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 ≥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.
Asymptomatic internal carotid artery (ICA) disease carries a 1% to 2% annual risk of ischemic stroke.1 2 3 4 5 6 Known factors associated with further increased risk are progression of ICA stenosis or ≥80% luminal narrowing.1 3 6 Recent studies using transcranial Doppler sonography (TCD) in symptomatic and asymptomatic patients with ICA disease have suggested that the detectability of clinically silent cerebral microemboli in the ipsilateral middle cerebral artery may constitute another unfavorable prognostic factor.7 8 9 10 11 However, this possible risk increase has not been defined prospectively. The aim of our pilot study was to estimate the risk of cerebral or retinal ischemia associated with cerebral microembolism in asymptomatic patients with high-grade ICA stenosis and thereby to determine the clinical importance of TCD-detected microembolism in this condition.
Subjects and Methods
Sixty-four patients with unilateral 70% to 90% ICA stenosis were recruited from our outpatient clinic. None of them had a history of retinal or cerebral ischemic symptoms. Beside their willingness to participate (informed consent), the only other selection criteria were detectability of an adequate TCD signal (temporal bone window) and absence of atrial fibrillation or artificial heart valve. The degree of ICA stenosis was determined noninvasively using continuous-wave Doppler sonography and color Doppler–assisted duplex imaging as described and validated elsewhere.12 The group characteristics are listed in Table 1⇓. Retinal and cerebral ischemic symptoms were carefully explained to the patients. They were asked to contact us immediately in the case of possible symptoms or, if symptom-free, to visit us again after approximately 6 months. In cases with no contact after 8 months, telephone interviews were obtained. During the study period, it was our policy to recommend conservative treatment for asymptomatic ICA stenosis of ≤90% unless progression in stenosis severity was documented.
Cerebral microemboli detection was performed for 1 hour at each patient visit. We insonated the middle cerebral artery ipsilateral to the stenosis with a transtemporal insonation depth of 45 to 55 mm using 2-MHz pulsed-wave transducers.8 13 The audible TCD output signal was recorded on tape for off-line analysis by a blinded observer using the following auditory and visual (fast-Fourier–transformed power spectra) criteria to define a microembolic signal: unidirectional high-intensity signal within the blood flow velocity spectrum, signal duration <300 milliseconds, signal intensity >9 dB compared with the background blood flow signal, and characteristic sound. Our interobserver reliability for detecting so-defined cerebral microemboli was 0.91 (mean proportion of specific agreement).13
The study end point was the development of an ischemic symptom or sign attributable to the diseased ICA. Reasons for study drop out were death due to other cause (4 patients) or carotid endarterectomy despite an asymptomatic course (12 patients). Cause of death was ascertained from hospital records or interviews with physicians and relatives. The study was stopped when preliminary results of the Asymptomatic Carotid Atherosclerosis Study had been communicated.5
We obtained 154 TCD recordings from 64 patients. No patient was lost to follow-up. Mean±SD duration of the interval between the two patient visits was 29±21 weeks (range, 0.3 to 116). Mean±SD duration of total follow-up was 72±34 weeks (range, 4.5 to 136). Eight TCD recordings of 8 patients showed ≥2 cerebral microemboli per hour ipsilateral to high-grade ICA stenosis. Five patients developed ischemic symptoms of the affected carotid territory (Table 2⇓). Their baseline characteristics (Table 3⇓) were comparable to those of the entire study population (Table 1⇑). Using Fisher’s exact test, the overall association between a microembolic rate of ≥2 per hour detected at one patient visit and the occurrence of a subsequent ipsilateral cerebral or retinal ischemic event within the study period was highly significant (P=.005; odds ratio, 31; 95% confidence interval, 3 to 302; n=48 excluding the 16 patients who dropped out). To obtain a better estimate of the short-term risk associated with a positive TCD recording, we also calculated odds ratios for the occurrence of an ischemic event within 4 or 6 months after a TCD recording (122 TCD recordings with 4-month follow-up information from 53 patients; 91 TCD recordings with 6-month follow-up information from 44 patients). These odds ratios are given in Table 4⇓ for increasing microembolic “thresholds” of ≥2, ≥3, or ≥4 per hour, respectively.
We found a substantially increased risk of ischemia associated with cerebral microembolism distal to asymptomatic high-grade ICA disease. Three of five ischemic events downstream of asymptomatic ICA stenosis were accurately predicted by a threshold criterion of ≥2 microemboli per hour detected in the ipsilateral middle cerebral artery (Table 2⇑). This corresponded to an odds ratio of 31, with a lower limit of the 95% confidence interval of 3 (mean follow-up, 72 weeks). Additional calculations suggest that the risk increase is even more pronounced during the first months after a positive TCD recording (Table 4⇑). Thus, cerebral microembolism may provide information useful for risk stratification in future studies of asymptomatic carotid artery disease.
Two recent investigations using endarterectomy specimens have shown that ulceration and lumen thrombus of the ICA plaque are the main pathoanatomic correlates of cerebral microembolism.11 14 The same pathoanatomic features have been reported to play an important role in symptom development.11 15 16 By adding a relationship between cerebral microembolism and symptom development, the present study also provides further support of these previous findings.
This work was supported by the Deutsche Forschungsgemeinschaft (Si 370/4-1) and the Hermann-und-Lilly-Schilling Stiftung (Dr Steinmetz). We thank Lutz Jäncke, PhD, Institute of General Psychology I, Heinrich-Heine-Universität Düsseldorf, for statistical advice.
- Received May 15, 1995.
- Revision received July 27, 1995.
- Accepted July 27, 1995.
- Copyright © 1995 by American Heart Association
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