Evaluation of Subclinical Cerebral Injury and Neuropsychologic Function in Patients Undergoing Carotid Endarterectomy

Article Outline

• Abstract
• Introduction
• Methods
  • Subjects
  • Anesthesia and Surgery
  • Neurological Tests
  • Neuropsychological Evaluation
  • Laboratory Analyses
  • Statistical Analyses
• Results
• Discussion
• Conclusion
• Acknowledgment
• References
• Copyright

We examined subclinical alterations of cerebral function during carotid endarterectomy (CEA) and predictability of minor cerebral damage by perioperative levels of biochemical markers of brain damage (S100B and neuron-specific enolase [NSE]). Twenty consecutive patients with ≥70% asymptomatic carotid stenosis undergoing elective CEA were enrolled. Pre- and postoperative testing included magnetic resonance imaging (MRI) of the head, a standardized neurological exam, a battery of neuropsychological tests, and measurement of serum levels of S100B and NSE. There were no major ischemic strokes. In one patient, a mild weakness of the contralateral lower extremity was discovered on neurological examination; in another individual, postoperative MRI revealed two new small subcortical lesions without clinical correlate. While S100B increased significantly early after opening of the carotid clamp (p = 0.015), the NSE increase did not reach statistical significance. As a group, participants obtained a significantly higher mean overall neuropsychological score at follow-up testing (p < 0.05). In one patient, a significant decline of cognitive function was observed. This was the only individual to obtain a consistently high S100B and NSE increase. Neuropsychological testing combined with measurements of S100B and NSE may improve sensitivity when assessing subtle cerebral damage following CEA.

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Introduction 

Carotid endarterectomy (CEA) is an effective procedure for primary¹, ² as well as secondary³, ⁴ prevention of stroke in patients with significant carotid stenosis. Although the incidence of perioperative ischemic stroke is relatively low, the risk of more subtle neurological injury remains controversial. Conflicting results have been published concerning the influence of CEA on cognitive function. While some authors did not observe a relevant change in neuropsychological functioning,⁵ others have described deterioration in the early postoperative phase that may persist for at least a few weeks.⁶, ⁷, ⁸ Fearn et al.⁹ found a significant improvement in average reaction time and memory scores. However, a wide variety of neuropsychological tests were used in the different studies, and there is no consensus concerning the ideal timing of the examinations.¹⁰

Serum concentrations of neuron-specific enolase (NSE) and the calcium-binding protein S100B have been described as markers of severe neurological injury¹¹ and are associated with short- and long-term neuropsychological outcome after traumatic brain injury.¹² S100 is an intracellular dimeric calcium-binding protein. The heterodimer (αβ isoform) and homodimer (ββ isoform, also called S100B) are found in high concentrations in astrocytes and Schwann cells.¹³ The half-life of S100B in serum is 2 hr.¹⁴ S100B levels peak within 2-3 days after stroke, and concentrations correlate with infarct volume and clinical outcome.¹¹ Although potential release of S100B from fat and skeletal muscle tissue has raised concerns about the specificity of serum S100B analysis for detection of cerebral damage during surgical procedures,¹⁵ a recent article suggested that surgery to the neck including CEA and thyroidectomy did not increase serum S100B levels.¹⁶

NSE, the homodimeric γγ isoform of the glycolytic enzyme enolase, is found in the cytoplasm of neurons.¹⁷ The half-life in human serum is 24 hr.¹³ Serum concentrations of NSE peak between 7 and 48 hr after cerebral injury, and levels also correlate with infarct volume.¹¹

To investigate the risk of minimal cerebral damage, we designed a prospective study focusing on neuropsychological functioning. We combined a battery of neuropsychological tests with a standardized neurological exam, magnetic resonance imaging (MRI), as well as laboratory testing. Neuropsychological tests were performed within 30 days prior to surgery and at two separate occasions thereafter, leaving sufficient postoperative recovery time to avoid bias caused by postoperative fatigue. The tests focused on a combination of cognitive domains, with an emphasis on tasks considered sensitive to frontal and subcortical injury because emboli from the carotid arteries are more likely to affect brain areas supplied by the anterior and middle cerebral arteries. In order to exclude bias from mood disturbance, we applied the Beck Depression Inventory–II. In addition, a reliable change index was calculated to evaluate whether changes in individual neuropsychological performance could be considered to be beyond a practice effect from repeated evaluations. This study was designed as a pilot study with the intent that if a significant trend was identified, a trial would be designed with sufficient numbers to reach clinical significance.

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Methods 

Subjects 

Twenty consecutive patients undergoing elective CEA were enrolled in this study and gave written informed consent. Inclusion criteria were patient age between 55 and 80 years and asymptomatic carotid stenosis ≥70%, based on duplex ultrasound examinations. Patients with bilateral carotid stenosis were eligible, but treatment of the nonstudy artery had to take place 180 days prior to or after the study procedure. Exclusion criteria were evolving stroke or a history of stroke, significant cortical infarct on computed tomography (CT) or diffusion-weighted MRI (DWI), knowledge of cardiac sources of emboli, and a history of other neurological diseases, endocrine tumors, or alcoholism. All patients underwent MRI of the head within 30 days prior to surgery and after 2 months. A standardized neurological exam, based on the National Institutes of Health (NIH) Stroke Scale, as well as a battery of neuropsychological tests were performed within 30 days prior to surgery and at standardized intervals thereafter. The study protocol was approved by the institutional review board, and all participants gave written informed consent.

Anesthesia and Surgery 

All procedures were performed under general anesthesia with standard anesthetic monitoring and continuous electroencephalographic (EEG) measurement. General endotracheal anesthesia was introduced with fentanyl, midazolam, and vercuronium and was maintained with isoflurane or sevoflurane. Unfractionated heparin (5,000 units) was given intravenously to all patients prior to carotid clamping. A Sundt shunt was only used when changes in the intraoperative EEG were observed. CEA was performed using a standard open technique on the common carotid artery (CCA) and internal carotid artery (ICA) with eversion endarterectomy of the external carotid artery (ECA). The patch angioplasty was closed using a bovine pericardium patch (Vascuguard^®; Bio-Vascular, St. Paul, MN) and running monofilament 6-0 Prolene sutures.¹⁸ In two patients, an eversion endarterectomy of the ICA was performed. All patients were administered aspirin therapy, unless on anticoagulants, beginning preoperatively and continuing postoperatively.

Neurological Tests 

A standardized neurological exam was performed prior to surgery and at postoperative day 2, prior to discharge, as well as after 1 and 6 months. The NIH Stroke Scale is an 11-item clinical evaluation instrument widely used in clinical trials and practice to assess neurological function and degree of recovery. The instrument's reliability¹⁹, ²⁰, ²¹ and validity²², ²³ are well-documented.

Neuropsychological Evaluation 

Patients underwent neurocognitive testing 1-10 days before surgery and 7-10 days as well as 6 months following the surgical procedure. The Mini-Mental State Examination²⁴ and the North American Adult Reading Test²⁵ were conducted to exclude major disturbances of cerebral functioning and intelligence. Then, a battery of 11 tests was administered (see Table I). These included a sampling of cognitive domains with an emphasis on tasks of processing speed and executive function considered sensitive to frontal and subcortical injury. The tests were administered in an outpatient setting and took 1-1.5 hr to complete. These neurocognitive measures have well-established administrative standardization and normative data.²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹ In addition, since mood may affect cognitive function, a screen for depression was included using the Beck Depression Inventory–II.³²

Table I. Neuropsychological test battery

Laboratory Analyses 

Blood samples were drawn from an antecubital vein before surgery in the holding area and at 1, 4, 24, 48, and 96 hr after opening of the carotid clamp. Samples were centrifuged within 30 min, and serum was frozen and stored at −30°C until analysis.

S100B was determined using a commercially available test kit (Sangtec^® 100 ELISA; DiaSorin, Bromma, Sweden). Measurements were performed on an automated device (Molecular Devices, Palo Alto, CA; SpectraMAX 340 plate reader). A detection limit of 0.14 μg/L was determined for this test. Because of the preliminary nature of this study, a cut-off value was not determined for this test.

The NSE assay was a sandwich immunochemiluminometric assay and utilized a test kit from Hybritech (San Diego, CA). Measurements were performed using the Magic Lite Analyzer II tube reader (CIBA-Corning, Medfield, MA). The detection limit was 1.6 μg/L, and the cut-off level was 30 μg/L.

Statistical Analyses 

Changes in serum concentrations of biochemical markers and in raw and age-adjusted scaled scores on neuropsychological tests were analyzed using paired t-test analyses. To examine overall cognitive functioning at each time point, a composite measure of neuropsychological test performance was calculated by averaging all age-adjusted scaled scores. The potential relationship between age and depression (scores on the Beck Depression Inventory Scale–II) and biochemical markers was evaluated through Pearson correlation coefficients. In addition, a reliable change index (RCI) was calculated to evaluate whether test–retest changes in individual neuropsychological measures represented changes considered to be significant beyond what would be considered a practice effect from repeated evaluations.³³, ³⁴ To obtain the RCI, we first calculated the practice effects for each neuropsychological test, which consisted of the retest score minus the baseline score. Then, the test–retest reliability coefficient (r_xy) was calculated for each neuropsychological test. A 90% confidence interval (CI) was then calculated based on the standard error of the difference (SE_diff):

The 90% CI was obtained by multiplying SE_diff by the corresponding value from the z-distribution (±1.64). This provides an upper and lower boundary around the mean practice effect. Scores beyond this interval represent statistically significant change. The practice-adjusted RCI was then used to measure how many tests changed significantly for each study participant. For participants who demonstrated reliable change, the relationship between the neuropsychological test scores and the biochemical markers was analyzed further.

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Results 

Twenty patients (13 male, 7 female) were recruited to take part in this study. Mean age was 71.6 ± 4.7 years (range 55.2-76.1), and mean education time was 14.3 ± 3.0 years (range 12-20). Estimated premorbid verbal intellectual function was as shown in Table II (range from a low average estimated IQ of 80 to superior estimated IQ of 121). One participant scored at the low average range, 65% were average, while 30% of the sample had IQ estimates of either high average or above average. On the Mini-Mental State Examination, a global screen of mental status, all patients performed above the cut-off of 23 with no decline in global functioning postoperatively (see Table II).

Table II. Estimated premorbid verbal intellect, global mental status, and depression

M, mean; SD, standard deviation. NAART scores are age-corrected standard scores (mean 100 ± 15), paired t-test comparisons between baseline and retest 7-10 days and between baseline and retest 6 months.

One patient was excluded when his surgery was canceled after he developed chest pain in the preoperative holding area. Two patients did not undergo postoperative MRI, and three patients did not return for the 6-month postoperative examination.

Average operating time was 124.2 min (range 95-193), and mean clamping time was 51.5 min (range 39-76). EEG changes were observed in four patients after carotid clamping. These resolved spontaneously in two cases and resulted in insertion of a Sundt shunt in the two other patients, with subsequent normalization of the EEG.

Postoperative MRI revealed two new small subcortical lesions in one patient on DWI; however, this individual had normal postoperative neurological testing, and laboratory parameters remained at baseline. There were no major perioperative neurological events. New neurological signs upon postoperative testing included one case of ipsilateral hypoglossal neuropathy that resulted in a mild transient dysarthria and one case of transient ipsilateral facial numbness. In one clinically asymptomatic patient, a mild weakness of the contralateral lower extremity and a mildly reduced patellar reflex of the same extremity were discovered by close neurological testing, and the weakness persisted at least until the 6-month follow-up. These symptoms of peripheral neurological damage were not related to biochemical or neuropsychological alterations or abnormalities on follow-up imaging.

Time courses of S100B and NSE serum concentrations are given in Figures 1 and 2. S100B increased in 14 patients (70%). Compared to baseline, the average S100B increase was significant 1 hr after opening of the carotid clamp (p = 0.015) and returned to baseline within 24 hr. One patient (patient 3) showed a sustained S100B increase above the 99% CI across the observed time period (see Fig. 1). NSE increased in 18 patients (90%), but none of the patients had NSE concentrations above the cut-off value. The average NSE increase did not reach statistical significance (see Fig. 2). S100B and NSE time courses were not correlated.

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• Fig. 1 

  Mean S100B levels at baseline and 1, 4, 24, 28, and 96 hours postoperatively.

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• Fig. 2 

  Mean NSE levels at baseline and 1, 4, 24, 48, and 96 hours postoperatively.

There was no significant association between participant age at baseline testing and the biochemical markers. There was no relationship between depression scores and biochemical markers or performance on the neuropsychological tests.

Mean age-adjusted scaled scores for neuropsychological tests at baseline and follow-up are presented in Table III. There was significant improvement in attention/visual-motor speed (Digit Symbol performance: time 2 t = 4.19, p = 0.001; time 3 t = 2.82, p = 0.01), verbal memory (delayed recall: time 2 t = 2.73, p = 0.014; time 3 t = 3.87, p < 0.001; and percent retention on the Auditory Verbal Learning Test: time 2 t = 1.83, p = 0.08; time 3 t = 2.59, p = 0.02). The improvement in delayed recall was inversely associated with the absolute increase of S100B (r = −0.50, p < 0.05) but not with NSE (r = −0.01, p = 0.98). Conversely, there was a significant decline on one test assessing processing speed at the 6-month follow-up examination (Word reading trial of the Stroop Color-Word Test: t = −2.83, p = 0.01).

Table III. Neurocognitive performance at baseline and at 7-10 days and 6 months postoperative follow-up

M, mean; SD, standard deviation. Scores reflect age-corrected scale scores (mean 10 ± 3). Paired t-test comparisons between baseline and retest 7-10 days and baseline and retest 6 months.

Overall, participants showed significant cognitive improvement at initial follow-up 7-10 days after surgery (t = 2.79, p = 0.012), with these gains maintained at the 6-month follow-up assessment (t = 2.54, p = 0.02). Three participants, however, demonstrated a decline at the initial follow-up testing, and three different patients had a deterioration of the overall scaled score at 6-month follow-up testing. To determine if these declines were statistically relevant, reliable change indices were calculated for each neuropsychological test. Given the number of tests included in this battery, only two tests per participant would be expected to exceed the 90% CI by chance alone. Results from the reliable change analyses indicated that at the 6-month follow-up exam, one of the three participants (patient 3) demonstrating cognitive decline had five neuropsychological tests below the lower cut-off value, suggesting a statistically significant change and demonstrating the largest decline in neuropsychological test performance. This patient was the only one to sustain a S100B increase outside the 99% CI across the observed time period, and the NSE increase was above the 99% CI at three different time points. However, neither the 2-month postoperative MRI nor an additional MRI performed 7 months after surgery revealed a morphological correlate.

Self-report of mood was obtained using the Beck Depression Inventory-II³² (see Table II). Overall postoperative scores revealed improvement compared to baseline evaluation. When scores were examined for each patient, three patients endorsed signs and symptoms of depression above a cut-off of 13 at baseline, one patient had a score above cut-off at the 7- to 10-day follow-up (Beck Depression Inventory-II score 23), but no patients had scores above 13 at the 6-month follow-up assessment.

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Discussion 

We observed an initial significant increase of the serum concentration of S100B. This increase did not correlate with carotid clamping time, EEG changes, or levels of NSE. S100 levels also failed to predict adverse neurological outcome or cognitive decline in group performance, but this sample showed overall cognitive improvement as a function of endarterectomy. Earlier investigations utilizing S100B or NSE as a laboratory marker were carried out in patients with severe brain injury.¹¹, ¹², ¹³ Although sustained elevations of S100B serum levels have been shown to correlate with minor ischemic brain injury during CEA in other studies,¹⁶, ³⁵, ³⁶ it is also possible that early, brief elevations result from a temporary disruption of the blood–brain barrier following low-level hypoperfusion during carotid clamping that does not necessarily indicate brain injury.³⁷, ³⁸ The limited results regarding S100 and NSE correlates in our series may reflect the fact that few patients sustained cerebrovascular events following CEA and, as such, may reflect a restricted sample.

The changes in the MRI on one patient in whom there were no corresponding elevations in S100 and NSE at the time of surgery may reflect a timing issue. Since the first MRI was performed within 30 days prior to the procedure, these infarcts could have occurred within the preoperative time interval. This would allow for a remission of potential neurological deficits, and elevated laboratory parameters may have returned to normal before the first preoperative blood sample was drawn.

One patient had a reduced right patellar reflex postsurgery. Reduced reflexes are a sign of peripheral neurological damage. Occasionally, peripheral nerve damage may occur during surgery, depending on positioning. As expected, no corresponding brain injury on DWI or an increase of laboratory parameters could be verified.

Our neurocognitive results revealed a significant increase in mean cognitive performance scores with an emphasis on memory and attention at both postoperative examinations. On an individual basis, all but one patient showed stable cognitive performance or mild cognitive improvement, even when practice effects of repeated assessments were taken into account through use of RCIs. One patient did show evidence of statistically significant cognitive decline and performed worse on five neuropsychological tests assessing attention and memory. This participant had also a marked increase of S100B and NSE serum levels, and the difference was sustained for S100B. Although this patient endorsed signs and symptoms of depression at baseline and at 7- to 10-day follow-up, his mood improved and fell below the Beck Depression Inventory-II cut-off at the 6-month follow-up. As such, mood is not responsible for the continued cognitive impairment at 6 months postsurgery. Rasmussen et al.⁸ described a similar late deterioration of cognitive function 3 months after CEA and speculated that this may be related to restenosis of the endarterectomized vessel. In our patient, we could not verify such a process, though the results suggest a potential role of S100B in predicting cognitive decline following CEA. The lack of cognitive decline may represent problems with power but may also reflect an unexpected sampling bias, whereas the participants were fairly well educated, with premorbid estimates of verbal intellectual function ranging from average to above average and only one patient with a premorbid estimated IQ in the low average range.

Previous studies on the effect of CEA on cognitive function have produced conflicting results. Postoperative improvement has been reported after CEA in symptomatic patients.⁹, ³⁹ The authors related the preoperative depression of cognitive function and subsequent improvement after CEA to recurrent embolizations or an exhausted cerebrovascular reserve. However, these gains could be attributed to the natural course of recovery of cerebral function after transient ischemic attack or stroke. Also, the effect of learned response (practice effects of repeated cognitive testing) must be taken into account, and a comparison with a carefully selected control group failed to detect improvement in symptomatic patients.⁴⁰ In contrast, Heyer et al.⁶ found a deterioration of cognitive function that persisted for several weeks after CEA as well as a correlation between S100B and subclinical cognitive dysfunction assessed 24 hr postsurgery.⁷ This brief interval between surgery and cognitive testing cannot differentiate changes caused by ischemic damage as opposed to reversible postoperative fatigue and the effects of anesthesia. To avoid this bias, we allowed for a 7- to 10-day interval or rehabilitation phase before performing the first postoperative neurocognitive evaluation.

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Conclusion 

Neuropsychological testing may reveal subtle neurocognitive changes in the absence of structural MRI findings after CEA. The RCI is a useful tool to identify real neurocognitive changes as opposed to learning effects. The overall neuropsychological mean scores improved after CEA, but when looking at the possibility of learned response, we did not find a relevant individual improvement. While serum concentrations of S100B increased significantly early after removal of the carotid clamp and returned to normal within 24 hr, the NSE increase was not significant. Combined measurements of S100B and NSE may improve the sensitivity of detecting minor cerebral damage following CEA.

To accurately assess the relationship between S100B, NSE, and changes in neuropsychological functioning following CEA, prospective evaluation of a larger sample size would be required.

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The Mayo Foundation supported J. F. A Vascular Surgery Research Grant from the J. William Von Liebig Foundation supported the work of M. B., J. K., B. H., and B. N. at Mayo Clinic Jacksonville.

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