After carotid endarterectomy (CEA), cerebral hyperperfusion sometimes develops. This phenomenon is a major increase in ipsilateral cerebral blood flow (CBF) that far exceeds the metabolic requirements of neural tissue.1,2 Cerebral hyperperfusion occasionally induces characteristic signs and symptoms such as unilateral headache, facial or eye pain, seizures, and focal symptoms that are very occasionally followed by intracerebral hemorrhage.1–4 Around 1% of patients undergoing CEA will develop postoperative intracerebral hemorrhage, and the prognosis is poor.5
The post-CEA hyperperfusion phenomenon, even when asymptomatic, also causes a reduction in cerebral metabolism6 as well as mild, but diffuse, damage to cortical neurotransmitter receptor function and white matter microstructures in the ipsilateral cerebral hemisphere.7,8 This phenomenon of cerebral metabolic reduction and cerebral damage due to hyperperfusion is the main cause of the postoperative cognitive decline that is observed in 10% of patients following CEA.1–8 However, how the hyperperfusion phenomenon reduces cerebral metabolism and damages the cerebral cortex and white matter remains unclear. We hypothesized that hyperperfusion breaks down the blood-brain barrier and that toxic substances leak through the broken barrier and injure neural tissue.
Small, dot-like lesions of low signal intensity on gradient echo T2*-weighted MRI or susceptibility-weighted imaging (SWI) are sometimes seen in the brains of healthy elderly subjects as well as in patients with hypertension or hemorrhagic or ischemic strokes.9–11 These small hypointensities, which are called “microbleeds,” are due to local magnetic field nonhomogeneous regions that are the result of the paramagnetic properties of hemosiderin, which is released by lysed erythrocytes.12 Histological studies have shown that microbleeds indeed result from local leakage of hemosiderin from small, abnormal blood vessels in the brain.13 Several investigators have suggested that the presence of cerebral microbleeds (CMBs) is independently associated with a decline in global cognitive function.14,15 Others have shown that CMBs sometimes develop after carotid revascularization such as carotid artery stenting.16 Thus, we hypothesized that CMBs leak through the broken down blood-brain barrier because of cerebral hyperperfusion and injure neural tissue, resulting in cognitive decline following CEA.
The purpose of this prospective study was to determine whether cerebral hyperperfusion following CEA leads to the development of CMBs and if postoperative cognitive decline is related to the CMBs.
Methods
Study Design
This was a prospective observational study. This study and all procedures were conducted in accordance with the ethical standards established by our institutional research committee. All patients or their next of kin provided written informed consent before the patient participated in this study.
Patient Selection
Inclusion criteria for participation in this study were 1) an age ≤ 75 years; 2) ≥ 70% stenosis in the affected internal carotid artery (ICA) on MRA, CTA, or angiography with arterial catheterization; 3) the absence of symptoms for at least 6 months prior to hospitalization (defined as asymptomatic) or the presence of symptoms of ipsilateral carotid territory ischemia 2 weeks to 6 months before hospitalization (defined as symptomatic); and 4) a modified Rankin Scale disability score of 0, 1, or 2. Exclusion criteria were as follows: 1) the patient had implantable electronic devices or metals including coronary artery stents, pacemakers, or implants to repair broken bones (contraindicated for 3-T MRI); and 2) the presence of new ischemic lesions on fluid-attenuated inversion recovery MRI that was done at the time of postoperative SWI.
Brain MRI and Definition of CMBs
A 3-T MRI scanner (Trillium Oval, Hitachi Medical Corp.) was used for SWI, which was performed from the magnitude and phase images from 3D T2*-weighted imaging. For all patients, SWI was performed within 3 days before surgery and 2 months after surgery.
CMBs were defined as round, homogeneous, low-signal-intensity regions (diameter > 2 and < 10 mm) on SWI.17,18 The number of preoperative CMBs was counted, and the postoperative increase in CMBs in the cerebral hemisphere ipsilateral to surgery was determined.
To determine interobserver variability of the number of preoperative CMBs and the increase in CMBs after surgery, MR images obtained before and after surgery were independently assessed by two experienced neuroradiologists who had not been informed of the patient’s clinical information or the assessment of the other neuroradiologist. To assess intraobserver variability, one radiologist studied the same images two times (3-month interval).
Measurement of CBF and Definition of Cerebral Hyperperfusion Following CEA
Quantitative brain perfusion SPECT with 123I-N-isopropyl-p-iodoamphetamine was used to observe cerebral hyperperfusion within 3 days before and immediately after surgery.3,19 A similar third brain perfusion SPECT analysis was done in patients with post-CEA hyperperfusion 3 days after surgery. CBF images were quantitated with the autoradiography method.3,19
For anatomical standardization, SPM2 software (Fujifilm RI Pharma) was used to overlay SPECT images on a standard brain template with linear and nonlinear transformation.3,20 Three hundred eighteen constant regions of interest (ROIs) were automatically placed in the cerebral and cerebellar hemispheres using a 3D stereotaxic ROI template and SPM2.3,21 ROIs were analyzed in the callosomarginal, pericallosal, precentral, central, parietal, angular, temporal, posterior, and hippocampus regions in each hemisphere according to the arterial supply. The combination of seven of these regions, including the callosomarginal, pericallosal, precentral, central, parietal, angular, and temporal regions, was considered the hemispheric ROI.3
For all SPECT images, the mean value of all pixels in the ipsilateral hemispheric ROI was calculated. For each patient, hyperperfusion after surgery was defined as a doubling of CBF relative to presurgical values in the same hemispheric ROI.3
Neuropsychological Testing and Definition of Postoperative Cognitive Decline
Each patient was assessed with the following neuropsychological tests: Wechsler Adult Intelligence Scale–Revised (WAIS-R),22 Wechsler Memory Scale (WMS),23 and Rey-Osterrieth Complex Figure Test (RCFT).24 The WAIS-R assesses overall intellectual function and yields a verbal IQ (VIQ) and performance IQ (PIQ). The WMS yields a memory quotient (MQ). The RCFT assesses the patient’s ability to copy and recall a complex figure. Therefore, we assessed cognitive function with results from the WAIS-R VIQ, WAIS-R PIQ, WMS-MQ, RCFT copy, and RCFT recall.
An experienced neuropsychologist with no knowledge of the patient’s clinical information administered the above tests to a patient within 3 days prior to CEA and 2 months postoperatively. The presurgical test score was subtracted from the postsurgical score for each patient. Control test scores were obtained from 40 healthy volunteers on two separate measurements,25 and the difference between the second and first scores was determined. For the patients, a significant decrease in the score difference was considered to be a score difference that was less than the mean minus 2 SDs of the control differences as follows: WAIS-R VIQ, −5.6; WAIS-R PIQ, −5.1; WMS-MQ, −7.5; RCFT copy, −1.8; and RCFT recall, −4.1.25 Cognitive decline after surgery was considered a significant decrease in the score difference in at least one test.25
Pre-, Intra-, and Postoperative Management
All patients received 75 mg/day of clopidogrel until the morning of the CEA, which was performed with the patient under general anesthesia.3 Prior to ICA clamping, 5000 IU heparin was given as a bolus.3 On the basis of intraoperative electroencephalography with a 12-channel montage, an intraluminal shunt was placed in some patients.3,26 In patients with hyperperfusion on brain perfusion SPECT immediately postoperatively, systolic arterial blood pressure was controlled between 100 and 140 mm Hg with intravenous antihypertensive drugs.3 Intravenous blood pressure control was halted if CBF was reduced and hyperperfusion had resolved according to brain perfusion SPECT performed 3 days after surgery.3 If hyperperfusion persisted, systolic arterial blood pressure was controlled to 140 mm Hg.3 If hyperperfusion syndrome developed, the patient was placed in a propofol coma.3 The criteria for hyperperfusion syndrome were 1) seizures, altered level of consciousness, and/or focal neurological signs including new or worse motor weakness that were seen 24 hours to 30 days after CEA; and 2) hyperperfusion as seen with brain perfusion SPECT.3
Statistical Analysis
We determined the necessary sample size based on a previous study.7 The development of cognitive decline after CEA was estimated to occur in 55% and 6% of patients with and without postsurgical hyperperfusion, respectively. We estimated that the ratio of the number of patients with postsurgical hyperperfusion to the number without postsurgical hyperperfusion was 0.17. Thus, 74 patients were required for a statistical power of 90% and an α error of 5% to detect a 49% difference in the development of post-CEA cognitive decline with two-sided significance. Considering that there would be some dropout cases after surgery, we sought to preoperatively enroll 80 patients in this study.
Data are expressed as the mean ± standard deviation. κ statistics were calculated using data from the two observers to obtain the interobserver and intraobserver agreement on the number of pre-CEA CMBs and the post-CEA increase in CMBs on SWI. κ values ≤ 0.40 were considered poor agreement, values > 0.40 and ≤ 0.65 were considered fair agreement, values > 0.65 and ≤ 0.75 were considered good agreement, and values > 0.75 were considered excellent agreement. Analyses of the first SWI assessments by the first observer were used. However, when assessments by the two observers were not in agreement, disagreements were resolved by consensus. Univariate analysis with the Mann-Whitney U-test or the chi-square test was used to evaluate the relationship between a given parameter and the increase in CMBs or cognitive decline after surgery. The sequential backward elimination approach was used for logistic regression analysis of variables related to the increase in CMBs or cognitive decline after surgery. Exclusion of factors was halted when the p value of the remaining variables reached < 0.2. For the subgroup of patients with post-CEA hyperperfusion, the relationship between the increase in CMBs and cognitive decline after surgery was evaluated with the chi-square test. A p value < 0.05 was considered statistically significant for all analyses.
Results
During the 27-month period of the study, 86 patients met the inclusion criteria. Of these patients, 3 declined to participate in this study. We excluded 3 patients given the presence of implantable electronic devices or implantable metals. Thus, 80 patients were preoperatively included in the study. However, 2 patients had new ischemic lesions on postoperative MRI and another 3 patients did not undergo any postoperative testing. Thus, these patients were excluded, and the remaining 75 patients who had undergone all testing were ultimately analyzed.
The 75 patients (73 males, 2 females) had a mean age of 69 ± 6 years (range 51–75 years). Seventy-one patients had hypertension, 26 had diabetes mellitus, and 51 had dyslipidemia. Forty-seven patients had ipsilateral carotid territory symptoms, and 28 had asymptomatic ICA stenosis. The average ICA stenosis was 89% ± 8% (range 70%–99%). Twenty-seven patients had stenoocclusive disease in the contralateral ICA. The ICA was clamped for a mean of 36 minutes (range 25–48 minutes), and 4 patients required an intraluminal shunt.
Twelve patients (16%) met the CBF criteria for postsurgical hyperperfusion as seen on quantitative brain perfusion SPECT images immediately after surgery; 9 of these 12 patients did not show hyperperfusion on SPECT 3 days after surgery, and the postoperative course was uneventful in each patient. In the remaining 3 patients with cerebral hyperperfusion immediately after surgery, a progressive increase in CBF was observed on the brain perfusion SPECT performed 3 days after surgery, and cerebral hyperperfusion syndrome with hemiparesis in the side contralateral to surgery or aphasia developed 4, 6, and 7 days postoperatively, respectively. These 3 patients were placed in a propofol coma, and full neurological recovery occurred after the propofol coma was halted.
Six patients (8%) had CMBs in the cerebral hemisphere ipsilateral to surgery on preoperative SWI: 4 patients had 1 CMB, 1 patient had 2 CMBs, and 1 patient had 4 CMBs. Interobserver (κ = 0.83) and intraobserver (κ = 0.93) agreements in the number of preoperative CMBs were excellent. Seven patients (9%) had an increase in CMBs in the cerebral hemisphere ipsilateral to surgery on postoperative SWI: the number of CMBs was increased by 1 in all 7 patients. Interobserver and intraobserver agreements in the postoperative increase in CMBs were 100%. Table 1 shows the results of univariate analysis of the parameters related to an increase in CMBs after surgery. Postoperative hyperperfusion developed significantly more frequently in patients with an increase in CMBs than in those without. No other parameters including the presence of CMBs before surgery were associated with an increase in CMBs after CEA. Logistic regression analysis revealed that post-CEA hyperperfusion (95% CI 5.08–31.25, p < 0.0001) was significantly associated with an increase in CMBs after surgery.
Risk factors for an increase in CMBs after surgery
| Increase in CMBs After Surgery | |||
|---|---|---|---|
| Risk Factor | Yes (n = 7) | No (n = 68) | p Value |
| Mean age in yrs | 70.6 ± 7.3 | 69.3 ± 5.5 | 0.2807 |
| Male sex | 7 (100) | 66 (97) | >0.9999 |
| Hypertension | 7 (100) | 64 (94) | >0.9999 |
| Diabetes mellitus | 3 (43) | 23 (34) | 0.6878 |
| Dyslipidemia | 5 (71) | 46 (68) | >0.9999 |
| Presence of CMBs before surgery | 1 (14) | 5 (7) | >0.9999 |
| Symptomatic lesion | 5 (71) | 42 (62) | 0.7056 |
| Mean degree of ICA stenosis in % | 91.4 ± 4.8 | 88.9 ± 8.2 | 0.5719 |
| Bilat lesions | 4 (57) | 23 (34) | 0.2435 |
| Mean duration of ICA clamping in mins | 35.8 ± 3.5 | 35.5 ± 5.5 | 0.6810 |
| Use of intraluminal shunt | 0 (0) | 4 (6) | >0.9999 |
| Post-CEA hyperperfusion | 7 (100) | 5 (7) | <0.0001 |
Values are expressed as the mean ± standard deviation or as number (%), unless indicated otherwise. Boldface type indicates statistical significance.
Ten patients (13%) had postoperative cognitive decline as determined with neuropsychological tests performed pre- and postoperatively. Table 2 shows the results of univariate analysis of parameters related to post-CEA cognitive decline. Postoperative hyperperfusion and an increase in CMBs developed significantly more often in patients with post-CEA cognitive decline than in those without. No other factors, including the presence of CMBs before surgery, were associated with post-CEA cognitive decline. Because a postoperative increase in CMBs was associated with postsurgical hyperperfusion, logistic regression analysis was performed separately as follows: postsurgical hyperperfusion was included and an increase in CMBs postsurgically was excluded, and postoperative hyperperfusion was excluded and an increase in CMBs postsurgically was included. These analyses revealed that post-CEA hyperperfusion (95% CI 9.59–388.20, p < 0.0001) or an increase in CMBs after surgery (95% CI 6.80–66.67, p < 0.0001) was significantly associated with postoperative cognitive decline.
Risk factors for cognitive decline after surgery
| Cognitive Decline After Surgery | |||
|---|---|---|---|
| Risk Factor | Yes (n = 10) | No (n = 65) | p Value |
| Mean age in yrs | 70.1 ± 6.7 | 69.3 ± 5.5 | 0.4875 |
| Male sex | 10 (100) | 62 (95) | >0.9999 |
| Hypertension | 9 (90) | 62 (95) | 0.4430 |
| Diabetes mellitus | 4 (40) | 22 (34) | 0.7306 |
| Dyslipidemia | 6 (60) | 45 (69) | 0.7173 |
| Presence of CMBs before surgery | 1 (10) | 5 (8) | >0.9999 |
| Symptomatic lesion | 7 (70) | 40 (62) | 0.7348 |
| Mean degree of ICA stenosis in % | 90.0 ± 8.2 | 89.0 ± 8.0 | 0.6112 |
| Bilat lesions | 4 (40) | 23 (35) | >0.9999 |
| Mean duration of ICA clamping in mins | 36.6 ± 6.2 | 35.3 ± 5.3 | 0.5682 |
| Use of intraluminal shunt | 0 (0) | 4 (6) | >0.9999 |
| Post-CEA hyperperfusion | 8 (80) | 4 (6) | <0.0001 |
| Increase in CMBs after surgery | 7 (70) | 0 (0) | <0.0001 |
Values are expressed as the mean ± standard deviation or as number (%), unless indicated otherwise. Boldface type indicates statistical significance.
Figure 1 shows the relationships among patients with an increase in CMBs, cerebral hyperperfusion, and cognitive decline after surgery. For the 12 patients with post-CEA hyperperfusion, all 7 with an increase in CMBs after surgery exhibited postoperative cognitive decline, but only 1 of 5 without this increase (20%) had postoperative cognitive decline. These two incidences differed significantly (p = 0.0101). All 3 patients with cerebral hyperperfusion syndrome exhibited postoperative cognitive decline with an increase in CMBs after surgery (Fig. 2). None of the patients without cerebral hyperperfusion had an increase in CMBs after surgery.
Venn diagram showing the overlap among patients with an increase in CMBs, cerebral hyperperfusion, and cognitive decline after surgery. ACH = asymptomatic cerebral hyperperfusion; CHS = cerebral hyperperfusion syndrome.
Images from a 67-year-old man with symptomatic left ICA stenosis (95%) and exhibiting cognitive decline after CEA. Cerebral hyperperfusion syndrome with confusion and right motor weakness developed on postoperative day 4. A preoperative brain perfusion SPECT image shows slightly decreased perfusion in the left cerebral hemisphere compared with the right (A). Immediately after surgery, perfusion in the left cerebral hemisphere was markedly increased (B). Preoperative SWI revealed no microbleeds in the left cerebral hemisphere (C). At 2 months after surgery, a microbleed developed in that hemisphere (D).
Discussion
This study demonstrated that cerebral hyperperfusion following CEA leads to the development of CMBs and that postoperative cognitive decline is related to these developed CMBs.
Kakumoto et al. showed that 8% of patients undergoing carotid artery stenting had new postoperative CMBs in the cerebral hemisphere ipsilateral to surgery.16 They speculated about the mechanism underlying the formation of CMBs as follows: hemodynamic changes caused by carotid artery revascularization may disrupt the tight junction of cerebral blood vessels, resulting in CMBs.16 Other investigators demonstrated contrast agent leakage as a marker of blood-brain barrier disruption in CMBs in patients with intracerebral hemorrhage.27 Histological studies showed that CMBs result from local leakage of hemosiderin from small, abnormal blood vessels with blood-brain barrier disruption.13 A study using animal models demonstrated that cerebral hyperperfusion following reperfusion after 3 days of hemispheric hypoperfusion induces blood-brain barrier breakdown.28 These findings support our conclusion that cerebral hyperperfusion following CEA leads to the development of CMBs. This may also explain why cerebral hyperperfusion following carotid revascularization can result in intracerebral hemorrhage.16
Neuropsychological examinations have been used to assess cognitive function after CEA.25,29,30 However, no guidelines have been developed to define a significant decrease in cognitive ability. Changes in test scores may sometimes be the result of a practice effect, in which scores increase with repeated testing.25 The patient’s family members or doctors may report perceived subjective cognitive changes after CEA.25 Using receiver operating characteristic curves, Yoshida et al. determined the optimal cutoff points for a postsurgical decrease in neuropsychological test scores (including the five tests we used) for an otherwise subjective decrease in cognitive function postoperatively.25 The cutoff points established by Yoshida et al. indicate a decrease in cognitive function with positive and negative predictive values > 80%.25 When we examined our data using these definitions, 13% of patients who had undergone CEA showed postsurgical cognitive decline; our data are consistent with previous findings.25
Hirooka et al. studied injury to brain structures as seen with conventional MRI in patients with cerebral hyperperfusion and a post-CEA decrease in cognitive function.31 These authors observed that although post-CEA cerebral hyperperfusion syndrome may lead to reversible brain edema that can be seen on MRI, even asymptomatic postsurgical cerebral hyperperfusion may lead to a decrease in cognitive function in the absence of structural brain injury on conventional MRI, including diffusion-weighted imaging.31 Thus, we did not include conventional MRI findings in the present analyses.
A main finding in the present study was that postoperative cognitive decline is related to CMBs that developed due to cerebral hyperperfusion. In our study, all patients who developed cerebral hyperperfusion syndrome also showed a postsurgical decrease in cognitive function and an increase in CMBs after surgery. Histopathologically, CMBs indicate the presence of surrounding gliosis and necrosis as well as hemosiderin deposition.32 Akoudad et al. used diffusion tensor imaging and showed that the presence of CMBs, even a single CMB, is associated with global disruptions to the microstructural integrity of white matter.33 Thus, CMBs may indicate widespread injury to the brain,15 and CMBs may directly damage the structure of the adjacent neural tissue, leading to disconnections in critical cortical and subcortical structures.12 The phenomenon of hyperperfusion after CEA, even in the absence of symptoms, causes mild, but widespread, functional damage to cortical neurotransmitter receptors and white matter microstructures in the ipsilateral cerebral hemisphere.7,8 In addition, a study using animal models has shown that cerebral hyperperfusion following reperfusion after 3 days of hemispheric hypoperfusion induces white matter injury, inflammation, and subsequent cognitive decline as well as blood-brain barrier breakdown.28 Thus, CMBs as toxic substances may leak through the blood-brain barrier that is disrupted by cerebral hyperperfusion and injure neural tissue, resulting in cognitive decline.
All patients who were included in the present study received antiplatelet monotherapy until the morning of the CEA. This could potentially predispose patients to the development of CMBs, resulting in cognitive decline. In contrast, another study demonstrated that the risk of perioperative stroke or death was significantly lower in patients with perioperative antiplatelet monotherapy than in those without any perioperative antiplatelet therapy, suggesting that perioperative antiplatelet therapy may be essential for CEA.34 Another study showed that the intraoperative administration of the free radical scavenger edaravone immediately before ICA clamping prevents the development of cerebral hyperperfusion after CEA.35 Considering our result that none of the patients without cerebral hyperperfusion had an increase in CMBs after surgery, the optimal perioperative management strategy may be as follows: patients receive antiplatelet monotherapy such as clopidogrel until the immediate preoperative period and a free radical scavenger such as edaravone immediately before ICA clamping during CEA.
The present study has serious limitations. First, although we determined the necessary sample size based on a previous study,7 the sample size is relatively small, and a subsequent multicenter trial with a standard protocol including brain perfusion measurement is needed to confirm our findings. Second, most patients included in the present study were men. The largest sample size in studies of CEA published in our country was 500 patients, and women made up only 8% of the sample.3 The prevalence of smokers, heavy drinkers, and patients with hypertension is lower among women than among men in our country. Lifestyle habits or lifestyle diseases in addition to ethnic characteristics may be the cause of the very low percent of women among patients with atherosclerotic severe stenosis of the cervical ICA. These characteristics may explain the very low percent of women in our patient population. Thus, our findings may be limited to male patients. Third, two reviewers blinded to all clinical information visually and subjectively determined the increases in CMBs after surgery. Although interobserver and intraobserver agreements for the postoperative increases in CMBs were excellent, objective or quantitative assessment of hemosiderin deposition is needed for the present study. Quantitative susceptibility mapping, which is readily performed with commercial scanners, is a postprocessing technique for quantifying the magnetic susceptibility of blood vessel structures and the brain parenchyma from T2*-weighted magnitude/phase images.36 This mapping quantitatively measures iron deposition in the brain. Further studies using such tools would be of benefit.
Conclusions
The present study demonstrated that cerebral hyperperfusion following CEA leads to the development of CMBs, and postoperative cognitive decline is related to these developed CMBs.
Acknowledgments
This work was partly supported by Grants-in-Aid for Strategic Medical Science Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (S1491001) and for Scientific Research from the Japan Society for the Promotion of Science (JP18K09002).
Disclosures
Dr. Ogasawara receives consigned research funds from Nihon Medi-Physics Co., Ltd.
Author Contributions
Conception and design: Ogasawara, Kobayashi, K Yoshida, Fujiwara, Kubo. Acquisition of data: Igarashi, Ando, Takahashi, J Yoshida, Terasaki. Analysis and interpretation of data: Ogasawara, Igarashi, Ando, Takahashi, J Yoshida, Terasaki. Drafting the article: Ogasawara, Igarashi, Ando, Takahashi. Critically revising the article: J Yoshida, Kobayashi, K Yoshida, Fujiwara. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ogasawara. Statistical analysis: Fujiwara. Study supervision: Kubo.
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