Transcranial Color-Coded Duplex Sonography and Digital Subtraction Angiography in Acute Stroke Patients


 Background: Stroke is the most common neurological disorder with a high incidence in Middle-eastern regions. We aimed to assess the diagnostic accuracy of transcranial color-coded duplex sonography (TCCS) for detection of cerebral artery stenosis compared to digital subtraction angiography (DSA) as a gold standard method.Methods: Eighty patients presenting with symptoms of cerebral ischemia were enrolled in the study. They were examined by color-coded Doppler and TCCS to determine stenosis of extracranial and intracranial arteries, respectively. DSA was performed 24-48 hours after the initial examination. The sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy of TCCS in comparison to DSA was calculated. The agreement between the two methods was determined by kappa statistics. Results: Eighty patients (60% male, 40% female) with a mean age of 61.32±12.6 years were included. In 65% of cases, pathology in carotid artery was responsible for ischemia. We did not observe any abnormalities in the anterior cerebral artery (ACA), posterior cerebral artery (PCA) as well as basilar artery (BA). The agreement between TCCS and DSA in various arterial vessels were 0.9 for common carotid artery (CCA), 0.86 for internal carotid artery (ICA), 0.78 for middle cerebral artery (MCA), and 0.86 for vertebral artery (VA). The sensitivity, specificity, PPV, NPV, accuracy, and kappa value of TCCS for detection of stenosis regarding the arterial segments were 84.8%, 81%, 92.6%, 65.4%, 83.8, and 0.71, respectively. Conclusion: TCCS is a valuable, non-invasive, and repeatable method to investigate cerebral artery stenosis with high diagnostic accuracy.


Background
Stroke is considered as the second most common cause of death and disability-adjusted life year (DALY), globally [1]. Although age-standardized stroke death rate and incidence have been decreased in developed countries, it is still prevalent with increasing incidence especially in east Asia, southern sub-Saharan Africa, and Middle-Eastern regions [2,3]. According to a systematic review done by Hosseini et.al, the incidence rate of stroke in different age groups of Iranian population accounted 23 to 103 per 100000 person [4]. Acute occlusion of cervical or intracranial arteries is the leading cause of ischemic stroke which accounts for approximately 87 % of all stroke events [5,6]. Signi cant stenosis of carotid artery with subsequent embolism or hypoperfusion is seen in twenty percent of ischemic stroke patients [7,8]. Atherosclerosis is a primary mechanism of stenosis and occlusion of intracranial great arteries responsible for ischemic stroke in 8-29 % of general population [9,10]. In the middle aged population asymptomatic atherosclerosis of carotid artery is common. On the other hand, 8-15 % of patients with ischemic stroke had internal carotid artery stenosis as a result of atherosclerosis [11,12]. Patients with total carotid artery occlusion are at increased risk of recurrence about 6 percent per year which could be up to 10 percent with diminished cerebral blood ow reserve capacity although the best therapy [13]. In about 70% of patients presenting with ischemic stroke during the rst 6 hours of onset of symptoms, arterial occlusion is detectable [5,14]. Therefore, diagnosing intracranial arteries stenosis is crucial to manage the stroke and identify high risk patients for vascular events [15]. In addition, early evaluation of intracranial arteries is considered as criterion of effective treatment in many countries [16].
Digital subtraction angiography (DSA) is the "gold standard" for the assessment of cerebral artery stenosis despite some limitations. It is expensive, invasive, and hemodynamic changes are not presented [17]. Nevertheless, other modalities such as magnetic resonance angiography (MRA) as well as computed tomography angiography (CTA) used in stroke patients especially with growing use of mechanical thrombectomy, are not available on a 24/7 basis worldwide. Lesion's morphology and real time hemodynamic information are not determined in these two modalities [16]. Moreover, patients who undergo CTA are exposed to ionizing radiation and are at risk of contrast induced nephropathy and allergic reactions [17].
Ultrasound is the safest imaging modality applicable at bedside by which frequent evaluation and real time monitoring are attainable [18]. Vessel wall and plaques in the extracranial arteries has been assessed for more than four decades by brightness-mode (B-mode) of ultrasound imaging [16]. In 1982, Aaslid et al. introduced transcranial Doppler (TCD) as a successful insonation of intracranial arteries via skull by placement of a probe of a ultrasound Doppler instrument in the temporal area [19]. Despite the advancement in the technology of TCD, which made it applicable of use in a broad range in clinical practice, it has some limitations. These limitations including poor spatial resolution, identi cation of blood vessels based on indirect parameters, nonvisualization of anatomical landmarks, incorrect blood velocity benchmark (metric), and misordered distinct blood vessels in presence of normal anatomic variants were the reasons for invention of transcranial color duplex sonography (TCCS) [20]. It provides two-dimensional imaging of intracranial structures and color Doppler description of vasculature additionally to hemodynamic information [21]. By B-mode parenchymal structures and by color-coded ow blood ow is visible simultaneously [22]. TCCS has some advantages in diagnosing intra-axial intracranial hematomas (intraparenchymal hematomas), extra-axial intracranial hematomas (epidural and subdural hematomas), brain midline shift, hydrocephaly, brain tumors, cerebral aneurysms, and arteriovenous malformations [21]. Although real-time dynamic morphological information is achieved via color or power Doppler ow imaging of TCCS [23], it has been reported that only 55-80% of basal cerebral arteries can be determined via unenhanced TCCS [24].
In the present study we aimed to appraise the accuracy of color-coded Doppler sonography for detection of extra-and intracranial stenosis in comparison to DSA as a gold standard.

Study population
Men and women aged over 18 years old with clinical signs and symptoms of cerebral ischemia who were admitted within six hours of onset of symptoms between January 2018 and February 2020 were eligible. Hemorrhagic stroke, receiving anticoagulant drugs, suffering from blood dyscrasia, hepatic and renal failure, bronchial asthma, history of endarterectomy, pregnancy, allergy to iodine contrast material, and poor acoustic window for TCCS were exclusion criteria.
On admission all patients underwent carefully neurologic examination and patient age and gender, history of underlying disease such as hypertension, diabetes, hyperlipidemia, and hypercoagulopathy were collected.
Transcranial color-coded sonography (TCCS) An expert neurologist with at least 5 years of experience of the Doppler sonography of cerebral supplying arteries (F.A) examined extracranial and intracranial arteries with TCCS prior to DSA. No contrast enhancement was used. A high resolution color-coded duplex sonography system with a linear probe 5-10 MHz (high frequency) for the cervical arteries and phased-array probe 2-5 MHz (low frequency) for intracranial arteries was used.
Cervical Doppler was performed to evaluate left and right common carotid arteries, extracranial internal carotid arteries, and vertebral arteries. In addition, intracranial internal carotid artery, anterior cerebral artery (ACA), middle cerebral artery (MCA), and posterior cerebral artery (PCA) were examined through transtemporal window. Through transoccipital (also called transforaminal) window terminal vertebral arteries and proximal basilar arteries were evaluated. The results reported as normal and stenotic. The stenosis was sub-classi ed as < 50%, 50-69%, 70-99% and 100% (occluded). Velocity criteria for grading the stenosis was based on the consensus panel gray scale and Doppler US criteria for diagnosis of ICA stenosis [26]. The crucial peak systolic velocity (PSV), end diastolic velocity (EDV), and the peak systolic internal carotid artery/common carotid artery (ICA/CCA) velocity ratio were assessed. PSV and EDV were measured in three segments: pre-stenotic, stenotic, and post-stenotic. Occlusion was considered when the color signals or pulse-waved Doppler was absent. Details of ultrasound grading criteria for carotid and intracranial stenosis are shown in Tables 1 and 2.

Results
Cervical and intracranial arteries of 80 patients who ful lled the eligibility criteria of the study were examined by TCCS and DSA. The study group contained 48 (60%) males and 32 (40%) females. The mean age of patients was 61.32 ± 12.6 years. Eighty-ve percent of patients were suffering from an underlying disease. The clinical and characteristic variables were shown in Table 3. The time between the two examinations did not exceed 48 hours in any case. The mean interval of time between two methods was 27.1 ± 2.5 hours.
As is shown in Table 6, weighted kappa values were 0.9 for CCA (almost perfect agreement), 0.86 for ICA (almost perfect agreement), 0.78 for MCA (substantial agreement), and 0.82 for VA (almost perfect agreement) (p < 0.001). The Sensitivity, speci city, predictive values, accuracy as well as kappa values are reported in Table 6.

Discussion
Transcranial ultrasound, as noninvasive neurovascular imaging, can be used in acute ischemic stroke patients to detect normal, stenosed as well as occluded vessels [32]. In the current study, we compared the pathology of cervical and intracranial arteries by TCCS to the gold standard method, DSA. Signi cant stenosis (> 50%) in carotid artery was reported in 65% of patients. Vertebral artery was responsible for the patients' symptoms in about 30% of cases.
Ultrasound of carotid artery provides precious information about echogenicity of plaque, ulceration, risk of thrombosis, and rupture [9]. Comparing color-coded Doppler sonography to DSA to detect common carotid abnormalities showed almost perfect agreement (k = 0.9) with 100% sensitivity, 100% speci city, and 100% accuracy. In three cases, sonography reported mild stenosis (< 50%) while the report of DSA was normal. Contrarily, one patient with normal sonography was diagnosed with mild stenosis by DSA. As is apparent, these discrepancies were observed in stenosis less than 50%, which was reported by Baumgartner et al., who stated that the prevalence of false-positive ndings in mild stenosis increases up to three times [33]. Our results indicated fair agreement between these two methods for the detection of a mild grade of stenosis (k = 0.41).
TCCS detected stenosis of ICA with high sensitivity (87.1%), speci city (89.8%), accuracy (88.8%) as well as almost perfect agreement level which was comparable to the study of Simon et al. who reported 90.9% sensitivity with high speci city (98.1%) and almost perfect agreement level [18]. Navarro et al. found 90% sensitivity and 83% speci city of TCD in the diagnosis of abnormalities in terminal ICA [34]. Other research reported high accuracy of TCCS in the diagnosis of hemodynamically signi cant stenosis of intracranial arteries [15].
In the present study, TCCS could only detect 60% of the patients with signi cant symptomatic MCA stenosis (> 50%) diagnosed by DSA. The investigation of Chen et al. showed a sensitivity of 54% with low PPV (10.5%) compared to angiography in detection of MCA stem occlusion [35]. Although TCCS detected 6 out of 10 cases with signi cant (> 50%) stenosis, in two cases with severe stenosis the grade of stenosis was misdiagnosed. Half of four patients with missed diagnosis of severe MCA stenosis by TCCS were female with a mean age of 70 years old. It has been announced that some undesired conditions of acoustic window, like the skull eburnation, especially in women in the menopausal or climacteric period, led to vague or non-visualization and consequently misdiagnosis. It emphasizes the importance of clinical symptoms in the diagnosis of vascular occlusion [35]. Furthermore, one male patient had simultaneous occlusion in the ipsilateral ICA. Some possible reasons for such discrepancies between TCCS and DSA diagnosis could be described by the collateral circulation of occlusive vessels [36]. Recanalization of the MCA occlusion which may happen within several days to more than one week may contribute to differences in TCCS and DSA [35]. In a study by Gerriets et al., the symptomatic MCA examination was possible only in 55% of patients by unenhanced TCCS. The diagnosis was con rmed in 97% after performing angiography [37]. This is also reported by another survey in which only 52 % of patients with symptomatic MCA pathology were determined by unenhanced TCCS [38]. Poster with his colleges found 97% sensitivity of TCCS in detecting MCA stenosis in comparison to CTA [39].  [5].
The diagnosis and classi cation of VA stenosis by sonography are challenging because asymmetry in VA is prevalent and hypoplastic, and also, it could terminate in the posterior inferior cerebellar artery.
Stroke as a result of ACA occlusion is less common compared to MCA. Furthermore, the accuracy of TCCS in the detection of ACA occlusion is not well studied [40]. In our study, TCCS and DSA examinations did not report any abnormality in ACA. The sensitivity and speci city of 100% with the almost perfect agreement have been reported previously [18].
P2 segment of PCA is one of the most common sites of intracranial arterial stenosis [40]. The diagnosis of PCA occlusion by TCCS may be demanding because of frequent variation like fetal type PCA which arises directly from ICA as well as misinterpreting the nearby superior cerebellar artery as the PCA [40]. In our study, none of our patients presented with symptomatic PCA stenosis, and investigation by two methods did not discover any pathology. Evaluation of PCA in a study revealed 33.3% sensitivity, 98.1% speci city, 50% PPV, and NPV 98.2% because of the distal part of P1 or P1-P2 junction stenosis with poor angle correction [18].
Because basilar artery occlusion is life-threatening, early accurate diagnosis is crucial. However, visualization of the distal part of the basilar artery by TCCS is somehow tricky, especially in obese patients with short necks or in patients with variation in the morphology of vessels. These di culties could be overcome by the transtemporal approach instead of transformainal [40]. In this study, the primary evaluation of basilar arteries by TCCS was normal with a con rmatory DSA test.
In all evaluated cerebral arteries, we found high PPV and NPV indicative of a lower portion of falsepositive and false-negative results, respectively. Overall sensitivity, speci city, PPV, NPV, accuracy as well as kappa value of TCCS for detection of cervical and intracranial arteries pathologies were 84.8%, 81%, 92.6%, 65.4%, 83.8%, and 0.71, respectively. The study of Hou et al. revealed 72.9% sensitivity, 82.9% speci city, 78.2% accuracy, 74.9%PPV, 77.3% NPV, and kappa 0.56 [36]. In addition, the investigation of the accuracy of TCCS by Roubec et al. in 67 patients, showed higher sensitivity, speci city, and NPV with lower PPV and agreement in comparison to our results [41].
In nine patients of our study, TCCS detected severe stenosis which was consistent with the patients' symptoms while DSA did not con rm any pathology. This discrepancy could be explained by the hypothesis that with the increasing the interval of time between the onset of stroke and angiographic examination vessel recanalization rapidly occurs [42]. In the current study, a fair agreement between these two methods was observed for diagnosis of mild to severe stenosis while for occlusion detection almost perfect agreement was found.
The present study has both strengths and limitations. Despite most previous studies, all cerebral arteries of the anterior and posterior cerebral circulation were examined with a more detailed classi cation of stenosis into mild (< 50%), moderate (50-69%), severe (70-99%) as well as occlusion. In this study, we combined TCCS with color-coded Doppler sonography of the extracranial carotid artery to provide additional information. Digital subtraction angiography has been used as a gold standard method. On the other hand, we did not use an ultrasound contrast agent, and DSA was performed at least 24 h after TCCS.
TCCS is a noninvasive, safe, and inexpensive method which can be performed at the bedside, and provides a more precise measurement of cerebral blood ow velocities than transcranial Doppler through color imaging of course of the intracranial vessels. Blood ow velocities of extracranial vessels in the neck help interpretation of cerebral blood ow velocities [17]. Furthermore, TCCS could be used to follow up of patients who require further monitoring of the disease progression. However, it has some limitations. Proper interpretation requires an experienced sonographer as well as adequate temporal bone window [41]. An Ultrasound contrast agent helps to overcome this limitation.

Conclusion
In conclusion, our study indicated high sensitivity, speci city and accuracy of TCCS for the detection of vascular abnormalities in patients presenting with ischemic symptoms. Ethics approval and consent to participate: This single-center, prospective study was consistent with the principles of the Declaration of Helsinki [25] and approved by local Ethics Committee of Shahid Beheshti medical University. Written informed consent was obtained from each patient