European Journal of Vascular & Endovascular Surgery
Volume 35, Issue 5 , Pages 534-540, May 2008

Prevalence of Micro-Emboli in Symptomatic High Grade Carotid Artery Disease: A Transcranial Doppler Study

  • T. Zuromskis

      Affiliations

    • Department of Clinical Physiology, Sahlgrenska Academy, Göteborg
    • Neurology, Kaunas Medical University, Lithuania
    • Department of Neurology, Scarborough General Hospital, Scarborough, UK
    • ,
  • R. Wetterholm

      Affiliations

    • Department of Clinical Physiology, Sahlgrenska Academy, Göteborg
    • ,
  • J.F. Lindqvist

      Affiliations

    • Department of Clinical Physiology, Sahlgrenska Academy, Göteborg
    • ,
  • S. Svedlund

      Affiliations

    • Department of Clinical Physiology, Sahlgrenska Academy, Göteborg
    • ,
  • C. Sixt

      Affiliations

    • Department of Clinical Physiology, Sahlgrenska Academy, Göteborg
    • ,
  • D. Jatuzis

      Affiliations

    • Neurology & Neurosurgery, Vilnius University, Lithuania
    • ,
  • D. Obelieniene

      Affiliations

    • Neurology, Kaunas Medical University, Lithuania
    • ,
  • K. Caidahl

      Affiliations

    • Department of Clinical Physiology, Sahlgrenska Academy, Göteborg
    • Department of Clinical Physiology, Karolinska Institutet, Stockholm, Sweden
    • ,
  • R. Volkmann

      Affiliations

    • Department of Clinical Physiology, Sahlgrenska Academy, Göteborg
    • Corresponding Author InformationCorresponding author. R. Volkmann, Department of Molecular and Clinical Medicine, Clinical Physiology, SE 41345 Göteborg, Sweden.

Accepted 4 January 2008. published online 21 February 2008.

Article Outline

Background and purpose

Echolucent carotid plaques, as well as downstream micro-embolisation, may be associated with an increased risk of stroke. However, the relationship between carotid plaque ultrasound characteristics and micro-embolic signals (MES) detected in the middle cerebral artery (MCA) is still controversial. The purpose of this study was to investigate the prevalence of MES in patients with symptomatic high-grade internal carotid artery (ICA) stenosis and to identify predisposing factors, such as plaque echogenicity and intra stenotic blood flow velocity pattern.

Methods

197 patients (mean age 69.5±8.6, 161 males) with confirmed symptomatic high-grade ICA stenosis and anti-platelet treatment underwent bilateral MES monitoring for 30 minutes within the anterior circulation, using Power M-mode transcranial Doppler techniques (TCD). Carotid artery plaques were characterized by Gray-Weale scaling.

Results

In 32.0% of the patients, we detected MES by TCD within the MCA on the symptomatic side, but the same finding was made in only 4.5% on the corresponding asymptomatic site (p<0.0001). The presence or absence of MES was associated with neither ultrasonic plaque characteristics nor the intrastenotic blood flow velocities at peak systole and end diastole. The median time since the last ischemic event symptoms was shorter in the patient group with MES [+] than in MES [−] (p=0.013).

Conclusions

Despite optimum standard anti-platelet therapy, cerebral micro-embolisation occurs in 30% of patients with symptomatic carotid artery disease, which might therefore be a possible risk factor for recurrent neurological symptoms. However, the presence of MES is independent of intrastenotic blood flow disturbances and grey scale ultrasound plaque characteristics. The presence of MES as an indicator of unstable plaque and thereby a possible risk factor for stroke should be evaluated prospectively using various algorithms for plaque classifications.

Keywords: Carotid artery stenosis, Micro-embolic signals, Carotid plaque characteristics, Duplex ultrasound, Transcranial Doppler

 

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Introduction 

Stroke is the third leading cause of death in the developed countries after heart diseases and cancer. A significant percentage of strokes are caused by emboli arising from atherothrombotic carotid artery stenosis, which therefore is a risk factor for ischemic stroke.1, 2 Carotid endarterectomy (CEA) significantly reduces the incidence of stroke in patients with symptomatic extracranial carotid artery stenosis of 70–99%.3, 4 However, CEA is not free from risk and not all patients with a transient ischemic attack (TIA) or stroke caused by ipsilateral carotid stenosis will suffer of recurrent stroke on medical treatment alone. In addition, the management of patients with either high-grade asymptomatic internal carotid artery (ICA) stenosis, or those with a mild to moderate symptomatic stenosis accompanied by heterogeneous irregular (“unstable”) plaque, is still uncertain. In these cases, the indications for CEA can still be discussed. Potentially the selection of patients for CEA might be improved if the evidence based data about the degree of stenosis is complemented by plaque instability markers such as cerebral micro-emboli.

Transcranial Doppler (TCD) detects spontaneous micro-embolic signals (MES) within the relevant intracranial arteries as a probable risk of future stroke.5, 6, 7 In 79% of patients with ulcerated carotid plaque, as confirmed by CEA, MES were detected in the middle cerebral artery (MCA).8 Hypo-echogenic carotid plaques were also associated with a higher probability of intracranial MES.9 Clinically silent micro-emboli might indicate the presence of fragile macro-thrombi which might cause major stroke.10 However, the important question of whether the detection of MES is an independent risk factor for the occurrence of stroke still remains.

The purpose of this study was to investigate the prevalence and frequency of micro-embolisation to the relevant MCA/ACA in patients with symptomatic severe carotid stenosis. We correlated the occurrence of MES to the grey-scale ultrasound characteristics of the carotid plaque, the intra stenotic blood flow velocity, stroke risk factors and the time since the last ischemic event.

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Patients and Methods 

Between January 2004 and July 2005, 214 consecutive patients (mean age 68.4±8.4yrs) were prospectively recruited at Sahlgrenska University Hospital (Göteborg, Sweden). All subjects had been referred for preoperative TCD investigation due to a high-grade ICA stenosis according to the ECST definitions11 and a history of recent ischemic events within the ipsilateral carotid artery circulation. In 17 (7.9%) patients the transtemporal TCD investigations were inconclusive because of absent temporal windows. The remaining 197 patients (161 males and 36 females, mean age 69.5±8.6 yrs) with symptomatic ICA 70–99% stenoses were monitored by power M-mode TCD. In 19 patients the transtemporal TCD investigations on the asymptomatic side were inconclusive because of absent temporal windows. As a result, 178 asymptomatic ICA vessels were successfully monitored for MES and included for further analysis. A recent ischemic event was considered if amaurosis fugax (AFX), TIA or minor stroke occurred within a six-month period. All patients were on anti-platelet therapy (aspirin and/or dipyridamole and/or clopidogrel). Besides the common exclusion criteria for CEA, patients with atrial fibrillation or flutter; cardiac valve prosthesis; or evidence of other sources of embolism (cardiogenic or paradoxical); were excluded. Therefore, transesophageal echocardiography was not performed due to the lack of clinical indications. The TCD investigations were part of the local routines for pre-operative carotid evaluations and approved by the local ethics committee.

The severity of the carotid stenosis was defined by colour-coded ultrasound (CDI, Sequoia 512, Siemens Acuson Corp.) using linear transducers (6–8MHz) to measure the intra-stenotic peak systolic and end diastolic velocities.12, 13, 14 The local techniques of CDI had been previously validated against selective carotid angiography with outcomes comparable with other Swedish materials.12, 14 Patients were subdivided with respect to the maximum systolic blood flow velocities into groups with <70%, ≥70% diameter reductions or ICA occlusions and high-grade stenosis with string flow pattern. Peak systolic velocities of >1.9m/s [Doppler beam angulations 40°, calculated from,14 (Table 4)] or >2.5m/s [Doppler angulations of 60°, 14] were the cut-off velocities for ICA stenosis of ≥70%. There are significant inter individual spreads of the blood flow velocities in similar grades of ICA stenosis disturbing attempts to array carotid artery disease into 10% incremental steps.15, 16, 17 However, in our hands, TCD gave additional hemodynamic information for more reliable carotid artery disease gradations.

Table 1. Number of patients with and without spontaneous micro-embolisation on asymptomatic and symptomatic sides as related to the functional degree of ICA stenosis
Symptomatic side (N=197)Asymptomatic side (N=178)
MES [+] (N=63)MES [−] (N=134)MES [+] (N=8)MES [−] (N=170)
<70%––2/129 (1.6%)127/129 (98.4%)
≥70%61/191 (31.9%)130/191 (68.1%)2/38 (5.3%)36/38 (94.7%)
ICA stenosis with string flow pattern2/6 (33.3%)4/6 (66.7%)1/4 (25.0%)3/4 (75.0%)
100% (occlusion)––3/7 (42.9%)∗4/7 (57.1%)

MES [+] – patients with micro-emboli during 30 minutes of TCD monitoring;

MES [−] – patients without micro-embolisations;

∗in all cases, MES were collateral.

Table 2. Incidence of various stroke risk factors in subjects with and without micro-embolic signals
MES [+] (N=63)MES [−] (N=134)p-value (chi-χ2 test)
Age (m±SD)∗70.3±8.069.1±8.90.3
Gender (male), n (%)49 (77.8)112 (83.6)0.4
Hypertension, n (%)50 (79.3)99 (73.9)0.4
Hyperlipidaemia, n (%)43 (68.3)98 (73.1)0.7
Diabetes, n (%)13 (20.6)32 (23.9)0.3
Angina pectoris, n (%)13 (20.6)24 (17.9)0.7
Myocardial infarct, n (%)11 (17.4)23 (17.2)0.8
Current smokers, n (%)17 (27.0)44 (32.8)0.4
Symptomatic event-stroke, n (%)24 (38.1)53 (39.6)0.9
Symptomatic event-TIA, n (%)39 (61.9)81 (60.4)0.8
Number of days since last event (m±SD)∗∗33.1±34.849.9±41.20.013

Symbols as in Table 1.

The table presents absolute numbers and percentage in brackets of cases with and without detected micro-embolic events.

∗Student's unpaired two-tailed t test;

∗∗Mann-Whitney U test;

Table 3. Intrastenotic blood flow velocities within symptomatic ICA stenosis ≥70% with presence (MES [+]) or absence of micro-embolic signals (MES [−])
Intrastenotic velocitiesMES [+] (N=61)MES [−] (N=130)p-value
PSV (m/s)4.47±1.464.45±1.660.9
EDV (m/s)1.78±0.881.77±0.930.9

PSV – peak systolic velocity;

EDV – end diastolic velocity;

Student's unpaired two-tailed t test;

Note: 6 cases with string blood flow pattern were excluded.

Table 4. Atherosclerotic plaque type according to Gray-Weale in MES [+] and MES [−] patients with symptomatic ICA disease
Atherosclerotic plaque typeMES [+] (N=62)MES [−] (N=135)
Type 1, N (%)6 (9.7)10 (7.4)
Type 2, N (%)25 (40.3)39 (28.9)
Type 3, N (%)22 (35.5)63 (46.7)
Type 4, N (%)0 (0)2 (1.5)
Type 5, N (%)7 (11.3)12 (8.9)
Unidentified type (echolucent-echogenic)2 (3.2)9 (6.7)

MES [+] – patients with detected microemboli;

MES [−] – patients without detected microemboli;

Fisher's exact test 4.9, p=0.42.

Plaque characteristics were assessed by Gray-Weale scaling as modified by Geroulakos & Sabetai:18, 19

Type 1: predominantly echolucent lesions with a thin echogenic cap;

Type 2: intermediate echolucent lesions with small areas of echogenicity;

Type 3: intermediate echogenic lesions with small areas of echolucency (< 25%);

Type 4: uniformly echogenic lesions (equivalent to homogeneous);

Type 5: plaque with acoustic shadowing artefact.

Independently of the TCD outcomes, this subjective scaling has been performed by two trained investigators since its introduction in the department's clinical routines,20 but inter observer variations of the ultrasound plaque characterization was not evaluated in this study.

MES detection was performed according to Moehring et al.,21 using the transcranial Power M-mode (PMD) technique (PMD100, Spencer Technologies). 2MHz ultrasound transducers were fixed over each side's temporal window to insonate the distal ICA siphon, the MCA and the anterior cerebral artery (ACA). MES were monitored within a multigated PMD spectrum using 33 sample volumes arrayed within a depth range of 28–82mm from the temporal bone (Fig. 1). An additional sample volume channel presented the blood flow velocity spectrogram at depths ranging between 50–60mm (Fig. 1). The patients underwent continuous 30-minute monitoring the days before CEA. MES were detected and counted within the Doppler spectrum using basic identification criteria of Doppler micro-embolic signals22 and according to embolic signatures within the Power M-Mode spectrum, which should be visible at least 3dB higher than the highest spontaneous PMD display of background blood flow signal; and reflect motion in one direction. MES within the MCA move towards the probe with a positively sloping track. MES within the ACA move away from the probe with a negatively sloping track.23

  • View full-size image.
  • Fig. 1 

    Detection of microembolic signals by transcranial Power M-Mode (PMD) Doppler. Upper display shows a red PMD-spectrum representing distal parts of the siphon and proximal parts of the MCA. ACA flow spectrum not visible. The line at 60mm depth represents position of the sample volume for spectral analysis of the Doppler flow velocities. Note a MES in red colour moving from around 70mm depth to M1, and another one in blue colour from the same origin into the ACA region. The lower display shows the velocity spectrum, which is disturbed only by the MCA MES but not by the ACA MES. MCA – middle cerebral artery; ACA – anterior cerebral artery; ‘A’ and arrow indicates detected MES within the PMD and Doppler spectrum.

In order to test the collateral compensation through the circle of Willis and to verify the flow of MCA and ACA, a manual compression of the proximal common carotid artery (comp-CCA) was performed during 10 heartbeats.24

Analysis and statistics 

Statistical analysis was performed using SPSS v.11.0 data analysis package. Normally distributed variables were reported as absolute values and percentages, or mean values and standard deviations. Variables that do not follow the normal distribution were expressed as median and interquartile range (IQR). McNemar test was applied evaluating the difference of microembolic activity on symptomatic and asymptomatic sides. Spearman's rank correlation coefficient was used to assess correlation between number of MES and number of days since the last ischemic event. Student's unpaired two-tailed t test was used to compare the means of normal distributed variables. Nonparametric Kruskal-Wallis and Mann-Whitney U tests were applied comparing variables that did not follow normal distribution (non-normal). χ2 test and Fisher's exact test were performed to test the null hypothesis that the distribution of a discontinuous variable is the same in two groups. A p-value<0.05 was considered to prove statistically significant difference. For statistical analysis all successfully monitored patients were subdivided into two groups (MES [+] and MES [–]) according to the presence of detected MES.

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Results 

The number of MES detected within 30 minute TCD monitoring ranged from one to 24. Spontaneous MES were registered in 63/197 (32.0%) cases on the symptomatic side and in 8/178 (4.5%) cases on the asymptomatic side. Registered MES have never been accompanied by evolution of new neurological symptoms. Table 1 shows the occurrence of MES in asymptomatic and symptomatic sides and patient subgroups with different severities of the ICA stenosis. The incidence of MES did not change in subgroups of blood flow velocities above the cut-off value of ≥70% stenosis on the symptomatic side. Successful bilateral TCD monitoring of 178 patients with unilateral symptoms revealed MES within the symptomatic side in 33.7% subjects while only in 4.5% within the asymptomatic side (McNemar's test, p<0.0001). Furthermore, comparing the occurrence of MES in the presence of bilateral ≥70% ICA stenosis, the symptomatic side was five times more embologenic (15/42, 35.7%) than the asymptomatic one (3/42, 7.1%) (McNemar's test, p<0.0001).

In two cases, MES (1 MES/30min and 6 MES/30min respectively) were registered on the asymptomatic side with ICA stenosis of <70% and with signs of intracranial ICA siphon stenosis. In another three cases PMD-TCD proved paradoxical MES through the anterior communicating artery from the symptomatic side to the contralateral side with asymptomatic ICA occlusion.

The stroke risk factors in patients with and without MES are presented in Table 2. There were no significant differences in age, gender, current smoking, hypertension, hyperlipidemia, grade of symptomatic side ICA stenosis and type of last ischemic event before TCD monitoring.

The results suggest an inverse correlation between the time since the last symptoms and the number of MES within 30 minute monitoring (Spearman's rank correlation coefficient −0.189, p=0.009). Furthermore, the median (IQR) time since the last ischemic event symptoms was shorter in the patient group with MES [+] than in MES [−] (19 (33.5) vs. 38 (55.5) days; Mann-Whitney U test, p=0.013).

In 7/197 symptomatic vessels (3.6%), MES were elicited by proximal comp-CCA. But in six out of seven spontaneous MES were recorded within 30 minute monitoring. No MES appeared on the asymptomatic side during comp-CCA. Comp-CCA showed poor intracranial collateral compensation on the symptomatic side in another six patients, in whom MCA flow velocities almost disappeared during ipsilateral comp-CCA. Two of these six patients experienced mild hypoesthesia in the contralateral hand but it resolved immediately after stopping the test, and micro-embolic signals were not detected.

Data of 191 symptomatic ICA stenoses were used to correlate the occurrence of MES with the intra-stenotic peak systolic and end diastolic velocities (Table 3). No significant differences in blood flow velocities between MES [+] and MES [−] ICA stenoses were found.

The ultrasound plaque characteristics of the symptomatic side were evaluated in all 197 patients. Plaque types in MES [+] and MES [−] groups are presented in Table 4. In 11 cases plaques were not classified and attributed to any particular type in Gray-Weale Scale. They were defined as ‘unidentified type’ in the study. The result failed to demonstrate any predominance in embolic activity comparing different types of symptomatic side plaques (Fisher's exact test, p>0.05). Additionally, the number of MES detected within 30 minute monitoring did not differ in subgroups with different type of plaque (Kruskal-Wallis, p>0.05).

Furthermore, we correlated the occurrence of MES with plaque types excluding all shadowing and unclassified plaques (Table 5). The embologenic activity showed a tendency to be more prevalent in patients with plaque type 1–2 (predominantly echolucent) rather than 3–4 (predominantly echogenic) respectively, (p=0.07).

Table 5. Atherosclerotic plaque subtypes in MES [+] and MES [−] patients with symptomatic ICA disease
Atherosclerotic plaque subtypeMES [+] (N=53)MES [−] (N=114)
Predominantly echolucent (Type 1+2), N /Total (%)31/80 (39%)49/80 (61%)
Predominantly echogenic (Type 3+4), N/Total (%)22/87 (25%)65/87 (75%)

MES [+] – patients with detected microemboli;

MES [−] – patients without detected microemboli;

χ2 3.49, df 1, p=0.07.

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Discussion 

CEA significantly reduces the incidence of stroke in patients with symptomatic extracranial carotid artery stenosis, but in some cases this evidence may be of limited help to the clinician who has to make decisions for the individual patient. In patients with symptomatic 70–90% stenosis, the three-year overall risk of ischemic stroke could be reduced by about 50%. However, only 20% of these patients will have a major stroke on medical treatment alone. Surgery is therefore of no value in 80% of patients who, despite having severe symptomatic carotid stenosis, will remain stroke-free on medical treatment alone.2 The percentage of unnecessary carotid interventions might even increase, adding statins or other new anti-hypertensive medications to the standard anti-platelet therapy.25, 26 In both carotid endarterectomy trials (ECST and NASCET),3, 4, 27 the randomization of patients for CEA was exclusively based on the outcome of carotid angiography, disregarding the carotid plaque structure and its embologenic potential.

The statistically significant difference between the incidence of MES on the symptomatic and asymptomatic sides respectively suggests possible associations between the occurrence of ischemic events and micro-emboli. In almost 70% of high grade ICA stenosis no MES were present, but this could be partly related to the brevity of our sampling period. MES were not associated with concurrent symptoms. Our findings support other reports, that clinically silent MES can be detected in 21–100% of cases when monitored with varying recording times from 20 minutes to four hours.28, 29 The time delay between MES monitoring and the last ischemic event appears to be an important issue. Our study supports the findings of Markus HS et al.,30 showing that the earlier after the last event MES registrations are performed, the higher is the prevalence and frequency of micro-emboli.

Echolucent plaques have been associated with an increased risk of stroke, since MES were more frequently observed in an-echogenic/hypo-echogenic plaque than in iso-echogenic/hyper-echogenic carotid lesions.9, 31, 32 However, Droste et al. found that the echogenicity of the plaque did not affect the number or the presence of MES.33 Our study showed a tendency towards an association between plaque echolucency and the presence of MES (p=0.07). This trend suggests that the sample size for echolucent plaques and the time period for TCD monitoring could be optimized in further studies. Thirty minutes MES monitoring might not be long enough to identify all patients with cerebral micro-emboli. However, there are no objective criteria available for optimum TCD recording times or for the number of MES needed per time unit enabling a prediction of unstable plaque formations.

High blood flow velocities including turbulence within the stenosis might mechanically provoke micro-emboli, but we could not find any correlation between intra-stenotic blood flow velocities in ICA and the occurrence of MES. However, our data agrees with observations by Goertler et al.34 that low post-stenotic blood flow velocities (<20cm/s) behind >90% ICA stenosis reduces the appearance of embolic signals in recently symptomatic patients.

Cardiac source of cerebral micro-emboli was not excluded in our patients. However, we performed bilateral MES monitoring and found only two patients with MES from the contralateral side. Therefore, it is unlikely that we were exposed to significant cardiac micro-embolisation, since only a bilateral MES–detection could be a sufficient explanation for emboli arising from the heart or aortic arch.8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 The fact that MES were mostly detected unilaterally on the symptomatic side supports the hypothesis that bilateral TCD monitoring can facilitate the differentiation between cardiac and carotid embolic sources. We believe therefore, that the occurrence of MES is an indicator of plaque instability in symptomatic high-grade ICA stenosis, which must be rapidly treated by CEA according to the meta-analysis of ECST and NASCET4, 11, 36, 37, 38 and the “Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology”.39

Comp CCA helps to identify the intracranial vessels and to assess the collateral capacity within the circle of Willis.25 Its complication rate is very low when performed as proximally as possible25 and as long as common carotid artery stenosis and carotid artery dissection is excluded by CDI. During the last decade, we have routinely performed approximately 4,000 TCD investigations with comp-CCA without any complications. In this study, 6/197 patients had short-lasting symptoms of numbness in the contralateral hand during comp-CCA. These symptoms resolved completely immediately after stopping the test and are explained by insufficient collateral compensations during comp CCA. As a result, the surgeons were prepared for intra-operative shunting which was performed in four of these patients because of low carotid stump pressures. MES were provoked by comp-CCA in seven cases, six of these also displayed MES spontaneously during TCD monitoring.

Collateral embolisation through the anterior communicating artery from one side to another has been described in the literature.40 One of the sources for those MES could be fragmentations of the soft distal thrombus tail within an occluded ICA. However, this was not the case in our study, since PMD-TCD proved in all three cases a paradox MES movement through the anterior communicating artery.

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Conclusion 

Cerebral micro-embolisation occurs predominantly in the ipsilateral hemisphere of symptomatic carotid artery disease. Our study showed that time since the last ischemic event is essential in MES detection. We did not found any correlation between incidents of MES, intra-stenotic blood flow disturbances and stroke risk factors. Plaque echogenicity as described by modified Gray-Weale scaling showed only a tendency to correlation with MES occurrence and is therefore of limited value in clinical decision making. Future studies are therefore needed to design plaque morphology algorithms that identify vulnerable plaques.

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PII: S1078-5884(08)00004-X

doi:10.1016/j.ejvs.2008.01.001

European Journal of Vascular & Endovascular Surgery
Volume 35, Issue 5 , Pages 534-540, May 2008

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