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Editor's Choice – Effect of Carotid Interventions on Cognitive Function in Patients With Asymptomatic Carotid Stenosis: A Systematic Review

Open ArchivePublished:August 30, 2021DOI:https://doi.org/10.1016/j.ejvs.2021.07.012

      Objective

      To determine the effect of carotid endarterectomy (CEA) and carotid artery stenting (CAS) on early (baseline vs. maximum three months) and late (baseline vs. at least five months) cognitive function in patients with exclusively asymptomatic carotid stenoses (ACS).

      Method

      Searches were conducted in PubMed/Medline, Embase, Scopus, and the Cochrane library. This systematic review includes 31 non-randomised studies.

      Results

      Early post-operative period: In 24 CEA/CAS/CEA+CAS cohorts (n = 2 059), two cohorts (representing 91/2 059, 4.4% of the overall study population) reported significant improvement in cognitive function, while one (28/2 059, 1%) reported significant decline. Three cohorts (250/2 059, 12.5% reported “mixed findings” where some cognitive scores significantly improved, and a similar proportion declined. The majority (nine cohorts; 1 086/2 059, 53%) reported no change. Seven cohorts (250/2 059, 12.1%) were mostly unchanged but one to two individual test scores improved, while two cohorts (347/2 059, 16.8%) were mostly unchanged with one to two individual test scores worse. Late post-operative period: In 21 cohorts (n = 1 554), one (28/1 554, 1.8%) reported significantly worse cognitive function, one reported significant improvement (24/1 554, 1.5%), while a third (19/1 554, 1.2%) reported “mixed findings”. The majority were unchanged (six cohorts; 1 073/1 554, 69%) or mostly unchanged, but with one to two cognitive tests showing significant improvement (11 cohorts; 386/1 554, 24.8%). Overall, there was a similar distribution of findings in small, medium, and large studies, in studies with controls vs. no controls, in studies comparing CEA vs. CAS, and in studies with shorter/longer late follow up.

      Conclusion

      Notwithstanding accepted limitations regarding heterogeneity within non-randomised studies, CEA/CAS rarely improved overall late cognitive function in ACS patients (< 2%) and the risk of significant cognitive decline was equally low (< 2%). In the long term, the majority were either unchanged (69%) or mostly unchanged with one to two test scores improved (24.8%). Until new research identifies vulnerable ACS subgroups (e.g., impaired cerebral vascular reserve) or provides evidence that silent embolisation from ACS causes cognitive impairment, evidence supporting intervention in ACS patients to prevent/reverse cognitive decline is lacking.

      Keywords

      The role of carotid endarterectomy (CEA) or carotid stenting (CAS) to prevent cognitive decline in asymptomatic carotid stenosis (ACS) patients is controversial. This is the first systematic review evaluating CEA/CAS on post-operative cognition in exclusively ACS patients. At late review, the majority were unchanged (69% of study population) or mostly unchanged with one to two tests showing improvement (25%). Few were significantly improved (1.5%), but significant deterioration was rare (1.8%). Until new research identifies vulnerable ACS subgroups or provides evidence that silent embolisation from ACS causes cognitive impairment, evidence supporting intervention in ACS patients to prevent/reverse cognitive decline is lacking.

      Introduction

      The debate about whether carotid interventions should be considered in patients with severe asymptomatic carotid stenoses (ACS) for the purpose of preventing/reversing cognitive decline is controversial, but involves two key questions.
      • Naylor A.R.
      • Ricco J.B.
      • de Borst G.J.
      • Debus S.
      • de Haro J.
      • Halliday A.
      • et al.
      ESVS Guidelines Committee. Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
      Firstly, is there evidence that ACS is directly responsible for cognitive impairment, and secondly, is there evidence that carotid endarterectomy (CEA) or carotid artery stenting (CAS) can improve/reverse cognitive impairment in ACS patients?
      In an earlier systematic review (35 non-randomised studies), 94% of studies reported an association between ACS and cognitive impairment.
      • Paraskevas K.I.
      • Faggioli G.
      • Ancetti S.
      • Naylor A.R.
      Asymptomatic carotid stenosis and cognitive impairment: a systematic review.
      However, while there was evidence supporting a direct causal link between ACS and cognitive impairment in patients with significant haemodynamic impairment, the review found no published evidence supporting a silent embolic pathophysiological mechanism, largely because virtually no studies have evaluated the relationship between ACS, silent cortical infarction, and cognitive impairment.
      • Paraskevas K.I.
      • Faggioli G.
      • Ancetti S.
      • Naylor A.R.
      Asymptomatic carotid stenosis and cognitive impairment: a systematic review.
      Several studies have evaluated the effect of CEA and CAS on cognitive function and previous systematic reviews have highlighted problems when interpreting the data, most notably the varying time points at which repeat neuropsychological (NP) testing was performed, heterogeneity in the choice of NP tests, and (most importantly) the confounding effect of combining data from symptomatic and asymptomatic patients.
      • De Rango P.
      • Caso V.
      • Leys D.
      • Paciaroni M.
      • Lenti M.
      • Cao P.
      The role of Carotid artery stenting and carotid endarterectomy in cognitive performance: a systematic review.
      ,
      • Paraskevas K.
      • Lazaridis C.
      • Andrews C.M.
      • Veith F.J.
      • Giannoukas A.
      Comparison of cognitive function after carotid stenting versus carotid endarterectomy.
      The aim of the current systematic review was to determine the effect of CEA/CAS on cognitive function in the early post-operative period (baseline vs. maximum three months) and in the late post-operative period (baseline vs. at least five months) in studies that published outcome data in patients with asymptomatic carotid stenoses (i.e., symptomatic patients were specifically excluded).

      Materials and methods

      A systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      (Fig. 1). PubMed/MedLine, Scopus, and the Cochrane library were independently searched by two teams of investigators (SA/GF and KIP) until 1 March 2021 to identify studies evaluating the effect of CEA and/or CAS on cognitive function. The following search terms were used “carotid endarterectomy AND cognitive function”, and “carotid artery stenting AND cognitive function”. A manual search also reviewed reference lists in the gathered reports. Only studies in English were considered. Studies evaluating the effect of CEA/CAS on cognitive function in symptomatic patients were not considered. Studies including symptomatic and asymptomatic patients were only included if data on asymptomatic patients were presented separately. Case reports, letters/commentaries, and editorials were excluded.
      Figure 1
      Figure 1Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram of studies on asymptomatic carotid interventions and cognitive function.
      A total of 467 studies were identified. After excluding duplicate/overlapping publications, 349 were screened and 115 excluded (Fig. 1). The remaining 234 articles were assessed for eligibility and (when relevant), full text articles were retrieved. Thirty-one were included in the systematic review (Supplementary Table S1). The quality of the studies was assessed using the Newcastle-Ottawa scale (NOS),

      Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp [Accessed 26 January 2021].

      which is based on three domains (selection of study group, comparability of groups, and reporting of outcomes). The scores are detailed in Supplementary Table S1 and were 6/9 in 19 studies, 7/9 in two studies, and 8/9 in 10 studies.
      For the purpose of this systematic review, the effect of carotid interventions on “early” post-operative cognitive function adopted an assessment threshold of a maximum of three months after CEA/CAS (compared with baseline). The “late” effect of carotid interventions on cognitive function involved follow up assessment of cognitive function at least five months after CEA/CAS (compared with baseline). Studies varied in the choice and complexity of NP testing. A minority (n = 4) adopted the less complex Mini Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA) score (Supplementary Table S1), while the remainder adopted a more comprehensive battery of NP domain testing involving assessment of attention, psychomotor speed, memory, language, speed of information, executive function, and visuospatial, although the exact choice of individual tests within each domain varied between studies as different options were available (Supplementary Table S1). In view of the heterogeneity regarding choice of NP testing, cohort size, how data were presented (proportions, composite averaged z scores), and inconsistency regarding the inclusion of non-operated ACS patients as controls (vs. age matched patients with non-vascular pathologies), it was not possible to formally meta-analyse the data.
      Accordingly, descriptive statistics are presented for study cohorts undergoing CEA, CAS, or CEA+CAS within the following categories: (1) significant improvement in cognitive testing with all domains/tests significantly improved, (2) most cognitive domains/tests unchanged, but one to two tests showed significant improvement, (3) mixed findings, where some domains/tests were significantly improved while a similar proportion were significantly worse, (4) no significant change in cognitive function, (5) most cognitive domains/tests unchanged, but one to two tests showed significant worsening, and (6) significant deterioration in cognitive testing with all domains/tests significantly worse. This method of presenting data also permitted visual comparison between smaller and larger study cohorts, those with/without controls, and (for late outcomes) studies with follow up ≥ 12 months.

      Results

      The systematic review identified 31 studies describing the effect of carotid interventions on post-operative cognitive function in ACS patients.
      • Aharon-Peretz J.
      • Tomer R.
      • Gabrieli I.
      • Aharonov D.
      • Nitecki S.
      • Hoffman A.
      Cognitive performance following endarterectomy in asymptomatic carotid stenosis.
      • Baracchini C.
      • Mazzalai F.
      • Gruppo M.
      • Lorenzetti R.
      • Ermani M.
      • Ballotta E.
      Carotid endarterectomy protects elderly patients from cognitive decline: a prospective study.
      • Yoshida K.
      • Ogasawara K.
      • Kobayashi M.
      • Yoshida K.
      • Kubo Y.
      • Otawara Y.
      • et al.
      Improvement and impairment in cognitive function after carotid endarterectomy: Comparison of objective and subjective assessments.
      • Kojima D.
      • Ogasawara K.
      • Kobayashi M.
      • Yoshida K.
      • Kubo Y.
      • Chida K.
      • et al.
      Effects of uncomplicated carotid endarterectomy on cognitive function and brain perfusion in patients with unilateral asymptomatic severe stenosis of the internal carotid artery by comparison with unoperated patients.
      • Pettigrew L.C.
      • Thomas N.
      • Howard V.J.
      • Veltkamp R.
      • Toole J.F.
      Low mini-mental status predicts mortality in asymptomatic carotid arterial stenosis.
      • Bo M.
      • Massaia M.
      • Speme S.
      • Cappa G.
      • Strumia K.
      • Cerrato P.
      • et al.
      Cognitive function after carotid endarterectomy: greater risk of decline in symptomatic patients with left internal carotid artery disease.
      • Falkensammer J.
      • Oldenvurg W.A.
      • Hendrzak A.J.
      • Neuhauser B.
      • Pedraza O.
      • Ferman T.
      • et al.
      Evaluation of subclinical cerebral injury and neuropsychologic function in patients undergoing carotid endarterectomy.
      • Gremigni P.
      • Sciarroni L.
      • Pedrini L.
      Cognitive changes after carotid endarterectomy.
      • Ghogawala Z.
      • Amin-Hanjani S.
      • Curran J.
      • Ciarleglio M.
      • Berenstein A.
      • Stabile L.
      • et al.
      The effect of carotid endarterectomy on cerebral blood flow and cognitive function.
      • Heyer E.J.
      • Mergeche J.L.
      • Bruce S.S.
      • Ward J.T.
      • Stern Y.
      • Anastasian Z.H.
      • et al.
      Statins reduce neurologic injury in asymptomatic carotid endarterectomy patients.
      • Takaiwa A.
      • Kuwayama N.
      • Akioka N.
      • Kurosaki K.
      • Hayashi N.
      • Endo S.
      • et al.
      Effect of carotid endarterectomy on cognitive function in patients with asymptomatic carotid artery stenosis.
      • Dempsey R.J.
      • Jackson D.C.
      • Wilbrand S.M.
      • Mitchell C.C.
      • Berman S.E.
      • Johnson S.C.
      • et al.
      The preservation of cognition 1 year after carotid endarterectomy in patients with prior cognitive decline.
      • Kostal P.
      • Mrhalek T.
      • Kajanova A.
      • Bombic M.
      • Kubale J.
      • Sterba L.
      • et al.
      Changes in cognition and hemodynamics 1 year after carotid endarterectomy for asymptomatic stenosis.
      • Ortega G.
      • Alvarez B.
      • Quintana M.
      • Yugueros X.
      • Alvarez-Sabin J.
      • Matas M.
      Asymptomatic carotid stenosis and cognition improvement using transcervical stenting with protective flow reversal technique.
      • Mendiz O.
      • Sposato L.A.
      • Fabbro N.
      • Lev G.A.
      • Calle A.
      • Valdivieso L.R.
      • et al.
      Improvement in executive function after unilateral carotid artery stenting for severe asymptomatic stenosis.
      • Yoon B.A.
      • Sohn S.W.
      • Cheon S.M.
      • Kim D.H.
      • Cha J.K.
      • Yi S.
      • et al.
      Effect of carotid artery stenting on cognitive function in patients with carotid artery stenosis: a prospective 3-month follow-up study.
      • Lin C.J.
      • Chang F.C.
      • Chou K.H.
      • Tu P.C.
      • Lee Y.H.
      • Lin C.P.
      • et al.
      Intervention versus aggressive medical therapy for cognition in severe asymptomatic carotid stenosis.
      • Wang L.
      • Li X.
      • Song J.
      • Jiang T.
      • Wu X.
      • Zhou S.
      Comparisons of cognitive function and serum S-100B level between diabetic and non-diabetic patients after the implantation of carotids artery stent.
      • Tiemann L.
      • Reidt J.H.
      • Esposito L.
      • Sander D.
      • Theiss W.
      • Poppert H.
      Neuropsychological sequelae of carotid angioplasty with stent placement: correlation with ischemic lesions in diffusion weighted imaging.
      • Grunwald I.Q.
      • Papanagiotou P.
      • Reith W.
      • Backens M.
      • Supprian T.
      • Politi M.
      • et al.
      Influence of carotid artery stenting on cognitive function.
      • Lin C.J.
      • Chang F.C.
      • Lin C.J.
      • Liaw Y.C.
      • Tu P.C.
      • Wang P.N.
      • et al.
      Long term cognitive and multimodal imaging outcomes after carotid artery stenting vs intensive medication alone for severe asymptomatic carotid stenosis.
      • Chen Y.-H.
      • Lin M.-S.
      • Lee J.-K.
      • Chao C.-L.
      • Tang S.-C.
      • Chao C.-C.
      • et al.
      Carotid stenting improves cognitive function in asymptomatic cerebral ischaemia.
      • Whooley J.L.
      • David B.C.
      • Woo H.H.
      • Hoh B.L.
      • Raftery K.B.
      • Siddiqui A.H.
      • et al.
      Carotid revascularization and its effect on cognitive function: a prospective nonrandomized multicenter clinical study.
      • Turowicz A.
      • Czapiga A.
      • Malinowski M.
      • Majcherek J.
      • Litarski A.
      • Janczak D.
      Carotid revascularization improves cognition in patients with asymptomatic carotid artery stenosis and cognitive decline. greater improvement in younger patients with more disordered neuropsychological performance.
      • Feliziani F.T.
      • Polidori M.C.
      • De Rango P.
      • Mangialasche F.
      • Monastero R.
      • Ercolani S.
      • et al.
      Cognitive performance in elderly patients undergoing carotid endarterectomy or carotid artery stenting: a twelve-month follow-up study.
      • Lal B.K.
      • Youbes M.
      • Cruz G.
      • Kapadia I.
      • Jamil Z.
      • Pappas P.J.
      Cognitive changes after surgery vs stenting for carotid artery stenosis.
      • Capoccia L.
      • Sbarigia E.
      • Rizzo A.
      • Mansour W.
      • Speziale F.
      Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization.
      • Kougias P.
      • Collins R.
      • Pastorek N.
      • Sharath S.
      • Barshes N.R.
      • McCulloch K.
      • et al.
      Comparison of domain-specific cognitive function after carotid endarterectomy and stenting.
      • Schröder J.
      • Heinze M.
      • Günther M.
      • Cheng B.
      • Nickel A.
      • Schröder T.
      • et al.
      Dynamics of brain perfusion and cognitive performance in revascularisation of carotid artery stenosis.
      • Casas-Hernanz L.
      • Garolera M.
      • Badenes D.
      • Quintana S.
      • Millán S.
      • Calzado N.
      • et al.
      Neuropsychological outcome one year after carotid revascularisation: a before and after study.
      • Picchetto L.
      • Spalletta G.
      • Casolla B.
      • Cacciari C.
      • Cavallari M.
      • Fantozzi C.
      • et al.
      Cognitive performance following carotid endarterectomy or stenting in asymptomatic patients with severe ICA stenosis.
      Thirteen reported outcomes after CEA, nine after CAS, and nine included both CEA and CAS patients. Overall, 18 studies reported outcomes in 2 028 CEA patients, while 15 reported outcomes in 327 CAS patients. Four studies combined outcomes for CEA and CAS (n = 169). Supplementary Table S1 details patient demographics, NOS scores, vascular risk factors (VRFs), whether magnetic resonance imaging (MRI) or computed tomographic (CT) scans were performed, and details regarding the battery of NP tests. Table 1 provides details regarding ACS severity, exclusion criteria, and timing of post-operative NP testing, along with significant early and late post-operative NP findings.
      Table 1Principal findings from the 31 constituent studies on the effect of carotid interventions on cognitive function in patients with asymptomatic carotid stenosis (ACS)
      Study (year)ACS severity – %Exclusions
      Apart from transient ischaemic attack, stroke, or amaurosis fugax.
      Timing of post-op cognitive testsMain cognitive test findingsAdditional findings
      Aharon-Peretz
      • Aharon-Peretz J.
      • Tomer R.
      • Gabrieli I.
      • Aharonov D.
      • Nitecki S.
      • Hoffman A.
      Cognitive performance following endarterectomy in asymptomatic carotid stenosis.
      (2003)
      70–99Dem1 moMixed better/worse at 1 mo: some domains improved, some worse at 1 mo. No overall improvement vs. controlsVRF patients scored worse than controls whether they had ACS or not
      Baracchini
      • Baracchini C.
      • Mazzalai F.
      • Gruppo M.
      • Lorenzetti R.
      • Ermani M.
      • Ballotta E.
      Carotid endarterectomy protects elderly patients from cognitive decline: a prospective study.
      (2012)
      60–99Dem, PD, BACS3 mo + 1 yNo change at 3 mo vs. pre-op or vs. controls

      No change at 1 y vs. pre-op or vs. controls
      Yoshida
      • Yoshida K.
      • Ogasawara K.
      • Kobayashi M.
      • Yoshida K.
      • Kubo Y.
      • Otawara Y.
      • et al.
      Improvement and impairment in cognitive function after carotid endarterectomy: Comparison of objective and subjective assessments.
      (2012)
      70–992 moMixed better/worse at 2 mo: 81% unchanged at 1 mo, 9% worse and 9% improved
      Kojima
      • Kojima D.
      • Ogasawara K.
      • Kobayashi M.
      • Yoshida K.
      • Kubo Y.
      • Chida K.
      • et al.
      Effects of uncomplicated carotid endarterectomy on cognitive function and brain perfusion in patients with unilateral asymptomatic severe stenosis of the internal carotid artery by comparison with unoperated patients.
      (2016)
      70–99ND, SBI, BACS1 moMost domains unchanged at 1 mo but 9% had significant improvement in cognitive function vs. controls (no improvement)Post-op cognitive improvement most marked in those with CBF increases
      Pettigrew
      • Pettigrew L.C.
      • Thomas N.
      • Howard V.J.
      • Veltkamp R.
      • Toole J.F.
      Low mini-mental status predicts mortality in asymptomatic carotid arterial stenosis.
      (2000)
      60–99NR3 mo, 6 mo, 5 yNo change over 5 y in MMSE: both within group and vs. controls (controls had 60–99% ACS)Patients with lower MMSE scores had higher mortality rates during follow up
      Bo
      • Bo M.
      • Massaia M.
      • Speme S.
      • Cappa G.
      • Strumia K.
      • Cerrato P.
      • et al.
      Cognitive function after carotid endarterectomy: greater risk of decline in symptomatic patients with left internal carotid artery disease.
      (2005)
      70–99Dem3 yNo post-op data

      No change at 3 y compared with pre-op
      Falkensammer
      • Falkensammer J.
      • Oldenvurg W.A.
      • Hendrzak A.J.
      • Neuhauser B.
      • Pedraza O.
      • Ferman T.
      • et al.
      Evaluation of subclinical cerebral injury and neuropsychologic function in patients undergoing carotid endarterectomy.
      (2008)
      70–99SBI, ND2 d, 1 mo, 6 moMostly unchanged at 1 mo with improvement in psychomotor speed and verbal memory. Mostly unchanged at 6 mo with improvement in psychomotor speed, verbal memory, and processing speedS100-B and NSE had no association with changes in cognitive impairment
      Gremigni
      • Gremigni P.
      • Sciarroni L.
      • Pedrini L.
      Cognitive changes after carotid endarterectomy.
      (2009)
      75–99NR3 moIncrease in MMSE at 3 mo in patients with (and without) pre-op cognitive impairmentIncrease in MMSE in patients with MCI pre-operatively also noted
      Ghogawala
      • Ghogawala Z.
      • Amin-Hanjani S.
      • Curran J.
      • Ciarleglio M.
      • Berenstein A.
      • Stabile L.
      • et al.
      The effect of carotid endarterectomy on cerebral blood flow and cognitive function.
      (2013)
      60–99BACS, Dem, PD, CEA6 mo, 1yNo early post-op data. Improved cognition at 1 y. Most marked in patients with increased MCA territory blood flow (attention, executive function)Lower pre-op MCA flow had greatest increases in post-op cognitive function
      Heyer
      • Heyer E.J.
      • Mergeche J.L.
      • Bruce S.S.
      • Ward J.T.
      • Stern Y.
      • Anastasian Z.H.
      • et al.
      Statins reduce neurologic injury in asymptomatic carotid endarterectomy patients.
      (2013)
      60–99NR1 dMost patients unchanged 1 d post-op, but 14% developed cognitive impairment compared with pre-opPre-op statin use: less post-op cognitive dysfunction vs. statin naive patients: 11% vs. 20% (OR 0.51, 95% CI 0.27–0.96; p = .04)
      Takaiwa
      • Takaiwa A.
      • Kuwayama N.
      • Akioka N.
      • Kurosaki K.
      • Hayashi N.
      • Endo S.
      • et al.
      Effect of carotid endarterectomy on cognitive function in patients with asymptomatic carotid artery stenosis.
      (2013)
      80–99NR3 moMostly unchanged with improvement in immediate memory, attention, and RBANS
      Dempsey
      • Dempsey R.J.
      • Jackson D.C.
      • Wilbrand S.M.
      • Mitchell C.C.
      • Berman S.E.
      • Johnson S.C.
      • et al.
      The preservation of cognition 1 year after carotid endarterectomy in patients with prior cognitive decline.
      (2018)
      60–991 yNo early post-op data. Most domains unchanged at 1 y, but there was significant improvement in verbal memory testing
      Kostal
      • Kostal P.
      • Mrhalek T.
      • Kajanova A.
      • Bombic M.
      • Kubale J.
      • Sterba L.
      • et al.
      Changes in cognition and hemodynamics 1 year after carotid endarterectomy for asymptomatic stenosis.
      (2021)
      60–99IC, SBI, Dem, ND, PD1 yNo early post-op data. Mixed: improvement in immediate memory, visuospatial perception but worse in speech/language at 1 y
      Ortega
      • Ortega G.
      • Alvarez B.
      • Quintana M.
      • Yugueros X.
      • Alvarez-Sabin J.
      • Matas M.
      Asymptomatic carotid stenosis and cognition improvement using transcervical stenting with protective flow reversal technique.
      (2014)
      70–99NR6 moNo early post-op data. Most domains unchanged at 6 mo: significant improvement in information processing speed (p = .18)
      Mendiz
      • Mendiz O.
      • Sposato L.A.
      • Fabbro N.
      • Lev G.A.
      • Calle A.
      • Valdivieso L.R.
      • et al.
      Improvement in executive function after unilateral carotid artery stenting for severe asymptomatic stenosis.
      (2012)
      60–99BACS, CEA, CAS3 moMost domains unchanged at 3 mo but executive function significantly improved
      Yoon
      • Yoon B.A.
      • Sohn S.W.
      • Cheon S.M.
      • Kim D.H.
      • Cha J.K.
      • Yi S.
      • et al.
      Effect of carotid artery stenting on cognitive function in patients with carotid artery stenosis: a prospective 3-month follow-up study.
      (2015)
      70–99ND, PD3 moMost domains unchanged at 3 mo, but tests for frontal executive function were significantly worseMore cognitive impairment with pre-op perfusion impairment: improved by CAS
      Lin
      • Lin C.J.
      • Chang F.C.
      • Chou K.H.
      • Tu P.C.
      • Lee Y.H.
      • Lin C.P.
      • et al.
      Intervention versus aggressive medical therapy for cognition in severe asymptomatic carotid stenosis.
      (2016)
      70–99BACS, ND, PD, Dem3 moNo change in cognition vs. controls at 3 mo
      Wang
      • Wang L.
      • Li X.
      • Song J.
      • Jiang T.
      • Wu X.
      • Zhou S.
      Comparisons of cognitive function and serum S-100B level between diabetic and non-diabetic patients after the implantation of carotids artery stent.
      (2014)
      70–99BACS, MCI, ND, PD3 moSignificant improvement in MMSE, verbal memory, and RAVLT delayed recall at 3 mo. No change in MoCA, RAVLT immediate recall, or Digit symbol. No patients worse
      Tiemann
      • Tiemann L.
      • Reidt J.H.
      • Esposito L.
      • Sander D.
      • Theiss W.
      • Poppert H.
      Neuropsychological sequelae of carotid angioplasty with stent placement: correlation with ischemic lesions in diffusion weighted imaging.
      (2009)
      70–99NR6 wMixed better/worse: 36% improved, 27% worse at 6 wNew post-op DWI lesions not associated with poorer cognition post-op
      Grunwald
      • Grunwald I.Q.
      • Papanagiotou P.
      • Reith W.
      • Backens M.
      • Supprian T.
      • Politi M.
      • et al.
      Influence of carotid artery stenting on cognitive function.
      (2010)
      70–99PD, SBI, Dem1 d + 3 moMost domains unchanged at 3 mo, but significant improvement in cognitive speed (p < .001)New post-op DWI lesions not associated with poorer cognition post-op
      Lin
      • Lin C.J.
      • Chang F.C.
      • Lin C.J.
      • Liaw Y.C.
      • Tu P.C.
      • Wang P.N.
      • et al.
      Long term cognitive and multimodal imaging outcomes after carotid artery stenting vs intensive medication alone for severe asymptomatic carotid stenosis.
      (2021)
      70–99BACS, MCI, ND, PD2 yNo early post-op data. Most domains unchanged at 2 y, but significant improvement in delayed verbal memory (p = .04)CAS group had significant increase in brain perfusion at 2 y vs. no change in controls. New DWI lesions associated with worse cognitive function at 2 y
      Chen
      • Chen Y.-H.
      • Lin M.-S.
      • Lee J.-K.
      • Chao C.-L.
      • Tang S.-C.
      • Chao C.-C.
      • et al.
      Carotid stenting improves cognitive function in asymptomatic cerebral ischaemia.
      (2012)
      80–99NR3 moCAS + impaired CVR pre-op had significant improvements in all cognitive domains at 3 mo. CAS + normal CVR pre-op had no change in cognitive function at 3 mo. ACS controls + impaired CVR had no change in cognitive function at 3 mo94% with impaired CVR pre-op were reversed post-op. Patients with impaired CVR had improved cognition post-op
      Whooley
      • Whooley J.L.
      • David B.C.
      • Woo H.H.
      • Hoh B.L.
      • Raftery K.B.
      • Siddiqui A.H.
      • et al.
      Carotid revascularization and its effect on cognitive function: a prospective nonrandomized multicenter clinical study.
      (2020)
      80–99PD, ND, CEA, MCI6 mo + 1 yNo early post-op data. Most domains unchanged at 6 mo, but significant improvement in executive function after CEA and CAS vs. controlsPatients with post-op increases in CBF had greater improvement in executive function
      Turowicz
      • Turowicz A.
      • Czapiga A.
      • Malinowski M.
      • Majcherek J.
      • Litarski A.
      • Janczak D.
      Carotid revascularization improves cognition in patients with asymptomatic carotid artery stenosis and cognitive decline. greater improvement in younger patients with more disordered neuropsychological performance.
      (2021)
      70–99ND6 moNo early post-op data. Improvement in MoCA score after CEA at 6 mo; (24.68 to 26.2, p < .001). After CAS, MoCA increased from 24.39 to 26.28 (p = .002). CANTAB showed significant improvement in paired associated learning and spatial working memory after both CEA and CAS at 6 moImprovement greatest in younger patients with more impaired cognition pre-op
      Feliziani
      • Feliziani F.T.
      • Polidori M.C.
      • De Rango P.
      • Mangialasche F.
      • Monastero R.
      • Ercolani S.
      • et al.
      Cognitive performance in elderly patients undergoing carotid endarterectomy or carotid artery stenting: a twelve-month follow-up study.
      (2010)
      70–99Dem, PD3 mo + 1 yNo change in domain scores at 3 mo after CAS and CEA

      No change in domain scores at 12 mo after CEA. Most domains unchanged after CAS at 12 mo except for significant decline in visuospatial and construction abilities
      Lal
      • Lal B.K.
      • Youbes M.
      • Cruz G.
      • Kapadia I.
      • Jamil Z.
      • Pappas P.J.
      Cognitive changes after surgery vs stenting for carotid artery stenosis.
      (2011)
      70–99Dem5 moMost domain scores improved after CEA/CAS. Only executive function after CEA was significantly improved (p = .04)
      Capoccia
      • Capoccia L.
      • Sbarigia E.
      • Rizzo A.
      • Mansour W.
      • Speziale F.
      Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization.
      (2012)
      70–99SBI1 d, 6 mo, 1 yNo MMSE change after CEA at 1 d, significantly worse MMSE after CAS at 1 d. No change in MMSE after CEA at 6 mo and 1 y. Still significant decline in MMSE after CAS at 6 mo, which remained worse at 1 y, but with some improvement since 6 moNew post-op DWI lesions associated with significant MMSE decline at 6 mo and 1 y
      Kougias
      • Kougias P.
      • Collins R.
      • Pastorek N.
      • Sharath S.
      • Barshes N.R.
      • McCulloch K.
      • et al.
      Comparison of domain-specific cognitive function after carotid endarterectomy and stenting.
      (2015)
      80–99DXT, MCI tracheostomy6 w + 6 moNo change after CEA/CAS (combined) at 6 w. Mostly unchanged after CEA and CAS at 6 mo with improvement in verbal and visual memory and attention
      Schroder
      • Schröder J.
      • Heinze M.
      • Günther M.
      • Cheng B.
      • Nickel A.
      • Schröder T.
      • et al.
      Dynamics of brain perfusion and cognitive performance in revascularisation of carotid artery stenosis.
      (2019)
      70–99SBI, ND, PD, MCI2 moCEA and CAS data combined. No change in cognitive domains at 2m.Post-operative cognitive function not related to changes in CBF
      Casas-Hernanz
      • Casas-Hernanz L.
      • Garolera M.
      • Badenes D.
      • Quintana S.
      • Millán S.
      • Calzado N.
      • et al.
      Neuropsychological outcome one year after carotid revascularisation: a before and after study.
      (2017)
      70–99MCI, ND, PD1 yCEA and CAS data combined. No early post-op data. Most domains unchanged at 1 y, but improvement in visuospatial and psychomotor speed testsPoorer post-op cognitive function with brain atrophy, WMHs, older age
      Picchetto
      • Picchetto L.
      • Spalletta G.
      • Casolla B.
      • Cacciari C.
      • Cavallari M.
      • Fantozzi C.
      • et al.
      Cognitive performance following carotid endarterectomy or stenting in asymptomatic patients with severe ICA stenosis.
      (2013)
      70–99Dem, PD3 moCEA and CAS data combined. Most domains unchanged at 3 mo but significant improvement in phonological verbal fluency and Rey’s 15-word immediate recall
      BACS = bilateral asymptomatic carotid stenoses; CANTAB = Cambridge Neuropsychological Test Automated Battery; CBF = cerebral blood flow; CEA = carotid endarterectomy; CAS = carotid artery stenting; CVR = cerebral vascular reserve; Dem = dementia; DWI = diffusion weighted imaging; DXT = radiotherapy; IC = intracranial stenosis; MCA = middle cerebral artery; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; ND = neurological diseases; NR = not recorded; NSE = neurone specific enolase; PD = psychiatric disease; RAVLT = Rey Auditory Verbal Learning Test; RBANS = Repeatable Battery for the Neuropsychological Status; SBI = silent brain infarction; S100-B = S100 calcium binding protein B; WMHs = white matter hyperintensities; VRF = vascular risk factor.
      Apart from transient ischaemic attack, stroke, or amaurosis fugax.

      Effect of carotid interventions on early post-operative cognitive function

      Twenty-one studies reported early post-operative data (maximum three months vs. baseline) in 24 patient cohorts involving 2 059 patients. There were 12 cohorts of CEA patients (n = 1 761), nine cohorts of CAS patients (n = 199), and three cohorts where CEA and CAS data were combined (n = 99). Three performed NP testing on post-operative day 1, three at one month, two at six weeks, two at two months, and 11 at three months (Table 1). Nine studies included control subjects (non-operated severe ACS [n = 5], non-ACS with VRFs [n = 1], age matched, non-vascular pathologies [n = 2], “healthy volunteers” [n = 1]). In five studies, outcomes following CEA were compared with CAS, rather than controls. Seven studies did not include controls (Supplementary Table S1).
      Fig. 2 and Table 2 summarise the main findings in the 24 cohorts (n = 2 059 patients). Two cohorts reported significant improvement in cognitive function (representing 91/2 059, 4% of the overall study population), while three cohorts reported mixed findings with some domain scores being significantly improved, with a similar proportion being significantly worse (250/2 059, 12%). Seven cohorts reported that most domain scores were unchanged post-operatively, but one to two individual test scores showed significant improvement (257/2 059, 12%). Nine cohorts showed no significant change in early post-operative cognition (1 086/2 059, 53%). Two cohorts reported that most domain scores were unchanged post-operatively, but that one to two individual test scores showed significant worsening (347/2 059, 17%). Only one cohort reported that cognitive scores were significantly worse in the early post-operative period (28/2 059, 1%). This involved a cohort of 28 CAS patients whose MMSE scores deteriorated significantly in the early post-operative period.
      • Capoccia L.
      • Sbarigia E.
      • Rizzo A.
      • Mansour W.
      • Speziale F.
      Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization.
      Figure 2
      Figure 2Effect of carotid endarterectomy (CEA) or stenting (CAS) on early and late post-operative cognitive function based on literature search and reported 24 cohorts with total 2 059 patients. The number in each shape indicates the number of patients in each cohort. Red text indicates studies with controls and black text studies without controls. Black shape outline indicates studies with less than one year of follow up and red shape outline studies with greater than one year of follow up. MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; NP = neuropsychological.
      Table 2Effect of carotid interventions on early and late post-operative cognitive function in patients with asymptomatic carotid stenosis in 2 059 patients in 24 reported cohorts
      Early (baseline vs. < 3 mo)Late (baseline vs. > 5 mo)
      CohortsPatientsCohortsPatients
      All domains/tests significantly improved2/2491/2 059 (4.4)1/2124/1 554 (1.5)
      Most domains unchanged, one to two tests significantly improved7/24250/2 059 (12.1)11/21386/1 554 (24.8)
      Mixed findings (some domains improved; similar proportion worse)3/24257/2 059 (12.5)1/2119/1 554 (1.2)
      No change in cognitive function9/241086/2 059 (52.7)6/211 073/1 554 (69.0)
      Most domains unchanged, one to two significantly worse2/24347/2 059 (16.8)1/2124/1 554 (1.5)
      All domains/tests significantly worse1/1428/2 059 (1.4)1/2128/1 554 (1.8)
      Data are presented as n or n (%).
      Fig. 2 also demonstrates a similar distribution of findings in small, medium, and large sized studies, in studies including controls vs. those that did not, and in outcomes after CEA vs. CAS. Table 3 details studies reporting that cognitive testing was mostly unchanged in the early post-operative period, but that some cohorts reported significant improvement or deterioration in one to two test scores in the early post-operative period.
      Table 3Summary of nine studies reporting that cognitive testing was mostly unchanged, but that some cohorts reported significant improvement or deterioration in one to two domains in the early post-operative period after carotid interventions
      Treatment modalityTime of cognitive assessment after treatmentDescription for improvement or worsening
      Mostly unchanged, significant improvement one to two cognitive domains
       CEA+CAS3 moPhonological verbal fluency and Rey’s 15-word immediate recall
      • Picchetto L.
      • Spalletta G.
      • Casolla B.
      • Cacciari C.
      • Cavallari M.
      • Fantozzi C.
      • et al.
      Cognitive performance following carotid endarterectomy or stenting in asymptomatic patients with severe ICA stenosis.
       CEA2 d + 1 moPsychomotor speed and verbal memory
      • Falkensammer J.
      • Oldenvurg W.A.
      • Hendrzak A.J.
      • Neuhauser B.
      • Pedraza O.
      • Ferman T.
      • et al.
      Evaluation of subclinical cerebral injury and neuropsychologic function in patients undergoing carotid endarterectomy.
       CEA1 mo9% improvement in cognitive function
      • Kojima D.
      • Ogasawara K.
      • Kobayashi M.
      • Yoshida K.
      • Kubo Y.
      • Chida K.
      • et al.
      Effects of uncomplicated carotid endarterectomy on cognitive function and brain perfusion in patients with unilateral asymptomatic severe stenosis of the internal carotid artery by comparison with unoperated patients.
       CEA3 moImmediate memory and RBANS
      • Takaiwa A.
      • Kuwayama N.
      • Akioka N.
      • Kurosaki K.
      • Hayashi N.
      • Endo S.
      • et al.
      Effect of carotid endarterectomy on cognitive function in patients with asymptomatic carotid artery stenosis.
       CAS3 moCognitive speed
      • Grunwald I.Q.
      • Papanagiotou P.
      • Reith W.
      • Backens M.
      • Supprian T.
      • Politi M.
      • et al.
      Influence of carotid artery stenting on cognitive function.
       CAS3 moVerbal memory and RAVLT delayed recall
      • Wang L.
      • Li X.
      • Song J.
      • Jiang T.
      • Wu X.
      • Zhou S.
      Comparisons of cognitive function and serum S-100B level between diabetic and non-diabetic patients after the implantation of carotids artery stent.
       CAS3 moExecutive function
      • Mendiz O.
      • Sposato L.A.
      • Fabbro N.
      • Lev G.A.
      • Calle A.
      • Valdivieso L.R.
      • et al.
      Improvement in executive function after unilateral carotid artery stenting for severe asymptomatic stenosis.
      Mostly unchanged, significant worsening in one to two cognitive domains
       CEA1 d14% developed new cognitive impairment
      • Heyer E.J.
      • Mergeche J.L.
      • Bruce S.S.
      • Ward J.T.
      • Stern Y.
      • Anastasian Z.H.
      • et al.
      Statins reduce neurologic injury in asymptomatic carotid endarterectomy patients.
       CAS3 moFrontal executive function
      • Yoon B.A.
      • Sohn S.W.
      • Cheon S.M.
      • Kim D.H.
      • Cha J.K.
      • Yi S.
      • et al.
      Effect of carotid artery stenting on cognitive function in patients with carotid artery stenosis: a prospective 3-month follow-up study.
      CEA = carotid endarterectomy; CAS = carotid artery stenting; RAVLT = Rey Auditory Verbal Learning Test; RBANS = Repeatable Battery for the Neuropsychological Status.

      Effect of carotid interventions on late post-operative cognitive function.

      Sixteen studies reported late post-operative data (at least five months vs. baseline) in 21 patient cohorts involving 1 554 patients. There were 12 cohorts of CEA patients (n = 1 264), seven cohorts of CAS patients (n = 160), and two cohorts where CEA and CAS data were combined (n = 130). Five studies included control subjects (non-operated severe ACS [n = 3], age matched, non-vascular pathologies [n = 2]). In five studies, outcomes following CEA were compared with CAS, rather than using controls. Six studies did not include controls (Supplementary Table S1). One study performed cognitive assessment five months post-operatively, five were at six months, seven at one year, one at two years, one at three years, and one (serially) out to five years (Table 1).
      Fig. 2 and Table 2 summarise the main findings in the 21 cohorts (n = 1 554 patients). One cohort reported a significant improvement in cognitive function (24/1 554, representing 1.5% of the overall study population), while another cohort reported “mixed” findings with some domain/test scores being significantly improved, with a similar proportion being significantly worse (19/1 554, 1.2%). Eleven cohorts reported that most domain scores were unchanged post-operatively, but that one to two individual test scores showed significant improvement (386/2 059, 24.8%). Six cohorts showed no significant change in late post-operative cognition (1 073/1 554, 69%). One cohort reported that most domain scores were unchanged post-operatively, but that one to two individual test scores showed significant worsening (24/1 554, 1.5%). Only one cohort reported that cognitive scores were significantly worse in the late post-operative period (28/2 059, 1.8%). This was the same cohort of 28 CAS patients whose MMSE scores deteriorated significantly in the early post-operative period. By one year, scores had improved but were not back to baseline.
      • Capoccia L.
      • Sbarigia E.
      • Rizzo A.
      • Mansour W.
      • Speziale F.
      Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization.
      As with the early data, Fig. 2 demonstrates a similar distribution of findings in small, medium, and large sized studies, in studies including controls vs. those that did not, and in patients undergoing CEA vs. CAS. There was also a similar distribution in findings in the 14 cohorts undergoing cognitive assessment after more than one year had elapsed vs. the seven cohorts with reassessment at five to six months. Table 4 details those studies which reported that cognitive testing was mostly unchanged in the late post-operative period, but that some cohorts reported significant improvement or deterioration in one to two test scores in the late post-operative period.
      Table 4Summary of 12 studies reporting cognitive testing was mostly unchanged, but some cohorts reported significant improvement or deterioration in one to two domains in the late post-operative period after carotid interventions
      Treatment modalityTime for cognitive assessment after treatmentImprovement description
      Mostly unchanged, significant improvement in a few cognitive domains
       CEA + CAS6 moVerbal and visual memory and attention
      • Kougias P.
      • Collins R.
      • Pastorek N.
      • Sharath S.
      • Barshes N.R.
      • McCulloch K.
      • et al.
      Comparison of domain-specific cognitive function after carotid endarterectomy and stenting.
       CEA + CAS1 yVisuospatial and psychomotor speed tests
      • Casas-Hernanz L.
      • Garolera M.
      • Badenes D.
      • Quintana S.
      • Millán S.
      • Calzado N.
      • et al.
      Neuropsychological outcome one year after carotid revascularisation: a before and after study.
       CEA5 moExecutive function
      • Lal B.K.
      • Youbes M.
      • Cruz G.
      • Kapadia I.
      • Jamil Z.
      • Pappas P.J.
      Cognitive changes after surgery vs stenting for carotid artery stenosis.
       CEA6 moPaired associated learning and spatial working memory
      • Turowicz A.
      • Czapiga A.
      • Malinowski M.
      • Majcherek J.
      • Litarski A.
      • Janczak D.
      Carotid revascularization improves cognition in patients with asymptomatic carotid artery stenosis and cognitive decline. greater improvement in younger patients with more disordered neuropsychological performance.
       CEA6 moPsychomotor speed, verbal memory and processing speed
      • Falkensammer J.
      • Oldenvurg W.A.
      • Hendrzak A.J.
      • Neuhauser B.
      • Pedraza O.
      • Ferman T.
      • et al.
      Evaluation of subclinical cerebral injury and neuropsychologic function in patients undergoing carotid endarterectomy.
       CEA1 yVerbal memory testing
      • Dempsey R.J.
      • Jackson D.C.
      • Wilbrand S.M.
      • Mitchell C.C.
      • Berman S.E.
      • Johnson S.C.
      • et al.
      The preservation of cognition 1 year after carotid endarterectomy in patients with prior cognitive decline.
       CEA1 yExecutive function
      • Whooley J.L.
      • David B.C.
      • Woo H.H.
      • Hoh B.L.
      • Raftery K.B.
      • Siddiqui A.H.
      • et al.
      Carotid revascularization and its effect on cognitive function: a prospective nonrandomized multicenter clinical study.
       CAS6 moInformation processing speed
      • Ortega G.
      • Alvarez B.
      • Quintana M.
      • Yugueros X.
      • Alvarez-Sabin J.
      • Matas M.
      Asymptomatic carotid stenosis and cognition improvement using transcervical stenting with protective flow reversal technique.
       CAS6 moPaired associated learning and spatial working memory
      • Turowicz A.
      • Czapiga A.
      • Malinowski M.
      • Majcherek J.
      • Litarski A.
      • Janczak D.
      Carotid revascularization improves cognition in patients with asymptomatic carotid artery stenosis and cognitive decline. greater improvement in younger patients with more disordered neuropsychological performance.
       CAS1 yExecutive function
      • Whooley J.L.
      • David B.C.
      • Woo H.H.
      • Hoh B.L.
      • Raftery K.B.
      • Siddiqui A.H.
      • et al.
      Carotid revascularization and its effect on cognitive function: a prospective nonrandomized multicenter clinical study.
       CAS2 yDelayed verbal memory
      • Lin C.J.
      • Chang F.C.
      • Lin C.J.
      • Liaw Y.C.
      • Tu P.C.
      • Wang P.N.
      • et al.
      Long term cognitive and multimodal imaging outcomes after carotid artery stenting vs intensive medication alone for severe asymptomatic carotid stenosis.
      Mostly unchanged, significant worsening in a few cognitive domains
       CAS1 yearVisuospatial and construction abilities
      • Feliziani F.T.
      • Polidori M.C.
      • De Rango P.
      • Mangialasche F.
      • Monastero R.
      • Ercolani S.
      • et al.
      Cognitive performance in elderly patients undergoing carotid endarterectomy or carotid artery stenting: a twelve-month follow-up study.
      CEA = carotid endarterectomy; CAS = carotid artery stenting.

      Carotid endarterectomy vs. carotid artery stenting

      Nine studies recruited CEA and CAS patients, but only one was randomised.
      • Kougias P.
      • Collins R.
      • Pastorek N.
      • Sharath S.
      • Barshes N.R.
      • McCulloch K.
      • et al.
      Comparison of domain-specific cognitive function after carotid endarterectomy and stenting.
      Three combined CEA and CAS data,
      • Schröder J.
      • Heinze M.
      • Günther M.
      • Cheng B.
      • Nickel A.
      • Schröder T.
      • et al.
      Dynamics of brain perfusion and cognitive performance in revascularisation of carotid artery stenosis.
      • Casas-Hernanz L.
      • Garolera M.
      • Badenes D.
      • Quintana S.
      • Millán S.
      • Calzado N.
      • et al.
      Neuropsychological outcome one year after carotid revascularisation: a before and after study.
      • Picchetto L.
      • Spalletta G.
      • Casolla B.
      • Cacciari C.
      • Cavallari M.
      • Fantozzi C.
      • et al.
      Cognitive performance following carotid endarterectomy or stenting in asymptomatic patients with severe ICA stenosis.
      while six provided comparative information for CEA vs. CAS.
      • Whooley J.L.
      • David B.C.
      • Woo H.H.
      • Hoh B.L.
      • Raftery K.B.
      • Siddiqui A.H.
      • et al.
      Carotid revascularization and its effect on cognitive function: a prospective nonrandomized multicenter clinical study.
      • Turowicz A.
      • Czapiga A.
      • Malinowski M.
      • Majcherek J.
      • Litarski A.
      • Janczak D.
      Carotid revascularization improves cognition in patients with asymptomatic carotid artery stenosis and cognitive decline. greater improvement in younger patients with more disordered neuropsychological performance.
      • Feliziani F.T.
      • Polidori M.C.
      • De Rango P.
      • Mangialasche F.
      • Monastero R.
      • Ercolani S.
      • et al.
      Cognitive performance in elderly patients undergoing carotid endarterectomy or carotid artery stenting: a twelve-month follow-up study.
      • Lal B.K.
      • Youbes M.
      • Cruz G.
      • Kapadia I.
      • Jamil Z.
      • Pappas P.J.
      Cognitive changes after surgery vs stenting for carotid artery stenosis.
      • Capoccia L.
      • Sbarigia E.
      • Rizzo A.
      • Mansour W.
      • Speziale F.
      Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization.
      • Kougias P.
      • Collins R.
      • Pastorek N.
      • Sharath S.
      • Barshes N.R.
      • McCulloch K.
      • et al.
      Comparison of domain-specific cognitive function after carotid endarterectomy and stenting.
      Three studies provided data regarding early post-operative cognitive function.
      • Feliziani F.T.
      • Polidori M.C.
      • De Rango P.
      • Mangialasche F.
      • Monastero R.
      • Ercolani S.
      • et al.
      Cognitive performance in elderly patients undergoing carotid endarterectomy or carotid artery stenting: a twelve-month follow-up study.
      ,
      • Capoccia L.
      • Sbarigia E.
      • Rizzo A.
      • Mansour W.
      • Speziale F.
      Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization.
      ,
      • Kougias P.
      • Collins R.
      • Pastorek N.
      • Sharath S.
      • Barshes N.R.
      • McCulloch K.
      • et al.
      Comparison of domain-specific cognitive function after carotid endarterectomy and stenting.
      One reported no difference.
      • Feliziani F.T.
      • Polidori M.C.
      • De Rango P.
      • Mangialasche F.
      • Monastero R.
      • Ercolani S.
      • et al.
      Cognitive performance in elderly patients undergoing carotid endarterectomy or carotid artery stenting: a twelve-month follow-up study.
      Capoccia reported a significant decline in MMSE on day 1 after CAS, with no change after CEA.
      • Capoccia L.
      • Sbarigia E.
      • Rizzo A.
      • Mansour W.
      • Speziale F.
      Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization.
      Kougias observed no difference between CEA and CAS across most domains, but CAS was associated with significantly better cognitive processing speeds (vs. CEA), although this difference was lost by six months.
      • Kougias P.
      • Collins R.
      • Pastorek N.
      • Sharath S.
      • Barshes N.R.
      • McCulloch K.
      • et al.
      Comparison of domain-specific cognitive function after carotid endarterectomy and stenting.
      Six studies provided comparative data on late cognitive function.
      • Whooley J.L.
      • David B.C.
      • Woo H.H.
      • Hoh B.L.
      • Raftery K.B.
      • Siddiqui A.H.
      • et al.
      Carotid revascularization and its effect on cognitive function: a prospective nonrandomized multicenter clinical study.
      • Turowicz A.
      • Czapiga A.
      • Malinowski M.
      • Majcherek J.
      • Litarski A.
      • Janczak D.
      Carotid revascularization improves cognition in patients with asymptomatic carotid artery stenosis and cognitive decline. greater improvement in younger patients with more disordered neuropsychological performance.
      • Feliziani F.T.
      • Polidori M.C.
      • De Rango P.
      • Mangialasche F.
      • Monastero R.
      • Ercolani S.
      • et al.
      Cognitive performance in elderly patients undergoing carotid endarterectomy or carotid artery stenting: a twelve-month follow-up study.
      • Lal B.K.
      • Youbes M.
      • Cruz G.
      • Kapadia I.
      • Jamil Z.
      • Pappas P.J.
      Cognitive changes after surgery vs stenting for carotid artery stenosis.
      • Capoccia L.
      • Sbarigia E.
      • Rizzo A.
      • Mansour W.
      • Speziale F.
      Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization.
      • Kougias P.
      • Collins R.
      • Pastorek N.
      • Sharath S.
      • Barshes N.R.
      • McCulloch K.
      • et al.
      Comparison of domain-specific cognitive function after carotid endarterectomy and stenting.
      Three reported no differences between CEA and CAS.
      • Whooley J.L.
      • David B.C.
      • Woo H.H.
      • Hoh B.L.
      • Raftery K.B.
      • Siddiqui A.H.
      • et al.
      Carotid revascularization and its effect on cognitive function: a prospective nonrandomized multicenter clinical study.
      ,
      • Turowicz A.
      • Czapiga A.
      • Malinowski M.
      • Majcherek J.
      • Litarski A.
      • Janczak D.
      Carotid revascularization improves cognition in patients with asymptomatic carotid artery stenosis and cognitive decline. greater improvement in younger patients with more disordered neuropsychological performance.
      ,
      • Capoccia L.
      • Sbarigia E.
      • Rizzo A.
      • Mansour W.
      • Speziale F.
      Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization.
      The remainder reported no significant differences across most domains, but that CEA was associated with improvement in one to two domains including working memory index,
      • Lal B.K.
      • Youbes M.
      • Cruz G.
      • Kapadia I.
      • Jamil Z.
      • Pappas P.J.
      Cognitive changes after surgery vs stenting for carotid artery stenosis.
      while CAS was associated with improvements in one to two domains including executive and motor function,
      • Kougias P.
      • Collins R.
      • Pastorek N.
      • Sharath S.
      • Barshes N.R.
      • McCulloch K.
      • et al.
      Comparison of domain-specific cognitive function after carotid endarterectomy and stenting.
      psychomotor speed,
      • Lal B.K.
      • Youbes M.
      • Cruz G.
      • Kapadia I.
      • Jamil Z.
      • Pappas P.J.
      Cognitive changes after surgery vs stenting for carotid artery stenosis.
      and visuospatial and constructional abilities.
      • Feliziani F.T.
      • Polidori M.C.
      • De Rango P.
      • Mangialasche F.
      • Monastero R.
      • Ercolani S.
      • et al.
      Cognitive performance in elderly patients undergoing carotid endarterectomy or carotid artery stenting: a twelve-month follow-up study.

      Additional findings

      Five studies reported that patients with significant increases in cerebral blood flow/regional perfusion after their carotid intervention had the greatest improvements in post-operative cognitive function,
      • Kojima D.
      • Ogasawara K.
      • Kobayashi M.
      • Yoshida K.
      • Kubo Y.
      • Chida K.
      • et al.
      Effects of uncomplicated carotid endarterectomy on cognitive function and brain perfusion in patients with unilateral asymptomatic severe stenosis of the internal carotid artery by comparison with unoperated patients.
      ,
      • Ghogawala Z.
      • Amin-Hanjani S.
      • Curran J.
      • Ciarleglio M.
      • Berenstein A.
      • Stabile L.
      • et al.
      The effect of carotid endarterectomy on cerebral blood flow and cognitive function.
      ,
      • Yoon B.A.
      • Sohn S.W.
      • Cheon S.M.
      • Kim D.H.
      • Cha J.K.
      • Yi S.
      • et al.
      Effect of carotid artery stenting on cognitive function in patients with carotid artery stenosis: a prospective 3-month follow-up study.
      ,
      • Chen Y.-H.
      • Lin M.-S.
      • Lee J.-K.
      • Chao C.-L.
      • Tang S.-C.
      • Chao C.-C.
      • et al.
      Carotid stenting improves cognitive function in asymptomatic cerebral ischaemia.
      ,
      • Whooley J.L.
      • David B.C.
      • Woo H.H.
      • Hoh B.L.
      • Raftery K.B.
      • Siddiqui A.H.
      • et al.
      Carotid revascularization and its effect on cognitive function: a prospective nonrandomized multicenter clinical study.
      while one found no association.
      • Schröder J.
      • Heinze M.
      • Günther M.
      • Cheng B.
      • Nickel A.
      • Schröder T.
      • et al.
      Dynamics of brain perfusion and cognitive performance in revascularisation of carotid artery stenosis.
      Two studies
      • Lin C.J.
      • Chang F.C.
      • Chou K.H.
      • Tu P.C.
      • Lee Y.H.
      • Lin C.P.
      • et al.
      Intervention versus aggressive medical therapy for cognition in severe asymptomatic carotid stenosis.
      ,
      • Capoccia L.
      • Sbarigia E.
      • Rizzo A.
      • Mansour W.
      • Speziale F.
      Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization.
      reported that new post-operative diffusion weighted imaging (DWI) lesions on MRI were associated with significantly poorer post-operative cognitive function, while two found no association.
      • Tiemann L.
      • Reidt J.H.
      • Esposito L.
      • Sander D.
      • Theiss W.
      • Poppert H.
      Neuropsychological sequelae of carotid angioplasty with stent placement: correlation with ischemic lesions in diffusion weighted imaging.
      ,
      • Grunwald I.Q.
      • Papanagiotou P.
      • Reith W.
      • Backens M.
      • Supprian T.
      • Politi M.
      • et al.
      Influence of carotid artery stenting on cognitive function.
      Two studies reported that “younger” ACS patients had significantly greater improvements in post-operative cognitive function.
      • Turowicz A.
      • Czapiga A.
      • Malinowski M.
      • Majcherek J.
      • Litarski A.
      • Janczak D.
      Carotid revascularization improves cognition in patients with asymptomatic carotid artery stenosis and cognitive decline. greater improvement in younger patients with more disordered neuropsychological performance.
      ,
      • Picchetto L.
      • Spalletta G.
      • Casolla B.
      • Cacciari C.
      • Cavallari M.
      • Fantozzi C.
      • et al.
      Cognitive performance following carotid endarterectomy or stenting in asymptomatic patients with severe ICA stenosis.
      Heyer reported that patients taking statins prior to CEA had significantly less post-operative cognitive dysfunction, compared with statin naive patients (11% vs. 20%; OR 0.51, 95% CI 0.27 – 0.96, p = .04).
      • Heyer E.J.
      • Mergeche J.L.
      • Bruce S.S.
      • Ward J.T.
      • Stern Y.
      • Anastasian Z.H.
      • et al.
      Statins reduce neurologic injury in asymptomatic carotid endarterectomy patients.
      Falkensammer reported that changes in brain injury biomarkers (S100 calcium binding protein B [S100B]) and neuron specific enolase (NSE) had no association with changes in post-operative cognitive function.
      • Falkensammer J.
      • Oldenvurg W.A.
      • Hendrzak A.J.
      • Neuhauser B.
      • Pedraza O.
      • Ferman T.
      • et al.
      Evaluation of subclinical cerebral injury and neuropsychologic function in patients undergoing carotid endarterectomy.
      Seventeen patients with 80% – 99% ACS with impaired CVR had significant improvement in early post-operative cognitive function, compared with six non-operated controls who had 80% – 99% ACS with impaired CVR. Eleven patients with 80% – 99% ACS and normal CVR had no change in early post-operative cognitive function after CAS, compared with controls.
      • Chen Y.-H.
      • Lin M.-S.
      • Lee J.-K.
      • Chao C.-L.
      • Tang S.-C.
      • Chao C.-C.
      • et al.
      Carotid stenting improves cognitive function in asymptomatic cerebral ischaemia.

      Discussion

      In the first systematic review (35 studies), 94% of studies reported an association between ACS and cognitive impairment, but this did not translate into a proven causal relationship.
      • Paraskevas K.I.
      • Faggioli G.
      • Ancetti S.
      • Naylor A.R.
      Asymptomatic carotid stenosis and cognitive impairment: a systematic review.
      There was no evidence that ACS was responsible for cognitive impairment secondary to silent cortical infarction (few studies have actually addressed this question), or that ACS was causally involved in the pathophysiology of lacunar infarction or white matter hyperintensities,
      • Paraskevas K.I.
      • Faggioli G.
      • Ancetti S.
      • Naylor A.R.
      Asymptomatic carotid stenosis and cognitive impairment: a systematic review.
      both of which are known to cause cognitive impairment and dementia.
      • Debette S.
      • Schilling S.
      • Duperron M.-G.
      • Larsson S.
      • Markus H.S.
      Clinical significance of magnetic resonance imaging of vascular brain injury: a systematic review and meta-analysis.
      Previous attempts at determining whether CEA/CAS can prevent/reverse cognitive decline have produced conflicting results. In a 2008 systematic review, 15 studies evaluated the effect of CEA on post-operative cognition and reported no change in six studies, deterioration in five, and improvement in four.
      • De Rango P.
      • Caso V.
      • Leys D.
      • Paciaroni M.
      • Lenti M.
      • Cao P.
      The role of Carotid artery stenting and carotid endarterectomy in cognitive performance: a systematic review.
      Four studies reported the effect of CAS on post-operative cognitive function, observing no change in one, while three reported improvement.
      • De Rango P.
      • Caso V.
      • Leys D.
      • Paciaroni M.
      • Lenti M.
      • Cao P.
      The role of Carotid artery stenting and carotid endarterectomy in cognitive performance: a systematic review.
      A 2014 systematic review compared changes in post-operative cognitive function after CEA vs. CAS.
      • Paraskevas K.
      • Lazaridis C.
      • Andrews C.M.
      • Veith F.J.
      • Giannoukas A.
      Comparison of cognitive function after carotid stenting versus carotid endarterectomy.
      Six reported no difference, three found cognitive function deteriorated significantly after CAS (vs. CEA), while in another cognitive function deteriorated after both CEA and CAS, with the effect being more persistent after CEA.
      • Paraskevas K.
      • Lazaridis C.
      • Andrews C.M.
      • Veith F.J.
      • Giannoukas A.
      Comparison of cognitive function after carotid stenting versus carotid endarterectomy.
      These systematic reviews highlighted problems associated with trying to evaluate how carotid interventions affect cognitive function resulting from heterogeneity in study methodologies, small sample sizes, non-standardised NP testing, the wide spectrum of timings when post-operative NP testing was performed, the “practice effect” associated with repeat cognitive testing, and, most importantly, by combining data from symptomatic and asymptomatic patients without stratifying for symptom status.
      • De Rango P.
      • Caso V.
      • Leys D.
      • Paciaroni M.
      • Lenti M.
      • Cao P.
      The role of Carotid artery stenting and carotid endarterectomy in cognitive performance: a systematic review.
      ,
      • Paraskevas K.
      • Lazaridis C.
      • Andrews C.M.
      • Veith F.J.
      • Giannoukas A.
      Comparison of cognitive function after carotid stenting versus carotid endarterectomy.
      It is well recognised that symptomatic patients have a higher prevalence of cognitive impairment.
      • Sachdev P.S.
      • Brodaty H.
      • Valenzuela M.J.
      • Lorentz L.
      • Looi J.C.L.
      • Wen W.
      • et al.
      The neuropsychological profile of vascular cognitive impairment in stroke and TIA patients.
      The main advantages of the current systematic review were that it focussed exclusively on the effect of CEA/CAS in neurologically asymptomatic patients, and it divided post-operative data into a defined “early” time period, where post-operative NP testing was undertaken between day one and three months after CEA/CAS and a “later” time period, where repeat NP testing was undertaken after more than five months had elapsed. In 13/21 patient cohorts, one year or more had elapsed after the baseline studies.
      While surgeons/interventionists have probably been more interested in whether CEA/CAS can prevent or improve cognitive decline, neurologists/stroke physicians have probably been equally concerned that carotid interventions might also cause post-operative cognitive impairment because of intra-operative embolisation, hypoperfusion, or post-operative hyperperfusion. In the current systematic review, only one cohort (involving 1.4% of the overall study population) had evidence of significant early post-operative cognitive decline, while two cohorts (16.8% of study population) were mostly unchanged but one to two individual test scores were significantly worse. By the time of late cognitive assessment, only one cohort (1.8% of the overall study population) had evidence of significant cognitive impairment, while another cohort (1.5% of the overall study population) was mostly unchanged but with evidence of cognitive impairment in one to two individual test scores. The available data would suggest, therefore, that performing CEA/CAS in ACS patients is rarely associated with significant cognitive decline (early or late).
      Conversely, Fig. 2 and Table 2 show that only a small minority had significant improvement in overall early post-operative cognitive function (two cohorts; 4.4% of the overall study population) or in late post-operative cognitive function (one cohort; 1.5% of the overall study population). Accordingly, in most ACS patients undergoing CEA/CAS, there is no significant improvement across multiple domains of cognitive function testing.
      The majority of studies reported no significant change in either early cognitive function (nine cohorts; 52.7% of the overall study population) or late cognitive function (six cohorts; 69% of the overall study population). However, in a significant proportion, cognitive function will be mostly unchanged (but with significant improvements in one to two individual test scores) in both the early post-operative period (seven cohorts; 12.1% of the overall study population) and late post-operative period (11 cohorts; 24.8% of the overall study population). These partial improvements may be a “true” finding, but they might also reflect a reduction in patient anxiety (following successful CEA/CAS without peri-operative stroke), which may then be associated with improved test scores. The partial improvement may also reflect the well recognised “practice effect” achieved by learning through repeat testing, which may compromise meaningful interpretation of any observed improvement in cognitive function, especially in studies with small sample sizes.
      • Beglinger L.J.
      • Gaydos B.
      • Tangphao-Daniels O.
      • Duff K.
      • Kareken D.A.
      • Crawford J.
      • et al.
      Practice effects and the use of alternate forms in serial neuropsychological testing.
      It is also possible that partial improvements in post-operative cognition may be relatively subtle and (while interesting) may not impact meaningfully on either quality of life or in the development of dementia. Put simply, if it were that obvious, it is likely that this association would have been confirmed by now. Two large, randomised trials have considered this question. The Asymptomatic Carotid Atherosclerosis Study (ACAS) performed serial measurement of the MMSE score in 1 659 ACS patients randomised to CEA or best medical therapy (BMT) over a five year period, during which time there were no significant inter- or intra-group declines in MMSE scores.
      • Pettigrew L.C.
      • Thomas N.
      • Howard V.J.
      • Veltkamp R.
      • Toole J.F.
      Low mini-mental status predicts mortality in asymptomatic carotid arterial stenosis.
      In the Asymptomatic Carotid Surgery Trial, 1 601 UK and Swedish participants were followed up using linkage to electronic health records for diagnosing incident dementia and via the IQCODE questionnaire in surviving UK participants. The 10 year risk of incident dementia in ACST-1 was 9.3% in CEA patients vs. 9.3% in those randomised to BMT and was 18.6% and 20% at 15 years, respectively,
      • Halliday A.
      • Gottsater A.
      • Sneade M.
      • Whitely W.
      • Llewellyn-Bennett R.
      • Parish S.
      • et al.
      Stroke prevention and dementia: 15-year follow-up of the Asymptomatic Carotid Surgery Trial-1 (ACST-1).
      suggesting that CEA conferred no obvious beneficial effect in reducing long term incident rates of dementia.
      The first systematic review, which evaluated the relationship between ACS and cognitive impairment, observed that ACS might be an important aetiological factor in a subgroup of ACS patients who had co-existent impaired CVR.
      • Paraskevas K.I.
      • Faggioli G.
      • Ancetti S.
      • Naylor A.R.
      Asymptomatic carotid stenosis and cognitive impairment: a systematic review.
      As the extracranial ACS becomes more severe, patients with an incomplete CoW (and inadequate collateral recruitment) compensate by progressive vasodilation of ipsilateral intracranial arterioles. This maintains cerebral blood flow (CBF), but a point arises where arterioles cannot dilate anymore, whereupon the patient enters a state of impaired or exhausted CVR, with limited (or no) capacity to dilate further. Thereafter, further increases in stenosis severity result in reduced brain perfusion. In the first systematic review, nine studies evaluated the relationship between ACS and impaired CVR and cognitive function.
      • Paraskevas K.I.
      • Faggioli G.
      • Ancetti S.
      • Naylor A.R.
      Asymptomatic carotid stenosis and cognitive impairment: a systematic review.
      There was evidence of a stepwise increase in the severity of cognitive impairment from normal cognitive function in patients with severe ACS but normal CVR (bilaterally), through unilateral impaired CVR (increased cognitive impairment), with maximum cognitive dysfunction being observed in patients with bilaterally impaired CVR. Patients with severe ACS (unilateral or bilateral) but no evidence of impaired CVR had cognitive test scores that were no different to controls. There was also evidence from longitudinal studies that patients with severe ACS and impaired CVR were significantly more likely to suffer further cognitive decline over time compared with patients with severe ACS and normal CVR.
      • Paraskevas K.I.
      • Faggioli G.
      • Ancetti S.
      • Naylor A.R.
      Asymptomatic carotid stenosis and cognitive impairment: a systematic review.
      Unfortunately, only one study in the current systematic review specifically evaluated whether carotid interventions influenced post-operative cognitive function in ACS patients with impaired CVR.
      • Chen Y.-H.
      • Lin M.-S.
      • Lee J.-K.
      • Chao C.-L.
      • Tang S.-C.
      • Chao C.-C.
      • et al.
      Carotid stenting improves cognitive function in asymptomatic cerebral ischaemia.
      In this study, patients with 80–99% ACS with normal CVR who underwent CAS had no change in post-operative cognition, as did control patients with 80–99% ACS and impaired CVR who did not undergo carotid revascularisation. By contrast, patients with 80–99% ACS and impaired CVR who underwent CAS had significant improvements across all cognitive domains post-operatively.
      • Chen Y.-H.
      • Lin M.-S.
      • Lee J.-K.
      • Chao C.-L.
      • Tang S.-C.
      • Chao C.-C.
      • et al.
      Carotid stenting improves cognitive function in asymptomatic cerebral ischaemia.
      There are accepted limitations to the current systematic review. These include study heterogeneity, the spectrum of NP tests involved, varying sample sizes, a lack of controls in a significant proportion of studies, a lack of routine pre-operative brain imaging, and no consensus regarding the optimal battery of NP tests that should be adopted in studies involving ACS patients. Very few studies documented whether alternate test forms were available to minimise “practice effects” associated with repeat testing. In addition, only four studies included control subjects with follow up extending to one year or beyond. However, Fig. 2 shows a similar distribution of findings in small, medium, and large sized studies, in studies including controls vs. those that did not, and in patients undergoing CEA vs. CAS, as well as a similar distribution of findings in the 10 studies performing cognitive assessments after more than one year had elapsed vs. the six studies with reassessment at five to six months following CEA/CAS.
      Accordingly, the results from this systematic review represent a baseline for developing further knowledge and support the need for well designed, adequately funded research studies which should involve dedicated neuropsychologists in its design and performance (preferably with a control group involving non-operated ACS patients), a comprehensive battery of NP tests (with alternate forms to minimise practice effects), pre- and post-operative MRI scans (to quantify silent brain infarction, white matter hyperintensities, and new post-operative ischaemic brain lesions) as well as a method for assessing CVR. It should also be adequately powered and include follow up for a minimum of three years, and preferably five.
      In conclusion, carotid interventions in ACS patients were rarely associated with significant overall cognitive improvement, but neither were they associated with late cognitive decline. The clear majority were either unchanged (69%) or mostly unchanged with one to two test scores improved (24.8%). Until new research identifies vulnerable ACS subgroups (e.g., impaired cerebral vascular reserve) or provides evidence that silent embolisation from ACS causes cognitive impairment, evidence supporting intervening in ACS patients to prevent/reverse cognitive decline is lacking.

      Conflict of interest

      None.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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