Paradoxical Embolism: Role of Imaging in Diagnosis and Treatment

Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights. Paradoxical Embolism: Role of Imaging in Diagnosis and Treatment Planning 1 Farhood Saremi, MD Neelmini Emmanuel, MD Philip F. Wu, BS Lauren Ihde, MD David Shavelle, MD John L. Go, MD Damián Sánchez-Quintana, MD, PhD Abbreviations: DVT = deep venous thrombosis, IVC = inferior vena cava, PDE = paradoxical embolism, PFO = patent foramen ovale RadioGraphics 2014; 34:1571 1592 Published online 10.1148/rg.346135008 Content Codes: 1 From the Departments of Radiology (F.S., N.E., P.F.W., L.I., J.L.G.) and Cardiovascular Medicine (D.S.), University of Southern California, USC University Hospital, 1500 San Pablo St, Los Angeles, CA 90033; and Department of Human Anatomy, University of Extremadura, Badajoz, Spain (D.S.Q.). Recipient of a Certificate of Merit award for an education exhibit at the 2012 RSNA Annual Meeting. Received January 3, 2013; revision requested April 4 and received July 13; accepted July 19. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships. Address correspondence to F.S. (e-mail: fsaremi@usc.edu). SA-CME LEARNING OBJECTIVES After completing this journal-based SA- CME activity, participants will be able to: Describe the causes of PDE and sequelae in target organs. Discuss the specific uses of various imaging modalities in the diagnosis of PDE. Recognize CT and MR imaging features that are pertinent for the diagnosis of PDE and for posttreatment evaluation. See www.rsna.org/education/search/rg. 1571 Paradoxical embolism (PDE) is an uncommon cause of acute arterial occlusion that may have catastrophic sequelae. The possibility of its presence should be considered in all patients with an arterial embolus in the absence of a cardiac or proximal arterial source. Despite advancements in radiologic imaging technology, the use of various complementary modalities is usually necessary to exclude other possibilities from the differential diagnosis and achieve an accurate imaging-based diagnosis of PDE. In current practice, the imaging workup of a patient with symptoms of PDE usually starts with computed tomography (CT) and magnetic resonance (MR) imaging to identify the cause of the symptoms and any thromboembolic complications in target organs (eg, stroke, peripheral arterial occlusion, or visceral organ ischemia). Additional imaging studies with modalities such as peripheral venous Doppler ultrasonography (US), transcranial Doppler US, echocardiography, and CT or MR imaging are required to detect peripheral and central sources of embolism, identify cardiac and/ or extracardiac shunts, and determine whether arterial disease is present. To guide radiologists in selecting the optimal modalities for use in various diagnostic settings, the article provides detailed information about the imaging of PDE, with numerous radiologic and pathologic images illustrating the wide variety of features that may accompany and contribute to the pathologic process. The roles of CT and MR imaging in the diagnosis and exclusion of PDE are described, and the use of imaging for planning surgical treatment and interventional procedures is discussed. RSNA, 2014 radiographics.rsna.org Introduction Paradoxical embolism (PDE) is usually definitively diagnosed at autopsy or at radiologic imaging when a thrombus that crosses an intracardiac defect is seen in the setting of arterial embolic damage in end organs (eg, stroke). Imaging evaluation of patients in whom the presence of PDE is suspected usually necessitates the use of more than one modality. Peripheral Doppler ultrasonography (US) and echocardiography are well-established methods for assessing thromboembolic processes. Although echocardiography is the prime modality for depicting a shunt across a patent foramen ovale (PFO), no single modality can cover the whole spectrum of findings in the imaging workup of PDE. PARADOXICAL EMBOLISM

1572 October Special Issue 2014 radiographics.rsna.org The article outlines the optimal imaging approach in various clinical settings and the value contributed by each imaging modality for accurate diagnosis of PDE. The current roles of computed tomography (CT) and magnetic resonance (MR) imaging in identifying cardiac and extracardiac abnormalities known to contribute to the development of PDE and detecting sequelae in target organs are emphasized, and the utility of supplemental US studies is reviewed. Strategies for treating PDE, including interventional techniques, also are described. Historical Background and Definitions In 1877, Cohnheim (1) reported the first case of PDE by describing the path of an embolus through a septal defect in the heart. In 1881, Zahn (2) reported an autopsy study in which thrombosis of the uterine vein, multiple systemic emboli, and a branched thrombus within a PFO were seen in the same cadaver. Later, in 1885, he used the term paradoxical embolism to describe a condition in which emboli derived from the venous system reached the systemic arterial system through an abnormal communication between the heart chambers (3). Four essential elements contribute to the development of PDE: systemic embolism, an embolic source, a right-to-left shunt, and a pressure gradient across the shunt (Table 1) (3 6). The diagnosis of PDE is considered definitive when it is based on a finding at autopsy or at imaging of a thrombus that crosses an intracardiac defect in the setting of an arterial embolus (4). A diagnosis of PDE in the absence of these findings is considered presumptive (4,6). The triad of systemic embolism, venous thrombosis, and intracardiac communication defines the clinical diagnosis of PDE and allows treatment with a high level of confidence (7,8). The diagnosis of PDE is termed possible if an arterial embolus and PFO are detected; many physicians treat patients on the basis of a diagnosis of possible PDE (9). Most early case reports of paradoxical embolus were based on autopsy findings (4). Later, an intracardiac right-to-left shunt was demonstrated in a living patient when dye injected into the inferior vena cava (IVC) appeared earlier than expected at the left brachial artery (6). Limited catheterization of the right side of the heart was proposed as a method for excluding an intracardiac shunt in patients with coexistent venous thrombosis or pulmonary embolism and arterial embolism. In current practice, the imaging workup of a patient for PDE usually starts with CT and MR imaging. These modalities are used to diagnose thromboembolic sequelae of arterial embolism in Table 1: Essential Elements of PDE Systemic embolism confirmed by clinical, angiographic, or pathologic findings without an apparent source on the left side of the heart or in the proximal arterial tree (ascending aorta) Embolic source within the venous system Abnormal intracardiac or intrapulmonary communication between the right and left circulations Pressure gradient that promotes a right-to-left shunt at some point during the cardiac cycle target organs. Additional imaging studies, including peripheral venous Doppler US, transcranial Doppler US, echocardiography, and CT, are used to detect peripheral and central sources of embolism, arterial disease, and cardiac or extracardiac shunts. Further diagnostic testing often includes continuous long-term electrocardiographic recordings, blood chemistry panels, and coagulation tests. Types of Embolism Thrombi from tributaries of the IVC are the major sources of embolism, but emboli of fat, air, amniotic fluid, and tumor tissue have also been described (10 15). Fat embolism syndrome is primarily a pulmonary disease (10). Shunting of fat or other material across a PFO can be precipitated by increased right atrial pressure for a variety of reasons, including changes in body position, breathing patterns, and intrathoracic pressure. Paradoxical air embolism can lead to cerebral lesions in scuba divers (11). Cerebral air embolism can occur through central venous catheters (12). Patients undergoing neurosurgery in a sitting position have a risk for paradoxical air embolism (13). In these cases, preoperative detection of PFO and additional monitoring and special care during surgery are advised. Amniotic fluid embolism can rarely be complicated by PDE resulting from increased pressure in the right side of the heart due to the release of vasoactive substances when amniotic fluid enters the pulmonary circulation (14). Imaging findings of PDE complications in the brain are probably similar for different types of embolism, and the clinical history is important for final diagnosis. Air emboli absorb quickly and are best depicted in an early stage at CT. Peripheral Sources of Venous Thromboembolism Venous thrombosis in the legs may be the most common source of embolus. Approximately 90% of symptomatic pulmonary emboli arise from thrombi located in the leg veins (8,16). In most

RG Volume 34 Number 6 Saremi et al 1573 studies, the prevalence of deep venous thrombosis (DVT) in patients with acute pulmonary embolism appears to be higher than that in patients with a cryptogenic stroke and PFO (16,17). In many cases of PDE, the source of the embolus in peripheral veins cannot be found (8). The reportedly low rate of DVT in patients with a PFO and cryptogenic stroke may be an effect of the delay between the initiation of anticoagulation therapy and the imaging evaluation, complete thrombus migration, inability to detect residual thrombus, or undetected thrombosis in a calf or pelvic vein (10%) (8,18). Another possibility is that the embolic source remains undetected in the upperextremity veins (19). Duplex US is the most common method for evaluating DVT. Most US studies of the lower extremity are limited to veins at or above the level of the popliteal veins, which may lead to underestimation of the true incidence of venous thrombosis (20). US is more accurate than venography for depicting peripheral DVT but is much less accurate for showing central (ie, pelvic) DVT (20,21). A small proportion (2% 7%) of thrombi that can be diagnosed at venography or CT venography are limited to the pelvic veins or vena cava and may therefore remain undetected at US (22). Contrast material enhanced MR venography seems to be more accurate than color Doppler US in depicting a central (toward the pelvis) extension of DVT (23). Nonenhanced balanced steady-state free precession MR venography is more accurate than US for the diagnosis of lower-extremity DVT and is capable of depicting greater central extension of the thrombus (24). Nonenhanced MR venography can be performed when intravenous administration of gadoliniumbased contrast material is contraindicated. The reported incidence of DVT associated with PFO and PDE ranges widely between different patient series (8,17,25), depending on the imaging modality used, anatomic location of the venous thrombus, time interval between the onset of symptoms and imaging, and duration of anticoagulation therapy before imaging. For example, Stöllberger et al (8) reported that DVT was found at lower-extremity venography performed within 90 days after symptom onset in 57% of patients with a PFO and arterial emboli without evident arterial or cardiac sources. By contrast, in a study by Lethen et al (17), venography depicted DVT in only 10% of patients with a PFO as the sole identifiable cardiac risk factor for PDE; most of those patients had undergone heparin therapy before venography. In a recent study of 37 patients who underwent duplex US of the lower extremity and pelvic MR venography for evaluation after a stroke, DVT was found within 3.25 days after the occurrence of a stroke in 27% of those with cryptogenic brain ischemia and an interatrial communication, half of the thrombi being isolated within a calf or pelvic vein (25). In a related multicenter study, pelvic DVT was found at MR venography performed within 3 days after the occurrence of a cryptogenic stroke in 20% of 46 patients with a PFO or atrial septal defect (26). With the use of MR venography, Kiernan et al (27) found pelvic venous thrombosis (May-Thurner syndrome) in 6.3% of patients who underwent PFO closure after a cryptogenic stroke. Eighty percent of the patients were female, and 54% of the female patients were receiving oral contraceptive therapy. Overall, the results of the preceding studies show that (a) PDE from the lower extremity and possibly the pelvis is one mechanism that accounts for ischemia related to systemic embolization in a subset of patients and (b) pelvic CT or MR imaging may be useful for determining whether pelvic DVT is present in patients in whom findings are negative for DVT of the lower extremities. Upper-extremity sources of PDE include spontaneous DVT (Paget-Schroetter syndrome) and catheter-related DVT. The occurrence of PDE as a complication of Paget-Schroetter syndrome is rare, but at least one case has been reported (28). Catheter-related thrombosis accounts for approximately 80% of cases of upperextremity DVT (29). Thrombogenesis associated with catheters has been well documented, with an incidence ranging from 2% to 67%, depending on the catheter type and location, diagnostic criteria, and population studied (29,30). The published literature about catheter-associated paradoxical thromboembolus is limited to case reports of coronary arterial, limb, or brain involvement (31,32). Sequelae of PDE in Target Organs Although PDE is an uncommon cause of acute arterial occlusion, it can have catastrophic sequelae, and the possibility that it is present should be considered in all patients with an arterial embolus in the absence of a cardiac or proximal arterial source. PDE is frequently associated with cryptogenic stroke and peripheral embolism (33) (Fig 1). Uncommon complications include brain abscess (34), decompression sickness in underwater divers (11), myocardial infarction (35), and mesenteric infarction (7). Hypoxemia due to a transient right-to-left shunt is also possible. In Loscalzo s (7) study based on findings in 30 patients, the five sites of arterial emboli

1574 October Special Issue 2014 radiographics.rsna.org Figure 1. Axial diffusion-weighted MR images demonstrate paradoxical embolic infarcts. (a) Multiple bilateral nonterritorial subcortical infarcts (light gray foci) are seen in a patient with tetralogy of Fallot and an anomalous connection of a left-sided superior vena cava with the left atrium. (b) A single territorial infarct (arrow) that originated from right subclavian venous thrombus is depicted in a patient with a PFO. (c) A large lobar infarct (light gray whitish area) is evident in the right temporoparietal region in a patient with an atrial septal defect. were peripheral (49%), cerebral (37%), coronary (9%), renal (1%), and splenic (1%). Among cases of PDE reported by Travis et al (9), the most frequent clinical manifestations were (in order of decreasing frequency) lower-extremity ischemia, upper-extremity ischemia, respiratory distress, cerebral infarction or amaurosis fugax, and abdominal and/or flank pain. Cryptogenic Stroke Ischemic strokes can be classified into two major categories: (a) those due to a known cause such as large-artery atherosclerosis, intracardiac thrombus, or small-artery occlusion and (b) those due to an undetermined cause or cryptogenic infarction (36,37). One-third of ischemic strokes are cryptogenic in origin (38). The cause of cryptogenic stroke remains undetermined in most cases because the event is transitory or reversible, investigators cannot look for all possible causes, and some causes remain unknown. The detection of a PFO in a patient with a confirmed stroke does not necessarily mean that the cause of the stroke has been identified. Establishing a causal relationship between the presence of a PFO and the occurrence of a stroke remains the crucial point in the diagnosis of PDE. The four criteria described earlier for the diagnosis of PDE may not always be met. The presence of other contributing factors, such as the morphologic characteristics of the PFO and associated structures, may increase the probability that PDE is present (37,38).

RG Volume 34 Number 6 Saremi et al 1575 Table 2: Potential Routes of PDE (Right-to-Left Shunt) Intracardiac PFO Iatrogenic connection (baffle defect, Fontan conduit, Rashkind device) Enlarged thebesian veins (ie, interatrial muscle bundle) Congenital anomaly (atrial septal defect, unroofed coronary sinus, ventricular septal defect, atrioventricular septal defect) Extracardiac Pulmonary arteriovenous malformation (congenital, secondary to cavopulmonary shunts) Systemic to pulmonary venous communication (congenital, acquired) Arterioarterial communication (patent ductus arteriosus) or venovenous communication Embolic and Nonembolic Infarcts PFO is thought to be an important causal mechanism of embolic stroke in young patients (38,39). Some investigators believe that various imaging patterns can support a diagnosis of PDE (40). Theoretically, paradoxical emboli are expected to cause brain infarcts with an imaging appearance resembling that of brain infarcts due to other (cardiac or arterial) embolic causes. At brain imaging, the occlusion of a superficial arterial branch or the presence of a large infarct involving more than one lobe is strongly suggestive of embolic infarction (40). Scattered lesions or cortical-subcortical territorial lesions also are indicative of embolic infarction (Fig 1). Multiple acute infarcts, especially those that are bilateral and affect various networks of cerebral circulation, are strong indicators of a proximal embolic source or a systemic cause, and diffusion-weighted imaging is an excellent MR imaging technique for depicting multiple small infarcts (40,41). Patients with a large PFO are more likely to demonstrate embolic infarcts after a cryptogenic stroke than are patients with a small or no PFO (42). Patients with a medium or large PFO more frequently have occipital and infratentorial (posterior circulation) strokes than do patients with a small PFO (57% versus 27%) (42,43) or patients with a history of atrial fibrillation; they also tend to have multiple infarcts (44). Cryptogenic stroke with an embolic pattern is more common when PFO and atrial septal aneurysm coexist (45). Although the presence of hemorrhagic transformation is a strong indicator of embolic infarction, published data do not demonstrate an association between PFO and hemorrhagic infarcts (42). Anatomic and Physiologic Considerations in Patients with a PFO Potential routes of PDE are classified in Table 2. Both intracardiac and extracardiac shunts can lead to PDE. However, intracardiac causes are more common; of these, most arise from the presence of a PFO. In Loscalzo s (7) series of cases with a clinical diagnosis of PDE, 72% had a PFO, and the remaining potential routes included atrial septal defect, pulmonary arteriovenous malformation, and ventricular septal defect. Some shunts, such as those produced by muscular and membranous ventricular septal defects, may be small and found incidentally at clinical and imaging examinations (Fig 2). A PFO has been known to be a common finding since 1930, when Thompson and Evans (4) identified a probe patent foramen (0.2 0.5 cm in diameter) in 29% of unselected autopsy cases and a pencil patent defect (0.6 1.0 cm in diameter) within the atrial septum in 6%. Hagen et al (46) found a PFO in 27% of 965 autopsied hearts. The prevalence of PFO and the size of the defect did not differ significantly according to sex but varied significantly with age: 34% of PFOs were found in those who had died in the first 3 decades of life; 25% of PFOs, in those who had died in the 4th to 8th decades of life; and 20% of PFOs, in those who had died in the 9th or 10th decade of life. The size of the PFOs seen in the cadavers ranged from 1 to 19 mm (mean, 4.9 mm), increasing progressively from a mean of 3.4 mm in those who had died in the 1st decade of life to 5.8 mm in those who had died in the 10th decade of life, perhaps because smaller PFOs close spontaneously with age. PFO has been implicated in the pathogenesis of many diseases (11,37). The precise frequency with which PDE complicates PFO is unknown; PDE occurs in a minority of patients with venous thromboembolic disease who also have a PFO. This is thought to be because the foramen ovale is normally closed by the higher left-toright atrial pressure gradient. Case control studies that demonstrate a higher prevalence of PFO

1576 October Special Issue 2014 radiographics.rsna.org Figure 2. Still MR images from a cine sequence depict interventricular membranous septal aneurysm and defect. LV = left ventricle. (a) Coronal view shows an aneurysm of the interventricular membranous septum (arrow). (b, c) Three-chamber views obtained during systole (b) and diastole (c) show the same aneurysm (arrow in b), along with a linear region void of signal in diastole (arrow in c). The latter finding is suggestive of a small ventricular septal defect, a potential cause of PDE. The ventricular portion of the membranous septum may become aneurysmal, usually bulging toward the right. The protruding aneurysm may limit intracardiac shunting, with resultant spontaneous closure of the ventricular septal defect. among patients with cryptogenic strokes led to the acceptance of PFO as a potential risk factor for stroke (38,39). However, whether a PFO has a direct causal role in the occurrence of stroke or whether the relationship is merely an association remains controversial. In support of a causal relationship, case reports have described direct visualization of thrombus in migration through a PFO tunnel (47) (Fig 3). The proportion of cryptogenic strokes due to PDE is believed to be around 20% (48). Obviously this proportion may vary, depending on patient age and the presence of predisposing factors (Table 3). Hemodynamic Parameters That Influence PFO-related Right-to-Left Shunt The etiology of a right-to-left shunt through a PFO despite normal intracardiac pressures and normal or near-normal pulmonary function has not yet been completely elucidated. The results of population-based studies suggest that the annual risk of cryptogenic stroke in otherwise healthy people with a PFO may be as low as 0.1% (49). This observation suggests that other factors contribute to the increased risk of stroke in people with a PFO. Diagnostic studies performed with contrast agent enhanced echocardiography while the patient performed the Valsalva maneuver demonstrated pressure-dependent shunts in 50% 60% of all patients with a detectable PFO (50). Concurrent risk factors for venous thromboembolism, such as trauma, recent surgery, use of oral contraceptives, and various hypercoagulable states, also influence the clinical relevance of a PFO. A transient spontaneous physiologic reversal of the pressure gradient between the left and right atria is present during early diastole and during isovolumetric contraction of the right ventricle during each cardiac cycle (51,52). This so-called reversal gradient may increase when the patient performs physiologic maneuvers leading to increased right atrial pressure, such as postural changes, inspiration, vigorous coughing, or the Valsalva maneuver. The reversal gra-

RG Volume 34 Number 6 Saremi et al 1577 Figure 3. Thrombus in migration through a PFO tunnel (black arrows) in a 43-year-old woman. (a) CT angiography of the chest demonstrates multiple pulmonary emboli (arrowheads). (b) The presence of a thrombus (arrow) was confirmed at transthoracic four-chamber echocardiography, which provided better depiction. LA = left atrium, RA = right atrium. Table 3: Predisposing Factors for Right-to-Left Shunt through a PFO or for Intracardiac Shunt Increased pressure in the right side of the heart Physiologic cause (eg, Valsalva maneuver, coughing) Chronic obstructive pulmonary disease Extensive pulmonary embolism Primary pulmonary hypertension Intracardiac anatomic factors Chiari network Septal aneurysm (atrial, interventricular) Large eustachian valve PFO morphologic features Short flap length Large opening Gross anatomic position Supine more than sitting dient also may be increased in the presence of a pathologic condition that results in high pulmonary vascular resistance (eg, acute pulmonary embolism, hypoxemia due to obstructive sleep apnea, severe chronic obstructive pulmonary disease, right ventricular infarction, and positive end-expiratory pressure during neurosurgical procedures performed with the patient in a sitting position) (13,51,52). Another mechanism that helps explain a transient right-to-left shunt is preferential directionality of blood flow from the IVC toward the interatrial septum (53). The IVC flow enters from the posterior of the right atrium and is directed upward and backward through the flap valve of the fossa ovalis (Fig 4). The eustachian valve plays a crucial role in deflecting the flow through the PFO. Horizontal reorientation of the plane of the interatrial septum may facilitate flow from the IVC directly into the left atrium through the PFO. This reorientation of the septum has been observed in patients with a right pneumonectomy, aortic aneurysm, or large pleural effusion (54,55). In patients with a PFO, pulmonary embolism is thought to be associated with a small but definite risk for PDE and with findings of silent brain infarcts at MR imaging (56). Patients with a PFO and hemodynamically important pulmonary embolism are more likely to experience an ischemic stroke (13% vs 2.2%), peripheral arterial embolism (15% vs 0%) (57), and arterial hypoxemia possibly due to PDE (58). Effect of PFO Morphology on Right-to-Left Shunt The functional and morphologic characteristics of a PFO are closely related. The magnitude of a shunt through a PFO depends not only on hemodynamic parameters but also on the anatomy of the PFO (Fig 5). These include the size of the opening into the right atrium, length of the PFO tunnel, and extent of excursion of the flap membrane. The magnitude of a shunt through a PFO appears to be directly related to the degree of risk for a first stroke (42). Medium to large PFOs are found more often in patients with cryptogenic

1578 October Special Issue 2014 radiographics.rsna.org Figure 4. IVC flow and the eustachian valve. (a) Shortaxis CT image shows preferential IVC flow toward the fossa ovalis (FO) and eustachian valve (EV). In the posterior half of the right atrial (RA) chamber, blood enters from the IVC, flowing upward through the flap valve of the fossa ovalis and backward through the eustachian valve. The eustachian valve plays a crucial role in deflecting blood flow toward a PFO. LA = left atrium, SVC = superior vena cava. (b) Axial CT image demonstrates a prominent eustachian valve (EV) guarding the anterior ostial margin of the IVC. RV = right ventricle. (c, d) Axial MR images acquired at end diastole (c) and systole (d) show dynamic movement of the eustachian valve (arrow) during the cardiac cycle. infarcts than in those with infarcts with a known cause (26% vs 6%) (42). Moreover, the risk of stroke appears to be increased in the presence of structures that direct flow toward a PFO (eg, a prominent eustachian valve) or hemodynamic changes that increase right-sided pressure (eg, a large pulmonary embolism) (Table 3). Homma et al (59) characterized PFOs in patients with findings of cryptogenic stroke to assess morphologic factors that might be conducive to the development of PDE. PFO size was measured as the maximum separation of the septum primum and septum secundum in millimeters. A PFO was classified as large when the separation was 2 mm or greater and small when the separation was less than 2 mm. The severity of a shunt was classified as mild, moderate, or severe on the basis of the number of microbubbles appearing in the left atrium during an agitated saline study: a mild shunt was characterized by the presence of 3 9 microbubbles; a moderate shunt, by 10 30 microbubbles; and a severe shunt, by more than 30 microbubbles. Patients with a cryptogenic stroke had a larger PFO with a more severe rightto-left interatrial shunt than did patients with a stroke of determined cause (59). PFO tunnel length is another important determinant of the presence and severity of a rightto-left shunt (60,61). In a study performed by Natanzon and Goldman (62), the magnitude of the right-to-left shunt in patients with a stroke was greater than that in control subjects, but no significant difference was found between the two groups with regard to entry zone diameter (mean ± standard deviation, 2.5 mm ± 2.0 vs 1.9 mm ± 1.6 for patients vs control subjects). This finding led Natanzon and Goldman to speculate about whether other measures could also affect the presence and magnitude of a shunt through a PFO. They reported a shorter flap length in patients with a

RG Volume 34 Number 6 Saremi et al 1579 Figure 5. CT angiography demonstrates components of the interatrial septum in three different patients. Magnified view for each case is presented in the right column. (a, b) Four-chamber views show a small fossa ovalis (FO) with fatty infiltration of the interatrial groove and the atrioventricular sandwich (AVS). IVS = interventricular septum, mav = muscular atrioventricular septum, MV = mitral valve, P = posterior margin of the fossa ovalis, RA = right atrium, SI = septal isthmus, STV = septal leaflet of the tricuspid valve. (c f) Short-axis images show a PFO (c, d) and a large fossa ovalis (FO) with a short interatrial groove (e, f). The septum secundum forms the interatrial groove, which covers the superior (S), posterior, and inferior (I) margins of the fossa ovalis. Blue line denotes the septum primum. LA = left atrium, RA = right atrium. cryptogenic stroke than in those with incidental detection of a PFO at transesophageal echocardiography (7.5 mm ± 3.4 vs 9.9 mm ± 6.0). We have observed similar findings at cardiac CT (Fig 6). In a recent study performed with multidetector CT in asymptomatic individuals with a PFO, 92% of shunts occurred in the presence of a PFO tunnel length of 6 mm or less (60). Such information may be important for determining the feasibility of percutaneous closure of a PFO. PDE is more common in patients with a bidirectional shunt through a PFO than in those with a right-to-left shunt only (Fig 6). However, a bidirectional shunt is a relatively uncommon finding (50). When the flap length is very short, a bidirectional shunt is more probable. Patients with an atrial septal aneurysm also have a very short PFO tunnel length. In a recent postmortem study, Ho et al (61) described two types of PFO: valve competent and valve incompetent.

1580 October Special Issue 2014 radiographics.rsna.org Figure 6. Valve-incompetent PFO at CT angiography. (a) Short-axis CT image shows the free flap of the PFO valve (arrowheads), which is too short to cover the superior rim of the septum secundum and form a PFO tunnel (black arrow). Note the free flow of contrast material through the PFO (white arrows). (b) Short-axis CT image from another patient shows an atrial septal aneurysm (arrowheads) and a very short PFO tunnel (black arrow) causing a leftto-right shunt (white arrow). LA = left atrium, RA = right atrium. PFOs with a short overlapping flap in the presence of an atrial septal aneurysm were classified as incompetent, with a high likelihood of bidirectional flow. Similar morphologic features of valve incompetence observed at multidetector CT in patients with a PFO included a short PFO tunnel length and an atrial septal aneurysm (Fig 6) (60). Effect of Structures Occurring in Association with a PFO The presence of one or more aberrant anatomic structures in association with a PFO can increase the probability that PDE will occur. These abnormal structures include a Chiari network, an atrial septal aneurysm, and a persistent eustachian valve. Chiari Network. The Chiari network consists of coarse or fine fibers within the right atrium, arising from the eustachian or thebesian valve and connecting them with the crista terminalis, right atrial wall, or interatrial septum (Fig 7a). This structure is a remnant of the embryonic right valve of the sinus venosus (63) and should be differentiated from a large eustachian valve by looking carefully for attachments to other parts of the right atrium. A Chiari network has been reported in 2% 4% of autopsy studies (63) and is generally thought to have no clinical significance. In rare instances, however, a Chiari network may be the site of thrombus formation (64) (Fig 7b, 7c). In a large patient series, a Chiari network diagnosed at transesophageal echocardiography was seen in 2% of patients (64). This feature was more frequently seen in patients with a PFO (83%) and a right-toleft shunt (55%) than in subjects within the control group. A Chiari network was also frequently associated with an atrial septal aneurysm, which was seen in 24% of patients. Fine Chiari networks may be difficult to visualize at CT or MR imaging. However, a dedicated multidetector CT study of the right side of the heart may produce artifactfree images of the right atrium that depict a Chiari network (Fig 7b, 7c). Atrial Septal Aneurysm. An atrial septal aneurysm is another important anatomic feature to consider when evaluating PFO. An atrial septal aneurysm is defined as a bulge that protrudes more than 15 mm beyond the plane of the atrial septum (65). Pearson et al (66) used the Hanley diagnostic criteria (65) to classify findings of atrial septal aneurysm into two groups on the basis of the direction and timing of the protrusion. Generally, right atrial protrusion is the most common (76%) direction and is followed by transient motion toward the left atrium during systole or with the Valsalva maneuver (65) (Fig 8). Increased interatrial septal mobility is believed to increase the probability of PDE by mechanically redirecting blood flow from the IVC through the PFO into the left atrium. The detection rate for atrial septal aneurysm is 4.6% 10% at transesophageal echocardiography (67,68). An atrial septal aneurysm associated with a PFO has a prevalence of 30% 60%

RG Volume 34 Number 6 Saremi et al 1581 Figure 7. Chiari network. (a) Photograph of a cadaveric heart provides a four-chamber view of the right atrium (RA), with the Chiari network (*) in the anatomic region of the eustachian valve, anterior to the IVC and extending to the ostium of the coronary sinus (CS). (b, c) Axial (b) and two-chamber (c) CT angiograms of the right ventricle (RV) in a live patient show rounded and bandlike structures (arrows) attached to the walls of the IVC and coronary sinus (CS) ostium at the inferior cavoatrial junction. This finding was confirmed at echocardiography, which showed a possible thrombus covering the Chiari network. The patient had a history of right ventricular endocardial pacemaker. FO = fossa ovalis, LA = left atrium, TV = tricuspid valve. (67,68) and is most likely associated with an increased rate of embolic events (67). Among patients with normal patency of the carotid arteries, atrial septal aneurysm is more prevalent in those with cerebral ischemia (28%) than in those without cerebral ischemia (10%) (67). An atrial septal aneurysm can easily be assessed at CT and MR imaging. In one study performed with multidetector CT, an atrial septal aneurysm was seen in 4% of patients, and 63% of patients with an atrial septal aneurysm were found to have a leftto-right shunt (60) (Fig 6). Persistent Eustachian Valve in Adults. The eustachian valve, which guards the anteroinferior aspect of the IVC, is a remnant of the embryonic right valve of the sinus venosus (Fig 9a). During embryonic development, the eustachian valve directs oxygenated blood from the IVC through the PFO into the systemic circulation (69). By directing the blood from the IVC toward the interatrial septum, a persistent eustachian valve may prevent spontaneous closure of the PFO after birth and thereby indirectly contribute to the development of PDE. A prominent eustachian valve is a common finding at cardiothoracic CT and MR imaging (Fig 9b). In echocardiographic studies performed by Schuchlenz et al (69), a persistent eustachian valve was seen in 57% of patients, with a mean valve diameter of 1.0 cm ± 0.4 (range, 0.5 2.0 cm). Seventy percent of patients with a eustachian valve also had a PFO. A persistent eustachian valve was more common in patients with presumed PDE than in control subjects (68% vs 33%), but there was no significant difference in the size of the eustachian valve between the two groups. Imaging-based Diagnosis of Intracardiac Shunts Various imaging modalities can be used to diagnose an intracardiac shunt either directly or indirectly (Table 4). Echocardiography is the most popular modality for this purpose; it is widely available, noninvasive, accurate, and relatively inexpensive. An intracardiac shunt can be directly

1582 October Special Issue 2014 radiographics.rsna.org Figure 8. Atrial septal aneurysm. LA = left atrium, RA = right atrium. (a, b) Short-axis CT angiograms demonstrate an atrial septal aneurysm (arrow) protruding into the right atrium in diastole (a) and toward the left atrium in systole (b). Right atrial protrusion of an atrial septal aneurysm is the most common morphologic feature, whereas motion toward the left atrium during systole or with the Valsalva maneuver is transient. (c e) Transesophageal echocardiograms obtained during an agitated saline contrastenhanced CT study show the atrial septal aneurysm (arrow in c and e) with right-toleft shunting visible in d and e. assessed with echocardiography and MR imaging; to evaluate extracardiac shunts, CT or MR imaging is commonly performed. However, given the widespread use of cardiac CT for other indications, CT is increasingly relevant for assessments of intracardiac shunt and PFO as well. An intracardiac shunt may also be indirectly diagnosed on the basis of findings at transcranial Doppler US. MR imaging enables direct flow quantification and provides valuable information about the size, shape, and location of the PFO and its spatial relationship to other structures (70). Mohrs et al (70) found a good correlation between dynamic contrast-enhanced MR angiography and transesophageal echocardiography in the grading of PFO shunts. In their study, a right-to-left shunt through the PFO was demonstrated by comparing time-intensity curves for contrast material arrival in the left atrium and in a pulmonary vein. However, contrast-enhanced MR angi-

RG Volume 34 Number 6 Saremi et al 1583 Figure 9. Eustachian valve or ridge. (a) Photograph of a cadaveric heart shows the right atrium, with a large eustachian valve or ridge (*) extending between the IVC and the coronary sinus (CS) ostium. C = crista terminalis, FO = fossa ovalis, TV = tricuspid valve. (b) Longaxis two-chamber black-blood MR image of the right ventricle (RV) shows a large eustachian valve (arrows) in the anteroinferior ostial margin of the IVC. RA = right atrium. ography may be inferior to contrast-enhanced transesophageal echocardiography for detecting a right-to-left shunt and identifying an atrial septal aneurysm (71). Electrocardiographically gated multidetector CT is a fast and easy method that may obviate invasive imaging studies by depicting a completely closed interatrial septum. Demonstration of a PFO tunnel at multidetector CT may help predict the presence of a shunt. Only a limited number of studies have involved comparison of multidetector CT with transesophageal echocardiography (60,72). Current CT techniques for coronary angiography are capable of showing a left-to-right shunt. This can be important because the demonstration of a left-to-right shunt, particularly when a short flap valve length or atrial septal aneurysm exists, is indicative of an incompetent valve mechanism and a high likelihood that the shunt is bidirectional. No provocative test is necessary to demonstrate a left-to-right shunt at multidetector CT. For CT evaluation of intracardiac shunts, data must be collected for the entire cardiac cycle. This requires radiation-intensive retrospective electrocardiographic gating. Detection of a small right-to-left shunt at the level of the PFO indicates a need for dedicated retrospectively gated right atrial CT angiography, preferably performed while the patient performs the Valsalva maneuver. The acquisition of high-quality right atrial CT angiograms is challenging and requires homogeneous enhancement of the right atrium, correct scanning timing, a small field of view limited to the atria, and a heart rate of less than 70 beats per minute. Homogeneous enhancement of the right atrium can be obtained with simultaneous injections of moderately concentrated contrast material into the antecubital and femoral veins (73). Transcranial Doppler US of the middle cerebral artery performed during the injection of contrast material can be used as an alternative method for indirect detection of a PFO or shunt (Fig 10). If both echocardiography and transcranial Doppler US are performed when the presence of a PFO is suspected, the PFO detection rate is higher than that with either method used alone (74). Results of comparative studies with transesophageal echocardiography suggest that the sensitivity of transcranial Doppler US is higher than 90% but the specificity is low (approximately 65% 90%). The low specificity of transcranial Doppler US may be due to technical limitations of the study or the presence of extracardiac shunts. Imaging for Percutaneous PFO Closure Table 5 lists the anatomic information required to prepare for percutaneous PFO closure. Current techniques for placement of PFO closure devices rely on fluoroscopic landmarks combined with either transesophageal or intracardiac echocardiographic guidance. Transesophageal echocardiography for device closure usually involves conscious sedation but may require general anesthesia in patients with airway issues or a body habitus that makes transesophageal access difficult. CT has been used for localization of the fossa ovalis to aid in transseptal catheterization (75). Given that a PFO is a three-dimensional structure with dynamic opening and closing, as well as a channel-like structure in some patients, one-dimensional measurements may not

1584 October Special Issue 2014 radiographics.rsna.org Table 4: Comparison of Different Imaging Modalities for Clinical Workup of PDE Modality Imaging Workup Optimal Uses Advantages Limitations Multidetector CT Initial assessment of target organ damage (ie, peripheral emboli and infarction); supplemental studies MR imaging Initial assessment of target organ damage (ie, brain emboli and infarction) Transesophageal echocardiography Peripheral venous Doppler US Transcranial Doppler US Detection of intracardiac and extracardiac shunts, direct depiction of thrombus Intracardiac and extracardiac shunts, direct thrombus imaging Supplemental Intracardiac shunt, direct thrombus imaging Supplemental Extracardiac embolic sources Supplemental Indirect evaluation of shunt Noninvasive, rapidly performed study of the chest, abdomen, and pelvis that may exclude predisposing factors and other causes of embolic events; provides information about PFO size, which is important to avoid inadvertent puncture of the septum secundum with resultant extracardiac perforation; shows complete closure of the interatrial septum or a PFO tunnel, findings predictive of the probability of an intracardiac shunt (presence of complete closure may obviate more invasive imaging studies); shows cardiac and extracardiac anatomic pathways for preprocedural transatrial intervention assessment; depicts acute pulmonary embolism Used to assess cardiac or extracardiac shunts and quantify direct flow; depicts anomalous venous drainage; allows exclusion of predisposing factors and differentiation of possible causes of embolic events; provides detailed information on size, shape, and spatial relationship to other structures Best modality for depicting a left atrial appendage thrombus; when used in conjunction with transcranial Doppler US, the PFO detection rate is higher Radiation dose; inferiority to transesophageal echocardiography for detecting a right-to-left shunt through a PFO Inferior to transesophageal echocardiography for the detection of a right-to-left PFO shunt; inferior to transesophageal echocardiography for the identification of atrial septal aneurysms Invasive; limited acoustic windows; patient must perform the Valsalva maneuver to allow identification of a shunt Easiest means for directly depicting thrombi in the extremities Low sensitivity for detection of intrapelvic thrombi Specificity for detection of When performed with an injection of microbubble contrast material, it can be a reliable alternative method for detection of PFO or intracardiac shunt; when used in conjunction with echocardiography, the PFO detection rate is higher intracardiac shunts may be low in patients with an extracardiac shunt

RG Volume 34 Number 6 Saremi et al 1585 Figure 10. (a, b) Transcranial Doppler US was performed for PFO in two patients after injection of agitated saline and during the Valsalva maneuver. (a) Doppler waveform from the first patient shows a positive test result, with a mild to moderate shunt ( shower effect). (b) Doppler waveform from the second patient shows a moderate to severe shunt ( curtain effect). At transcranial Doppler US, passage of a single bubble leads to an instantaneous increase in signal amplitude. A diagnosis of PFO is based on the number of Doppler signals detected and the time elapsed between the end of the contrast material injection and the appearance of signal. Table 5: Imaging Analysis before Percutaneous PFO Closure Imaging Features Sought and Assessed Figure(s) Showing the Feature PFO morphology: size of opening, tunnel length, Figures 5, 6 patency Thickness and length of superior interatrial groove Figure 11 (septum secundum) Dimensions of fossa ovalis on short-axis and fourchamber views Figures 5, 11 Presence of atrial septal aneurysm Figures 6, 8 Distance between the PFO and both the vena cava Figures 5, 11 and the aortic root Presence of atrial septal and sinus venosus defects Integrity of pulmonary venous anatomy seen on axial CT or MR images Presence of an anatomic abnormality that could Figures 4, 7, 9 interfere with device placement (eg, eustachian valve, Chiari network) Presence of thrombus in the left atrial appendage be accurate. With CT, detailed three-dimensional information can easily be obtained (Fig 11a). CT can demonstrate the relationship of important cardiac structures to the PFO and allows a determination of the length of the interatrial groove, distance to the aortic root, anomalous coronary arterial course, and location of the coronary sinus ostium. Knowledge of the length of the interatrial groove and distance to the aortic root is crucial when planning the placement of a closure device (60). The presence of a markedly thickened (eg, in lipomatosis) or unusually short interatrial groove may interfere with appropriate placement of the PFO closure device and may increase the likelihood of complications such as dislodgment of the closure device or injury of adjacent structures such as the aortic root. The criteria for PFO closure are not standardized (76). Some authors recommend PFO closure in the presence of a large PFO, a permanent right-to-left shunt (versus a Valsalva maneuver induced shunt), or an atrial septal aneurysm (76). In this regard, cardiac CT can provide important information about the morphologic characteristics of the PFO; a permanent right-to-left shunt is less likely to be present when the PFO tunnel

1586 October Special Issue 2014 radiographics.rsna.org Figure 11. Percutaneous closure of PFO. (a) Short-axis preprocedural reformatted CT image of the IVC at the level of the fossa ovalis (fo) shows the most important parameters of measurement (bidirectional arrows): the length of the superior interatrial groove (s) and the length of the membranous flap covering the fossa ovalis. AA = ascending aorta, LA = left atrium, RA = right atrium. (b) Postprocedural transesophageal echocardiogram shows septal occlusion (Amplatzer Septal Occluder; AGA Medical, Golden Valley, Minn) (arrows). LA = left atrium. (c, d) Short-axis (c) and four-chamber (d) postprocedural CT images show occlusion of a PFO (Cardioseal; NMT Medical, Boston, Mass) (arrows) in a patient with an atrial septal aneurysm. Inset in d shows an axial view of the occlusive device. LA = left atrium. is well formed and narrow (Fig 5). CT and MR imaging are complementary to transesophageal echocardiography for assessing the effectiveness of a percutaneously placed occlusive device (77,78) (Fig 11b, 11c). However, a small residual shunt is common after placement of an occlusive device, and complete endothelialization of the device takes 3 6 months, so early postprocedural imaging may not be relevant. Congenital Heart Malformations and the Risk of PDE The presence of an intracardiac shunt due to an atrial or ventricular septal defect can increase the risk of thromboembolism especially in patients with a permanent pacemaker, because the pacemaker leads create a predisposition to thrombus formation (79). Patients with transposition of the great arteries and a concomitant baffle leak may also have an increased risk of PDE (Fig 12). For this reason, patients who require pacemaker implantation typically undergo a thorough preprocedural imaging evaluation to determine whether a baffle leak is present (79). Potential pathways of interatrial communication that may be seen at cardiac CT are enlarged thebesian veins passing along the superior interatrial muscle bundle (Bachmann bundle) between the right and left atrial appendages (73). Pulmonary arteriovenous communications are a known complication after some types of cavopulmonary anastomoses because of the diversion of normal hepatic venous

RG Volume 34 Number 6 Saremi et al 1587 Figure 12. Mustard procedure for transposition of the great arteries in a 24-year-old man. PDE-related embolic events caused infarctions in the spleen, brain, and left kidney. (a) Short-axis MR image shows a large baffle defect (arrow). RA = right atrium, SVC = superior vena cava. (b) Axial abdominal CT image shows splenic infarction (arrow). (c) Axial CT image shows the cardiac appearance after closure of the baffle defect with an occlusive device (Amplatzer Septal Occluder) (arrow). flow from the pulmonary circulation, which may lead to additional complications, including PDE. Extracardiac Causes of Right-to-Left Shunt Abnormal Venous Return The source of cryptogenic stroke remains unexplained in approximately 50% of patients who undergo imaging to determine whether PDE is present (80). One important role of CT or MR imaging in the evaluation of PDE is to exclude any anomalous venous drainage that may have gone undetected at previous echocardiography. Among the possible congenital causes of a right-to-left shunt, anomalous drainage of the left superior vena cava into the left atrium and fenestrated coronary sinus should be investigated. In less than 10% of patients with a persistent left superior vena cava, that vein drains into the left atrium either directly or through an unroofed coronary sinus, creating a right-to-left shunt (81) (Fig 13). Large collateral mediastinal veins may cause a visible right-to-left shunt (systemic-to-pulmonary venous shunt). PDE can develop with stenosis, thrombosis, or absence of the left brachiocephalic vein and severe stenosis or occlusion of the superior vena cava (81). Collateral venous pathways frequently extend between the left brachiocephalic vein and left atrium, through an arcade comprising the left superior intercostal vein or left vertical vein and a pulmonary vein, to the left atrium. These collateral pathways are best appreciated at CT (Fig 14). Arteriovenous Malformations Paradoxical neurologic complications can occur in patients with a pulmonary arteriovenous malformation, a defect most often associated with Osler-Weber-Rendu disease or hereditary hemorrhagic telangiectasia (82) (Fig 15). These patients should be screened for lung arteriovenous malformations by using MR imaging or CT. It is inevitable that some of these patients will have a pulmonary arteriovenous malformation, with or without an associated PFO (which may be the sole cause of PDE), and that the malformation may remain a source of continued embolization

1588 October Special Issue 2014 radiographics.rsna.org Figure 13. Extracardiac causes of PDE in a patient with repaired tetralogy of Fallot and multiple episodes of PDE-related brain infarction. (a) MR angiographic image obtained after contrast material was injected into the patient s left arm demonstrates a right-to-left shunt due to direct communication of the left superior vena cava (arrow) with the left atrium (LA). (b) Transesophageal echocardiogram obtained after injection of agitated saline into the patient s left arm shows bubbles (arrows) entering the left atrium (LA), a finding that confirms the presence of the right-to-left shunt. Images obtained after an agitated saline injection into the patient s right arm showed no evidence of a PFO. Embolization of the left-sided communication was performed with a coil device. RA = right atrium. even after PFO closure (82). Echocardiography would not be adequate for identifying such abnormalities, and CT might be more reliable. Differential Diagnosis When evaluating patients in whom the presence of PDE is suspected, it is important to determine whether other possible causes of embolic events are present. CT or MR imaging is helpful for identifying predisposing conditions such as aortic atherosclerotic disease, aortic dissection, intracardiac masses, and intracardiac thrombi. An associated acute pulmonary embolism is an important finding that is easily detected at CT. Cardiac sources of non-pde-related embolic events are generally located in the left side of the heart. Embolic sources in the left side of the heart include a left atrial appendage thrombus associated with atrial fibrillation, left ventricular mural clot occurring in the setting of myocardial infarction, mitral or aortic valve vegetation, and tumor (83). Embolic phenomena are indicated by presenting symptoms in as many as 20% of patients and may be caused by detached tumor fragments or thrombi (83). Atherosclerotic plaques of the aortic arch are an important source of extracardiac thromboembolism. The highest risk is associated with proximal arch plaques with a maximal diameter of more than 4 mm (84). Nonvalvular atrial fibrillation is a common cause of embolic brain infarction in the elderly Figure 14. Coronal CT image obtained after contrast material injection into the left arm of a 17-year-old female patient with hemoptysis, hypoxemia, and mild cyanosis after a Fontan procedure for a double-outlet right ventricle demonstrates an extracardiac cause of PDE: partial occlusion of the left brachiocephalic vein and extensive mediastinal venous collateral (Collat.) formation. A relatively large network of collateral vessels connected to the right superior pulmonary vein (RSPV) causes early filling of the left atrium (LA), an indication of a right-to-left shunt. Venous thrombosis combined with the right-to-left shunt led to the development of PDE. RPA = right pulmonary artery. (85). A left atrial appendage thrombus might occur in patients of any age, and every imaging study obtained for evaluation of PDE should be inspected carefully. At present, for the exclusion of thrombus in the left atrial appendage, MR

RG Volume 34 Number 6 Saremi et al 1589 Figure 15. Axial CT image shows an extracardiac cause of PDE in a patient with Osler-Weber-Rendu disease: multiple pulmonary arteriovenous malformations (arrows). imaging and CT cannot replace transesophageal echocardiography (86). However, both MR imaging and CT may be attractive noninvasive alternatives if transesophageal echocardiography is technically unfeasible or is declined by the patient (77,86). If the left atrial appendage has a normal appearance at CT (a finding with a negative predictive value of >95%), transesophageal echocardiography may not be needed (86). Incomplete mixing of contrast material with blood in the left atrial appendage, especially in patients with atrial fibrillation, may result in many falsepositive findings at CT. However, in a study in which transesophageal echocardiography was compared with CT, a two-phase CT protocol (an early arterial phase and a phase delayed after 30 seconds) was found to have high sensitivity and specificity for the diagnosis of left atrial appendage thrombus (87). Conclusion Imaging assessment for PDE usually requires complementary use of different modalities to allow an accurate diagnosis excluding various differential possibilities. No single imaging modality is capable of depicting the entire spectrum of possible findings in PDE. MR imaging plays a primary role in the diagnosis of target lesions in the brain, and CT can easily show these lesions in other parts of the body. An embolic source in the peripheral veins can be detected with high sensitivity with US, whereas MR imaging and CT are better for the diagnosis of central venous thrombosis. An intracardiac shunt through a PFO, and the associated anatomic details, is best depicted with transesophageal echocardiography. Electrocardiographically gated CT also can show the anatomic details of a PFO and may be helpful in selected cases. MR imaging is not an ideal modality for assessing a PFO. In patients with a large intracardiac shunt, MR imaging and echocardiography play a major role and can be used to quantify the shunt and demonstrate its exact location. In patients with an extracardiac shunt, the use of echocardiography is limited; in this setting, CT and MR angiography are better choices because they provide valuable data about extracardiac lesions such as anomalous venous return and pulmonary arteriovenous malformation. MR angiography can provide additional functional information about vascular malformations (eg, the direction, amount, and rapidity of flow through the vessel) without exposing the patient to iodinated contrast agents and ionizing radiation. In summary, the following algorithm may be followed for the diagnostic imaging evaluation of patients in whom the presence of PDE is suspected. First, initial studies are performed to detect target lesions: MR imaging or CT of the brain, heart, abdomen, or extremities may be used, depending on the clinical manifestations. Second, predisposing intracardiac abnormalities are sought by performing contrast-enhanced echocardiography (preferably with a transesophageal approach) to identify PFO, intracardiac shunt, left-heart thrombus or mass, or aortic or mitral valve vegetation. Cardiac MR imaging or CT should be performed if echocardiography is not feasible or if the echocardiographic findings are not convincing. Third, if the presence of DVT is suspected, Doppler US of the lower or upper extremity is performed. Fourth, if the presence of arterial lesions is indicated, additional studies with Doppler US, CT, or MR angiography of the aorta and carotid arteries are performed. Last, if there is evidence of a possible extracardiac predisposing cause, CT is performed to allow the detection of anomalous venous return and arteriovenous malformation. References 1. Cohnheim J. Thrombose und embolie. In: Vorlesungen über allgemeine pathologie. Vol. 1. Berlin, Germany: Hirschwald, 1877. 2. Zahn FW. Thrombose de plusieurs branches de la veine cave inférieure avec embolies consécutives dans les artères. Rev Med Suisse Rom, 1881;1: 227 237. 3. Zahn FW. Beiträge zur geschwustlehre. Dtsch Z Chir 1885;22(1-2):1 35. 4. Johnson BI. Paradoxical embolism. J Clin Pathol 1951;4(3):316 332. 5. Thompson T, Evans W. Paradoxical embolism. Q J Med 1930;os-23(90):135 150. 6. Swan HJ, Burchell HB, Wood EH. The presence of venoarterial shunts in patients with interatrial communications. Circulation 1954;10(5):705 713. 7. Loscalzo J. Paradoxical embolism: clinical presentation, diagnostic strategies, and therapeutic options. Am Heart J 1986;112(1):141 145.