Paradoxical Embolic Stroke : Diagnosis and Management

Pathophysiology of Patent Foramen Ovale in Stroke

PFO is a common congenital cardiac finding. While in utero, the positioning of the septum primum and secundum acts as a one-way valve, facilitating right-to-left shunting of oxygenated blood provided via the umbilical vein. At the time of birth, pulmonary ventilation dramatically increases pulmonary perfusion and reverses the previous right-to-left pressure gradient, leading to a functional closure of the foramen ovale. In about 75% of healthy adults, permanent anatomical closure occurs via fibrous adhesions, while in the remaining 25%, the shunt persists, resulting in a PFO. The one-way nature of the valve is often preserved, so right-to-left shunting can occur when right-sided cardiac pressures increase, such as with Valsalva maneuver, coughing, or a number of pathologic conditions. Importantly, the right-to-left shunt acts as a potential conduit for paradoxical embolization, or it may also foster stagnant blood, ultimately promoting in situ thrombus formation. PFO may also be associated with increased risk of atrial arrhythmia.

The relationship between PFO and stroke is strongest among young patients with cryptogenic stroke in case-control studies. The Risk of Paradoxical Embolism (RoPE) study merged 12 cohorts of cryptogenic stroke patients, 2546 total patients, in order to investigate factors associated with the presence of PFO and to determine the likelihood that a patient's PFO was pathogenically related to the stroke ( Box 39.1 ). In brief, the younger the patient, and the fewer traditional risk factors present, the more likely a PFO is to be identified during the workup, and thus the more likely it was to have been involved in the genesis of the stroke. The score can help physicians counsel patients and determine a course of action. The higher the number, the more likely the PFO was to be related to the stroke, with a score of ≥6 suggesting that it is more likely than not that the PFO was pathogenic. While observational studies have been inconsistent, the presence of certain echocardiographic features may convey a higher risk of stroke ( Box 39.2 ). Finally, some clinical clues may suggest that a PFO was causally related to the stroke, including history of DVT or pulmonary embolism, recent prolonged travel, migraine, and a Valsalva-type maneuver at onset of the stroke.

Complete Evaluation of A Young Patient With Stroke

It is first important to discuss that there are multiple conditions that cause focal neurologic dysfunction that can mimic a stroke, but these would entail a different workup and treatment, as described in Table 39.1 . If a stroke is confirmed, secondary prevention depends on identifying the mechanism of the first event, if possible. Thus a thorough workup following a stroke is critical to optimally reducing stroke risk. Because of the high prevalence of PFO in the general population, and low risk of stroke related to PFO, it should not be considered the proximate cause until the workup is complete and an alternative source of stroke has been ruled out.

Table 39.2 reviews the various potential stroke etiologies that should be considered in a young patient. While stroke is a clinical diagnosis, evaluation typically starts with brain imaging. Computed tomography (CT) is useful in the emergency setting in order to exclude an intracerebral hemorrhage, but in the absence of clear ischemic injury on CT, magnetic resonance imaging (MRI) may provide more information regarding the size and distribution of infarcts, timing, and evidence of chronic strokes. While MRI is not always necessary, in the context of young patients with unclear cause of stroke, MRI is helpful to identify acute and/or chronic infarcts in multiple territories, which would be consistent with cardioembolism. Alternatively, MRI may confirm that the injury is exclusively small-vessel disease.

Vascular imaging is critical to addressing the possibility of a large artery process. If the stroke occurred within the distribution of the carotid arteries, Doppler ultrasonography is a reasonable minimal screening test for carotid bifurcation disease. However, it is important to note that dissection is a common mechanism for stroke in young patients, and ultrasound is not as sensitive to detect dissection, as the lesion is often more distal than ultrasound can insonate. Thus CT angiogram or MR angiogram (MRA) of the head and neck is appropriate to more thoroughly evaluate the complete cervicocephalic vasculature, in addition to the posterior circulation (vertebrobasilar system). This may also provide insight into the possibility of an underlying vasculopathy. If a vasculopathy is identified and is of uncertain cause, a conventional angiogram may also be warranted.

A complete cardiac workup is critical to ruling out a cardiac source of embolism. Although it is considerably less prevalent in younger populations, atrial fibrillation is a well-characterized cause of stroke. All patients should have an EKG and at least 24 hours of rhythm monitoring during admission. After discharge, long-term monitoring increases the likelihood of capturing occult atrial fibrillation, but the low rate of atrial fibrillation in patients under 45 likely limits the utility in that population. Every stroke patient should undergo an echocardiogram to assess for cardioembolic sources such as reduced ejection fraction, cardiomyopathy, regional wall motion abnormalities, noncompaction, valvular vegetations, tumors, intracardiac thrombus, aortic arch atheroma, and of course PFO. The gold standard for PFO detection is direct visualization of intracardiac shunting with agitated saline during transesophageal echocardiogram (TEE). TEE is also most sensitive to detect valve lesions, left atrial appendage thrombus, and aortic pathology. Transthoracic echocardiography is most helpful to identify ventricular pathology and is generally less sensitive for detection of PFO. For detection of right-to-left shunt, transcranial Doppler ultrasonography (TCD) of the cerebral vessels during intravenous injection of agitated saline is comparable to TEE, but fails to directly visualize the PFO, cannot differentiate cardiac from noncardiac right-to-left shunts, and most importantly, does not allow for detection of other mechanisms of stroke and transient ischemic attack (TIA) originating in the heart and aorta.

Laboratory studies address a number of common and uncommon causes of stroke. As a part of the initial evaluation, a complete blood count, prothrombin time, partial thromboplastin time, cholesterol panel, and hemoglobin A1C should be collected. Inflammatory markers such as ESR or CRP are an appropriate screen for vasculitis—in particular temporal arteritis in the older population. If there is concern for vasculopathy or vasculitis, a more comprehensive autoimmune screen is warranted, but will not be described in detail here. In patients thought to be at risk of cancer with an otherwise unexplained stroke mechanism, an elevated D-dimer may increase concern for hypercoagulability of malignancy, and elevated pro-BNP may increase the suspicion of occult atrial fibrillation. A toxicology screen should be performed in all patients because of the relationship between sympathomimetic drugs and stroke with or without vasculopathy. The potential relationship between stroke and marijuana remains controversial, but there are recent reports of stroke associated with use of synthetic cannabinoids. In young patients with first stroke, strong family history of early stroke or known thrombophilia, or recurrent unexplained stroke, a hypercoagulable screen beyond basic coagulation studies should be performed. In the acute setting, this should include prothrombin gene mutation, factor V Leiden, homocysteine, and antiphospholipid antibody panel (including lupus anticoagulant, anticardiolipin antibodies, and beta-2-glycoprotein). After the acute phase, protein C, protein S, and antithrombin III can be measured, as these values may be perturbed in the setting of acute thrombosis. For a more detailed description of the thrombophilia workup, please refer to Chapter 22 , Box 22.1 .

If a complete stroke workup ( Box 39.3 ) reveals a potential cause of stroke, such as large vessel atherosclerosis, arterial dissection, or atrial fibrillation, secondary stroke prevention should target this known mechanism. Because PFO is common, associated with a low risk of stroke relative to other known mechanisms, and can reasonably be treated with antiplatelet or anticoagulant medication described as follows, it should generally be considered incidental if another compelling mechanism is identified.