Cardioembolism Cardioembolism accounts for approximately 30% of all stroke and 25-30% of strokes in the young (age <45 years).42 1 AF accounts for a large proportion of these strokes (15-25%). Symptoms may be suggestive, but they are not diagnostic. Repetitive, stereotyped, transient ischemic attacks (TIAs) are unusual in embolic stroke. The classic presentation for cardioembolism is the sudden onset of maximal symptoms. The size of the embolic material determines, in part, the course of the embolic material. Small emboli can cause retinal ischemic or lacunar symptoms. Posterior cerebral artery territory infarcts, in particular, are often due to cardiac embolism. This predilection is not completely consistent across the various cardiac structural abnormalities that predispose to stroke, and may be due to patterns of blood flow associated with specific cardiac pathologies.
An ischemic stroke is considered cardioembolic if the clinical and neuroimaging findings support this diagnosis and a cardiac source of embolism is identified. Other stroke subtypes should be excluded before assigning a cardioembolic etiology by ensuring that there is not a >50% stenosis or occlusion of a large artery supplying the ischemic territory, a clinical and radiographic syndrome consistent with a small vessel (lacunar) stroke, an established diagnosis of vasculitis or other unusual cause of stroke, or a >4 mm atheroma of the aortic arch.
Neuroimaging data can support a diagnosis of cardioembolism. Multifocal infarctions that involve more than one vascular territory favor a proximal source of embolism. Recurrent ischemic events in a single vascular territory in the absence of a proximal large artery stenosis may also be due to cardioembolism. Embolic-appearing infarcts on neuroimaging may be clinically "silent."
It is extremely important to exclude infective endocarditis as a cause for cardioem-bolism. Stroke occurs in 15-20% of infective endocarditis, usually within the first 48 hours. Appropriate antibiotic therapy dramatically reduces the risk of recurrent stroke. Late embolism occurs in less than 5% of cases.43 An elevated erythrocyte sedimentation rate in the setting of cerebral ischemic symptoms, fever or a new murmur should trigger a diagnostic evaluation, including blood cultures, a transthoracic echocardiogram, and if a high level of suspicion remains, a transesophageal echocar-diogram. The most common organisms causing native valve endocarditis are streptococci, staphylococci, and enterococci, although other species of bacteria, fungi, spirochetes, and rickettsiae can infect valves. The risk of subarachnoid hemorrhage from mycotic aneurysms represents a contraindication to the use of anticoagulation in infectious endocarditis.
Event-loop recording and 24-48 hours Holter monitoring are more sensitive than a standard 12-lead ECG for detecting AF in stroke patients. In one study of 465 consecutive patients admitted with a diagnosis of new ischemic stroke, 210 underwent Holter monitoring. The mean duration of monitoring was 22.8 ± 4.0 hours. Previously undiscovered AF was identified in five cases (2.4%), all of which represented nonrheumatic AF. In three cases, the Holter test was negative despite AF documented on an admission electrocardiogram. Thus, the standard 24-hour duration of monitoring probably underestimates the prevalence of paroxysmal AF in this population.44 Studies from Switzerland have reported similarly low rates of PAF in stroke patients on Holter monitoring (2.7-5%) and slightly higher rates of detection using an ambulatory 7-day monitor (5.7%).45'46
Many patients have a rhythm that varies between atrial flutter and AF. Atrial flutter is associated with a 40% higher risk of stroke. Given that the concordance of the AF and atrial flutter is high, anticoagulation should be considered in patients with atrial flutter and coexisting cardiac pathology predisposing to left atrial thrombus.
Transesophageal echocardiography (TEE) has greater sensitivity for detecting abnormalities in the left atrium such as spontaneous echo contrast, left atrial thrombus, reduced left atrial appendage velocity, and complex aortic arch atheroma, which are markers of increased stroke risk. In a study of 227 patients with acute cerebral ischemia and an "undetermined" etiology after TTE and vascular imaging, 8% had a high-risk source requiring anticoagulation identified on TEE. An additional 22% had a possible cardioembolic source (e.g., patent foramen ovale, atrial septal aneurysm, aortic plaque <4 mm identified on TEE).47 Another similar study found that in 231 patients with ischemic stroke or TIA of unknown mechanism, TTE identified a high-risk source in 16%, but TEE identified a source in an additional 39%, and roughly a third were subsequently anticoagulated for the condition, although warfarin was not proven to be superior to antiplatelet therapy for many of the diagnoses.48 Left atrial thrombus was the most common abnormality requiring anticoagulation, detected in 16% of TEE subjects. The increased utility of TEE was seen in both young (age <45) and older patients (Table 9.3).
Five randomized primary and secondary prevention trials49,50 have demonstrated the efficacy and safety of warfarin in preventing AF-related stroke. Pooled data from these trials demonstrated a 68% reduction in ischemic stroke (95% CI 50-79) and an intracerebral hemorrhage rate of < 1% per year. The data for aspirin suggested that it had a lesser effect, with a 36% risk reduction (95% CI 4-57).
It is important to obtain a baseline EKG and cardiac enzymes to evaluate the possibility of an acute myocardial infarction. The short-term (2-4 weeks) stroke risk after acute myocardial infarction (AMI) is 2.5%.51 Stroke is usually an early (within 14 days) complication of AMI and is more common in anterior wall (4-12%) than in inferior wall infarction (1%).51-53 Approximately 40% of patients with an anterior wall myocardial infarction develop left ventricular thrombus,
TABLE 9.3 Additional Diagnostic Evaluations for Stroke in the Young or Other Unusual Circumstances.
I. TTE with agitated saline
II. Blood cultures and tranesophageal echocardiography (if SBE suspected), ESR
Protein C, protein S, antithrombin III, activated protein C resistance, lipoprotein(a) anticardiolipin antibodies, lupus anticoagulant, prothrombin gene mutation 20210a
IV. Lumbar puncture
V. Conventional angiography (optional)
usually in the first 2 weeks. Patients with low ejection fraction after AMI have a cumulative 5-year stroke risk of 8.1%.
Carotid artery disease is one of the major causes of ischemic stroke.1'2 The predominant mechanisms by which it causes stroke are (a) arterial embolism from atherosclerotic plaques; (b) hemodynamic changes, leading to "watershed" infarcts; and (c) distal propagation of thrombus originating from acute carotid occlusion.3
The degree of carotid stenosis is a major predictor of subsequent stroke. In the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and in the European Carotid Surgery Trial (ECST), patients with >69% stenosis of a symptomatic carotid had a significant reduction in stroke risk with carotid endarterectomy, provided the surgical risk was less than 3%.54'55 However, in patients with moderate carotid stenosis, the benefit of surgical treatment is less clear. The NASCET investigators subsequently demonstrated a small but significant reduction in the 5-year rate of ipsilateral stroke in symptomatic patients with 50-69% carotid stenosis when treated with endarterectomy, as compared to patients treated medically; and a nonsignificant reduction in symptomatic patients with <50% carotid stenosis when treated surgically, again compared to patients that received medical therapy.56
The noninvasive studies commonly performed to directly image the extracranial carotid disease include:
• Carotid duplex ultrasound (CDUS)
CTA and MRA are described in more detail in Chapter 2; therefore, this section will focus on CDUS. CDUS is widely available, well-validated, and is free of the risks and complications of radiographic contrast administration. Using ROC analysis, velocity criteria for detecting a residual lumen diameter of <1.5 mm have been developed based on pathological correlation with CEA plaques.57 In addition, transcranial Doppler can play an adjunctive role in defining the hemody-namic significance of a lesion.58
When MRA, CTA, and CDUS were compared in 67 patients, there was good agreement with angiography to predict "surgical" disease.59 In vivo determination of plaque correlates slightly better with ultrasound (r = 0.8) than MRA (r = 0.76).60 In the CARMEDAS multicenter study, the concordance rates among ultrasound, contrast-enhanced MRA (89%), ultrasound/CTA (83%), and CTA/MRA (89%) for diagnosing a >50% stenosis were not significantly different.61 Although this study identified a subgroup of asymptomatic surgical patients in whom ultrasound was more concordant than CTA, the absence of a biological rationale for this suggests that it is a type I error.
Johnston and Goldstein62 found that compared to DSA, there was a misclassifi-cation rate of 7.9% for combined US and time-of-flight (TOF) MRA compared to either alone (CDUS 28%, TOF MRA 18%). They repeated this study with contrast-enhanced MRA (CEMRA) and found that 24% of patients would be misclassified as a surgical candidate with CEMRA and 36% with CDUS as compared to 17% for both CEMRA and CDUS.63 Other studies have also shown that concordant results between contrast-enhanced MRA and duplex ultrasonography have a high sensitivity (100%) and specificity (81.4%) compared with DSA.64
For detecting >70% stenosis, the sensitivity and specificity for MRA alone have been reported as 92.2% (86.2-92.2%) and 75.7% (68.6-82.5%), and for CDUS, 87.5% (82.1-92.9%) and 75.7% (69.3-82.2%), respectively. Combined, they are 96.3% (90.8-99%) and 80.2% (73.1-87.3%).65 In a later study by the same group comparing CDUS and CEMRA, the sensitivity/specificity were 86% (84-89%)/ 87% (84-90%) and 95% (92-97%)/90% (86-93%), respectively.66 In another study, CEMRA had a sensitivity of 94.9% and specificity of 79.1% for identifying a stenosis of 70% or greater.63 Below 50%, ultrasound is inaccurate in assessing the degree of stenosis.67
In the past, conventional ultrasound detected only 27% of pseudo-occlusions, whereas the addition of color flow Doppler increased detection to 94%. The accuracy of color-coded duplex sonography (CCDS) was tested in 401 consecutive patients with CCDS followed by ICA angiography. The sensitivity of CCDS was 88% with a specificity of 99% in preocclusive lesions, as compared to sensitivity of 87% and specificity of 99% for complete occlusions. Of note, in this study, carotid endarterectomies were performed in two of three angiographically occluded vessels deemed to be patent with CCDS. At surgery, they had residual flow confirming the CCDS findings.68 For detecting occlusion, the sensitivity of CEMRA and CDUS have been reported as 98% (94-100%) versus 100% (99-100%), and a specificity of 96% (94-98%) versus 100% (99-100%), respectively.66
There are limitations to ultrasound, however. A high-grade stenosis of the contralateral carotid artery can falsely elevate velocities and overestimate the degree of stenosis.69 For discriminating between a high-grade stenosis and a total occlusion, ultrasound is imperfect. Calcification is a limiting factor in duplex imaging. Roughly 9-12% of symptomatic patients have >1 cm of calcification that impairs color flow imaging.70-72 Carotid bifurcations above the mandible, tortuous vessels, and echolucent plaques also pose diagnostic imaging challenges using ultrasound. CDUS is most informative when combined with imaging of the intracranial circulation in order to exclude tandem lesions and identify potentially dangerous intracranial pathology (e.g., cerebral aneurysms) prior to reperfusion interventions. This can be accomplished with ultrasound (transcranial Doppler) or by combining CDUS with computed tomographic or magnetic resonance imaging of the brain and intracranial vessels.
In patients who have not had a large infarction, or who have suffered a TIA, CEA should be undertaken preferably early (within 3-30 days poststroke/TIA) rather than 6-8 weeks after the ictus.73,74 Patients with non-significant carotid stenosis are not stroke-risk free. Although the risk of having a stroke with <50% stenosis is small, the attributable risk of stroke is high, since the prevalence of low-grade carotid stenosis is elevated in the general population.75
Antiplatelet agents have been the mainstay of medical management for secondary prevention of strokes in patients with symptomatic carotid disease. Antiplatelets can reduce the risk of stroke by 11-15%.76 The combination of antiplatelets, however, increases the risk of major bleeding. In a recent study (Clopidogrel and Aspirin Regimen for the Reduction of Emboli in the Symptomatic Carotid Stenosis (CARESS) Trial), patients with symptomatic carotid disease and microembolic signals (MES) on TCD were randomized to clopidogrel plus aspirin or aspirin monotherapy. Intention-to-treat analysis revealed a significant reduction in MES: 43.8% of dual-therapy patients had MES at day 7, as compared with 72.7% of monotherapy patients (relative risk reduction 39.8%, 95% CI 13.8-58.0, p = 0.0046). The risk of ischemic stroke or TIA within the first week postrandomization was also higher in the monotherapy group.77
The potential anti-inflammatory role of statins has also been studied. Statins have been shown to reduce stroke risk, due to its effect on multiple predisposing factors.78 Patients with symptomatic carotid stenosis treated with pravastatin for 3 months prior to carotid endarterectomy had fewer macrophages (15 ± 10% vs. 25.3 ± 12.5%), less lipid (8.2 ± 8.4% vs. 23.9 ± 21.1%), less oxidized LDL immu-noreactivity, greater TIMP-1 immunoreactivity, and higher collagen content than those treated with placebo. ICAM-1, VCAM-1, MMP-1, MMP-9, TIMP-2 immunoreactivity, and nuclear factor-kappa B (NF-kB) immunoreactivity were not significantly different in the two groups.79 Similarly, 18 patients with asymptomatic aortic and/or carotid plaques and hypercholesterolemia were treated with simvasta-tin with demonstrable reduction in wall thickness and wall area, but not lumen area, on in vivo black-blood MRI scans after 12 months of therapy. There were no changes observable after 6 months of therapy.80
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