The Role of Carotid Artery Stenting and Carotid
Endarterectomy in Cognitive Performance
A Systematic Review
Paola De Rango, MD; Valeria Caso, MD, PhD; Didier Leys, MD; Maurizio Paciaroni, MD;
Massimo Lenti, MD; Piergiorgio Cao, MD, FRCS
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Background and Purpose—Change in cognition is being increasingly recognized as an important outcome measure;
however, the role of carotid revascularization on this issue remains to be determined. It is still under debate
whether carotid artery stenting and carotid endarterectomy have the same influence on neuropsychological
functions.
Summary of Review—This article systematically reviews recent literature in an attempt to clarify this issue. A total of 32
papers reporting on neurocognition after carotid endarterectomy (n⫽25), carotid artery stenting (n⫽4), or carotid artery
stenting versus carotid endarterectomy (n⫽3) were identified. The studies were different for many methodological
factors, eg, sample size, type of patients and control group, statistical measure, type of test, timing of assessment, and
so on. There was a lack of consensus in defining the improvement or impairment after either carotid artery stenting or
carotid endarterectomy. Furthermore, there were nonuneqivocal results regarding the same domain of assessment
(memory, visuomotor, attention). Based on available evidence, it is probable that carotid endarterectomy as well as
carotid artery stenting do not change neuropsychological function “per se.”
Conclusions—Assessment of cognition after carotid revascularization is probably influenced by many confounding factors
such as learning effect, type of test, type of patients, and control group, which are often minimized in their importance.
The role of carotid revascularization is to prevent stroke in patients with severe carotid stenosis as highlighted by
previous large randomized trials. Although an effect of carotid revascularization on cognition could be missed as a
consequence of underpowered studies included in this review, at this time, no prediction can be done regarding its
repercussions on higher intellectual functions. Larger studies appropriately designed and powered to assess cognition
after carotid revascularization might change this view. (Stroke. 2008;39:3116-3127.)
Key Words: angioplasty and stenting 䡲 carotid endarterectomy 䡲 carotid stenosis 䡲 cognition
䡲 stenting 䡲 systematic review
C
hange in cognition is one of the most threatening
diseases of recent years. With the progressive aging of
the population, the burden of dementia disorders has become
even more challenging. Cerebrovascular disease plays a main
role in the development of dementia as reported by the
stroke– dementia association.1,2 Carotid endarterectomy
(CEA) in patients with severe carotid stenosis reduces stroke
risk.3,4 However, the influence of CEA, if any, on silent
cerebral ischemia and cognition is less defined. A possible
link between improved cognitive function and better cerebral
perfusion has been hypothesized, whereas subclinical microembolic cerebral patterns occurring during revascularization
may worsen neuropsychological function.5 This effect on
cognition has further challenged the role of carotid artery
stenting (CAS) in carotid stenosis. In addition to the ques-
tionable safety of CAS in preventing stroke, higher frequency
of microembolism in CAS compared with CEA has been
observed by transcranial Doppler (TCD) and diffusionweighted MR brain imaging.6
Previous reviews on cognition after carotid revascularization, mainly reporting on studies published before 1990, have
provided uncertain results regarding the potential benefit of
CEA.7–10 Although the validity of cognitive tests persists over
time, patient characteristics, brain pharmacological support,
and surgical skills have improved over the past 2 decades.
Furthermore, very little information has been obtained on
these functions after CAS. To investigate the effect of
cerebral revascularization on cognition, we performed a
systematic review of recent articles on neuropsychological
testing after CAS and/or CEA.
Received February 22, 2008; accepted March 14, 2008.
From the Division of Vascular and Endovascular Surgery (P.D.R., M.L., P.C.) and the Stroke Unit (V.C., M.P.), University of Perugia, Ospedale S.
Maria della Misericordia, Perugia, Italy; and the Department of Neurology (L.D.), Stroke Unit, University of Lille, Lille, France.
Correspondence to Piergiorgio Cao, MD, FRCS, University of Perugia, Vascular and Endovascular Surgery, Ospedale S. Maria della Misericordia, Loc.
S. Andrea delle Fratte, 06156 Perugia, Italy. E-mail [email protected]
© 2008 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.108.518357
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De Rango et al
Cognition After CAS or CEA: A Systematic Review
Methods
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A search strategy was designed to identify all relevant studies on
cognitive testing in carotid revascularization. This search was restricted to papers published between January 1990 and May 2007.
Studies were initially identified from the Medline/PubMed database,
EMBASE, and the Cochrane Database using the search terms
“cognitive function,” “carotid endarterectomy,” “carotid angioplasty,” “carotid stenting,” “carotid revascularization,” “neuropsychological outcome,” and “cognitive tests.” Additional papers were
identified from reference lists of retrieved articles, abstract lists of
recent scientific meetings, and Internet-based sources (www.tctmd.com,
www.cxvascular.com) of information.
Studies were included if they reported on cognitive tests comparing pre- and postoperative performances in CAS and/or CEA with
numbers of examined population and results of cognitive evaluation
and enrolled at least 10 cases.
Studies were excluded when reporting: (1) quality of life without
neuropsychological assessment or cognitive assessment limited to
the anesthesia waning phase; (2) cognitive function in nonsurgical
patients, patients with intracranial stenosis or without postoperative
assessment; and (3) on case reports and review articles without
personal data.
Papers from the same authors were not excluded when reporting
additional information as different tests, measurements, and populations.
Two researchers (P.D.R. and V.C.) separately screened the reference list to identify relevant reports. A data extraction form was
specifically developed to record study population, control group,
analysis, cognitive tests (type and domain), assessment timing, and
outcomes. Data were checked for quality independently by the 2
researchers.
Because a battery of cognitive tests specifically addressing the
issues related to carotid stenosis and revascularization has not been
yet devised, we attempted to simplify the results by: (1) grouping
studies in 3 categories according to whether they were reporting on
CEA alone, CAS alone, or CAS and CEA together; and (2)
assembling study results according to the 3 most commonly investigated cognitive domains: (a) memory, (b) executive function, and
(c) attention and language. Although some tests may examine
combined categories, most of them were designed to examine
individual domains. We combined tests into these 3 major domains
to make classification easier and for better access for physicians,
because a direct comparison of studies is problematic in view of the
disparate measurements of neuropsychological functions.
Global assessment, depression, and dementia scores were not
specifically analyzed.
Due to the heterogeneity in definition, method, timing of assessment, and type of tests and to avoid misleading results from
differences in measurements, data from this systematic review could
not be combined in a formal meta-analysis. This was in accordance
with the QUality Of Reporting Of Meta-analyses (QUOROM)
recommendations (www.consort-statement.org/QUOROM.pdf).
Results
Search Results
Forty-five potentially relevant articles were identified, 32 of
which satisfied the inclusion criteria. Studies were excluded
when dealing with pharmacology recovery after anesthesia
(n⫽2),11,12 lacking postoperative assessment (n⫽1),13 case
reports (n⫽2),14,15 review articles (n⫽4),7–10 or ongoing trials
without available results (n⫽3). One study was considered a
duplicate16 of another included study17 (Figure).
The 32 included studies, published between 1990 and
2007, are listed in Tables 1 and 2.5,17– 47 Twenty-five reported
on cognitive outcome after CEA,5,17–26,28 – 42 4 after CAS,43– 46
and 3 after CEA versus CAS.18,27,47 Overall, 16 used one or
more control groups varying from healthy subjects to patients
affected by different diseases.18 –21,25,27–29,30,33,34,38,41,42,44,46,47
3117
Ten focused exclusively on symptomatic5,17,21,28,33,35,43,45,27,47
and one on asymptomatic patients.19 Time of cognitive assessment varied from 24 hours to 8 years after revascularization and
4 reported at 1 year or later (3 and 8 years). In 13 of 31,
neurological assessment was repeated more than once.
A range of tests (from 3 to 18) investigating several
domains was used in each study. In addition to cognition, 3
studies also reported on quality of life25,36,42 and 17 on
depression, anxiety, and dementia.
The methodological quality of the included studies was
rated as “fair” in all except 3, all published before 2000 and
graded as “poor”5,18,37 on a formal assessment checklist (one
published only as an abstract18). All studies were published in
peer-reviewed journals. Authors used specific methodology
(repeated calculations, statistical correction for practice, control group, inclusion criteria, threshold for significance) to try
to overcome chance effects and straighten the reliability of
results. However, a sample size was not a priori calculated to
power the study in any.
The definition of improvement or impairment varied significantly among the included studies and different statistical
measurements were used to quantify score changes; changes
of 1 or 2 SD or a probability value ⬍0.05 using variance tests
could be accepted for significance.
Neuropsychological Outcome After
Carotid Endarterectomy
The main characteristics of the 25 reports on CEA are shown
in Table 1.5,17–26,28 – 42 The study population varied from 22 to
189. To compare cognitive outcome, 12 studies used single or
multiple control groups varying from healthy people
(n⫽7),19,25,29,33,34,41,42 to patients with vascular risk factors
(n⫽1),19 to those with peripheral disease (n⫽2),20,25 those
undergoing orthopedic surgery (n⫽3),21,30,38 or those undergoing urologic surgery (n⫽1).28 One study analyzed cognitive outcome exclusively in asymptomatic19 and 5 in symptomatic carotid stenosis.5,21,28,33,35 Comparing post-CEA
assessment with preoperative condition with a control group,
6 reported no substantial changes after CEA,20,23,30,33,40,42 5
highlighted impairment, 5,19,24,31,38 and 4 improvement,21,22,35,41 although not all psychological tests were consistently changed. In the remaining, percentages of improvement varied among different domains. Improvement was
reported to be higher at later evaluations.21,28
Neuropsychological Outcome After Carotid
Artery Stenting
The main characteristics of the 4 studies reporting cognitive
tests after CAS are shown in Table 2.43– 46 Populations ranged
from 10 to 100. Two were controlled studies.44,46 In the
Moftakhar paper, along with CAS, intracranial carotid and
vertebral stenosis procedures were also included and reported
separately.45 In all 4 studies, a stent was applied to perform
CAS; however, only the 2 most recent43,46 used cerebral
protection (CPD). One,44 which did not use CPD, showed no
significant changes in cognition, whereas the other 3 showed
improvement in most of the tests regardless of the use of
CPD. A transient impairment in the Boston Naming Test
reversing at 2 weeks was found in another study.46 Improve-
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November 2008
Figure. Flow chart of search results.
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ment was detected particularly in memory tests43,46 and in
older patients.43
Neuropsychological Outcome After Carotid
Endarterectomy and Carotid Artery Stenting
The 3 studies directly comparing CAS versus CEA were all
performed within 2 randomized, controlled trials, either the
CAVATAS18,27 or the SPACE.47 However, because only a
small subgroup of the overall randomized population in both
trials was analyzed for cognitive assessment, the sample to
assess neurocognition could be unbalanced(Table 2). In the
first 2 studies,18,27 analyzing a subgroup of patients within
CAVATAS, all procedures except one were performed by
angioplasty alone, whereas in the SPACE subgroup,47 a stent
was systematically used. No use of CPD was reported. All
these studies were unable to find any significant difference in
cognition between the 2 populations after revascularization,18,27,47 although patients undergoing CAS performed
worse on a single visuomotor test in the study by Crawley
et al.27
Although microembolism was higher during CAS, no
association between TCD-detected microembolism and cognitive impairment was reported.27 Similarly, no significant
changes in the S100␤ protein values were noted in patients
undergoing CAS versus those undergoing CEA in the subgroup of the SPACE trial.47
Neuropsychological Outcomes According
to Domain
Changes reported within the 3 major domains are shown in
Tables 3, 4, and 5.
Almost all of the studies reported on memory function
(Table 3). A variety of tests were used to assess short,
immediate, or delayed recall. In half of the CAS studies, there
was improvement in verbal memory. The results from CEA
were not homogeneous. Five studies19,20,32,38,42 suggested a
decline in cognitive performance, whereas 9 found the
greatest improvement in tests on memory, either in the early
or the later postoperative assessments.22,25,26,28,34 –37,41
Tests for the attention domain are reported in Table 4,
the Trail Making Test being one of the most commonly
used (14 studies). 19,20,23,27,30 –32,38,40,41,44,46,47 Grunwald
used the Number Collection Test as a substitute for the
Trail Making Test.43
Trail tests measuring problem-solving, attention, motor
control, and set-shifting were used to assess psychomotor
speed (Part A), sustained attention (Part B), or to encompass a number of frontal lobe aspects. We analyzed these
tests within the attention domain (although they explore
other cognitive functions) to compare the results from
different studies in the same type of test. Overall, no
significant changes were detected in 6 studies using Trail
tests.20,27,30,40,44,47 From the 3 CAS studies using these tests, 2
De Rango et al
Table 1.
Cognition After CAS or CEA: A Systematic Review
3119
Studies Comparing Pre- and Postoperative Performance on Neuropsychological Tests in Patients Undergoing CEA
Author, Year
Aharon-Peretz,19 2003
No. CEA
Controls
Follow-Up
Major Findings
22 asympt
14 VRF versus 24
healthy
30 days
Compared with controls: impairment: verbal
memory, attention
33 sympt or asympt under
local anesthesia
25 peripheral bypass
3 days
No significant changes
4 months
Most tests impair at 3 days and improve at
4 months
1 week
Improvement: total score, verbal memory,
motor ability, attention, language
Improvement: motor ability, visual memory
Aleksic,20 2006
Impairment: long-term memory
Antonelli Incalzi,21 1997†
28 sympt
30 orthopedic surgery
4 months
Unchanged: visual memory
Improvement higher in late assessment
†No side-specific effect
Bo,17 2006†‡
103 sympt or asympt
53 right CEA versus
50 left CEA
3 years (44.4⫹14
months)
Impairment: MMSE, motor ability in left
symptomatic CEA
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46% impairment at 3 years
†Side-specific effect
22
Borroni, 2004‡
78 sympt or asympt
48 CEA unimpaired
versus 30 CEA
impaired
Bossema,25 2005*
51 sympt or asympt
䡠䡠䡠
3 months
Overall improvement: in the impaired
group, higher improvement in verbal
memory
3 months
No significant changes in cognitive function
12 months
Small improvement in quality
38% impairment on 3 tests; impairment
does not correlate with embolism
12-month improvement: memory, attention,
motor ability
Bossema,24 2005
58 sympt or asympt
䡠䡠䡠
3 months
Bossema,23 2005
56 sympt or asympt
46 healthy versus 23
REA
3 months
Brand and Bossema,26 2003†‡
36 sympt or asympt
19 left CEA versus 17
right CEA
3 months
Improvement: memory†
Impairment: motor ability
†Side-specific effect
159 sympt
20 urology department
5 days
Improvement: memory (5 days, 2 months),
attention (2 months)
2 months
Impairment 5 days: overall attention and
accuracy
12 months
Fearn,28 2003
Attention improved at 2 months and
improvement was higher in patients with
reduced cerebral reserve
Impairment associated with ⬎10
microembolism
Fukunaga,29 2006
24 sympt or asympt
17 healthy
3 weeks
Improvement: motor ability; no significant
improvement: attention
Improvement higher in patients with
reduced cerebral reserve (SPECT)
Gaunt,5 1994
100 sympt
䡠䡠䡠
5–7 days
4% impaired in (all) 4 tests
26% impaired in one test
Impairment associated with microembolism
Heyer,30 2002†
80 sympt or asympt
25 lumbar spine
surgery
1 day
No pre/post significant changes
30 days
Compared with controls: impairment
attention (1 day), motor ability (1/30 days)
28% impair at day 1; 23% impair at 30 days
†No side-specific effect
(Continued)
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Table 1.
Continued
November 2008
Author, Year
No. CEA
Controls
Follow-Up
Major Findings
Heyer,32 2006
34 sympt or asympt
䡠䡠䡠
1 day
Impairment: attention, language, motor ability
8% Impairment; not associated with DWI lesion
Heyer,31 1998
112 sympt or asympt
䡠䡠䡠
1 month
Improvement: attention, motor ability
(5 months)
Mocco,38 2006
186 sympt or asympt
67 lumbar
laminectomy
Iddon,33 1997
34
Kishikawa, 2003
5 months
Impairment: memory (1–5 months)
1 day
18% impair at 1 day; 9% impair 30 days
30 days
Advanced age and diabetes: impairment
predictors
30 sympt
30 healthy
48–72 hours
No significant changes
23 sympt or asympt
17 healthy
4 weeks
Improvement: visual memory, motor ability
䡠䡠䡠
Immediate
Improvement: attention, visual memory
14 months
Improvement in memory, better in younger
and †Side-specific effect
6 months
Impairment: attention, language
Unchanged: verbal memory
Lind,35 1993†
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Lloyd,36 2004*
25 sympt
100 sympt or asympt
䡠䡠䡠
Improvement: memory
Impairment related to particulate
microembolism
Mononen,37 1990†‡
46 sympt or vertebral
30 CEA–TIA versus 16
CEA–cerebral infarct
2 weeks
Improvement
2 months
Group TIA: improve in verbal and visual
tests: language, attention, memory
Group infarct: improve in verbal memory
(2 weeks) and later, in visual memory
2 months
Other verbal test unchanged
Patients with TIA improve more in
visual/verbal (especially memory) and
earlier; †side-specific effect
Ogasawara,39 2005†
92 sympt or asympt
1, 3, 6 months
䡠䡠䡠
(1 month): all tests improve except motor ability
Impairment in 12% of patients correlated to
hyperperfusion on SPECT
†No side-specific effect
Pearson,40 2003
37 sympt or asympt
䡠䡠䡠
Sinforiani,41 2001
64 sympt or asympt
32 healthy
Sirkka,42 1992*
44 sympt or asympt
18 carotid stenosis
versus 29 healthy
7 days
No overall significant changes
3 months
No significant impairment in attention,
language, and memory only in patients
with previous stroke
2 weeks
3 months
Improvement 3 months: memory, attention
8 years
No overall significant pre/post changes
Compared with health: impairment in
attention, motor ability
Impairment in memory and language only
in patients operated twice
*Quality-of-life assessment.
†Specific assessment of effect side (right versus left carotid) by authors.
‡No true control group (subgroup analysis).
Sympt indicates symptomatic; asympt, asymptomatic; VRF, vascular risk factors; REA, remote endarterectomy superficial femoral artery; TIA, transient ischemic
attack; MMSE, Mini-Mental State Examination; SPECT, single photon emission CT; DWI, diffusion-weighted imaging.
showed improvement,43,46 whereas the remaining had unchanged results.44 In CEA studies, the results were improved
in 4 of 10.22,25,32,41 Attention tests tended to improve at the
later assessment time19,20,28 (Table 4).
Language is one of the most complex cognitive fields to be
investigated. We analyzed the side and dominance of the
treated carotid, when available, to assess the possible laterality effect of neuropsychological dysfunction on language
De Rango et al
Cognition After CAS or CEA: A Systematic Review
3121
Table 2. Studies Comparing Pre- and Postoperative Performance on Neuropsychological Tests in Patients Undergoing CAS or CAS
versus CEA
Studies on Cognitive Assessment After CAS
Author, Year
No. CAS
Grunwald,43 2006
10 stent
Controls
Follow-Up
Major Findings
䡠䡠䡠
48 hours
Improvement: attention
CPD yes
Borderline improvement: memory,
language
sympt
Older patients: higher improvement
No correlation with DWI lesion
44
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Lehrner, 2004
20 stent
No CPD sympt or asympt
Moftakhar,45 2005
21 symptomatic stent: 10 CAS,4 intracranial stenosis,
7 vertebral stenosis; no CPD
Xu,46 2007
54 stent
20 carotid stenosis
66 carotid angiography
CPD yes
6 months versus 3
months
No significant changes; concentration:
10% improve, 90% unchanged; motor
ability: 11% improve; 61%
unchanged, 28% impair; verbal
fluency: 5% unchanged, 15%
improve, 5% impair; sustained
attention: 94% unchanged, 6% impair
6 months (3–14 months)
Overall improvement in 79% patients
Improvement in 92% patients with
carotid stenosis
MRI improved perfusion as predictor
of improvement
1 week
Improvement evident in verbal
memory Improvement (1 and 12
weeks): memory, attention
12 weeks
Impairment 1 week: language
(reversing at 12 weeks)
1, 6, 12 months
Nonrandomized Phase III uncontrolled
trial on acute versus delayed
neuropsychological changes and
MRI-DWI
Sympt or asympt
Raabe, 2003 Carotid Artery Stenting
With Protection Registry
www.ClinicalTrials.gov
Unchanged: short memory
100 sympt or asympt
Studies Comparing CAS Versus CEA
Author, Year
Crawley,27 2000
No. CAS
Controls
Follow-Up
Major Findings
26 CEA sympt
20 angioplasty (one stent)
6 weeks
No significant difference between CAS
and CEA overall score
No CPD
6 months
Impairment for CAS in: Motor ability
All symptomatic
No significant correlation with TCD
microembolism (higher in CAS)
Sivaguru,18 1999
63 CEA sympt
53 angioplasty
No stent (?)
No CPD
All symptomatic
6 months
No significant difference between CAS
and CEA overall score
Witt,47 2007
24 CEA sympt
21 CAS with stent
6 days
No significant differences between
CAS and CEA in tests score change
No CPD
1 month
No significant differences in S100␤
protein values between CAS versus
CEA
6 months
Ongoing randomized trial from
February 2006
All symptomatic
Altinbas, Van der Worp
100 CEA sympt
100 CAS sympt
Lal, NEST: Neurocognition after
Endarterectomy versus Stent Trial
Proposed randomized trial
Sympt indicates symptomatic; asympt, asymptomatic; DWI, diffusion-weighted imaging.
(Table 4). Language tests did not change significantly.
Similarly, in analyzing the laterality effect, only 4 of the 7
available studies examining this effect17,21,26,30,34,37,39 found
impairment related to the side.17,26,34,37
The largest degree of overlap with other domains occurred
in the Executive Function, in which tests investigating visuomotor and visual– constructive ability were included. The
most commonly used were Rey Osterrieth, Complex Figure,
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Table 3. Main Results From Studies Comparing Pre- and Postoperative Performance on Neuropsychological Memory Tests in
Patients Undergoing Carotid Revascularization
Author, Year
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Population
Type of Tests (subdomain)
Major Findings
Aharon-Peretz,19 2003
Aleksic,20 2006
22 CEA
33 CEA
RAVLT (verbal memory); Digit Span (short/working memory)
Letter no. span (working/short memory); verbal memory:
AVLT1–5; AVTL-SD (short), AVLT-LD (long), AVLT-R
(recognition)
Compared with controls, impairment: RAVLT
Impairment AVLT-LD
Most test impaired at 3 days and improve at 4 months
Antonelli Incalzi,21
1997
28 CEA
Improvement: total score; verbal memory
Unchanged: visual memory
Borroni,22 2004
78 CEA
Bossema,23 2005
56 CEA
Rey Word Memory (verbal memory: short, delayed
learning); Digit Span (short/working memory); spatial span,
Immediate Visual Memory Test (visual memory, short)
ROCF recall (nonverbal memory); Digit Span, Story Recall
(verbal memory, short/long)
Digit span (verbal working memory); Word Learning Test
(verbal memory: retrieval); Doors Test (visual memory:
recognition)
Brand and Bossema,26
2003
Crawley,27 2000
36 CEA
Dichotic listening (left right ear; verbal working memory)
Improvement: dichotic listening left ear
20 CEA versus
26 CAS
RAVLT (verbal memory); nonverbal memory test (nonverbal
memory)
No significant changes
Fearn,28 2003
Grunwald,43 2006
159 CEA
10 CAS
Improvement
Borderline improvement: delayed recall
Heyer,31 1998
112 CEA
Iddon,33 1997
30 CEA
Kishikawa,34 2003
23 CEA
Overall memory reaction time
Word list memory (short memory); delayed recall (long
memory)
Busche Selective Remind List (verbal memory)
LTR (long/retrieval)
CLTR (consistency)
Pattern Recognition (visual memory); Spatial Recognition
(spatial memory); Spatial Span (short memory); Spatial
Working Memory
Word Recall Test (verbal memory); BVRT (visual retention
short and delayed)
Lind,35 1993
Lloyd,36 2004
25 CEA
100 CEA
BVRT (visual memory)
Rivermead behavioral memory battery (immediate/delayed
prose recall)
Moftakhar,45
2005*
Mononen,37 1990
21 stent
Immediate memory tests
Overall improvement
46 CEA
Ogasawara,39 2005
92 CEA
Improvement group TIA: serial learning, visual memory
Group infarct: serial learning; and later visual memory
(2 months)
1 month: all tests improve
Pearson,40 2003
37 CEA
Sinforiani,41 2001
64 CEA
Sirkka,42 1992
44 CEA
Verbal tests: Serial Learning, Digit Span
Visual tests: Facial Recognition, Visual Memory,
Recognition Design, Recognition Concrete Picture
Digit Span, new learning (verbal memory: short/working,
learning); ROCF recall (visual memory)
BVRT (visual retention); RAVLT (verbal memory:
immediate/learning, retention)
Digit Span (verbal short memory); Corsi span (visual short
memory); RAVLT (verbal memory: short/long)
Digit Span (short memory); Kim Test, BVRT, ROCF recall
(visual memory); associative memory (verbal memory)
Xu,46 2007
54 CAS
Witt,47 2007
24 CEA versus
21 CAS
RAVLT (verbal memory); ROCF recall (visual memory); Digit
Span (short/working memory)
RAVLT (verbal memory); ROCF and Taylor recall and CFT
(nonverbal memory)
Overall improvement. long/short verbal memory (Story
Recall/Digit Span)
Improvement (12 months):
Word Learning Test
Impairment: LTR and CLTR (1 month)
LTR (5 months)
No significant changes
Improvement: visual retention
No significant changes: Word Recall Test
Improvement: BVRT (14 months)
Improvement
No significant changes
Improvement 3 months: verbal memory
No overall significant pre/post changes
Compared with health: impairment in visual memory
(Kim) only in patients operated twice
Improvement: verbal memory (RAVLT)
Unchanged: Digit Span
No significant changes between CAS and CEA
*Ten extra cranial carotid, 4 intracranial, 7 vertebral.
RAVLT indicates Rey Auditory Verbal Learning Test; AVLT, Auditory Verbal Learning Test; AVLT-1, after 1° trial; AVLT-5, after 5° trial; AVLT-SD, after short delay;
AVLT-LD, after long delay; AVLT-R, recognition; ROCF, Rey Osterrieth Complex Figure recall; LTR, Longer Term Retrieval; CLTR, Consistency with Longer Term
Retrieval; BVRT, Benton Visual Retention test; CFT, Complex Figure Test; TIA, transient ischemic attack.
and Grooved Pegboard, the former mainly used for the
nondominant hemisphere, whereas the latter included varieties for the dominant and nondominant hemisphere assessment. Other details and tests are reported in Table 5.
Only one of the 4 CAS studies analyzed this domain and
reported unchanged results.46 Another study comparing CAS
versus CEA found that the Grooved Pegboard was the only
impaired test in the CAS population after the procedure.27
De Rango et al
Cognition After CAS or CEA: A Systematic Review
3123
Table 4. Main Results From Studies Comparing Pre- and Postoperative Performance on Attention/Concentration and Language
Neuropsychological Tests in Patients Undergoing Carotid Revascularization
Author, Year
Side
Population
Type of Tests
Major Findings
Aharon-Peretz, 2003
22 CEA
Trail A and Trail B
Compared with controls, impairment
Aleksic,20 2006
33 CEA
Trail A and Trail B
No significant changes
28 CEA
Phonologic Word Fluency, Semantic
Word Fluency, Sentence
Construction Test
Improvement: total score visual
attention, verbal attainment
Double Barrage Simple Analogies,
RCPM
Improvement higher in late
assessment
19
Antonelli Incalzi,21
1997*
Left side: 18
†No side-specific effect
Borroni,22 2004
45 left side: (29 unimpaired
group 16 impaired group)
78 CEA
Controlled Oral Word Association
Set Test, Trail A
Bossema,24 2005
?
58 CEA
Trail A and Trail B, Verbal Fluency
38% impairment on 3 tests
Bossema,23 2005
27 left side; 46 Right hand
56 CEA
Trail A and Trail B, Verbal Fluency
12-month improvement: Trail B
19 left side
36 CEA
Verbal Fluency
No significant changes; no
improvement in language
Brand and Bossema,26
2003*
Overall improvement
Downloaded from http://stroke.ahajournals.org/ by guest on July 31, 2017
†Side-specific effect
27
Crawley, 2000
Fearn,28 2003
26 CEA versus
20 CAS
Symbol Digit, Letter Cancellation,
Trail A and B, 2choice Reaction
Time, Displaced Reaction Time
159 CEA
Overall Attention Reaction Time
No significant difference between
CAS and CEA
Improvement
Attention improved at the later
assessment (2 months)
Fukunaga,29 2006
24 CEA
RCPM (abstract think)
No significant improvement
Gaunt,5 1994
100 CEA
Wechsler Orientation A and B,
Wechsler Concentration
4% impaired in all tests, 26%
impaired in one test
10 CAS
Verbal Fluency, Symbol Digit, NCT
Grunwald,43 2006
3 left side
Improvement: NCT
Borderline improvement: Verbal
Fluency
Heyer,30 2002*
Left side?, Right hand 74?
80 CEA
Trail A and B, Controlled Oral Word
Association
No pre/post significant changes.
Compared with controls: impairment
Trail B (at 1 day); †no side specific
effect
Heyer,32 2006
Left side?, right hand 31
34 CEA
Boston Naming Test, Controlled
Oral Word Association Trail A and
Trail B
Impairment: Trail B, Controlled Oral
Word Association
112 CEA
Trail A and Trail B
Improvement
Mocco,38 2006
Left side 89
186 CEA
Total deficit score (TDS):Boston
Naming Test, Trail A and Trail B,
Controlled Oral Word Association
18% impairment at 1 day; 9%
impairment 30 days
Iddon,33 1997
Left side?
30 CEA
Verbal Fluency, attention set
shifting paradigm
No significant changes
Left side: 11
20 CAS
Trails A and B, Symbol Digit, Verbal
Fluency, Interference (Stroop Test)
No significant changes
25 CEA
verbal attention
Improvement
Left side?
100 CEA
Test of Everyday Attention,
Speed/capacity language
processing
Impairment
Left side: 12
46 CEA
Word Fluency, Stroop Color Test
Improvement only for patients in TIA
group
21 stenting
Decision-making tests, calculation
skill
Improvement in 92% patients with
carotid stenosis
92 CEA
WMS (Japanese version)
1 month: significant improvement
Heyer,31 1998
Lehrner,44 2004
Lind,35 1993*
Lloyd,36 2004
Mononen,37 1990*
†Side-specific effect
Moftakhar,45 2005
Ogasawara,39 2005*
Left side: 41
†No side-specific effect
(Continued)
3124
Stroke
Table 4.
Continued
Author, Year
November 2008
Side
Population
Type of Tests
Major Findings
Pearson,40 2003
Left side: 21
37 CEA
Trail A and Trail B, Controlled Oral
Word Association
No significant changes; no significant
improvement Trail A; no significant
impairment: Trail B, Verbal Fluency
only in patients with previous stroke
Sinforiani,41 2001
Left side 41, right hand: 60
64 CEA
Trail A and Trail B, Token Test
Improvement 3 months: Trail A and
Trail B
Sirkka,42 1992
Left side 19 in CEA versus
12 in carotid stenosis
44 CEA
Stroop, Symbol Digit, Similarities
No significant pre/post changes
Compared with health: impairment in
attention (Stroop)
Impairment in verbal (similarity) only
in patients operated twice
Xu,46 2007
Left side?
Right hand: 48 CAS versus
59 controls
54 CAS
Boston Naming Test, Trail A and
Trail B
Improvement: Trail A and Trail B
Impairment 1 week: Boston Naming
test (reversing at 12 week)
Witt,47 2007
Left side?, right hand: 23
CEA versus 20 CAS
24 CEA versus
21 CAS
Stroop, Trail A and Trail B,
PVERSUSAT, RNGT, Verbal Fluency
No significant changes between CAS
and CEA
Downloaded from http://stroke.ahajournals.org/ by guest on July 31, 2017
RCPM indicates Raven’s Colored Progressive Matrices Test; NCT, Number Connection Test; PVSAT, Paced Visual Serial Addition Test; RNGT, Random Number
Generation Task; TIA, transient ischemic attack.
*Quality of life assessment.
†Specific assessment of effect side (right versus left carotid) by authors.
Other Findings
Many studies have incorporated brain imaging into the
assessment of neuropsychological function to establish possible correlations with cerebrovascular flow, cerebral reserve,
and microembolism.
The effect of microembolism by diffusion-weighted
MRI31,43 tended to exclude any correlation, whereas TCD
studies either suggested5,28,36 or failed to find any possible
impairment.27
A correlation between flow modification by single photon
emission CT and cognitive improvement after revascularization has been shown, especially in patients with reduced
cerebral reserve.29,34,39
There were overall 5 studies analyzing CAS without use of
CPD.21,27,47,44,45 In all except one (which showed improved
results),45 no changes in cognition could be found after CAS.
On the other side, of the 2 studies reporting on CAS with
CPD,43,46 both showed improvements.
The confounding effect of other variables (education,
gender, age, symptoms, redo, and so on) on cognition has
been reported; older patients appear to improve after CAS43
and worsen after CEA.35,38,40
Two other studies reported improvement in patients with
clinical mild cerebral impairment.22,28
Discussion
This review shows that CAS as well as CEA does not clearly
affect neurocognition. Cognitive impairment and improvement are both detectable after CAS or CEA. The conflicting
results are attributable to differences in several methodological (nonpowered study, type of test, statistic measure,
follow-up schedule, presence of a control group) and patientrelated variables (older, diabetic, symptomatic patients).
Conversely, previous review articles on cognition after
CEA published before 2000 reported an improvement in
neuropsychological outcome.7–9 Lunn et al found improve-
ment in cognitive function after CEA in 16 of the 28 studies
analyzed.9 This was even more evident in the studies published before 1984.9
In the present review, only 4 of the 25 CEA studies
published after 1990 showed clear improvement in cognitive
function after surgery; in the remaining, no change, impairment, or contradictory results were detected in the different
tests. However, we cannot definitely exclude an effect of
carotid revascularization on cognition because results were
derived from many small studies probably underpowered to
demonstrate a true difference in outcome. Type II errors
could have influenced these negative results. Although half of
the included studies analyzed more than 50 cases, an a priori
calculation of the study power was not given in any, possibly
providing underpowered results.
Lessons learned from previous reviews and publications on
cognition after carotid revascularization might have improved
the quality of the most recent experience on this topic. Indeed,
a number of methodological biases appropriately raised by
previous authors analyzing cognitive studies after CEA7–9 might
be, at least in part, encompassed in these more recent experiences published after 1990, which are reported here.
The learning effect in patients re-evaluated at short interval
schedules was probably a major and often disregarded flaw
affecting a number of earlier studies favorable for an
improvement in neurocognition after carotid revascularization. However, the majority of investigators in the present
review have tried to control the fact that subjects improve
their cognitive score with practice by adding a control
group,18,20 –29,30,33,34,38,41,42,44,46,47 by using reassessment after a minimum of 3 months17–27,31,35,36,39 – 42,44,45 or by correcting for practical effect in statistical evaluation.44 Nevertheless, important limitations still remain even in the recent
experiences, as evidenced previously. As a further step, the
standardization of tests designed for vascular cognitive assessment could lead to a more accurate and reliable data
collection on this topic.10
De Rango et al
Cognition After CAS or CEA: A Systematic Review
3125
Table 5. Main Results From Studies Comparing Pre- and Postoperative Performance on Executive Function Neuropsychological Tests
in Patients Undergoing Carotid Revascularization
Author, Year
Population
Type of Tests
Major Findings
Aharon-Peretz, 2003
22 CEA
TOL, WCST, ROCF, Grooved Pegboard, Corsi tapping
test
Compared with controls, improvement: TOL, Corsi
tapping
Antonelli Incalzi,21 1997*
28 CEA
Simple Copy design, Copy with Landmarks
Improvement: improvement higher in late
assessment
Bo,21 2006*
103 CEA
Clock drawing test (CLOX): CLOX 1, CLOX 2 copy
impairment: CLOX 1 and 2 in left symptomatic
Borroni,22 2004
78 CEA
ROCF copy, Grooved Pegboard
Overall improvement
Bossema,24 2005
58 CEA
Motor Planning Test, Finger Tapping Test
38% impairment on 3 tests (which?)
Bossema,23 2005
56 CEA
Motor Planning Test
Finger Tapping Test
Improvement 12 months
Brand and Bossema,26
2003
36 CEA
Motor Planning Test, Finger Tapping Test, Complex
Figure Test copy
Impairment: motor planning test
Impairment for CAS in: Grooved Pegboard
19
†No side-specific effect
†No side-specific effect
Crawley,27 2000
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26 CEA versus 20 CAS
Finger Tapping, Grooved Pegboard Symbol digit
Fukunaga,29 2006
24 CEA
WCST
Improvement
Heyer,30 2002*
80 CEA
ROCF
No pre/post significant changes
Compared with controls: impairment
†No side-specific effect
Heyer, 322006
34 CEA
ROCF
Impairment
Heyer, 311998
112 CEA
Grooved Pegboard, Finger Tapping
Improvement
Iddon,33 1997
30CEA
Paired associated learning task, simultaneous/delayed
matching to sample
No significant changes
Kishikawa,34 2003
23 CEA
Kohs block-design tests
Improvement
44
20 CAS
Psychomotor speed
Lehrner, 2004
No Significant changes
11% improve, 28% impair, 61% unchanged
Ogasawara,39 2005*
92 CEA
ROCF
No significant changes
†No side-specific effect
Sinforiani,41 2001
64 CEA
Grooved Pegboard, copy drawing
No significant changes
Sirkka,42 1992
44 CEA
Block Design, ROCF copy
No pre/post significant changes
Compared with healthy: impairment in
BlockDesign
Xu, 2007
Witt,47 2007
54 CAS
ROCF copy, Finger Tapping Test
No significant changes
24 CEA versus 21 CAS
Purdue Pegboard, Finger Tapping Test
No significant changes between CAS and CEA
*Specific assessment of effect side (right versus left carotid) by authors.
TOL indicates Tower of London; WCST, Wisconsin Card Sorting Test, ROCF: Rey Osterrieth Complex Figure.
To our knowledge, this is the first systematic review
analyzing cognitive function after CAS. Nevertheless, only 7
studies analyzed this procedure, 3 of which in comparison
with CEA.21,27,43– 47 Surprisingly, approximately half of the
CAS studies reported improvement in cognitive function,
especially in memory tests,43,46 contradicting previous reports
suggesting a potential cognitive damage from CAS due to
microembolism.48 –51 However, due to the small numbers and
lack of controls in 2 of the CAS studies, conclusions should
be drawn cautiously.
It is generally accepted that CAS carries a higher cerebral
embolic risk. Subclinical microembolic events, revealed by
imaging, might negatively affect cognitive performance. Indeed, cognitive decline has been associated with silent
microembolic cerebral injury in other clinical settings such as
cardiac catheterization and surgical procedures.48,49 In the
present review, no clear evidence of higher cognitive impair-
ment was detected after CAS. Even if no direct comparison
between CAS and CEA was available in large populations, in
the 3 studies comparing CAS with CEA,21,27,47 no differences in
cognitive performance were found despite a higher rate of
microembolism in the CAS group.27 This apparent discrepancy
may be explained by the disparate composition of microembolisms; gaseous embolisms are less hazardous than particulate
ones and lead to less serious clinical consequences.50,51
Diffusion-weighted MRI31,43 or some TCD27 studies
tended to exclude any correlation, whereas other TCD experiences suggested a possible impairment.5,28,36
To this regard, the 2 studies in which CAS was performed
with CPD43,46 both showed improvements in cognition after
CAS. Of the other 5 studies analyzing CAS without CPD,21,27,47,44
all but one45 showed unchanged cognition. However, differences
in sample size, time of assessment, and type of test among these
small studies could have affected the differences.
3126
Stroke
November 2008
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In addition to embolism,5,28,36 another 2 mechanisms for
cognitive impairment during carotid revascularization have
been suggested. Intraprocedural changes in cerebral blood
flow due to clamping or ballooning might correlate with
neuropsychological impairment.14 Other studies have shown
benefit from improved perfusion after carotid revascularization, particularly in patients with reduced cerebral reserve.22,29,34,39 However, cognitive deterioration might also
occur in the context of cerebral hyperperfusion.14 From this
literature review, it appears that there are more data supporting an effect from flow variation than from microembolism
on cognitive performance after carotid revascularization.
Three studies analyzing flow modification by single photon
emission CT found a correlation between flow modification
and cognitive improvement in patients with reduced cerebral
reserve.29,34,39 The effect of microembolism was extensively
analyzed but contradictorily defined.
Many investigators are working to discover what exactly
occurs in the brain “behind the scenes” during and after
carotid revascularization. Based on available evidence, it is
likely that CEA as well as CAS does not affect neuropsychological function per se. Cognitive function is influenced by
more than one confounding factors (learning effect, type of
test, type of patients and control subjects) that are frequently
minimized or disregarded.
This review presents limitations. Studies might not be
adequately powered to assess a true effect of revascularization of cognition and conclusions should be interpreted with
caution due to a possible Type II error. A direct comparison
among the studies was problematic in view of the diversity in
measuring neuropsychological function. We analyzed tests
assessing specific cognitive domains (ie, attention and language, executive function including visuomotor skill, and
memory). This categorization, however, is not used universally because no standardization and overlap for domains
exists. Global assessment, depression, and dementia scores
were not evaluated.
Conclusions
Whether and to what extent the neurocognitive functions of
patients is affected by CAS or CEA remains unclear.
Patients with carotid stenosis and their relatives are
strongly interested in knowing whether carotid revascularization may affect neuropsychological functions. This is particularly true for asymptomatic patients for whom the role of
revascularization is still under debate, and the change in
cognitive functions may play a role in assessing the risk/
benefit ratio of the treatment choice. As revealed in this
review, there are no data indicating a cognitive change after
CAS or CEA in patients who do not experience stroke
complications, even if new silent embolic lesions, especially
after CAS, were detected on cerebral imaging. However,
larger studies appropriately designed and properly powered to
assess cognition after carotid revascularization might also
change this opinion.
Carotid revascularization is the best proven measure for
stroke prevention in patients with large-vessel disease. Physicians, neurologists, and vascular surgeons should thoroughly inform their patients on the expected outcomes after
carotid revascularization on the basis of data from randomized trials without any false expectations in cognition.
Acknowledgments
We thank Francesca Zannetti and Eileen Mahoney for
editing assistance.
Disclosures
None.
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Stroke. 2008;39:3116-3127; originally published online August 21, 2008;
doi: 10.1161/STROKEAHA.108.518357
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