Matthias Sitzer

Plaque Ulceration and Lumen Thrombus Are the Main Sources of Cerebral Microemboli in High-grade Internal Carotid Artery Stenosis

BACKGROUND AND PURPOSE Previous work has shown that rates of cerebral microemboli downstream of high-grade internal carotid artery stenosis are higher in recently symptomatic compared with asymptomatic patients. In addition, microembolic rates decline after carotid endarterectomy. We conducted a prospective investigation of 40 consecutive asymptomatic or recently symptomatic patients undergoing carotid endarterectomy for 70% to 95% internal carotid artery stenosis to determine the relationship between microembolic rate and pathoanatomic features of the carotid plaque. METHODS Transcranial Doppler monitoring including automated emboli detection was performed preoperatively to assess the rate of cerebral microemboli of the ipsilateral middle cerebral artery. The corresponding endarterectomy specimens were evaluated histologically with respect to the occurrence of plaque fissuring, intraplaque hemorrhage, plaque ulceration, or intraluminal thrombosis. RESULTS There were strong associations between plaque ulceration, intraluminal thrombosis, and downstream cerebral microemboli (P < or = .005, respectively). There were no correlations of microembolism with plaque fissuring or intraplaque hemorrhage (P = .82 and P = .28, respectively). CONCLUSIONS We conclude that ulceration and luminal thrombosis of the atheromatous plaque are the main sources of downstream cerebral microemboli in patients with high-grade internal carotid artery stenosis. Our data support the view that these pathoanatomic features may also play a key role in symptom development.

Inflammation in High-Grade Carotid Stenosis A Possible Role for Macrophages and T Cells in Plaque Destabilization

BACKGROUND AND PURPOSE Inflammatory mechanisms have been implicated in the pathogenesis of atherosclerosis. In this study, we investigated whether the extent of inflammatory infiltration in high-grade stenoses of the internal carotid artery (ICA) correlates to clinical features of plaque destabilization. METHODS Endarterectomy specimens from 37 consecutive patients undergoing surgery for high-grade ICA stenosis were stained immunocytochemically for macrophages (CD68) and T cells (CD3). The staining was quantified by planimetry of immunostained areas (CD68) or counting individual cells (CD3). Clinical evidence of plaque instability was provided by the preoperative assessment of recent ischemic symptoms attributable to the stenosis and of the occurrence of cerebral microembolism in transcranial Doppler ultrasound monitoring of the ipsilateral middle cerebral artery. RESULTS The percentage of macrophage-rich areas and number of T cells per mm2 section area were larger in recently symptomatic patients than in asymptomatic patients (macrophages: 18+/-10% versus 11+/-4%, P=0.005; T cells: 71.2+/-34.4 versus 40.5+/-31.4 mm2, P=0.005). The presence of microembolism was associated with an increase in macrophage-rich areas (P=0.011). Macrophage (19+/-10% versus 9+/-3%, P=0.0009) and T cell (71.5+/-39.0 versus 46.4+/-22 mm2, P=0.045) infiltration were more pronounced in predominantly atheromatous than in fibrous plaques, but did not correlate significantly to the presence of surface ulceration or luminal thrombosis. CONCLUSIONS Our data suggest a role of plaque-infiltrating macrophages and T cells in the clinical destabilization of high-grade ICA stenoses. Inflammatory mechanisms may be a therapeutic target in patients with symptomatic ICA disease.

Cerebral Microembolism and the Risk of Ischemia in Asymptomatic High-Grade Internal Carotid Artery Stenosis

BACKGROUND AND PURPOSE Previous work has shown that cerebral microembolism detected with transcranial Doppler sonography distal to internal carotid artery stenosis occurs more frequently in recently symptomatic compared with asymptomatic patients. It has remained unclear whether cerebral microembolism also indicates a higher risk of future cerebral or retinal ischemia. SUMMARY OF REPORT Sixty-four asymptomatic patients with unilateral 70% to 90% internal carotid artery stenosis were investigated prospectively (mean follow-up, 72 weeks). Five patients developed ischemic symptoms attributable to the stenosis (transient ischemic attack, 2 patients; stroke, 3 patients). A microembolic rate of > or = 2 per hour in the ipsilateral middle cerebral artery was associated with a substantially increased risk of developing ischemia of the corresponding carotid territory (odds ratio, 31; 95% confidence interval, 3 to 302; P = .005). CONCLUSIONS This prospective pilot study suggests that cerebral microembolism detected with transcranial Doppler sonography may define a high-risk subgroup among patients with asymptomatic high-grade internal carotid artery stenosis.

Reliability and Validity of Noninvasive Imaging of Internal Carotid Artery Pseudo-Occlusion

BACKGROUND AND PURPOSE Our study evaluated noninvasive tests for the diagnosis of atheromatous internal carotid artery (ICA) pseudo-occlusion. METHODS Twenty patients (17 men, 3 women; mean age +/-SD, 64.3+/-11.6 years) with angiographically proven atheromatous ICA pseudo-occlusion (20 vessels) were prospectively examined with MR angiography (MRA; 2D and 3D time-of-flight techniques), color Doppler-assisted duplex imaging (CDDI) and power-flow imaging (PFI) with and without an intravenous ultrasonic contrast agent. As a control group, 13 patients (13 men; mean+/-SD age, 63.0+/-9.0 years) with angiographically proven ICA occlusion (13 vessels) were studied with the same techniques. For the determination of interobserver agreement (kappa statistics), the findings of each diagnostic technique were read by 2 blinded and independent observers who were not involved in patient recruitment and initial data acquisition. Specificity and sensitivity were calculated for all noninvasive techniques (observer consensus) in comparison to the standard of reference (intra-arterial angiography). RESULTS Interobserver reliabilities were kappa=0.86 for intra-arterial angiography, kappa=0.90 for unenhanced CDDI, kappa=0. 93 for enhanced CDDI, kappa=0.93 for unenhanced PFI, kappa=1.0 for enhanced PFI, kappa=0.93 for 2D MRA, and kappa=0.77 for 3D MRA, respectively (P<0.0001). Specificities and sensitivities were 0.92 and 0.70 for unenhanced CDDI, 0.92 and 0.83 for enhanced CDDI, 0.92 and 0.95 for unenhanced PFI, 1.0 and 0.94 for enhanced PFI, 1.0 and 0.65 for 2D MRA, and 0.89 and 0.47 for 3D MRA, respectively. CONCLUSIONS Advanced ultrasonographic techniques, especially PFI (with only 1 false-positive diagnosis of occlusion in the present series), can provide reliable and valid data to differentiate between ICA pseudo-occlusion and complete occlusion. In contrast, time-of-flight MRA at its present state is not capable of predicting minimal residual flow within a nearly occluded ICA.

Detection of intracranial emboli in patients with symptomatic extracranial carotid artery disease.

Background and Purpose: Cerebral embolism from extracranial sources is an important cause of ischemic stroke. The purpose of this limited study using long-term transcranial Doppler ultrasonographic monitoring was to estimate the frequency of clinically silent intracranial embolisms in patients with symptomatic extracranial carotid artery disease. Summary of Report: By means of a 2-MHz pulsed-wave transcranial Doppler instrumentation, three consecutive patients with extracranial internal carotid artery stenosis (n=2) or occlusion (n=1) and recurrent ipsilateral ischemic events were monitored (19 hours total recording time). In addition, 10 control subjects without cerebrovascular disease were studied (25 hours total recording time). Formedelement emboli were defined as distinct signals within the fast Fourier-transform Doppler spectrum that were <70 msec in duration and >9 dB greater in intensity than the background signal. Clinically silent formed-element embolism of ophthalmic or cerebral arteries was demonstrated in all three patients. Embolic events occurred only in the territory of the symptomatic internal carotid artery. The average rate of cerebral embolization at transcranial Doppler ultrasonography was 4.1/hr, with a mean signal duration of 47 msec. No emboli were found in control subjects. Conclusions: The observed high frequency of silent embolism of the intracranial arteries detected by transcranial Doppler monitoring in patients with recurrently symptomatic extracranial carotid artery disease should encourage studies of the prognostic and therapeutic implications of this method.

Between-method correlation in quantifying internal carotid stenosis.

Background and Purpose The degree of internal carotid stenosis has emerged as the most important predictor of ischemic stroke in extracranial carotid artery disease. The purpose of this study was to assess the validity of the noninvasive techniques for quantifying internal carotid stenosis with respect to the accepted standard of intra-arterial angiography. Methods We measured the maximum percentage reduction in luminal diameter on the intra-arterial digital subtraction angiograms of 56 symptomatic patients with extracranial internal carotid stenosis (n=77) or occlusion (n=20). These data were compared with independent measurements based on continuous-wave Doppler ultrasonography, pulsed-wave Doppler spectrum analysis, color Doppler-assisted duplex imaging, and magnetic resonance angiography. Results Correlations with intra-arterial angiography were equally strong (r>.90) for magnetic resonance angiography, continuous-wave Doppler, and color duplex analysis. Positive and negative predictive values for (therapeutically relevant) 70% to 99% stenosis were higher for continuous-wave Doppler (.82, .97) and color duplex (.84, .98) than for magnetic resonance angiography (.79, .81). Also, accuracy in quantifying high-grade stenosis was better for both of these ultrasonographic techniques, mainly due to the frequent occurrence of a “flow gap” on the magnetic resonance angiograms. Continuous-wave Doppler and magnetic resonance angiography, but not color duplex, failed to detect slow residual arterial flow in one and two cases of symptomatic “pseudo-occlusion” of the internal carotid, respectively. Conclusions (1) Several noninvasive methods compare well with intra-arterial angiography in identifying and quantifying high-grade internal carotid stenosis; (2) the use of these noninvasive methods may suffice for treatment decisions; and (3) because residual between-method disagreement is partly explained by principles of physics, the validity of continuous-wave Doppler and color duplex in quantifying 60% to 99% stenosis is likely to be underestimated by correlation with intra-arterial angiography.

Usefulness of an intravenous contrast medium in the characterization of high-grade internal carotid stenosis with color Doppler-assisted duplex imaging.

BACKGROUND AND PURPOSE The remaining limitations of ultrasonographic imaging in accurately quantifying internal carotid stenosis or diagnosing internal carotid occlusion may be overcome by enhancing the echogenicity of flowing arterial blood with contrast agents. This study assessed the usefulness of the intravenous (transpulmonary) contrast medium SH U 508 A in improving the characterization and quantification of severe internal carotid stenosis. METHODS We examined 32 patients (30 had vessels with a stenosis of greater than 70% luminal narrowing and 2 had vessel occlusions) using a 7.5-MHz linear-array transducer for color Doppler-assisted duplex imaging before and after injection of the contrast medium. RESULTS The SH U 508 A-induced increase in carotid blood echogenicity began 11 +/- 2 (mean +/- SD) seconds after the start of the bolus injection, peaked at 21 +/- 2 dB, and showed a half-life of 75 seconds. Quantitative vascular measurements (cross-sectional luminal area reduction and plaque length, respectively) obtained before and after contrast application were highly correlated (r > .90). Visualization of the entire length of the intrastenotic residual flow lumen, however, was significantly improved by contrast enhancement (52% versus 83%, P = .01). CONCLUSIONS This pilot study on patients with extracranial carotid artery disease suggested that ultrasonic contrast media may be most useful in improving the ultrasonography-based diagnosis of internal carotid occlusion.

Expression of Tissue Factor in High-Grade Carotid Artery Stenosis: Association With Plaque Destabilization

Background and Purpose— The procoagulant protein tissue factor (TF) has been implicated in thromboembolic complications associated with advanced atherosclerosis. In this study, we investigated whether TF expression in high-grade stenoses of the internal carotid artery (ICA) is associated with clinical features of plaque destabilization and addressed the relationship between TF expression and plaque inflammation. Methods— In 36 consecutive patients undergoing surgery for high-grade ICA stenosis, clinical evidence of plaque instability was provided by the recent occurrence of ischemic symptoms attributable to the stenosis and the detection of cerebral microembolism by means of transcranial Doppler ultrasound monitoring of the ipsilateral middle cerebral artery. Endarterectomy specimens were stained immunocytochemically for TF expression as well as macrophage (CD68) and T cell (CD3) infiltration. Results— Morphologically, TF immunoreactivity was codistributed with plaque inflammation and predominantly localized to CD68+ macrophages. Accordingly, statistical analysis revealed a significant association of TF expression with plaque infiltration by macrophages (P <0.0001) and T cells (P =0.013). Plaques extensively stained for TF (median of TF+ total section area >40% in semiquantitative assessment) were more frequent in symptomatic (12/27) than in asymptomatic patients (1/9). Conversely, plaques exhibiting little TF expression (median of TF+ section area <20%) were more frequent in asymptomatic (3/9) than in symptomatic (1/27) patients (P =0.016). Likewise, we found a highly significant association of TF expression with the occurrence of cerebral microembolism (P =0.008). Conclusions— Induction of TF at sites of plaque inflammation may play an important role in the destabilization of high-grade ICA stenosis.

Color-flow doppler-assisted duplex imaging fails to detect ulceration in high-grade internal carotid artery stenosis

PURPOSE Pathoanatomic studies suggest that plaque surface disruption, particularly ulceration, plays a key role in the destabilization of internal carotid artery stenosis. Until now, the validity of color-flow Doppler-assisted duplex imaging in detecting such pathoanatomically defined plaque surface abnormalities is unclear. METHODS We prospectively determined the interobserver reliability and validity of detecting plaque ulceration by means of preoperative color-flow Doppler-assisted duplex imaging in 43 consecutive patients with high-grade (> or = 70%) internal carotid artery stenosis, comparing these ultrasonographic findings with pathoanatomic evaluations of the corresponding endarterectomy specimens. RESULTS Interobserver reliabilities for detecting carotid plaque ulceration were kappa= 0.57 for ultrasonography and kappa = 0.82 for the pathologic reference method. Color-flow Doppler-assisted duplex imaging (observer consensus) failed to detect pathoanatomically defined ulceration (chi square = 0.43; p = 0.51). Likewise, sensitivity, specificity, overall accuracy, and positive predictive value were poor (33%, 67%, 56%, and 46%, respectively). CONCLUSIONS We conclude from our data that color-flow Doppler-assisted duplex imaging is not a reliable or valid means to identify plaque ulceration in high-grade carotid artery lesions.

Magnetic Resonance Imaging of Regional Cerebral Blood Oxygenation Changes Under Acetazolamide in Carotid Occlusive Disease

BACKGROUND Gradient-echo magnetic resonance imaging can demonstrate changes in cerebral blood oxygenation with high spatiotemporal resolution. We have previously shown that this technique allows monitoring of autoregulatory responses under vasodilatory stress in the healthy human brain. Here the approach has been extended to assess impairment of the autoregulatory reserve capacity in patients with carotid occlusive disease. SUMMARY OF REPORT We studied four patients with unilateral occlusion of the internal carotid artery on a 2.0-T clinical high-field magnetic resonance system. Oxygenation-sensitive imaging was based on long-echo-time, gradient-echo sequences (repetition time, 62.5 milliseconds; echo time, 30 milliseconds) with low flip angles (10 degrees) to emphasize changes in blood oxygenation rather than flow velocity. Dynamic recording monitored signal intensities before and after injecting 1 g of acetazolamide. In sections covering the hand area of the primary sensorimotor cortex, acetazolamide-induced magnetic resonance signal increases were attenuated in the vascular territories of occluded arteries. Lateralization of responses in the left and right hemispheric parts of the section corresponded to decreased hemodynamic reserve capacity as measured globally by transcranial Doppler ultrasonography. CONCLUSIONS The present findings indicate that magnetic resonance imaging can demonstrate exhaustion of the autoregulatory reserve capacity when monitoring cerebral blood oxygenation changes during vasodilatory stress. We suggest that this method can help to evaluate regional cerebral hemodynamics in patients with carotid occlusive disease.