(Stroke. 1995;26:813-815.)
© 1995 American Heart Association, Inc.
Articles |
From the Departments of Neurology (L.V., V.L., G.G., A.B.) and Neuroradiology (P.A.), Rangueil University Hospital, Toulouse, France.
Correspondence to Vincent Larrue, MD, Service de Neurologie, Hôpital Rangueil, 31054 Toulouse, France.
| Abstract |
|---|
|
|
|---|
Methods Doppler signals from 48 MCAs in 26 patients with carotid stenosis that was either symptomatic (n=20) or asymptomatic (n=6) were recorded for 40 minutes. The grade of carotid stenosis and the ulcerated or nonulcerated appearance of the plaque were assessed using the criteria of the North American Symptomatic Carotid Endarterectomy Trial.
Results Embolic signals were detected in 8 MCAs from 7 patients; 4 (50%) of these MCAs were clinically symptomatic compared with 16 (40%) without embolic signal. Although there was a trend toward more severe stenosis in the cases with embolic signals, this was not significant (mean±SD, 67±29% versus 55±36%). In contrast, an image of ulceration was found on ipsilateral carotid angiography in 5 cases (63%) with embolic signals and in only 9 cases (23%) without embolic signals (odds ratio, 5.74; 95% confidence interval, 1.15 to 28.79, by multivariate regression analysis).
Conclusions This study demonstrates that the occurrence of embolic signals in patients with carotid stenosis is associated with the appearance of plaque ulceration on angiography.
Key Words: carotid artery diseases cerebral embolism and thrombosis ultrasonics
| Introduction |
|---|
|
|
|---|
Transcranial Doppler (TCD) ultrasonography monitoring of the middle cerebral arteries (MCAs) can reveal abnormal high-intensity transient signals (HITS) occurring without any clinical symptoms and indicating cerebral emboli. HITS were first reported in patients with high-grade stenosis by Spencer et al.7 Since then, both animal models8 9 and flow-circuit models10 have allowed definition of the features of HITS caused by solid emboli. Several studies have confirmed that embolic signals can be detected in patients with carotid artery disease,11 12 13 14 15 16 17 and some of these studies have demonstrated an association with the previous occurrence of clinical symptoms and the degree of carotid narrowing.15 17 The aim of our study was to determine whether the ulcerated appearance of the plaque on carotid angiography is a predictor of HITS.
| Subjects and Methods |
|---|
|
|
|---|
The patients were receiving the following antithrombotic treatments when TCD monitoring was performed: full-dose heparin (5 patients), aspirin (4), ticlopidine (1), either clopidogrel or aspirin (1), low-dose heparin plus aspirin (11), or no antithrombotic treatment (4).
All patients underwent bilateral selective carotid angiography. The angiograms were independently reviewed by two neuroradiologists who were blinded to the clinical data and to the results of TCD monitoring. Carotid stenoses were graded using the method described in the North American Symptomatic Carotid Endarterectomy Trial (NASCET).18 Plaques were further classified according to their ulcerated or nonulcerated appearance, also using NASCET criteria.19
Long-term monitoring of the MCA was performed for 40 minutes on both sides in 22 patients and, due to the lack of a bone window, on only one side in 4 patients. We used a 2-MHz pulsed-wave transducer (Diadop 500, Diatecnic). The Doppler probe was attached with an elastic headband. The depth was chosen from 45 to 50 mm to obtain optimum insonation of the MCA. The audible Doppler shift and the fast-Fourier transformed TCD spectra were continuously observed by an experienced investigator who noted all the events that could be potential sources of artifacts. Video recordings were analyzed off-line by two independent observers (L.V. and V.L.) who were blinded to the clinical data and to the results of carotid angiography. Embolic signals were identified according to their previously defined features12 : short-duration, unidirectional, high-intensity signals visible in the Doppler spectrum, occurring randomly within the cardiac cycle, accompanied by a characteristic "chirping" or "clicking" sound, and without any possible cause of artifact at the same time.
Univariate analysis was performed using the
2
test for categorical variables and Student's t test for
continuous ones. Significance was set at P<.05. To assess
the effect of selected variables on the probability of HITS, a
multivariate regression analysis using a logistic model was
performed. The explanatory variables included in the initial model were
the previous occurrence of clinical symptoms, carotid stenosis >50%,
and an image of ulceration in the carotid plaque on angiography. A
backward selection procedure allowed only significant variables to be
retained in the model. The cutoff to exclude a variable from the
initial model was defined as a ratio of the absolute value of the
estimate to the standard error smaller than 1. Analysis was conducted
using GLIM software (Royal Statistical Society). Results
are expressed as means±SD.
| Results |
|---|
|
|
|---|
index for
interobserver agreement was 0.83. The rate of HITS was 2.8±1.9 per
hour. Among symptomatic patients, the time between symptoms and recordings was 31±50 days in patients with HITS and 22±23 days in those without HITS. The difference was not significant. The number of symptomatic patients with HITS was too small to allow assessment of the relationship between the time since the last symptoms and the rate of HITS.
Four (50%) MCAs with HITS were clinically symptomatic compared with 16 (40%) without HITS. The proportion of cases with antithrombotic treatment was exactly the same in cases with HITS (7/8) as in cases without HITS (35/40). The time between angiography and recordings was 4±8 days in cases with HITS and 8±12 days in those without HITS (P=.4).
The degree of carotid narrowing was 67±29% in cases with HITS and
55±36% in those without HITS. This trend was not significant. In
contrast, an image of ulceration was found on ipsilateral carotid
angiograms in 5 cases (63%) with HITS and in only 9 cases (23%)
without HITS (P=.02) (Table 1
). The
index
for interobserver agreement in the diagnosis of ulceration was 0.85.
The values of the estimates and standard errors observed in the
regression model are given in Table 2
. The backward
procedure selected the ulcerated appearance of the carotid plaque as
the only significant explanatory variable. The corresponding odds ratio
was 5.74, and the 95% confidence interval was 1.15 to 28.79.
|
|
| Discussion |
|---|
|
|
|---|
All the signals detected in our study and in previous ones were asymptomatic.12 14 16 This may be due to the small size of the emboli. Indeed, it has been demonstrated that injections of microspheres of a diameter <105 µm into the common carotid artery of rabbits cause no overt neurological dysfunction.20 Similarly, routine fundoscopic examination may disclose small retinal emboli that have caused no symptoms.21 22
There are strong disparities in the results from different ultrasound laboratories on the incidence of HITS in patients with carotid stenosis. For instance, Grosset et al23 reported HITS in all the patients they monitored. In contrast, Markus et al12 found HITS in only 6 of 25 patients, a proportion close to that observed in our study. These discrepancies may be due to differences in methods, such as TCD and recording equipment, level of background noise, intensity threshold, sample volume, gain, and duration of recording. Moreover, although the features of artifacts from probe motion are well known, the level of false-positives may be higher in unblinded studies.24
Some previous studies also have identified biological variables that are associated with HITS. Siebler et al17 found HITS in 27 of 33 symptomatic patients and in only 9 of 56 patients with asymptomatic stenosis. All patients had stenosis of >70%. It must be noted, however, that symptomatic patients had not been taking antiplatelet drugs for more than 5 days, whereas more than half of the asymptomatic patients were taking antiplatelet treatment at the time of TCD monitoring. This may have decreased the incidence of HITS in asymptomatic patients.25 Ries et al16 reported that they detected HITS in 7 of 36 symptomatic patients and in none of 18 patients with asymptomatic stenosis. Babikian et al15 found HITS in 10 of 37 symptomatic arteries and in only 1 of 34 asymptomatic arteries. In the same sample, they also demonstrated a higher rate of HITS distal to >50% carotid stenosis. However, because they used only univariate analysis, their results do not account for any possibly mutually confounding effects of the two variables.
In our study, neither the previous occurrence of clinical symptoms nor the degree of carotid stenosis were significantly associated with HITS. As the sample was small, these negative results may be due to a lack of power. Moreover, monitoring our symptomatic patients sooner after the occurrence of clinical symptoms might have increased the rate of HITS. Indeed, the findings of Siebler et al14 suggest a decrease with time in the rate of HITS from the last occurrence of ischemic symptoms. However, in our study, multivariate regression analysis, including previous occurrence of clinical symptoms and degree of carotid stenosis as independent variables, revealed that an image of ulceration on carotid angiography was the stronger and only significant predictor of HITS. There is some inaccuracy in the angiographic diagnosis of plaque ulceration: specificity is rather high, but sensitivity is low, ranging from 46% to 56%.19 26 Nevertheless, an image of ulceration on carotid angiography is a powerful predictor of subsequent ipsilateral stroke.6 Assuming that HITS are asymptomatic emboli, our results demonstrate a significant link between the occurrence of asymptomatic cerebral emboli and the presence of an ipsilateral source of emboli. In this regard, HITS detection by TCD monitoring might become a useful and noninvasive tool to assess the thromboembolic risk of carotid plaques. Whether HITS indicate a higher risk for subsequent stroke remains, however, to be determined by the proper longitudinal study.
| Acknowledgments |
|---|
Received December 19, 1994; revision received February 16, 1995; accepted February 17, 1995.
| References |
|---|
|
|
|---|
2. Pessin MS, Hinton RC, Davis KR, Duncan GW, Roberson GH, Ackerman RH, Mohr JP. Mechanisms of acute carotid stroke. Ann Neurol. 1979;6:245-252. [Medline] [Order article via Infotrieve]
3.
Ringelstein EB, Zeumer H, Angelou D. The pathogenesis of
strokes from internal carotid artery occlusion: diagnostic and
therapeutic implications. Stroke. 1983;14:867-875.
4. European Carotid Surgery Trialists' Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet. 1991;337:1235-1243. [Medline] [Order article via Infotrieve]
5. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445-453. [Abstract]
6. Eliasziw M, Streifler JY, Fox AJ, Hachinski VC, Ferguson GG, Barnett HJM. Significance of plaque ulceration in symptomatic patients with high-grade carotid stenosis. Stroke. 1994;25:304-308. [Abstract]
7.
Spencer MP, Thomas GI, Nicholls SC, Sauvage LR. Detection of
middle cerebral artery emboli during carotid endarterectomy using
transcranial Doppler ultrasonography. Stroke. 1990;21:415-423.
8. Markus HS, Loh A, Brown MM. Detection of circulating cerebral emboli using Doppler ultrasound in a sheep model. J Neurol Sci. 1994;122:117-124. [Medline] [Order article via Infotrieve]
9.
Russell D, Madden KP, Clark WM, Sandset PM, Zivin JA.
Detection of arterial emboli using Doppler ultrasound in rabbits.
Stroke. 1991;22:253-258.
10.
Markus HS, Brown MM. Differentiation between different
pathological cerebral embolic materials using transcranial Doppler in
an in vitro model. Stroke. 1993;24:1-5.
11. Georgiadis D, Grosset DG, Quin RO, Nichol JAR, Bone I, Lees KR. Detection of intracranial emboli in patients with carotid disease. Eur J Vasc Surg. 1994;8:309-314. [Medline] [Order article via Infotrieve]
12. Markus HS, Droste DW, Brown MM. Detection of asymptomatic circulating cerebral emboli signals in patients with potential emboli sources. Lancet. 1994;343:1011-1012. [Medline] [Order article via Infotrieve]
13.
Siebler M, Sitzer M, Steinmetz H. Detection of intracranial
emboli in patients with symptomatic extracranial carotid artery
disease. Stroke. 1992;23:1652-1654.
14.
Siebler M, Sitzer M, Rose G, Bendfeldt D, Steinmetz H. Silent
cerebral embolism caused by neurologically symptomatic high-grade
carotid stenosis. Brain. 1993;116:1005-1015.
15. Babikian VL, Hyde C, Pochay V, Winter MR. Clinical correlates of high-intensity transient signals detected on transcranial Doppler sonography in patients with cerebrovascular disease. Stroke. 1994;25:1570-1573. [Abstract]
16. Ries S, Schminke U, Daffertshofer M, Schindlmayr C, Hennerici M. HITS in patients with atherosclerotic carotid disease. Cerebrovasc Dis. 1994;4:256. Abstract.
17.
Siebler M, Kleinschmidt A, Sitzer M, Steinmetz H, Freund HJ.
Cerebral microembolism in symptomatic and asymptomatic high-grade
internal carotid artery stenosis. Neurology. 1994;44:615-618.
18.
North American Symptomatic Carotid Endarterectomy Trial
(NASCET) Steering Committee. North American Symptomatic Carotid
Endarterectomy Trial: methods, patient characteristics, and progress.
Stroke. 1991;22:711-720.
19. Streifler JY, Eliasziw M, Fox AJ, Benavente OR, Hachinski VC, Ferguson GG, Barnett HJM. Angiographic detection of carotid plaque ulceration: comparison with surgical observations in a multicenter study. Stroke. 1994;25:1130-1132. [Abstract]
20. Winding O. Cerebral microembolization following carotid injection of dextran microspheres in rabbits. Neuroradiology. 1981;21:123-126. [Medline] [Order article via Infotrieve]
21. Ross Russell RW. Atheromatous retinal embolism Lancet. 1963;2:1354-1356. [Medline] [Order article via Infotrieve]
22. Hollenhorst RW. Vascular status of patients who have cholesterol emboli in the retina. Am J Ophthalmol. 1966;61:1159-1165. [Medline] [Order article via Infotrieve]
23.
Grosset DG, Georgiadis D, Kelman AW, Lees KR. Quantification
of ultrasound emboli signals in patients with cardiac and carotid
disease. Stroke. 1993;24:1922-1924.
24.
Markus HS. Transcranial Doppler detection of circulating
cerebral emboli. Stroke. 1993;24:1246-1250.
25. Siebler M, Nachtmann A, Sitzer M, Steinmetz H. Anticoagulation monitoring and cerebral microemboli detection. Lancet. 1994;244:555. Letter.
26.
Estol C, Claassen D, Hirsch W, Wechsler L, Moossy J.
Correlative angiographic and pathologic findings in the diagnosis of
ulcerated plaques in carotid artery. Arch Neurol. 1991;48:692-694.
This article has been cited by other articles:
![]() |
A. D. Mackinnon, R. Aaslid, and H. S. Markus Ambulatory Transcranial Doppler Cerebral Embolic Signal Detection in Symptomatic and Asymptomatic Carotid Stenosis Stroke, August 1, 2005; 36(8): 1726 - 1730. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. S. Markus, D. W. Droste, M. Kaps, V. Larrue, K. R. Lees, M. Siebler, and E. B. Ringelstein Dual Antiplatelet Therapy With Clopidogrel and Aspirin in Symptomatic Carotid Stenosis Evaluated Using Doppler Embolic Signal Detection: The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) Trial Circulation, May 3, 2005; 111(17): 2233 - 2240. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. S. Markus and A. MacKinnon Asymptomatic Embolization Detected by Doppler Ultrasound Predicts Stroke Risk in Symptomatic Carotid Artery Stenosis Stroke, May 1, 2005; 36(5): 971 - 975. [Abstract] [Full Text] [PDF] |
||||
![]() |
I. Momjian-Mayor and J.-C. Baron The Pathophysiology of Watershed Infarction in Internal Carotid Artery Disease: Review of Cerebral Perfusion Studies Stroke, March 1, 2005; 36(3): 567 - 577. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Gao, K. S. Wong, T. Hansberg, W. W. M. Lam, D. W. Droste, and E. B. Ringelstein Microembolic Signal Predicts Recurrent Cerebral Ischemic Events in Acute Stroke Patients With Middle Cerebral Artery Stenosis Stroke, December 1, 2004; 35(12): 2832 - 2836. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. G. Nabavi, J. Stockmann, C. Schmid, M. Schneider, D. Hammel, H. H. Scheld, and E. B. Ringelstein Doppler microembolic load predicts risk of thromboembolic complications in Novacor patients J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 160 - 167. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. L. Stork, K. Kimura, C. R. Levi, B. R. Chambers, A. L. Abbott, and G. A. Donnan Source of Microembolic Signals in Patients With High-Grade Carotid Stenosis Stroke, August 1, 2002; 33(8): 2014 - 2018. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Hutchinson, G. Riding, S. Coull, and C. N. McCollum Are Spontaneous Cerebral Microemboli Consistent in Carotid Disease? Stroke, March 1, 2002; 33(3): 685 - 688. [Abstract] [Full Text] [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] |
||||
![]() |
D. W Droste, R. Dittrich, V. Kemeny, G. Schulte-Altedorneburg, and E B. Ringelstein Prevalence and frequency of microembolic signals in 105 patients with extracranial carotid artery occlusive disease J. Neurol. Neurosurg. Psychiatry, October 1, 1999; 67(4): 525 - 528. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Molloy and H. S. Markus Asymptomatic Embolization Predicts Stroke and TIA Risk in Patients With Carotid Artery Stenosis Stroke, July 1, 1999; 30(7): 1440 - 1443. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. T.F. Cheung, L. Valton, and V. Larrue Early Ischemic Recurrence and Microembolic Signals Detected by Transcranial Doppler • Response Stroke, June 1, 1999; 30(6): 1290 - 1290. [Full Text] [PDF] |
||||
![]() |
L. Valton, V. Larrue, A. P. le Traon, P. Massabuau, and G. Geraud Microembolic Signals and Risk of Early Recurrence in Patients With Stroke or Transient Ischemic Attack Stroke, October 1, 1998; 29(10): 2125 - 2128. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Cullinane, R. Wainwright, A. Brown, M. Monaghan, and H. S. Markus Asymptomatic Embolization in Subjects With Atrial Fibrillation Not Taking Anticoagulants : A Prospective Study Stroke, September 1, 1998; 29(9): 1810 - 1815. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Molloy, N. Khan, and H. S. Markus Temporal Variability of Asymptomatic Embolization in Carotid Artery Stenosis and Optimal Recording Protocols Stroke, June 1, 1998; 29(6): 1129 - 1132. [Abstract] [Full Text] [PDF] |
||||
![]() |
L Valton, V Larrue, A P. Le Traon, and G Geraud Cerebral microembolism in patients with stroke or transient ischaemic attack as a risk factor for early recurrence J. Neurol. Neurosurg. Psychiatry, December 1, 1997; 63(6): 784 - 787. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. S. Markus, R. Ackerstaff, V. Babikian, C. Bladin, D. Droste, D. Grosset, C. Levi, D. Russell, M. Siebler, and C. Tegeler Intercenter Agreement in Reading Doppler Embolic Signals : A Multicenter International Study Stroke, July 1, 1997; 28(7): 1307 - 1310. [Abstract] [Full Text] |
||||
![]() |
H. S. Markus and J. Molloy Use of a Decibel Threshold in Detecting Doppler Embolic Signals Stroke, April 1, 1997; 28(4): 692 - 695. [Abstract] [Full Text] |
||||
![]() |
H.-C. Koennecke, H. Mast, S. S. Trocio Jr, R. L. Sacco, J. L. P. Thompson, and J. P. Mohr Microemboli in Patients With Vertebrobasilar Ischemia : Association With Vertebrobasilar and Cardiac Lesions Stroke, March 1, 1997; 28(3): 593 - 596. [Abstract] [Full Text] |
||||
![]() |
U. Sliwka, A. Lingnau, W.-D. Stohlmann, P. Schmidt, M. Mull, R. R. Diehl, and J. Noth Prevalence and Time Course of Microembolic Signals in Patients With Acute Stroke: A Prospective Study Stroke, February 1, 1997; 28(2): 358 - 363. [Abstract] [Full Text] |
||||
![]() |
H. Markus, J. M. Bland, G. Rose, M. Sitzer, and M. Siebler How Good Is Intercenter Agreement in the Identification of Embolic Signals in Carotid Artery Disease? Stroke, July 1, 1996; 27(7): 1249 - 1252. [Abstract] [Full Text] |
||||
![]() |
A.M. Forteza, V.L. Babikian, C. Hyde, M. Winter, and V. Pochay Effect of Time and Cerebrovascular Symptoms on the Prevalence of Microembolic Signals in Patients With Cervical Carotid Stenosis Stroke, April 1, 1996; 27(4): 687 - 690. [Abstract] [Full Text] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Stroke Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 1995 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |