Can Microembolic Signals Identify Unstable Plaques Affecting Symptomatology in Carotid Stenosis?
To the Editor:
We read with interest the article by Liapis et al1 on factors affecting symptomatology in carotid stenosis and agree that factors other than the degree of stenosis are important in determining increased risk of neurological events. Authors observed that ultrasonically echolucent plaques show a trend toward higher frequency of neurological events likely due to an increased lipid content, rendering them more vulnerable to rupture. Nevertheless, ultrasonographic evaluation of plaque morphology may fail to identify unstable plaques showing embolic activity likely due to inflammatory factors2 able to determine from time to time fluctuations of the risk of neurological events. Previous small studies have suggested that asymptomatic microembolic signals (MES) detected by transcranial Doppler (TCD) in middle cerebral arteries may predict symptoms occurrence,3,4⇓ and a large multicenter study was planned to determine whether MES are an independent predictor of neurological events in patients with asymptomatic ≥70% carotid stenosis.5
We evaluated 21 patients (13 males and 8 females, mean age 75.2 years, range 62 to 84 years) with asymptomatic ≥70% carotid stenosis documented by selective angiography according to NASCET criteria. Echocardiography was performed to exclude cardioembolic sources, and antiplatelet treatment (acetylsalicylic acid 100 mg daily in 15 cases and ticlopidine 500 mg daily in 6 cases) was administered. All the patients were submitted to TCD monitoring (DWL MultiDop X TCD7 FRG device) prolonged for 60 minutes to detect MES in middle cerebral arteries. MES were identified according to the criteria of the Ninth International Cerebral Hemodynamic Symposium6 and the recommendations of the International Consensus Group on Microembolus Detection.7 Monitoring was repeated with the same method after 6, 12, 18, and 24 months, and clinical follow-up aimed to identify onset of symptoms (amaurosis fugax, transient ischemic attack, stroke) related to carotid stenosis was performed during such period. Six of 21 (28.6%) patients showed MES in the middle cerebral artery on the same side as carotid stenosis during at least one of the monitoring times, and 5 of these 6 (83.3%) patients became symptomatic (transient ischemic attack in 2 cases and stroke in 3 cases). MES occurrence was intermittent at different monitoring times but always preceded symptoms onset and in 3 cases occurred also during the following monitoring (Table). No change of carotid stenosis degree was observed at ultrasounds performed at the time of follow-up monitoring. Two symptomatic patients underwent surgical (75-year-old male) or endovascular (72-year-old male) treatment at the end of 24-month follow-up, and medical therapy alone was administered in 2 cases with disabling stroke (84-year-old male and 80-year-old female) and in 1 case (76-year-old male) with no consent to endarterectomy.
These data suggest that MES detection may also affect symptomatology in ≥70% carotid stenosis. Moreover, since the majority of plaques remain clinically silent with time,8 MES occurrence may be useful in selecting high-risk subgroups of asymptomatic patients for appropriate surgical treatment. Indeed, such transient and changeable-with-time microembolic events may reflect fluctuations of plaque activity and then may help us to identify plaque destabilization periods during which chronic atherosclerosis changes into a brain killer. It is to be hoped that results of larger prospective investigations will be able to shed additional light on this intriguing subject.
- ↵Liapis CS, Kakisis JD, Kostakis AG. Carotid stenosis: factors affecting symptomatology. Stroke. 2001; 32: 2782–2786.
- ↵Jander S, Sitzer M, Schumann R, Schroeder M, Siebler M, Steinmetz H, Stoll G. Inflammation in high-grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilization. Stroke. 1998; 29: 1625–1630.
- ↵Siebler M, Nachtmann A, Sitzer M, Rose G, Kleinschmidt A, Rademacher J, Steinmetz H. Cerebral microembolism and the risk of ischemia in asymptomatic high-grade internal carotid artery stenosis. Stroke. 1995; 26: 2184–2186.
- ↵Valton L, Larrue V, le Traon AP, Massabuau P, Geraud G. Microembolic signals and risk of early recurrence in patients with stroke or transient ischemic attack. Stroke. 1998; 29: 2125–2128.
- ↵Asymptomatic Carotid Emboli Study (ACES). Stroke. 2001; 32: 1450.
- ↵Consensus Committee of the Ninth International Cerebral Hemodynamic Symposium. Basic identification criteria of Doppler microembolic signals. Stroke. 1995; 26: 1123.
- ↵Markus HS, Ackerstaff R, Babikian V, Bladin C, Droste D, Grosset D, Levi C, Russel D, Siebler M, Tegeler C. Intercenter agreement in reading Doppler embolic signals: a multicenter international study. Stroke. 1997; 28: 1307–1310.
- ↵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.
We thank Orlandi et al for their interest in our study.1 Their comments give us the opportunity to address several issues with regard to the detection of microembolic signals (MES) in patients with asymptomatic internal carotid artery stenosis.
Echolucent plaques and MES may actually be correlated, with echolucency representing the ultrasonographic picture of unstable plaques and MES their result. In support of this theory, Tegos et al2 recently showed that emboli detected by transcranial Doppler (TCD) were more frequent in the presence of low plaque echogenicity. This finding, however, is in contrast to the results of a previous study by Droste et al,3 according to which echolucency of the plaque was not related to the presence or number of MES. Whatever the case may be, factors such as the degree of carotid stenosis, plaque echolucency, and surface morphology should be included in any multivariate analysis aiming to determine the independent prognostic significance of MES in the development of future stroke.
With respect to the time-course of the increased risk of neurologic events, echolucent plaques are associated with a high long-term risk due to the fragility of the lipid-rich plaque. On the contrary, microemboli most probably originate from already ruptured plaques with resultant surface ulceration and luminal thrombus and are related to an increased risk of neurologic events within the following few days or months. In the study of Siebler et al,4 neurologic events occurred within 2 days to 6 months in 4 of the 5 patients who became symptomatic, while in the study of Molloy and Markus5 both cerebrovascular ischemic events in previously asymptomatic patients occurred within 3 to 4 months of the positive TCD recording. This fact may represent a major advantage of the method but at the same time it may be a drawback in terms of using TCD as a screening tool in patients with asymptomatic carotid stenosis. Indeed, it seems that very frequent monitoring by TCD is required in order to timely detect plaque destabilization periods. In the series of Orlandi et al, for example, only 1 of the 5 patients, who eventually showed MES in the middle cerebral artery, had a positive TCD recording on his first scan. The appropriate frequency as well as the cost-effectiveness of this technique are questions that need to be answered by large-scale multicenter studies that are currently underway.
Given the above-mentioned reservations, we believe that a negative predictive value of 100%, as that described by Orlandi et al, is somewhat optimistic and rather due to the small number of patients in their series. As Molloy and Markus5 remark, a sample size of approximately 600 patients is required for a study to determine the predictive value of Doppler embolic signals in patients with asymptomatic carotid stenosis. Level 1 evidence deriving from such a study will give the technique the place that it deserves in the diagnostic armamentarium of carotid disease. We would like to share with Orlandi et al the hope that this study will verify the existing promising data.
- ↵Liapis CD, Kakisis JD, Kostakis AG. Carotid stenosis: factors affecting symptomatology. Stroke. 2001; 32: 2782–2786.
- ↵Droste DW, Dittrich R, Kemény V, Schulte-Altedorneburg G, Ringelstein EB. Prevalence and frequency of microembolic signals in 105 patients with extracranial carotid artery occlusive disease. J Neurol Neurosurg Psychiatry. 1999; 67: 525–528.
- ↵Siebler M, Nachtmann A, Sitzer M, Rose G, Kleinschmidt J, Rademacher J, Steinmetz H. Cerebral microembolism and the risk of ischemia in asymptomatic high-grade internal carotid artery stenosis. Stroke. 1995; 26: 2184–2186.
- ↵Molloy J, Markus HS. Asymptomatic embolization predicts stroke and TIA risk in patients with carotid artery stenosis. Stroke. 1999; 30: 1440–1443.