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Cerebral hemodynamic benefits after carotid artery stenting in patients with near occlusion
Cerebral hemodynamic benefits after carotid artery stenting in patients with near occlusion Fumiaki Oka, MD, PhD,a Hideyuki Ishihara, MD, PhD,a Shoichi Kato, MD, PhD,a Takayuki Oku, MD, PhD,a Akiko Yamane, MD,a Ichiro Kunitugu, MD, PhD,b and Michiyasu Suzuki, MD, PhD,a Yamaguchi, Japan Objective: The natural history and management of patients with near occlusion (NO) of the internal carotid artery are controversial. In particular, it is unclear whether cerebral hemodynamics are compromised in these patients and whether improvement by carotid revascularization leads to the prevention of ischemic stroke. In this study, we measured cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) using single-photon emission computed tomography before and after carotid artery stenting (CAS) for NO to examine the effectiveness of CAS from the perspective of cerebral hemodynamics. Methods: CAS was performed in 15 patients with NO and in 78 with severe stenosis ($70%) but without NO at our institution. Resting CBF and CVR to acetazolamide were measured using N-isopropyl-p-[I-123] iodoamphetamine single-photon emission computed tomography before and at 3 to 6 months after CAS. We also measured CBF using the same method for healthy individuals and compared the results among the three groups. Results: CAS was successfully performed in all patients. Before CAS, the mean resting CBF was 26.68 6 4.23 mL/100 g/min, and the mean CVR was L0.8% 6 15.1% in the patients with NO, both of which were significantly lower than in patients with severe stenosis without NO and in healthy individuals. After CAS, the mean resting CBF and mean CVR in patients with NO increased significantly to 30.07 6 5.67 mL/100 g/min and 37.0% 6 21.4%, respectively, and there were no significant differences among the three groups. Conclusions: Before CAS, patients with NO were more hemodynamically compromised than those with severe stenosis without NO. After CAS, significant cerebral hemodynamic improvement and normalization occurred long-term. Thus, from a hemodynamic perspective, CAS was effective in patients with NO. (J Vasc Surg 2013;-:1-6.)
Near occlusion (NO) of the cervical internal carotid artery (ICA) was first described as a poststenotic carotid slim sign by Lippman et al.1 NO of the ICA is now defined as the presence in the ICA of an atheromatous plaque causing severe stenosis, a drop in perfusion pressure distal to the stenosis, and diminished or absent perfusion of the ipsilateral intracranial carotid flow.2 The natural history and management of patients with NO are controversial. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) found that NO or poststenotic narrowing of the ICA is associated with a low risk of stroke with medical treatment and that carotid endarterectomy (CEA) was less beneficial than for severe stenosis without NO or poststenotic narrowing of the ICA.3-5 Distal embolism and decreased cerebral perfusion are important mechanisms of stroke in patients with carotid artery stenosis. However, the significant reduction of blood
From the Departments of Neurosurgerya and Public Health,b Yamaguchi University School of Medicine. Author conflict of interest: none. Reprint requests: Fumiaki Oka, MD, PhD, Department of Neurosurgery, Yamaguchi University School of Medicine, 1-1-1, Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214/$36.00 Copyright Ó 2013 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvs.2013.05.103
flow across the stenosis in patients with NO reduces the risk of brain embolization and may be a major reason the incidence of ischemic stroke for medically treated patients with NO is lower than that in patients with severe stenosis without NO.2,4 On the other hand, cerebral hemodynamics might be more compromised in patients with NO, and carotid revascularization may improve cerebral hemodynamics and, consequently, prevent ischemic stroke. The cerebral hemodynamic consequences of NO have not been examined, however. Carotid artery stenting (CAS) has recently become recognized as a therapeutic alternative for patients with ICA stenosis, and the safety and efficacy of CAS for patients with NO have also been described.2,6-8 In this study, we used single-photon emission computed tomography (SPECT) to investigate the hemodynamic effects of CAS in patients with NO. METHODS The Yamaguchi University Ethics Committee approved the CAS procedure and the study. All patients gave informed consent to treatment and participation in the study. Patients. The participants were 15 consecutive patients (14 men) with NO who underwent CAS at our hospital between July 2006 and June 2012. Patients were a mean age of 70.6 years (range, 60-77 years). Ten patients were symptomatic, with minor stokes or transient ischemic attacks, and five were asymptomatic. Two patients had contralateral ICA stenosis of $70%. 1
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In the same period, we performed CAS and examined cerebral hemodynamics in 78 patients (68 men) with severe stenosis ($70%) but without NO of the ICA, and their data were used for comparison with patients with NO of the ICA. The patients without NO were a mean age of 71.0 years (range, 47-83 years), 40 were symptomatic with minor stokes or transient ischemic attacks, 17 had contralateral ICA stenosis of $70%, and seven had contralateral ICA occlusion. Before CAS, all patients underwent four-vessel angiography for confirmation of NO of the ICA. The criteria for identification of NO were (1) delayed cranial arrival of ICA contrast compared with the external carotid artery (ECA); (2) intracranial collaterals seen as cross-filling of contralateral vessels or ipsilateral contrast dilution; (3) obvious diameter reduction (>50%) of the ICA compared with the opposite ICA; or (4) ICA diameter reduction compared with the ipsilateral ECA, as defined by Fox et al, with some modification. As noted by Fox et al,9 NO was considered to be present when two or more of these criteria were recognized. The 15 patients classified with NO in this study met three or more of the criteria. Of the 78 patients classified without NO, 45 met one criterion and all had visible collaterals (criterion 2). During angiography, collateral flow was evaluated from the anterior communicating artery, posterior communicating artery, ECA, and leptomeningeal arteries. In the patients without NO, the degree of stenosis was determined using the NASCET criteria, and the mean degree of stenosis was 85.0% 6 6.5% (range, 70%-95%).10 Within 2 weeks before the procedure, all patients were assessed with duplex and color flow Doppler ultrasound imaging, brain computed tomography (CT), and magnetic resonance (MR) imaging, including MR angiography and SPECT. All patients received two of three antiplatelet drugs before treatment (100 mg aspirin, 75 mg clopidogrel, 200 mg cilostazol). CAS was performed by two operators at our hospital, with the patient under local anesthesia. A distal protection device was used in all cases. Brain CT was performed in all patients immediately after CAS. To confirm vessel patency and detect possible restenosis, duplex ultrasound imaging was performed 1 week after the procedure, at 3, 6, and 12 months for the first year, and then annually. SPECT was performed 3 to 6 months after the procedure. Using the same methods, we performed SPECT in 13 healthy individuals (five men and eight women) to obtain control values for resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). These individuals were a mean age of 61.2 years (range, 47-78 years), and none had stenosis or occlusion of cervical or intracranial arteries. Informed consent was obtained from each participant. CBF measurement and image analysis. CBF was evaluated using SPECT, which was performed twice #2 weeks before and 3 to 6 months after CAS for patients with NO and for those with severe stenosis but without NO of the ICA. Resting CBF and CVR were measured in one session using the dual-table autoradiographic
(DTARG) method and dual administration of N-isopropyl-p-[I-123] iodoamphetamine(123I-IMP), as described in detail elsewhere.11,12 For SPECT with drug challenge, acetazolamide (17 mg/kg, 1000-mg maximum) was administered intravenously. Whole-blood radioactivity was measured with a well counter calibrated to the SPECT apparatus. For the first and second scans, all frames were summed and images were reconstructed as described below. SPECT was performed with a three-headed gamma-camera (GCA-9300A/PI; Toshiba Medical Systems, Tokyo, Japan) and a low-energy, high-resolution fan beam collimator. GMS-550A/PI (Toshiba Medical Systems) was used to convert fan beam data to parallel data. The tomography images were reconstructed and CBF quantification was performed using the QSPECT image reconstruction package developed by Kim et al11 and Iida et al.13 After image reconstruction, image processing was achieved with the program based on stereotactic extraction estimation from the Japanese EC-IC bypass trial, with three-dimensional stereotactic surface projection.14 This program automatically measures CBF values at rest and after acetazolamide challenge for the territories of the anterior cerebral artery, middle cerebral artery (MCA), and posterior cerebral artery, and can also calculate the CVR, as follows: [CVR ¼ 100 (acetazolamide CBF e resting CBF)/resting CBF]. In patients who received CAS, data from the MCA territory on the ipsilateral side to CAS were used in the analysis. Normal control values of resting CBF (32.23 6 2.36 mL/100 g/min) and CVR (42.3% 6 16.0%) in the territory of the MCA in our hospital were obtained in 13 healthy individuals. There was no significant difference in age and sex between the controls and the patient groups. The reproducibility and accuracy of quantitative CBF measurements using the QSPECT/DTARG method have been reported.11,13,15 Statistical analysis. Descriptive data are presented as means 6 standard deviation. A paired t-test was used to compare paired data from preoperative and postoperative SPECT. An analysis of variance, followed by the post hoc Bonferroni test, was used to compare SPECT data between patients with NO, those with severe stenosis without NO, and the healthy controls. The Fisher test was used to compare clinical characteristics and postoperative outcome between patients with NO and those with severe stenosis without NO. Differences were deemed significant if the probability value was <.05. All calculations were performed using StatView 5.0 software (SAS Institute, Cary, NC). RESULTS CAS was successfully performed in all patients. One patients with NO developed transient motor aphasia due to ischemic stroke 1 day after the procedure, which was confirmed by diffusion-weighed MRI; however, this disappeared in a few days, and he was discharged with no neurologic deficit. In another patient, CT immediately after CAS detected an asymptomatic slight subarachnoid hemorrhage. The cause was thought to be hyperperfusion, and
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Table I. Summary of patient characteristics
Characteristica
NO (n ¼ 15)
Severe stenosis without NO (n ¼ 78)
and CVR were significantly lower in both groups than in healthy controls, and those differences disappeared after the procedure (Fig 1). P
Age, years 70.6 (60-77) 71.9 (47-83) .47 Male-to-female ratio 14:1 68:10 .69 Degree of stenosis, % e 85.0 6 6.5 Symptomatic lesion 10 (66.7) 40 (51.3) .40 Contralateral stenosis ($70%) 2 (13.3) 17 (30.8) .73 Contralateral occlusion 0 (0) 7 (8.9) .59 Outcome #30 days after CAS Ischemic stroke 1 (6.6) 1 (1.2) .30 0 (0) .16 Intracranial hemorrhage 1b (6.6) >30 days after CAS Ipsilateral ischemic stroke 0 (0) 0 (0) >.99 Restenosis (>50%) 0 (0) 4 (5.1) >.99 CAS, Carotid artery stenting; NO, near occlusion. a Continuous data are shown as mean (range) or mean 6 standard deviation and categoric data as number (%). b Subarachnoid hemorrhage.
strict control of blood pressure eliminated the hemorrhage. No other complication occurred in the 30-day period after the procedure. Clinical follow-up was performed for all patients, and no cerebral ischemic attacks occurred on the side ipsilateral to CAS during a mean follow-up of 40 months. No patient showed restenosis >50%. Among the patients without NO, one developed minor ischemic stroke, but no intracranial hemorrhage was observed. No other complication occurred in the 30-day period after the procedure. Clinical follow-up was performed for all patients, and the mean follow-up period was 38 months. No patient experienced ischemic stroke ipsilateral to CAS. Asymptomatic restenosis of >50% occurred in four patients and was >70% in one of these patients. This patient was successfully treated with percutaneous transluminal angioplasty. The basic characteristics and postoperative outcome for the 15 patients with NO and 78 patients with severe stenosis without NO are reported in Table I. Before CAS, the mean resting CBF on the ipsilateral side of the MCA area was 26.68 6 4.23 mL/100 g/min, and the mean CVR was 0.8% 6 15.1% in the 15 patients with NO. In 12 these patients (80%) the CVR was <10%, and eight (53%) had decreased CBF after the Diamox challenge; a so-called steal phenomenon (Table II). In patients without NO, mean resting CBF and mean CVR were 29.51 6 4.89 mL/100 g/min and 19.3% 6 20.0%, respectively, and results were significantly lower in patients with NO than in those with severe stenosis without NO of the ICA (Fig 1). After CAS, the mean resting CBF and mean CVR were both significantly increased to 30.07 6 5.67 mL/100 g/min and 37.0% 6 21.4%, respectively, in the patients with NO (Table II). In patients without NO, CVR increased significantly after CAS, and the mean resting CBF showed a tendency for an increase, but this was not significant (Fig 2). There were no significant differences between the two groups (Fig 1). Before CAS, mean resting CBF
DISCUSSION In this study, we investigated cerebral hemodynamics quantitatively using SPECT before and after CAS in patients with NO of the ICA. We also measured CBF in patients with severe stenosis but without NO of the ICA and in healthy controls. The results showed that cerebral hemodynamics were further compromised before CAS in patients with NO. However, resting CBF and CVR both increased chronically after CAS, and significant differences among the three groups disappeared. In patients with NO, reduction of blood flow across the stenosis may reduce the risk of brain embolization. Using transcranial Doppler scanning, Molloy and Markus16 found a significant reduction of microemboli when the degree of stenosis >90%, and this might be particularly in patients with poststenotic narrowing.4 This may be a major reason the incidence of ischemic stroke for medically treated patients with NO is lower than that in patients with severe stenosis without NO.3,5,9 In contrast, cerebral perfusion might decrease more in patients with NO. Previous studies have examined cerebral hemodynamics of patients with NO, but a quantitative analysis has not been performed. Using transcranial Doppler ultrasound imaging, Gonzalez et al2 found that one-third of 116 patients with NO of the ICA had exhausted or diminished vasoreactivity in response to apnea. In brain perfusion analysis by MR or SPECT in 27 of 48 patients with NO, Choi et al6 found perfusion deficits were severe in 17 and moderate in 10, and no patients had normal perfusion. In SPECT in 12 of 20 patients with NO, Terada et al7 found that six showed reduction of CBF and poor reactivity to a Diamox challenge test. However, these three studies did not include a quantitative analysis or a comparison with patients without NO, making it difficult to understand if NO patients are hemodynamically compromised. In this study, we quantified CBF using SPECT and compared the results for patients with NO and those with severe stenosis without NO. Resting CBF and CVR were both significantly lower in the patients with NO, consistent with our hypothesis of compromised hemodynamics in these patients. After CAS, resting CBF and CVR were significantly improved in patients with NO, and these values became similar to those for patients with severe stenosis without NO and for those in the healthy controls. Improvement of CBF and CVR after CEA has been shown in many reports,17-21 and thus, CEA is also expected to improve cerebral hemodynamics in patients with NO. The effect of improved cerebral hemodynamics after revascularization on prevention of ischemic stroke is uncertain, but decreased resting CBF and CVR measured by SPECT have been reported as risk factors for future ischemic stroke.22,23
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Table II. Hemodynamic changes in the ipsilateral middle cerebral artery (MCA) area before and at 3 to 6 months after carotid artery stenting (CAS) in patients with near occlusion (NO) Resting CBF, mL/100 g/min Patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
CVR, %
Before CAS
After CAS (3-6 months)
Before CAS
After CAS (3-6 months)
29.02 30.99 16.95 27.83 20.59 31.99 30.36 26.57 28.98 26.11 26 29.85 22.04 30.5 22.47
42.06 27.43 21.68 25.64 32.75 34.23 36.16 27.5 28.97 27.61 36.3 30.96 21.97 34.29 23.53
8.9 21.2 0.3 20.5 3.3 0.1 7.2 19.5 9.5 6.8 9 27.1 14.6 28.9 5.8
40.3 62.7 82.2 44.4 17.8 40.5 16.3 21.5 20.7 10.5 40.1 26.7 73.9 13.4 44.1
Mean 6 SD
Mean 6 SD
Mean 6 SD
Mean 6 SD
26.68 6 4.23
30.07 6 5.67a
0.8 6 15.1
37.0 6 21.4b
CBF, Cerebral blood flow; CVR, cerebrovascular reactivity; SD, standard deviation. a P < .05 vs preoperative investigation. b P < .01 vs preoperative investigation.
Fig 1. Comparison of mean (left) resting cerebral blood flow (CBF) and (right) mean cerebrovascular reactivity (CVR) before and after carotid artery stenting (CAS) in patients with near occlusion (NO), in those with stenosis without NO, and in healthy controls. The error bars indicate the standard deviation. *P < .05; **P < .01.
In a repeat review of data from the NASCET and ECST, Fox et al9 found a 3-year risk of ipsilateral stroke of 15.1% for medically treated patients with NO. In our patients, no cerebral ischemic attacks occurred on the side ipsilateral to CAS during a mean follow-up of 40 months beginning after the 30-day postprocedural period. In a study of 116 patients with NO of the ICA, Gonzalez et al2 found that only one patient (0.8%) experienced a stroke on the side ipsilateral to CAS during a median follow-up of 36 months, and Terada et al7 also
showed that CAS in patients with NO of the ICA has a long-term effect on prevention of stroke. Data from the ESCT on long-term outcomes of CEA for patients with NO showed no benefit in surgically treated patients with NO, but NASCET and many other studies have reported a benefit of CEA for preventing ischemic stroke.3,5,9,24-29 In a study of 53 patients with NO, Greiner et al26 reported that 95% of patients who underwent successful CEA had good patency of the treated artery, without any new neurologic deficits for 4 years.
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Fig 2. Changes in mean resting (left) cerebral blood flow (CBF) and (right) cerebrovascular reactivity (CVR) before and after carotid artery stenting (CAS) in patients with near occlusion (NO) and in those with stenosis without NO. The error bars indicate standard deviation. *P < .05; **P < .01.
Recently, Radak et al29 reported the efficacy of eversion carotid endarterectomy over medical treatment for patients with NO. On the basis of these results, the benefit of carotid revascularization for patients with NO is still uncertain; however, revascularization seems to be effective for prevention of ischemic stroke in patients with NO of the ICA, and improvement of cerebral hemodynamics seems to play an important role. However, a direct comparison is required to determine the superiority of CEA or CAS for patients with NO. In our series, minor ischemic stroke developed in one patient 1 day after the procedure. Distal embolism is a major complication of CAS, but a low incidence of embolic complications during CAS for patients with NO has been reported. In the largest series of NO patients treated with CAS, Gonzalez et al2 found that the risk of ischemic complication was only 3.4% and that all symptoms were transient. In two other series, there was no distal embolism during the procedure.6,7 Protection devices are effective for preventing distal embolism,7 and we used a distal protection device in all cases, with the result of no distal embolism during the procedure. However, patients with NO may have more plaque, and use of postprocedural intravenous anticoagulants should also be considered.2 A second patient in our series developed an asymptomatic subarachnoid hemorrhage associated with hyperperfusion after the procedure. The risk of hyperperfusion after carotid revascularization is high in patients with severe hemodynamic compromise.30,31 Choi et al6 found an incidence of hyperperfusion of up to 10% and one death from hyperperfusion-related intracerebral hemorrhage after CAS in patients with NO of the ICA.6 In contrast, Gonzalez et al2 and Terada et al7 found no hyperperfusion in 116 and 20 patients with NO, respectively. The reason for this discrepancy is uncertain, but the possible occurrence of hyperperfusion should be recognized. To prevent this syndrome, strict control of blood
pressure during the postoperative period has been emphasized in many reports.32-34 To improve the effectiveness of carotid revascularization for patients with NO, appropriate patient selection seems to be required. Some patients in our series had relatively well-maintained cerebral hemodynamics. In patients with NO, revascularization may have a low benefit in patients with maintained CBF, who seem to be at a low risk of stroke with medical treatment. Although the cutoff value is uncertain and further research is required, assessment of the cerebral hemodynamic status is likely to be useful to establish the indication for revascularization in patients with NO. This study has some limitations that require discussion. First, the small number of patients requires further studies to confirm the effectiveness of carotid revascularization for improving cerebral hemodynamics and preventing ischemic stroke in patients with NO. Second, we used SPECT, whereas the most reliable method for hemodynamic assessment is positron-emission tomography (PET). However, PET facilities are limited by cost and technical complexity, and decreased resting CBF and CVR to acetazolamide are related to the increased oxygen extraction fraction assessed by PET, indicating that this approach could be useful for screening of patients with misery perfusion.35 The reproducibility and the accuracy of quantitative CBF measurement using the QSPECT/DTARG method that we used in this study have been reported.11,13,15 CONCLUSIONS This is the first quantitative study of hemodynamic changes after CAS in patients with NO. Before CAS, patients with NO were more hemodynamically compromised than those with severe stenosis without NO. After CAS, significant cerebral hemodynamic improvements and normalization were seen long-term. Further studies are needed to see if these improvements are effective for preventing ischemic stroke.
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AUTHOR CONTRIBUTIONS Conception and design: FO Analysis and interpretation: FO Data collection: HI, SK, AY Writing the article: FO Critical revision of the article: FO, HI Final approval of the article: MS Statistical analysis: TO, IK Obtained funding: Not applicable Overall responsibility: FO
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Submitted Apr 1, 2013; accepted May 21, 2013.
Near occlusion (NO) of the cervical internal carotid artery (ICA) was first described as a poststenotic carotid slim sign by Lippman et al.1 NO of the ICA is now defined as the presence in the ICA of an atheromatous plaque causing severe stenosis, a drop in perfusion pressure distal to the stenosis, and diminished or absent perfusion of the ipsilateral intracranial carotid flow.2 The natural history and management of patients with NO are controversial. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) found that NO or poststenotic narrowing of the ICA is associated with a low risk of stroke with medical treatment and that carotid endarterectomy (CEA) was less beneficial than for severe stenosis without NO or poststenotic narrowing of the ICA.3-5 Distal embolism and decreased cerebral perfusion are important mechanisms of stroke in patients with carotid artery stenosis. However, the significant reduction of blood
From the Departments of Neurosurgerya and Public Health,b Yamaguchi University School of Medicine. Author conflict of interest: none. Reprint requests: Fumiaki Oka, MD, PhD, Department of Neurosurgery, Yamaguchi University School of Medicine, 1-1-1, Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214/$36.00 Copyright Ó 2013 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvs.2013.05.103
flow across the stenosis in patients with NO reduces the risk of brain embolization and may be a major reason the incidence of ischemic stroke for medically treated patients with NO is lower than that in patients with severe stenosis without NO.2,4 On the other hand, cerebral hemodynamics might be more compromised in patients with NO, and carotid revascularization may improve cerebral hemodynamics and, consequently, prevent ischemic stroke. The cerebral hemodynamic consequences of NO have not been examined, however. Carotid artery stenting (CAS) has recently become recognized as a therapeutic alternative for patients with ICA stenosis, and the safety and efficacy of CAS for patients with NO have also been described.2,6-8 In this study, we used single-photon emission computed tomography (SPECT) to investigate the hemodynamic effects of CAS in patients with NO. METHODS The Yamaguchi University Ethics Committee approved the CAS procedure and the study. All patients gave informed consent to treatment and participation in the study. Patients. The participants were 15 consecutive patients (14 men) with NO who underwent CAS at our hospital between July 2006 and June 2012. Patients were a mean age of 70.6 years (range, 60-77 years). Ten patients were symptomatic, with minor stokes or transient ischemic attacks, and five were asymptomatic. Two patients had contralateral ICA stenosis of $70%. 1
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In the same period, we performed CAS and examined cerebral hemodynamics in 78 patients (68 men) with severe stenosis ($70%) but without NO of the ICA, and their data were used for comparison with patients with NO of the ICA. The patients without NO were a mean age of 71.0 years (range, 47-83 years), 40 were symptomatic with minor stokes or transient ischemic attacks, 17 had contralateral ICA stenosis of $70%, and seven had contralateral ICA occlusion. Before CAS, all patients underwent four-vessel angiography for confirmation of NO of the ICA. The criteria for identification of NO were (1) delayed cranial arrival of ICA contrast compared with the external carotid artery (ECA); (2) intracranial collaterals seen as cross-filling of contralateral vessels or ipsilateral contrast dilution; (3) obvious diameter reduction (>50%) of the ICA compared with the opposite ICA; or (4) ICA diameter reduction compared with the ipsilateral ECA, as defined by Fox et al, with some modification. As noted by Fox et al,9 NO was considered to be present when two or more of these criteria were recognized. The 15 patients classified with NO in this study met three or more of the criteria. Of the 78 patients classified without NO, 45 met one criterion and all had visible collaterals (criterion 2). During angiography, collateral flow was evaluated from the anterior communicating artery, posterior communicating artery, ECA, and leptomeningeal arteries. In the patients without NO, the degree of stenosis was determined using the NASCET criteria, and the mean degree of stenosis was 85.0% 6 6.5% (range, 70%-95%).10 Within 2 weeks before the procedure, all patients were assessed with duplex and color flow Doppler ultrasound imaging, brain computed tomography (CT), and magnetic resonance (MR) imaging, including MR angiography and SPECT. All patients received two of three antiplatelet drugs before treatment (100 mg aspirin, 75 mg clopidogrel, 200 mg cilostazol). CAS was performed by two operators at our hospital, with the patient under local anesthesia. A distal protection device was used in all cases. Brain CT was performed in all patients immediately after CAS. To confirm vessel patency and detect possible restenosis, duplex ultrasound imaging was performed 1 week after the procedure, at 3, 6, and 12 months for the first year, and then annually. SPECT was performed 3 to 6 months after the procedure. Using the same methods, we performed SPECT in 13 healthy individuals (five men and eight women) to obtain control values for resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). These individuals were a mean age of 61.2 years (range, 47-78 years), and none had stenosis or occlusion of cervical or intracranial arteries. Informed consent was obtained from each participant. CBF measurement and image analysis. CBF was evaluated using SPECT, which was performed twice #2 weeks before and 3 to 6 months after CAS for patients with NO and for those with severe stenosis but without NO of the ICA. Resting CBF and CVR were measured in one session using the dual-table autoradiographic
(DTARG) method and dual administration of N-isopropyl-p-[I-123] iodoamphetamine(123I-IMP), as described in detail elsewhere.11,12 For SPECT with drug challenge, acetazolamide (17 mg/kg, 1000-mg maximum) was administered intravenously. Whole-blood radioactivity was measured with a well counter calibrated to the SPECT apparatus. For the first and second scans, all frames were summed and images were reconstructed as described below. SPECT was performed with a three-headed gamma-camera (GCA-9300A/PI; Toshiba Medical Systems, Tokyo, Japan) and a low-energy, high-resolution fan beam collimator. GMS-550A/PI (Toshiba Medical Systems) was used to convert fan beam data to parallel data. The tomography images were reconstructed and CBF quantification was performed using the QSPECT image reconstruction package developed by Kim et al11 and Iida et al.13 After image reconstruction, image processing was achieved with the program based on stereotactic extraction estimation from the Japanese EC-IC bypass trial, with three-dimensional stereotactic surface projection.14 This program automatically measures CBF values at rest and after acetazolamide challenge for the territories of the anterior cerebral artery, middle cerebral artery (MCA), and posterior cerebral artery, and can also calculate the CVR, as follows: [CVR ¼ 100 (acetazolamide CBF e resting CBF)/resting CBF]. In patients who received CAS, data from the MCA territory on the ipsilateral side to CAS were used in the analysis. Normal control values of resting CBF (32.23 6 2.36 mL/100 g/min) and CVR (42.3% 6 16.0%) in the territory of the MCA in our hospital were obtained in 13 healthy individuals. There was no significant difference in age and sex between the controls and the patient groups. The reproducibility and accuracy of quantitative CBF measurements using the QSPECT/DTARG method have been reported.11,13,15 Statistical analysis. Descriptive data are presented as means 6 standard deviation. A paired t-test was used to compare paired data from preoperative and postoperative SPECT. An analysis of variance, followed by the post hoc Bonferroni test, was used to compare SPECT data between patients with NO, those with severe stenosis without NO, and the healthy controls. The Fisher test was used to compare clinical characteristics and postoperative outcome between patients with NO and those with severe stenosis without NO. Differences were deemed significant if the probability value was <.05. All calculations were performed using StatView 5.0 software (SAS Institute, Cary, NC). RESULTS CAS was successfully performed in all patients. One patients with NO developed transient motor aphasia due to ischemic stroke 1 day after the procedure, which was confirmed by diffusion-weighed MRI; however, this disappeared in a few days, and he was discharged with no neurologic deficit. In another patient, CT immediately after CAS detected an asymptomatic slight subarachnoid hemorrhage. The cause was thought to be hyperperfusion, and
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Table I. Summary of patient characteristics
Characteristica
NO (n ¼ 15)
Severe stenosis without NO (n ¼ 78)
and CVR were significantly lower in both groups than in healthy controls, and those differences disappeared after the procedure (Fig 1). P
Age, years 70.6 (60-77) 71.9 (47-83) .47 Male-to-female ratio 14:1 68:10 .69 Degree of stenosis, % e 85.0 6 6.5 Symptomatic lesion 10 (66.7) 40 (51.3) .40 Contralateral stenosis ($70%) 2 (13.3) 17 (30.8) .73 Contralateral occlusion 0 (0) 7 (8.9) .59 Outcome #30 days after CAS Ischemic stroke 1 (6.6) 1 (1.2) .30 0 (0) .16 Intracranial hemorrhage 1b (6.6) >30 days after CAS Ipsilateral ischemic stroke 0 (0) 0 (0) >.99 Restenosis (>50%) 0 (0) 4 (5.1) >.99 CAS, Carotid artery stenting; NO, near occlusion. a Continuous data are shown as mean (range) or mean 6 standard deviation and categoric data as number (%). b Subarachnoid hemorrhage.
strict control of blood pressure eliminated the hemorrhage. No other complication occurred in the 30-day period after the procedure. Clinical follow-up was performed for all patients, and no cerebral ischemic attacks occurred on the side ipsilateral to CAS during a mean follow-up of 40 months. No patient showed restenosis >50%. Among the patients without NO, one developed minor ischemic stroke, but no intracranial hemorrhage was observed. No other complication occurred in the 30-day period after the procedure. Clinical follow-up was performed for all patients, and the mean follow-up period was 38 months. No patient experienced ischemic stroke ipsilateral to CAS. Asymptomatic restenosis of >50% occurred in four patients and was >70% in one of these patients. This patient was successfully treated with percutaneous transluminal angioplasty. The basic characteristics and postoperative outcome for the 15 patients with NO and 78 patients with severe stenosis without NO are reported in Table I. Before CAS, the mean resting CBF on the ipsilateral side of the MCA area was 26.68 6 4.23 mL/100 g/min, and the mean CVR was 0.8% 6 15.1% in the 15 patients with NO. In 12 these patients (80%) the CVR was <10%, and eight (53%) had decreased CBF after the Diamox challenge; a so-called steal phenomenon (Table II). In patients without NO, mean resting CBF and mean CVR were 29.51 6 4.89 mL/100 g/min and 19.3% 6 20.0%, respectively, and results were significantly lower in patients with NO than in those with severe stenosis without NO of the ICA (Fig 1). After CAS, the mean resting CBF and mean CVR were both significantly increased to 30.07 6 5.67 mL/100 g/min and 37.0% 6 21.4%, respectively, in the patients with NO (Table II). In patients without NO, CVR increased significantly after CAS, and the mean resting CBF showed a tendency for an increase, but this was not significant (Fig 2). There were no significant differences between the two groups (Fig 1). Before CAS, mean resting CBF
DISCUSSION In this study, we investigated cerebral hemodynamics quantitatively using SPECT before and after CAS in patients with NO of the ICA. We also measured CBF in patients with severe stenosis but without NO of the ICA and in healthy controls. The results showed that cerebral hemodynamics were further compromised before CAS in patients with NO. However, resting CBF and CVR both increased chronically after CAS, and significant differences among the three groups disappeared. In patients with NO, reduction of blood flow across the stenosis may reduce the risk of brain embolization. Using transcranial Doppler scanning, Molloy and Markus16 found a significant reduction of microemboli when the degree of stenosis >90%, and this might be particularly in patients with poststenotic narrowing.4 This may be a major reason the incidence of ischemic stroke for medically treated patients with NO is lower than that in patients with severe stenosis without NO.3,5,9 In contrast, cerebral perfusion might decrease more in patients with NO. Previous studies have examined cerebral hemodynamics of patients with NO, but a quantitative analysis has not been performed. Using transcranial Doppler ultrasound imaging, Gonzalez et al2 found that one-third of 116 patients with NO of the ICA had exhausted or diminished vasoreactivity in response to apnea. In brain perfusion analysis by MR or SPECT in 27 of 48 patients with NO, Choi et al6 found perfusion deficits were severe in 17 and moderate in 10, and no patients had normal perfusion. In SPECT in 12 of 20 patients with NO, Terada et al7 found that six showed reduction of CBF and poor reactivity to a Diamox challenge test. However, these three studies did not include a quantitative analysis or a comparison with patients without NO, making it difficult to understand if NO patients are hemodynamically compromised. In this study, we quantified CBF using SPECT and compared the results for patients with NO and those with severe stenosis without NO. Resting CBF and CVR were both significantly lower in the patients with NO, consistent with our hypothesis of compromised hemodynamics in these patients. After CAS, resting CBF and CVR were significantly improved in patients with NO, and these values became similar to those for patients with severe stenosis without NO and for those in the healthy controls. Improvement of CBF and CVR after CEA has been shown in many reports,17-21 and thus, CEA is also expected to improve cerebral hemodynamics in patients with NO. The effect of improved cerebral hemodynamics after revascularization on prevention of ischemic stroke is uncertain, but decreased resting CBF and CVR measured by SPECT have been reported as risk factors for future ischemic stroke.22,23
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Table II. Hemodynamic changes in the ipsilateral middle cerebral artery (MCA) area before and at 3 to 6 months after carotid artery stenting (CAS) in patients with near occlusion (NO) Resting CBF, mL/100 g/min Patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
CVR, %
Before CAS
After CAS (3-6 months)
Before CAS
After CAS (3-6 months)
29.02 30.99 16.95 27.83 20.59 31.99 30.36 26.57 28.98 26.11 26 29.85 22.04 30.5 22.47
42.06 27.43 21.68 25.64 32.75 34.23 36.16 27.5 28.97 27.61 36.3 30.96 21.97 34.29 23.53
8.9 21.2 0.3 20.5 3.3 0.1 7.2 19.5 9.5 6.8 9 27.1 14.6 28.9 5.8
40.3 62.7 82.2 44.4 17.8 40.5 16.3 21.5 20.7 10.5 40.1 26.7 73.9 13.4 44.1
Mean 6 SD
Mean 6 SD
Mean 6 SD
Mean 6 SD
26.68 6 4.23
30.07 6 5.67a
0.8 6 15.1
37.0 6 21.4b
CBF, Cerebral blood flow; CVR, cerebrovascular reactivity; SD, standard deviation. a P < .05 vs preoperative investigation. b P < .01 vs preoperative investigation.
Fig 1. Comparison of mean (left) resting cerebral blood flow (CBF) and (right) mean cerebrovascular reactivity (CVR) before and after carotid artery stenting (CAS) in patients with near occlusion (NO), in those with stenosis without NO, and in healthy controls. The error bars indicate the standard deviation. *P < .05; **P < .01.
In a repeat review of data from the NASCET and ECST, Fox et al9 found a 3-year risk of ipsilateral stroke of 15.1% for medically treated patients with NO. In our patients, no cerebral ischemic attacks occurred on the side ipsilateral to CAS during a mean follow-up of 40 months beginning after the 30-day postprocedural period. In a study of 116 patients with NO of the ICA, Gonzalez et al2 found that only one patient (0.8%) experienced a stroke on the side ipsilateral to CAS during a median follow-up of 36 months, and Terada et al7 also
showed that CAS in patients with NO of the ICA has a long-term effect on prevention of stroke. Data from the ESCT on long-term outcomes of CEA for patients with NO showed no benefit in surgically treated patients with NO, but NASCET and many other studies have reported a benefit of CEA for preventing ischemic stroke.3,5,9,24-29 In a study of 53 patients with NO, Greiner et al26 reported that 95% of patients who underwent successful CEA had good patency of the treated artery, without any new neurologic deficits for 4 years.
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Fig 2. Changes in mean resting (left) cerebral blood flow (CBF) and (right) cerebrovascular reactivity (CVR) before and after carotid artery stenting (CAS) in patients with near occlusion (NO) and in those with stenosis without NO. The error bars indicate standard deviation. *P < .05; **P < .01.
Recently, Radak et al29 reported the efficacy of eversion carotid endarterectomy over medical treatment for patients with NO. On the basis of these results, the benefit of carotid revascularization for patients with NO is still uncertain; however, revascularization seems to be effective for prevention of ischemic stroke in patients with NO of the ICA, and improvement of cerebral hemodynamics seems to play an important role. However, a direct comparison is required to determine the superiority of CEA or CAS for patients with NO. In our series, minor ischemic stroke developed in one patient 1 day after the procedure. Distal embolism is a major complication of CAS, but a low incidence of embolic complications during CAS for patients with NO has been reported. In the largest series of NO patients treated with CAS, Gonzalez et al2 found that the risk of ischemic complication was only 3.4% and that all symptoms were transient. In two other series, there was no distal embolism during the procedure.6,7 Protection devices are effective for preventing distal embolism,7 and we used a distal protection device in all cases, with the result of no distal embolism during the procedure. However, patients with NO may have more plaque, and use of postprocedural intravenous anticoagulants should also be considered.2 A second patient in our series developed an asymptomatic subarachnoid hemorrhage associated with hyperperfusion after the procedure. The risk of hyperperfusion after carotid revascularization is high in patients with severe hemodynamic compromise.30,31 Choi et al6 found an incidence of hyperperfusion of up to 10% and one death from hyperperfusion-related intracerebral hemorrhage after CAS in patients with NO of the ICA.6 In contrast, Gonzalez et al2 and Terada et al7 found no hyperperfusion in 116 and 20 patients with NO, respectively. The reason for this discrepancy is uncertain, but the possible occurrence of hyperperfusion should be recognized. To prevent this syndrome, strict control of blood
pressure during the postoperative period has been emphasized in many reports.32-34 To improve the effectiveness of carotid revascularization for patients with NO, appropriate patient selection seems to be required. Some patients in our series had relatively well-maintained cerebral hemodynamics. In patients with NO, revascularization may have a low benefit in patients with maintained CBF, who seem to be at a low risk of stroke with medical treatment. Although the cutoff value is uncertain and further research is required, assessment of the cerebral hemodynamic status is likely to be useful to establish the indication for revascularization in patients with NO. This study has some limitations that require discussion. First, the small number of patients requires further studies to confirm the effectiveness of carotid revascularization for improving cerebral hemodynamics and preventing ischemic stroke in patients with NO. Second, we used SPECT, whereas the most reliable method for hemodynamic assessment is positron-emission tomography (PET). However, PET facilities are limited by cost and technical complexity, and decreased resting CBF and CVR to acetazolamide are related to the increased oxygen extraction fraction assessed by PET, indicating that this approach could be useful for screening of patients with misery perfusion.35 The reproducibility and the accuracy of quantitative CBF measurement using the QSPECT/DTARG method that we used in this study have been reported.11,13,15 CONCLUSIONS This is the first quantitative study of hemodynamic changes after CAS in patients with NO. Before CAS, patients with NO were more hemodynamically compromised than those with severe stenosis without NO. After CAS, significant cerebral hemodynamic improvements and normalization were seen long-term. Further studies are needed to see if these improvements are effective for preventing ischemic stroke.
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AUTHOR CONTRIBUTIONS Conception and design: FO Analysis and interpretation: FO Data collection: HI, SK, AY Writing the article: FO Critical revision of the article: FO, HI Final approval of the article: MS Statistical analysis: TO, IK Obtained funding: Not applicable Overall responsibility: FO
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Submitted Apr 1, 2013; accepted May 21, 2013.