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Embolic Stroke
Introduction
Stroke is the most common cause of morbidity and the fifth leading cause of mortality in the United States.[1] Different underlying mechanisms can cause a stroke. It is essential to determine the underlying etiology of the stroke to guide evidence-based therapy for secondary prevention, such as anticoagulation for atrial fibrillation and revascularization in cervical carotid artery stenosis.
In 1993, The Trial of Org 10172 in Acute Stroke Treatment (TOAST) was published, and it classified stroke into large artery atherosclerosis, cardioembolic, small vessel, other determined etiology such as arterial dissection, and undetermined etiology.[2] On the other hand, the ASCOD classification classifies stroke etiology into atherosclerosis, small vessel disease, cardiac pathology, arterial Dissection, and other causes.[3] Embolic strokes can have a cardiac source, artery to artery, paradoxical embolism from a venous source in patients with patent foramen ovale (PFO), aortic source, or embolic stroke due to undetermined source (ESUS).
Etiology
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Etiology
Three main mechanisms can cause an ischemic stroke: thrombosis, hypoperfusion, or embolic phenomena.[4] Embolic strokes occur when clots migrate from the source to block more distal cerebral arteries, causing cessation of brain tissue perfusion and ischemia. The embolic source can be cardiac, aortic, or arterial, from a venous origin in the pelvis or lower limbs, with a cardiac shunt resulting in paradoxical embolism or an unknown source. Therefore, if needed, careful evaluation and workup for an embolic source with a transthoracic or transesophageal echocardiogram, Holter monitoring, and vascular imaging are mandatory to guide appropriate evidence-based treatment and prevent stroke recurrence.
Emboli can happen due to different mechanisms, including blood stasis in an abnormal, structurally enlarged left cardiac chamber such as left ventricular aneurysm with subsequent thrombus formation, material detachment from structurally abnormal calcific degenerative valves, or embolus passage from the venous to the arterial circulation (paradoxical embolism) because of the presence of right to left cardiac shunt such as Patent Foramen Ovale (PFO).[5]
Ischemic strokes of the cardioembolic source are generally the most severe ischemic stroke subtype. Although cardiac emboli can be variable in size, the emboli arising from blood stasis within the left cardiac chambers are usually large. They may cause large vessel occlusions such as middle cerebral artery (MCA) and basilar artery occlusions, and hence severe strokes with higher rates of morbidity and mortality. They also carry a higher risk of stroke recurrence.[6][7]
The risk of embolism is variable. The most common potential high-risk cardiac conditions that can cause embolic ischemic stroke include atrial fibrillation (AF), recent myocardial infarction, mechanical prosthetic valve, dilated myocardiopathy, and mitral rheumatic stenosis, respectively. However, other identifiable high-risk cardioembolic sources include infective bacterial endocarditis, nonbacterial marantic endocarditis, and left atrial myxoma, which is a rare condition but the most common tumor originating from the heart. Minor cardioembolism sources include patent foramen ovale (PFO), calcific aortic valve stenosis, mitral valve annular calcification, atrial septal aneurysm, ventricular (VSD), or atrial septal defects (ASD).
AF is the most common sustained cardiac arrhythmia and cause of cardioembolic stroke. This is related to associated low cardiac output and blood stasis, which is associated with increased concentration of prothrombotic fibrinogen, D-dimer, and von Willebrand factor, and results in thrombus formation within the atrial appendage and hence increased risk for cardioembolic strokes. The prevalence of AF increases with age, particularly in people over 65, reaching a peak of 5% in this age group. Hypertensive heart disease remains the most common underlying cause of AF in developed countries. Other associated causes of AF include heavy alcohol drinking, valvular heart disease, especially in developing countries, and thyrotoxicosis.[8]
Acute myocardial infarction (MI) is another common risk factor for embolic strokes mainly because of left ventricular dysfunction, low cardiac output, blood stasis, mural thrombus formation, and associated arrhythmias, including AF. Ischemic cardiomyopathy increases the risk of embolism. The stroke risk is inversely proportional to the ejection fraction (EF). Studies showed that patients with an EF of less than 28% had a relative risk of stroke of 1.86 compared to patients with an EF greater than 35%. Data showed that about 2.5% of patients with acute MI will develop embolic stroke within the first 2 to 4 weeks following the infarction. The presence of a mural thrombus that may be mobile or protrudes into the ventricles carries a very high risk of 22 % of developing embolic stroke within the first 2 to 4 weeks. However, ischemic strokes can also be a late complication to MI, as data showed that 11% of affected female patients and 8% of affected male patients will have an ischemic stroke within 6 years following acute MI.[7]
Valvular heart disease carries embolic stroke risk even with the absence of associated AF. Mechanical prosthetic valves are a well-recognized risk factor. The mitral mechanical valves carry a higher risk than aortic mechanical valves, which is particularly higher in patients inadequately treated, resistant, or noncompliant with warfarin. Another cause is calcific aortic stenosis. In developing countries, rheumatic heart disease affecting the mitral and aortic valves remains a well-recognized cause of embolic stroke in young patients.[5]
Treatment of patients with septic embolic strokes from bacterial infective endocarditis is challenging because of the high risk of hemorrhagic transformation and multiple emboli. Ten percent of affected patients will develop embolic stroke, particularly early within the first 2 weeks of the disease course, even during the administration of appropriate antibiotic therapy. The risk of multiple strokes is higher in infected prosthetic valve cases with staphylococcus aureus. Infective endocarditis can also cause mycotic aneurysms, which is a less common complication (1%-5%); however, it may be a fatal one as these aneurysms may enlarge and rupture, causing severe intracranial bleeding. Endocarditis can also be non-infective and associated with underlying malignancy or autoimmune disease such as systemic lupus erythematosus antiphospholipid syndrome.[6]
Although myxomas are rare, they are the most common primary cardiac tumors. They account for more than 50 primary cardiac tumor cases, and they usually manifest clinically by causing thromboembolic strokes, occurring mostly in young patients. Less common is papillary fibroelastoma.
COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel virus proven to be associated with an increased risk of strokes, whether embolic or small vessel disease strokes. Embolic strokes are most likely related to the associated hypercoagulable state and associated with high inflammatory markers, including C-reactive protein, D-dimer, and ferritin. However, it is still unknown if anticoagulation may decrease the risk of embolic strokes in this category of patients. Associated cardiac complications such as myocarditis with decreased EF causing blood stasis may result in embolic strokes as well.[9]
Epidemiology
Stroke is the most common cause of morbidity and the fifth leading cause of mortality in the United States. Risk factors include hypertension, diabetes, atrial fibrillation, dyslipidemia, smoking, sedentary lifestyle, kidney disease, sleep apnea, and heavy alcohol intake. AF may cause embolic strokes, and the risk increases with age. AF is the most common identifiable cause of embolic stroke.
In the United States, about 25 % of strokes are cryptogenic, and one-sixth are considered Embolic Strokes of Undetermined Source (ESUS). ESUS was first defined in 2014 as a stroke that appears nonlacunar in Neuroimaging with no evidence of underlying atrial fibrillation, carotid stenosis, or dissection.[10]
History and Physical
As for other types of strokes, embolic stroke patients’ presentation depends on the cerebral region affected. However, they may usually clinically differ from patients with underlying small vessel disease etiology.
The onset of symptoms in embolic strokes is usually very rapid. It may show a rapid regression (4.7%-12% of cases) compared to short onset (minutes to hours) and subsequent typical worsening of symptoms in lacunar infarcts. Some stroke experts call this phenomenon the "spectacular shrinking deficit syndrome," which carries a high clinical suspicion of the cardioembolic origin of stroke. This dramatic improvement of a severe neurological deficit may be due to the distal migration of the embolus, followed by the occluded vessel's recanalization.[4]
In one study, altered consciousness was found to be a more predictive presentation of cardioembolic infarction rather than atherothrombotic infarction.
Cortical signs, including Wernicke's aphasia, Broca's or global aphasia, hemianopia, gaze deviation, and neglect are other common cardioembolism secondary symptoms. Cardioembolism can produce lateral medullary syndrome, cerebellar infarcts, multi-level infarcts, and basilar occlusion in the posterior circulation, which may be fatal and top of the basilar syndrome. Cardioembolism may cause posterior cerebral artery infarcts presenting with visual field cuts without associated weakness.[11]
Procedures and activities that increase the right atrial pressure could also lead to cardioembolic strokes, such as Valsalva-provoking activities. Symptoms could occur after bending and severe coughing, suggesting an underlying right to left shunt such as PFO, leading to a paradoxical embolism.[12] On the other hand, patients presenting with lacunar strokes due to an underlying small vessel disease have no cortical signs. Typically, they present with pure motor hemiparesis, pure sensory syndrome, ataxic hemiparesis stroke, sensorimotor stroke, and dysarthria clumsy hand syndrome, among others.[13]
Evaluation
In addition to history and physical examination, neuroimaging is crucial for stroke evaluation to confirm the stroke and understand the underlying etiology. Lacunar infarcts, particularly multiple lacunar infarcts of different ages, make an underlying cardioembolic cause unlikely. Lacunar infarcts are small (0.2 to 15 mm in diameter) noncortical infarcts caused by occlusion of a single penetrating branch of a large cerebral artery. It is mainly related to small vessel disease, and hypertension remains the most common vascular risk factor associated with this condition.[14]
In contrast, embolic strokes are nonlacunar and may be multiple, simultaneous, or sequential in different vascular territories such as anterior and posterior circulation. Cardiac emboli have large sizes therefore, may cause large single or multiple infarcts involving the large vessels, such as the middle cerebral artery, with subsequent disabling symptoms. Embolic strokes are associated with an increased risk for hemorrhagic transformation, particularly cardioembolic strokes, because of early vessel recanalization and reperfusion injury.[15][16]
Patients with non-lacunar strokes should be monitored for underlying atrial fibrillation. Without a clear etiology despite continuous cardiac rhythm monitoring, patients should be discharged on Holter monitoring. Although the ideal recommended monitoring time is unknown, the longer the duration, the higher the chance of detecting an underlying paroxysmal AF. In such patients, post-hospitalization monitoring may detect AF in 10% to 25% of cases.[17]
Treatment / Management
The standard of care treatment of acute stroke within the first 4.5 hours remains IV thrombolysis with recombinant tissue plasminogen activator (tPA) in patients with no contraindication, regardless of the underlying etiology. Emergency imaging of the brain with a nonenhanced CT scan is mandatory to rule out intracranial bleeding.[18](A1)
Emboli may result in large vessel occlusion and cause severe strokes. Such patients may benefit from mechanical thrombectomy, which can be done within the first 6 hours as demonstrated in 5 different randomized controlled clinical trials, including MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND-1A, and up to 24 hours from symptoms onset in selected patients to save the viable brain tissues at risk as demonstrated in the DAWN and DEFUSE 3 trials. If endovascular therapy is contemplated, a noninvasive intracranial vascular study, such as a head and neck CT angiogram, is strongly recommended. Still, it should not delay intravenous rtPA for patients who qualify, according to guidelines from professional medical societies. In patients presenting beyond 6 hours from symptoms onset, a CT perfusion scan of the head is mandatory to guide the selection of mechanical thrombectomy candidates.[19][20][21][22][23][24][25](A1)
If there is evidence of AF during hospitalization or in continuous Holter monitoring at home following discharge, patients should be started on full anticoagulation therapy, as demonstrated in the SPAF1 study. Anticoagulation decreased the risk of embolization by almost 70% in AF patients. Warfarin remains superior to use in patients with valvular heart disease. Still, new direct thrombin and factor Xa inhibitors such as dabigatran, apixaban, and rivaroxaban should be considered in nonvalvular AF patients.[26][27](A1)
Patients with PFO and younger than 60 years of age should be evaluated for the risk of paradoxical embolism. The Risk of Paradoxical Embolism (RoPE) score can be used, and it depends on the patient's age and the absence of other vascular risk factors for stroke. PFO closure may be beneficial in such patients based on 3 randomized clinical trials that demonstrated decreased stroke risk by almost 60 % in the PFO closure group compared to medical therapy alone.[28][29][30]
Two large multicenter randomized trials were done to compare antiplatelet therapy versus anticoagulation in ESUS patients. The Dabigatran Etexilate for Secondary Stroke Prevention in Patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS) published in 2019 showed no difference in stroke recurrence in patients taking dabigatran 150 mg twice daily compared to patients taking aspirin 100 mg daily. The same was concluded from the prior New Approach, Rivaroxaban Inhibition of Factor Xa in a Global Trial versus Aspirin (ASA) to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS), which compared Rivaroxaban 15 mg to aspirin 100 mg. Therefore, based on these 2 trials, single antiplatelet therapy is recommended for secondary stroke prevention in patients with ESUS.[31][32]
It’s hypothesized that left atrial cardiopathy without AF may cause embolic strokes. Ongoing trials such as ARCADIA (Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke) evaluate whether anticoagulation benefits such patients.[33](A1)
Differential Diagnosis
Stroke mimics should be considered when evaluating patients with suspected embolic strokes in the Emergency department. A brain CT scan should be considered to exclude intracranial hemorrhage (ICH) in patients presenting with focal neurological symptoms. ICH includes intraparenchymal hemorrhage secondary to hypertension or amyloid angiopathy in addition to subarachnoid and subdural hematomas.
Seizures with unilateral postictal weakness (Todd paralysis) should be considered. They're usually short with, at times, prolonged postictal states. Migraine aura may manifest as positive or negative neurological symptoms, including visual and sensory symptoms, which are usually gradual and slower in onset. Another important differential diagnosis to consider with focal neurological deficits is hypoglycemia. Therefore, the blood sugar level is mandatory before administering IV TPA. Psychogenic causes should be considered when the exam is inconsistent; however, in an acute setting, it may be difficult to distinguish. Still, IV TPA should be administered if no contraindications are found.
Other less frequent differential diagnoses to consider include multiple sclerosis, brain tumors, compressive myelopathy, pressure or position-related peripheral nerve or nerve root compression, and toxic metabolic encephalopathy, especially in patients with previous strokes who may develop recrudescence of old symptoms.[34]
Prognosis
There are certain predictors of embolic stroke prognosis in the acute phase, including the patient's age and associated comorbidities, in addition to the stroke size and location on neuroimaging. However, clinical assessment remains the most important predictor of long-term outcomes. Large embolic strokes with altered mentation and severe motor, language, and visual deficits are associated with poor prognosis.
Evidence shows that early regaining of finger extension, shoulder abduction, and grasp release are associated with good clinical outcomes after 6 months.[35][36] Data suggest excessive corticospinal tract damage is a poor predictor of recovery and is associated with poor prognosis.[37]
Complications
Stroke mortality rates have declined in recent years due to better medical care. The mortality rate following the first ischemic stroke and within the first month of onset is 16% to 23%. This also is proportionally associated with increased morbidity rates. Stroke is the most common neurological cause of lost disability-adjusted life years in developing and developed countries.[38]
Disability caused by an embolic stroke after 6 months may be severe, especially because of cortical functional deficits such as aphasia, hemianopia, and cognitive impairment, in addition to the sensory and motor deficits with impaired gait. Speech and swallow evaluations are mandatory for all stroke patients to screen for dysphagias and, therefore, avoid the risk of aspiration pneumonia, which may be fatal. We should also consider screening for depression, in addition to infections secondary to bedsores and urinary tract infections.[39] Early clinical deterioration in the course of acute stroke is associated with poor prognosis and increased morbidity and mortality.[40]
Postoperative and Rehabilitation Care
Physical rehabilitation assists in faster recovery and improves outcomes following acute stroke. Most recovery happens within the first 6 months following the stroke onset.[35][36] All embolic stroke patients should be evaluated for potential rehabilitation by the rehabilitation team. Depression screening is essential for all stroke patients. According to the FLAME trial, starting fluoxetine early following the stroke onset in patients with moderate to severe motor deficits improves outcomes at 3 months.[41]
Enhancing Healthcare Team Outcomes
Embolic stroke commonly causes morbidity and mortality if not recognized and treated early, as time is crucial for acute stroke management. To improve the outcome, it is essential to educate the public, the first responders and the health care team to recognize the clinical features of stroke and act accordingly. In addition, it is of utmost importance to improve the healthcare practitioners' understanding of how to promptly evaluate and treat embolic strokes efficiently to impact patients' outcomes and decrease stroke recurrence rates positively. While the stroke neurologist is almost always involved in caring for patients with an acute embolic stroke, it is important to work and communicate with an interprofessional team that includes the emergency department physician, the neuroradiologist, and the interventionist.
In acute stroke patients who are TPA candidates, the pharmacist ensures that the patient has no contraindication for TPA, prepares TPA, and calculates the appropriate weight-based dose. The neuroradiologist also plays a vital role in determining the cause of embolic stroke and identifying large vessel occlusions and candidates for mechanical thrombectomy. Without proper history and communication, the neuroradiologist may be unsure of what to look for and miss subtle findings. The nurses are also vital members of the interprofessional team as they monitor the patient's vital signs, especially emergency department and intensive care unit nurses who closely monitor the neurological status post-TPA and inform the caring physician if any neurological exam changes concern complications. Stroke coordinators in comprehensive stroke centers assist with educating the patient and family. Psychologists screen stroke patients for depression, and administration of a structured depression inventory is recommended to routinely screen for poststroke depression according to the American Heart Association/American Stroke Association (AHA/ASA) guidelines.[42]
An interprofessional team, including a physical therapist, occupational therapist, speech therapist, and rehabilitation team, is essential to improve outcomes. The AHA/ASA evidence-based guidelines recommended the use of comprehensive specialized stroke care (stroke units) that incorporates rehabilitation.[42] Prompt consultation with interprofessional specialists is recommended to improve embolic stroke outcomes.
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