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Paradoxical Embolism: Differential Diagnoses & Workup

Author: Igor A Laskowski, MD, Assistant Professor of Surgery, Section of Vascular Surgery, New York Medical College, Westchester Medical Center
Coauthor(s): Sateesh C Babu, MD, Professor of Clinical Surgery, New York Medical College; Associate Director, Vascular Surgery, Co-chief Endovascular Surgery, Westchester Medical Center, Valhalla NY; Oladayo Osinuga, MD, Attending Physician, Department of Internal Medicine, Atlanta Medical Center; Maurice Rachko, MD, FACC, FACP, Director of Coronary Care Unit, Brooklyn Hospital Center; Clinical Assistant Professor, Department of Medicine, Weill Medical College of Cornell University; Klaus-Dieter Lessnau, MD, FCCP, Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital; Nelson Menezes, MD, RVT, Chief of Vascular Surgery, Assistant Professor, Department of Surgery, Division of Vascular Surgery, The Brooklyn Hospital Center and Cornell University
Contributor Information and Disclosures

Updated: Sep 17, 2009

Differential Diagnoses

Deep Venous Thrombosis

Other Problems to Be Considered

Paradoxical embolism (PDE) is a diagnosis of exclusion. Other diseases causing cerebral and peripheral arterial embolisms easily mimic paradoxical embolism (PDE). The major difference is that thrombus forms on the left side of the heart, including the atrial or ventricular wall and the mitral or aortic valve. The arterial embolism may lead to permanent damage, resulting in stroke, infarction of organs, or gangrene of extremities, commonly the lower extremities.

Cardioembolism causes approximately 15% of all strokes.

Paradoxical embolism (PDE) plays a causative role in the etiology of cerebral embolism. Other causes include atrial fibrillation, ischemic cardiomyopathy, myocardial infarction, mitral stenosis with or without atrial fibrillation, prosthetic valves, septic endocarditis, atrial myxoma, fat emboli, septal aneurysm, and ascending aortic atherosclerosis.

Peripheral arterial embolism from paradoxical embolism (PDE) must be differentiated from an embolism of unknown source. Paradoxical embolism (PDE) may be associated with a hypercoagulable state, carcinoma (eg, pancreatic), factor C or S deficiency, factor V Leiden (resistance to activated protein C), and prothrombin mutations. Atherothrombotic arterial manifestations may be difficult to differentiate when trying to rule out the source of the embolus.

The arterial embolism may fragment or lyse, and the circulation may be restored over a period of time or immediately, mimicking TIA from a different source. TIA may be a warning sign for eventual permanent neurological damage.

Workup

Laboratory Studies

• Current diagnosis of paradoxical embolism (PDE) requires the following criteria:
  • DVT with or without PE
  • Abnormal communication between right (venous) and left (systemic) circulation
  • Clinical, angiographic, or pathologic evidence for systemic embolism
  • Presence of a favorable pressure gradient, promoting right-to-left shunting
• When a PFO is detected in a patient with embolism, leg DVT is present in approximately 90%. DVT may be occult upon physical examination.
• The laboratory studies in paradoxical embolism (PDE) are performed to evaluate for hypercoagulability that increases the risk of DVT. Younger patients (eg, <50 y) have a higher percentage of congenital abnormalities, and testing may be warranted after the first DVT episode. As a general rule and recommendation, order blood tests after a recurrent DVT episode. For more information, see the eMedicine topic Deep Venous Thrombosis.
• Perform measurements of prothrombin time, International Normalized Ratio (INR), and activated partial thromboplastin time before anticoagulation commences.
• CBC count assesses the platelet count to decide whether heparin use is plausible in the presence of thrombocytopenia.
• Factor V Leiden assay determines the level of hypercoagulability.
• Protein C and S activity are affected by warfarin (Coumadin). Protein C and S antigen levels may still be obtainable.
• Obtain homocysteine levels to exclude elevation.
• Lupus anticoagulant, anticardiolipin antibodies, and syphilis serology should be evaluated in patients in a prothrombotic state.
• Measuring protein C, protein S, and antithrombin deficiencies helps assess hypercoagulability states.
• A prothrombin gene mutation assay evaluates genetic risk factors for thrombus formation.
• PE is present in most reported cases of paradoxical embolism (PDE); acute PE generally is considered a prerequisite for paradoxical embolism (PDE). The quantitative plasma D-dimer enzyme-linked immunosorbent assay is elevated (>500 ng/mL) in more than 90% of patients with PE.
• Protein C and S are affected by warfarin (Coumadin), and antithrombin III is affected by heparin. The labs now can run a hypercoagulation panel on patients taking warfarin (Coumadin), but the clinician must tell the lab about the warfarin (Coumadin).
• Prothrombin gene mutation, homocysteine levels, and antiphospholipid antibodies may not be affected by anticoagulation.

Imaging Studies

• DVT as an initial source of paradoxical embolism (PDE) must be excluded clinically and investigated with noninvasive studies such as duplex venous ultrasonography (B-mode [2-dimensional] imaging and pulse-wave Doppler interrogation) with compression studies to evaluate thrombus either by direct visualization or by inference when the vein does not collapse. Flow abnormalities occur when DVT is present.
  • Impedance plethysmography is less sensitive for diagnosing DVT of the calves.
  • MRI is another noninvasive means to detect DVT. It is used accurately in patients with suspected thrombosis of the superior and inferior venae cavae or pelvic veins.
  • Patients who present with unilateral limb swelling whose duplex scan findings are negative for femoral or popliteal vein DVT should undergo CT scan with intravenous contrast or MR venogram to rule out iliac vein thrombosis.
• Contrast echocardiography has evolved as the diagnostic method of choice for the assessment of PFO in view of direct visualization of the atria, atrial septum, and the site of contrast passage. PFO can be detected using contrast echocardiography that includes contrast transthoracic echocardiogram (TTE) and contrast transesophageal echocardiogram (TEE).
  • TEE is minimally invasive, involving use of a modified gastroscope that is passed blindly into the esophagus. The nearness of the esophagus to the posterior heart and the use of higher frequency imaging transducers allows enhanced spatial resolution and detection of intracardiac thrombi, PFO, and spontaneous left atrial echo contrast, which is the most common TEE finding among patients being evaluated for intracardiac thrombus as a source of embolism.
  • TEE is superior to TTE in detecting intracardiac masses and PFO. The echocardiographic characteristics of an intracardiac thrombus are those of a mobile mass of irregular, serpentine, or lobulated shape, the configuration of which changes with each cardiac cycle. TTE is limited in its capability to differentiate between an intracardiac thrombus and a myxoma. Contrast TEE is more sensitive than contrast TTE in detecting PFO (100% vs 63%) and has similar specificity at approximately 78%. Contrast TEE has 100% sensitivity and 99% specificity for diagnosis of intracardiac thrombus.
  • The cough test is superior to the Valsalva maneuver in the diagnosis of PFO during contrast TEE or contrast TTE. Valsalva maneuvers cause the right atrial pressure to be greater than the left atrial pressure transiently, thereby reversing the normal left-to-right gradient that keeps the flap closed. Valsalva or cough could potentially dislodge an entrapped thrombus because of increased right atrial pressure. Impending paradoxical embolism (PDE) may result in a false-negative result on contrast echocardiography because of thrombotic occlusion of the PFO.
• Bubble-contrast studies can help assess and exclude the diagnosis of paradoxical embolism (PDE) qualitatively. A positive result from the contrast study for a PFO occurs when 2-5 microbubbles measuring 3-5 micrometer pass the interatrial septum within 3 cycles of complete opacification of the right atrium.
• Second harmonic imaging (SHI) is a new imaging modality that is based on the system of receiving double the emitted ultrasound frequency. It has been demonstrated to improve the visualization of the left heart echo-contrast agents and to improve transthoracic 2-dimensional image quality. TEE and TTE with SHI in combination with intravenous contrast have a comparable yield for the detection of atrial right-to-right shunt. In young patients with stroke without clinical evidence of cardiac disease or arrhythmia in whom TEE is indicated, the noninvasive TTE with SHI is a reasonable diagnostic alternative.
• Transcranial Doppler ultrasonography (TCD) employs monitoring of right-middle cerebral artery blood flow using microbubble contrast medium. Perform TCD with the Doppler probe placed against the side of the skull just above the zygomatic arch. Sensitivity and specificity are close to 100%. This is an alternative to TEE in the detection of right-to-left shunting.
• PE imaging studies are important in paradoxical embolism (PDE) because of the association between PE and paradoxical embolism (PDE).
  • Chest roentgenogram findings are normal or near normal. Abnormalities include focal oligemia, a peripheral wedge-shaped density above the diaphragm, or an enlarged right descending pulmonary artery.
  • Ventilation and perfusion lung scanning is the main test for the diagnosis of PE. A high-probability scan for PE is defined as having 2 or more perfusion defects despite normal ventilation.
  • Spiral computed tomography (CT) scan with intravenous contrast is used commonly to help diagnose PE. It has sensitivity close to that of pulmonary angiography, which has been the criterion standard for PE.
• Noncontrast CT scans of the head are important in evaluating any intracranial bleeding, space-occupying lesions, midline shifts, or herniation, which are contraindications to treatment with thrombolytics and anticoagulation.

Other Tests

• Arterial blood gas determinations evaluate the partial pressures of oxygen and carbon dioxide. This also indicates the metabolic state of the patient and provides an estimation of the alveolar-arterial oxygen gradient.
• Paradoxical embolism (PDE) can often be classified as proven if a venothrombus is found within an intracardiac defect, usually a PFO, at autopsy. Impending paradoxical embolism (PDE) has been described prior to death and at autopsy.
• ECG may demonstrate classic findings in PE, which include sinus tachycardia, right axis deviation, and T-wave inversion in leads V₁ through V₃, reflecting right ventricular strain.
• ECG changes in paradoxical embolism (PDE) may involve ventricular tachycardia or fibrillation, leading to cardiac arrest, especially in impending paradoxical embolism (PDE).

Procedures

• Venography: DVT can be diagnosed using venography, using contrast medium to highlight filling defects in the deep venous system.
• Cardiac catheterization: Intracardiac shunts can be demonstrated by right heart catheterization by using atrial pressure gradients, typical oxygen saturation (oxygen step-up), and visual evidence of contrast medium traversing the abnormal communication with cough or Valsalva enhancement.
• Pulmonary angiography: This is the most specific test available for the diagnosis of PE, and it can detect emboli as small as 1 mm. The drawback is that it is an invasive study, therefore conferring a greater risk to the patient.
• Peripheral arterial embolisms are evaluated depending on the site that is involved (ie, mesenteric, splenic, renal). Angiographic/arteriographic studies include mesenteric, renal, and peripheral studies or magnetic resonance angiography.

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