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(Stroke. 1995;26:1231-1233.)
© 1995 American Heart Association, Inc.

Articles

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

M. Sitzer, MD; W. Müller, MD; M. Siebler, MD; W. Hort, MD; H.-W. Kniemeyer, MD; L. Jäncke, PhD H. Steinmetz, MD

From the Department of Neurology (M. Sitzer, M. Siebler, H.S.), Department of Pathology (W.M., W.H.), Department of Vascular Surgery and Renal Transplantation (H.-W.K.), and Institute of General Psychology (L.J.), Heinrich-Heine-University, Düsseldorf, Germany.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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.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.

Key Words: carotid artery diseases • carotid endarterectomy • embolism • pathology • ultrasonics

	Introduction

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Noninvasive long-term transcranial Doppler (TCD) ultrasonography of intracranial arterial blood flow velocity spectra can reveal abnormal, high-pitched intensity signals suggesting clinically silent cerebral formed-element embolism.^{1 2} Several groups have shown that the rate of cerebral microemboli downstream of internal carotid artery (ICA) stenosis is higher in recently symptomatic than in asymptomatic patients^{3 4 5 6} and that it declines after carotid endarterectomy.^{7 8} This suggests that cerebral microembolism may reflect a pathogenically relevant process located at the ICA atheroma ("unstable ICA disease"⁶ ). The main purpose of our study was to investigate the relationship between individual microembolic rates and pathoanatomic features of the corresponding carotid endarterectomy specimens in patients with high-grade ICA stenosis.

	Subjects and Methods

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Patients
This study prospectively included 40 consecutive inpatients (13 women, 27 men; age range, 41 to 84 years; median, 61 years) enlisted to undergo carotid endarterectomy for extracranial high-grade ICA stenosis (70% luminal narrowing) as determined by intra-arterial cerebral angiography also showing a contribution to the blood supply of the ipsilateral middle cerebral artery via the stenosed ICA. The degree of ICA stenosis was determined according to the criteria of the North American Symptomatic Carotid Endarterectomy Trial (NASCET).⁹ Also according to NASCET criteria, patients were defined as symptomatic (n=28) if they had recently (<121 days before enlistment) experienced transient retinal or cerebral symptoms or minor ischemic stroke attributable to the high-grade ICA lesion. Asymptomatic patients were defined as those who had a history of no (n=10) or only remote (>120 days before enlistment; n=2) ischemic symptoms. Antiplatelet drugs or oral anticoagulants had been discontinued for more than 5 days in all patients before TCD monitoring. Informed consent was obtained from all patients before each examination.

Transcranial Doppler Monitoring
In all 40 patients, we performed long-term TCD monitoring (at least two 1-hour recordings on successive days) to measure the rate of microembolic signals of the middle cerebral artery ipsilateral to high-grade ICA stenosis. Our technique of TCD monitoring has been described elsewhere.^{6 7 10} In brief, a 2-MHz pulsed-wave transducer was used with the Doppler probe fixed to the left or right temporal region for transcranial insonation of the middle cerebral artery. Axial width of the sample volume was set at 15 mm; the middle cerebral artery was insonated at a depth of 45 to 55 mm. The TCD criteria for microembolic events, the interobserver reliability with the use of these criteria (mean proportion of specific agreement=0.91), and an automated detection method that uses a neural network have been reported previously.¹⁰ In the present study rates of cerebral microemboli are based on events concordantly identified as emboli by both a human observer blind for pathological data (on-line) and the neural net (off-line).

In the symptomatic patients the time interval between the last ischemic symptom and TCD monitoring was 1 to 118 days (median, 11 days). For all patients the interval between TCD monitoring and carotid endarterectomy was 1 to 21 days (median, 4.5 days).

Pathoanatomic Examination
After longitudinal arteriotomy, the carotid atherosclerotic plaque was excised en bloc by the vascular surgeon (routine endarterectomy). The fresh specimen was fixed immediately in 4% paraformaldehyde solution, and a gross photograph was taken on which areas of particular interest were marked by a pathologist for consecutive sectioning. After decalcification, the whole specimen was transversely sectioned into 2-mm-thick slices starting proximally. After the slices were embedded in paraffin, three or four 5-µm sections were obtained from each slice and stained with hematoxylin-eosin and van Gieson's stain.

The following four pathoanatomic features were assessed during gross morphological and histological examinations performed independently by two pathologists blind for clinical data and microembolic rates. We defined plaque fissuring as vertical or oblique plaque surface disruption of no more than 1000 µm in width, of varying depth, and without large intimal defects. Interobserver reliability for detecting so-defined plaque fissuring was =0.74 for the present sample (see below for statistical analysis). We defined intraplaque hemorrhage as bleeding within the plaque of greater than 1500 µm in largest diameter. Interobserver reliability for detecting intraplaque hemorrhage was =0.92 for the present sample. We defined plaque ulceration as intimal defect larger than 1000 µm in width, exposing the necrotic core of the atheromatous plaque. Interobserver reliability for detecting plaque ulceration was =0.75 for the present sample. We defined lumen thrombus as thrombotic material of more than 300 µm maximum thickness adherent to the plaque surface. Interobserver reliability for detecting lumen thrombus was =0.78 for the present sample. Sizes of pathological abnormalities reported in the following were obtained from histological examination after the specimens were fixed in paraformaldehyde. Prevalences of these four pathoanatomic features are based on the consensus achieved between both pathologists at joint reevaluation of their data previously obtained independently.

Statistical Analysis
With the use of statistics, the reliabilities between both pathologists for detecting the aforementioned pathoanatomic abnormalities were calculated from their independent evaluations of the entire sample (values given above). We evaluated the four pathoanatomic features with respect to an association with microembolic rate detected at TCD (four consecutive ² tests). For this purpose, we subdivided the patients into tertiles according to individual microembolic rates (0/h, n=13; 5/h, n=14; >5/h, n=12). A significance level of P=.05 was chosen. Because we performed four statistical comparisons, values of P<.01 (.05/4) were considered to indicate significant findings (-adjustment according to the modified Bonferroni procedure).¹¹ Additionally, the proportions of asymptomatic or symptomatic patients in the microemboli tertiles were compared with the use of ² analyses.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In the 12 asymptomatic patients, TCD monitoring of the middle cerebral artery ipsilateral to high-grade ICA stenosis revealed 36 microembolic events during a total investigation time of 24 hours. All events occurred in two patients with individual microembolic rates of 8/h and 10/h (Table 1). In the 28 symptomatic patients, 615 microemboli were detected in the middle cerebral artery distal to ICA stenosis during a total recording time of 58.5 hours. Here the individual rates of microemboli per hour ranged from 0 in three subjects up to 90 in one (Table 1). No concomitant neurological symptoms were reported or observed. Symptomatic patients had significantly higher rates of microemboli than asymptomatic patients (Table 1; P<.001).

View this table: [in this window] [in a new window]   Table 1. Number of Asymptomatic or Symptomatic Patients With High-grade Internal Carotid Stenosis in the Three Microembolic Tertiles

One carotid endarterectomy specimen of a symptomatic patient was excluded from pathoanatomic examination because of severe distortion (individual microembolic rate, 13/h). Among the remaining 39 specimens plaque fissuring was diagnosed in 49% (n=19), intraplaque hemorrhage in 21% (n=8), plaque ulceration in 44% (n=17), and lumen thrombus in 64% (n=25). The mean widths of plaque fissuring and plaque ulceration were 410±190 (SD) µm and 3770±2130 (SD) µm, respectively. The mean diameter of plaque hemorrhage was 2820±940 (SD) µm. In six specimens plaque hemorrhage showed continuity with the vessel lumen.

The relationship between TCD-detected microembolism and the pathoanatomic findings is shown in Table 2. Microembolism was strongly associated with plaque ulceration (P=.005) and lumen thrombus (P=.0003), whereas no correlation emerged with intraplaque hemorrhage or plaque fissuring. Because these data suggested a relationship between lumen thrombus and plaque ulceration, we performed an additional ² analysis for these pathoanatomic features. The results confirmed the assumption (Table 3). As already suggested by Tables 1 and 2, lumen thrombus and plaque ulceration were also more frequent in symptomatic compared with asymptomatic patients (Table 4).

View this table: [in this window] [in a new window]   Table 2. Relationships Between Preoperative Microembolic Rates and Four Pathoanatomic Features in 39 Carotid Endarterectomy Specimens From 39 Patients With High-grade Internal Carotid Artery Stenosis

View this table: [in this window] [in a new window]   Table 3. Strong Relationship Between Lumen Thrombus and Plaque Ulceration in 39 Carotid Endarterectomy Specimens

View this table: [in this window] [in a new window]   Table 4. Relationships Between a History of Recent Ischemic Symptoms Attributable to High-grade Internal Carotid Artery Stenosis and Four Pathoanatomic Features in 39 Corresponding Carotid Endarterectomy Specimens From 39 Patients

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our data provide evidence that ICA plaque ulceration and intraluminal thrombosis are the main sources of ipsilateral microembolism of the middle cerebral artery in patients with high-grade ICA stenosis (Table 2). In addition, there is a strong relationship between both of these pathoanatomic features (Table 3). Thus, the histological hallmarks of unstable ICA stenosis as defined in our study were the same as those described postmortem for unstable coronary heart disease and acute peripheral thrombo-occlusive disease.^{12 13}

In contrast, intraplaque hemorrhage and plaque fissuring were not associated with cerebral microembolism (Table 2). Thus, we conclude that TCD is the first noninvasive method capable of detecting and monitoring plaque ulceration and lumen thrombus as the main pathoanatomic features of unstable ICA stenosis. Although it is tempting to speculate on possible clinical implications of this observation, ongoing prospective studies will have to clarify whether cerebral microembolism can also predict ischemic events in atherosclerotic ICA disease.

Numerous previous investigations that used carotid endarterectomy specimens have provided conflicting data on whether lumen thrombus, plaque ulceration, or intraplaque hemorrhage are associated with a history of ischemic symptoms in ICA disease.^{14 15 16 17 18 19 20 21 22 23 24 25} In our relatively small sample, there was an association between plaque ulceration and lumen thrombus and recent ischemic symptoms (Table 4). This concurs with preliminary pathoanatomic results of the NASCET and Asymptomatic Carotid Atherosclerosis Study²⁶ that also suggest that disruption and resultant intraluminal thrombosis, but not primary intraplaque hematoma, are the key events leading to symptom development in atherosclerotic ICA disease.

	Acknowledgments

 
This study was supported by grants from the Deutsche Forschungsgemeinschaft (Si 370/4-1) and the Hermann-und-Lilly-Schilling-Stiftung (Dr Steinmetz). We are indebted to B. Frahm, C. Hache, A. Nachtmann, and D. Bendfeldt for expert technical assistance and to Dr G. Rose, PhD, for computing the neural net–based data analysis.

	Footnotes

 
Reprint requests to Dr Helmuth Steinmetz, Department of Neurology, Heinrich-Heine-University, Moorenstraße 5, PO Box 101007, D-40001 Düsseldorf, Germany.

Received February 22, 1995; revision received April 3, 1995; accepted April 4, 1995.

	References

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				P.M. Rothwell The Interrelation between carotid, femoral and coronary artery disease Eur. Heart J., January 1, 2001; 22(1): 11 - 14. [PDF]

				T. J. Tegos, E. Kalodiki, M. M. Sabetai, and A. N. Nicolaides Stroke: Pathogenesis, Investigations, and Prognosis: Part II of III Angiology, November 1, 2000; 51(11): 885 - 894. [Abstract] [PDF]

				T. Omae, O. Mayzel-Oreg, F. Li, C. H. Sotak, M. Fisher, and E. C. Haley Jr Inapparent Hemodynamic Insufficiency Exacerbates Ischemic Damage in a Rat Microembolic Stroke Model Editorial Comment Stroke, October 1, 2000; 31(10): 2494 - 2499. [Abstract] [Full Text] [PDF]

				B. Axisa, A. R. Naylor, N. London, P. R. F. Bell, and M. M. Thompson The Influence of Carotid Plaque Morphology on the Development of Cerebral Symptoms Vascular and Endovascular Surgery, July 1, 2000; 34(4): 309 - 318. [Abstract] [PDF]

				P. M. Rothwell, R. Gibson, and C. P. Warlow Interrelation Between Plaque Surface Morphology and Degree of Stenosis on Carotid Angiograms and the Risk of Ischemic Stroke in Patients With Symptomatic Carotid Stenosis Stroke, March 1, 2000; 31(3): 615 - 621. [Abstract] [Full Text] [PDF]

P. M. Rothwell and C. P. Warlow Low Risk of Ischemic Stroke in Patients With Reduced Internal Carotid Artery Lumen Diameter Distal to Severe Symptomatic Carotid Stenosis : Cerebral Protection Due to Low Poststenotic Flow? Stroke, March 1, 2000; 31(3): 622 - 630. [Abstract] [Full Text] [PDF]