Contrast-Enhanced Transcranial Color-Coded Duplex Sonography in Ischemic Cerebrovascular Disease
Background and Purpose Echo contrast agents have been shown to provide conclusive examinations in most patients with insufficient ultrasound penetration through the temporal bone. We investigated the diagnostic value of contrast-enhanced (CE) transcranial color-coded duplex sonography (TCCD) in patients with ischemic cerebrovascular disease and insufficient temporal windows and evaluated TCCD criteria that predict whether CE-TCCD studies may become conclusive.
Methods Thirty-three patients presenting with ischemic strokes (n=21) and transient ischemic attacks (n=12) were investigated. Extracranial color duplex imaging showed normal findings in 24 patients, eight ≥70% stenoses and one occlusion of the carotid arteries in 8 patients, and severe occlusive disease of both vertebral arteries in 1 patient. Seven carotid stenoses and vertebral artery obstructions were confirmed by angiography. The galactose/palmitic acid–based echo contrast agent was injected intravenously as bolus of 200, 300, or 400 mg/mL in a dosage of 10, 5, and 5 mL, respectively.
Results Thirty-two of the 33 patients were completely examined because 1 patient who felt pain at the injection site declined further investigations. Twenty-one (66%) of 32 CE studies were conclusive and showed cross-flow through three anterior and two posterior communicating arteries, but no stenoses and occlusions. Precontrast identification of any cerebral artery provided an overall accuracy of 97% in predicting a conclusive CE investigation. Precontrast TCCD identified no arterial Doppler signals in patients with inconclusive CE studies.
Conclusions CE-TCCD provided conclusive examinations in two thirds of patients with ischemic cerebrovascular disease and ultrasound-refractory temporal windows. Precontrast detection of any cerebral artery reliably predicted a conclusive CE investigation.
Transcranial color-coded duplex and conventional transcranial Doppler sonography have been shown to be reliable techniques for noninvasive assessment of abnormal hemodynamics in the basal cerebral arteries.1 2 3 4 5 6 The major limitation of TCCD is the temporal bone window, which may prevent insonation in approximately 16% to 20% of patients.3 6 Transpulmonary ultrasound contrast agents such as galactose/palmitic acid–based microparticles7 8 9 and the spherosome BY96310 11 have been reported to overcome this drawback since they increase the echogenicity of blood through the addition of microscopic bubbles of air. Recently, Otis et al8 have shown that CE-TCCD investigations performed in patients with different cerebrovascular disorders and insufficient temporal bone windows have provided the establishment of firm diagnoses that significantly influenced clinical judgment and treatment. Published data regarding this issue in patients with ischemic cerebrovascular disease, however, are limited.8
Previous studies have indicated that some TCCD examinations may remain inconclusive even after the administration of ultrasonic contrast media.7 8 10 Thus, determination of TCCD criteria that predict whether CE studies become conclusive may prevent the inappropriate use of echo contrast agents.
The purpose of the present study was to evaluate the diagnostic value of CE-TCCD in patients with ischemic cerebrovascular disease and insufficient temporal bone windows, as well as to delineate TCCD criteria that predict whether CE-TCCD investigations become conclusive.
Subjects and Methods
Patients and Study Protocol
This study of the galactose/palmitic acid–based intravenous echo contrast agent Levovist (Schering AG) was approved by the ethical committee of the University of Bern (Switzerland).
Thirty-three patients (23 women, 10 men) with a mean age of 70±13 (range, 27 to 83) years were examined. They were referred for extracranial and transcranial color duplex studies because they had suffered ischemic strokes in 21 and transient ischemic attacks in 12 cases. All patients had inconclusive transtemporal TCCD examinations and underwent subsequent CE-TCCD studies. The presence of an insufficient temporal bone window leading to an inconclusive TCCD study was indicated when at least two experienced sonographers (M.A., R.W.B., A.R., C.H.) estimated that they were unable to evaluate the basal cerebral arteries by means of color and spectral Doppler imaging. Informed consent was obtained in all patients. Patients were excluded from this study if one of the following was applicable: they had galactosemia; they were younger than 18 years; they were mentally retarded; a clear medical history was not obtainable; they were considered critically ill or medically unstable and their clinical course was unpredictable; they had recent myocardial infarcts; an examination with any contrast agent was performed within the past 24 hours before the examination with the ultrasonic contrast agent or planned within 2 hours after receiving the contrast agent; they had received any investigational drug during the 30 days before entering this study; the same echo contrast agent had already been applied within this study; they were lactating women or women known or suspected to be pregnant.
The first 21 patients also participated in a phase-3 clinical multicenter Levovist trial. The last 12 patients were recruited after conclusion of the multicenter trial because Levovist was approved July 1, 1996 by the Swiss Interkantonale Kontrollstelle für Heilmittel.
Twenty-four patients had normal extracranial color duplex findings. They had suffered ischemic strokes in 16 and transient ischemic attacks in 8 cases. Seven patients had eight carotid stenoses with ≥70% diameter reduction that were confirmed by angiography in 6 patients who were scheduled for carotid endarterectomy. The seventh patient with carotid stenosis declined cerebral angiography and carotid surgery. The angiographic degree of narrowing was 78±5% (range, 70% to 85%) according to the criteria of the North American Symptomatic Carotid Endarterectomy Trial.12 Angiographic findings were used for definite classification of carotid stenoses. One patient had a unilateral occlusion of the carotid artery. Carotid lesions had caused ischemic strokes in 5 and transient ischemic attacks in 3 patients. Another patient had an occlusion of the right and an 80% stenosis of the left extracranial vertebral arteries causing transient ischemic attacks.
The sonographic contrast agent used in the present study was injected within 10 to 15 seconds through an intravenous line that was established in an antecubital medium.
In the first 21 patients contrast agent concentrations of 200, 300, and 400 mg/mL in a dosage of 10, 5, and 5 mL, respectively, were available. If the CE examination remained inconclusive when the lowest contrast agent concentration was used, the investigators repeated the injection using a higher concentration to a potential total of six injections. Repeated injections were performed at least 5 minutes apart, and contrast enhancement of Doppler signals had already subsided.
Extracranial Ultrasound Studies
The extracranial cerebral arteries were examined with the use of an Acuson 128 XP/10 equipped with a 5.0/7.0-MHz linear scan. Evaluation of stenoses and occlusions was performed according to previously published criteria.14 15
The basal cerebral arteries were investigated with the use of an Acuson 128 XP/10 equipped with a 2.0/2.5-MHz 90o sector scan, as reported previously.16 PSVs were measured in every insonated artery with insonation angles <30°. The sonographer was aware of extracranial ultrasound findings but was blinded to the results of cerebral angiography. All TCCD investigations were transferred to standard VHS videotape for off-line evaluation.
Previous studies have shown that PSVs17 18 increase after the administration of the aforementioned galactose/palmitic acid–based echo contrast agent. To obtain CE reference values we measured PSVs in the cerebral arteries of 16 patients (10 women, 6 men; mean±SD age, 44±14 years) undergoing TCCD and CE-TCCD investigations for the evaluation of sinovenous thrombosis delineated by MRI and two-dimensional time of flight MR angiography (relaxation time, 27 milliseconds; echo time, 9 milliseconds; flip angle, 50°). All 16 patients had normal basal cerebral artery findings as assessed by TCCD (and two-dimensional time of flight MR angiography). Mean PSV values before and after echo contrast agent administration were determined for the ACA, MCA, and P1 and P2 PCA. Age- and sex-matched reference values obtained without echo contrast enhancement from a previously reported group of 158 normal subjects (79 women, 79 men; mean±SD age, 50±18 years) aged 20 to 79 years3 were altered according to the average relative velocity change observed after echo contrast agent injection. Thus, reference CE-PSVs were calculated for each cerebral artery according to the formula (1+mean PSV after echo contrast agent administration/mean PSV before echo contrast agent administration)×(mean PSV of normal subjects +3 SDs).
A stenosis of a cerebral artery was appreciated when (1) intrastenotic CE-PSV was higher than the reference CE-PSV for the corresponding cerebral artery given in Table 1⇓; (2) prestenotic and/or poststenotic CE-PSV was >30% lower than intrastenotic CE-PSV; or (3) low-frequency, high-intensity components of the Doppler signal were present.4 An occlusion of a cerebral artery was diagnosed according to criteria reported by Kaps et al.19 Presence of cross-flow through the ACoA and PCoA to the MCA as well as of cross-flow through the PCoA to the PCA was assessed as reported previously.3
Analysis of TCCD Criteria That May Predict the Quality of CE-TCCD
All videotapes were systematically reviewed and inspected simultaneously by M.A. and R.W.B. for the presence of visualization of the midbrain as well as of partial and complete identification of the ACA, MCA, and P1 and P2 PCA.
Selective intra-arterial digital subtraction angiography was performed by a femoral artery approach in both internal carotid and vertebral arteries as described previously.20 The angiograms were reviewed for the presence of stenoses, occlusions, and collateral flow through the ACoA and PCoA.
Statistical analysis was performed with the Systatsoftware package. Comparison of relative PSV changes after echo contrast agent administration between different cerebral arteries was performed with Kruskal-Wallis tests. Comparison of detection of cerebral arteries before and after contrast-medium enhancement was performed with Wilcoxon signed rank tests. Two-sided values of P<.05 were considered significant.
CE-PSV Reference Data
After echo contrast medium administration, PSV increased by 23±11% in all cerebral arteries (mean±SD). There was no difference in velocity increase between the ACA (21±10%), MCA (23±9%), and P1 (25±11%) and P2 PCA (26±10%) (mean±SD). Thus, we used the overall PSV increase of 23% for calculating the reference CE-PSVs according to the formula given above. The corresponding cutoff PSVs for women/men were 178/171 cm/s for the ACA, 207/189 cm/s for the MCA, and 130/127 cm/s for the PCA for the group aged 20 to 39 years; 155/143 cm/s for the ACA, 177/173 for the MCA, and 125/113 cm/s for the PCA for the group aged 40 to 59 years; and 144/137 cm/s for the ACA, 172/156 cm/s for the MCA, and 121/97 cm/s for the PCA for the group aged 60 to 79 years.
Thirty-two patients were completely examined. One patient with an occluded extracranial carotid artery who felt transiently severe pain at the injection site due to paravenous administration of the echo contrast agent refused to continue in the study. Another patient felt mild pain at the injection site. No other patient discomforts, side effects, or adverse reactions occurred that were due to the intravenous administration of the ultrasonic contrast agent.
There were 85 contrast medium injections. Conclusive CE studies required an echo contrast agent concentration of ≥300 mg/mL. The mean duration of contrast enhancement providing conclusive Doppler signals was 216±94 seconds, with a range of 73 to 368 seconds.
The results of CE-TCCD examinations are shown in Table 1⇑. Twenty-one (66%) of 32 CE investigations were conclusive. Fifteen (63%) of 24 patients with normal extracranial ultrasound findings had conclusive CE examinations that showed no abnormalities (Fig 1⇓). Five of 7 patients with flow-restrictive carotid artery disease provided conclusive CE studies. Cross-flow through the ACoA was present in 3 and absent in 2 cases, and cross-flow through the PCoA was present in 2 (Fig 2⇓) and absent in 3 cases. The patient with bilateral severe vertebral artery disease had no collateralization through the PCoA. No intracranial stenosis and occlusion were detected. Cerebral angiography confirmed the findings obtained in patients with conclusive CE examinations and extracranial flow-restrictive cerebral artery disease.
The number and frequency of completely and partially depicted cerebral arteries before and after contrast medium administration are given in Table 2⇓. The frequency of completely visualized cerebral arteries on the side of the ultrasound transducer increased from 0% to 13% before to 69% to 81% after echo contrast enhancement (P<.001). On the opposite side, complete identification of the cerebral arteries increased from 0% to 6% before to 25% to 66% after contrast enhancement (P<.01).
TCCD Criteria That May Predict the Quality of CE-TCCD
The diagnostic value of several TCCD criteria to foresee whether CE investigations would become conclusive is given in Table 3⇓. Detection of any cerebral artery resulted in an overall accuracy of 97% in predicting a conclusive CE investigation (Figs 1⇑ and 2⇑). Detection of the midbrain in B-mode imaging was less reliable in foreseeing a conclusive CE study. All precontrast TCCD studies that detected neither arterial Doppler signals nor the midbrain remained inconclusive after echo contrast enhancement.
In the present study echo contrast agents provided a conclusive TCCD examination in 21 (66%) of 32 patients with ischemic cerebrovascular events and insufficient ultrasound penetration through the temporal bone. Our patients had a mean age of 70 years and were of female sex in 70% of cases. This indicates that we examined the characteristic patient with ultrasound-refractory temporal bone since the quality of this window decreases with age and is especially poor in old women.21 22 As expected, ultrasonic contrast agents significantly increased the number of completely detected cerebral arteries to 69% to 81% on the side ipsilateral and to 25% to 66% on the side contralateral to the ultrasound transducer.
TCCD studies performed without echo contrast enhancement have provided a conclusive evaluation of the basal cerebral arteries in 80% to 84%,3 6 the basilar arteries in 92%,23 24 and the intracranial vertebral arteries in 96% to 98%.23 25 Furthermore, ultrasonic contrast media have been reported to provide conclusive TCCD evaluation of the vertebrobasilar system in several patients with insufficient foramen magnum windows.7 8 26 These reports3 6 7 8 23 24 25 26 and our study indicate that echo contrast agents may provide a conclusive assessment of the intracranial cerebral arteries in >90% of patients with ischemic cerebrovascular disease. A recent conventional transcranial Doppler study has demonstrated that the combined use of several hemodynamic criteria provides reliable identification of patients with ≥70% angiographic carotid stenosis.27 This suggests that CE-TCCD may provide confirmation of severe carotid artery disease in the presence of inconclusive extracranial and transcranial ultrasound studies.
CE-TCCD and cerebral angiography showed no intracranial stenosis and occlusion in this series. These findings corroborate the results of previous studies indicating that intracranial occlusive vascular disease is rare.28 29 30 It is important to note that the PSV cutoff values used for CE diagnosis of intracranial stenosis were 23% higher than those used for nonenhanced investigations because we found an average PSV increase of 23% in 64 normal cerebral arteries after echo contrast agent injection. This finding is in accordance with the 17% to 26% peak velocity increase reported in previous flow phantom and extracranial human pulsed-wave Doppler studies17 18 after administration of the same ultrasonic contrast agent. Sitzer et al18 assume that this velocity increase results from a better detection of rare high-velocity components that remain below the sensitivity threshold without echo contrast enhancement. It is not clear, however, whether velocity increases occur after echo contrast enhancement in intracranial stenoses similar to those in normal cerebral arteries. Therefore, the reliability of the present CE-PSV cutoff values requires confirmation by an angiography-correlated CE-TCCD investigation in patients with intracranial stenoses, and further studies are suggested in this regard.
After echo contrast agent injection, collateral flow through the circle of Willis was conclusively evaluated in six of eight patients with flow-restrictive disease of the extracranial cerebral arteries. The ultrasonic findings were confirmed by cerebral angiography. It is noteworthy that a previous study has shown that the use of adequate injection pressure and volumes of contrast agent prevented the alteration of cerebral hemodynamics and provided reliable angiographic assessment of collateral flow through the circle of Willis.20
Eleven (34%) of 32 patients had inconclusive CE examinations in this series. Such patients provided no arterial Doppler signals before the administration of the echo contrast agent. On the contrary, precontrast identification of any basal cerebral artery predicted a conclusive CE investigation with an overall accuracy of 97%. Midbrain detection in B-mode imaging was less reliable in foretelling a conclusive CE study. Thus, the application of the aforementioned precontrast TCCD criterion may prevent the inappropriate use of ultrasound contrast media and reduce the resulting costs.
Two previous phase-2 Levovist studies reported that only 5% to 10% of CE-TCCD examinations performed in patients with inadequate temporal windows and different cerebrovascular disorders remained inconclusive.7 8 The contrast agent was administered by using the same concentrations, manner, and injection velocity as in the present study.7 8 The ultrasound transducers provided emission frequencies7 8 similar to those in the present investigation, and the maximal output energy that is applicable for transcranial insonation is defined by the Food and Drug Administration. Therefore, differences in ultrasound contrast agent and equipment are unlikely causes of the different occurrence of inconclusive CE examinations. In the study of Bogdahn et al,7 however, all nine patients with conclusive CE examinations provided precontrast detection of at least one cerebral artery. Conversely, the P2 segment of the PCA was missed in the only patient showing no Doppler signals before administration of Levovist.7 These findings corroborate the predictive value of precontrast detection of arterial Doppler signals observed in the present study and suggest that the patients described by Bogdahn et al7 had better ultrasound penetration through the temporal bone, causing less inconclusive CE investigations. The number of cerebral arteries that were identified before the administration of the echo contrast agent was not reported by Otis et al.8 Nevertheless, their patients were younger and more of them were women compared with the present study. This also indicates that the insonation windows of these patients were probably less insufficient and caused more conclusive CE-TCCD investigations because ultrasound attenuation caused by the temporal bone increases with age and is substantial in old women.21 22
It is noteworthy that we insonated white adults only. Because the failure of nonenhanced transtemporal ultrasound can be as high as 50% among nonwhites,31 it is also possible that CE investigations may be less successful in these patients.
In conclusion, we have shown that CE-TCCD provided conclusive examinations in two thirds of patients with ischemic cerebrovascular events and ultrasound-refractory temporal bone windows and that precontrast TCCD findings reliably predicted whether CE studies became conclusive.
Selected Abbreviations and Acronyms
|ACA||=||anterior cerebral artery|
|AcoA||=||anterior communicating artery|
|MCA||=||middle cerebral artery|
|PCA||=||posterior cerebral artery|
|PCoA||=||posterior communicating artery|
|PSV||=||peak systolic velocity|
|TCCD||=||transcranial color-coded duplex sonography|
- Received May 29, 1997.
- Revision received August 6, 1997.
- Accepted September 10, 1997.
- Copyright © 1997 by American Heart Association
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