatedly confirmed association of PFO with cryptogenic stroke [10,11,21,33,38,39] has prompted a neverending debate on which characteristics of the PFO are to be considered critical for stroke occurrence. This has been partly caused by the great variability of results in those studies that have attempted to define the risk of stroke recurrence in patients with cryptogenic stroke and PFO. The reported annual recurrence rate in patients with patent foramen ovale and cryptogenic stroke ranges from 3.8% to 16%, indicating the need for prevention [40,13]. 2.3. PFO and migraine An interesting and relatively recent finding has been the relationship between PFO and migraine headaches especially in patients with migraine and aura (MHA) [41]. The prevalence of MHA in the general population is 12% [42,43], but was 3.5 times higher (42%) in patients with interatrial communications in the survey of Azarbal et al. [44]. A further study examined the relationship between PFO and migraine with or without aura [41]: Patent foramen ovale prevalence was 48% in migraine patients, 23% in those without aura, and 20% in controls. A recent study [45] demonstrated transcatheter closure of PFO caused complete resolution or marked reduction in migraine frequency. In this study, 162 consecutive patients with paradoxic cerebral embolism undergoing transcatheter PFO closure were investigated. Complete migraine resolution occurred in 56% of patients, and 14% of patients reported a significant (N 50%) reduction in migraine frequency. But, the association between closure of interatrial communication and improvement of headache appears to be stronger with migraine and aura than with migraine without aura (75% of patients with migraine and aura had complete resolution of their headache after successful closure of the interatrial communication versus 31% of patients with migraine headache without aura). Several hypotheses have been proposed for the etiology of MHA. It has been postulated that a MHA is due to a small venous embolus that crosses the PFO paradoxically and

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passes to the cerebral circulation. Rather than inducing a stroke, the small embolus or platelet plug precipitates a spreading wave of depolarization that is recognized as the neurologic phenomenon of migraine. In favor of this hypothesis, the survey of Kruit [46] that had shown an impact 13.7 times more elevated of cerebral lesions to the magnetic resonance among the patients having a migraine with aura in relation to the witnesses. Another mechanism involved in migraine proposed by Sandler [47] is the possible role of lungs by releasing substances (circulating platelets, amines and other chemicals) that trigger attacks: migraine is precipitated in susceptible individuals by chemical substances that can pass directly through the atrial shunt before they can be detoxified in their first passage through the lungs. This substance, in elevated concentration, could cause migraine in susceptible individuals without a PFO, but if a PFO is present it could potentially shunt from the venous to the arterial system and reach the brain in a more concentrated packet than if a central shunt were not present [48]. Migraine is a risk factor for cryptogenic stroke, particularly in young patients without atherosclerosis risk factors [49]. The “migraine stroke” is probably not caused by intense vasospasm, but may be a manifestation of a paradoxical embolism through a PFO. In fact, the prevalence of subclinical lesions in the cerebellum in patients with migraine and aura, particularly women, is up to 15-fold higher than controls [46]. These findings suggest that the association of RLS with MHA is not merely coincidental but may play a crucial role in triggering the aura and ultimately leading to stroke in some as yet undetermined circumstances. Wilmshurst and Nightingale showed that migraine with aura occurred significantly more frequently in individuals who had a large shunt which was present at rest (38 of 80; 47.5%) compared with those who had a shunt which was smaller or only seen after a Valsalva maneuver (four of 40; 10%) or those with no shunt (11 of 80; 13.8%; P b 0.001 [50]. However, before PFO closure can be proposed, especially for severe migraine, a healthy scepticism should be in place, considering the high frequency of both migraine and PFO in the general population. It will be necessary to obtain definitive evidence with randomized controlled trials and to define the appropriate clinical indications [51]. 2.4. PFO and decompression sickness (DCS) Already in 1986, Wilmshurst and associates suggested that DCS may be relevant for paradoxical gas embolism among scuba divers [52]. A number of subsequent case — control studies have consistently confirmed that in divers with undeserved cerebral DS the prevalence of PFO is exceedingly high [53–56] and several reports have demonstrated the potential of PFO at rest in determining DCS in scuba divers through a paradoxic shunt of gases from venous to arterial circulation with multiple hyperintense lesions of the subcortical white matter [53,57]. Despite initial dispute,

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there is now robust evidence to claim that patency of foramen ovale increases the risk of developing DS by 2.5 to 4.5 times [58,59]. Patients with PFO-related DS tend to have early occurrence of symptoms after surfacing and a clinical presentation that indicates brain or upper cervical spinal cord involvement [55,48]. Therefore, in divers in whom cerebral symptoms occur early after surfacing, a systematic search for RLS seems warranted. Some concern on safety of scuba diving has been recently raised by neuroradiological studies that disclosed brain lesions significantly more frequently in asymptomatic divers as compared with non-diving subjects, particularly in divers with PFO [60–62]. PFO is supposed to increase the risk of DCS by the formation of bubbles in body fluids as ambient pressure is reduced. Arterial gas embolism is usually due to air emboli arising from pulmonary barotrauma or from bubbles in the systemic venous circulation entering the arterial system [63]. This category [64,48,65,66] applies to a small number of patients (about 2.3/10 000 divers)[58] but has substantial implications not only for career professionals but also recreational divers and may also apply to high altitude test pilots. Prospective studies are still needed to assess whether RLS is to be considered a contraindication to scuba diving. Divers with symptoms of decompression illness or ischemic brain lesions should be advised to abstain from diving. A preventive role of PFO closure in such individuals is intriguing but not yet defined. In asymptomatic divers, the presence of PFO at rest, when associated with high membrane mobility and wide patency diameter, represents a risk condition [67]. In this case, the diver must be strongly advised of the risk in continuing scuba practice, regardless of the presence of a previous DS event, and he/she should consider percutaneous transcatheter closure of the PFO to allow safer scuba activity. On another hand, the finding by Torti et al. [68] that a small PFO behaves like no PFO regarding the frequency of serious DS renders the recommendation, in this case, less strict for refraining from diving. 2.5. PFO and obstructive sleep apnea Obstructive sleep apnea (OSAS) is not a rare condition in the general population; its prevalence ranges from 0.3 to 8.5% [69,70]. The prevalence of PFO in OSAS is significantly higher when compared with the control group, Shanoudy et al. [71] found an increased prevalence of PFO in subjects with OSAS (69% vs. 17% in the control group). The observed trend towards a higher prevalence of PFO in subjects with OSAS compared with the control group could be explained by the enhanced effort on the right side of the heart due to transient but frequent elevations of right-sided pressure during apnea [72,73] which could cause the reopening of a previously closed foramen ovale [74]. In subjects with OSAS a higher risk for cerebrovascular disease compared to the normal population is well documented [75,76]. Previous studies, however, correlated the high prevalence of stroke in OSAS only with factors unre-

lated to the presence of PFO, especially hematological features [77]. The common final pathway of these features consists in the increase of whole blood viscosity [78]. These hematological alterations give rise to the reactive polycythemia in subjects with OSAS, increasing the likelihood of microemboli. Therefore, the presence of a PFO could increase the likelihood of microembolic passages during nocturnal sleep with obstructive apneas or other conditions similar to the Valsalva maneuver. 2.6. FOP and pulmonary embolism The frequency of PFO was 35% in patients with major pulmonary embolism in a prospective case series of 139 patients [79]. The detection of a PFO among the patients having a major pulmonary embolism with a right-to-left shunt showed to be an independent risk factor for mortality (odds ratio 11) and complicated in-hospital course (odds ratio 5) [79]. This has been related to the PFO mediated right-to-left shunt in the presence of elevated pulmonary artery pressures predisposing to arterial hypoxemia and paradoxical embolism. Aggressive treatment of the underlying disease (thrombolysis or embolectomy) and prevention of PFO-mediated right-to-left shunt are therefore important considerations in the management of these patients. Percutaneous PFO closure should be considered the treatment of choice under these circumstances [79]. 2.7. PFO and platypnea–orthodeoxia syndrome The platypnea–orthodeoxia syndrome (POS) is a rare syndrome of postural hypoxemia accompanied by breathlessness. It describes both dyspnea (platypnea) and arterial desaturation in the upright position with improvement in the supine position (orthodeoxia) [80,81]. The precise cause of the syndrome is unclear but patients develop right-to-left intracardiac shunting in the presence of normal right-sided cardiac pressures [82]. Most typically POS develops after pneumonectomy usually the right lung [83,84]. Anatomic distortions brought about by surgical manipulation have been postulated as the mechanism of disease in these cases. These distortions may result in a change of the anatomic relation of the fossa ovalis and the inferior vena cava (IVC) orifice. When the patient assumes a standing position, IVC blood flow may become aligned to flow through the PFO and into the left atrium. The diagnosis of a PFO with platypnea–orthodeoxia is made with a tilt table and saline contrast transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE). The definitive treatment for platypnea–orthodeoxia is closure of the atrial shunt [85]. 2.8. PFO and surgery Venous air embolism has been reported to occur in 23– 45% of patients undergoing neurosurgical procedures in the

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sitting position, which places the brain at risk for paradoxical air embolism in cases of PFO. A recent study reported an incidence of intraoperative venous air embolism of 33% in cases of cervical foraminotomy and of 75% in posterior fossa surgery as detected by contrast enhanced TEE [86]. Should these figures be confirmed, routine preoperative screening for a PFO would appear justified. 3. Diagnosis of a PFO Echocardiographic techniques have emerged as the principle means for diagnosis and assessment of PFO. PFO detection can be augmented by echocardiography with agitated peripheral saline contrast injection. Criteria for PFO diagnosis include contrast found in the LA within three cardiac cycles after RA opacification and detection of ≥ 5 bubbles in the LA (Fig. 4). Recently, a multicenter study by Daniëls et al. [87] demonstrates that transthoracic echocardiography with second harmonic imaging (TTE SH) in combination with an agitated saline injection can detect a right-to-left shunt as accurate as TEE. The advantage of TTE SH over TEE was explained by the difficulty patients had in performing the Valsalva maneuver due to the presence of an endoscope, and then TTE SH is much easier, cheaper and less invasive technique to detect a PFO. A methodologic study [88] (n = 70) in patients with arterial embolism compared antecubital vein to femoral vein contrast injection. These data revealed that cough or the Valsalva maneuver increase the sensitivity of TEE to PFO detection and that contrast injections via the femoral vein approach are superior to the antecubital route. A false–negative or false–positive TEE for PFO may occur. A false–negative TEE may result from inadequate visualization within the esophagus, elevated LA pressures preventing right-to-left passage of contrast [89], IVC directed flow along the IAS preventing impingement of antecubital bubbles against the IAS [88] or an improperly performed Valsalva maneuver. A TEE false–positive contrast

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study may occur with a true ASD or a pulmonary arteriovenous shunt (PAVS). Contrast that has a delayed appearance (N 3 cardiac cycles) within the LA after opacification of the RA may result from a PAVS in which contrast may also be observed traversing one or more pulmonary veins (PVs) [90]. Transcranial Doppler is comparable to contrast TEE for detecting PFO-related right-to-left shunts (type A, class II evidence) [91], and is easy to perform at the bedside. It has been used for PFO diagnosis by detection of air microemboli in a middle cerebral artery after peripheral injection of agitated saline. In experienced hands, the sensitivity and specificity of transcranial contrast Doppler ultrasound approaches that of transesophageal echocardiography, and the quantification of right-to-left shunt using provocative maneuvers may be more easily accomplished. Heckman et al. [92] compared TCD with TEE for PFO detection (n = 45). Transesophageal echocardiography detected PFO in 24/45 subjects (sensitivity = 92.3%). TCD was positive in only 22 of 45 subjects (sensitivity = 85.5%). However, four positive TEEdetected PFOs were negative by TCD, a second TCD was performed and has detected the PFO. An additional two positive TCD were not detected by TEE, and then a second TEE was performed and identified PFO. This data revealed that the association of the TCD and TEE is most sensitively for PFO detection than the use of one technique. However, echocardiography allows for sizing of the separation between septum primum and secundum, enables the definition of anatomic boundaries, the association with ASA and the demonstration of a right-to-left shunt by either color flow mapping or contrast bubble injection. In addition, it allows for reliable exclusion of other potential cardiac sources of embolism. TCD has recently been augmented by power Mmode, a new technology allowing power display with Doppler velocity and frequency signals over selectable depth ranges along the transducer beam [93]. Transcranial Doppler M-mode enhances sensitivity to contrast bubble emboli over single-gated TCD examination [94]. 4. PFO treatment Treatment options vary and include a medical option (antiplatelet agents: acetylsalicyclic acid, clopidogrel; anticoagulants: warfarin) or invasive methods (surgical option in the past and transcatheter device closure in recent years). No therapy has been evaluated conclusively to date and the choice of any option should be balanced with its risk. 4.1. Medical therapy

Fig. 4. Transesophageal echocardiogram showing a dense echo contrast inside the right atrium (RA) revealing a small PFO with more than 5 bubbles in the left atrium (LA).

The goals in medical therapy are to prevent reoccurrence of an event once a sentinel event has already occurred or prevent an initial occurrence of an event. Evaluation of the results of medical therapy is complicated for several reasons: 1) The most important is the strength of causation between the PFO and the central

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The role of the other antiplatelet agents like the clopidogrel owes to the future to be specified. 4.2. Percutaneous transcatheter closure

Fig. 5. (A) View of a deployed implant for closure of patent foramen ovale. (B) Transesophageal echocardiography of atrial chambers. Complete juxtaposition of both disks of the implant in both sides of the interatrial septum.

nervous system event. If the central nervous system event is from another cause such as atheromatous ascending aortic debris, then medical therapy or closure of a PFO surgically or percutaneously will obviously not be effective. 2) The specific anatomic pathology involved, e.g., the presence of a PFO versus an ASA versus the combination; in addition to this is the size of the PFO and shunting at rest. 3) The specific medical therapy used, e.g., aspirin versus warfarin. These issues have made assessment of the results of medical therapy difficult. Mas et al. [12] examined PFO treated with aspirin (300 mg/day) for secondary prevention of stroke or TIA among young patients after a single first event. At four years, aspirin therapy did not improve the frequency of recurrent cerebrovascular events for high-risk patients, such as those with septal abnormalities. The role of aspirin at a dose of 325 mg per day versus warfarin in patients with stroke was studied in the randomized Warfarin–Aspirin Recurrent Stroke Study of 2206 patients with prior stroke [95]. Patients were randomized to aspirin (325 mg/day) or warfarin (target INR 1.4 to 2.8). After two years, there were no significant differences between aspirin and warfarin treatment for recurrent stroke or death. In a substudy of this trial – PFO and Cryptogenic Stroke Study (PICSS) – 630 patients were enrolled [95]. In these 630 patients, 365 had a stroke of known cause, whereas in 265 the stroke was cryptogenic. In patients with cryptogenic stroke and PFO, the 2-year event rate was 16.7% in patients treated with warfarin versus 23.2% in those treated with aspirin. These 2 studies represent 2 extremes in outcome of treatment. The absolute event rates are considerably higher in PICSS [13] compared with the study by Mas et al. [12] This may be the result of the inclusion of older patients in the former (57.9 years) versus the latter (40.3 years). It is, therefore, possible that in PICSS, the PFO was a bystander and some of the initial or subsequent events were the result of another origin. Obviously, this subject has important implications for closure of a PFO; it has led some investigators to conclude that a PFO should only be closed if the patient has recurrent events on medical therapy whereas others have recommended closure in patients with an initial event without requiring failure of medical therapy [96].

The goals of PFO closure are to prevent neurologic events and to avoid the need for long-term anticoagulant therapy. Percutaneous PFO closure was initially advocated for prevention of recurrent stroke in 1992 [97]. It is a catheter-based technique using atrial septal occlusion devices (Fig. 5). The advantage is the option to stop any medical treatment about 6 months after a successful closure and with the claimed low risk of the procedure (b 1%) there are physicians who advocate its use without further studies [98]. Windecker et al. [99] in a retrospective study have compared 150 patients who underwent endovascular closure to 158 patients who received medical treatment alone. After 4 years of follow-up, percutaneous PFO closure was as effective as medical treatment for prevention of recurrent cerebrovascular events in cryptogenic stroke patients with PFO. It was more effective than medical treatment in patients with complete closure and more than one cerebrovascular event at baseline. Many other studies report that transcatheter PFO closure is safe and effective, with efficacy ranging from 86% to 100% [100,101]. In patients with PFO + ASA, Wahl et al. [37] demonstrated that compared to the treatment of PFO alone the transcatheter treatment of ASA + PFO: (1) was safe and long-term efficacious; (2) procedural success and complications were similar; (3) the additional presence of ASA did not adversely affect elimination of right-to-left shunt; and (4) the long-term risk of recurrent events after the transcatheter treatment was comparable. Recurrent neurologic and peripheral embolic events, after transcatheter treatment of PFO, are reported as 0% to 3.8% per year, possibly reflecting incomplete closure [102] or thrombus formation around the device. However, Krumsdorf et al. [103] have found that the incidence of thrombus on closure devices was low (2.5%), most of the thrombi (14 out of 20) were detected at the four-week TEE study, and that atrial fibrillation and persistent ASA after transcatheter closure are the significant risk factors for thrombus formation. In most of their patients the thrombus resolved under medical therapy without clinical consequences.

Table 1 Criteria for eligibility for interventional PFO closure (1–4 required) 1. Recurrent ischemic stroke with antiplatelet agents. 2. Age under 60 years and absence of overt atherosclerotic disease or more than one atherosclerotic risk factor. 3. Exclusion of other cardiac (atrial fibrillation, endocarditis, tumour) or vascular (carotid stenosis, spontaneous carotid or vertebral dissection, aortic atheromatosis) embolic sources. 4. PFO with high anatomic risk: important inducible shunting and large PFO, spontaneous right-to-left shunt at rest, long tunnel, ASA, Eustachan valve. 5. Contraindications against or unwillingness to undergo anticoagulation.

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There are two major groups of procedural complications: (1) those related to the transeptal technique; and (2) those related to device performance. Both groups of complications are uncommon in experienced centers when the procedure is performed by experienced operators. Complications of the transeptal technique can include perforation, which may result in tamponade, supraventricular arrhythmias from manipulation within the atria, embolization of air or thrombus, and venous access site problems. Device-related problems include, prominently, the potential for air embolism. These devices are large and can trap air either during device advancement through the sheath or if the device has air within its structure. Another complication is the potential for device embolization. This may occur if there is premature release of the device before fixation. It may also occur if the device is not optimally sized, placed, or fixed, leading to embolization into either the pulmonary or systemic circulation depending on the specific situation. A final device problem is that of persistent shunt across the PFO which was considered as the only factor of recurrence of neurologic events [37]. The devices used may take several months to endothelialize, as the surface area is large. Accordingly, during the first 3 months, adjunctive therapy with warfarin and aspirin is common. After that time, if there is no residual shunt, both medications can be discontinued, particularly the warfarin. In some institutions, however, aspirin and Copidogrel are used instead or even aspirin alone. Aspirin is continued indefinitely. Subacute bacterial endocarditis prophylaxis is recommended for approximately 6 months, and then is usually not routinely used [96]. In the absence of strict criteria identifying patients eligible for interventional PFO closure, some criteria based on recent literature [37,99,27,104] indicates patients to high risk of embolic events who have to undergo a closing of PFO (Table 1). 4.3. Surgical PFO closure In the age of excellent percutaneous PFO closure methods and results, surgical closure has become rare. It consists of direct suture closure by open thoracotomy. Several studies [105,106] have demonstrated that the right lateral minithoracotomy is as effective as percutaneous approach. The major inconvenience of this method is the invasive character and the elevated complication rate [105]. 5. Conclusion Patent foramen ovale is emerging as a “new disease” by its implication in a number of stroke and non-stroke conditions, either as causative factor or as associated condition predisposing to complications. However, it should be stated that the majority of individuals with PFO will never present any complications. The challenge that remains is to determine which PFOs and clinical contexts confer an increased risk of significant disease. Optimal technology development

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will require understanding the PFO at histologic, cellular, and tissue levels. The type and duration of medical therapy needs further evaluation, especially in high recurrence subsets. Multiple novel and exciting technologies are emerging for treating PFO percutaneously that promise rapid, safe, and effective PFO treatment. References [1] Thompson T, Evans N. Paradoxical embolism. Q J Med 1930;23:135–50. [2] Hausmann D, Mugge A, Becht I, Daniel WG. Diagnosis of patent foramen ovale by transoesophageal echocardiography and association with cerebral and peripheral emboli events. Am J Cardiol 1992;70: 668–72. [3] Ranoux D, Cohen A, Cabanes L, et al. Patent foramen ovale: is stroke due to paradoxical embolism? Stroke 1993;24:31–4. [4] Gallagher DL, Hopkins EN, Clark JB, Hawli TA. US navy experience with type II decompression sickness and the association with patent foramen ovale. Aviat Space Environ Med 1995;67:712. [5] Del Sette M, Angeli S, Leandri M, et al. Migraine with aura and rightto-left shunt on transcranial Doppler: a case-control study. Cerebrovasc Dis 1998;8:327–30. [6] Dear WE, Chen Z, Barasch E, et al. Sixty eight year old women with intermittent hypoxemia. Circulation 1995;91:2284–9. [7] Meissner I, Khandheria BK, Heit JA, et al. Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study. J Am Coll Cardiol 2006;47(2):440–5. [8] Anderson KR, Lic JT. Pathologie anatomy of the Ebstein anomaly of the heart revisited. Am J Cardiol 1978;41:739. [9] Amett EN, Aisner SC, Lewis KB, et al. Pulmonary stenosis, atrial septal defect and left to right shunt with intact ventricular septum. Chest 1980;78:759. [10] Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988;318:1148–52. [11] Di Tullio M, Sacco RL, Gopal A, Mohr GP, Homma S. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 19921;117:1–2. [12] Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001;345:1740–6. [13] Homma S, Sacco RR, Di Tullio M, Mohr JP. Effect of medical treatment in stroke patients with patent foramen ovale. Circulation 2002;105:2625–31. [14] Kawamata T, Takeshita M, Ishizuka N, Hori T. Patent foramen ovale as a possible risk factor for cryptogenic brain abscess. Report of two cases. Neurosurgery 2001;49:204–7. [15] Chotmongkol V, Kiatchoosakhun S. Brain abscess in a patient with atrial septal defect. J Med Assoc Thail Suppl 1999;82:1167–9. [16] Dethy S, Manto M, Kentos A, et al. Pet findings in a brain abscess associated with a silent atrial septal defect: case report. Clin Neurol Neurosurg 1995;97:349–53. [17] Albers GW, Comess KA, DeRook FA, et al. Transesophageal echocardiographic findings in stroke subtypes. Stroke 1994;25:23–8. [18] Jeanrenaud X, Bogousslavsky J, Payot M, et al. Patent foramen ovale and cerebral infarct in young patients (French). Schweiz Med Wochenschr 1990;120:823–9. [19] Overall JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta analysis of case control studies. Neurology 2000;55: 1172–9. [20] Yeung M, Khan KA, Shuaib A. Transcranial Doppler ultrasonography in the detection of venous to arterial shunting in acute stroke and transient ischaemic attacks. J Neurol Neurosurg Psychiatry 1996;61: 445–9. [21] Webster MW, Chancellor AM, Smith HJ, et al. Patent foramen ovale in young stroke patients. Lancet 1988;2:11–2.

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