European Journal of Radiology 81 (2012) 77–82
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Stenosis Asymmetry Index (SAI) between symptomatic and asymptomatic patients in the analysis of carotid arteries. A study using CT angiography Luca Saba a,∗ , Roberto Sanﬁlippo b , Michele Anzidei c , Luigi Pascalis d , Roberto Montisci b , Giorgio Mallarini a a
Department of Radiology, Azienda Ospedaliero Universitaria (A.O.U.), di Cagliari – Polo di Monserrato, s.s. 554 Monserrato (Cagliari) 09045, Italy Department of Vascular Surgery, Azienda Ospedaliero Universitaria (A.O.U.), di Cagliari – Polo di Monserrato, s.s. 554 Monserrato (Cagliari) 09045, Italy c Departments of Radiological Sciences, University of Rome La Sapienza, Viale Regina Elena 324, 00161 (Rome), Italy d Department of Internal Medicine, Azienda Ospedaliero Universitaria (A.O.U.), di Cagliari – Polo di Cagliari, Via Ospedale 1 (Cagliari) 09100, Italy b
a r t i c l e
i n f o
Article history: Received 25 September 2010 Accepted 1 December 2010 Keywords: Carotid artery MDCTA Stroke mm-method
a b s t r a c t Purpose: Extracranial carotid artery stenosis is accepted as a signiﬁcant risk factor for cerebrovascular events. The purpose of this paper was to evaluate whether the Stenosis Asymmetry Index (SAI) between carotid arteries (in symptomatic and asymptomatic patients) can be considered a further parameter in the stroke risk stratiﬁcation. Materials and methods: 60 consecutive symptomatic (males 36; median age 64) patients and 60 non symptomatic patients matched for gender and age, were analyzed using a 40-detector-row CT angiography. Each patient was analyzed by injecting 80 mL of contrast material at a 5 mL\s ﬂow rate. Stenosis degree of 240 carotids was calculated according to NASCET method. For each patient, the ratio between the most severe stenosis and the contralateral was calculated to obtain the SAI. Multiple logistic regression analysis was performed and ROC curve was also calculated. Results: Results of our study indicate a mean SAI of 1.48 (±0.35 SD) in the asymptomatic group and a mean SAI of 1.69 (±0.53 SD) in the symptomatic group with a statistically signiﬁcant difference (p value = 0.0204). The multiple logistic regression analysis did not ﬁnd statistically signiﬁcant association between SAI and symptoms. The ROC curve analysis indicated that an SAI value of 1.8 has a speciﬁcity of 84.31% presence of cerebral symptoms whereas using a 1.2 SAI we obtained a sensitivity of 88.24%. Conclusion: Results of our study suggest that a SAI > 1.8 has a good sensitivity in identifying the association with cerebrovascular events. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Ischaemic stroke is estimated to be responsible for 10% of all deaths and is the third cause of death behind heart disease and cancer in the Western World, moreover, it represents the most common cause of disability in adults . Atherosclerotic disease in the carotid artery is one important cause of ischaemic stroke . The degree of stenosis of the carotid artery is considered the most important parameter when choosing therapeutic options [3,4], but in the last decade a substantial number of articles have been published and they have resulted in a shift of opinion in identifying stroke risk in carotid atherosclerotic disease [5–12]. Nowadays it is widely accepted that the degree of stenosis is only one marker for future cerebrovascular events. If one wants to determine the risk of these events more accurately, other parameters have to be taken into account: plaque composition, the presence
and state of the ﬁbrous cap (FC), plaque ulceration, intra-plaque hemorrhage and plaque location. To the best of our knowledge an association between the difference in stenosis between both carotid arteries and their relationship with the presence of cerebrovascular symptoms has not been previously assessed by any imaging technique with the exclusion of Gasecki et al. , that showed that medically treated patients with contralateral occlusion were more than twice as likely to have an ipsilateral stroke as compared to less severe contralateral disease. The purpose of this work was to evaluate whether the Stenosis Asymmetry Index (SAI) between carotid arteries (in symptomatic and asymptomatic patients) can be considered a further parameter in the stroke risk stratiﬁcation 2. Materials and methods 2.1. Patient population
∗ Corresponding author. Tel.: +39 070 485980. E-mail address: [email protected]
(L. Saba). 0720-048X/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2010.12.014
60 consecutive symptomatic (males 36; age range 42–76 years, median age 64 years) patients and 60 non-symptomatic patients
L. Saba et al. / European Journal of Radiology 81 (2012) 77–82
matched for gender and age were selected from our internal database. Each patient underwent MDCTA for suspected carotid artery pathology. Each MDCTA examination was performed when it was clinically indicated and was ordered by the patient’s physician as part of routine clinical care. In our institute, the inclusion criteria for performing MDCTA are as follows: a prior given clinical indication for CT angiography of the supra-aortic vessels (when possible also conﬁrmed by US-ECD study) as stated by the referring physician and established by the attending radiologist. In particular, the main reason for referral to MDCTA is the presence of an ultrasound (US) examination that showed a pathological stenosis and/or a plaque alteration, or when US cannot provide sufﬁcient information about the degree of stenosis, as for example in the presence of large calciﬁed plaques with acoustic shadowing, high carotid bifurcation or a thick neck (oedema, obese patients). Plaque alteration, using the US, was considered as the presence of a heterogeneous plaque, an irregular surface, intra-plaque hemorrhage and/or the presence of ulceration in the plaque. Exclusion criteria for the MDCTA examination consisted of contraindications to iodinated contrast media, such as a known allergy to iodinated contrast material, or elevated renal function tests. We deﬁned symptomatic as a patient with a transitory ischaemic attack (TIA) or stroke. We considered a TIA as a brief (<24 h) episode of neurological dysfunction, such as dysarthria, dysphasia, hemiparesis, hemiparesthesia, or monocular blindness. If the episode of neurological dysfunction exceeded 24 h it was classiﬁed as a stroke. Moreover, for the purpose of this study the time window for a patient to be considered as symptomatic was considered 6 months. We deﬁned asymptomatic as descriptive of a patient who had no history of symptoms, either remote or present at the time of examination. The carotid arteries of asymptomatic patients were studied in our department in diabetics who were >50 years old and in patients who underwent cardiac interventions for coronary artery disease, aortic interventions and lower leg artery surgery. Vascular risk factors and coexisting co-morbidities and treatment known before stroke or transient ischaemic attack are systematically recorded in our institution as described previously (Blinded for peer review). Causes of stroke were classiﬁed according to TOAST criteria. Diabetes was indicated by an abnormal fasting plasma glucose level (>7.9 mmol/L) or the current use of insulin or an oral hypoglycaemic agent. Dyslipidemia was deﬁned as abnormal fasting plasma cholesterol (low-density lipoprotein cholesterol) levels (fasting cholesterol >5.0 mmol/L) or the current use of lipid-lowering agents. Essential hypertension was deﬁned as those individuals who had systolic blood pressure (SBP) > 140 mm Hg and/or diastolic blood pressure (DBP) > 90 mm Hg or were being treated with blood pressurelowering drugs. Cigarette smoking status was categorized as never\former (24 months) or current. This retrospective review evaluated existing clinical data and records. No additional procedures were performed. The review was conducted in accordance with the guidelines of our Institution’s research committee. Part of our patient cohort had been included in previous studies (Blinded for peer review).
(Iomeron 400; Bracco, Milan, Italy) followed by 30 mL of saline ﬂush were injected into a cubital vein, using a power injector at a ﬂow rate of 5 mL/s and an 18-gauge intravenous catheter. A bolus tracking technique was used to calculate the correct timing of the scan. Dynamic monitoring scanning began 6 s after the beginning of the intravenous injection of contrast material. The trigger threshold inside the ROI was set at +80 HU above the baseline and was positioned at the aortic arch. The delay between the acquisition of each monitoring scan was 1 s. When the threshold was reached the patient was instructed not to breathe and after an interval of 4 s the scan started in the caudocranial direction. CT technical parameters included: slice thickness 0.6 mm, interval 0.3 mm, matrix 512 × 512, ﬁeld of view (FOV) 14–19 cm; mAs 180–200; kV 120–140; angiographic acquisition included the carotid siphon. None of the patients included in the study had a medical history of cardiac output failure, or any contraindications to iodinated contrast media.
2.2. MDCTA technique
Before to start this study we choose to include 60 consecutive symptomatic patients. Our exclusion criteria were the presence of near-occlusion condition and\or complete carotid occlusion and the presence of anterior circulation symptoms. Moreover patients with other potentially confounding condition (i.e. suspected embolism from a cardiac source, follow-up after carotid endarterectomy, intra cerebral aneurysms, brain tumors) were excluded. According to this procedure the total number of consecutive patients analyzed was 71: four patients were excluded because in one case there was a complete left ICA occlusion and
All patients underwent MDCTA of the supra-aortic vessels using a 40-multi-detector-row CT system (Somatom Sensation, Siemens, Erlangen, Germany). Written consent to perform MDCTA was obtained from the patients after discussion about the associated risks with contrast enhanced MDCTA and the potential beneﬁts deriving from this examination. Patients were placed in the supine position, with the head tilted back in order to prevent dental artefacts on the images. Eighty microliters of a contrast medium
2.3. Image analysis Two radiologists, blinded to the clinical information, performed all measurements of luminal stenosis. Window/level settings were applied according to Saba and Mallarini  and Bartlett et al. . In general we usually applied W850:L300, progressing to very wide settings in the case of dense calciﬁcations in order to decrease beam-hardening artefacts. Stenosis degree of each carotid artery was calculated using the NASCET criteria [3,16–18]. With the NASCET criteria the ratio between the residual luminal surface (inner-to-inner lumen) at the stenosis and the surface of the distal normal lumen (inner-to-inner lumen) where there is no stenosis, was calculated. “inner to inner lumen” measures only the vessel lumen, apart the soft tissue walls. Stenosis degree was calculated by selecting a reformat plane perpendicular to the lumen centreline (Figs. 1 and 2). We tried to avoid the calculation key pitfalls of percent stenosis: ﬁrst step was to recognize the near occlusion (in this case, the attempt to calculate percent maybe fallacious) and for the purpose of this work near occlusions were identiﬁed by two criteria: (1) evidence of narrowed post-stenotic ICA and (2) that the post-stenotic ICA be similar to or smaller than the ipsilateral ECA . Second, we measured the diameter of normal ICA wall beyond the bulb where walls are parallel [16–19] at 4–6 cm distally of the plaque. We categorized different types of plaques, as described in a previous study , dividing them into (a) fatty plaques: a plaque with a density <50 HU; (b) mixed plaque: a plaque with a density between 50 and 119 HU and (c) calciﬁed plaque: a plaque with a density >120 HU. A circular or elliptical ROI (1 mm2 ) in the predominant area of the plaque was used to measure the HU value. Areas showing contamination by contrast material or calciﬁcation that did not contribute to the stenosis were avoided. Regions of beam-hardening in calciﬁed areas were also excluded. A plaque ulceration was considered to be an irregularity or break in the surface of the plaque with a depth of at least 1 mm . 2.4. Exclusion analysis and cohort composition
L. Saba et al. / European Journal of Radiology 81 (2012) 77–82
Fig. 1. CTA images of a 63 years old male patient with TIA. MIP post-processed image (1a) MIP source axial image orientation plane (1b) and CTA reformat images perpendicular to the lumen centreline. (1c and 1d) The anatomic site of measurement in the left internal carotid for the NASCET calculation. The white arrows indicate the narrowest point whereas the white open arrows indicate the distal normal lumen where there is no stenosis. The obtained NASCET value was 60%.
in three cases a near-occlusion condition. Other seven patients were excluded because they suffered posterior circulation symptoms (n = 2), follow-up after carotid endarterectomy (n = 2), brain arterio-venous malformation (n = 1), suspected embolism from a cardiac source (n = 2). The asymptomatic patients were selected in order to match (sex and mean age) with the asymptomatic group, so that they were not consecutive. 2.5. Stenosis Asymmetry Index The Stenosis Asymmetry Index was obtained from the ratio between the most stenosed percentage carotid artery and the contralateral. So to calculate the SAI in each patient, in the numerator there was the bigger NASCET value and in the denominator the NASCET contralateral value.
stenosis degree, SAI, and the other independent variables: hypertension, dyslipidemia, diabetes mellitus and smoking, type of plaque (fatty, mixed and calciﬁed) and plaque ulceration. The logistic regression analysis was performed by considering the stenosis as a continuous variable (while other variables were dichotomous). Receiver operating characteristics (ROC) curve analysis was performed in order to test the hypothesis and identify a SAI threshold, and the area under the ROC (Az) was calculated. A p value less than 0.05 was considered to indicate statistical signiﬁcance. R software (www.r-project.org) was employed for statistical analyses. 3. Results The clinical characteristics of the studied patients are shown in Table 1. In the 60 symptomatic patients 25 strokes, 19 transitory ischaemic attacks and 16 amaurosis fugax were observed.
2.6. Statistical analysis The normality of each continuous variable group was tested using the Kolmogorov–Smirnov Z test. Continuous data were described as the mean value ± standard deviation (SD) and they were compared using the unpaired Student t test. Correlation coefﬁcients (Pearson product moment) were calculated with two-tailed signiﬁcance to evaluate inter-observer agreement for all measurements. The percentage stenosis of each carotid stenosis was the average of the measurements of the two radiologists. Multiple logistic regression analysis (enter procedure) was performed to examine the relationship between the presence of symptoms,
Table 1 Patients characteristics. Agea
64 year (SDb ± 9.5 year)
Sex (male) Smoker Hypertension CAD Diabetes Dyslipidemia
60% 42% 41% 46% 14% 56%
Mean age. SD = standard deviation.
L. Saba et al. / European Journal of Radiology 81 (2012) 77–82
Fig. 2. CTA images of the same patient in Fig. 1. MIP post-processed image (1a) MIP source axial image orientation plane (1b) and CTA reformat images perpendicular to the lumen centreline. (1c and 1d) The anatomic site of measurement in the right internal carotid for the NASCET calculation. The white arrows indicate the narrowest point whereas the white open arrows indicate the distal normal lumen where there is no stenosis. The obtained NASCET value was 35%. The SAI obtained for this asymptomatic patient was 1.71.
In the stenosis quantiﬁcation the radiologists showed very good inter-observer agreement with a Pearson correlation coefﬁcient of 0.91. Symptomatic patients had a mean symptomatic stenosis of 72% compared with 43% on their asymptomatic side (p = 0.001). In the asymptomatic patients group there was no difference between the right and left carotid artery (48% vs. 45%; p = 0.429) but there is a signiﬁcant difference between the most stenosed carotid and the contra-lateral (56% vs. 37%; p = 0.019). The agreement between observers was very good in stenosis degree quantiﬁcation (rho = 0.87; p value = 0.001).
3.3. Logistic regression analysis The results of the multiple logistic regression analysis are described in Table 3. The multiple logistic regression analysis did not ﬁnd any statistically signiﬁcant association between SAI and symptoms. A statistically signiﬁcant association between increased percentage of stenosis and symptoms was observed with a p value of 0.001. A statistically association was also detected between symptoms and the presence of high blood pressure (p = 0.041). Other variables did not demonstrate a signiﬁcant statistical association with cerebrovascular symptoms.
3.1. ROC curve analysis 4. Discussion Using the ROC analysis we calculated the sensitivity, speciﬁcity, +LR and −LR values and a summary of these values is given in Table 2. The area under the curve (Az) was 0.619 (SD = 0.056; p value = 0.0439). By analysing threshold values we observed that a 1.8 SAI is associated with a speciﬁcity of 84.31% for the presence of cerebrovascular symptoms.
3.2. Symptomatic vs. non-symptomatic groups SAI ranged from 1 to 3.1 (mean 1.59 ± 0.45). The Kolmogorov–Smirnov Z test demonstrated an absence of normal Gaussian distribution (p = 0.001; coefﬁcient of Skewness = 1.3454 [p < 0.0001], coefﬁcient of Kurtosis = 1.7398 [p = 0.0115]). A statistically signiﬁcant difference (p value = 0.0204) was observed in SAI between patients with symptoms (1.69 ± 0.53 SD) and without symptoms (1.48 ± 0.35 SD).
The purpose of this work was to assess the association between the SAI in the symptomatic and asymptomatic patient’s group. People with substantial carotid narrowing are at increased risk of major stroke; however the degree of stenosis alone is a relatively poor prediction of neurological events; nowadays it is widely accepted that the degree of stenosis of the carotid artery represents only one of the parameters that are associated with the development of cerebrovascular symptoms [11,13]. In particular, the plaque composition and its characteristic, as well as the volume of the plaque itself, seems to play a signiﬁcant role in the stroke risk development [5,7,8,10,12,21,22]. The research and identiﬁcation of the parameters that can correctly stratify the stroke risk is important: patients symptoms and the degree of luminal narrowing, which have previously used as clinical grounds for surgical intervention, are no longer appropriate to be considered solely for decision making. To the best of our knowledge an association between the difference in
L. Saba et al. / European Journal of Radiology 81 (2012) 77–82
Table 2 ROC curve analysis. SAI
1 >1 >1.1 >1.2 >1.3 >1.4 >1.5 >1.6 >1.7 >1.8 >1.9 >2 >2.1 >2.3 >2.5 >3.0
100.00 96.08 94.12 88.24 74.51 54.90 43.14 35.29 35.29 29.41 23.53 21.57 17.65 11.76 9.80 0.00
93.0–100.0 86.5–99.4 83.7–98.7 76.1–95.5 60.4–85.7 40.3–68.9 29.4–57.8 22.4–49.9 22.4–49.9 17.5–43.8 12.8–37.5 11.3–35.3 8.4–30.9 4.5–23.9 3.3–21.4 0.0–7.0
0.00 11.76 15.69 23.53 35.29 54.90 66.67 74.51 76.47 84.31 90.20 92.16 96.08 98.04 100.00 100.00
0.0–7.0 4.5–23.9 7.0–28.6 12.8–37.5 22.4–49.9 40.3–68.9 52.1–79.2 60.4–85.7 62.5–87.2 71.4–93.0 78.6–96.7 81.1–97.8 86.5–99.4 89.5–99.7 93.0–100.0 93.0–100.0
1.00 1.09 1.12 1.15 1.15 1.22 1.29 1.38 1.50 1.87 2.40 2.75 4.50 6.00 NCa NCa
NCa 0.33 0.38 0.50 0.72 0.82 0.85 0.87 0.85 0.84 0.85 0.85 0.86 0.90 0.90 1.00
Table 3 Multiple logistic regression analysis. Variable
SAI Stenosis CAD Diabetes Age Hypertension Dyslipidemia Sex Smoker Ulceration Fatty Calciﬁed Mixed
0.18693 0.01277 0.09228 0.06388 0.00027 −0.21614 −0.06855 0.04646 −0.00675 0.13554 0.14892 0.03873 −0.09974
0.1052 0.00276 0.09222 0.12261 0.00382 0.10374 0.09199 0.09227 0.0921 0.1796 0.12334 0.11916 0.11447
1.777 4.633 1.001 0.521 0.07 −2.084 −0.745 0.503 −0.073 0.755 1.207 0.325 −0.871
0.079 <0.0001* 0.3197 0.6037 0.9446 0.0401* 0.4581 0.6159 0.9418 0.4524 0.2305 0.7459 0.3858
0.304 0.486 0.039 −0.029 −0.032 −0.129 −0.194 0 0.047 0.178 0.208 −0.127 −0.103
p < 0.05.
stenosis between both carotid arteries and their relationship with the presence of cerebrovascular symptoms has not been previously assessed by any imaging technique. In our study, a statistically signiﬁcant difference (p value = 0.0204) was observed in SAI values between patients with symptoms (1.69 ± 0.53 SD) and without symptoms (1.48 ± 0.35 SD). This was an unexpected result because, before the analysis of the results we believed that the lower the SAI the higher the stroke risk since the collateral circulation from the contralateral side becomes probably less efﬁcient. However, this results support the hypothesis that some local factors may be implicated in the development and consequent embolic activity of the carotid plaque. Although it is well demonstrated the truly systemic nature of the atherosclerosis [23,24], the presence of statistically signiﬁcant SAI between symptomatic and asymptomatic patients as well as the presence of statistically signiﬁcant difference in the percentage of stenosis within the symptomatic and asymptomatic group (with a p value respectively of 0.001 and 0.019), support the theory that a local trigger may determine the rapid development and volume of the vulnerable atheroma [25,26]. The symptomatic patients had a mean symptomatic stenosis of 72% compared with 43% on their asymptomatic side (p = 0.001). Other authors , in a symptomatic patient’s group (n = 20), measured the degree of stenosis in the symptomatic carotid artery and in the controlateral, by obtaining similar results of degree of stenosis (72% vs. 77% and 43% vs. 46%). The ROC curves demonstrated that a 1.8 SAI is associated with a speciﬁcity of 84.31% for the presence of cerebrovascular symptoms, by indicating that this parameter may be very speciﬁc. The
ROC curve analysis for symptoms vs. SAI showed an Az of 0.619 (SD = 0.056; p value = 0.0439). This is a statistically signiﬁcant value, but the association between SAI and cerebrovascular symptoms is not conﬁrmed in the multiple logistic regression analysis. This is probably due to the effect of the other independent variable that may have reduced the strength of association between SAI and symptoms. Only 2 statistically signiﬁcant associations with symptoms were observed, namely the percentage of stenosis (p = 0.001) and high blood pressure (p = 0.041). We are aware that our study suffers from some limitations. First, this is a retrospective analysis which may introduce a bias. Further to this point, we used the same techniques, hardware, operators and data standardization and so the variability in the retrospective analysis should have been reduced. Second, in order to exclude confounding effects of carotid disease on the presence of symptoms, patients with atrial ﬁbrillation suggesting cardiac embolic dispersion were not included in this study. However, we did not perform Holter monitoring or trans-thoracic or trans-oesophageal echocardiography to completely rule out other potential causes of stroke, such as cardiogenic sources or arch sources, and thus a confounding effect cannot be completely excluded.
5. Conclusion Results of our study suggest that a SAI > 1.8 has a good sensitivity in identifying the association with cerebrovascular events. Further studies should test if the SAI may be used as further parameter to stratify the stroke risk related to carotid artery pathology.
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