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. 2021 Sep 17;16(9):e0257697. doi: 10.1371/journal.pone.0257697

Ipsilateral internal carotid artery web and acute ischemic stroke: A cohort study, systematic review and meta-analysis

Brian Mac Grory 1,*, Erez Nossek 2, Michael E Reznik 3, Matthew Schrag 4, Mahesh Jayaraman 3,5, Ryan McTaggart 3,5, Adam de Havenon 6, Shadi Yaghi 3, Wuwei Feng 1, Karen Furie 3, Anusha Boyanpally 7
Editor: Aristeidis H Katsanos8
PMCID: PMC8448368  PMID: 34534252

Abstract

Introduction

The carotid web is a compelling potential mechanism of embolic ischemic stroke. In this study, we aim to determine the prevalence of ipsilateral carotid web in a cohort of ischemic stroke patients and to perform a systematic review and meta-analysis of similar cohorts.

Patients & methods

We performed a retrospective, observational, cohort study of acute ischemic stroke patients admitted to a comprehensive stroke center from June 2012 to September 2017. Carotid web was defined on computed tomography angiography (CTA) as a thin shelf of non-calcified tissue immediately distal to the carotid bifurcation. We described the prevalence of carotid artery webs in our cohort, then performed a systematic review and meta-analysis of similar cohorts in the published literature.

Results

We identified 1,435 potentially eligible patients of whom 879 met criteria for inclusion in our analysis. An ipsilateral carotid web was detected in 4 out of 879 (0.45%) patients, of which 4/4 (1.6%) were in 244 patients with cryptogenic stroke and 3/4 were in 66 (4.5%) patients <60 years old with cryptogenic stroke. Our systematic review yielded 3,192 patients. On meta-analysis, the pooled prevalence of ipsilateral carotid web in cryptogenic stroke patients <60 was 13% (95% CI: 7%-22%; I2 = 66.1%). The relative risk (RR) of ipsilateral versus contralateral carotid web in all patients was 2.5 (95% CI 1.5–4.2, p = 0.0009) whereas in patients less than 60 with cryptogenic stroke it was 3.0 (95% CI 1.6–5.8, p = 0.0011).

Discussion

Carotid webs are more common in young patients with cryptogenic stroke than in other stroke subtypes. Future studies concerning the diagnosis and secondary prevention of stroke associated with carotid web should focus on this population.

Introduction

One third of all ischemic strokes have no known cause [1] and there is a fundamental gap in knowledge about the mechanisms of these “cryptogenic” strokes. The carotid web is an intraluminal projection of hyperplastic intima arising from the carotid artery bulb which causes blood stagnation with the potential for distal embolization [2]. It has been theorized as a cause of ischemic stroke that may be associated with a high risk of recurrent stroke across multiple observational studies [3]. We sought to determine the prevalence of carotid webs in a cohort of patients presenting to a comprehensive stroke center and to combine this with similar studies in a meta-analysis. We hypothesized that ipsilateral carotid web is more common in cryptogenic stroke than in strokes with a known etiology.

Methods

Patient population

This study utilized a retrospective, observational, cohort design. We leveraged a large, institutional quality improvement database containing data from consecutive, well-phenotyped ischemic stroke patients presenting to Rhode Island Hospital between June 2012 and September 2017. Data were aggregated through RedCap (Vanderbilt University, Nashville, Tennessee) and this study was approved by the Rhode Island Hospital Institutional Review Board (IRB #1095514–14). The requirement for written, informed consent was waived by the IRB.

Baseline data acquisition

We enrolled patients who had evidence of acute anterior circulation infarction on neuroimaging (CT or MRI), and cervical vessel imaging with computed tomography angiography (CTA). Adjudication of stroke etiology was performed by a research associate then re-adjudicated by an attending vascular neurologist (BMG) according to the TOAST classification [4]. Within the subgroup of patients with cryptogenic stroke, we then applied separate criteria [5] to classify them as either “ESUS” or “other cryptogenic stroke” (a stroke with two or more competing mechanisms or an incomplete workup).

Imaging analysis

The carotid web was defined as a shelf-like projection in to the lumen of the proximal internal carotid artery, best visualized on sagittal imaging and corresponding to a septum on axial imaging in the absence of calcification or evidence of arterial dissection according to the method of Choi et al. [6]. After a period of training, each case was adjudicated by one of two investigators (BMG or AB) and ambiguous cases resolved by consensus and consultation with a third adjudicator. They were explicitly distinguished from other lesions that can mimic their radiographic appearance, including non-calcified atherosclerosis, arterial dissection, and intra-luminal thrombus [6]. Additional consideration was taken not to mislabel “small protruding lesions” (SPLs) as carotid webs. These lesions have the same appearance as carotid web on sagittal or sagittal-oblique imaging but do not have evidence of a septum on axial imaging [6].

Systematic review

A systematic literature review was performed according to the methodology described in S1 Method.

Statistical analysis

Clinical characteristics of the study cohort were presented using descriptive statistics. Owing to the small number of patients with ipsilateral carotid web, inferential statistical analysis was not performed. After meta-analysis, the combined prevalence rate of ipsilateral carotid web in other cohorts of young patients with cryptogenic stroke was estimated using a random effects model. We meta-analyzed relative risk of ipsilateral versus contralateral carotid web from all published cohorts of consecutive stroke patients in whom carotid web presence/absence was adjudicated and performed sensitivity analyses in which we included only patients with cryptogenic stroke and patients <60 with cryptogenic stroke. Statistical analysis was performed using R software v3.5.1 (R Foundation for Statistical Computing) and meta-analysis performed using the R meta package.

Results

Patient demographics

There were 1,435 patients in our institutional database during the study period, of whom 879 met criteria for inclusion in our final analysis. The flow chart of patient selection is demonstrated in S1 Fig. Within this cohort, 265 patients (30.1%) had cryptogenic stroke of which 244/265 (92.1%) met criteria for ESUS. Key demographic and clinical characteristics of patients within our cohort are outlined in Table 1.

Table 1. Key clinical characteristics of patients in the study sample.

All patients (N = 879) ESUS (n = 244) Non-ESUS (n = 635)
Age (mean±SD) 72.2±14.9 68.7±15.2 73.5±14.7
Sex (female) 443 (50.5%) 121 (49.6%) 322 (50.7%)
Black 58 (6.6%) 22 (9%) 36 (5.7%)
Hypertension 592 (67.3%) 159 (65.2%) 433 (68.2%)
Hyperlipidemia 375 (42.7%) 105 (43%) 270 (42.5%)
Diabetes 201 (22.9%) 70 (28.7%) 131 (20.6%)
Coronary Artery Disease 171 (19.5%) 46 (18.9%) 125 (19.7%)
Atrial Fibrillation 276 (31.4%) 0 (0%) 274 (43.1%)
Smoking 144 (16.4%) 37 (15.2%) 107 (16.9)
Admission NIHSS (mean±SD) 12.9±8.8 10.7±8.6 13.8±8.7
Ipsilateral carotid web 4 (0.46%) 4 (1.6%) 0 (0%)
Contralateral carotid web 3 (0.34%) 1 (0.4%) 2 (0.3%)
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Prevalence and imaging features of carotid webs

Carotid webs in either carotid artery were detected in 7 out of 879 (0.8%) patients and ipsilateral carotid webs in 4 out of 879 (0.45%). Of the 4 symptomatic carotid webs, all were detected in patients with ESUS. Illustrative imaging examples from our cohort are presented in Fig 1. Three patients with symptomatic carotid web were Black and one was White-Hispanic. Three patients had contralateral carotid webs and were older than the patients with ipsilateral carotid webs (61.6±15 vs. 50.3±16.1). No bilateral webs were identified in our study. None of the identified webs caused flow-limiting stenosis. Carotid webs were present in 4.5% of patients aged <60 with ESUS. In patients with ESUS, SPLs were present in equal measure both ipsilateral and contralateral to stroke– 2.1% of patients.

Fig 1. Representative examples of lesions observed in the proximal internal carotid artery within our cohort.

Fig 1

Open in a new tab

Panel A: Internal carotid artery web visible as a protruding lesion in to the lumen of the internal carotid artery seen as a septum on axial imaging (upper panel) and emanating from the posterior wall on oblique sagittal imaging (lower panel). Panel B: Small protruding lesion not visible on axial imaging (upper panel) but sharing imaging features with the carotid web on sagittal oblique imaging (lower panel). Panel C: Atherosclerotic plaque mimicking the conformation of carotid artery web on sagittal oblique imaging (lower panel) but with evidence of eccentric calcified atherosclerosis on axial imaging (upper panel).

Systematic review and meta-analysis

The PRISMA [7] diagram of study selection is included as S2 Fig. In addition to the present study, 9 studies [6, 8–15] were identified with a combined total of 3,192patients of whom 1,127 patients had cryptogenic stroke. We identified 4 studies [8–10, 12] in which we could derive data on patients <60 with cryptogenic stroke, a total of 332 patients. The other studies contained a higher proportion of patients of Black patients than our study (ranging from 54.5% [9] to 100% [8]). The relative risk of carotid web ipsilateral versus contralateral to ischemic stroke was 2.5 (95%: 1.5–4.2, p<0.01) in all patients with acute ischemic stroke and 3.0 (95% CI: 1.6–5.8, p<0.01) in patient less than 60 with cryptogenic stroke (Fig 2A–2C). The pooled prevalence of ipsilateral carotid web in patients <60 with cryptogenic stroke was 13% (95% CI: 7%-22%; I2 = 66.1%) (Fig 2D).

Fig 2. Meta-analysis of carotid web in ischemic stroke cohorts.

Fig 2

Open in a new tab

Panel A: Relative risk of ipsilateral versus contralateral carotid web in patients with stroke All studies. (I2 = 27.71%, p = 0.0009). Panel B: Cryptogenic stroke only. (I2 = 0%, p = 0.0001). Panel C: Cryptogenic stroke in patients less than 60 years old. (I2 = 0%, p = 0.001). Panel D: Pooled prevalence of ipsilateral carotid web in young (<60) patients with cryptogenic stroke combined via a random effects model. (I2 = 65.42%). Please note that “Mac Grory 2021” refers to the present study.

Discussion

In this study, we report the prevalence of carotid webs in a large cohort of consecutive ischemic stroke patients from an institutional registry. This study describes a low incidence of carotid web in an undifferentiated stroke population. Although rare in the stroke population at large, ipsilateral carotid webs were present in 4.6% of young patients with ESUS. Our findings are consistent with prior studies describing a low prevalence of carotid webs in the stroke population at-large but a higher prevalence in young patients with cryptogenic stroke particularly in samples with a high proportion of non-white subjects. Three of four patients with symptomatic carotid web in our study were Black and this is in keeping with trends seen in the literature to-date [3, 16]. On meta-analysis, the relative risk of carotid web ipsilateral versus contralateral to stroke was 3.0 in patients less than 60 with cryptogenic stroke. The lower prevalence of carotid web in our study may reflect the lower number of Black patients in our sample compared with other studies, and our results help further delineate potential ethnic and racial differences in prevalence.

Carotid web is an important potential stroke mechanism as, despite its rarity, it appears from multiple observational studies to be associated with a high risk of recurrent stroke [3]. Carotid webs further share some features of the demographics of FMD particularly the increased prevalence among young women, however, the reproducibly increased prevalence among Black patients is distinctive of carotid webs [17, 18]. FMD of the carotid is associated with a fairly lower stroke recurrence risk when treated with anti-platelet agents. By contrast, the high recurrence risk associated with carotid web means its early recognition and treatment is crucial to reduce the risk of further stroke.

Our study benefited from a large cohort of patients from a comprehensive stroke center in whom stroke etiology was adjudicated by two separate investigators. Our findings should be considered in terms of a number of limitations: 1) we did not have pathological confirmation of intimal FMD, which is definitively diagnostic of carotid web [19]; 2) within our meta-analysis, the estimated pooled prevalence of 13% of patients <60 with cryptogenic stroke may be an artificially high estimate in part mediated by publication bias; 3) only one other study [14] in the systematic review classified stroke as ESUS and thus there is a small limitation introduced through combining studies with different definitions of cryptogenic stroke and; 4) because our study sample is not population-based, we cannot draw inferences on the prevalence of carotid web in the population at large.

Conclusions

Carotid web may be detected in nearly 5% of younger patients with cryptogenic stroke, and the higher rate of carotid webs ipsilateral to ischemic strokes may further implicate their involvement as a potential stroke mechanism.

Supporting information

S1 Checklist. Preferred reporting items for systematic reviews and meta-analyses checklist.

(DOCX)

Click here for additional data file. (30.9KB, docx)
S1 Fig. Flowsheet of patients included in our analysis.

(DOCX)

Click here for additional data file. (38.3KB, docx)
S2 Fig. PRISMA diagram of study selection.

(DOCX)

Click here for additional data file. (53.3KB, docx)
S1 Methods. Supplementary methodology for systematic review and meta-analysis.

(DOCX)

Click here for additional data file. (14.1KB, docx)
S1 Dataset

(XLSX)

Click here for additional data file. (103.2KB, xlsx)

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Aristeidis H Katsanos

31 Aug 2021

PONE-D-21-21566

Ipsilateral Internal Carotid Artery Web and Acute Ischemic Stroke – A Cohort Study, Systematic Review and Meta-Analysis

PLOS ONE

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Reviewer #1: The manuscript by Mac Grory et al describes an observational study on patients with ischemic stroke and carotid webs as well as a systematic review and a meta-analysis. They found that an ipsilateral carotid web occurs in 0.45% of their cohort and in 4.5% in younger patients with a cryptogenic stroke. The pooled prevalence of an ipsilateral carotid web was 13%. The potential role of carotid webs in cryptogenic stroke is interesting. I have one comment:

The pooled prevalence of 13% of ipsilateral carotid web in younger patients with cryptogenic stroke seems rather high. Could this estimation be biased?

Reviewer #2: The present manuscript investigates the prevalence of carotid webs in stroke patients.

There are some ‘typos’ and inconsistencies in the text (for instance the phrase: Carotid web is an important possible stroke mechanism), please review for potential corrections.

Please also check and provide feedback for the following:

The study by Sajedy 2019 reports on the incidence of carotid web among consecutive CTA neck studies, not stroke patients, please explain how this may serve to calculate risk ratios for stroke. Moreover, Ospel et al reports mainly on carotid plaques, not webs. Alternatively, you may remove both studies from the analysis.

The studies by Yo, and Labeyrie et al, which are used in the meta-analysis are not referenced at al. Does Mc Grory et al 2020, reported in the meta-analysis refer to the present study or just to the review referenced in the Supl?

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PLoS One. 2021 Sep 17;16(9):e0257697. doi: 10.1371/journal.pone.0257697.r002

Author response to Decision Letter 0

4 Sep 2021

RESPONSE TO REVIEWERS & EDITORIAL BOARD

We wish to thank the reviewers and the members of the editorial board for the time they have taken in the thoughtful review of our manuscript. We feel that our work has been greatly enriched by the incorporation of these comments. Please find our point-by-point responses below.

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-Thank you. We apologize for this oversight. We have uploaded an accompanying file entitled “Anonymized data set” as supporting information. This has also been mentioned in the author cover letter.

3. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly.

-We have now included captions for our Supporting Information files at the end of the manuscript.

Reviewer #1:

The manuscript by Mac Grory et al describes an observational study on patients with ischemic stroke and carotid webs as well as a systematic review and a meta-analysis. They found that an ipsilateral carotid web occurs in 0.45% of their cohort and in 4.5% in younger patients with a cryptogenic stroke. The pooled prevalence of an ipsilateral carotid web was 13%. The potential role of carotid webs in cryptogenic stroke is interesting. I have one comment:

The pooled prevalence of 13% of ipsilateral carotid web in younger patients with cryptogenic stroke seems rather high. Could this estimation be biased?

-Thank you for this comment. This 13% estimate may certainly be a high estimate and may be in part mediated by publication bias. The confidence intervals are wide and there is a high degree of heterogeneity between studies. We have added the following limitation to the “Discussion” section:

“Our study benefited from a large cohort of patients from a comprehensive stroke center in whom stroke etiology was adjudicated by two separate investigators. Our findings should be considered in terms of a number of limitations: 1) we did not have pathological confirmation of intimal FMD, which is definitively diagnostic of carotid web(15); 2) within our meta-analysis, the estimated pooled prevalence of 13% of patients <60 with cryptogenic stroke may be an artificially high estimate in part mediated by publication bias 3) only one other study(16) in the systematic review classified stroke as ESUS and thus there is a small limitation introduced through combining studies with different definitions of cryptogenic stroke and; 4) because our study sample is not population-based, we cannot draw inferences on the prevalence of carotid web in the population at large.”

Reviewer #2:

The present manuscript investigates the prevalence of carotid webs in stroke patients.

There are some ‘typos’ and inconsistencies in the text (for instance the phrase: Carotid web is an important possible stroke mechanism), please review for potential corrections.

-Thank you very much for this comment. We have corrected the following typos and inconsistencies:

1. “In this study, we aim to determine the prevalence of ipsilateral carotid webs in a cohort of ischemic stroke patients and to perform a systematic review and meta-analysis of similar cohorts.”

2. “Carotid web was defined on computed tomography angiography (CTA) as a thin shelf of non-calcified tissue immediately distal to the carotid bifurcation.”

3. “Carotid web is an important potential stoke mechanism…”

4. “The lower prevalence of carotid web in our study may be a reflection of reflect the…”

Please also check and provide feedback for the following:

The study by Sajedy 2019 reports on the incidence of carotid web among consecutive CTA neck studies, not stroke patients, please explain how this may serve to calculate risk ratios for stroke.

-The authors greatly appreciate this comment. As this was study was a study of consecutive CT angiograms of the neck and not of patients with stroke, its inclusion was erroneous. We have removed it from the current analysis and updated Figure 2A, the abstract, results and PRISMA diagram to reflect this. The removal of this study from the analysis of relative risk of ipsilateral versus contralateral carotid web from 2.6 (95% CI:1.6-4.3) to 2.5 (95% CI:1.5-4.2).

Moreover, Ospel et al reports mainly on carotid plaques, not webs. Alternatively, you may remove both studies from the analysis.

-Thank you for this comment. Although the study of Ospel et al was primarily concerned with non-stenotic carotid plaques, they did report on consecutive stroke patients from a prospective study with CTAs of the neck performed. They provided sufficient granularity in their reported results to allow us to determine the number of carotid webs. The numbers abstracted from this paper refer to carotid web specifically and not atherosclerotic plaques.

The studies by Yo, and Labeyrie et al, which are used in the meta-analysis are not referenced at al. Does Mc Grory et al 2020, reported in the meta-analysis refer to the present study or just to the review referenced in the Supl?

-Thank you very much for this comment. We have added in references to Yu et al. and Labeyrie et al. in the section under Results: Systematic review and meta-analysis. Mac Grory et al. refers to the present cohort and not the prior review paper. We have added the following clarification to the study legend:

“Please note that “Mac Grory 2021” refers to the present study.”

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (21.6KB, docx)

Decision Letter 1

Aristeidis H Katsanos

8 Sep 2021

Ipsilateral Internal Carotid Artery Web and Acute Ischemic Stroke – A Cohort Study, Systematic Review and Meta-Analysis

PONE-D-21-21566R1

Dear Dr. Mac Grory,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Academic Editor

PLOS ONE

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Reviewers' comments:

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: (No Response)

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Acceptance letter

Aristeidis H Katsanos

10 Sep 2021

PONE-D-21-21566R1

Ipsilateral internal carotid artery web and acute ischemic stroke: A cohort study, systematic review and meta-analysis

Dear Dr. Mac Grory:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Aristeidis H. Katsanos

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. Preferred reporting items for systematic reviews and meta-analyses checklist.

    (DOCX)

    Click here for additional data file. (30.9KB, docx)
    S1 Fig. Flowsheet of patients included in our analysis.

    (DOCX)

    Click here for additional data file. (38.3KB, docx)
    S2 Fig. PRISMA diagram of study selection.

    (DOCX)

    Click here for additional data file. (53.3KB, docx)
    S1 Methods. Supplementary methodology for systematic review and meta-analysis.

    (DOCX)

    Click here for additional data file. (14.1KB, docx)
    S1 Dataset

    (XLSX)

    Click here for additional data file. (103.2KB, xlsx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (21.6KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting Information files.

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