Cardioembolic Stroke


Article Author:
Ashwin Pillai
Prasanna Tadi


Article Editor:
Arun Kanmanthareddy


Editors In Chief:
Mitchell Farrell
Brian Froelke


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
10/1/2019 10:03:24 PM

Introduction

Historically, one landmark of societal progress has been the pattern of disease - specifically, the emergence of non-communicable diseases as significant health problems, replacing infections. Strokes may well represent the flagship of these non-communicable diseases. That said, it is worth mentioning that the heavy burden of stroke continues to be in low-to-middle-income countries.[1] An estimated 26 million people suffer from a stroke every year, making it one of the most significant contributors to both mortality, and long-term disability. Up to two-thirds of these are ischemic.[1] Approximately 25% of all ischemic cases are believed to be cardioembolic in origin.[2] However, despite accounting for a relatively small proportion of all ischemic strokes, cardioembolic strokes are particularly important as they are frequently more severe than atherothrombotic strokes. Additionally, they are more prone to both early and late recurrences.[3]

Cardioembolic strokes can occur from at least a dozen specific cardiac disorders which include atrial fibrillation, left ventricular thrombi, cardiac tumors, valvular vegetations, and paradoxical emboli. For the most part, cardioembolic strokes can be prevented.

Etiology

Cardioembolic strokes can occur as a consequence of any cardiac insult that could cause the fulfillment of Virchow's triad of endothelial injury, stasis, and hypercoagulability.

Commonly encountered causes include:

  • Atrial disease:
    • Arrhythmias:
      • Atrial fibrillation, specifically non-valvular atrial fibrillation, is believed to be the most prevalent cause of cardioembolic strokes.[3] Considered the most frequently encountered sustained arrhythmia, it occurs in approximately 5% of people aged 65 years and above. In western populations, most cases are believed to occur secondary to ischemic or hypertensive heart disease. Other contributing factors include hyperthyroidism and heavy alcohol consumption. The contribution of valvular heart disease, particularly involvement of the mitral valve, is on the decline in terms of the number of cases. However, concerning relative risk, patients with valvular atrial fibrillation have a 17-fold increased risk of cardioembolic stroke, as opposed to the 2-7 fold increased risk in patients with non-valvular atrial fibrillation.[4] The CHADS2 risk stratification tool is often used to predict the stroke risk in patients with atrial fibrillation
      • Sick sinus syndrome, also known as the bradycardia-tachycardia syndrome, is also associated with an increased risk of stroke.
    • Structural disease:
      • Patent foramen ovale[5]: The role of a patent foramen ovale in strokes, particularly the so-called "cryptogenic strokes" is currently an area of great interest. Current evidence is insufficient to conclude about its role as a causative factor, or merely as a conduit for paradoxical emboli.
  • Valvular heart disease: Even with the absence of arrhythmias, valvular heart diseases correlate with an increased risk of stroke. These include:
    • Rheumatic valvular disease; the most common is rheumatic mitral stenosis. Without anticoagulation, the risk of stroke is very high.
    • Infective endocarditis: Approximately 10% of cases of infective endocarditis develop embolic strokes. The risk of stroke occurrence is highest before instituting, or within the first two weeks of antibiotic therapy.[4] Anticoagulation is contraindicated because usually they are associated with superimposed microhemorrhages. However, current recommendations are to start anticoagulation seven days after a stroke.
    • Non-infective endocarditis such as marantic endocarditis
    • Valvular calcifications: Native valvular calcification, particularly of the mitral valve increases the risk of developing a cardioembolic stroke. Mitral annular calcification correlates with a relative risk of 2.1, for the development of embolic stroke.[6]
    • Mechanical prosthetic heart valves have a stroke rate of 2%-4% even in patients maintained on oral anticoagulation. Permanent anticoagulation with an INR between 2.5-3.5 is mandatory. Bioprosthetic heart valves have a lower risk of stroke, and aspirin is recommended unless the patient has atrial fibrillation.
    • Mitral valve prolapse has a low risk of stroke, and anticoagulation is not recommended. However, long term aspirin is recommended.
  • Structural and functional ventricular diseases:
    • Ventricular aneurysms
    • Septal aneurysms
    • General ventricular hypokinesia (heart failure with reduced ejection fraction): The annual rate of stroke in patients with heart failure with reduced ejection fraction (HFrEF) is approximately 2%, with a direct correlation between the risk of a stroke, and the degree of ventricular compromise.[7]
  • Myocardial infarction: The occurrence of myocardial infarction increases the risk of development of a stroke, with the degree of left ventricular dysfunction, the presence of a ventricular aneurysm or mural thrombus, and the presence of arrhythmias significantly influencing the degree of risk. Approximately 2.5% of cases will develop a stroke within the first 4 weeks of the infarction, and nearly 10% will over six years.[4]

Epidemiology

Cardioembolic strokes appear to occur more frequently with increasing age. Studies have estimated that they account for 14.6% of cases below the age of 65 years, but this proportion has gone up to 36% for patients aged 85 years and older.[4]

About 20% of strokes are considered to cardioembolic. The risk of these strokes increases with age.

Pathophysiology

As with any thrombus, the fundamental pathophysiology is vested within Virchow's triad. Stasis of blood, as occurs with ventricular akinesia or aneurysms predisposes to thrombus formation. Similarly, the lack of atrial contractility in atrial fibrillation results in an increased predisposition to clot formation, particularly in the left atrial appendage. These thrombi can either remain indolent and later undergo organization, or embolize to systemic circulation - stroke being one of the potential consequences. With atrial fibrillation, this risk is greatest when converting a patient back to sinus rhythm.

The endothelial injury that accompanies valvular lesions also predisposes to hypercoagulability and thrombus formation, with similar potential consequences.

The cardiac emboli may consist of cholesterol, thrombus, platelet thrombi, calcium, or even bacterial clumps. Emboli from the heart can be distributed anywhere in the body, but more than 80% migrate to the brain. Of the emboli to the brain, the majority involve the anterior circulation with only about 20% involving the vertebrobasilar circulation.

When emboli enter the brain, they not only obstruct blood flow but may become detached and migrate further distally. Thus, reperfusion is another form of injury.

History and Physical

The classic clinical scenario is that of an abrupt onset neurologic deficit, that reaches maximal intensity within minutes, and then gradually improves.

As with all strokes, the clinical features depend on the extent and location of neurovascular compromise. However, depressed consciousness is usually a factor favoring a cardioembolic etiology, as opposed to an atherothrombotic stroke.[8] Further, eliciting a history of a Valsalva-like maneuver provoking the stroke also supports a cardioembolic etiology.[4] Cardioembolic strokes cause more seizures due to distal ischemia. 

Classic features of cardioembolic stroke include the following:

  • Abrupt decline in mental status
  • Change in the level of consciousness
  • Presence of neurological deficits

Cardiac findings may include:

  • Atrial fibrillation
  • Presence of a cardiac murmur
  • Signs of congestive heart failure
  • Recent myocardial infarction
  • Recent diagnosis of infective endocarditis

Evaluation

Cardiac Evaluation:

The preliminary cardiac evaluation must be directed towards evaluating both the electrophysiologic status of the heart as well as structural and functional status. As such, workup must include a 12-lead ECG and transthoracic echocardiography for all patients.

Electrophysiologic assessment:

  • A 12-lead ECG is useful only to the extent of detecting ongoing arrhythmias. Additionally, it may provide useful insight into ventricular myocardial status (evidence of ventricular hypertrophy) as well as indicate prior cardiac ischemic episodes. However, transient arrhythmias, particularly paroxysmal atrial fibrillation, will be missed.
  • Holter monitoring has now become a part of baseline evaluation of all cases of suspected cardioembolic strokes. Fundamentally similar to an ECG, it has the same drawback of evaluating the conduction system for a relatively limited period of 24 hours.
  • Implantable Loop Recorders (ILRs) can record activity for as long as three years. Their utility in clinical practice continues to increase, and their use has helped identify several cases of "missed" atrial fibrillation. Also, it is very important to note that a patient on oral anticoagulation with atrial fibrillation has to fall 295 times per year for the risk of traumatic subdural hematoma. 

Structural and Functional Assessment:

  • Transthoracic echocardiography: Transthoracic echocardiography forms the cornerstone of cardiac evaluation. Ventricular hypo- or akinesia, aneurysms, as well as most valvular lesions, can be identified. A key limitation is that visualization of the left atrial appendage is rarely possible using this imaging modality.
  • Transesophageal echocardiography: The transesophageal approach permits the use of higher-frequency probes that provide a significantly higher image resolution, and permit visualization of very minute pathologies, including intra-valvar abscesses. A steeper learning curve and lack of universal availability limit its utility as a primary modality of cardiac imaging. An echocardiogram may detect the following pathologies:
  • Atrial septal defect
  • Patent foramen ovale
  • Atrial septal aneurysm
  • Atrial thrombus
  • Atrial myxoma
  • Aortic arch thrombi
  • Mitral valve vegetations

Neurologic Evaluation:

Although the imaging modality of choice will differ based on the time of presentation of the patient (i.e., within the window period or outside it), the following principles govern the process of evaluation:

  • Parenchymal assessment:
    • MRI scans are, by far, the best available imaging modality to evaluate neural parenchymal status. The increasingly available 3 Tesla devices provide an unrivaled image resolution. Various imaging sequences help not only delineate the infarcted area but also help provide a temporal frame where history is sketchy. For instance, diffusion-weighted imaging (DWI) can help identify even hyper-acute infarcts by selecting the appropriate b-value. The presence of cortical stroke in multiple vascular territories should give suspicion for a cardioembolic etiology. The appearance of an infarct in the fluid-attenuated inversion recovery (FLAIR) sequence indicates that the infarct has developed, at least partially, over 6 hours back. MRI scans can even accurately detect hemorrhagic infarcts by means of susceptibility-weighted imaging (SWI). Key limitations, however, are the relatively long duration required for the scan - a formidable contraindication in hemodynamically unstable patients - and ensuring compliance in claustrophobic patients. The increasing availability of "open MRIs" and "virtual-reality based systems" help alleviate the latter, but the former remains a major problem.
    • CT scans: CT scans are excellent imaging modalities for detecting, or ruling out hemorrhage. Rapid imaging and ease of reporting even in settings with limited expertise remain its key redeeming features. That said, it shows limited sensitivity in detecting infarcts early on in their evolution. Large infarcts may exhibit subtle signs such as sulcal effacement or "the hyperdense middle cerebral artery (MCA) sign," although these are inconsistent features that may easily be missed.
  • Vascular status assessment:
    • MR angiography: Magnetic resonance angiography is a useful imaging modality, particularly in patients with renal impairment, as it does not require the use of intravenous contrast media. However, it is prone to various artifacts, including potentially overestimating stenotic lesions.
    • CT angiography: CT angiography remains the investigation of choice for evaluating cerebral vasculature; it's only drawback being that it is not an option in patients with renal impairment. 

Serological assessment:

Although most standard guidelines recommend against instituting this as a routine practice, the evaluation of patients for hyper-homocysteinemia secondary to metabolic vitamin B12 deficiency continues to have a role in the evaluation of a patient of stroke.[9] This is particularly significant in patients known to be following a vegan lifestyle.

Treatment / Management

The cornerstone of the management of cardioembolic strokes involves the use of anticoagulants for secondary prevention.

However, the exact timing of the initiation of anticoagulation remains a matter of controversy. The intention is to strike a delicate balance the risk of recurrence on the one hand, and the risk of a hemorrhagic transformation of the infarct on the other.

Current guidelines propose an arbitrary deferral of anticoagulation for two weeks after the event, based on the extrapolation of trials based on heparin use.[4]

Conventionally, vitamin K antagonists like warfarin are used for oral anticoagulation. Therapeutic response is monitored by serial assessment of prothrombin time and the international normalized ratio (PT/INR). The target INR is between 2.0 to -3.0. However, this target is scaled up to 2.5 to 3.5 for cases with metallic mitral valves. Although universally available and inexpensive, a poorly predictable dose-response curve, a penchant for drug interactions, and a heavy dependence on patient dietary compliance are key drawbacks of these agents.

Direct oral anticoagulants (DOACs) represent the new generation of oral anticoagulants that overcome the shortcomings of vitamin K antagonists. Available agents include apixaban, rivaroxaban, dabigatran, and edoxaban. These newer agents are believed to have a more predictable dose-response curve, and their use obviates the need for repeated monitoring. A key drawback of these DOACs was the lack of availability of a reversal agent; however, this is no longer always the case. Reversal agents for dabigatran (idarucizumab) and rivaroxaban and apixaban (recombinant factor Xa - Andexanet alfa) have received FDA approval and are available for clinical use.

Various devices have also received approval for stroke prevention, such as the "WATCHMAN" device for left atrial appendage closure. Such devices are useful in patients with atrial fibrillation unable to tolerate anticoagulation. By sealing off the left atrial appendage, these devices reduce the risk of atrial thrombi, that develop due to atrial fibrillation, embolizing into the systemic circulation.

Closure of the patent foramen ovale is also gaining recognition as a vital tool to prevent stroke recurrence. It has shown a clear superiority to antiplatelet therapy, and non-inferiority to anticoagulation.[10] Any patient who had cardioembolic stroke less than 60 years old should evaluate for patent foramen ovale.

For patients with left ventricular thrombus and myocardial infarction, we usually recommend anticoagulation at least for three months due to embolization risk.

Differential Diagnosis

Atherothrombotic strokes must be excluded.

Pertinent Studies and Ongoing Trials

The TIMING study, undertaken in 2017, is likely to provide useful clinical information regarding the optimal time of initiation of anticoagulation.

Prognosis

If not treated appropriately, cardioembolic strokes have a higher tendency than atherothrombotic strokes to show both early and late recurrences.

Complications

Hemorrhagic transformations - both spontaneous and post-anticoagulation therapy - are potentially grave consequences of this condition. Long-term disability, bed-rest related complications such as pressure sores, may all occur, but vary depending on the severity and extent of neuro deficit.

Deterrence and Patient Education

Avoiding excessive alcohol, adopting a Mediterranean-like or DASH (dietary approaches to stop hypertension) diet, and other measures that can combat both hypertension, as well as eliminate triggers of atrial fibrillation, are likely to be beneficial.

Patients on warfarin should be provided with a list of foods that contain vitamin K (avocado, broccoli, etc) which can limit the efficacy of warfarin.

Enhancing Healthcare Team Outcomes

A cardioembolic stroke is a classic example of a problem that requires an interprofessional approach to solve. Most hospitals have an interprofessional team dedicated to the management of patients with stroke. This stroke team consisting of a cardiologist, a neurologist, a dedicated radiologist (potentially an interventional neuro-radiologist if thrombectomy is warranted), and an internal medicine physician is vital in improving outcomes. In addition, the pharmacist must educate the patient on the importance of drug compliance, discontinuing tobacco and abstaining from alcohol. If the patient has atrial fibrillation, a cardiology nurse must follow these patients to ensure that the INR is therapeutic. Neuroscience and stroke certified nurses are involved in patient care and education and report status changes to the team. Serial ECG and echocardiograms are recommended in these patients. The interprofessional team should communicate so that the patient is offered the current standard of care therapy.

Current evidence regarding when to initiate treatment is still sketchy [Level V]. Trials such as the TIMING study are likely to add valuable information to the existing knowledge base.


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Cardioembolic Stroke - Questions

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Which of the following types of cerebral infarctions is most likely to become hemorrhagic after the initial infarction?



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A 71-year-old female with a prior history of type 2 diabetes mellitus and hypertension is seen in the emergency department because of a sudden onset of slurred speech. It is suspected that she is developing an acute stroke. Which of the following would absolutely contraindicate thrombolytic therapy with tPA?



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A 66-year-old male presents to the emergency department for evaluation after sudden onset of muscle weakness that started 2 hours ago. The patient has a history of hypercholesterolemia for which he takes medication. A physical exam shows hemiparesis of the left side of the face, arm, and leg. A full neurological exam does not reveal any additional significant clinical findings. No cortical signs of injury are found. Computed tomography is ordered. Which of the following vessels is most likely to be affected in this patient?



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A 65-year-old male with no prior history of medical disease presents with a history of palpitations. An electrocardiogram confirms the clinical suspicion of atrial fibrillation. An echocardiographic assessment reveals that he also suffers from mild calcific aortic stenosis. Being a vegan, his diet is rich in green, leafy vegetables, a choice he is unwilling to reconsider. After due evaluation, he is considered a candidate for long-term anticoagulation. Which of the following is the treatment of choice?



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A 22-year-old female with infective endocarditis complicated by a cardioembolic stroke is admitted to the hospital for intravenous antibiotic therapy. After a few days in the hospital, she suddenly exhibits a deterioration in her level of consciousness. Her vital signs are within normal limits. Which of the following is the next best investigation for this patient?



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A 68-year-old male presents to the emergency department with left-sided weakness and aphasia. His family reports episodic palpitations on exertion over the past few months. Based on radiographic imaging and cerebral angiography he is diagnosed with a cardioembolic stroke. A transesophageal echocardiogram did not reveal any abnormalities, except moderate diastolic dysfunction. His electrocardiogram (ECG) shows sinus rhythm with left axis deviation. He is started on aspirin and atorvastatin therapy. In addition to controlling his blood pressure, which of the following is the next best step in the management of this patient?



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Cardioembolic Stroke - References

References

Krishnamurthi RV,Feigin VL,Forouzanfar MH,Mensah GA,Connor M,Bennett DA,Moran AE,Sacco RL,Anderson LM,Truelsen T,O'Donnell M,Venketasubramanian N,Barker-Collo S,Lawes CM,Wang W,Shinohara Y,Witt E,Ezzati M,Naghavi M,Murray C, Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. The Lancet. Global health. 2013 Nov;     [PubMed]
Díaz Guzmán J, [Cardioembolic stroke: epidemiology]. Neurologia (Barcelona, Spain). 2012 Mar;     [PubMed]
Ferro JM, Cardioembolic stroke: an update. The Lancet. Neurology. 2003 Mar;     [PubMed]
Arboix A,Alió J, Cardioembolic stroke: clinical features, specific cardiac disorders and prognosis. Current cardiology reviews. 2010 Aug;     [PubMed]
Di Tullio MR,Homma S, Mechanisms of cardioembolic stroke. Current cardiology reports. 2002 Mar;     [PubMed]
Yuan K,Kasner SE, Patent foramen ovale and cryptogenic stroke: diagnosis and updates in secondary stroke prevention. Stroke and vascular neurology. 2018 Jun;     [PubMed]
Weir NU, An update on cardioembolic stroke. Postgraduate medical journal. 2008 Mar;     [PubMed]
Timsit SG,Sacco RL,Mohr JP,Foulkes MA,Tatemichi TK,Wolf PA,Price TR,Hier DB, Early clinical differentiation of cerebral infarction from severe atherosclerotic stenosis and cardioembolism. Stroke. 1992 Apr;     [PubMed]
Spence JD, Cardioembolic stroke: everything has changed. Stroke and vascular neurology. 2018 Jun;     [PubMed]
Mir H,Siemieniuk RAC,Ge LC,Foroutan F,Fralick M,Syed T,Lopes LC,Kuijpers T,Mas JL,Vandvik PO,Agoritsas T,Guyatt GH, Patent foramen ovale closure, antiplatelet therapy or anticoagulation in patients with patent foramen ovale and cryptogenic stroke: a systematic review and network meta-analysis incorporating complementary external evidence. BMJ open. 2018 Jul 25;     [PubMed]

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