Paradoxical Embolism: Role of Imaging in Diagnosis and Treatment Planning

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Paradoxical Embolism: Role of Imaging in Diagnosis and Treat- ment Planning1
Paradoxical embolism (PDE) is an uncommon cause of acute arterial occlusion that may have catastrophic sequelae. The pos- sibility 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
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 thrombo- sis, IVC = inferior vena cava, PDE = paradoxical embolism, PFO = patent foramen ovale
RadioGraphics 2014; 34:1571–1592
Published online 10.1148/rg.346135008
Content Codes: 1From the Departments of Radiology (F.S., N.E., P.F.W., L.I., J.L.G.) and Cardiovascular Medicine (D.S.), University of Southern Califor- nia, 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 Cer- tificate 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: [email protected]).
After completing this journal-based SA- CME activity, participants will be able to: Describe the causes of PDE and se-
quelae in target organs.
Discuss the specific uses of various im- aging modalities in the diagnosis of PDE.
Recognize CT and MR imaging fea- tures that are pertinent for the diagnosis of PDE and for posttreatment evaluation.
See www.rsna.org/education/search/RG.
SA-CME LEARNING OBJECTIVES
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.
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target organs. Additional imaging studies, includ- ing peripheral venous Doppler US, transcranial Doppler US, echocardiography, and CT, are used to detect peripheral and central sources of embo- lism, arterial disease, and cardiac or extracardiac shunts. Further diagnostic testing often includes continuous long-term electrocardiographic re- cordings, blood chemistry panels, and coagula- tion 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). Shunt- ing 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. Amni- otic fluid embolism can rarely be complicated by PDE resulting from increased pressure in the right side of the heart due to the release of vaso- active 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
The article outlines the optimal imaging ap- proach in various clinical settings and the value contributed by each imaging modality for accu- rate diagnosis of PDE. The current roles of com- puted tomography (CT) and magnetic resonance (MR) imaging in identifying cardiac and extra- cardiac 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 tech- niques, 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 ve- nous system reached the systemic arterial system through an abnormal communication between the heart chambers (3).
Four essential elements contribute to the devel- opment of PDE: systemic embolism, an embolic source, a right-to-left shunt, and a pressure gradi- ent 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 presump- tive (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 phy- sicians 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 in- tracardiac 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 catheter- ization 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, an- giographic, 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 commu-
nication between the right and left circulations Pressure gradient that promotes a right-to-left shunt
at some point during the cardiac cycle
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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 communica- tion, 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 con- traceptive 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 ac- counts for approximately 80% of cases of upper- extremity DVT (29). Thrombogenesis associated with catheters has been well documented, with an incidence ranging from 2% to 67%, depend- ing 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 in- volvement (31,32).
Sequelae of PDE in Target Organs
Although PDE is an uncommon cause of acute arterial occlusion, it can have catastrophic se- quelae, and the possibility that it is present should be considered in all patients with an arte- rial embolus in the absence of a cardiac or proxi- mal 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 pos- sible. In Loscalzo’s (7) study based on findings in 30 patients, the five sites of arterial emboli
studies, the prevalence of deep venous thrombo- sis (DVT) in patients with acute pulmonary em- bolism 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 report- edly 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 upper- extremity 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 underes- timation of the true incidence of venous throm- bosis (20).
US is more accurate than venography for de- picting 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 gadolinium- based contrast material is contraindicated.
The reported incidence of DVT associated with PFO and PDE ranges widely between dif- ferent 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 dura- tion 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 em- boli without evident arterial or cardiac sources. By contrast, in a study by Lethen et al (17), venography depicted DVT in only 10% of pa- tients 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
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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 ab- dominal and/or flank pain.
Cryptogenic Stroke Ischemic strokes can be classified into two ma- jor 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 cryp- togenic 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 relation- ship between the presence of a PFO and the oc- currence 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 fac- tors, such as the morphologic characteristics of the PFO and associated structures, may increase the probability that PDE is present (37,38).
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 su- perior vena cava with the left atrium. (b) A single territorial infarct (arrow) that origi- nated from right subclavian venous throm- bus 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.
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Embolic and Nonembolic Infarcts PFO is thought to be an important causal mecha- nism 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 involv- ing more than one lobe is strongly suggestive of embolic infarction (40). Scattered lesions or cor- tical-subcortical territorial lesions also are indica- tive 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 depict- ing 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 (pos- terior 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 transfor- mation is a strong indicator of embolic infarction, published data do not demonstrate an association between PFO and hemorrhagic infarcts (42).
Anatomic and Physiologic Con- siderations 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 sep- tal 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 find- ing 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 di- ameter) 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 ac- cording 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 ve- nous thromboembolic disease who also have a PFO. This is thought to be because the foramen ovale is normally closed by the higher left-to- right atrial pressure gradient. Case control stud- ies that demonstrate a higher prevalence of PFO
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, ventricu- lar septal defect, atrioventricular septal defect)
Extracardiac Pulmonary arteriovenous malformation (congenital, secondary to cavopul-
monary shunts) Systemic to pulmonary venous communication (congenital, acquired) Arterioarterial communication (patent ductus arteriosus) or venovenous
communication
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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…