Definition

  • paradoxical embolism generally refers to an event where any material (thrombus, gas, fat, amniotic fluid) arising from venous circulation passes through a shunt into arterial circulation (causing stroke, limb or mesenteric ischemia, etc)

Paradoxical embolism

The diagnosis of a paradoxical embolus can be confidently made only when four requirements are detected:

  • venous thrombus (or other material) as a source of emboli
    • venous thrombi typically form in the deep veins of the legs or pelvis due to factors such as prolonged immobility, hypercoagulable states, or venous injury
    • venous thrombosis must be reasonably distinguished as being a cause rather than a consequence of stroke (especially if detected > 3 days from stroke onset)
  • a shunt (PFO, atrial septal defect, PAVM) that provides a pathway for the embolus to bypass the pulmonary filter and enter the arterial circulation
  • a pressure gradient that promotes right to left shunt
    • elevated right atrial pressures, commonly seen during Valsalva maneuvers (urination, defecation), increase the likelihood of shunt opening
  • a thrombus lodged in the arterial circulation
    • the embolus can travel to various organs, causing ischemic events such as strokes, myocardial, mesenteric, or limb ischemia
  • convincing proof that a stroke is attributable to a paradoxical embolism is often challenging to obtain
    • rarely are all four of the above criteria diagnosed with high certainty
    • diagnosis is typically made per exclusionem
    • however, concurrent recent deep vein thrombosis and massive PFO or finding of a thrombus in PFO tunnel in stroke patient make the diagnosis of paradoxical embolization very likely
  • due to diagnostic uncertainty, a proportion of strokes caused by paradoxical embolism may be misclassified as cryptogenic stroke

Classification of shunts

Cardiac shunts Extracardiac shunts

PFO

atrial septal defects (ASD)

ventricular septal defects (VSD)

truncus arteriosus

pulmonary A-V malformation or fistula

persistent left superior vena cava (PLSVC)

Congenital cardiac defects

Patent Foramen Ovale (PFO)

  • anatomic closure of the foramen ovale normally follows functional closure after birth. However, autopsy studies have found that a patent interatrial communication remains in a significant proportion of healthy subjects (up to 25-30% have PFO with a mean diameter of 5 mm )
    • echocardiographic methods underestimate the prevalence and size of PFOs compared to autopsy findings (prevalence ~ 10-22%)
  • PFO is more prevalent in patients with cryptogenic stroke compared to patients with stroke of determined origin or healthy individuals
  • the coexistence of other cardiac findings strengthens the association between PFO and paradoxical embolism
    • concomitant atrial septal aneurysm (ASA)
      • ASA may promote local thrombosis at the site of dilatation
      • ASA may partially reflect a larger PFO size
      • flapping motion of the ASA may direct small thrombi coming from the inferior vena cava (IVC) into a PFO
    • persistent prominent eustachian valve and right atrial filamentous strands
  • rarely a thrombus can be found in the PFO tunnel (either traveling from the venous system or formed locally)
  • PFO size does not appear to be related to the risk of stroke recurrence
  • there is no specific brain imaging pattern associated with paradoxical embolization

Atrial Septal Defect (ASD)

  • a congenital defect in the atrial septum, allowing direct communication between the right and left atria, leading to a mix of oxygenated and deoxygenated blood
    • over time, this can cause enlargement of the right atrium and right ventricle, pulmonary hypertension, and potentially right heart failure
    • in some cases, the shunt can reverse (right-to-left), causing cyanosis (due to the mixing of deoxygenated blood in the systemic circulation) or paradoxical embolization
  • types of ASD based on their location within the atrial septum:
    • ostium secundum ASD –  the most common type, located in the middle of the atrial septum (75% of cases)
    • ostium primum ASD – located in the lower part of the atrial septum, often associated with mitral valve defect and ventricular septal defect
    • sinus venosus ASD – located near the superior vena cava or inferior vena cava junction with the right atrium
    • coronary sinus ASD – a rare type where the defect is near the coronary sinus
  • ASD is usually diagnosed with an echocardiogram, which can show the size and location of the defect and its effect on the heart
  • management of ASD depends on the size of the defect and the presence of symptoms
    • observation (small, asymptomatic ASDs)
    • medical management (arrhythmias or heart failure)
    • transcatheter closure or surgical repair
      • moderate to large ASDs
        • in symptomatic patients (shortness of breath, easy fatigability, or palpitations)  (ACC/AHA 2008 IIa/C)
        • in patients at risk of developing pulmonary hypertension (high blood pressure in the lungs)
      • ASD (irrespective of size, except for very small ASD in older patients) + history of paradoxical embolism

Ventricular Septal Defect (VSD)

  • a congenital heart defect characterized by an abnormal opening in the ventricular septum; this defect allows blood to flow between the ventricles, leading to a mix of oxygenated and deoxygenated blood and altering normal hemodynamics
    • this leads to increased pulmonary blood flow, elevated right ventricular pressure, and volume overload of the left atrium and left ventricle
    • over time, this can cause pulmonary hypertension, left ventricular hypertrophy, and congestive heart failure
    • in severe cases, the shunt may reverse (Eisenmenger syndrome), leading to cyanosis and right-to-left shunting
  • VSDs can occur as isolated defects or in conjunction with other congenital heart anomalies, such as tetralogy of Fallot or Down syndrome
  • VSDs are classified based on their location within the ventricular septum:
    • perimembranous VSD – the most common type, located in the membranous portion of the septum, near the tricuspid and aortic valves
    • muscular VSD – located in the muscular part of the septum and can occur anywhere within the septum; these defects can be multiple
    • inlet VSD – located near the tricuspid and mitral valves, associated with the atrioventricular canal
    • outlet VSD – located near the pulmonary and aortic valves, also known as supracristal or subpulmonary VSD
  • the management of VSD depends on the size of the defect, the presence of symptoms, and the hemodynamic impact ⇒ medical management, surgical repair, percutaneous closure

Pulmonary A-V shunts

  • pulmonary arteriovenous shunts (PAVMs) are abnormal connections between pulmonary arteries and veins, bypassing the normal capillary system ⇒ hypoxemia, paradoxical embolism, increased cardiac output
  • etiology
    • congenital PAVMs (associated with hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome. HHT is an autosomal dominant genetic disorder characterized by abnormal blood vessel formation)
    • acquired PAVMs  – less common, can occur due to conditions such as trauma, metastatic cancer, or as a complication of certain medical procedures like lung transplantation or thoracic surgery
  • this results in a direct passage of blood from the arterial to the venous system without oxygenation in the lungs, leading to various clinical complications
  • clinical presentation vary depending on the size and number of shunts:
    • asymptomatic – small PAVMs may be asymptomatic and discovered incidentally during imaging for other reasons
    • hypoxemia and increased cardiac output – dyspnea, cyanosis, fatigue, and exercise intolerance
    • neurological complications due to paradoxical emboli (strokes, brain abscesses, systemic embolic events, etc.)
    • hemoptysis – rare
  • diagnostic evaluation
    • chest X-ray – nodular or mass-like lesions
    • contrast echocardiography or TCCD bubble test – detects right-to-left shunts
    • HRCT + pulmonary CTA – the gold standard for diagnosing PAVMs, allowing direct visualization of the shunt and facilitating embolization procedures
  • management: embolization, resection

Rare anomalies

Persistent left superior vena cava (PLSVC)

  • a rare vascular anomaly that begins at the junction of the left subclavian and internal jugular veins and passes through the left side of the mediastinum adjacent to the aortic arc
  • it mostly drains into the right atrium via the coronary sinus (CS) but may end in the left atrium as well
  • mostly, PLSVC is asymptomatic and detected incidentally; however, it can be discovered as a component of complex cardiac pathologies and may lead to significant problems such as arrhythmia or paradoxical embolization (particularly if it drains into the left atrium or in the presence of concurrent PFO)
Persistent left superior vena cava - PLSVC (from Radiopaedia)

Truncus arteriosus

  • a rare congenital heart defect characterized by a single arterial trunk arising from the heart, supplying blood to both the systemic and pulmonary circulations.
  • it is associated with other anomalies
    • varying origins of the pulmonary arteries from the trunk
    • atrial or ventricular septal defect (VSD)
    • patent ductus arteriosus
  • heart surgery is required within the first weeks of life
  • rarely, some people (usually with type 1) can survive without surgery; they typically develop  heart failure and Eisenmenger syndrome (Abid, 2015)
Truncus arteriosus
  • type I (50-70%):
    • a short main pulmonary trunk arises from the truncus arteriosus, this trunk then branches into right and left pulmonary arteries
  • type II (20-30%):
    • no main pulmonary trunk
    • right and left pulmonary arteries arise separately but close together from the posterior aspect of the truncus
  • type III:
    • no main pulmonary trunk
    • right and left pulmonary arteries arise separately from widely separated points on the lateral aspects of the truncus
  • type IV:
    • no true pulmonary arteries arise from the truncus
    • pulmonary blood supply comes entirely from major aortopulmonary collateral arteries
    • now often classified separately as pulmonary atresia with ventricular septal defect (PA-VSD)

Venous thrombus sources

  • detection of a venous thrombosis influences the likelihood of diagnosing a cryptogenic stroke due to paradoxical embolism, but the venous evaluation is often incomplete
  • some methods may lack the sensitivity to consistently detect all relevant venous thrombi
    • clinical diagnosis of DVT is unreliable
    • routinely used laboratory screening tests such as D-dimer have high sensitivity but a very low specificity
    • contrast venography and ultrasonography are sensitive to DVT in the thigh but not in the pelvis
    • the sensitivity of contrast venography for pelvic vein pathology can be improved by selectively cannulating these veins, but this has infrequently been done because of the invasiveness of this procedure
  • it is essential to evaluate calf veins in stroke patients (in general medical practice, little emphasis is placed on the treatment of calf vein DVT without extension to popliteal veins)
    • in some institutions, lower extremity venous duplex examinations do not include the study of calf vein 
    • embolization can occur even without propagation to proximal segments
    • emboli from calf vein thrombi tend to be small and asymptomatic when reaching the lung but may become highly clinically significant in the cerebral circulation
  • another issue in the context of paradoxical stroke is the evaluation of the pelvic veins (use MR venography)
    • the most commonly involved pelvic veins are the external iliac vein and the common iliac vein
  • thrombosis in superficial lower extremity veins is also associated with pulmonary embolism in a surprising proportion of cases

 

  • diagnostic ultrasound criteria
    • primary: non-compressibility of the vein
    • secondary: echogenic thrombus within the vein lumen, venous distention, complete absence of spectral or color Doppler signal within the vein lumen, and loss of response to Valsalva or augmentation
    • in acute thrombosis, the vein is distended by hypoechoic thrombus and shows partial or no compressibility without collaterals
  • improved diagnostic methods of the venous system include:
    • MR or CT venography – offers a definite advantage of evaluating the pelvic veins and inferior vena cava (IVC), which are difficult to assess in the US
    • MR direct thrombus imaging (DTI)  (Westerbeek, 2008)
    • venous enhanced subtracted peak arterial MRV  (Frazer, 2003)
  • an important concern is a substantial increase in DVT prevalence that is found beginning approximately day 4 poststroke (such thrombosis is not the cause but a consequence of stroke)
Right-sided deep vein thrombosis on the utrasound examiantion
MR venography showing thrombosis of the right femoral vein. Large arrow shows hypointense thrombus, small arrow edema.
The left popliteal vein thrombosis on MRI

Therapeutical considerations

  • acute stroke therapy should proceed according to standard protocols
  • prevention of stroke recurrence depends on how certain about paradoxical embolism we are
    • when paradoxical embolism is confirmed with high confidence, PFO closure is considered (unless the reason for long-term anticoagulation exists)
    • however, in most cases, the evidence for a paradoxical embolism is circumstantial and/or incomplete and uncertainties exist at several levels

Management strategies include:

  • conservative approach (small shunt on TCCD bubble test, the causal connection of shunt with current stroke is questionable)
    • antiplatelet therapy
    • anticoagulation (VTE, hypercoagulable state)
  • intervention (massive shunt with a high probability of paradoxical embolization)
    • percutaneous closure (PFO, ASD)
    • embolization  (PAVM)
    • surgical intervention – in cases where percutaneous closure is not feasible

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Paradoxical embolism and stroke
link: https://www.stroke-manual.com/paradoxical-embolism-and-stroke/