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Cerebral microemboli and neurocognitive change after carotid artery stenting with different embolic protection devices
International Journal of Cardiology 176 (2014) 478–483
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Cerebral microemboli and neurocognitive change after carotid artery stenting with different embolic protection devices Emre Akkaya a,⁎, Ertan Vuruskan b, Zeynep Bastug Gul c, Aydın Yildirim a, Hamdi Pusuroglu a, Ozgur Surgit a, Ali Kemal Kalkan a, Ozgur Akgul a, Gamze Pinar Akgul d, Mehmet Gul a a
Department of Cardiology, Mehmet Akif Ersoy Thorasic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey Department of Cardiology, Gaziantep State Hospital, Gaziantep, Turkey Department of Neurology, Dr. Mazhar Osman Teaching and Research Hospital for Mental Health and Neurological Disorders, Istanbul, Turkey d Department of Neurology, Gaziantep State Hospital, Gaziantep, Turkey b c
a r t i c l e
i n f o
Article history: Received 26 April 2014 Accepted 28 July 2014 Available online 12 August 2014 Keywords: Cerebral microembolism Neurocognitive function Carotid artery stenting
a b s t r a c t Objectives: Proximal cerebral protection devices have been developed as an alternative to filter protection devices for reducing neurological complications during carotid artery stenting (CAS). The aim of the present study was to evaluate the frequency of silent cerebral embolism after CAS using different cerebral embolic protection devices and the impact of silent cerebral embolism on neurocognitive function. Methods: One hundred consecutive patients who underwent CAS were enrolled. The patients were randomized to either proximal balloon occlusion or filter protection. Neurocognitive tests were performed before and six months after CAS. Cerebral embolisms were evaluated with diffusion-weighted magnetic resonance imaging (DW-MRI). Results: The number and volume of new ischemic lesions found with DW-MRI were higher in the filter protection group than in the proximal balloon occlusion group. According to our definition, nine (21%) patients in the balloon occlusion group and 16 (36%) patients in the filter protection group showed neurocognitive decline, and ten (23%) patients in the balloon occlusion group and four (9%) patients in the filter protection group showed neurocognitive improvement (NS). Regarding the group of patients with new cerebral ischemic lesions on DW-MRI, neurocognitive decline occurred in 14 (31%) of 45 patients with DW-MRI lesions and 11 (26%) of 43 patients without DW-MRI lesions (NS). Conclusion: Neurocognitive outcome after CAS is unpredictable; both neurocognitive decline and improvement can occur. In this study, the proximal balloon occlusion system significantly decreased cerebral microemboli during CAS compared to filter protection. Cerebral microembolism was not found to be associated with neurocognitive decline. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction High-grade stenosis of the carotid artery, even when asymptomatic, is associated with cognitive impairment [1]. Treating carotid artery stenosis with carotid endarterectomy (CEA) can improve cognitive function [2]. Carotid artery stenting (CAS) with various protection devices has become an acceptable alternative to endarterectomy in the treatment of symptomatic stenosis or asymptomatic severe stenosis, especially in patients with high surgical risks [3–5]. However, the major drawback of this technique is that it can be complicated by cerebral embolism, which usually remains clinically silent. Periprocedural cerebral embolic events are associated with a high rate of patient morbidity
and can lead to cognitive impairment [6]. Although cerebral protection devices reduce the risk of perioperative apparent stroke during CAS [7, 8], the rate of procedure-related silent cerebral embolic events remains high, and the risk depends on the type of protection used [9]. Diffusion-weighted magnetic resonance imaging (DW-MRI) is highly sensitive and specific in the diagnosis of cerebral microemboli [10]. However, evidence suggesting that these microemboli might damage the brain is still unclear [11–14]. Neuropsychological tests are designed to diagnose brain damage or impairment. In this study, we prospectively investigated the impact of type of cerebral protection method on silent cerebral embolism and the impact of silent cerebral embolism on neurocognitive function. 2. Methods
⁎ Corresponding author at: Mehmet Akif Ersoy Thorasic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey. Tel.: + 90 2126922000; fax: + 90 2124719494. E-mail address: [email protected] (E. Akkaya).
http://dx.doi.org/10.1016/j.ijcard.2014.07.241 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
We prospectively enrolled 100 consecutive patients who underwent CAS in two different institutions. Internal carotid artery stenosis was diagnosed using carotid duplex ultrasonography with the following Doppler criteria: peak systolic velocity
E. Akkaya et al. / International Journal of Cardiology 176 (2014) 478–483 (PSV) N125 cm/s; internal carotid artery (ICA) to common carotid artery (CCA) PSV ratio N2; and stenosis diameter N50%. The patients were randomized to either the proximal balloon occlusion or filter protection system group, with equal numbers allocated to each cerebral protection method (Fig. 1). CAS was performed by two experienced interventional cardiologists. The study protocol was approved by the local ethics committee, and written informed consent was obtained from all of the patients. 2.1. Inclusion and exclusion criteria Inclusion criteria were ICA stenosis N80% in asymptomatic patients and N60% in symptomatic patients. The degree of stenosis diameter was calculated according to the European Carotid Surgery Trial method [15]. Exclusion criteria included 1) stroke within one month prior to the procedure; 2) previous major stroke; 3) total occlusion of the ICA or external carotid artery (ECA); 4) “string sign” stenosis of the ICA; 5) stenosis of the contralateral ICA N50%; 6) contraindications for antiplatelet agents; 7) severely tortuous and calcified aortic arch vessels; 8) contraindication for MRI; 9) inability to read; 10) previous atrial fibrillation; and 11) Mini-Mental State Examination (MMSE) score b24 points. 2.2. CAS procedure Clopidogrel (75 mg/day) and aspirin (100 mg/day) were administered for at least seven days before CAS. During the procedure, intravenous heparin (100 IU/kg of body weight) was administered to maintain an activated clotting time of 250–300 s. CAS was performed using a proximal balloon occlusion system (Mo.Ma; Invatec, Roncadelle, Italy) or filter-type distal protection device (Emboshield NAV6; Abbott, Santa Clara, CA). After the embolic protection device was inserted, lesions were treated with a hybrid design carotid stent. All stents were dilated with 5.0- or 5.5-mm balloons. All of the patients were prescribed aspirin (100 mg daily) for life and clopidogrel (75 mg daily) for three months after the procedure. 2.3. Cranial MRIx Prior to the CAS procedure, all of the patients underwent cranial MRI scans performed with a 1.5 Tesla scanner with the following parameters: T1-weighted sequence (repetition time [TR] 535 ms; echo time [TE] 10 ms; 16 slices; slice thickness 5 mm; field of view [FOV] 230 mm); T2-weighted sequence (TR/TE: 3000/60 ms; 16 slices; slice thickness 5 mm); FLAIR sequence (TR/TE: 5400/100 ms; 16 slices; slice thickness 5 mm; matrix size 256 × 256; reduced acquisition 90%); and DWI (RT/RE: 8000/100 ms; 16 slices; slice thickness 5 mm; gap 1 mm; FOV 230 mm; matrix size 128 × 128; reduced acquisition
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75%). DWI scans were acquired with three different b values: 0, 500, and 1000 s/mm2. After the CAS procedure, 93 patients underwent DW-MRI. The number and volume of new ischemic lesions were evaluated with DWI. Acute ischemic lesion was diagnosed by DWI when increased signal intensity was seen on either axial or coronal DWI images and confirmed on the apparent diffusion coefficient. Two radiologists analyzed each DWI lesion separately by measuring its volume. Quantification of cerebral infarct lesion volume was performed using image analysis software (FuncTool; GE Medical Systems, Milwaukee, WI).
2.4. Neuropsychological assessment The cognitive battery included eight neuropsychological tests to assess cognitive skill. Global cognitive functioning was assessed with the MMSE to exclude pre-existing cognitive impairment. The following tests were also administered: Rey Auditory Verbal Learning Test, forward and backward digit span tests, Trail Making Test (TMT) A and B, verbal fluency test (animals category), Stroop Color and Word Test, and Rey Complex Figure Test (Table 1). The neuropsychological tests were administered the day before the CAS procedure and six months after the procedure. The test results were analyzed using the reliable change index (RCI), which was first described by Jacobson and Traux [16] and designed to determine whether or not the change in a patient's score on a test of cognitive function is statistically significant. In the current study, RCI was computed using a modification suggested by Hageman and Arrindell [17], calculated as RCI = (Xpost − Xpre) rdd + (Mpost − Mpre) (1 − rdd)/(rdd)1/2 (2S2E)1/2 where Xpre = pretreatment score, Xpost = post-treatment score, Mpre = mean of sample at pretreatment, M post = mean of sample at post-treatment, r d d = reliability of difference scores, and S E = standard pffiffiffiffiffiffiffiffiffiffi error of the estimate. The standard error of the mean was computed as SE ¼ S 1−r , where S = standard deviation at pretreatment and r = internal consistency reliability coefficient. The patients were then separated into three groups based on their RCI scores: reliable decline (RCI b − 1.96), no reliable change (RCI between − 1.96 and + 1.96), and reliable improvement (RCI b +1.96). Neurocognitive decline or improvement were defined as RCI score b−1.96 or N+1.96, respectively, on two or more tests assessing different cognitive domains [18].
2.5. Statistical analysis Statistical analyses were performed using SPSS, version 20.0 (SPSS, Chicago, IL). The normality of distribution of the neuropsychological tests was examined using the Kolmogorov–Smirnov test. Group comparisons were made using the independent samples T test and chi-square test. Two-sided P values b0.05 were considered significant.
Fig. 1. Flow chart of patient enrollment.
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Table 1 Description of neuropsychological tests. Test
Description
Task
Rey Auditory Verbal Learning Test
The patients were read a list of 15 words five times and were asked to recall them (list A). After five repetitions of free recall, the examiner read a second list (list B) of 15 new words and the patients were asked to recall the words from list B. After a 20-min delay, the patients were asked to recall the words from list A again. The maximum number of items correctly recalled was taken as the score. In the forward test, the patients were asked to repeat the same order of a series of three digits. If the patient was successful in recalling all three digits, the length of the digit series was increased until the patient could no longer repeat them accurately. In the backward digit span test, the patients were asked to reverse the order of the numbers. The number of digits in the longest string recalled correctly was taken as the score The test consisted of two parts. In part A, the patients were asked to draw lines to connect 25 encircled numbers in ascending order (1, 2, 3, etc.). In part B, the patients were asked to connect numbers and letters in ascending order (e.g., 1, A, 2, B, 3, C, etc.). The score was the amount of time required to complete the task. The patients were asked to generate a list of items from a predefined category (animals) within 60 s. The number of correct answers was taken as the score. The test consisted of three parts. The patients were asked to read words (names of colors printed in black ink), name colors (words printed in colors), and name the ink color of the words (words and ink colors mismatched) in three subsequent time periods. The number of items completed on each of the three parts was taken as the score. The patients were asked to copy a line drawing. The model was then removed from sight, and after 30 min, the patients were asked to reproduce the figure from memory. The figure was partitioned into 18 scorable parts and awarded 0, 0.5, 1, and 2 points for each of the figure's parts. The total number of points was taken as the score.
Verbal learning, short- and long-term memory
Digit Span Test
Trail Making Test
Verbal fluency test Stroop Color and Word Test
Rey Complex Figure Test
3. Results Demographic, clinical, and lesion characteristics of the patients were not different between the two groups (Table 2). CAS was performed in all of the patients. In-hospital outcomes were not significantly different in terms of death and stroke: one stroke and one transient ischemic attack occurred in the balloon occlusion group, and two strokes and one death occurred in the filter protection group. 3.1. DW-MRI results MRIs were performed three days after the CAS procedure; 48 patients in the proximal balloon occlusion group and 46 patients in the filter protection group underwent MRI. Cerebral microemboli were detected in 19 (39%) patients in the balloon occlusion group and 30 (65%) patients in the filter protection group (p = 0.011) (Fig. 2). The median number of new ischemic lesions on DW-MRI was higher in the filter protection group than in the balloon occlusion group (median [range]: 2 [1–5] vs. 5 [1–11]; p = 0.018) (Fig. 3A). Two patients in the balloon occlusion group and three patients in the filter protection group developed microemboli in the contralateral hemisphere (p = 0.652). The volumes of the new ischemic lesions were also higher in the filter protection group (mean ± SD: 0.51 ± 0.33 cm3 vs. 0.82 ± 0.44 cm3; p = 0.01) (Fig. 3B). 3.2. Neurocognitive changes There were no differences in test scores between the groups before the procedure. Neuropsychological tests were performed on 44 patients in the proximal balloon occlusion group and 45 patients in the distal protection group at six months. The number of patients who showed reliable decline or improvement is displayed in Table 3. When comparing different tests, only TMT-B showed a significant difference (p = 0.029). According to our definition, nine (21%) patients in the balloon occlusion group and 16 (36%) patients in the filter protection group showed neurocognitive decline. Conversely, ten (23%) patients in the balloon occlusion group and four (9%) patients in the filter protection group showed neurocognitive improvement (p = 0.136) (Fig. 4A). One patient in the balloon occlusion group showed both decline and
Forward, verbal short-term memory; backward, verbal working memory
A, information processing efficiency; B, executive functioning
Short-term memory and good indicator of frontal lobe dysfunction Psychomotor speed
Visuospatial ability, memory, attention, and executive function
improvement on two or more tests. Regarding the group of patients with new cerebral ischemic lesions on DW-MRI, neurocognitive decline occurred in 14 (31%) of 45 patients with DW-MRI lesions and 11 (26%) of 43 patients without DW-MRI lesions (p = 0.065) (Fig. 4B). 4. Discussion Carotid angioplasty and stenting has been proposed as a valid therapeutic option to CEA in a select group of patients. Randomized trials have shown no difference in the incidence of ipsilateral strokes between CAS and CEA [19,20]. While cerebral protection with a filter significantly decreases cerebral embolism during CAS compared with unprotected
Table 2 Patient's characteristics.
Baseline characteristics Age, years Education, years MMSE test Male sex Symptomatic patient Hypertension Diabetes mellitus Hyperlipidemia Current smokers Ischemic heart disease Systolic heart failure
Balloon occlusion (n: 50)
Filter (n: 50)
P-value
71.2 ± 7.8 11.2 ± 2.4 27.1 ± 1.3 33 28 27 31 23 29 39 12
69.1 ± 6.8 12.1 ± 1,9 27.3 ± 1.4 24 33 24 28 18 30 42 12
0.225 0.320 0.570 0.053 0.206 0.345 0.342 0.232 0.500 0.500 0.592
86.1 ± 8
0.870 0.764
Lesion and procedural characteristics Degree of ICA stenosis 86.4 ± 8.2 Location of stenosis -Left ICA 36 -Right ICA 20 Ulceration 5 Type II/III aortic arch 11 Duration of procedure, min. 33.4 ± 9.2
27 17 2 9 31.8 ± 7.9
0.394 0.363 0.654
Values are mean ± SD or number of patients. MMSE indicates Mini-Mental State. Examination test, ICA indicates internal carotid artery. Aortic arch defined as Type II if the innominate artery orginates between the horizontal lines at the upper and lower borders of the aortic arch, and type III if the innominate artery orginates below the horizontal plane of the lower border of the aortic arch.
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Fig. 2. Brain MR imaging before (A) and three days after (B) the carotid artery stenting. DW-MRI shows an acute right-sided infarct on posterior limb of internal capsule (arrow).
CAS, the incidence of cerebral microembolism after CAS still remains high [21–23]. It has been shown that proximal balloon occlusion devices are more effective than filter protection in reducing cerebral microembolism [9]; however, its clinical significance is still unclear. The major finding of this study is that proximal balloon occlusion significantly reduces embolic load to the brain after CAS compared with filter protection, but neither cerebral protection method nor cerebral microembolism has an effect on neurocognitive alteration six months after CAS.
Distal protection filters have several disadvantages. Lesion crossing with the guidewire and the need for balloon dilation in some cases before placing the filter can cause microembolisms. Filters only capture debris larger than their pore sizes; embolic particles b200 μm in diameter can pass through filter pores [24]. There might also be a gap between the filter and the carotid wall due to inadequate apposition of the filter, allowing particles to pass around the system. In addition, retrieval of the filter may result in embolism. Different from filter protection, proximal balloon occlusion systems are inserted before any devices cross the lesion. Endovascular clamping of the ICA and ECA prevents antegrade blood flow and induces reversed flow, thus preventing particles dislodged during CAS from causing stroke, regardless of the particle size. These unique differences might partly explain the increased risk of cerebral microembolism with a filter compared with balloon occlusion. The definition of neurocognitive decline is controversial, and there is no consensus regarding the degree of change that is indicative of neurocognitive impairment. Most studies have defined neurocognitive decline as a decrease of 1 or 2 SDs in performance on one or more cognitive tests. We used the RCI to measure whether the individual change was significant or not. RCI provides an index of significant and reliable alteration in a patient's test performance, so change in test–retest performance is not affected by measurement errors. Comparisons of the test results before and after the CAS procedure revealed that only the TMT-B test results changed significantly during the followup period. The neurocognitive change analysis showed that 25 patients exhibited neurocognitive decline and 14 patients exhibited neurocognitive improvement. The literature and this study suggest that both neurocognitive decline and improvement can occur after carotid angioplasty [12,25–27]. The etiology of neurocognitive change after cardiovascular procedures is likely to be multifactorial. It has been presumed that cerebral embolism is the cause of neurocognitive dysfunction, but transcranial Doppler monitoring during cardiopulmonary bypass surgery has demonstrated no association between cerebral microembolism and postoperative cognitive dysfunction [28,29]. This study showed a similar result, in that there Table 3 Reliable change at 6 months. Test
Fig. 3. The number and volume of new ischemic lesions. A box plot of the total number (A) and volume (B) of cerebral microemboli detected with DW-MRI showing the effect of the different cerebral protection methods on the risk of silent cerebral embolism.
RAVLT Digit span test forward Digit span test backward Trail Making Test A Trail Making Test B Verbal fluency test Stroop test Rey Complex Figure Test
Filter (n: 45)
Filter (n: 45)
RD
RI
RD
RI
5 (11.4) 7 (16.3) 10 (22.7) 1 (2.3) 3 (6.8) 4 (9.1) 6 (13.6) 6 (13.6)
11 (25) 5 (11.6) 5 (11.4) 5 (11.4) 1 (2.3) 5 (11.4) 2 (4.5) 3 (6.8)
12 (26.7) 4 (8.9) 11 (24.4) 3 (6.7) 12 (26.7) 8 (17.8) 5 (11.1) 9 (20)
9 (20) 3 (6.7) 4 (8.9) 1 (2.2) 0 (0.0) 7 (15.6) 2 (4.4) 5 (11.1)
P-value
0.185 0.371 0.921 0.152 0.029 0.361 0.935 0.185
Values are number (%). RD: reliable decline, RI: reliable improvement, RAVLT: Rey Auditory Verbal Learning Test.
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decline in the absence of visible DWI lesions, suggesting that hemodynamic and metabolic factors play a role in the development of cognitive impairment. There are a number of limitations to this study. CAS was performed by different operators, which can affect the complication rates; however, all of the operators fulfilled the appropriate training criteria [39]. The patients were not screened for mood disturbance, which could affect test performance. MRIs were not performed at the time of the second cognitive status assessment, and cerebral embolization can persist over time and affect the test results. Another limitation is that the test battery used in this study might not be sensitive enough to evaluate brain damage caused by small and isolated lesions. In addition, all of the neuropsychological tests show a learning effect of repeated testing, which could affect the change in neuropsychological scores. In conclusion, it was found in this study that the proximal balloon occlusion system significantly decreased cerebral microemboli during CAS compared to filter protection. Neurocognitive outcomes after CAS are unpredictable; not all patients showing cognitive decline had new cerebral ischemic lesions, and some patients with new cerebral ischemic lesions did not develop cognitive decline, suggesting that cerebral microembolism itself may not be associated with cognitive impairment. However, alteration in neurocognitive status was seen some patients. For this reason, further studies are necessary to specify the factors responsible for neurocognitive decline or improvement.
Conflict of interest statement The authors report no relationships that could be construed as a conflict of interest. Fig. 4. Neurocognitive changes at six months follow-up. The number of patients who showed cognitive change after carotid artery stenting with different cerebral protection methods (A). Alteration in neurocognitive status isn't different between groups of patients with or without silent cerebral embolism (B). n.s = non-significant.
References
were no significant differences between the group of patients with new ischemic lesions on DWI and the group of patients without DWI lesions. This situation might be explained in part by the study conducted by Hauth et al. [30], who found that most ischemic DW lesions showed no manifestations in six-month MR followups and were clinically silent after CAS. In other words, cerebral ischemic lesions are potentially reversible and of no major neurologic sequelae. However, some studies have asserted that volume and number of microembolisms are associated with neurocognitive decline after CEA [31,32]. There is some uncertainty regarding these results. If neurocognitive impairment is caused by cerebral embolism, then it should occur more frequently, as almost all stages of cardiovascular procedures cause cerebral embolisms [28,33]. In addition, it should be expected that patients undergoing intracardiac surgery will suffer greater neurocognitive impairment than patients undergoing coronary artery bypass graft (CABG) surgery, as the former has a higher risk of embolization. However, cognitive decline is similar after openvalve surgery and after CABG surgery, and using “off-pump” surgery, which reduces microembolism, does not significantly improve cognitive outcomes [34,35]. On the other hand, it should be taken into consideration that long-term population-based studies have suggested that post-procedural brain injury, although initially silent, may trigger neurocognitive dysfunction over the long term [36,37]. However, the neuronal injury might depend on the size of the embolic particle. Although the minimum particle size that causes ischemic cerebral events has not been specified, a study showed that embolic particles 200–500 μm in diameter induced neuronal injury while particles b200 μm in diameter did not [38]. All filters have the ability to capture particles N200 μm in diameter. It might be deduced from these results that although there is an increased risk of microemboli associated with the use of filters, there might not be an increased risk of neurocognitive decline. Some patients have developed neurocognitive
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Cerebral microemboli and neurocognitive change after carotid artery stenting with different embolic protection devices Emre Akkaya a,⁎, Ertan Vuruskan b, Zeynep Bastug Gul c, Aydın Yildirim a, Hamdi Pusuroglu a, Ozgur Surgit a, Ali Kemal Kalkan a, Ozgur Akgul a, Gamze Pinar Akgul d, Mehmet Gul a a
Department of Cardiology, Mehmet Akif Ersoy Thorasic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey Department of Cardiology, Gaziantep State Hospital, Gaziantep, Turkey Department of Neurology, Dr. Mazhar Osman Teaching and Research Hospital for Mental Health and Neurological Disorders, Istanbul, Turkey d Department of Neurology, Gaziantep State Hospital, Gaziantep, Turkey b c
a r t i c l e
i n f o
Article history: Received 26 April 2014 Accepted 28 July 2014 Available online 12 August 2014 Keywords: Cerebral microembolism Neurocognitive function Carotid artery stenting
a b s t r a c t Objectives: Proximal cerebral protection devices have been developed as an alternative to filter protection devices for reducing neurological complications during carotid artery stenting (CAS). The aim of the present study was to evaluate the frequency of silent cerebral embolism after CAS using different cerebral embolic protection devices and the impact of silent cerebral embolism on neurocognitive function. Methods: One hundred consecutive patients who underwent CAS were enrolled. The patients were randomized to either proximal balloon occlusion or filter protection. Neurocognitive tests were performed before and six months after CAS. Cerebral embolisms were evaluated with diffusion-weighted magnetic resonance imaging (DW-MRI). Results: The number and volume of new ischemic lesions found with DW-MRI were higher in the filter protection group than in the proximal balloon occlusion group. According to our definition, nine (21%) patients in the balloon occlusion group and 16 (36%) patients in the filter protection group showed neurocognitive decline, and ten (23%) patients in the balloon occlusion group and four (9%) patients in the filter protection group showed neurocognitive improvement (NS). Regarding the group of patients with new cerebral ischemic lesions on DW-MRI, neurocognitive decline occurred in 14 (31%) of 45 patients with DW-MRI lesions and 11 (26%) of 43 patients without DW-MRI lesions (NS). Conclusion: Neurocognitive outcome after CAS is unpredictable; both neurocognitive decline and improvement can occur. In this study, the proximal balloon occlusion system significantly decreased cerebral microemboli during CAS compared to filter protection. Cerebral microembolism was not found to be associated with neurocognitive decline. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction High-grade stenosis of the carotid artery, even when asymptomatic, is associated with cognitive impairment [1]. Treating carotid artery stenosis with carotid endarterectomy (CEA) can improve cognitive function [2]. Carotid artery stenting (CAS) with various protection devices has become an acceptable alternative to endarterectomy in the treatment of symptomatic stenosis or asymptomatic severe stenosis, especially in patients with high surgical risks [3–5]. However, the major drawback of this technique is that it can be complicated by cerebral embolism, which usually remains clinically silent. Periprocedural cerebral embolic events are associated with a high rate of patient morbidity
and can lead to cognitive impairment [6]. Although cerebral protection devices reduce the risk of perioperative apparent stroke during CAS [7, 8], the rate of procedure-related silent cerebral embolic events remains high, and the risk depends on the type of protection used [9]. Diffusion-weighted magnetic resonance imaging (DW-MRI) is highly sensitive and specific in the diagnosis of cerebral microemboli [10]. However, evidence suggesting that these microemboli might damage the brain is still unclear [11–14]. Neuropsychological tests are designed to diagnose brain damage or impairment. In this study, we prospectively investigated the impact of type of cerebral protection method on silent cerebral embolism and the impact of silent cerebral embolism on neurocognitive function. 2. Methods
⁎ Corresponding author at: Mehmet Akif Ersoy Thorasic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey. Tel.: + 90 2126922000; fax: + 90 2124719494. E-mail address: [email protected] (E. Akkaya).
http://dx.doi.org/10.1016/j.ijcard.2014.07.241 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
We prospectively enrolled 100 consecutive patients who underwent CAS in two different institutions. Internal carotid artery stenosis was diagnosed using carotid duplex ultrasonography with the following Doppler criteria: peak systolic velocity
E. Akkaya et al. / International Journal of Cardiology 176 (2014) 478–483 (PSV) N125 cm/s; internal carotid artery (ICA) to common carotid artery (CCA) PSV ratio N2; and stenosis diameter N50%. The patients were randomized to either the proximal balloon occlusion or filter protection system group, with equal numbers allocated to each cerebral protection method (Fig. 1). CAS was performed by two experienced interventional cardiologists. The study protocol was approved by the local ethics committee, and written informed consent was obtained from all of the patients. 2.1. Inclusion and exclusion criteria Inclusion criteria were ICA stenosis N80% in asymptomatic patients and N60% in symptomatic patients. The degree of stenosis diameter was calculated according to the European Carotid Surgery Trial method [15]. Exclusion criteria included 1) stroke within one month prior to the procedure; 2) previous major stroke; 3) total occlusion of the ICA or external carotid artery (ECA); 4) “string sign” stenosis of the ICA; 5) stenosis of the contralateral ICA N50%; 6) contraindications for antiplatelet agents; 7) severely tortuous and calcified aortic arch vessels; 8) contraindication for MRI; 9) inability to read; 10) previous atrial fibrillation; and 11) Mini-Mental State Examination (MMSE) score b24 points. 2.2. CAS procedure Clopidogrel (75 mg/day) and aspirin (100 mg/day) were administered for at least seven days before CAS. During the procedure, intravenous heparin (100 IU/kg of body weight) was administered to maintain an activated clotting time of 250–300 s. CAS was performed using a proximal balloon occlusion system (Mo.Ma; Invatec, Roncadelle, Italy) or filter-type distal protection device (Emboshield NAV6; Abbott, Santa Clara, CA). After the embolic protection device was inserted, lesions were treated with a hybrid design carotid stent. All stents were dilated with 5.0- or 5.5-mm balloons. All of the patients were prescribed aspirin (100 mg daily) for life and clopidogrel (75 mg daily) for three months after the procedure. 2.3. Cranial MRIx Prior to the CAS procedure, all of the patients underwent cranial MRI scans performed with a 1.5 Tesla scanner with the following parameters: T1-weighted sequence (repetition time [TR] 535 ms; echo time [TE] 10 ms; 16 slices; slice thickness 5 mm; field of view [FOV] 230 mm); T2-weighted sequence (TR/TE: 3000/60 ms; 16 slices; slice thickness 5 mm); FLAIR sequence (TR/TE: 5400/100 ms; 16 slices; slice thickness 5 mm; matrix size 256 × 256; reduced acquisition 90%); and DWI (RT/RE: 8000/100 ms; 16 slices; slice thickness 5 mm; gap 1 mm; FOV 230 mm; matrix size 128 × 128; reduced acquisition
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75%). DWI scans were acquired with three different b values: 0, 500, and 1000 s/mm2. After the CAS procedure, 93 patients underwent DW-MRI. The number and volume of new ischemic lesions were evaluated with DWI. Acute ischemic lesion was diagnosed by DWI when increased signal intensity was seen on either axial or coronal DWI images and confirmed on the apparent diffusion coefficient. Two radiologists analyzed each DWI lesion separately by measuring its volume. Quantification of cerebral infarct lesion volume was performed using image analysis software (FuncTool; GE Medical Systems, Milwaukee, WI).
2.4. Neuropsychological assessment The cognitive battery included eight neuropsychological tests to assess cognitive skill. Global cognitive functioning was assessed with the MMSE to exclude pre-existing cognitive impairment. The following tests were also administered: Rey Auditory Verbal Learning Test, forward and backward digit span tests, Trail Making Test (TMT) A and B, verbal fluency test (animals category), Stroop Color and Word Test, and Rey Complex Figure Test (Table 1). The neuropsychological tests were administered the day before the CAS procedure and six months after the procedure. The test results were analyzed using the reliable change index (RCI), which was first described by Jacobson and Traux [16] and designed to determine whether or not the change in a patient's score on a test of cognitive function is statistically significant. In the current study, RCI was computed using a modification suggested by Hageman and Arrindell [17], calculated as RCI = (Xpost − Xpre) rdd + (Mpost − Mpre) (1 − rdd)/(rdd)1/2 (2S2E)1/2 where Xpre = pretreatment score, Xpost = post-treatment score, Mpre = mean of sample at pretreatment, M post = mean of sample at post-treatment, r d d = reliability of difference scores, and S E = standard pffiffiffiffiffiffiffiffiffiffi error of the estimate. The standard error of the mean was computed as SE ¼ S 1−r , where S = standard deviation at pretreatment and r = internal consistency reliability coefficient. The patients were then separated into three groups based on their RCI scores: reliable decline (RCI b − 1.96), no reliable change (RCI between − 1.96 and + 1.96), and reliable improvement (RCI b +1.96). Neurocognitive decline or improvement were defined as RCI score b−1.96 or N+1.96, respectively, on two or more tests assessing different cognitive domains [18].
2.5. Statistical analysis Statistical analyses were performed using SPSS, version 20.0 (SPSS, Chicago, IL). The normality of distribution of the neuropsychological tests was examined using the Kolmogorov–Smirnov test. Group comparisons were made using the independent samples T test and chi-square test. Two-sided P values b0.05 were considered significant.
Fig. 1. Flow chart of patient enrollment.
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Table 1 Description of neuropsychological tests. Test
Description
Task
Rey Auditory Verbal Learning Test
The patients were read a list of 15 words five times and were asked to recall them (list A). After five repetitions of free recall, the examiner read a second list (list B) of 15 new words and the patients were asked to recall the words from list B. After a 20-min delay, the patients were asked to recall the words from list A again. The maximum number of items correctly recalled was taken as the score. In the forward test, the patients were asked to repeat the same order of a series of three digits. If the patient was successful in recalling all three digits, the length of the digit series was increased until the patient could no longer repeat them accurately. In the backward digit span test, the patients were asked to reverse the order of the numbers. The number of digits in the longest string recalled correctly was taken as the score The test consisted of two parts. In part A, the patients were asked to draw lines to connect 25 encircled numbers in ascending order (1, 2, 3, etc.). In part B, the patients were asked to connect numbers and letters in ascending order (e.g., 1, A, 2, B, 3, C, etc.). The score was the amount of time required to complete the task. The patients were asked to generate a list of items from a predefined category (animals) within 60 s. The number of correct answers was taken as the score. The test consisted of three parts. The patients were asked to read words (names of colors printed in black ink), name colors (words printed in colors), and name the ink color of the words (words and ink colors mismatched) in three subsequent time periods. The number of items completed on each of the three parts was taken as the score. The patients were asked to copy a line drawing. The model was then removed from sight, and after 30 min, the patients were asked to reproduce the figure from memory. The figure was partitioned into 18 scorable parts and awarded 0, 0.5, 1, and 2 points for each of the figure's parts. The total number of points was taken as the score.
Verbal learning, short- and long-term memory
Digit Span Test
Trail Making Test
Verbal fluency test Stroop Color and Word Test
Rey Complex Figure Test
3. Results Demographic, clinical, and lesion characteristics of the patients were not different between the two groups (Table 2). CAS was performed in all of the patients. In-hospital outcomes were not significantly different in terms of death and stroke: one stroke and one transient ischemic attack occurred in the balloon occlusion group, and two strokes and one death occurred in the filter protection group. 3.1. DW-MRI results MRIs were performed three days after the CAS procedure; 48 patients in the proximal balloon occlusion group and 46 patients in the filter protection group underwent MRI. Cerebral microemboli were detected in 19 (39%) patients in the balloon occlusion group and 30 (65%) patients in the filter protection group (p = 0.011) (Fig. 2). The median number of new ischemic lesions on DW-MRI was higher in the filter protection group than in the balloon occlusion group (median [range]: 2 [1–5] vs. 5 [1–11]; p = 0.018) (Fig. 3A). Two patients in the balloon occlusion group and three patients in the filter protection group developed microemboli in the contralateral hemisphere (p = 0.652). The volumes of the new ischemic lesions were also higher in the filter protection group (mean ± SD: 0.51 ± 0.33 cm3 vs. 0.82 ± 0.44 cm3; p = 0.01) (Fig. 3B). 3.2. Neurocognitive changes There were no differences in test scores between the groups before the procedure. Neuropsychological tests were performed on 44 patients in the proximal balloon occlusion group and 45 patients in the distal protection group at six months. The number of patients who showed reliable decline or improvement is displayed in Table 3. When comparing different tests, only TMT-B showed a significant difference (p = 0.029). According to our definition, nine (21%) patients in the balloon occlusion group and 16 (36%) patients in the filter protection group showed neurocognitive decline. Conversely, ten (23%) patients in the balloon occlusion group and four (9%) patients in the filter protection group showed neurocognitive improvement (p = 0.136) (Fig. 4A). One patient in the balloon occlusion group showed both decline and
Forward, verbal short-term memory; backward, verbal working memory
A, information processing efficiency; B, executive functioning
Short-term memory and good indicator of frontal lobe dysfunction Psychomotor speed
Visuospatial ability, memory, attention, and executive function
improvement on two or more tests. Regarding the group of patients with new cerebral ischemic lesions on DW-MRI, neurocognitive decline occurred in 14 (31%) of 45 patients with DW-MRI lesions and 11 (26%) of 43 patients without DW-MRI lesions (p = 0.065) (Fig. 4B). 4. Discussion Carotid angioplasty and stenting has been proposed as a valid therapeutic option to CEA in a select group of patients. Randomized trials have shown no difference in the incidence of ipsilateral strokes between CAS and CEA [19,20]. While cerebral protection with a filter significantly decreases cerebral embolism during CAS compared with unprotected
Table 2 Patient's characteristics.
Baseline characteristics Age, years Education, years MMSE test Male sex Symptomatic patient Hypertension Diabetes mellitus Hyperlipidemia Current smokers Ischemic heart disease Systolic heart failure
Balloon occlusion (n: 50)
Filter (n: 50)
P-value
71.2 ± 7.8 11.2 ± 2.4 27.1 ± 1.3 33 28 27 31 23 29 39 12
69.1 ± 6.8 12.1 ± 1,9 27.3 ± 1.4 24 33 24 28 18 30 42 12
0.225 0.320 0.570 0.053 0.206 0.345 0.342 0.232 0.500 0.500 0.592
86.1 ± 8
0.870 0.764
Lesion and procedural characteristics Degree of ICA stenosis 86.4 ± 8.2 Location of stenosis -Left ICA 36 -Right ICA 20 Ulceration 5 Type II/III aortic arch 11 Duration of procedure, min. 33.4 ± 9.2
27 17 2 9 31.8 ± 7.9
0.394 0.363 0.654
Values are mean ± SD or number of patients. MMSE indicates Mini-Mental State. Examination test, ICA indicates internal carotid artery. Aortic arch defined as Type II if the innominate artery orginates between the horizontal lines at the upper and lower borders of the aortic arch, and type III if the innominate artery orginates below the horizontal plane of the lower border of the aortic arch.
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Fig. 2. Brain MR imaging before (A) and three days after (B) the carotid artery stenting. DW-MRI shows an acute right-sided infarct on posterior limb of internal capsule (arrow).
CAS, the incidence of cerebral microembolism after CAS still remains high [21–23]. It has been shown that proximal balloon occlusion devices are more effective than filter protection in reducing cerebral microembolism [9]; however, its clinical significance is still unclear. The major finding of this study is that proximal balloon occlusion significantly reduces embolic load to the brain after CAS compared with filter protection, but neither cerebral protection method nor cerebral microembolism has an effect on neurocognitive alteration six months after CAS.
Distal protection filters have several disadvantages. Lesion crossing with the guidewire and the need for balloon dilation in some cases before placing the filter can cause microembolisms. Filters only capture debris larger than their pore sizes; embolic particles b200 μm in diameter can pass through filter pores [24]. There might also be a gap between the filter and the carotid wall due to inadequate apposition of the filter, allowing particles to pass around the system. In addition, retrieval of the filter may result in embolism. Different from filter protection, proximal balloon occlusion systems are inserted before any devices cross the lesion. Endovascular clamping of the ICA and ECA prevents antegrade blood flow and induces reversed flow, thus preventing particles dislodged during CAS from causing stroke, regardless of the particle size. These unique differences might partly explain the increased risk of cerebral microembolism with a filter compared with balloon occlusion. The definition of neurocognitive decline is controversial, and there is no consensus regarding the degree of change that is indicative of neurocognitive impairment. Most studies have defined neurocognitive decline as a decrease of 1 or 2 SDs in performance on one or more cognitive tests. We used the RCI to measure whether the individual change was significant or not. RCI provides an index of significant and reliable alteration in a patient's test performance, so change in test–retest performance is not affected by measurement errors. Comparisons of the test results before and after the CAS procedure revealed that only the TMT-B test results changed significantly during the followup period. The neurocognitive change analysis showed that 25 patients exhibited neurocognitive decline and 14 patients exhibited neurocognitive improvement. The literature and this study suggest that both neurocognitive decline and improvement can occur after carotid angioplasty [12,25–27]. The etiology of neurocognitive change after cardiovascular procedures is likely to be multifactorial. It has been presumed that cerebral embolism is the cause of neurocognitive dysfunction, but transcranial Doppler monitoring during cardiopulmonary bypass surgery has demonstrated no association between cerebral microembolism and postoperative cognitive dysfunction [28,29]. This study showed a similar result, in that there Table 3 Reliable change at 6 months. Test
Fig. 3. The number and volume of new ischemic lesions. A box plot of the total number (A) and volume (B) of cerebral microemboli detected with DW-MRI showing the effect of the different cerebral protection methods on the risk of silent cerebral embolism.
RAVLT Digit span test forward Digit span test backward Trail Making Test A Trail Making Test B Verbal fluency test Stroop test Rey Complex Figure Test
Filter (n: 45)
Filter (n: 45)
RD
RI
RD
RI
5 (11.4) 7 (16.3) 10 (22.7) 1 (2.3) 3 (6.8) 4 (9.1) 6 (13.6) 6 (13.6)
11 (25) 5 (11.6) 5 (11.4) 5 (11.4) 1 (2.3) 5 (11.4) 2 (4.5) 3 (6.8)
12 (26.7) 4 (8.9) 11 (24.4) 3 (6.7) 12 (26.7) 8 (17.8) 5 (11.1) 9 (20)
9 (20) 3 (6.7) 4 (8.9) 1 (2.2) 0 (0.0) 7 (15.6) 2 (4.4) 5 (11.1)
P-value
0.185 0.371 0.921 0.152 0.029 0.361 0.935 0.185
Values are number (%). RD: reliable decline, RI: reliable improvement, RAVLT: Rey Auditory Verbal Learning Test.
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decline in the absence of visible DWI lesions, suggesting that hemodynamic and metabolic factors play a role in the development of cognitive impairment. There are a number of limitations to this study. CAS was performed by different operators, which can affect the complication rates; however, all of the operators fulfilled the appropriate training criteria [39]. The patients were not screened for mood disturbance, which could affect test performance. MRIs were not performed at the time of the second cognitive status assessment, and cerebral embolization can persist over time and affect the test results. Another limitation is that the test battery used in this study might not be sensitive enough to evaluate brain damage caused by small and isolated lesions. In addition, all of the neuropsychological tests show a learning effect of repeated testing, which could affect the change in neuropsychological scores. In conclusion, it was found in this study that the proximal balloon occlusion system significantly decreased cerebral microemboli during CAS compared to filter protection. Neurocognitive outcomes after CAS are unpredictable; not all patients showing cognitive decline had new cerebral ischemic lesions, and some patients with new cerebral ischemic lesions did not develop cognitive decline, suggesting that cerebral microembolism itself may not be associated with cognitive impairment. However, alteration in neurocognitive status was seen some patients. For this reason, further studies are necessary to specify the factors responsible for neurocognitive decline or improvement.
Conflict of interest statement The authors report no relationships that could be construed as a conflict of interest. Fig. 4. Neurocognitive changes at six months follow-up. The number of patients who showed cognitive change after carotid artery stenting with different cerebral protection methods (A). Alteration in neurocognitive status isn't different between groups of patients with or without silent cerebral embolism (B). n.s = non-significant.
References
were no significant differences between the group of patients with new ischemic lesions on DWI and the group of patients without DWI lesions. This situation might be explained in part by the study conducted by Hauth et al. [30], who found that most ischemic DW lesions showed no manifestations in six-month MR followups and were clinically silent after CAS. In other words, cerebral ischemic lesions are potentially reversible and of no major neurologic sequelae. However, some studies have asserted that volume and number of microembolisms are associated with neurocognitive decline after CEA [31,32]. There is some uncertainty regarding these results. If neurocognitive impairment is caused by cerebral embolism, then it should occur more frequently, as almost all stages of cardiovascular procedures cause cerebral embolisms [28,33]. In addition, it should be expected that patients undergoing intracardiac surgery will suffer greater neurocognitive impairment than patients undergoing coronary artery bypass graft (CABG) surgery, as the former has a higher risk of embolization. However, cognitive decline is similar after openvalve surgery and after CABG surgery, and using “off-pump” surgery, which reduces microembolism, does not significantly improve cognitive outcomes [34,35]. On the other hand, it should be taken into consideration that long-term population-based studies have suggested that post-procedural brain injury, although initially silent, may trigger neurocognitive dysfunction over the long term [36,37]. However, the neuronal injury might depend on the size of the embolic particle. Although the minimum particle size that causes ischemic cerebral events has not been specified, a study showed that embolic particles 200–500 μm in diameter induced neuronal injury while particles b200 μm in diameter did not [38]. All filters have the ability to capture particles N200 μm in diameter. It might be deduced from these results that although there is an increased risk of microemboli associated with the use of filters, there might not be an increased risk of neurocognitive decline. Some patients have developed neurocognitive
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