SECTION 1
CLINICAL CASE PRESENTATION
The patient is a 51-year-old man with a past history of hyperlipidemia and hypertension who presented with a right-sided headache, nausea, diaphoresis, and vertigo. He had a similar episode of vertigo for 30 minutes 6 weeks prior to his presentation.
General physical examination including cardiac exam was normal. Neurological examination was normal except for slight fine horizontal nystagmus to right gaze and rotatory nystagmus to left gaze. MR scan of the brain demonstrated a right inferior cerebellar infarct. MR angiogram of the head and neck was normal except the right posterior inferior cerebellar artery was not visualized. Transthoracic echocardiography revealed normal left ventricular size and function, no valvular disease. With saline contrast, a right-to-left shunt was seen consistent with a patent foramen ovale (Figure 8-1-1). Lower extremity duplex was normal. No venous thrombosis was identified. ECG and telemetry during his hospitalization revealed normal sinus rhythm. He was begun on aspirin 81 mg daily. His vertiginous symptoms resolved in 1 to 2 weeks.
FIGURE 8-1-1 Transthoracic echo demonstrating a hypermobile atrial septum (top panel) and an atrial level right-to-left shunt with Valsalva (bottom panel).
CLINICAL FEATURES
• A patent foramen ovale (PFO) is a functional anatomical opening in the interatrial septum that allows fetal shunting of oxygenated blood from systemic venous return to the left side of the heart in utero.
• When this anatomical remnant persists into childhood and adult life, it rarely results in pathology.
• In the setting of right-to-left heart shunting, PFOs have been implicated in contributing to postural desaturation syndromes, migraine headaches, decompression illness after deep-water scuba diving, and ischemic stroke related to paradoxical embolization.
EPIDEMIOLOGY
• PFOs are found in up to 27% of adults. Their incidence continues to decline with aging.1
• The relationship between PFO and embolic stroke related to paradoxical embolization is controversial. Some studies suggest that PFOs are more common in patients suffering a cryptogenic stroke, though ultimate causality has not been established.1
• Shunting may occur across a PFO during Valsalva or other causes of elevated right atrial pressures. The presence of a PFO with persistent/continuous right-to-left shunt may confer a higher stroke risk than intermittent shunting.
• An atrial septal aneurysm (ASA) is a hypermobile septum primum that demonstrates >10 mm of excursion into the alternating atria during the cardiac cycle (Figure 8-1-2). It is found in 2% of adults and may further increase the risk of stroke when associated with a PFO and right-to-left atrial shunting.6
FIGURE 8-1-2 Transesophageal echo demonstrating an atrial septal aneurysm with a right-to-left shunt via a patent foramen ovale (PFO).
PATHOPHYSIOLOGY AND ETIOLOGY
• Right-to-left shunting across a PFO occurs most commonly in early systole, when the right atrial pressure is highest.
• Stroke caused by paradoxical embolization requires introduction of thrombus, air, bone, fat, or other substances capable of entering the venous system and shunting through the PFO to avoid filtration within the lung.
ECHOCARDIOGRAPHY
• Multiplane transesophageal echocardiography (TEE) using Doppler imaging and contrast injection with the Valsalva maneuver is the gold standard for detection of PFO and associated septal pathology.7
• For contrast studies, 9 cc of saline is mixed with a small amount of air (eg, 0.5-1 cc) with or without the addition of a small amount of the patient’s blood (0.5-1 cc). This solution is then agitated between two 10-cc syringes attached to an antecubital IV through a triple port stopcock apparatus. After the solution has become opaque due to vigorous agitation, the contents are injected intravenously during a Valsalva maneuver. Contrast seen by echocardiography in the left atria during the first 3 to 5 cardiac cycles are suggestive of right-to-left shunting at the atrial level. Less than 20 bubbles are seen with small PFOs. Twenty to fifty bubbles are seen with moderate sized PFOs. Greater than 50 bubbles are noted with large PFOs.7
• Three-dimensional TEE allows for improved determination of PFO size and structure. Additionally, color flow Doppler can demonstrate flow through the PFO, which may be bidirectional.
• Some evidence exists favoring femoral, rather than antecubital, injection of echo contrast, since the trajectory of blood flow from the inferior vena cava may more readily reveal shunting.7
OTHER DIAGNOSTIC TESTING AND PROCEDURES
• Cardiac MRI has been used to identifying atrial septal pathology, though data regarding its sensitivity is mixed. Even less data is available for cardiac CT in the evaluation of PFO.
• Transcranial Doppler (TCD) is an ultrasonic technique that can identify emboli passing through the proximal intracranial vessels. Systemic shunting can be exhibited by peripheral agitated saline/contrast administration. TCD identifies emboli resulting from TEE-demonstrated PFOs with a high degree of sensitivity (94%) and has been shown to discover additional shunts not seen via TEE techniques.7 TCD detects emboli from pulmonary and systemic arterial venous malformations (AVMs) as well as other sources of shunting and arterial embolism. TCD and TEE are complimentary tools in the detection of cardioembolic disease.
• For patients with pathology allowing paradoxical embolism, lower extremity duplex or CT venogram of the pelvis and lower extremity can be used to identify deep vein thrombus at risk for paradoxical embolization.
DIFFERENTIAL DIAGNOSIS
• Atrial septal defects, including sinus venosus defects, and intrapulmonary AVMs may cause right-to-left shunting thought to be caused by PFOs. Pulmonary AVMs produce left atrial bubbles typically delayed greater than 3 to 5 cardiac cycles after intravenous injection.
DIAGNOSIS
• Echocardiography with a contrast bubble study is recommended for identification of PFO. TEE studies have greater sensitivity, though many institutions prefer to screen patients utilizing a transthoracic echocardiogram (TTE). Given the uncertain relationship between PFO and stroke, the aggressiveness of diagnostic testing should take into account the impact that this diagnosis may or may not have on subsequent stroke therapy.
MANAGEMENT
• In the PICSS study, a subset of patients having PFO were randomized to warfarin or aspirin and followed for 2 years for evidence of cerebral infarction. No difference in the stroke rate was seen between these two therapies.8 As a result, patients with PFO and stroke should be treated with antiplatelet agents for secondary stroke prevention.
• In a recently released randomized study evaluating the impact of PFO closure on recurrent stroke, rates of stroke were not reduced with PFO closure. Additionally, identification of recurrent stroke was associated with factors unrelated to the PFO, namely paroxysmal atrial fibrillation.9 The PRECISE study failed to show conclusive evidence that interventional PFO closure reduces cryptogenic stroke rate.10 Only 70% to 71% of patients had complete closure of their PFO on repeat TEE in each of these studies. While PFO closure may not reduce the risk of stroke, there is some evidence that postprocedure rates of atrial fibrillation are increased.
• Despite the possible increased risk of stroke with PFO with an ASA, there is no proven benefit in therapeutic anticoagulation for these patients.1
• Regardless of the suspicion of paradoxical embolization, noninfectious deep venous thrombosis should be treated with unfractionated or low molecular weight heparin followed by warfarin with a goal INR of 2.0 to 3.0. Inferior vena cava filters may be indicated for patients with contraindications to anticoagulant therapy.
FOLLOW-UP
• Given the lack of causality between PFO and embolic stroke, routine follow-up with echocardiography is not recommended. Recurrent stroke should prompt a reevaluation of the patient’s modifiable risks and perhaps exploration of other cardioembolic risks that would prompt changes in preventive strategy. Patients with recurrent events may be considered for enrollment in ongoing clinical trials exploring the role of PFO closure.
REFERENCES
1. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:227-276.
2. Dafer RM, Pasnoor M, Gorton ME, and Gollub S. Chordae tendinae tumor as the cause of cardioembolic stroke. J Stroke Cerebrovasc Dis. 2006;15(2):72-73.
3. Arboix A, and Alio J. Cardioembolic stroke: clinical features, specific cardiac disorders and prognosis. Curr Cardiol Rev. 2010;6:150-161.
4. Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography – summary article. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. (ACC/AHA/ASE 2003 Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). J Am Coll Cardiol. 2003;42:954-970.
5. Douglas PS, Garcia MJ, Haines DE, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 appropriate use criteria for echocardiography: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society of Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, and Society of Cardiovascular Magnetic Resonance. J Am Coll Cardiol. 2011;57(9):1126-1166. doi: 10.1016/j.jacc.2010.11.002.
6. Mas JL, Arquizan C, Lamy C, et al; Patent Foramen Ovale and Atrial Septal Aneurysm Study Group. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. New Engl J Med. 2001;345:1740-1746.
7. Buchholz S, Shakil A, Figtree GA, Hansen PS, Bhindi R. Diagnosis and management of patent foramen ovale. Postgrad Med J. 2012;88:217-225.
8. Homma S, Sacco RL, DiTullio MR, Sciacca RR, Mohr JP; PFO in Cryptogenic Stroke Study (PICSS) Investigators. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation. 2002;105:2625-1631.
9. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366:991-999.
10. Wohrle J, Bertrand B, Sondergaard L, et al. PFO closuRE and CryptogenIc StrokE (PRECISE) registry: a multi-center, international registry. Clin Res Cardiol. 2012;101(10):787-793. Epub 2012 Apr 10.
SECTION 2
CLINICAL CASE PRESENTATION
The patient is a 28-year-old woman with a past history of migraine headaches, and meningitis as a child who presented with aphasia and right-sided weakness. General physical examination including cardiac exam was normal. Neurological examination was normal except for decreased fluency but normal naming, repetition, comprehension, reading, and writing and mild right upper and lower extremity weakness. MR scan of the brain demonstrated a left medial frontal, parietal infarct. MR angiogram of the head and neck revealed a proximal left anterior cerebral artery occlusion. Transthoracic and transesophageal echocardiography revealed normal left ventricular size and function and no hemodynamically significant valvular disease or shunts. Valvular strands were seen on the aortic valve on transthoracic echocardiography (Figure 8-2-1) and on both the mitral and aortic valves on TEE (Figure 8-2-2). ECG and telemetry during her hospitalization revealed normal sinus rhythm.
FIGURE 8-2-1 Transthoracic echo demonstrating a large strand on the aortic valve.
FIGURE 8-2-2 Transesophageal echo demonstrating valve strands on the aortic valve (top panel) and mitral valve (bottom panel).
She was begun on aspirin 81 mg daily. Her symptoms improved over days and resolved within weeks.
CLINICAL FEATURES
• Valvular strands are also called Lambl’s excresences. They are filiform structures that can be found on native or prosthetic valves. They commonly occur on the ventricular side of the aortic valve, or the atrial side of the mitral valve.1
• Valvular strands are usually clinically asymptomatic.
EPIDEMIOLOGY
• Valvular strands can be found in 5.5% of the general population and tend to occur in younger individuals.2,3
• Strands are comprised of a fibroelastic avascular core covered by a single layer of endothelial cells.3 This single layer differentiates them from papillary fibroelastomas. The pathogenesis of Lambl’s excresences is unclear, but they may arise from valvular denuding that occurs under high shear stress that is subsequently covered by fibrin.
• Valvular strands are a potential embolic source, though their occurrence has not been consistently shown to increase stroke risk.4
PATHOPHYSIOLOGY AND ETIOLOGY
• Valvular strands, seen on both native and prosthetic valves, have been hypothesized to cause stroke or TIA from embolization. It is unclear if the strands embolize or if thrombus forms on the strands and subsequently embolizes.
ECHOCARDIOGRAPHY
• Excrescences are typically less than 2 mm in diameter and are elongated in shape.4 They are typically positioned near the leaflet closure lines, differentiating them from other valvular pathology.
• Strands are twice as common on the mitral valve and on valves that are thickened or redundant.5
• Mitral and aortic valves and other left heart structures are better seen on TEE than TTE.6
OTHER DIAGNOSTIC TESTING AND PROCEDURES
• Echocardiography is the primary modality for identification of valvular strands. Given the benign nature of this finding, diagnostic testing after stroke should be targeted toward tests capable of identifying more likely sources of emboli.
DIFFERENTIAL DIAGNOSIS
• Valvular strands must be differentiated from myxomas, valvular thrombi and vegetations, cardiac metastases, primary cardiac neoplasms, and fibroelastomas.3 Papillary fibroelastomas are the most common valvular tumor and are histopathologically distinct from strands in their multiple endothelial layers.7
DIAGNOSIS
• Diagnosis of valvular strands is made by echocardiography. Identification of strands after ischemic stroke does not alter the recommended treatment of antiplatelet therapy. Diagnostic rigor should follow the clinical concern for other valvular pathology.
MANAGEMENT
• In patients with valvular strands, no difference in recurrent stroke risk has been noted when comparing antiplatelet and anticoagulant therapy.8 Therefore, antiplatelet therapy is recommended for secondary stroke prevention.4
• These strands may be considered a potential embolic source or as a marker of potential embolic risk, especially when detected on prosthetic valves.9
• When valvular strands arise from mechanical prosthetic valves, warfarin anticoagulation with a goal INR between 2.5 and 3.5 is recommended. If stroke recurs despite this regimen, low-dose aspirin (75-100 mg) should be added to warfarin, if the patient has previously not been on aspirin therapy.4,9
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