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. Author manuscript; available in PMC: 2018 Mar 1.
Published in final edited form as: J Vasc Surg. 2016 Dec 23;65(3):686–694. doi: 10.1016/j.jvs.2016.09.057

Volume of Subclinical Embolic Infarct Correlates to Long-term Cognitive Changes following Carotid Revascularization

Wei Zhou 1,2, Brittanie D Baughman 1, Salil Soman 3, Max Wintermark 4, Laura C Lazzeroni 5, Elizabeth Hitchner 1, Jyoti Bhat 6, Allyson Rosen 5,6
PMCID: PMC5328795  NIHMSID: NIHMS830219  PMID: 28024850

Abstract

OBJECTIVE

Carotid intervention is safe and effective in stroke prevention in appropriately selected patients. Despite minimal neurologic complications, procedure-related subclinical microemboli are common and their cognitive effects are largely unknown. In this prospective longitudinal study, we sought to determine long-term cognitive effects of embolic infarcts.

METHODS

119 patients including 46% symptomatic patients who underwent carotid revascularization were recruited. Neuropsychological testing was administered preoperatively and at 1, 6, and 12 months postoperatively. Rey Auditory Learning Test (RAVLT) was the primary cognitive measure with parallel forms to avoid practice effort. All patients also received 3T brain MRIs with a diffusion-weighted sequence (DWI) preoperatively and within 48 hours postoperatively to identify procedure-related new embolic lesions. Each DWI lesion was manually traced and input into a neuroimaging program to define volume. Embolic infarct volumes were correlated with cognitive measures. Regression models were used to identify relationships between infarct volumes and cognitive measures.

RESULTS

A total 587 DWI lesions were identified on 3T MRI in 81.7% of CAS and 36.4% of CEA patients with a total volume of 29327mm3. Among them, 54 DWI lesions were found in CEA patients and 533 in the CAS patients. Four patients had transient postoperative neurologic symptoms and one had a stroke. CAS was an independent predictor of embolic infarct (OR: 6.6 [2.1–20.4], p<.01) and infarct volume (P=.004). Diabetes and contralateral carotid severe stenosis/occlusion had a trend of positive association with infarct volume, while systolic blood pressure more or equal to 140mmHg had a negative association (P=.1, .09, and .1, respectively). There was a trend of improved RAVLT scores overall following carotid revascularization. Significantly higher infarct volumes were observed among those with RAVLT decline. Within the CAS cohort, infarct volume was negatively correlated with short and long-term RAVLT changes (P<0.05).

CONCLUSIONS

Cognitive assessment of procedure-related subclinical microemboli is challenging. Volumes of embolic infarct correlates with long-term cognitive changes, suggesting that micro-embolization should be considered as a surrogate measure for carotid disease management.

Introduction

Carotid revascularization procedures including carotid endarterectomy (CEA) and carotid stenting (CAS) have been shown to be effective in stroke prevention in appropriately selected patients with low perioperative morbidities and mortality1–3. Recent advancements in medical therapy spark controversies on the efficacy of carotid revascularization and intense debates on the best treatment strategies for asymptomatic patients with severe carotid occlusive disease4. However, the on-going debates and most studies evaluating the effectiveness of carotid interventions focus on neurologic outcomes. Neurocognitive outcomes have not been fully considered.

With improved life expectancy and a growing aging population, cognitive dysfunction has become an important global population health concern. Cognitive impairment affects patients, families, and their social networks, representing a significant psychosocial and health-economic burden. Patients with carotid occlusive diseases are known to be at the highest risk for cognitive impairment 5, 6. In the recent years, cognitive effects of carotid interventions are increasingly recognized as an important outcome for carotid disease management and carotid interventions. Although revascularization procedures improve cerebral perfusion and theoretically brain health, procedure-related factors, such as micro-embolization, have been shown to adversely impact cognition following carotid interventions 7–9.

Procedure-related subclinical embolization can be detected by transcranial Doppler10 and diffusion weighted MRI sequence (DWI)11, 12. Subclinical microemboli are common (20–70%) despite an absence of neurologic symptoms 13–20. Studies that evaluated cognitive effects of microembolization have yielded mixed findings 7, 8, 21, 22. In an experimental animal models, dose-dependent effects of embolization on inflammation and neuronal injury have been observed and repeat embolization is shown to lead to cognitive impairment 23. We postulate that the inconsistency in the cognitive effects of subclinical embolization may be related to size of the emboli. To date, there is extremely limited information in the literature on quantification of volumes of procedure-related embolization following carotid revascularization procedures. How size of emboli influences procedure-related cognitive changes is largely unknown. In this study, we aim to evaluate the volume of procedure-related emboli in patients who undergo carotid endarterectomy (CEA) and carotid stenting (CAS), focusing on the effect of volume of emboli on cognitive changes in the CAS cohort.

Methods

Patient selection

The study was approved by Stanford Institutional Review Board and VA Palo Alto Health Care System Research and Development Committee. Patients who underwent carotid revascularization procedures for occlusive disease under the standard clinical practice guideline were prospectively recruited. Carotid revascularization was offered to patients with >80% asymptomatic carotid stenosis and >60% symptomatic stenosis based on duplex velocity criteria. The degree of stenosis was further confirmed with MR angiography or time of flight MRI of the neck. For those who underwent CAS, additional contrast angiography was performed before stenting. The decision to perform a CAS procedure was a consensus of vascular surgeons, patients, and families; and CAS was reserved for patients who were deemed high surgical or medical risk for CEA. Inclusion criteria for this study also required the patients to be 40 years of age or older; absence of psychiatric disorder or medical condition affecting cognitive function; voluntarily participate in the study; be able to sign an IRB-approved informed consent; able to undergo MRI; and be available for follow-up neuropsychological testing. Demographics and clinical risk factors were documented. Patients were considered to be symptomatic (prior symptoms) if they had experienced transient ischemic attack (TIA), amaurosis fugax, or stroke within 6 months leading to their referral for carotid revascularization evaluation.

Carotid intervention

All procedures were performed by experienced vascular surgeons who are proficient in CEA and/or CAS. All patients received intra-arterial blood pressure monitoring during the procedures. Anesthesiologists were present during the entire CEA and the critical portion of CAS procedures. CEA were performed under general anesthesia in an operating room with cerebral oxymitry monitoring. Shunts and patch were routinely used. The choices of shunt or patch were at the discretion of the operating surgeons. All CAS procedures were performed in an endovascular suite under local anesthesia with conscious sedation. An arch angiogram was not routinely performed to avoid unnecessary arch manipulation and common carotid artery cannulation was based on information from preoperative MRA using a telescope technique. All patients received a distal embolic protection device prior to stent placement. Post-stent dilation was performed for >30% residual stenosis. Following CEA and CAS, all patients were monitored in the Surgical Intensive Care Unite overnight. The majority of the patients were discharged home the following day.

Imaging evaluations

Preoperative and postoperative 3-Tesla MRIs (GE Medical Systems, Milwaukee, WI) with DWI sequence were performed to identify peri-procedural embolic infarcts. MRI studies were performed within 1 to 2 weeks prior to carotid revascularization and within 24–48 hours postoperatively prior to discharge. Postoperative DWI images and apparent diffusion coefficient maps were compared to the corresponding preoperative images to identify interval, peri-procedural embolic infarcts. Each individual embolic infarct was manually traced on individual MRI slices using MRICron neuroimaging software 24, which then incorporated slice thickness and interslice gap to calculate the volume of each infarct as well as their combined volume. Infarct distribution was analyzed using FMRIB Software Library (FSL) analytical tools25. Infarct analysis was performed under the supervision of board-certified neuroradiologists.

Cognitive evaluations

All patients underwent a battery of neurocognitive test at 1 to 2 weeks before, 1 month and 6 months after carotid revascularization procedures. The battery was designed to be briefly and reliably administered by trained research personnel. The Mini-Mental State Exam was performed to assess gross cognition and screen patients for severe cognitive deficits. The key outcome measure was the Rey Auditory Verbal Learning Test (RAVLT). RAVLT is a verbal learning test that assesses declarative memory. Word list learning is extremely sensitive in discriminating healthy older adults from non-demented older adults with focal memory dysfunction26. RAVLT consists of a list of 15 nouns read out aloud, at one-second intervals, for 5 consecutive trials, with each trial followed by a free-recall test. The critical measure was immediate recall task in which the correct numbers of items recalled over all the learning trials are combined into a sum (RAVLTsum). The order of presentation of words remained fixed across trials. Upon completion of trial 5, an interference list of 15 words was presented followed by a free-recall test for the interference list. Immediately following this, delayed recall of the original list was tested without further presentation of the original word list (RAVLT SD). After a 20-minute delay period, each subject was again asked to recall the original list, without further presentation of those words (RAVLT LD). Three parallel forms of RAVLT were used across the 3 test sessions to minimize the practice effect. Cognitive decline was defined as negative change in RAVLT from post-op to pre-op tests. To avoid anesthetic and surgical related effects, we evaluated post-op change at 1 month following interventions. Given our elderly patient population, a natural age-related decline is expected in our cohort. Therefore, a 6-month follow-up was chosen to assess long-term procedure-related changes.

Statistics

Descriptive analyses were performed for preoperative differences between CAS and CEA cohorts using Student’s t-test, Pearson chi-squared, or Fisher’s exact test when appropriate. Differences in cognitive scores across different time points were compared using paired sample T tests, and cognitive scores in patients with and without emboli were compared using two-sampled T tests with Welch correction. Variables predicting volume of infarct were analyzed using multiple regression and stepwise multiple regression. Logistic regression was used to identify variables predicting the presence of emboli. Relationships between embolic volume and cognitive scores were compared using pairwise correlations. A P value of less or equal to .05 is considered significant. All data were analyzed using Stata 14.1 for Mac (College Station, TX).

Results

A total of 119 patients including 55 (46%) symptomatic patients were prospectively enrolled. Demographic and medical comorbidities are listed in Table I. CAS patients had higher incidence of coronary artery disease (58.7% vs. 28.6%, P=.003), chronic renal insufficiency (34.9% vs. 9.1%, P=<.001), and contralateral carotid artery occlusion or severe stenosis (21% vs. 5.4%, P=.02). There was no difference in age, education level, hypertension with a systolic blood pressure (SBP)≥ 140mmHg, or histories of atrial fibrillation, chronic obstructive pulmonary disease (COPD), diabetes, or obesity between the two groups. Usage of antiplatelet therapy and preoperative symptomatic status were also similar between the two groups. In addition, the baseline cognitive scores represented by RAVLTsum, RAVLT SD, and RAVLT LD were similar between the two groups. There were 5 (4.2%) patients, including 4 symptomatic patients, who had postoperative neurologic complications, 4 of which occurred in the CAS cohort. Among the 5 patients, 4 had transient neurologic symptoms post-operatively and one had stroke. We observed an improved mean RAVLTsum score, albeit non-significant both at 1 month and 6-month post-CAS. There was a significant improvement in RAVLTsum at 1 month (38.2 vs. 35.9, p=.015) following CEA. The direction of improvement remained, but was non-significant, at 6 months following CEA, suggesting positive effects of carotid interventions on verbal learning memory function (Figure 1).

Table I.

Demographics, co-morbidities, symptomatology, and baseline memory measures between CEA and CAS patients

Patient Characteristics CEA (n= 56) CAS (n = 63) P value
Age in years: mean (SD) 68.8 (7.5) 69.9 (8.4) 0.36
Education in grades: mean (SD) 14.0 (2.1) 13.5 (2.4) 0.27
Diabetes: n (%) 18 (32%) 29 (46%) 0.12
SBP>140: n (%) 26 (46%) 22 (35%) 0.20
Obesity: n (%) 21 (37.5%) 25 (39.7%) 0.81
Coronary Artery Disease: n (%) 16 (28.6%) 37 (58.7%) 0.003*
Atrial fibrillation: n (%) 3 (5.5%) 4 (6.3%) 1.00
COPD: n (%) 7 (12.5%) 9 (14.3%) 0.78
Chronic Renal Insufficiency: n (%) 5 (9.1%) 22 (34.9%) 0.001*
Antiplatelets: n (%) 37 (67.3%) 44 (69.8%) 0.76
Contralateral Stenosis/Occlusion: n (%) 3 (5.4%) 13 (21%) 0.016*
Symptomatic Status: n (%) 28 (50%) 27 (42.9%) 0.44
Mini-mental State Examination: mean (SD) 28.1 (1.7) 27.7 (2.2) 0.26
Baseline Memory Scores (mean, SD) RAVLTsum 35.5 (10.1) 34.0 (9.2) 0.42
RAVLT SD 6.7 (3.3) 5.9 (2.3) 0.17
RAVLT LD 5.9 (3.3) 6.1 (2.8) 0.81
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Figure 1.

Figure 1

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Scores of RAVLTsum pre-operatively and post-operatively at 1-month and 6-month following carotid interventions. For CEA patients, there was a significant improvement in RAVLTsum at 1 month following carotid interventions compared to preoperative scores

One hundred and fifteen patients, including 55 CEA patients and 60 CAS patients, had pre-operative and postoperative MRI scans of sufficient quality for quantitative analysis. A total 587 new lesions were identified on postoperative DWI images, indicative of embolic infarcts. The cumulative volume of infarct was 29327mm3. Among them, 55 lesions with an average volume of 144.5mm3 were found in 20 (36.4%) CEA patients, and 533 lesions with an average volume of 471.1mm3 were present in 49 (81.7%) CAS patients (Figure 2a). The 3 patients who experienced postoperative complication had infarct volume of 118mm3, 635mm3, and 1898mm3. Multivariate logistic regression analysis showed that CAS is the only independent predictor of presence of procedure-related embolic infarct (OR: 6.6, CI: 2.1–20.4, and P=.001). Multiple regression analysis showed that CAS and contralateral carotid occlusion or severe stenosis were independent predictors of volume of infarction (P=.004 and .02 respectively), while hypertension (SBP>140) was protective (p=.037). Because the distribution of volume turned out to be highly skewed with a long upper tail, we perform a cube root transformation of volume (Figure 2b). We confirmed that CAS was an independent predictor of higher infarct volume (P=.004), and contralateral carotid artery occlusion/stenosis and diabetes had a trend of positive association with infarct volume (p=.09 and .1, respectively) while baseline SBP>140 had a negative trend (p=.1) (Table II).

Figure 2.

Figure 2

Figure 2

Figure 2

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Figure 2a: Distribution of infarct volumes between CEA and CAS patients

Figure 2b: Distribution of infarct volume with cube root transformation

Figure 2c: Significant correlation was shown between infarct volume (cube root transformation) and changes in RAVLT LD at 1 month and 6 months following carotid interventions among all patients who had procedure-related emboli

Table II.

Results of multiple regression analysis predicting total embolic volume (cube root transformation)

Coefficient P value 95% Confidence Interval
CAS 2.58 0.004* 0.87 4.29
Diabetes 1.24 0.10 −0.25 2.73
Age −0.0034 0.94 −0.09 0.09
SBP>140mmHg −1.24 0.10 −2.72 0.24
Obesity 0.12 0.87 −1.34 1.59
Coronary artery disease −0.007 0.99 −1.31 1.30
COPD 0.17 0.86 −1.72 2.07
Atrial fibrillation 2.19 0.19 −1.08 5.47
Chronic renal −0.19 0.83 −1.90 1.52
insufficiency
Anti-platelet −0.6 0.45 −2.17 0.97
Preoperative symptoms −0.27 0.71 −1.77 1.22
Contralateral Carotid Stenosis/Occlusion 1.79 0.09 −0.31 3.9
Constant 4.62 0.18 −2.25 11.49
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Patients with embolic infarcts had significantly decreased RAVLT SD at 1-month postop compared to those without embolic infarcts (change score −0.45 vs. 0.48, P=.048). However, there was no significant difference in change scores of RAVLTsum or RAVLT LD score at 1-month or 6-months between patients with or without infarction. When examining the infarct volume, we observed a significant correlation between infarct volumes and changes in RAVLT LD at 1-month and 6-month following interventions, particularly among those with procedure-related embolization (R=−0.49 and −0.48, P<.001 and .001 respectively) (Figure 2c). We also observed a significant correlation between infarct volume and change in RAVLTsum at 6 months following intervention (R=−0.32, P=.04). Similar non-significant trends of negative correlation for other RAVLT measures were also observed.

To better decipher the effects of embolic volume, The CAS patients were further divided into 3 cohorts based on procedure-related infarct volume >500mm3(n=19), 500–100mm3(n=23), and <100mm3(n=18). There was no significant difference in demographics, medical comorbidities, preoperative symptoms, or baseline memory scores among the three groups except that the group with high volume of infarction had lower incidence of SBP>140mmHg. The patients who suffered from high volume of infarction had less incidence of pre-operative SBP≥140mmHg compared to low and medium groups (16% vs. 33% and 52%, P=0.05) (Table III). We observed a non-significant trend of improvement in RAVLTsum among patients with low and medium infarct volumes compared to those with high volume of infarction both at 1 month (2 and 1 vs. −0.5, respectively) and at 6 months (2.4 and 1 vs. −0.5, respectively) following interventions. We also observed a similar trend for RAVLT LD, while RAVLT SD showed a significant difference in changes at 1 month (P=0.05) and near significance at 6 months post-intervention (p=0.07) between low (<100mm3) vs. high (>500mm3) groups (Figure 3a). We also observed that a higher proportion of patients experienced more than 10% of decline in RAVLTsum in the high volume group compared to lower volume groups both at 1 month (47%, 37%, and 18%, respectively) and at 6 months following interventions (50%, 46%, and 25%, respectively) (Figure 3b). Furthermore, a significant correlation was observed between infarct volume and changes in RAVLT SD both at 1-month and 6-month following CAS (R=−0.34 and −0.36; P=.021 and .026, respectively) (Figure 3c). Similar non-significant negative correlations were observed for RAVLTsum and RAVLT LD.

Table III.

Demographics, comorbidities, symptomatology, and baseline memory measures among CAS patients who experienced from low, medium, and high volumes of procedure-related infarction

Patient Characteristics Embolic Volume in CAS Cohort
<100mm3
N= 18		 100–500mm3
N=23		 >500mm3
N=19		 P values
Age in years: mean (SD) 68 (7) 71 (7) 70 (10) NS
Diabetes: n (%) 8 (44%) 10 (43%) 10 (53%) 0.8
Obesity: n (%) 6 (33%) 8 (35%) 10 (53%) 0.4
SBP >140mmHg: n (%) 6 (33%) 12 (52%) 3 (16%) 0.05*
COPD: n (%) 3 (17%) 3 (13%) 3(16%) 0.9
Coronary artery disease: n (%) 9 (50%) 14 (61%) 12 (63%) 0.76
Atrial fibrillation: n (%) 0 (0%) 2 (9%) 2 (11%) 0.5
Chronic renal insufficiency: n (%) 4 (22%) 11 (48%) 6 (32%) 0.22
Contralateral occlusion/stenosis: n(%) 3 (17%) 4 (17%) 5 (26%) 0.78
Anti-platelets: n (%) 13 (72%) 17 (74%) 12 (63%) 0.73
Pre-op symptoms: n (%) 8 (44%) 8 (35%) 9 (47%) 0.68
Baseline memory scores: mean (SD) RAVLTsum 33 (10) 33 (7) 35 (9) 0.57
RAVLT SD 5.1 (1.6) 6.3 (2.0) 6.5 (2.6) 0.13
RAVLT LD 5.7 (2.8) 6 (2.6) 6.5 (2.7) 0.7
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Figure 3.

Figure 3

Figure 3

Figure 3

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Figure 3a: Changes in RAVLT SD scores among CAS patients who experienced low, medium, and high volumes of procedure-related infarction. There was a significant different in changes at 1 month (P=0.05) and nearly significant change at 6 months post-intervention (p=0.07) between low (<100mm3) vs. high (>500mm3) volume groups

Figure 3b: Higher proportion of CAS patients experienced more than 10% of cognitive changes in the high embolic group compared to low embolic groups both at 1 month and at 6 months following carotid stenting

Figure 3c: A significant negative correlation was observed between infarct volume (cube root transformation) and changes in RAVLT SD at 1 and 6 months following carotid stenting

Discussion

In this prospective longitudinal evaluation, we evaluated infarct volume following carotid interventions and related the size of infarct to long-term cognitive change following carotid stenting procedures. To our knowledge, this is the first study demonstrating a significant correlation between volumes of procedure-related infarct and cognitive outcomes in patients with severe carotid occlusive disease who underwent carotid revascularizations.

Cognitive impairment is increasingly recognized as a major public health and socioeconomic concern 27, 28. A large natural history study on cognitive function in elderly individuals by Bennett and colleagues showed an annual rate of decline ranging from 0.021 standard units for episodic memory to 0.037 for semantic memory among individuals without baseline mild cognitive impairment (MCI) and even faster decline rate among those with MCI29. The patients with baseline MCI had 1.7 times higher mortality and 3.1 times faster progression to dementia. Patients with carotid occlusive diseases are known to be at the highest risk for cognitive impairment 30–32. Using 3 parallel forms to minimize practice effect, we observed a positive effect of carotid intervention on verbal learning memory, suggesting carotid revascularization may temporize the natural deterioration of cognitive function in elderly patients with severe carotid stenosis.

Although procedure-related subclinical embolization has been implied in cognitive deterioration following carotid interventions, conflicting findings in the literature have led to persistent debate on the cognitive effects of subclinical embolization 7, 8, 33, 34. In experimental models, several investigators have shown that embolization can lead to neuronal damage and that degree of cognitive impairment correlates to the size of embolization in rats 9, 23, 35. Our finding confirms the laboratory investigations, and, for the first time, showed that volume of infarction significantly influences long-term cognitive effects in patients who underwent carotid interventions. We showed that patients with medium and high infarct volumes had memory deterioration in various RAVLT measures, while those with low volume did not experience the same extent of cognitive insult. This study provides objective evidence that subclinical embolization contributes to heterogeneous cognitive outcomes following carotid interventions, suggesting that the higher percentage of cognitive decline in patients who receive CAS may be due to higher procedure-related subclinical embolization.

Consistent with our previous studies and others, we showed that procedure-related subclinical embolization is common following carotid interventions, particularly CAS7, 36–38. However, we observed a high incidence of DWI lesions in both CEA and CAS groups in this study. We attributed this to our high percentage of symptomatic patients of nearly 50%, dedicated neuroradiologists, and 3T MRI techniques. There was no change in patient selection, practice pattern, or clinical personnel from our previous studies. 3T MRI provides a higher resolution power for DWI lesion identification and measurement; and each lesion was carefully traced and evaluated by the study team. Despite a higher incidence of DWI lesions observed on 3T in our study cohort, only 3 patients experienced neurologic complications. Similar observation was reported by Bonati and colleagues in the International Carotid Stenting Study (ICSS). The authors showed higher numbers of new DWI lesions detected on 3T than 1.5T MRI (44% vs. 31%) despite there being more CEA patients in the 3T MRI group 38.

In addition to CAS procedure, we also observed that contralateral carotid stenosis/occlusion showed a trend association with larger infarct volume while SBP≥ 140mmHg was protective in patients with severe carotid stenosis who undergo carotid interventions, suggesting that low cerebral perfusion pressure subjects this group of patients to larger infarct volume and consequent cognitive decline following carotid interventions.

Despite numerous strengths, the study is not without limitations. This is a single center, non-randomized study. We examined difference between CEA and CAS, but CAS is only reserved for high surgical risk patients. Although there was no difference in baseline pre-op symptomatic status, age, and memory scores between CAS and CEA patients, the two cohorts were not entirely comparable. Therefore, to understand procedure-related infarction, we separately evaluated the CAS cohort. Another concern is that there is no control for our study. Bennett et al have shown a consistent cognitive deterioration in episodic and semantic memories in a population with similar age and education levels. We expect that patients with carotid disease have more rapid cognitive decline. Future studies with a control cohort of patients with severe carotid stenosis who undergo unrelated procedures are needed to further validate our findings on cognitive benefits of carotid interventions. Furthermore, our study subjects are recruited from a Veterans hospital system that is comprised of predominantly male patients, therefore our findings may not apply to female patients. Lastly, although our study is one of the largest comprehensive evaluations of procedure-related embolization, the total number is relatively small; a larger multi-center study is warranted to further validate these findings.

Conclusion

Carotid stenting and baseline low cerebral perfusion are predictors of high volume of embolic infarct associated with carotid revascularization procedures. Subclinical embolization is not benign and volume of infarction directly influences cognitive outcome of procedure-related embolization. Cognitive evaluation should be considered in carotid disease management.

Acknowledgments

Grant Funding: NIH/NINDS R01NS070308 (Zhou) and R21NS081416 (Zhou/Rosen)

Footnotes

Presented at the Vascular Annual Meeting. Washington DC. June 6–9, 2016.

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