Paradoxical Embolism

Etiology

Patent foramen ovale (PFO) is a left to right shunt that occurs between the septum primum and septum secundum.  The magnitude of the right to left shunt may be associated with an increased risk of cryptogenic stroke. [4]  Valsalva maneuvers such as coughing, squatting, or defecating can transiently increase right atrial pressure leading to a transient shunt reversal and the transfer of potential thrombi into the systemic circulation. [1] 

Atrial septal defects (ASD) are congenital defects that vary in size and location, with clinical manifestations that range from atrial tachyarrhythmias to dyspnea. ASDs lead to a left to right shunt as well as a fixed split S2 on cardiac exam.  A transient reversal of blood flow can reverse the shunt. ASDs are associated with a paradoxical embolism in up to 14% of patients[5].

Ventricular septal defects commonly result in left to right shunts, however certain conditions that increase right atrial pressure like Eisenmenger syndrome can reverse the shunt, allowing for paradoxical embolism.

Pulmonary arteriovenous malformations are usually hereditary and are a pathological connection between the pulmonary arteries to the pulmonary veins returning to the left atrium. This leads to a permanent right to left shunt. Patients with a history of hereditary hemorrhagic telangiectasia are at increased risk for PAVM and subsequent paradoxical embolism[6].

Epidemiology

Cerebrovascular accidents are the second most common cause of mortality worldwide and are the most frequent and relevant sequela of paradoxical embolism.[1]  Up to 45% of ischemic strokes do not have identifiable causes, such as atrial fibrillation, and are referred to as cryptogenic strokes.  The prevalence of paradoxical embolism is difficult to quantify because of the difficulty in diagnosing proven or impending embolic events[1].   A PFO may be found in up to 30% of the population and studies have suggested that the annual risk of cryptogenic and recurrent strokes in patients with a PFO is 0.1% and 1% respectively. [1][4]   ASDs are 2 to 3 times more common in females and are responsible for over 30% of congenital heart defects in adults.[1]  Paradoxical embolism should be suspected in all patients with an ischemic stroke without an identifiable cause.

Pathophysiology

A paradoxical embolism can occur when a thrombus in the deep venous circulation embolizes through an intracardiac shunt or pulmonary artery venous malformation (PAVM) into the systemic circulation. [1]  Deep venous thrombosis is a risk factor for paradoxical embolism.  Studies have shown that cryptogenic stroke is 5 times more likely with pelvic vein thrombosis.[7][8]   The pathophysiological mechanism of a paradoxical embolism does vary.  In the setting of a PFO, any permanent increase in right-sided cardiac pressures can increase the risk of a paradoxical embolism.[1]

History and Physical

Paradoxical Embolism can be difficult to diagnose and have an insidious onset.  Physicians should strongly suspect paradoxical embolism in patients with an embolic event with a non-identifiable source, such as atrial fibrillation, and when a concomitant intracardiac shunt or PAVM is known or suspected.[1]  A thorough history and physical examination are paramount.  Depending on the organ affected, the symptoms may vary.

Important Questions:[1][3][4]

1. Evaluation of factors that lead to the event (ie: coughing or straining)
2. Screening for HTN, DVT, CVD, DM, hypercholesterolemia, atrial fibrillation, stroke, and syncope. 
3. History of migraines (migraines occurs in up to 50% of patients with an intracardiac shunt).
4. History of congenital heart disease, structural heart disease, or patent foramen ovale.
5. Family history
6. Social history, tobacco use.

Physical Examination Findings:[3][4][1]

1. Physicians should look for signs of congenital heart defects such as right ventricular hypertrophy, digital clubbing, or fixed S2 splitting.
2. Full neurological evaluation (ie: speech or visual abnormality, unilateral weakness, seizures, and swallowing difficulties).
3. Peripheral pulse evaluation and assessment for limb ischemia (ie: extremity involved may present with a sudden onset, be cold,  pulseless, and painful)

Evaluation

The diagnosis of paradoxical embolism is one of exclusion.  Other causes for the patient's signs and symptoms should be considered first.

The evaluation should include:[9][1][3][4][2]

• EKG to assess for arrhythmia or atrial fibrillation.
• Transthoracic echocardiogram (TTE) with color-flow Doppler to evaluate for intracardiac shunts, cardiac myxomas, and thrombus formations. Agitated saline or contrast can also be injected during TTE to help visualize and diagnose an intracardiac shunt. However, to accurately diagnose a PFO, the saline or contrast needs to be injected at the end of a Valsalva maneuver where the left of right shunt transiently reverses. TTE can also be used to evaluate for the presence of aortic plaques in the ascending aorta.
• Transcranial Doppler sonography (TCD) to detect any shunt, including PAVM. TCD is non-invasive and can be done at the bedside by injecting agitated contrast into a peripheral line and looking for microemboli in the middle cerebral artery.
• Ear oximetry is a simple screening tool for intracardiac shunts that can be utilized with high sensitivity and specificity. When the patient performs a Valsalva maneuver, the left to right shunt transiently turns into a right to left shunt, resulting in a transient decrease in the arterial oxygen saturation, which is detected by the ear oximeter.
• Coagulation studies, including tests for protein C and S antigen levels.
• D-Dimer levels if pulmonary embolism is suspected
• Arterial blood gas will help determine the oxygenation and ventilation status.
• Ultrasound to evaluate for a DVT
• CT angiography scan of the chest to assess for a pulmonary embolus.
• Noncontrast CT scan of the brain to assess for intracranial hemorrhage.
• CT angiogram or MRI for acute occlusion of the extremity, kidneys, or bowel.
• Ancillary blood chemistries and urinalysis as indicated to assess for other metabolic causes.

Treatment / Management

The treatment of paradoxical embolism is based on both medical and surgical approaches.  The treatment pathways are divided into three general approaches:[1][4][3](B3)

1. Elimination of the pathway allowing embolization (through surgical or percutaneous approach)
2. Medical treatment to prevent recurrent episodes of venous thrombosis.
3. Combination of medical and surgical approaches

The choice of either and its specific plan is dependent on the risk of stroke recurrence, the lifelong benefit/risk ratio between antithrombotic therapy and surgery, as well as the cost of each intervention. The surgical approach includes occlusion of intracardiac shunts and PAVMs. Medical therapy is comprised of antithrombotic therapy, which includes aspirin, or clopidogrel as monotherapy or taken in combination with warfarin for the prevention of thrombotic events.

The initial treatment is always anticoagulation. If the patient has an intracardiac communication, it may be closed percutaneously or with open-heart surgery. Today, many types of devices are available to close cardiac shunts percutaneously with minimal morbidity.

Thrombolysis is often used in acute cases where the patient is hemodynamically unstable. Both DVT and pulmonary embolus need long term anticoagulation treatment. Some patients may need to be on antiplatelet therapy for life.

Differential Diagnosis

• Deep vein thrombosis
• Septic phlebitis
• Varicose veins
• Endocarditis

Prognosis

The prognosis after paradoxical embolism depends on the organ affected and the extent of the injury. Patients with CNS events usually tend to fare worse. Those who suffer mesenteric ischemia or a cold leg may be salvaged with surgery. On the other hand, renal infarction usually never recovers.

Complications

Complications include:

• Hemiplegia
• Seizures
• Aphasia
• Weakness
• Speech deficits
• Acute myocardial infarction
• Arrhythmias
• Kidney failure
• Loss of limb function due to amputation
• Death