Clinical Neurology and Neurosurgery 133 (2015) 24–29
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Brain diffusion changes in unilateral carotid artery stenosis with non-shunt endarterectomy: Correlation with white matter lesions Neslin Sahin a,∗ , Aynur Solak a , Berhan Genc a , Mehmet Besir Akpinar b , Ugur Kulu c , Hakan Cengiz d a
Department of Radiology, Sifa University School of Medicine, Fevzipasa Boulevard No. 172/2, 35240 Basmane Izmir, Turkey Department of Cardiovascular and Thoracic Surgery, Sifa University School of Medicine, Fevzipasa Boulevard No. 172/2, 35240 Basmane Izmir, Turkey c Department of Neurology, Sifa University School of Medicine, Fevzipasa Boulevard No. 172/2, 35240 Basmane Izmir, Turkey d Sifa University, Department of Biostatistics & Medical Informatics, Ankara Cd, 35100 I˙ zmir, Turkey b
a r t i c l e
i n f o
Article history: Received 7 December 2014 Received in revised form 26 December 2014 Accepted 2 March 2015 Available online 16 March 2015 Keywords: Carotid stenosis Diffusion-weighted imaging Endarterectomy Ischemia White matter hyperintensities
a b s t r a c t Objective: Carotid stenosis is associated with hemodynamic cerebral ischemia. Diffusion-weighted MR imaging allows for the assessment of changes related to alterations in tissue integrity. The aim of this study was to investigate (a) whether white matter lesions (WML) and apparent diffusion coefficient (ADC) values differ between ipsilateral and contralateral hemispheres, (b) whether ADC values are related to WMLs and common vascular risk factors, and (c) whether ADC values differ after carotid endarterectomy (CEA) without a shunt in patients with unilateral internal carotid artery stenosis (ICAS). Methods: Twenty-five patients (16 men, 9 women; mean age of 68 years) with unilateral ICAS (≥70% carotid stenosis) were assessed with brain MRI before and after CEA, prospectively. Two experienced radiologists scored the WMLs. Bilateral ADC values in anterior and posterior periventricular WM, occipital WM, and thalamus were evaluated on preoperative and postoperative MRI. Differences in ADC values and WML scores between the two hemispheres were assessed and associations between ADC values, WML scores, and explanatory variables (e.g., age, sex, vascular risk factors) were analyzed. Results: WMLs were significantly greater and ADC values were elevated in the ipsilateral cerebral WM. After CEA, ADC values rapidly decreased but remained higher than within the contralateral hemisphere. Ipsilateral hemispheric ADC values were associated with basal ganglia WMLs. No association between ADC values and vascular risk factors was found. Conclusion: ICAS is associated with increased diffusion in normal-appearing WM in comparison to more prominent chronic ischemic lesions. CEA has a partial effect on diffusion. These cerebral changes may be related to chronic low-grade ischemic damage that is induced by ICAS. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Carotid artery stenosis (CAS) is related to an increased risk of stroke and more prominent chronic ischemic lesions [1,2]. In several randomized clinical trials, carotid endarterectomy (CEA) has been proven to be effective in decreasing the risk of stroke [3]. White matter lesions (WMLs), which are also termed “leukoaraiosis,” are common radiological findings of uncertain pathogenesis that are frequently observed in the periventricular white matter as bilateral diffuse or patchy hyperintensities on T2-weighted magnetic resonance imaging (MRI) [4]. Epidemiological studies demonstrate an increasing frequency of WMLs with
∗ Corresponding author. Tel.: +90 232 343 44 45; fax: +90 232 343 56 56. E-mail address: [email protected] (N. Sahin). http://dx.doi.org/10.1016/j.clineuro.2015.03.002 0303-8467/© 2015 Elsevier B.V. All rights reserved.
advancing age [5]. WMLs have been investigated in numerous studies as potential markers of vascular disease [6–8]. Furthermore, it has been postulated that tissue damage associated with white matter diseases, such as multiple sclerosis, may extend beyond the areas of visible signal abnormalities within routine MRI [9]. Diffusion-weighted MR imaging (DWI) depends on the random diffusion of water molecules within cellular and extracellular tissue compartments [10]. The apparent diffusion coefficient (ADC), a measure of in vivo diffusion at the cellular level, is the net diffusion of water molecules. DWI allows for the assessment of changes associated with alterations in tissue integrity. Thus, they can be useful in quantifying the extent of tissue damage both within and even beyond areas of apparent signal abnormality [9–11]. DWI has been proven to be an essential technique for the detection and differentiation of acute stroke in the early phase, and has also been applied in different phases, of brain ischemia, as well as various
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clinical conditions that are continuously expanding [4,12]. Furthermore, ADC elevation in normal-appearing WM (NAWM) has been reported in patients with a variety of cerebrovascular diseases that may represent low-grade ischemic insult [4,11,13]. However, scarce information exists on the utility and feasibility of DWI applications in patients with CAS. Carotid stenosis is associated with hemodynamic cerebral ischemia. Therefore, we investigated the impact of unilateral internal CAS (ICAS) on brain parenchyma. The aim of this study was to investigate (a) whether WMLs and water diffusibility (ADC values) in NAWM differ between ipsilateral and contralateral hemispheres, (b) whether ADC values are related to WMLs and common vascular risk factors, and (c) whether ADC values differ between hemispheres after CEA without a shunt. 2. Material and methods Patients with unilateral ICAS who were undergoing carotid endarterectomy were prospectively recruited. The study was approved by the Local Research Ethics Committee, and all patients (or their relatives) gave written informed consent. 2.1. Patients Using carotid computed tomography angiography (CTA), carotid MR angiography (MRA), and/or carotid digital subtraction angiography (DSA), a total of 32 patients were identified as having unilateral ICAS. Two patients with confluent infarction were excluded because of inadequate analysis for ADC values, and two patients were excluded because of motion artifacts. In addition, three patients were excluded because of the absence of postoperative imaging. Finally, a total of 25 consecutive patients with unilateral ICAS were included in the present study. ICA stenosis was determined by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. All patients met the following inclusion criteria: (1) ≥70% stenosis in unilateral ICA, (2) less than 50% stenosis in contralateral ICA, and (3) no history of ICA stenosis treatment and absence of potential cardiogenic origin for emboli. Baseline demographics of the patients and medical data were prospectively acquired. Vascular risk factors, such as diabetes, coronary artery disease, hypercholesterolemia, lower extremity peripheral arterial disease, hypertension, and cerebrovascular disease (previous stroke or transient ischemic attack) were recorded. Smoking status was categorized as former, never, or current. Vascular risk factors were determined according to standard clinical guidelines as previously described [14]. 2.2. MR imaging protocol MR imaging was performed on a 1.5 T clinical scanner (Espree; Siemens, Erlangen, Germany) using a 12-channel phased array head coil the day before and within 2 days after CEA. The preoperative MRI protocol included the following axial sequences: (1) fluidattenuated inversion recovery (FLAIR, TR/TE/TI = 11.000/140/2600, section thickness = 3.0 mm), (2) T1-weighted inversion recovery (TR/TE/TI 6000/25/300, section thickness = 3.0 mm), (3) variableecho, fast spin echo (TR/TE1/TE2 = 5500/20/90, section thickness = 3.0 mm), (4) diffusion-weighted imaging (DWI) with a spin-echo echo-planar imaging sequence (TR/TE = 4200/114, section thickness = 5.0 mm, flip angle = 90◦ ). Diffusion was measured in three orthogonal directions (x, y, and z) with b values of 0, 500, and 1000 s/mm2 . ADC maps were automatically generated using a pixel-by-pixel approach. For all sequences, the FOV was 230 mm × 230 mm and the matrix was 256 × 256. Variable-echo and T1-weighted images were obtained with the same orientation
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Table 1 WML scoring system. White matter (WM) lesions 1. 2. 3. 4.
Periventricular WM (frontal, parietal, and occipital) 0 = none, 1 = 5 mm thick Deep WM (frontal, parietal, temporal, occipital) Basal ganglia (BG) (lentiform nucleus (LN), caudate nucleus (CN), thalamus, internal capsule) Brain stem (cerebellar WM, midbrain and pontine reticular formations, medulla) For 2, 3, and 4 0 = none; 1 = 5 or fewer ≤3 mm, 2 = 6 or more ≤ 3 mm, 3 = 5 or fewer 4–10 mm, 4 = 6 or more 4–10 mm, 5 = ≥11 mm, and 6 = confluent
as the FLAIR images. The postoperative MRI protocol included DWI and FLAIR sequences with the same parameters. 2.3. Data analysis All images were transferred to a separate imaging workstation (Leonardo; Siemens Medical Solutions). Two radiologists (N.S., A.S.) who were blinded to the clinical data with 10 and 18 years of experience in neuroradiology, respectively, reviewed all images independently and recorded old infarcts. All image analyses were then compared; disagreements were resolved through consensus. White matter lesions were analyzed on all matched sequences and were rated using Scheltens scale as the scoring system [15]. This scale has four subscales, including evaluation of periventricular and deep white matter, basal ganglia, and brain stem. A modified version of the scale was used as previously described [7] in which WMLs of the lentiform nucleus were rated in a single group without further classification into the globus pallidus and putamen. The details are shown in Table 1. ADC measurements were performed based on consensus of the same two observers. Four regions of interest (ROI) were drawn in each hemisphere including anterior and posterior periventricular white matter, thalamus and occipital white matter (Fig. 1). ROIs were first drawn on the T2-weighted (b = 0) images and they were subsequently transferred onto the corresponding ADC maps. Care was taken to avoid contamination of the ROIs with any T2-weighted signal intensity changes. The area of each ROI was 0.3–1 cm2 . 2.4. Statistical analysis Differences in WML scores and preoperative ADC values between the ipsilateral hemisphere with ICA stenosis and contralateral hemisphere without significant stenosis were assessed by the Wilcoxon signed-rank test. In addition, preoperative and postoperative ADC values were compared in each hemisphere by the Wilcoxon signed-rank test. Spearman’s Rho correlation test was performed to determine associations between ADC values, WML scores and explanatory variables (e.g., age, sex, and vascular risk factors). All probability values were two-tailed; p < 0.05 was considered to be statistically significant. All statistical analyses were performed using IBM Statistical Package for the Social Sciences (SPSS) Statistics for Windows, Version 20.0 (Armonk, NY, USA: IBM Corp). 3. Results Representative images of WML scoring and corresponding ADC measurements are shown in Figs. 2 and 3. Twenty-five patients (16 men, 9 women) had unilateral ICA stenosis and had a mean age of 68.04 (±8.97) years. Table 2 demonstrates the baseline characteristics of the study sample.
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Fig. 1. Location of regions of interest on apparent diffusion coefficient maps. 1 = anterior periventricular white matter, 2 = posterior periventricular white matter, 3 = thalamus, 4 = occipital white matter.
ADC values are given in units of mm2 /s × 10−3 . The statistical results for ADC values and WML scores are presented in Tables 3 and 4. New silent ischemic lesions were preoperatively detected in 1 of the 25 patients and were postoperatively detected in 3 (12%) patients within the territory of the treated carotid artery.
Periventricular, deep, and basal ganglia WML scores were significantly greater in the ipsilateral hemispheres. Although significant differences were observed in ADC values of anterior and posterior periventricular and occipital white matter between ipsilateral and contralateral hemispheres, no significant differences were found in ADC values of the thalami on preoperative MRI. Ipsilateral hemispheric WM ADC values were
Fig. 2. Sixty-one year old man with 80% left ICA stenosis. FLAIR images (A–D) demonstrate bilateral thick periventricular (score 2, arrows), large (score 5, thick arrowheads) and small (thin arrowheads) deep white matter lesions. Basal ganglia white matter lesion, which is found to be associated with hemispheric ADC values, is only present on the ipsilateral left hemisphere (D, paired arrow).
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Fig. 3. Sixty-one year old man with 80% left ICA stenosis (shown in Fig. 2). On preoperative diffusion-weighted ADC maps, hemispheric ADC values are higher on the ipsilateral left hemisphere than the contralateral hemisphere (A, B). Bilateral thalami reveal no ADC value change before and after carotid endarterectomy (C, F). Ipsilateral left hemispheric ADC values decrease after surgery (D, E), but remain higher than the contralateral hemisphere.
Table 4 Comparison of the WM lesion scores between ipsilateral and contralateral hemispheres.
Table 2 Baseline characteristics of patients (n = 25). Characteristics Mean age in years (SD) Male gender n (%) ICA stenosis % (SD) Coronary artery disease n (%) Hypertension n (%) Diabetes n (%) Lower extremity arterial disease n (%) Hypercholesterolemia n (%) Cerebrovascular disease n (%) Current smoker n (%) Old infarct in the ipsilateral hemisphere n (%) Chronic lacunar infarct in the ipsilateral hemisphere n (%)
68.04 (8.97) 16 (64) 80.76 (10.89) 18 (72) 18 (72) 9 (3) 2 (8) 17 (68) 4 (16) 9 (36) 9 (36) 8 (32)
associated with scores of basal ganglia WMLs. Contralateral anterior periventricular WM ADC values were associated with scores of periventricular WMLs. On postoperative MRI, ipsilateral hemispheric WM ADC values decreased but ADC values were higher than the contralateral
Table 3 Comparison of the ADC values between ipsilateral and contralateral hemispheres.
PV anterior Preoperative Postoperative PV posterior Preoperative Postoperative Thalamus Preoperative Postoperative Occipital Preoperative Postoperative
Ipsilateral hemisphere mean (SD)
Contralateral hemisphere mean (SD)
0.808 (0.061) 0.776 (0.059)
0.768 (0.063) 0.767 (0.059)
0.805 (0.039) 0.786 (0.039)
0.779 (0.040) 0.779 (0.041)
0.750 (0.038) 0.751 (0.038)
0.753 (0.038) 0.754 (0.038)
0.813 (0.040) 0.793 (0.040)
0.793 (0.034) 0.789 (0.035)
ADC values are given as 10−3 mm2 /s. ADC, apparent diffusion coefficient; PV, periventricular.
WML score Deep WM PV WM BG Infratentorial
Ipsilateral hemisphere mean (SD)
Contralateral hemisphere mean (SD)
5.72 (4.00) 3.72 (1.70) 1.40 (2.08) 0.32 (0.80)
4.52 (3.97) 3.20 (1.92) 0.64 (1.44) 0.36 (0.91)
BG, basal ganglia; PV, periventricular; WM, white matter.
hemisphere. No significant differences were observed in thalamic and contralateral hemispheric WM ADC values postoperatively. There was no association between the ADC values and vascular risk factors including chronic lacunar infarctions and old infarcts. 4. Discussion Because severe carotid stenosis has been reported to cause hemodynamic cerebral ischemia, ADC values and WMLs were considered for the detection and quantification of cerebral tissue changes associated with unilateral ICAS in this study. The findings showed that WMLs were significantly greater and ADC values were elevated in the WM of the hemisphere ipsilateral to carotid stenosis. After CEA without shunting, ADC values rapidly decreased but remained higher than within the contralateral hemisphere. Few studies have applied DWI and ADC mapping to evaluate chronic hypoperfusion induced by ICAS [11,16]. Soinne et al. [11] reported increased ADC values on the ipsilateral hemisphere in 45 patients with carotid stenosis, similar to the results of a recent study [16]. In agreement with the literature, significantly higher ADC values were found on the ipsilateral hemisphere of ICAS, most likely reflecting the effects of chronic hypoperfusion because of stenosis on the brain parenchyma. Previous investigators [11,16] proposed that the elevation of ADC values in ICAS, which is partly reversible after CEA, may be associated with vasogenic edema because the surgical removal
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of the stenosis resulted in a rapid decrease of the ADC values in the ipsilateral hemisphere. However, the ADC levels were higher than those of the contralateral hemisphere, which suggests partial reversible ischemia induced by ICAS within 2 days in the early postoperative period. After CEA, restoration of cerebral blood flow may provide further improvements in functionally but not irreversibly damaged cells at a slow rate in the course of time. On the contrary, higher postoperative ADC values of the ipsilateral hemisphere may be the initial step in the development of irreversible ischemia-induced brain damage progressing to WMLs. Because this study only involved early postoperative MR imaging, the pathophysiology of increased ADC in ICAS remains obscure. Therefore, long-term follow-up data of WMLs and ADC values and correlations are required to determine the overall effects of stenosis and CEA on the ipsilateral WM. Carotid stenosis may compromise cerebral hemodynamics. A relationship between cerebral hemodynamics and the risk of stroke in patients with CAS has been reported [1]. However, the relationship between CAS and hemodynamic factors is controversial. Soinne et al. [17] have shown decreased perfusion preoperatively and improvements in MTT values without a change in CBV after the operation. Previous studies indicated ADC elevations in the NAWM of patients with leukoaraiosis in addition to leukoaraiotic regions [4]. O’Sullivan et al. [18] have also found evidence that hypoperfusion has a role in the development of periventricular ischemic lesions. Therefore, postoperatively higher ADC values in the ipsilateral hemisphere suggest other physiologic mechanisms. These mechanisms also cause changes in brain structure that are associated with leukoaraiotic evolution which have not yet resulted in irreversible ischemia other than the short-term direct effect of reduced perfusion induced by CAS, as mentioned above. No ADC value change was detected in the contralateral hemisphere after CEA; this was in agreement with a previous study. No comparison group was used in this study, but Soinne et al. [11] noted higher ADC values in the contralateral hemispheres in comparison to control groups. The ADC values were similar in ipsilateral and contralateral thalami before and after CEA and were consistent with recent publications. The difference in the blood flow of the thalamus and WM can explain this finding. Leukoaraiosis was commonly observed among elderly patients with symptomatic CAS. More extensive lesions were associated with a worse prognosis and a higher occurrence of stroke [2]. The global WML volume was reported to be related to carotid stenosis [19] and an association between WMLs and the carotid stenosis class [20] was shown in previous studies. We also demonstrated more WMLs in the ipsilateral hemispheres, thus supporting the hypothesis of the leukoaraiogenic potential of carotid stenosis in accord with these previous studies. In contrast, no relationship was noted between WMLs and unilateral carotid stenosis by Potter et al. [8], but relatively few patients (10–11%) had an asymmetric stenosis in their study. Numerous potential causes have been suggested to contribute to the etiology of leukoaraiosis, with chronic ischemia and hypoperfusion being the main hypothesis [5]. A correlation between the increased ADC values of NAWM and the severity of WMLs in ICA patients has been reported previously [4,9]. In this study, ipsilateral basal ganglia WMLs were correlated with the degree of hemispheric WM ADC elevation, and the contralateral periventricular WMLs were correlated with the degree of anterior periventricular WM ADC values. Chronic vascular stenosis is a primarily systemic disease that affects small vessels as well as carotid arteries. The effects of the associated microvascular disease can explain these WM changes in unilateral ICAS. However, an assessment of NAWM by histogram analysis, as Ropele et al. [9] suggested, might provide different results from the operator-dependent manual ROI analysis
that was used in this study. Whether the relation of ADC and WMLs was due to structural or functional changes related to the contributions of small vessel disease, in addition to ICAS, or was a mere statistical artifact remains to be shown. In all patients, CEA was performed without shunting. Shunt usage in CEA is protective for cerebral hypoperfusion in comparison to non-shunting, but it was not preventive for emboli [21]. The incidence of new silent ischemic lesions was similar to the reported incidence of routine shunt usage in this study [22]. After revascularization with CEA, the ipsilateral ADC values decreased in a finding that was similar to a previous study [11], but the type of CEA (with or without shunt) was not determined in that study. These findings suggest that the impact of perioperative hypoperfusion induced by non-shunting is less than measurable ADC values. However, further studies that include CEA patients with and without shunting are needed to assess whether shunt usage is related to cerebral diffusion and perfusion. In several studies, the correlation between the degree of elevated ADC and the degree of cognitive decline has been suggested in patients with ICAS [13]. Additionally, some studies indicated that changes in the ADC values of NAWM in patients with leukoaraiosis were correlated to the degree of cognitive dysfunction [11,18]. Furthermore, a recent systematic review that included 11 studies found improvements in cognition in approximately 10% of patients after CEA and a decrease over time in 10–15% of patients [23]. Differences in preoperative ADC values and/or the severity of WMLs as evidence of chronic hypoperfusion may be helpful in explaining conflicting results in cognitive performance after CEA. However, a possible relationship between MRI findings and cognitive deficit has not been evaluated and is the subject of a separate study. Small elevations of ADC values in WM with aging have been observed by some investigators [9], while no change has been found in a previous study [4]. In patients with unilateral ICAS, no association was detected between the ADC values and age or the vascular risk factors analyzed in this study. The effects of aging and other vascular risk factors in ADC values might be underestimated due to the small number of the patients. Additionally, the association between age and ADC values may not be revealed because of the participants’ advanced age. There are some limitations in this study. The major shortcoming is the relatively small sample size because half of the patients with bilateral ICAS and/or a history of treatment for ICAS were excluded. Ipsilateral and contralateral hemispheres of patients with ICAS were compared to evaluate the impact of the carotid stenosis and minimize the possible factors that can attribute to WML and ADC values. However, the contralateral hemisphere, as the control group, may still have some limitations. In the present study, the ADC value was derived from DWI in three independent directions, thus showing an average diffusivity, and operator-dependent manual ROI analysis was applied. A more comprehensive diffusion analysis using orientation-independent diffusion tensor imaging may be more robust for detection of subtle alterations between two hemispheres. In contrast, the scan time for DTI is longer and the spatial resolution of DTI tends to be lower than with a trace ADC measurement. Another limitation includes visual WML scores instead of lesion volumes. Although volumes can measure WMLs with more accuracy, visual WML scores may be more specific because they are not related to problems caused by artifacts. In addition, scores and volumes have been reported to be closely related [24]. This is an observational study with a small sample size. In addition, the statistical significance of observed differences may be dependent on several factors. Therefore, these findings must be considered and interpreted with caution. However, the data with a limited sample of patients provides important feedback in unilateral ICAS and warrants further prospective studies with larger populations and
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a longer follow-up time correlated with patients without ICAS and clinical outcomes of CEA including neurocognitive tests. In conclusion, ICAS is associated with increased diffusion in normal-appearing WM. It is also significantly associated with greater WMLs in ipsilateral hemispheres than contralateral hemispheres. Ipsilateral ADC values rapidly decrease after CEA without shunting. These cerebral changes may be related to chronic lowgrade ischemic damage that is induced by ICAS. Financial disclosure The authors declared that this study has received no financial support. Ethical approval The research was approved by the Local Research Ethics Committee. Informed consent Written informed consent was obtained from patients (or their relatives) who participated in this study. Conflict of interest No conflict of interest was declared by the authors. Acknowledgements The support of technologists Sevgi Dalkilic, Ozlem Dincer, Gunisik Karacan, Neslihan Karadeniz, and Serife Yildizlar is gratefully acknowledged. References [1] Yamauchi H, Fukuyama H, Nagahama Y, Nabatame H, Nakamura K, Yamamoto Y, et al. Evidence of misery perfusion and risk for recurrent stroke in major cerebral arterial occlusive diseases from PET. J Neurol Neurosurg Psychiatry 1996;61:18–25. [2] Streifler JY, Eliasziw M, Benavente OR, Alamowitch S, Fox AJ, Hachinski V, et al. Development and progression of leukoaraiosis in patients with brain ischemia and carotid artery disease. Stroke 2003;34: 1913–6. [3] Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998;339:1415–25. [4] Helenius J, Soinne L, Salonen O, Kaste M, Tatlisumak T. Leukoaraiosis, ischemic stroke, and normal white matter on diffusion-weighted MRI. Stroke 2002;33:45–50.
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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Brain diffusion changes in unilateral carotid artery stenosis with non-shunt endarterectomy: Correlation with white matter lesions Neslin Sahin a,∗ , Aynur Solak a , Berhan Genc a , Mehmet Besir Akpinar b , Ugur Kulu c , Hakan Cengiz d a
Department of Radiology, Sifa University School of Medicine, Fevzipasa Boulevard No. 172/2, 35240 Basmane Izmir, Turkey Department of Cardiovascular and Thoracic Surgery, Sifa University School of Medicine, Fevzipasa Boulevard No. 172/2, 35240 Basmane Izmir, Turkey c Department of Neurology, Sifa University School of Medicine, Fevzipasa Boulevard No. 172/2, 35240 Basmane Izmir, Turkey d Sifa University, Department of Biostatistics & Medical Informatics, Ankara Cd, 35100 I˙ zmir, Turkey b
a r t i c l e
i n f o
Article history: Received 7 December 2014 Received in revised form 26 December 2014 Accepted 2 March 2015 Available online 16 March 2015 Keywords: Carotid stenosis Diffusion-weighted imaging Endarterectomy Ischemia White matter hyperintensities
a b s t r a c t Objective: Carotid stenosis is associated with hemodynamic cerebral ischemia. Diffusion-weighted MR imaging allows for the assessment of changes related to alterations in tissue integrity. The aim of this study was to investigate (a) whether white matter lesions (WML) and apparent diffusion coefficient (ADC) values differ between ipsilateral and contralateral hemispheres, (b) whether ADC values are related to WMLs and common vascular risk factors, and (c) whether ADC values differ after carotid endarterectomy (CEA) without a shunt in patients with unilateral internal carotid artery stenosis (ICAS). Methods: Twenty-five patients (16 men, 9 women; mean age of 68 years) with unilateral ICAS (≥70% carotid stenosis) were assessed with brain MRI before and after CEA, prospectively. Two experienced radiologists scored the WMLs. Bilateral ADC values in anterior and posterior periventricular WM, occipital WM, and thalamus were evaluated on preoperative and postoperative MRI. Differences in ADC values and WML scores between the two hemispheres were assessed and associations between ADC values, WML scores, and explanatory variables (e.g., age, sex, vascular risk factors) were analyzed. Results: WMLs were significantly greater and ADC values were elevated in the ipsilateral cerebral WM. After CEA, ADC values rapidly decreased but remained higher than within the contralateral hemisphere. Ipsilateral hemispheric ADC values were associated with basal ganglia WMLs. No association between ADC values and vascular risk factors was found. Conclusion: ICAS is associated with increased diffusion in normal-appearing WM in comparison to more prominent chronic ischemic lesions. CEA has a partial effect on diffusion. These cerebral changes may be related to chronic low-grade ischemic damage that is induced by ICAS. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Carotid artery stenosis (CAS) is related to an increased risk of stroke and more prominent chronic ischemic lesions [1,2]. In several randomized clinical trials, carotid endarterectomy (CEA) has been proven to be effective in decreasing the risk of stroke [3]. White matter lesions (WMLs), which are also termed “leukoaraiosis,” are common radiological findings of uncertain pathogenesis that are frequently observed in the periventricular white matter as bilateral diffuse or patchy hyperintensities on T2-weighted magnetic resonance imaging (MRI) [4]. Epidemiological studies demonstrate an increasing frequency of WMLs with
∗ Corresponding author. Tel.: +90 232 343 44 45; fax: +90 232 343 56 56. E-mail address: [email protected] (N. Sahin). http://dx.doi.org/10.1016/j.clineuro.2015.03.002 0303-8467/© 2015 Elsevier B.V. All rights reserved.
advancing age [5]. WMLs have been investigated in numerous studies as potential markers of vascular disease [6–8]. Furthermore, it has been postulated that tissue damage associated with white matter diseases, such as multiple sclerosis, may extend beyond the areas of visible signal abnormalities within routine MRI [9]. Diffusion-weighted MR imaging (DWI) depends on the random diffusion of water molecules within cellular and extracellular tissue compartments [10]. The apparent diffusion coefficient (ADC), a measure of in vivo diffusion at the cellular level, is the net diffusion of water molecules. DWI allows for the assessment of changes associated with alterations in tissue integrity. Thus, they can be useful in quantifying the extent of tissue damage both within and even beyond areas of apparent signal abnormality [9–11]. DWI has been proven to be an essential technique for the detection and differentiation of acute stroke in the early phase, and has also been applied in different phases, of brain ischemia, as well as various
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clinical conditions that are continuously expanding [4,12]. Furthermore, ADC elevation in normal-appearing WM (NAWM) has been reported in patients with a variety of cerebrovascular diseases that may represent low-grade ischemic insult [4,11,13]. However, scarce information exists on the utility and feasibility of DWI applications in patients with CAS. Carotid stenosis is associated with hemodynamic cerebral ischemia. Therefore, we investigated the impact of unilateral internal CAS (ICAS) on brain parenchyma. The aim of this study was to investigate (a) whether WMLs and water diffusibility (ADC values) in NAWM differ between ipsilateral and contralateral hemispheres, (b) whether ADC values are related to WMLs and common vascular risk factors, and (c) whether ADC values differ between hemispheres after CEA without a shunt. 2. Material and methods Patients with unilateral ICAS who were undergoing carotid endarterectomy were prospectively recruited. The study was approved by the Local Research Ethics Committee, and all patients (or their relatives) gave written informed consent. 2.1. Patients Using carotid computed tomography angiography (CTA), carotid MR angiography (MRA), and/or carotid digital subtraction angiography (DSA), a total of 32 patients were identified as having unilateral ICAS. Two patients with confluent infarction were excluded because of inadequate analysis for ADC values, and two patients were excluded because of motion artifacts. In addition, three patients were excluded because of the absence of postoperative imaging. Finally, a total of 25 consecutive patients with unilateral ICAS were included in the present study. ICA stenosis was determined by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. All patients met the following inclusion criteria: (1) ≥70% stenosis in unilateral ICA, (2) less than 50% stenosis in contralateral ICA, and (3) no history of ICA stenosis treatment and absence of potential cardiogenic origin for emboli. Baseline demographics of the patients and medical data were prospectively acquired. Vascular risk factors, such as diabetes, coronary artery disease, hypercholesterolemia, lower extremity peripheral arterial disease, hypertension, and cerebrovascular disease (previous stroke or transient ischemic attack) were recorded. Smoking status was categorized as former, never, or current. Vascular risk factors were determined according to standard clinical guidelines as previously described [14]. 2.2. MR imaging protocol MR imaging was performed on a 1.5 T clinical scanner (Espree; Siemens, Erlangen, Germany) using a 12-channel phased array head coil the day before and within 2 days after CEA. The preoperative MRI protocol included the following axial sequences: (1) fluidattenuated inversion recovery (FLAIR, TR/TE/TI = 11.000/140/2600, section thickness = 3.0 mm), (2) T1-weighted inversion recovery (TR/TE/TI 6000/25/300, section thickness = 3.0 mm), (3) variableecho, fast spin echo (TR/TE1/TE2 = 5500/20/90, section thickness = 3.0 mm), (4) diffusion-weighted imaging (DWI) with a spin-echo echo-planar imaging sequence (TR/TE = 4200/114, section thickness = 5.0 mm, flip angle = 90◦ ). Diffusion was measured in three orthogonal directions (x, y, and z) with b values of 0, 500, and 1000 s/mm2 . ADC maps were automatically generated using a pixel-by-pixel approach. For all sequences, the FOV was 230 mm × 230 mm and the matrix was 256 × 256. Variable-echo and T1-weighted images were obtained with the same orientation
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Table 1 WML scoring system. White matter (WM) lesions 1. 2. 3. 4.
Periventricular WM (frontal, parietal, and occipital) 0 = none, 1 = 5 mm thick Deep WM (frontal, parietal, temporal, occipital) Basal ganglia (BG) (lentiform nucleus (LN), caudate nucleus (CN), thalamus, internal capsule) Brain stem (cerebellar WM, midbrain and pontine reticular formations, medulla) For 2, 3, and 4 0 = none; 1 = 5 or fewer ≤3 mm, 2 = 6 or more ≤ 3 mm, 3 = 5 or fewer 4–10 mm, 4 = 6 or more 4–10 mm, 5 = ≥11 mm, and 6 = confluent
as the FLAIR images. The postoperative MRI protocol included DWI and FLAIR sequences with the same parameters. 2.3. Data analysis All images were transferred to a separate imaging workstation (Leonardo; Siemens Medical Solutions). Two radiologists (N.S., A.S.) who were blinded to the clinical data with 10 and 18 years of experience in neuroradiology, respectively, reviewed all images independently and recorded old infarcts. All image analyses were then compared; disagreements were resolved through consensus. White matter lesions were analyzed on all matched sequences and were rated using Scheltens scale as the scoring system [15]. This scale has four subscales, including evaluation of periventricular and deep white matter, basal ganglia, and brain stem. A modified version of the scale was used as previously described [7] in which WMLs of the lentiform nucleus were rated in a single group without further classification into the globus pallidus and putamen. The details are shown in Table 1. ADC measurements were performed based on consensus of the same two observers. Four regions of interest (ROI) were drawn in each hemisphere including anterior and posterior periventricular white matter, thalamus and occipital white matter (Fig. 1). ROIs were first drawn on the T2-weighted (b = 0) images and they were subsequently transferred onto the corresponding ADC maps. Care was taken to avoid contamination of the ROIs with any T2-weighted signal intensity changes. The area of each ROI was 0.3–1 cm2 . 2.4. Statistical analysis Differences in WML scores and preoperative ADC values between the ipsilateral hemisphere with ICA stenosis and contralateral hemisphere without significant stenosis were assessed by the Wilcoxon signed-rank test. In addition, preoperative and postoperative ADC values were compared in each hemisphere by the Wilcoxon signed-rank test. Spearman’s Rho correlation test was performed to determine associations between ADC values, WML scores and explanatory variables (e.g., age, sex, and vascular risk factors). All probability values were two-tailed; p < 0.05 was considered to be statistically significant. All statistical analyses were performed using IBM Statistical Package for the Social Sciences (SPSS) Statistics for Windows, Version 20.0 (Armonk, NY, USA: IBM Corp). 3. Results Representative images of WML scoring and corresponding ADC measurements are shown in Figs. 2 and 3. Twenty-five patients (16 men, 9 women) had unilateral ICA stenosis and had a mean age of 68.04 (±8.97) years. Table 2 demonstrates the baseline characteristics of the study sample.
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Fig. 1. Location of regions of interest on apparent diffusion coefficient maps. 1 = anterior periventricular white matter, 2 = posterior periventricular white matter, 3 = thalamus, 4 = occipital white matter.
ADC values are given in units of mm2 /s × 10−3 . The statistical results for ADC values and WML scores are presented in Tables 3 and 4. New silent ischemic lesions were preoperatively detected in 1 of the 25 patients and were postoperatively detected in 3 (12%) patients within the territory of the treated carotid artery.
Periventricular, deep, and basal ganglia WML scores were significantly greater in the ipsilateral hemispheres. Although significant differences were observed in ADC values of anterior and posterior periventricular and occipital white matter between ipsilateral and contralateral hemispheres, no significant differences were found in ADC values of the thalami on preoperative MRI. Ipsilateral hemispheric WM ADC values were
Fig. 2. Sixty-one year old man with 80% left ICA stenosis. FLAIR images (A–D) demonstrate bilateral thick periventricular (score 2, arrows), large (score 5, thick arrowheads) and small (thin arrowheads) deep white matter lesions. Basal ganglia white matter lesion, which is found to be associated with hemispheric ADC values, is only present on the ipsilateral left hemisphere (D, paired arrow).
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Fig. 3. Sixty-one year old man with 80% left ICA stenosis (shown in Fig. 2). On preoperative diffusion-weighted ADC maps, hemispheric ADC values are higher on the ipsilateral left hemisphere than the contralateral hemisphere (A, B). Bilateral thalami reveal no ADC value change before and after carotid endarterectomy (C, F). Ipsilateral left hemispheric ADC values decrease after surgery (D, E), but remain higher than the contralateral hemisphere.
Table 4 Comparison of the WM lesion scores between ipsilateral and contralateral hemispheres.
Table 2 Baseline characteristics of patients (n = 25). Characteristics Mean age in years (SD) Male gender n (%) ICA stenosis % (SD) Coronary artery disease n (%) Hypertension n (%) Diabetes n (%) Lower extremity arterial disease n (%) Hypercholesterolemia n (%) Cerebrovascular disease n (%) Current smoker n (%) Old infarct in the ipsilateral hemisphere n (%) Chronic lacunar infarct in the ipsilateral hemisphere n (%)
68.04 (8.97) 16 (64) 80.76 (10.89) 18 (72) 18 (72) 9 (3) 2 (8) 17 (68) 4 (16) 9 (36) 9 (36) 8 (32)
associated with scores of basal ganglia WMLs. Contralateral anterior periventricular WM ADC values were associated with scores of periventricular WMLs. On postoperative MRI, ipsilateral hemispheric WM ADC values decreased but ADC values were higher than the contralateral
Table 3 Comparison of the ADC values between ipsilateral and contralateral hemispheres.
PV anterior Preoperative Postoperative PV posterior Preoperative Postoperative Thalamus Preoperative Postoperative Occipital Preoperative Postoperative
Ipsilateral hemisphere mean (SD)
Contralateral hemisphere mean (SD)
0.808 (0.061) 0.776 (0.059)
0.768 (0.063) 0.767 (0.059)
0.805 (0.039) 0.786 (0.039)
0.779 (0.040) 0.779 (0.041)
0.750 (0.038) 0.751 (0.038)
0.753 (0.038) 0.754 (0.038)
0.813 (0.040) 0.793 (0.040)
0.793 (0.034) 0.789 (0.035)
ADC values are given as 10−3 mm2 /s. ADC, apparent diffusion coefficient; PV, periventricular.
WML score Deep WM PV WM BG Infratentorial
Ipsilateral hemisphere mean (SD)
Contralateral hemisphere mean (SD)
5.72 (4.00) 3.72 (1.70) 1.40 (2.08) 0.32 (0.80)
4.52 (3.97) 3.20 (1.92) 0.64 (1.44) 0.36 (0.91)
BG, basal ganglia; PV, periventricular; WM, white matter.
hemisphere. No significant differences were observed in thalamic and contralateral hemispheric WM ADC values postoperatively. There was no association between the ADC values and vascular risk factors including chronic lacunar infarctions and old infarcts. 4. Discussion Because severe carotid stenosis has been reported to cause hemodynamic cerebral ischemia, ADC values and WMLs were considered for the detection and quantification of cerebral tissue changes associated with unilateral ICAS in this study. The findings showed that WMLs were significantly greater and ADC values were elevated in the WM of the hemisphere ipsilateral to carotid stenosis. After CEA without shunting, ADC values rapidly decreased but remained higher than within the contralateral hemisphere. Few studies have applied DWI and ADC mapping to evaluate chronic hypoperfusion induced by ICAS [11,16]. Soinne et al. [11] reported increased ADC values on the ipsilateral hemisphere in 45 patients with carotid stenosis, similar to the results of a recent study [16]. In agreement with the literature, significantly higher ADC values were found on the ipsilateral hemisphere of ICAS, most likely reflecting the effects of chronic hypoperfusion because of stenosis on the brain parenchyma. Previous investigators [11,16] proposed that the elevation of ADC values in ICAS, which is partly reversible after CEA, may be associated with vasogenic edema because the surgical removal
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of the stenosis resulted in a rapid decrease of the ADC values in the ipsilateral hemisphere. However, the ADC levels were higher than those of the contralateral hemisphere, which suggests partial reversible ischemia induced by ICAS within 2 days in the early postoperative period. After CEA, restoration of cerebral blood flow may provide further improvements in functionally but not irreversibly damaged cells at a slow rate in the course of time. On the contrary, higher postoperative ADC values of the ipsilateral hemisphere may be the initial step in the development of irreversible ischemia-induced brain damage progressing to WMLs. Because this study only involved early postoperative MR imaging, the pathophysiology of increased ADC in ICAS remains obscure. Therefore, long-term follow-up data of WMLs and ADC values and correlations are required to determine the overall effects of stenosis and CEA on the ipsilateral WM. Carotid stenosis may compromise cerebral hemodynamics. A relationship between cerebral hemodynamics and the risk of stroke in patients with CAS has been reported [1]. However, the relationship between CAS and hemodynamic factors is controversial. Soinne et al. [17] have shown decreased perfusion preoperatively and improvements in MTT values without a change in CBV after the operation. Previous studies indicated ADC elevations in the NAWM of patients with leukoaraiosis in addition to leukoaraiotic regions [4]. O’Sullivan et al. [18] have also found evidence that hypoperfusion has a role in the development of periventricular ischemic lesions. Therefore, postoperatively higher ADC values in the ipsilateral hemisphere suggest other physiologic mechanisms. These mechanisms also cause changes in brain structure that are associated with leukoaraiotic evolution which have not yet resulted in irreversible ischemia other than the short-term direct effect of reduced perfusion induced by CAS, as mentioned above. No ADC value change was detected in the contralateral hemisphere after CEA; this was in agreement with a previous study. No comparison group was used in this study, but Soinne et al. [11] noted higher ADC values in the contralateral hemispheres in comparison to control groups. The ADC values were similar in ipsilateral and contralateral thalami before and after CEA and were consistent with recent publications. The difference in the blood flow of the thalamus and WM can explain this finding. Leukoaraiosis was commonly observed among elderly patients with symptomatic CAS. More extensive lesions were associated with a worse prognosis and a higher occurrence of stroke [2]. The global WML volume was reported to be related to carotid stenosis [19] and an association between WMLs and the carotid stenosis class [20] was shown in previous studies. We also demonstrated more WMLs in the ipsilateral hemispheres, thus supporting the hypothesis of the leukoaraiogenic potential of carotid stenosis in accord with these previous studies. In contrast, no relationship was noted between WMLs and unilateral carotid stenosis by Potter et al. [8], but relatively few patients (10–11%) had an asymmetric stenosis in their study. Numerous potential causes have been suggested to contribute to the etiology of leukoaraiosis, with chronic ischemia and hypoperfusion being the main hypothesis [5]. A correlation between the increased ADC values of NAWM and the severity of WMLs in ICA patients has been reported previously [4,9]. In this study, ipsilateral basal ganglia WMLs were correlated with the degree of hemispheric WM ADC elevation, and the contralateral periventricular WMLs were correlated with the degree of anterior periventricular WM ADC values. Chronic vascular stenosis is a primarily systemic disease that affects small vessels as well as carotid arteries. The effects of the associated microvascular disease can explain these WM changes in unilateral ICAS. However, an assessment of NAWM by histogram analysis, as Ropele et al. [9] suggested, might provide different results from the operator-dependent manual ROI analysis
that was used in this study. Whether the relation of ADC and WMLs was due to structural or functional changes related to the contributions of small vessel disease, in addition to ICAS, or was a mere statistical artifact remains to be shown. In all patients, CEA was performed without shunting. Shunt usage in CEA is protective for cerebral hypoperfusion in comparison to non-shunting, but it was not preventive for emboli [21]. The incidence of new silent ischemic lesions was similar to the reported incidence of routine shunt usage in this study [22]. After revascularization with CEA, the ipsilateral ADC values decreased in a finding that was similar to a previous study [11], but the type of CEA (with or without shunt) was not determined in that study. These findings suggest that the impact of perioperative hypoperfusion induced by non-shunting is less than measurable ADC values. However, further studies that include CEA patients with and without shunting are needed to assess whether shunt usage is related to cerebral diffusion and perfusion. In several studies, the correlation between the degree of elevated ADC and the degree of cognitive decline has been suggested in patients with ICAS [13]. Additionally, some studies indicated that changes in the ADC values of NAWM in patients with leukoaraiosis were correlated to the degree of cognitive dysfunction [11,18]. Furthermore, a recent systematic review that included 11 studies found improvements in cognition in approximately 10% of patients after CEA and a decrease over time in 10–15% of patients [23]. Differences in preoperative ADC values and/or the severity of WMLs as evidence of chronic hypoperfusion may be helpful in explaining conflicting results in cognitive performance after CEA. However, a possible relationship between MRI findings and cognitive deficit has not been evaluated and is the subject of a separate study. Small elevations of ADC values in WM with aging have been observed by some investigators [9], while no change has been found in a previous study [4]. In patients with unilateral ICAS, no association was detected between the ADC values and age or the vascular risk factors analyzed in this study. The effects of aging and other vascular risk factors in ADC values might be underestimated due to the small number of the patients. Additionally, the association between age and ADC values may not be revealed because of the participants’ advanced age. There are some limitations in this study. The major shortcoming is the relatively small sample size because half of the patients with bilateral ICAS and/or a history of treatment for ICAS were excluded. Ipsilateral and contralateral hemispheres of patients with ICAS were compared to evaluate the impact of the carotid stenosis and minimize the possible factors that can attribute to WML and ADC values. However, the contralateral hemisphere, as the control group, may still have some limitations. In the present study, the ADC value was derived from DWI in three independent directions, thus showing an average diffusivity, and operator-dependent manual ROI analysis was applied. A more comprehensive diffusion analysis using orientation-independent diffusion tensor imaging may be more robust for detection of subtle alterations between two hemispheres. In contrast, the scan time for DTI is longer and the spatial resolution of DTI tends to be lower than with a trace ADC measurement. Another limitation includes visual WML scores instead of lesion volumes. Although volumes can measure WMLs with more accuracy, visual WML scores may be more specific because they are not related to problems caused by artifacts. In addition, scores and volumes have been reported to be closely related [24]. This is an observational study with a small sample size. In addition, the statistical significance of observed differences may be dependent on several factors. Therefore, these findings must be considered and interpreted with caution. However, the data with a limited sample of patients provides important feedback in unilateral ICAS and warrants further prospective studies with larger populations and
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a longer follow-up time correlated with patients without ICAS and clinical outcomes of CEA including neurocognitive tests. In conclusion, ICAS is associated with increased diffusion in normal-appearing WM. It is also significantly associated with greater WMLs in ipsilateral hemispheres than contralateral hemispheres. Ipsilateral ADC values rapidly decrease after CEA without shunting. These cerebral changes may be related to chronic lowgrade ischemic damage that is induced by ICAS. Financial disclosure The authors declared that this study has received no financial support. Ethical approval The research was approved by the Local Research Ethics Committee. Informed consent Written informed consent was obtained from patients (or their relatives) who participated in this study. Conflict of interest No conflict of interest was declared by the authors. Acknowledgements The support of technologists Sevgi Dalkilic, Ozlem Dincer, Gunisik Karacan, Neslihan Karadeniz, and Serife Yildizlar is gratefully acknowledged. References [1] Yamauchi H, Fukuyama H, Nagahama Y, Nabatame H, Nakamura K, Yamamoto Y, et al. Evidence of misery perfusion and risk for recurrent stroke in major cerebral arterial occlusive diseases from PET. J Neurol Neurosurg Psychiatry 1996;61:18–25. [2] Streifler JY, Eliasziw M, Benavente OR, Alamowitch S, Fox AJ, Hachinski V, et al. Development and progression of leukoaraiosis in patients with brain ischemia and carotid artery disease. Stroke 2003;34: 1913–6. [3] Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998;339:1415–25. [4] Helenius J, Soinne L, Salonen O, Kaste M, Tatlisumak T. Leukoaraiosis, ischemic stroke, and normal white matter on diffusion-weighted MRI. Stroke 2002;33:45–50.
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