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Transesophageal Echocardiography in Source-of-Embolism Evaluation: The Search for a Better Therapeutic Rationale

      Etiology and Evaluation of Stroke

      The search for an underlying etiology in individual stroke patients is born of a desire to use safe and effective secondary preventive therapy specific to the cause of the initial event. Current estimates of the frequency of various etiologies of nonhemorrhagic stroke were recently reviewed authoritatively by Albers et al in the American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy (Figure 1).
      • Albers GW
      • Eastern JD
      • Sacco RL
      • Tea] P
      Antithrombotic and thrombolytic therapy for Ischemie stroke.
      Initial attempts to distinguish among these causes begin with computed tomographic scanning to differentiate hemorrhagic from nonhemorrhagic stroke, neurologic and cardiovascular assessments (history, examination, electrocardiogram, chest radiograph), complete blood cell count with sedimentation rate and coagulation time, chemistry, and lipid studies, and a neurovascular study, usually with carotid duplex ultrasonography. If these fail to document a cause for stroke, further study with magnetic resonance imaging (MRI) of the brain, magnetic resonance angiography, cerebral angiography, or specialized studies for hypercoagu-lable states may be undertaken.
      • Brown Jr, RD
      • Evans BA
      • Wiebers DO
      • Petty GW
      • Meissner I
      • Dale AJD
      Mayo Clinic Division of Cerebrovascular Diseases. Transient ischcmic attack and minor sischcmic stroke: an algorithm for evaluation and treatment.
      Figure thumbnail gr1
      Fig. 1Sources of ischemie stroke.
      Data from Albers et al.
      • Albers GW
      • Eastern JD
      • Sacco RL
      • Tea] P
      Antithrombotic and thrombolytic therapy for Ischemie stroke.
      Unfortunately, such evaluations fail to define the cause of stroke in 30% to 40% of nonhemorrhagic, nonlacunar, abrupt-onset strokes. The suspicion that cardiogenic embolism accounts for many of these so-called cryptogenic strokes serves as an impetus to perform source-of-embolism transesophageal echocardiography (SOE-TEE). An SOE determination is the most frequent reason for referral for TEE.
      • Khandheria BK
      • Seward JB
      • Tajik AJ
      Transesophageal echocardiography.
      However, past associations between TEE findings and stroke were often based on case-control analyses in which the “controls” were actually other cardiac patients referred to laboratories for TEE. It is therefore reassuring to see the results of the Stroke Prevention: Assessment of Risk in a Community (SPARC) investigators
      • Meissner L
      • Whisnant JP
      • Khandheria BK
      • et al.
      Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study.
      in a randomly selected adult TEE population, to note their similarity to a much smaller prior study,
      • Roijer A
      • Lindgrcn A
      • Rudling O
      • et al.
      Potential cardioembolic sources in an elderly population without stroke.
      and to juxtapose these results beside case series of patients with consecutive
      • Amarenco P
      • Cohen A
      • Tzourio C
      • et al.
      Atherosclerotic disease of the aortic arch and the risk of ischcmic stroke.
      • Jones EF
      • Kaiman JM
      • Calafiore P
      • Tonkin AM
      • Donnan GA
      Proximal aortic atheroma; an independent risk factor for cerebral ischemia.
      or cryptogenic stroke
      • Di Tullio M
      • Sacco RL
      • Gopal A
      • Mohr JP
      • Homma S
      Patent foramen ovale as a risk factor for cryptogenic stroke.
      • Petty GW
      • Khandheria BK
      • Chu CP
      • Sicks JD
      • Whisnant JP
      Patent foramen ovale in patients with cerebral infarction: a transesophageal echocardiographic study.
      • Serena J
      • Segura T
      • Perez-Ayuso MJ
      • Bassaganyas J
      • Molins A
      • Davalos A
      The need to quantify right-to-left shunt in acute ischcmic stroke: a case-control study.
      who underwent extensive SOE work-ups (Table 1).
      Table 1Prevalence of Specific Entities Associated With Stroke or Controls in Persons Studied With Clinical Evaluation, Electrocardiography, Transesophageal Echocardiography, and Carotid Imaging
      Ellipses indicate data not available.
      Controls
      • Roijer A
      • Lindgrcn A
      • Rudling O
      • et al.
      Potential cardioembolic sources in an elderly population without stroke.
      SPARC
      • Meissner L
      • Whisnant JP
      • Khandheria BK
      • et al.
      Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study.
      Consecutive stroke
      • Amarenco P
      • Cohen A
      • Tzourio C
      • et al.
      Atherosclerotic disease of the aortic arch and the risk of ischcmic stroke.
      Consecutive stroke
      • Jones EF
      • Kaiman JM
      • Calafiore P
      • Tonkin AM
      • Donnan GA
      Proximal aortic atheroma; an independent risk factor for cerebral ischemia.
      Cryptogenic stroke
      • Di Tullio M
      • Sacco RL
      • Gopal A
      • Mohr JP
      • Homma S
      Patent foramen ovale as a risk factor for cryptogenic stroke.
      • Petty GW
      • Khandheria BK
      • Chu CP
      • Sicks JD
      • Whisnant JP
      Patent foramen ovale in patients with cerebral infarction: a transesophageal echocardiographic study.
      • Serena J
      • Segura T
      • Perez-Ayuso MJ
      • Bassaganyas J
      • Molins A
      • Davalos A
      The need to quantify right-to-left shunt in acute ischcmic stroke: a case-control study.
      Atrial fibrillation4%4.7%30%18%
      Patent foramen ovale22%25.6%40%-69%
      Carotid stenosis >70%-80%0.2%13%8%
      Atrial septal aneurysm13%2.1%
      Complex aortic ascending or arch plaque >4-5 mm thick or mobile4%2%14%21%
      * Ellipses indicate data not available.
      Consistent with current concepts of stroke pathogenesis, the consecutive stroke populations demonstrate an excess of atrial fibrillation and carotid stenosis. Of great interest, there also appear to be differences in the frequency of ascending or transverse aortic complex plaque and, in comparison with cryptogenic stroke, of patent foramen ovale (PFO). These findings are important, because transthoracic echocardiography (TTE) cannot detect aortic plaque, and the semiquantitation of the degree of shunt in PFO by TEE appears to be superior to that by TTE.
      • Serena J
      • Segura T
      • Perez-Ayuso MJ
      • Bassaganyas J
      • Molins A
      • Davalos A
      The need to quantify right-to-left shunt in acute ischcmic stroke: a case-control study.
      This offsets, to some extent, prior arguments that have suggested that the cardiac lesions that are proven sources of stroke and for which definitive therapy is known are readily defined without TEE, and that the principal “yield” of SOE-TEE is in detecting cardiac lesions that are putative, minor, or uncertain risks. It does not offset the other principal contention, that routine SOE-TEE may not be justified in the absence of randomized clinical trial data indicating a lesion-specific therapeutic significance of TEE findings.
      • DeRook FA
      • Pearlman AS
      Transesophageal echocardiographic assessment of embolie sources.
      • Autore C
      • Cartoni D
      • Piccininno M
      Multiplane transesophageal echocardiography and stroke.

      Secondary Prevention

      A review of secondary prevention of presumed cardiogenic stroke indicates the extent to which current recommendations, which largely favor anticoagulation, are based on observational studies and expert opinion (class C ACCP recommendation) rather than randomized clinical trials (class A).
      • DeRook FA
      • Pearlman AS
      Transesophageal echocardiographic assessment of embolie sources.
      • Meissner L
      • Whisnant JP
      • Khandheria BK
      • et al.
      Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study.
      • Roijer A
      • Lindgrcn A
      • Rudling O
      • et al.
      Potential cardioembolic sources in an elderly population without stroke.
      • Amarenco P
      • Cohen A
      • Tzourio C
      • et al.
      Atherosclerotic disease of the aortic arch and the risk of ischcmic stroke.
      • Jones EF
      • Kaiman JM
      • Calafiore P
      • Tonkin AM
      • Donnan GA
      Proximal aortic atheroma; an independent risk factor for cerebral ischemia.
      • Di Tullio M
      • Sacco RL
      • Gopal A
      • Mohr JP
      • Homma S
      Patent foramen ovale as a risk factor for cryptogenic stroke.
      • Petty GW
      • Khandheria BK
      • Chu CP
      • Sicks JD
      • Whisnant JP
      Patent foramen ovale in patients with cerebral infarction: a transesophageal echocardiographic study.
      • Serena J
      • Segura T
      • Perez-Ayuso MJ
      • Bassaganyas J
      • Molins A
      • Davalos A
      The need to quantify right-to-left shunt in acute ischcmic stroke: a case-control study.
      • DeRook FA
      • Pearlman AS
      Transesophageal echocardiographic assessment of embolie sources.
      • Warner MF
      • Momah KI
      Routine transesophageal echocardiography for cerebral ischemia.
      • Autore C
      • Cartoni D
      • Piccininno M
      Multiplane transesophageal echocardiography and stroke.
      • Laupacis A
      • Albers G
      • Dalcn J
      • Dunn MI
      • Jacobson AK
      • Singer DE
      Antithrombotic therapy in atrial fibrillation.
      • Stein PD
      • Alpert JS
      • Dalen JE
      • Horstkotte D
      • Turpie AG
      Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.
      • Cairns JA
      • Theroux P
      • Lewis Jr, HD
      • Ezekowitz M
      • Meade TW
      • Sutton GC
      Antithrombotic agents in coronary artery disease.
      • Salem DN
      • Levine HJ
      • Pauker SG
      • Eckman MH
      • Daudelin DH
      Antithrombotic therapy in valvular heart disease.
      Table 2 lists these and, when appropriate, the recommendations from the published American Heart Association/American College of Cardiology (AHA/ACC) guidelines for the management of valvular heart disease and guidelines for the evaluation and management of heart failure.
      • Albers GW
      • Eastern JD
      • Sacco RL
      • Tea] P
      Antithrombotic and thrombolytic therapy for Ischemie stroke.
      • Laupacis A
      • Albers G
      • Dalcn J
      • Dunn MI
      • Jacobson AK
      • Singer DE
      Antithrombotic therapy in atrial fibrillation.
      • Stein PD
      • Alpert JS
      • Dalen JE
      • Horstkotte D
      • Turpie AG
      Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.
      • Cairns JA
      • Theroux P
      • Lewis Jr, HD
      • Ezekowitz M
      • Meade TW
      • Sutton GC
      Antithrombotic agents in coronary artery disease.
      • Salem DN
      • Levine HJ
      • Pauker SG
      • Eckman MH
      • Daudelin DH
      Antithrombotic therapy in valvular heart disease.
      • Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease)
      ACC/AHA guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association.
      • Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure)
      Guidelines for the evaluation and management of heart failure: report of the American College of Cardiology/American Heart Association.
      It seems reasonable to ask whether SOE-TEE contributes meaningfully in determining the choice of therapy in a patient with recent embolism and specific cardiac lesions.
      Table 2Secondary Prevention Therapy for Cardiogenic Stroke, Systemic Embolism, or Transient ischemic Attack
      AC = anticoagulation; INR = international normalized ratio; TIA = transient ischemic attack. Ellipses indicate no recommendation.
      Level of recommendation
      According to American College of Chest Physicians (ACCP)'14–17: Al = methods strong, effect clear; A2 = methods strong, effect equivocal; Cl = methods weak, effect clear; C2 = methods weak, effect equivocal. According to American College of Cardiology/American Heart Association (ACC/AHA)18–19:1 = evidence and/or general agreement regarding safety and efficacy; Ha = conflicting evidence but weight of opinion in favor.
      RisksRecommended therapyACCPACC/AHA
      Major
       Atrial fibrillationAC, INR 2-3AlI
       Mitral stenosisAC, INR 2-3ClI
       Mechanical prosthesisAC, INR 2.5-3.5 + aspirin, 81 mg/dA2 + C2I + IIa
       Recent myocardial infarction Left ventricular thrombusAC, INR 2-3 AC, INR 2-3α2
      For combined end point of death, reinfarction, or stroke.
       Dilated cardiomyopathy?
      Anticoagulation is supported by the weight of opinion, based on natural history, and observations of anticoagulation and outcome in the SAVE and SOLVD studies.
      C2
      ACCP did not favor anticoagulation in left ventricular aneurysm with thrombus; the issue of left ventricular aneurysm and thrombus with recent stroke was not addressed.
      I
       Infective endocarditisAntimicrobials, possible surgery
      ACC/AHA recommends replacing oral anticoagulant with heparin in prosthetic mechanical valve endocarditis; the ACCP recommends continuation of oral anticoagulant.
      ClI
       Cardiac tumorsSurgery
      Minor, uncertain
       Mitral valve prolapseAspirin (TIA)ClI
      AC, INR 2-3 (stroke)ClI
       Mitral annular calcificationAC, INR 2-3
      AC not recommended if embolus identified to be calcific.
      9
       Patent foramen ovaleAC, INR 2-3
      AC recommended if demonstrable venous thrombosis or pulmonary embolism, unless venous interruption or surgical patent foramen ovale closure are considered preferred.
      Cl
       Valve strands?
      Nonbacterial thromboendocarditis vegetations are defined as rounded, sessile, >3-mm lesions with no independent mobility. Valve strands or excrescences are thin (<2 mm), elongated (>3 mm) structures seen near leaflet close lines with independent mobility.17
       Nonbacterial thromboendocarditisHeparin
      • Amarenco P
      • Cohen A
      • Tzourio C
      • et al.
      Atherosclerotic disease of the aortic arch and the risk of ischcmic stroke.
      Cl
       Upstream complex aortic plaque?
      * AC = anticoagulation; INR = international normalized ratio; TIA = transient ischemic attack. Ellipses indicate no recommendation.
      According to American College of Chest Physicians (ACCP)'
      • Laupacis A
      • Albers G
      • Dalcn J
      • Dunn MI
      • Jacobson AK
      • Singer DE
      Antithrombotic therapy in atrial fibrillation.
      • Stein PD
      • Alpert JS
      • Dalen JE
      • Horstkotte D
      • Turpie AG
      Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.
      • Cairns JA
      • Theroux P
      • Lewis Jr, HD
      • Ezekowitz M
      • Meade TW
      • Sutton GC
      Antithrombotic agents in coronary artery disease.
      • Salem DN
      • Levine HJ
      • Pauker SG
      • Eckman MH
      • Daudelin DH
      Antithrombotic therapy in valvular heart disease.
      : Al = methods strong, effect clear; A2 = methods strong, effect equivocal; Cl = methods weak, effect clear; C2 = methods weak, effect equivocal. According to American College of Cardiology/American Heart Association (ACC/AHA)
      • Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease)
      ACC/AHA guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association.
      • Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure)
      Guidelines for the evaluation and management of heart failure: report of the American College of Cardiology/American Heart Association.
      :1 = evidence and/or general agreement regarding safety and efficacy; Ha = conflicting evidence but weight of opinion in favor.
      For combined end point of death, reinfarction, or stroke.
      § ACCP did not favor anticoagulation in left ventricular aneurysm with thrombus; the issue of left ventricular aneurysm and thrombus with recent stroke was not addressed.
      Anticoagulation is supported by the weight of opinion, based on natural history, and observations of anticoagulation and outcome in the SAVE and SOLVD studies.
      ACC/AHA recommends replacing oral anticoagulant with heparin in prosthetic mechanical valve endocarditis; the ACCP recommends continuation of oral anticoagulant.
      # AC not recommended if embolus identified to be calcific.
      ** AC recommended if demonstrable venous thrombosis or pulmonary embolism, unless venous interruption or surgical patent foramen ovale closure are considered preferred.
      †† Nonbacterial thromboendocarditis vegetations are defined as rounded, sessile, >3-mm lesions with no independent mobility. Valve strands or excrescences are thin (<2 mm), elongated (>3 mm) structures seen near leaflet close lines with independent mobility.
      • Salem DN
      • Levine HJ
      • Pauker SG
      • Eckman MH
      • Daudelin DH
      Antithrombotic therapy in valvular heart disease.
      Dilated Cardiomyopathy.—It is controversial whether or not to recommend anticoagulation for patients with dilated cardiomyopathy and sinus rhythm.
      • Baker DW
      • Wright RF
      Management of heart failure, [V: anticoagulation for patients with heart failure due to left ventricular systolic dysfunction.
      However, an AHA/ACC guideline supports anticoagulation for patients with systolic dysfunction and prior pulmonary or systemic embolization (Table 2).
      • Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure)
      Guidelines for the evaluation and management of heart failure: report of the American College of Cardiology/American Heart Association.
      The ACCP recommendations do not directly address secondary prevention of thromboembolism in dilated cardiomyopathy. Recent observations on outcomes of patients managed with and without anticoagulation in the Survival and Ventricular Enlargement (SAVE) and Studies of Left Ventricular Dysfunction (SOLVD) protocols have suggested the benefit of anticoagulation.
      • Ezekowitz M
      Antithrombotics for left-ventricular impairment?.
      • Al-Khadra AS
      • Salem DN
      • Rand WM
      • Udelson JE
      • Smith JJ
      • Konstant MA
      Warfarin anticoagulation and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction.
      Since the recommendation is based on observational data rather than on randomized trial data, the AHA/ACC guideline would equate to a qualified C1 ACCP recommendation. The Warfarin Aspirin Reduced Cardiac Ejection Fraction (WARCEF) Study is a multicenter grant proposal that has been submitted to the National Institutes of Health. In it, patients with reduced ejection fraction with or without prior nondisabling stroke will be eligible for randomization to anticoagulation vs aspirin protocols. If completed, this study would provide important data on primary and secondary stroke prevention in patients with ischemic and dilated cardiomyopathy.
      Either TEE or TTE can assess left ventricular performance adequately, while TEE would likely detect smaller chamber-based thrombi than TTE.
      Patent Foramen Ovale.—There is evidence to suggest that physicians are making therapeutic decisions in patients with PFO on the basis of findings of TEE. In Table 3, studies are cited in which physicians used different treatments—anticoagulant or antiplatelet therapy or surgical closure of PFOs—in patients meeting certain criteria.
      • Devuyst G
      • Bogousslavsky J
      • Ruchat P
      • et al.
      Prognosis after stroke followed by surgical closure of patent foramen ovale: a prospective follow-up study with brain MRL and simultaneous transesophageal and transcranial Doppler ultrasound.
      • Mas JL
      • Zuber M
      • French Study Group on Patent Foramen Ovale and Atrial Septal Aneurysm
      Recurrent cerebrovascular events in patients with patent foramen ovale, atrial septal aneurysm, or both and cryptogenic stroke or transient ischcmic attack.
      While TTE can detect PFO, the superior resolution of TEE increases the sensitivity of the examination, allows easier measurement of diameter, and makes it easier to semi-quantitate the number of contrast targets that cross the defect from the right to the left atrium.
      • Serena J
      • Segura T
      • Perez-Ayuso MJ
      • Bassaganyas J
      • Molins A
      • Davalos A
      The need to quantify right-to-left shunt in acute ischcmic stroke: a case-control study.
      Devuyst et al
      • Devuyst G
      • Bogousslavsky J
      • Ruchat P
      • et al.
      Prognosis after stroke followed by surgical closure of patent foramen ovale: a prospective follow-up study with brain MRL and simultaneous transesophageal and transcranial Doppler ultrasound.
      have suggested criteria for surgical closure of PFO, including recurrent cerebrovascular events or multiple infarcts on MRI, PFO with greater than 50 microbubbles in the left atrium on contrast TEE, and history of Valsalva maneuver immediately before the onset stroke or transient ischemic attack. However, these criteria do not incorporate a concurrent diagnosis of deep vein thrombosis or pulmonary embolism (DVT/PE) as a necessary condition for use of anticoagulation, venous interruption, or surgical PFO closure, as is recommended by the ACCP. Because PFO is so common, but paradoxical embolism is uncommon, we too favor a rigorous diagnosis of DVT/PE as a necessary condition to use anticoagulants or surgery in suspected PFO-paradoxical embolism.
      Table 3Stroke, Transesophageal Echocardiography, and Therapeutic Variability
      ReferenceNo.SurgeryAnticoagulationAntiplatelet
      Patent foramen ovaleDevuyst et al
      • Devuyst G
      • Bogousslavsky J
      • Ruchat P
      • et al.
      Prognosis after stroke followed by surgical closure of patent foramen ovale: a prospective follow-up study with brain MRL and simultaneous transesophageal and transcranial Doppler ultrasound.
      1388%26%66%
      Cujec et al
      • Cujec B
      • Mainra R
      • Johnson DH
      Prevention of recurrent cerebral ischcmic events in patients with patent foramen ovale and cryptogenic strokes or transient ischcmic attacks.
      9016%42%40%
      Mas & Zuber
      • Mas JL
      • Zuber M
      • French Study Group on Patent Foramen Ovale and Atrial Septal Aneurysm
      Recurrent cerebrovascular events in patients with patent foramen ovale, atrial septal aneurysm, or both and cryptogenic stroke or transient ischcmic attack.
      19% of this population had atrial sept.al aneurysm without patent foramen ovale.
      132025%45%
      Complex
      Aortic ascending or arch plaque >4 mm or mobile components.
      arch plaque
      French Study of4520%53%
       Aortic Plaques in Stroke
      • French Study of Aortic Plaques in Stroke Group
      Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischcmic stroke.
      Mitusch et al
      • Mitusch R
      • Doherty C
      • Wucherpfennig H
      • et al.
      Vascular events during follow-up in patients with aortic arch atherosclerosis.
      4730%52%
      Ferrari et al
      • Ferrari E
      • Vidal R
      • Chevallier T
      • Baudouy M
      Atherosclerosis of the thoracic aorta and aortic debris as a marker of poor prognosis: benefit of oral anticoagulants.
      8457%43%
      * 19% of this population had atrial sept.al aneurysm without patent foramen ovale.
      Aortic ascending or arch plaque >4 mm or mobile components.
      To detect PFO-related stroke, evaluation for DVT/PE must be conducted early after stroke presentation, since DVT/PE secondary to stroke disability is common, especially in nonambulatory patients.
      • Harvey RL
      • Roth EJ
      • Yamold PR
      • Durham JR
      • Green D
      Deep vein thrombosis in stroke: the use of plasma D-dimer level as a screening test in the rehabilitation setting.
      DVT/PE can be effectively excluded if the level of plasma D-dimer, a degradation product of cross-linked fibrin, is less than 500 μg/L
      • Perrier A
      • Bounameaux H
      • Morabia A
      • et al.
      Diagnosis of pulmonary embolism by a decision analysis-based strategy including clinical probability, D-dimer levels, and ultrasonography: a management study.
      • Ginsberg JS
      • Wells PS
      • Kearon C
      • et al.
      Sensitivity and specificity of a rapid whole-blood assay for D-dimer in the diagnosis of pulmonary embolism.
      (by enzyme-linked immunosorbent assay; recent data suggest lesser specificity for the latex agglutination D-dimer assay
      • Kutinsky L
      • Blakley S
      • Roche V
      Normal D-dimer levels in patients with pulmonary embolism.
      ). In consecutive stroke patients, D-dimer level within 1 week of presentation for all cardioembolic strokes averaged near 500 mg/L, but mean + 1 SD values for D-dimer were less than 500 mg/L for atherothrombotic and lacunar subtypes.
      • Feinberg WM
      • Erickson LP
      • Bruck D
      • Kittelson J
      Hemostatic markers in acute ischcmic stroke: association with stroke type, severity, and outcome.
      • Uchiyama S
      • Yamazaki M
      • Hara Y
      • Iwata M
      Alterations of platelet, coagulation, and fibrinolysis markers in patients with acute ischcmic stroke.
      Venous ultrasonography has been advocated for screening but is unreliable for isolated calf vein thrombi, and two thirds of thrombi documented with venography in patients without leg symptoms are localized in the calf.
      • Kearon C
      • Ginsberg JS
      • Hirsh J
      The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism.
      In a study of 42 of 49 patients with stroke and PFO who underwent venography and duplex ultra-sonographic evaluation, 15 of 24 venographic DVTs were isolated to the calf.
      • Stollberger C
      • Slany J
      • Schuster I
      • Leitner H
      • Winkler WB
      • Karnik R
      The prevalence of deep venous thrombosis in patients with suspected paradoxical embolism [published correction appears in Ann Intern Med. 1994; 120:347].
      This suggests that an algorithm, + D-dimer→TEE (+ PFO)→ venous ultrasonography (– for DVT)→venography, may be necessary to attempt to discriminate “bystander” PFOs from those associated with stroke. In proposing to amend the criteria of Devuyst et al,
      • Devuyst G
      • Bogousslavsky J
      • Ruchat P
      • et al.
      Prognosis after stroke followed by surgical closure of patent foramen ovale: a prospective follow-up study with brain MRL and simultaneous transesophageal and transcranial Doppler ultrasound.
      one might suggest that a single embolie event with a large PFO and documentation of DVT/PE warrants a class C recommendation for anticoagulation, venous interruption, or surgical PFO closure (ACCP recommendation, Table 3).
      Complex Aortic Atheroma—Complex aortic atheroma has been associated with a 3.5- to 4.3-fold increased risk of cardiovascular events and a recurrent stroke rate of 27% over 3 years.
      • Jones EF
      • Kaiman JM
      • Calafiore P
      • Tonkin AM
      • Donnan GA
      Proximal aortic atheroma; an independent risk factor for cerebral ischemia.
      • French Study of Aortic Plaques in Stroke Group
      Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischcmic stroke.
      The TEE identification of aortic plaque and plaque–based thrombus appears to be excellent, with sensitivity and specificity in excess of 90%, while this finding is rarely documented with TTE. Findings on TEE appear to have altered secondary prevention therapy in this lesion as well. Resections of complex aortic atheroma in patients with recurrent embolism have been made in at least 20 patients.
      • Kronzon I
      • Tunick PA
      Transesophageal echocardiography as a tool in the evaluation of patients with embolie disorders.
      • Lapcrche T
      • Laurian C
      • Roudaut R
      • Steg PG
      Filiale Echocardiographic de la Société Française de Cardiologie. Mobile thromboses of the aortic arch without aortic debris: a transesophageal echocardiographic finding associated with unexplained arterial embolism.
      Serial TEE was used to document the disappearance on anticoagulation of mobile, pedunculated, aortic plaque-based thrombi.
      • Lapcrche T
      • Laurian C
      • Roudaut R
      • Steg PG
      Filiale Echocardiographic de la Société Française de Cardiologie. Mobile thromboses of the aortic arch without aortic debris: a transesophageal echocardiographic finding associated with unexplained arterial embolism.
      The strong conviction that aortic atherothrombosis and thromboembolism are the mechanisms responsible for many cerebral infarcts has led to the use of anticoagulants for many patients (see Table 3)
      • French Study of Aortic Plaques in Stroke Group
      Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischcmic stroke.
      • Mitusch R
      • Doherty C
      • Wucherpfennig H
      • et al.
      Vascular events during follow-up in patients with aortic arch atherosclerosis.
      • Ferrari E
      • Vidal R
      • Chevallier T
      • Baudouy M
      Atherosclerosis of the thoracic aorta and aortic debris as a marker of poor prognosis: benefit of oral anticoagulants.
      which in unrandomized comparison with aspirin therapy suggests the superiority of anticoagulation.
      • Ferrari E
      • Vidal R
      • Chevallier T
      • Baudouy M
      Atherosclerosis of the thoracic aorta and aortic debris as a marker of poor prognosis: benefit of oral anticoagulants.
      The safety of anticoagulation in patients with complex aortic plaque was recently suggested by observations in an atrial fibrillation-TEE population.
      • Blackshear JL
      • Zabalgoitia M
      • Pennock G
      • et al.
      Stroke Prevention and Atrial Fibrillation Transesophageal Echocardiography Investigators. Warfarin safety and efficacy in patients with thoracic aortic plaque and atrial fibrillation. Transesophageal echocardiography.
      Current therapy is uncertain.
      The Aortic plaque–Related Cerebral Hazard (ARCH) and Anticoagulant Antiplatelet Aortic Atherosclerosis (4A) studies have been submitted to funding agencies in Europe, Australia, and North America. In these proposed studies, in which a shared steering committee and protocol would be used, patients with recent embolism attributed to upstream complex aortic plaque would be assigned randomly to anti–coagulation, aspirin, or combined aspirin plus clopidogrel. If completed, these studies would provide a much stronger basis for therapy for this lesion, which appears to be over-represented in consecutive stroke cohorts.
      Valve Strands.—Valve strands are detected more frequently with TEE vs TTE. Unlike intracardiac thrombi, they persist on serial examinations.
      • Roldan CA
      • Shivcly BK
      • Crawford MH
      Valve excrescences: prevalence, evolution and risk for cardioembolism.
      • Ntghoghossian N
      • Derex L
      • Perinetti M
      • et al.
      Course of valvular strands in patients with stroke: cooperative study with transesophageal echocardiography.
      However, the SPARC results appear to weaken those of prior studies that have suggested an increased risk of stroke associated with valve strands. Strand prevalence in principal reports of ischcmic stroke was 22.5%, 41%, and 47%,
      • Roldan CA
      • Shivcly BK
      • Crawford MH
      Valve excrescences: prevalence, evolution and risk for cardioembolism.
      • Cohen A
      • Tzourio C
      • Chauvcl C
      • Bertrand B
      • French Study of Aortic Plaques in Stroke (FAPS) Investigators
      • et al.
      Mitral valve strands and the risk of ischcmic stroke in elderly patients.
      • Roberts JK
      • Omarali I
      • Di Tullio MR
      • Sciacca RR
      • Sacco RL
      • Homma S
      Valvular strands and cerebral ischemia: effect of demographics and strand characteristics.
      which is strikingly similar to the SPARC value of 46.4% and to the value of 38% reported by Roldan et al
      • Roldan CA
      • Shivcly BK
      • Crawford MH
      Valve excrescences: prevalence, evolution and risk for cardioembolism.
      in normal volunteers. Control values from prior studies were sometimes drawn from other patients referred for TEE, in whom rates of strands were 12.1% and 16%,
      • Cohen A
      • Tzourio C
      • Chauvcl C
      • Bertrand B
      • French Study of Aortic Plaques in Stroke (FAPS) Investigators
      • et al.
      Mitral valve strands and the risk of ischcmic stroke in elderly patients.
      • Roberts JK
      • Omarali I
      • Di Tullio MR
      • Sciacca RR
      • Sacco RL
      • Homma S
      Valvular strands and cerebral ischemia: effect of demographics and strand characteristics.
      suggesting under-detection or underreporting in a non-SOE referral population. These data do not support therapeutic decision making for secondary prevention on the basis of strands alone.

      Ongoing Stroke Trials

      Prior trials in stroke and atrial fibrillation have demonstrated excessive major hemorrhage associated with high intensity of anticoagulation, international normalized ratios (INRs) of 3.0 to 4.5; unfortunately low anticoagulation intensity, INRs of 1.2 to 1.5, was found to be ineffective when combined with aspirin for stroke prophylaxis in atrial fibrillation and, following myocardial infarction, did not add benefit to aspirin alone for prevention of reinfarction, stroke, or cardiovascular death.
      • Albers GW
      • Eastern JD
      • Sacco RL
      • Tea] P
      Antithrombotic and thrombolytic therapy for Ischemie stroke.
      • Cairns JA
      • Theroux P
      • Lewis Jr, HD
      • Ezekowitz M
      • Meade TW
      • Sutton GC
      Antithrombotic agents in coronary artery disease.
      Within the next 2 years the results of a clinical trial of an intermediate intensity of anticoagulation as secondary prophylaxis for cryptogenic stroke will be presented. In the Warfarin-Aspirin Recurrent Stroke Study (WARSS), nearly 2000 persons with ischemic stroke within 30 days underwent randomization to aspirin, 325 mg/d, vs warfarin, with target INRs of 1.4 to 2.8.
      • Mohr JP
      • WARSS Group
      Design considerations for the Warfarin-Antiplatelet Recurrent Stroke Study.
      Excluded were patients with carotid endarterectomy undertaken for index stroke, valvular prosthesis, atrial fibrillation, ventricular aneurysm, cardiomyopathy, or demonstrated intracardiac thrombus or vegetation. A subset of patients underwent TEE at randomization, and so comparison data on the efficacy and safety of anticoagulant vs aspirin therapy will become available for patients with PFO, complex aortic plaque, and mitral annular calcification.
      • Major ongoing stroke trials
      WARSS may find an across-the-board benefit of anticoagulation or only trends toward benefit confined to specific anatomic subgroups. How we use TEE in the future will likely be affected one way or the other. Importantly, rates of bleeding for patients with recent ischemic stroke managed with an intermediate level of anticoagulation (INR, 1.4-2.8) vs aspirin will be defined by the study.
      In a prior Proceedings Editorial evaluating a work-up-of-stroke algorithm, Caplan
      • Caplan LR
      Of stroke treatment, algorithms, trials, and such [editorial].
      wrote, “A precise diagnosis has considerable intrinsic value” and “Logical although unproven treatments can be tried if the situation warrants.” This philosophy is consonant with use of TEE and the tone of the current ACCP recommendations, which, despite the limited clinical trial base, favor aggressive therapy when permitted by the individual risk-benefit relationship and supported by concepts of pathogenesis. It is incumbent on advocates and practitioners of TEE to continuously prove that the logic of treatments suggested by a precise anatomic diagnosis is supported by the results of clinical trials.

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