- Email: [email protected]
Longitudinal Evaluation of Neurobehavioral Outcomes After Carotid Revascularization
Longitudinal Evaluation of Neurobehavioral Outcomes After Carotid Revascularization Matthew A. Corriere, Matthew S. Edwards, Carol P. Geer, Donna R. Keith, Dwight D. Deal, and David A. Stump, Winston-Salem, North Carolina
Background: Carotid revascularization, including carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAS), is performed for stroke risk reduction but may also impact cognitive function. Cognitive outcomes observed after carotid revascularization have been inconsistent, and mechanistic relationships with procedural factors are poorly understood. To further explore associations between carotid revascularization and cognitive outcomes, a prospective longitudinal evaluation was conducted of patients undergoing elective CEA or CAS for hemodynamically significant carotid stenosis. Methods: Patients undergoing primary carotid artery revascularization for hemodynamically significant stenosis were evaluated with neurologic and neuropsychological testing at baseline and at 1 and 6 months after revascularization. A subgroup of patients was also studied with baseline and postoperative magnetic resonance imaging (MRI). Outcomes included neurologic or neuropsychological deficits and imaging findings (including quantitative assessment of cerebral blood flow). Results: Sixteen patients underwent carotid revascularization with both preoperative and postoperative neurologic and neuropsychological testing; preoperative and postoperative MRIs were also performed on eight patients. Five of 16 treated carotid lesions (31%) were considered symptomatic, and severity of carotid stenosis was 60e79% for 6 of 16 lesions and 80% or more in all others. A single perioperative neurologic deficit was identified; all other patients (15/16) had no abnormalities detected by neurologic examination. Neuropsychological testing identified new postoperative deficits in 3 patients (19%), among whom 2 had a normal neurologic examination at all time points, whereas 1 had clinical evidence of stroke. Quantitative analysis of mean cerebral blood flow revealed postrevascularization increases for both gray matter (48.6 ± 13.9 mL per 100 g/min vs 75.3 ± 70.8 mL per 100 g/min) and white matter (31.8 ± 10.6 mL per 100 g/min vs 55.2 ± 30.1 mL per 100 g/min)(P ¼ 0.04). New postoperative MRI foci of restricted diffusion were identified in 2 patients, both of whom had no neurologic or neuropsychological deficit. Among patients with postoperative neuropsychological deficits, MRI revealed globally increased cerebral perfusion without new postoperative abnormalities in 2 of 3. Conclusions: The relationship between carotid revascularization and cognitive function is complex, and cognitive deficits may occur in the presence of increased cerebral perfusion without detectable embolization.
INTRODUCTION Departments of Vascular and Endovascular Surgery, Radiology, Cardiothoracic Surgery and Anesthesia, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Correspondence to: Matthew A. Corriere, MD, MS, Department of Vascular and Endovascular Surgery, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA; E-mail: [email protected] Ann Vasc Surg 2014; 28: 874–881 http://dx.doi.org/10.1016/j.avsg.2013.06.032 Ó 2014 Elsevier Inc. All rights reserved. Manuscript received: January 2, 2013; manuscript accepted: June 16, 2013; published online: November 4, 2013.
874
Carotid artery atherosclerosis is associated with increased risk of stroke, cognitive impairment, and cognitive decline.1e3 Carotid revascularization, including carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAS), is commonly performed in the setting of hemodynamically significant stenosis for stroke risk reduction, but may also impact cognitive function. Because cognitive function is associated with quality of life, disability, and mortality,4,5 procedure-related changes in
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cognitive function have significant implications for patients undergoing carotid revascularization, particularly among asymptomatic individuals. Cognitive outcomes observed after carotid revascularization have been inconsistent, with prospective studies reporting postrevascularization decline and improvement and significant heterogeneity between studies with regard to patient selection, testing, and end point definitions. Rates of new postprocedure cognitive deficits as high as 19e41% have been reported from prospective studies using categorical end point definitions,6e10 contrasting with analyses based on group-wise changes in mean scores reporting postprocedure cognitive improvement. Mechanistic relationships between procedural intervention and cognitive outcomes are also poorly understood. Cerebral embolization and alterations in global cerebral perfusion have been proposed as factors that may be responsible for cognitive changes, but correlation between imaging results and cognitive outcomes has been poor. New postrevascularization imaging findings consistent with ischemia or embolization (including diffusion-weighted imaging defects) have not been consistently associated with cognitive deficits; conversely, postrevascularization cognitive impairment may be observed in the absence of any cerebral imaging abnormality. To further explore associations between carotid revascularization and cognitive outcomes, the authors conducted a prospective longitudinal evaluation of patients undergoing elective CEA or CAS for hemodynamically significant carotid stenosis. Preoperative and postoperative evaluations with neurologic testing, neuropsychological testing, and cerebral magnetic resonance imaging (MRI) were compared to assess postrevascularization changes in cognitive function, neurologic function, and cerebral perfusion.
METHODS Patient Cohort and Clinical Data Collection This prospective longitudinal study was conducted with approval from the Wake Forest University Health Sciences Institutional Review Board. Adult patients at least 45 years old undergoing primary carotid revascularization for symptomatic or asymptomatic hemodynamically significant carotid artery stenosis were considered eligible for participation. Patients undergoing urgent or emergent carotid intervention, secondary treatment for restenosis, or treatment for nonatherosclerotic disease were
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excluded from consideration for enrollment. Neuropsychological testing was conducted at baseline and then postoperatively at 1 and 6 months; these intervals were selected to limit bias related to perioperative factors such as fatigue, pain, and residual effects of anesthetic or analgesic medications. Clinical data collected included medical history, vital and demographic data, medications, and procedure-related characteristics. Carotid stenosis was categorized as either symptomatic or asymptomatic based on clinical history. Severity of carotid stenosis was categorized based on duplex ultrasound using pulse velocity criteria and confirmed with contrast imaging (either preoperative computed tomography angiography, magnetic resonance angiography, or intraoperative contrast angiography) measured in a fashion consistent with the North American Symptomatic Carotid Endarterectomy Trial.11 MRI studies were performed on a 1.5 T TwinSpeed scanner (G.E. Healthcare, Milwaukee, WI) using a standardized, research specific protocol that included axial diffusion-weighted imaging, coronal fluid-attenuated inversion recovery (FLAIR), and pulsed arterial spin labeling (PASL). MRI studies were reviewed by a neuroradiologist (C.G.) blinded to the procedural details and neurobehavioral testing outcomes. Quantity and laterality of new diffusion and FLAIR abnormalities were determined through comparison of preoperative and postoperative images. Changes in PASL imaging were also assessed through comparisons between preoperative and postoperative images to determine effects of carotid revascularization on global cerebral perfusion. Neurobehavioral Assessments Components of the neuropsychological test battery included tests of higher cortical and language functioning (split-half version vocabulary test from the Wechsler Adult Intelligence Scale-Revised), tests of memory functioning (Rey Auditory Verbal Learning Test for verbal and nonverbal memory), and tests of attention, concentration, and psychomotor performance (Trail Making Test Parts A and B, Grooved Pegboard Test, finger tapping test, Digit Symbol Substitution Task, letter cancellation task, and visual reaction time test) (Table I). Neuropsychological functional assessments were administered by computer tool when compatible to this format to minimize observer-based variance. Postoperative neuropsychological change was assessed based on a 20% or greater deficit from preoperative levels on 2 or more neuropsychological tests at 1 or 6 months; this categorical definition was selected to maximize end point specificity while avoiding
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Table I. Neuropsychological test battery stratified by domains assessed with each test
Table II. Preoperative patient characteristics, anatomic, and procedural data
Domains assessed
Variable
Number (%) Mean ± SD
Female sex Age (years) Symptomatic carotid stenosis Medical history Hypertension Coronary artery disease Diabetes Stroke Congestive heart failure Chronic obstructive pulmonary disease Preoperative medications Aspirin Clopidogrel Statin Anatomic characteristics Percent carotid stenosis 60e79% 80% Previous laryngectomy or neck radiation Left-sided lesion Contralateral internal carotid artery occlusion Procedural characteristics Carotid endarterectomy Carotid angioplasty and stenting General anesthesia Carotid shunt
11 (69)
Tests
Higher cortical and language functioning
Vocabulary test (split-half version from the Wechsler Adult Intelligence ScaleRevised) Memory functioning Rey Auditory Verbal Learning Test Nonverbal memory Attention, concentration, Trail Making Test Parts A & B Grooved pegboard test and psychomotor Finger tapping test performance Digit Symbol Substitution Task/symbol digit task Letter cancellation task Visual reaction time test
misclassification of minor but statistically significant changes in performance as clinically meaningful events. Categorical assessments of postoperative deficits or improvements were also compared with mean changes in overall and domain-specific scores. Neurologic function was assessed based on the National Institutes of Health Stroke Scale (NIHSS),12 which was performed at baseline and then postintervention within 48 hours, at 1 month, and at 6 months. All NIHSS assessments were conducted by a nurse with instrument-specific training and certification who was blinded to neuropsychological testing results. Postoperative neurologic deficit was defined as presence of a new neurologic deficit or exacerbation of a preoperative neurologic deficit based on change in NIHSS. Statistical Analysis Descriptive statistics are displayed as mean ± standard deviation for normally distributed continuous variables, median (interquartile range) for nonparametrically distributed variables, and number (%) for categorical variables. Group-wise differences between preoperative and postoperative mean cerebral blood flow and neuropsychological test results were assessed using the signed rank test based on exact distributions. All statistical analyses were conducted using SAS version 9.2 (SAS Institute; Cary, NC, USA).
RESULTS Twenty-one patients underwent preoperative neurobehavioral testing and NIHSS assessment during the study period. Among these patients, 4 did not undergo postoperative neuropsychological evaluation,
69.8 ± 9.8 5 (31) 13 6 5 4 3 2
(81) (38) (31) (25) (19) (13)
12 (75) 8 (50) 14 (88)
6 (38) 10 (63) 1 (6) 10 (63) 3 (19)
15 (94) 1 (6) 4 (16) 2 (13)
Data displayed as number (%) for categorical variables and mean ± standard deviation for continuous variables.
and 1 did not undergo subsequent carotid intervention. The remaining 16 patients underwent carotid revascularization with both preoperative and postoperative neurobehavioral testing and constitute the study cohort. Patient and procedural characteristics are summarized in Table II. Mean participant age was 67.8 ± 9.8 years, and 11 of 16 participants (69%) were women. Hypertension and coronary artery disease were highly prevalent among participants, as were preoperative use of antiplatelet and statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase) medications. Four participants (25%) had a history of previous stroke, and 5 of 16 treated carotid lesions (31%) were considered symptomatic. Based on preoperative duplex ultrasound, severity of carotid stenosis was 60e79% for 6 of 16 lesions and 80% or greater in all others. A total of 15 patients (94%) were treated with carotid endarterectomy, and 1 patient with a history of previous laryngectomy was treated with CAS. General anesthesia was used
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Table III. Changes in neuropsychiatric test scores following carotid revascularization 1 Month Test a
Verbal memory Nonverbal memorya Trail Making Test Part Ab Trail Making Test Part Bb Grooved Pegboard Test (dominant hand)b Grooved Pegboard Test (nondominant hand)b Finger tapping test (dominant hand)a Finger tapping test (nondominant hand)a Digit Symbol Substitution Taskb Letter cancellation taskb Visual reaction timeb
6 Months
Median change (IQR)
P-value
Median change (IQR)
P-value
2.0 1.0 11.0 13.0 4.0 5.0 3.0 1.0 0.46 0.15 0.07
0.79 0.05 0.03 0.07 0.50 0.12 0.97 0.30 0.02 0.54 0.58
3.5 1.0 11.0 8.0 7.0 1.0 1.0 8.5 0.75 0.05 0.15
0.02 0.19 0.04 0.24 0.18 0.68 0.55 0.38 <0.01 0.84 0.06
(8.0) (3.0) (23.5) (29.0) (20.0) (24.0) (29.0) (16.0) (0.98) (0.50) (0.28)
(7.0) (3.0) (9.0) (66.0) (14.0) (18) (66.0) (17.0) (1.39) (0.21) (0.53)
Median change (interquartile range [IQR]) from preoperative scores among patients tested at each interval displayed stratified by domain category and test. a Increase ¼ improvement; decrease ¼ deficit. b Increase ¼ deficit; decrease ¼ improvement.
for 4 revascularization procedures; all other procedures were performed with monitored sedation plus local anesthesia. Based on NIHSS evaluation (NIHSS ¼ 2 at 48 hours, NIHSS ¼ 1 at 1 month, and NIHSS ¼ 0 at 6 months postrevascularization), a single perioperative stroke was identified in a patient treated with CEA for a symptomatic lesion. All other patients (15/16) had no abnormalities detected through neurologic examination (NIHSS ¼ 0 at all preoperative and postoperative evaluations). Changes in neuropsychological testing scores from baseline to postrevascularization are displayed in Table III. Neuropsychological testing identified new postoperative deficits (assessed based on 20% deficit in 2 domains) in 3 patients (19%), all of whom were treated with CEA. Among the 3 patients with a new postoperative neuropsychological deficit, 2 had a normal neurologic examination (NIHSS ¼ 0) at all time points, whereas one had clinical evidence of stroke. In addition to neurologic and neuropsychological testing, 8 participants (50%) underwent additional evaluation with preoperative and postoperative MRI. Diffusion-weighted imaging revealed new, focal postprocedure abnormalities in 2 patients: 1 treated with CEA and 1 treated with CAS. Pulsed arterial spin-labeling sequences consistently showed increased bilateral hemispheric cerebral blood flow after revascularization (Fig. 1). Quantitative analysis of changes in mean cerebral blood flow based on PASL imaging sequences revealed postrevascularization increases for both gray matter (48.6 ± 13.9 mL per 100 g/min vs 75.3 ± 70.8 mL per 100 g/min) and white matter (31.8 ± 10.6 mL per 100 g/min vs. 55.2 ± 30.1 mL per 100 g/min) (P ¼ 0.04 for
both comparisons). (Fig. 2). Of the 3 patients who developed new cognitive deficits, 2 were studied with MRI; both had globally increased postrevascularization cerebral perfusion without evidence of embolization, ischemia, or other abnormality.
DISCUSSION In this pilot study of patients undergoing elective carotid revascularization for hemodynamically significant stenosis, the authors observed a 19% incidence of new postoperative cognitive deficits. Cognitive deficits developed in the setting of postoperative MRI studies showed increased global cerebral perfusion without evidence of embolization or focal ischemia. Conversely, new postoperative MRI foci of restricted diffusion consistent with embolization were identified in 2 patients who had no evidence of neurologic or cognitive deficits. Although MRI studies in this analysis showed consistent postrevascularization improvement of both gray and white matter perfusion, improved perfusion did not eliminate the potential for procedure-related cognitive decline, even in the absence of embolization. Cerebral embolism and hypoperfusion have been suggested as potential mechanisms responsible for postoperative cognitive dysfunction after carotid revascularization.13 These results, which include MRI-based quantitative cerebral blood flow analysis, underscore the complex relationship between carotid revascularization and cognitive function, and show that cognitive deficits may occur in the presence of increased cerebral perfusion without detectable embolization. Although population-based
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Fig. 1. Masked PASL cerebral blood flow map based on MRI from a patient undergoing carotid endarterectomy. Comparison between preoperative (A) versus postoperative (B) images show global, bihemispheric increase in cerebral perfusion.
studies have shown associations between carotid stenosis and cognitive impairment and/or decline,1e3,14 the authors also believe that these results argue against the notion that increases in cerebral perfusion secondary to carotid revascularization are categorically protective against cognitive decline. To the contrary, the incidence of postoperative cognitive impairment observed in this study, wherein the cohort was predominantly female and most lesions were asymptomatic, suggests that the
potential benefits should be carefully considered before proceeding with intervention. The incidence of postrevascularization cognitive decline observed in this study is consistent with previous reports by others. Cognitive deficits have been identified in 19e41% of patients undergoing CEA or CAS.6e10 Lack of correlation between new brain lesions after carotid revascularization and cognitive performance has been described.8,15e17 Similar to the present findings, Heyer et al.8 noted that most
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Fig. 2. Comparison of baseline versus postrevascularization mean cerebral blood flow. Gray matter blood flow indicated by gray boxes; white matter blood flow indicated by white boxes. Error bars represent standard error of the mean.
cognitive deficits after CEA occurred without a corresponding MRI lesion, and vice versa. Although the small cohort size in the present study excluded multivariable modeling of cognitive outcomes, others have identified factors associated with increased risk for cognitive deterioration after carotid revascularization, including symptomatic left internal carotid artery stenosis,18,19 advanced age,20,21 diabetes,20,21 and elevated monocyte count.20 Soinne et al.22 reported a trend toward postoperative cognitive impairment but improvement in cerebral perfusion after CEA, with resolution of prerevascularization perfusion deficits ipsilateral to carotid stenosis. These authors noted subsequent cognitive improvement similar to that observed in control patients, however, with greatest improvement in patients with lower baseline perfusion. In contrast, others have reported the lack of significant change or postintervention cognitive improvement after carotid revascularization.17,23e28 The present study used a categorical definition of postintervention cognitive decline based on a 20% or greater decline in 2 or more domains. The authors did not, however, regard a similar increase in neuropsychiatric test results as indicative of cognitive improvement, because of inability to rule out a practice effect. Practice effects have been identified in prospective studies in which similar cognitive improvement has occurred in healthy controls without carotid stenosis versus patients with carotid stenosis undergoing procedural intervention.22
Although several studies have considered postoperative increases in mean neuropsychological test scores without adjustment for practice effects to be indicative of cognitive improvement,23e28 consensus guidelines have recommended consideration of practice effects when interpreting results of neuropsychological testing.29,30 Using mean changes without adjustment potentially reduces the sensitivity to detect postoperative deficits through allowing practice-related increases among individuals without deficits to cancel out declines in performance in individuals with cognitive impairment. The authors are therefore hesitant to interpret increases in mean test scores as indicative of improved cognitive function, and favor a definition based on a minimum threshold decline in performance that permits determination of the incidence of change based on individual patients. Their approach therefore permitted identification of patients with cognitive deficits, but did not include cognitive improvement as a potential outcome. Approaches that may allow detection of improvement while accounting for practice effects in future investigations include score adjustment or use of a control group. This study has several limitations, which deserve specific mention. Lack of power as a result of the small sample size, and the absence of a control group limit broad generalization of the findings. These power limitations, and the imbalance between revascularization approaches within the study cohort, also prevented stratified analysis of
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results using revascularization technique. The authors had no reason to exclude patients treated with CAS from this study, and the single CAS in the participant cohort reflects the conservative and relatively selective use of this revascularization approach within their clinical practice. Because all patients did not undergo MRI, the results of the imaging analysis are not representative of the entire study cohort, and therefore may be biased. Despite these limitations, the results further characterize cognitive outcomes associated with carotid revascularization and provide novel comparative data related to postrevascularization changes in global cerebral perfusion. Areas for future investigation include identification of imaging findings associated with cognitive outcomes, characterization of modifiable factors associated with cognitive outcomes in the setting of carotid revascularization, and characterization of the long-term impact of postoperative cognitive impairment.
This project was supported by funding from the Peripheral Vascular Surgery Society Academic Award. The authors would also like to acknowledge the contributions of the Wake Forest Center for Biomolecular Imaging and Dr. Padraig P. Morris toward the conduct of this study.
REFERENCES 1. Arntzen KA, Schirmer H, Johnsen SH, et al. Carotid atherosclerosis predicts lower cognitive test results: a 7-year follow-up study of 4,371 stroke-free subjects - the Tromso study. Cerebrovasc Dis 2012;33:159e65. 2. Johnston SC, O’Meara ES, Manolio TA, et al. Cognitive impairment and decline are associated with carotid artery disease in patients without clinically evident cerebrovascular disease. Ann Intern Med 2004;140:237e47. 3. Zhong W, Cruickshanks KJ, Huang GH, et al. Carotid atherosclerosis and cognitive function in midlife: the Beaver Dam Offspring Study. Atherosclerosis 2011;219:330e3. 4. McGuire LC, Ford ES, Ajani UA. Cognitive functioning as a predictor of functional disability in later life. Am J Geriatr Psychiatry 2006;14:36e42. 5. Patel MD, McKevitt C, Lawrence E, et al. Clinical determinants of long-term quality of life after stroke. Age Ageing 2007;36:316e22. 6. Crawley F, Stygall J, Lunn S, et al. Comparison of microembolism detected by transcranial Doppler and neuropsychological sequelae of carotid surgery and percutaneous transluminal angioplasty. Stroke 2000;31:1329e34. 7. Gaudet JG, Meyers PM, McKinsey JF, et al. Incidence of moderate to severe cognitive dysfunction in patients treated with carotid artery stenting. Neurosurgery 2009;65:325e9. discussion 9e30. 8. Heyer EJ, DeLaPaz R, Halazun HJ, et al. Neuropsychological dysfunction in the absence of structural evidence for cerebral ischemia after uncomplicated carotid endarterectomy. Neurosurgery 2006;58:474e80. discussion e80.
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9. Wilson DA, Mocco J, D’Ambrosio AL, et al. Post-carotid endarterectomy neurocognitive decline is associated with cerebral blood flow asymmetry on post-operative magnetic resonance perfusion brain scans. Neurol Res 2008;30: 302e6. 10. Witt K, Borsch K, Daniels C, et al. Neuropsychological consequences of endarterectomy and endovascular angioplasty with stent placement for treatment of symptomatic carotid stenosis: a prospective randomised study. J Neurol 2007;254:1524e32. 11. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445e53. 12. NIH Stroke Scale. Available at: http://www.nihstrokescale. org/. Accessed December 16, 2012. 13. Ghogawala Z, Westerveld M, Amin-Hanjani S. Cognitive outcomes after carotid revascularization: the role of cerebral emboli and hypoperfusion. Neurosurgery 2008;62:385e95. discussion 93e5. 14. Romero JR, Beiser A, Seshadri S, et al. Carotid artery atherosclerosis, MRI indices of brain ischemia, aging, and cognitive impairment: the Framingham study. Stroke 2009;40: 1590e6. 15. Wasser K, Pilgram-Pastor SM, Schnaudigel S, et al. New brain lesions after carotid revascularization are not associated with cognitive performance. J Vasc Surg 2011;53: 61e70. 16. Hirooka R, Ogasawara K, Sasaki M, et al. Magnetic resonance imaging in patients with cerebral hyperperfusion and cognitive impairment after carotid endarterectomy. J Neurosurg 2008;108:1178e83. 17. Raabe RD, Burr RB, Short R. One-year cognitive outcomes associated with carotid artery stent placement. J Vasc Interv Radiol 2010;21:983e8. quiz 9. 18. Bo M, Massaia M, Speme S, et al. Cognitive function after carotid endarterectomy: greater risk of decline in symptomatic patients with left internal carotid artery disease. J Stroke Cerebrovasc Dis 2005;14:221e8. 19. Bo M, Massaia M, Speme S, et al. Risk of cognitive decline in older patients after carotid endarterectomy: an observational study. J Am Geriatr Soc 2006;54:932e6. 20. Mocco J, Wilson DA, Ducruet AF, et al. Elevations in preoperative monocyte count predispose to acute neurocognitive decline after carotid endarterectomy for asymptomatic carotid artery stenosis. Stroke 2006;37:240e2. 21. Mocco J, Wilson DA, Komotar RJ, et al. Predictors of neurocognitive decline after carotid endarterectomy. Neurosurgery 2006;58:844e50. discussion 844e850. 22. Soinne L, Helenius J, Tikkala I, et al. The effect of severe carotid occlusive disease and its surgical treatment on cognitive functions of the brain. Brain Cogn 2009;69:353e9. 23. Baracchini C, Mazzalai F, Gruppo M, et al. Carotid endarterectomy protects elderly patients from cognitive decline: a prospective study. Surgery 2012;151:99e106. 24. Chen YH, Lin MS, Lee JK, et al. Carotid stenting improves cognitive function in asymptomatic cerebral ischemia. Int J Cardiol 2012;157:104e7. 25. Lal BK, Younes M, Cruz G, et al. Cognitive changes after surgery vs stenting for carotid artery stenosis. J Vasc Surg 2011;54:691e8. 26. Mendiz OA, Sposato LA, Fabbro N, et al. Improvement in executive function after unilateral carotid artery stenting for severe asymptomatic stenosis. J Neurosurg 2012;116: 179e84.
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27. Mlekusch W, Mlekusch I, Haumer M, et al. Improvement of neurocognitive function after protected carotid artery stenting. Catheter Cardiovasc Interv 2008;71:114e9. 28. Turk AS, Chaudry I, Haughton VM, et al. Effect of carotid artery stenting on cognitive function in patients with carotid artery stenosis: preliminary results. AJNR Am J Neuroradiol 2008;29:265e8.
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29. Murkin JM, Newman SP, Stump DA, et al. Statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery. Ann Thorac Surg 1995;59:1289e95. 30. Murkin JM, Stump DA, Blumenthal JA, et al. Defining dysfunction: group means versus incidence analysise a statement of consensus. Ann Thorac Surg 1997;64: 904e5.
Background: Carotid revascularization, including carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAS), is performed for stroke risk reduction but may also impact cognitive function. Cognitive outcomes observed after carotid revascularization have been inconsistent, and mechanistic relationships with procedural factors are poorly understood. To further explore associations between carotid revascularization and cognitive outcomes, a prospective longitudinal evaluation was conducted of patients undergoing elective CEA or CAS for hemodynamically significant carotid stenosis. Methods: Patients undergoing primary carotid artery revascularization for hemodynamically significant stenosis were evaluated with neurologic and neuropsychological testing at baseline and at 1 and 6 months after revascularization. A subgroup of patients was also studied with baseline and postoperative magnetic resonance imaging (MRI). Outcomes included neurologic or neuropsychological deficits and imaging findings (including quantitative assessment of cerebral blood flow). Results: Sixteen patients underwent carotid revascularization with both preoperative and postoperative neurologic and neuropsychological testing; preoperative and postoperative MRIs were also performed on eight patients. Five of 16 treated carotid lesions (31%) were considered symptomatic, and severity of carotid stenosis was 60e79% for 6 of 16 lesions and 80% or more in all others. A single perioperative neurologic deficit was identified; all other patients (15/16) had no abnormalities detected by neurologic examination. Neuropsychological testing identified new postoperative deficits in 3 patients (19%), among whom 2 had a normal neurologic examination at all time points, whereas 1 had clinical evidence of stroke. Quantitative analysis of mean cerebral blood flow revealed postrevascularization increases for both gray matter (48.6 ± 13.9 mL per 100 g/min vs 75.3 ± 70.8 mL per 100 g/min) and white matter (31.8 ± 10.6 mL per 100 g/min vs 55.2 ± 30.1 mL per 100 g/min)(P ¼ 0.04). New postoperative MRI foci of restricted diffusion were identified in 2 patients, both of whom had no neurologic or neuropsychological deficit. Among patients with postoperative neuropsychological deficits, MRI revealed globally increased cerebral perfusion without new postoperative abnormalities in 2 of 3. Conclusions: The relationship between carotid revascularization and cognitive function is complex, and cognitive deficits may occur in the presence of increased cerebral perfusion without detectable embolization.
INTRODUCTION Departments of Vascular and Endovascular Surgery, Radiology, Cardiothoracic Surgery and Anesthesia, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Correspondence to: Matthew A. Corriere, MD, MS, Department of Vascular and Endovascular Surgery, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA; E-mail: [email protected] Ann Vasc Surg 2014; 28: 874–881 http://dx.doi.org/10.1016/j.avsg.2013.06.032 Ó 2014 Elsevier Inc. All rights reserved. Manuscript received: January 2, 2013; manuscript accepted: June 16, 2013; published online: November 4, 2013.
874
Carotid artery atherosclerosis is associated with increased risk of stroke, cognitive impairment, and cognitive decline.1e3 Carotid revascularization, including carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAS), is commonly performed in the setting of hemodynamically significant stenosis for stroke risk reduction, but may also impact cognitive function. Because cognitive function is associated with quality of life, disability, and mortality,4,5 procedure-related changes in
Vol. 28, No. 4, May 2014
cognitive function have significant implications for patients undergoing carotid revascularization, particularly among asymptomatic individuals. Cognitive outcomes observed after carotid revascularization have been inconsistent, with prospective studies reporting postrevascularization decline and improvement and significant heterogeneity between studies with regard to patient selection, testing, and end point definitions. Rates of new postprocedure cognitive deficits as high as 19e41% have been reported from prospective studies using categorical end point definitions,6e10 contrasting with analyses based on group-wise changes in mean scores reporting postprocedure cognitive improvement. Mechanistic relationships between procedural intervention and cognitive outcomes are also poorly understood. Cerebral embolization and alterations in global cerebral perfusion have been proposed as factors that may be responsible for cognitive changes, but correlation between imaging results and cognitive outcomes has been poor. New postrevascularization imaging findings consistent with ischemia or embolization (including diffusion-weighted imaging defects) have not been consistently associated with cognitive deficits; conversely, postrevascularization cognitive impairment may be observed in the absence of any cerebral imaging abnormality. To further explore associations between carotid revascularization and cognitive outcomes, the authors conducted a prospective longitudinal evaluation of patients undergoing elective CEA or CAS for hemodynamically significant carotid stenosis. Preoperative and postoperative evaluations with neurologic testing, neuropsychological testing, and cerebral magnetic resonance imaging (MRI) were compared to assess postrevascularization changes in cognitive function, neurologic function, and cerebral perfusion.
METHODS Patient Cohort and Clinical Data Collection This prospective longitudinal study was conducted with approval from the Wake Forest University Health Sciences Institutional Review Board. Adult patients at least 45 years old undergoing primary carotid revascularization for symptomatic or asymptomatic hemodynamically significant carotid artery stenosis were considered eligible for participation. Patients undergoing urgent or emergent carotid intervention, secondary treatment for restenosis, or treatment for nonatherosclerotic disease were
Cognitive function after carotid revascularization
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excluded from consideration for enrollment. Neuropsychological testing was conducted at baseline and then postoperatively at 1 and 6 months; these intervals were selected to limit bias related to perioperative factors such as fatigue, pain, and residual effects of anesthetic or analgesic medications. Clinical data collected included medical history, vital and demographic data, medications, and procedure-related characteristics. Carotid stenosis was categorized as either symptomatic or asymptomatic based on clinical history. Severity of carotid stenosis was categorized based on duplex ultrasound using pulse velocity criteria and confirmed with contrast imaging (either preoperative computed tomography angiography, magnetic resonance angiography, or intraoperative contrast angiography) measured in a fashion consistent with the North American Symptomatic Carotid Endarterectomy Trial.11 MRI studies were performed on a 1.5 T TwinSpeed scanner (G.E. Healthcare, Milwaukee, WI) using a standardized, research specific protocol that included axial diffusion-weighted imaging, coronal fluid-attenuated inversion recovery (FLAIR), and pulsed arterial spin labeling (PASL). MRI studies were reviewed by a neuroradiologist (C.G.) blinded to the procedural details and neurobehavioral testing outcomes. Quantity and laterality of new diffusion and FLAIR abnormalities were determined through comparison of preoperative and postoperative images. Changes in PASL imaging were also assessed through comparisons between preoperative and postoperative images to determine effects of carotid revascularization on global cerebral perfusion. Neurobehavioral Assessments Components of the neuropsychological test battery included tests of higher cortical and language functioning (split-half version vocabulary test from the Wechsler Adult Intelligence Scale-Revised), tests of memory functioning (Rey Auditory Verbal Learning Test for verbal and nonverbal memory), and tests of attention, concentration, and psychomotor performance (Trail Making Test Parts A and B, Grooved Pegboard Test, finger tapping test, Digit Symbol Substitution Task, letter cancellation task, and visual reaction time test) (Table I). Neuropsychological functional assessments were administered by computer tool when compatible to this format to minimize observer-based variance. Postoperative neuropsychological change was assessed based on a 20% or greater deficit from preoperative levels on 2 or more neuropsychological tests at 1 or 6 months; this categorical definition was selected to maximize end point specificity while avoiding
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Table I. Neuropsychological test battery stratified by domains assessed with each test
Table II. Preoperative patient characteristics, anatomic, and procedural data
Domains assessed
Variable
Number (%) Mean ± SD
Female sex Age (years) Symptomatic carotid stenosis Medical history Hypertension Coronary artery disease Diabetes Stroke Congestive heart failure Chronic obstructive pulmonary disease Preoperative medications Aspirin Clopidogrel Statin Anatomic characteristics Percent carotid stenosis 60e79% 80% Previous laryngectomy or neck radiation Left-sided lesion Contralateral internal carotid artery occlusion Procedural characteristics Carotid endarterectomy Carotid angioplasty and stenting General anesthesia Carotid shunt
11 (69)
Tests
Higher cortical and language functioning
Vocabulary test (split-half version from the Wechsler Adult Intelligence ScaleRevised) Memory functioning Rey Auditory Verbal Learning Test Nonverbal memory Attention, concentration, Trail Making Test Parts A & B Grooved pegboard test and psychomotor Finger tapping test performance Digit Symbol Substitution Task/symbol digit task Letter cancellation task Visual reaction time test
misclassification of minor but statistically significant changes in performance as clinically meaningful events. Categorical assessments of postoperative deficits or improvements were also compared with mean changes in overall and domain-specific scores. Neurologic function was assessed based on the National Institutes of Health Stroke Scale (NIHSS),12 which was performed at baseline and then postintervention within 48 hours, at 1 month, and at 6 months. All NIHSS assessments were conducted by a nurse with instrument-specific training and certification who was blinded to neuropsychological testing results. Postoperative neurologic deficit was defined as presence of a new neurologic deficit or exacerbation of a preoperative neurologic deficit based on change in NIHSS. Statistical Analysis Descriptive statistics are displayed as mean ± standard deviation for normally distributed continuous variables, median (interquartile range) for nonparametrically distributed variables, and number (%) for categorical variables. Group-wise differences between preoperative and postoperative mean cerebral blood flow and neuropsychological test results were assessed using the signed rank test based on exact distributions. All statistical analyses were conducted using SAS version 9.2 (SAS Institute; Cary, NC, USA).
RESULTS Twenty-one patients underwent preoperative neurobehavioral testing and NIHSS assessment during the study period. Among these patients, 4 did not undergo postoperative neuropsychological evaluation,
69.8 ± 9.8 5 (31) 13 6 5 4 3 2
(81) (38) (31) (25) (19) (13)
12 (75) 8 (50) 14 (88)
6 (38) 10 (63) 1 (6) 10 (63) 3 (19)
15 (94) 1 (6) 4 (16) 2 (13)
Data displayed as number (%) for categorical variables and mean ± standard deviation for continuous variables.
and 1 did not undergo subsequent carotid intervention. The remaining 16 patients underwent carotid revascularization with both preoperative and postoperative neurobehavioral testing and constitute the study cohort. Patient and procedural characteristics are summarized in Table II. Mean participant age was 67.8 ± 9.8 years, and 11 of 16 participants (69%) were women. Hypertension and coronary artery disease were highly prevalent among participants, as were preoperative use of antiplatelet and statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase) medications. Four participants (25%) had a history of previous stroke, and 5 of 16 treated carotid lesions (31%) were considered symptomatic. Based on preoperative duplex ultrasound, severity of carotid stenosis was 60e79% for 6 of 16 lesions and 80% or greater in all others. A total of 15 patients (94%) were treated with carotid endarterectomy, and 1 patient with a history of previous laryngectomy was treated with CAS. General anesthesia was used
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Table III. Changes in neuropsychiatric test scores following carotid revascularization 1 Month Test a
Verbal memory Nonverbal memorya Trail Making Test Part Ab Trail Making Test Part Bb Grooved Pegboard Test (dominant hand)b Grooved Pegboard Test (nondominant hand)b Finger tapping test (dominant hand)a Finger tapping test (nondominant hand)a Digit Symbol Substitution Taskb Letter cancellation taskb Visual reaction timeb
6 Months
Median change (IQR)
P-value
Median change (IQR)
P-value
2.0 1.0 11.0 13.0 4.0 5.0 3.0 1.0 0.46 0.15 0.07
0.79 0.05 0.03 0.07 0.50 0.12 0.97 0.30 0.02 0.54 0.58
3.5 1.0 11.0 8.0 7.0 1.0 1.0 8.5 0.75 0.05 0.15
0.02 0.19 0.04 0.24 0.18 0.68 0.55 0.38 <0.01 0.84 0.06
(8.0) (3.0) (23.5) (29.0) (20.0) (24.0) (29.0) (16.0) (0.98) (0.50) (0.28)
(7.0) (3.0) (9.0) (66.0) (14.0) (18) (66.0) (17.0) (1.39) (0.21) (0.53)
Median change (interquartile range [IQR]) from preoperative scores among patients tested at each interval displayed stratified by domain category and test. a Increase ¼ improvement; decrease ¼ deficit. b Increase ¼ deficit; decrease ¼ improvement.
for 4 revascularization procedures; all other procedures were performed with monitored sedation plus local anesthesia. Based on NIHSS evaluation (NIHSS ¼ 2 at 48 hours, NIHSS ¼ 1 at 1 month, and NIHSS ¼ 0 at 6 months postrevascularization), a single perioperative stroke was identified in a patient treated with CEA for a symptomatic lesion. All other patients (15/16) had no abnormalities detected through neurologic examination (NIHSS ¼ 0 at all preoperative and postoperative evaluations). Changes in neuropsychological testing scores from baseline to postrevascularization are displayed in Table III. Neuropsychological testing identified new postoperative deficits (assessed based on 20% deficit in 2 domains) in 3 patients (19%), all of whom were treated with CEA. Among the 3 patients with a new postoperative neuropsychological deficit, 2 had a normal neurologic examination (NIHSS ¼ 0) at all time points, whereas one had clinical evidence of stroke. In addition to neurologic and neuropsychological testing, 8 participants (50%) underwent additional evaluation with preoperative and postoperative MRI. Diffusion-weighted imaging revealed new, focal postprocedure abnormalities in 2 patients: 1 treated with CEA and 1 treated with CAS. Pulsed arterial spin-labeling sequences consistently showed increased bilateral hemispheric cerebral blood flow after revascularization (Fig. 1). Quantitative analysis of changes in mean cerebral blood flow based on PASL imaging sequences revealed postrevascularization increases for both gray matter (48.6 ± 13.9 mL per 100 g/min vs 75.3 ± 70.8 mL per 100 g/min) and white matter (31.8 ± 10.6 mL per 100 g/min vs. 55.2 ± 30.1 mL per 100 g/min) (P ¼ 0.04 for
both comparisons). (Fig. 2). Of the 3 patients who developed new cognitive deficits, 2 were studied with MRI; both had globally increased postrevascularization cerebral perfusion without evidence of embolization, ischemia, or other abnormality.
DISCUSSION In this pilot study of patients undergoing elective carotid revascularization for hemodynamically significant stenosis, the authors observed a 19% incidence of new postoperative cognitive deficits. Cognitive deficits developed in the setting of postoperative MRI studies showed increased global cerebral perfusion without evidence of embolization or focal ischemia. Conversely, new postoperative MRI foci of restricted diffusion consistent with embolization were identified in 2 patients who had no evidence of neurologic or cognitive deficits. Although MRI studies in this analysis showed consistent postrevascularization improvement of both gray and white matter perfusion, improved perfusion did not eliminate the potential for procedure-related cognitive decline, even in the absence of embolization. Cerebral embolism and hypoperfusion have been suggested as potential mechanisms responsible for postoperative cognitive dysfunction after carotid revascularization.13 These results, which include MRI-based quantitative cerebral blood flow analysis, underscore the complex relationship between carotid revascularization and cognitive function, and show that cognitive deficits may occur in the presence of increased cerebral perfusion without detectable embolization. Although population-based
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Fig. 1. Masked PASL cerebral blood flow map based on MRI from a patient undergoing carotid endarterectomy. Comparison between preoperative (A) versus postoperative (B) images show global, bihemispheric increase in cerebral perfusion.
studies have shown associations between carotid stenosis and cognitive impairment and/or decline,1e3,14 the authors also believe that these results argue against the notion that increases in cerebral perfusion secondary to carotid revascularization are categorically protective against cognitive decline. To the contrary, the incidence of postoperative cognitive impairment observed in this study, wherein the cohort was predominantly female and most lesions were asymptomatic, suggests that the
potential benefits should be carefully considered before proceeding with intervention. The incidence of postrevascularization cognitive decline observed in this study is consistent with previous reports by others. Cognitive deficits have been identified in 19e41% of patients undergoing CEA or CAS.6e10 Lack of correlation between new brain lesions after carotid revascularization and cognitive performance has been described.8,15e17 Similar to the present findings, Heyer et al.8 noted that most
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Fig. 2. Comparison of baseline versus postrevascularization mean cerebral blood flow. Gray matter blood flow indicated by gray boxes; white matter blood flow indicated by white boxes. Error bars represent standard error of the mean.
cognitive deficits after CEA occurred without a corresponding MRI lesion, and vice versa. Although the small cohort size in the present study excluded multivariable modeling of cognitive outcomes, others have identified factors associated with increased risk for cognitive deterioration after carotid revascularization, including symptomatic left internal carotid artery stenosis,18,19 advanced age,20,21 diabetes,20,21 and elevated monocyte count.20 Soinne et al.22 reported a trend toward postoperative cognitive impairment but improvement in cerebral perfusion after CEA, with resolution of prerevascularization perfusion deficits ipsilateral to carotid stenosis. These authors noted subsequent cognitive improvement similar to that observed in control patients, however, with greatest improvement in patients with lower baseline perfusion. In contrast, others have reported the lack of significant change or postintervention cognitive improvement after carotid revascularization.17,23e28 The present study used a categorical definition of postintervention cognitive decline based on a 20% or greater decline in 2 or more domains. The authors did not, however, regard a similar increase in neuropsychiatric test results as indicative of cognitive improvement, because of inability to rule out a practice effect. Practice effects have been identified in prospective studies in which similar cognitive improvement has occurred in healthy controls without carotid stenosis versus patients with carotid stenosis undergoing procedural intervention.22
Although several studies have considered postoperative increases in mean neuropsychological test scores without adjustment for practice effects to be indicative of cognitive improvement,23e28 consensus guidelines have recommended consideration of practice effects when interpreting results of neuropsychological testing.29,30 Using mean changes without adjustment potentially reduces the sensitivity to detect postoperative deficits through allowing practice-related increases among individuals without deficits to cancel out declines in performance in individuals with cognitive impairment. The authors are therefore hesitant to interpret increases in mean test scores as indicative of improved cognitive function, and favor a definition based on a minimum threshold decline in performance that permits determination of the incidence of change based on individual patients. Their approach therefore permitted identification of patients with cognitive deficits, but did not include cognitive improvement as a potential outcome. Approaches that may allow detection of improvement while accounting for practice effects in future investigations include score adjustment or use of a control group. This study has several limitations, which deserve specific mention. Lack of power as a result of the small sample size, and the absence of a control group limit broad generalization of the findings. These power limitations, and the imbalance between revascularization approaches within the study cohort, also prevented stratified analysis of
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results using revascularization technique. The authors had no reason to exclude patients treated with CAS from this study, and the single CAS in the participant cohort reflects the conservative and relatively selective use of this revascularization approach within their clinical practice. Because all patients did not undergo MRI, the results of the imaging analysis are not representative of the entire study cohort, and therefore may be biased. Despite these limitations, the results further characterize cognitive outcomes associated with carotid revascularization and provide novel comparative data related to postrevascularization changes in global cerebral perfusion. Areas for future investigation include identification of imaging findings associated with cognitive outcomes, characterization of modifiable factors associated with cognitive outcomes in the setting of carotid revascularization, and characterization of the long-term impact of postoperative cognitive impairment.
This project was supported by funding from the Peripheral Vascular Surgery Society Academic Award. The authors would also like to acknowledge the contributions of the Wake Forest Center for Biomolecular Imaging and Dr. Padraig P. Morris toward the conduct of this study.
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27. Mlekusch W, Mlekusch I, Haumer M, et al. Improvement of neurocognitive function after protected carotid artery stenting. Catheter Cardiovasc Interv 2008;71:114e9. 28. Turk AS, Chaudry I, Haughton VM, et al. Effect of carotid artery stenting on cognitive function in patients with carotid artery stenosis: preliminary results. AJNR Am J Neuroradiol 2008;29:265e8.
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