ETIOLOGY OF ISCHEMIC STROKE

• 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)

• proving that a stroke is caused by a paradoxical embolism is often difficult
  • rarely are all four of the above criteria diagnosed with high certainty
  • diagnosis is typically made per exclusionem
  • however, if recent deep vein thrombosis is found along with a significant PFO or a thrombus in the PFO tunnel in a stroke patient, paradoxical embolization is very likely
• due to diagnostic uncertainty, some strokes caused by paradoxical embolism may be misclassified as cryptogenic stroke

• 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
• symptoms 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
  • 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 – used to detect right-to-left shunts
  • HRCT + pulmonary CTA – considered the gold standard for diagnosing PAVMs, allowing direct visualization of the shunt
• management: embolization, resection (typically where embolization is not feasible or unsuccessful)

• 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 very low specificity
  • contrast venography and ultrasonography are sensitive for detecting 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, though this is infrequent due to the procedure’s invasiveness
• 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 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 for DVT
  • 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/CT venography offers the advantage of evaluating the pelvic veins and inferior vena cava (IVC), which are difficult to assess with ultrasound
  • 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 usually a consequence rather than a cause of the stroke)

• acute stroke therapy should follow established protocols
• prevention of stroke recurrence depends on the certainty of paradoxical embolism involvement
  • when paradoxical embolism is confirmed with high confidence (e.g., presence of PFO with associated thrombus or concurrent DVT), PFO closure is considered (unless there is a compelling reason for long-term anticoagulation)
  • 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, questionable causal connection of the shunt with the current stroke)
  • antiplatelet therapy
  • anticoagulation (cases of 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