Vascular neurology
J NeuroIntervent Surg: first published as 10.1136/jnis-2022-020005 on 17 April 2023. Downloaded from http://jnis.bmj.com/ on March 14, 2024 by luiz mattos. Protected by copyright.
►► Additional supplemental
material is published online
only. To view, please visit
the journal online (http://​dx.​
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020005).
1
Departments of Diagnostic
Imaging and Clinical
Neurosciences, University of
Calgary Cumming School of
Medicine, Calgary, Alberta,
Canada
2
Radiology and Nuclear
Medicine, Amsterdam UMC
Location AMC, Amsterdam,
Noord-­Holland, The Netherlands
3
Clinical Neurosciences,
University of Calgary Cumming
School of Medicine, Calgary,
Alberta, Canada
4
Radiology, Mayo Clinic,
Rochester, Minnesota, USA
5
Mayo Clinic Minnesota,
Rochester, Minnesota, USA
6
Diagnostic Imaging, University
of Calgary, Calgary, Alberta,
Canada
Correspondence to
Dr Mayank Goyal, Diagnostic
Imaging, University of Calgary,
Calgary, AB T2N 4Z6, Canada; ​
mgoyal2412@​gmail.​com
Received 17 February 2023
Accepted 2 April 2023
Published Online First
17 April 2023
© Author(s) (or their
employer(s)) 2024. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Ospel JM,
Kappelhof M, Ganesh A, et al.
J NeuroIntervent Surg
2024;16:418–424.
Review
Symptomatic non-­stenotic carotid disease: current
challenges and opportunities for diagnosis
and treatment
Johanna Maria Ospel,1 Manon Kappelhof ‍ ‍,2 Aravind Ganesh ‍ ‍,3 David F Kallmes,4
Waleed Brinjikji ‍ ‍,5 Mayank Goyal ‍ ‍6
Abstract
Symptomatic non-­stenotic carotid plaques (SyNC) are an
under-­researched and under-­recognized source of stroke.
Various imaging markers of non-­stenotic carotid plaques
that are associated with stroke risk have been identified,
but these causal relationships need to be confirmed in
additional prospective studies. Currently, there exists
neither a standardized SyNC definition nor a dedicated
set of imaging protocols, although researchers have
started to address these shortcomings. Moreover, many
neuroradiologists are still unaware of the condition, and
hence do not comment on high-­risk plaque features
other than stenosis in their reports. Regarding SyNC
treatment, scant data exist as to whether and to what
extent medical, interventional and surgical treatments
could influence the course of the disease; the relative
lack of data on the ’natural’ history of untreated SyNC
makes treatment comparisons difficult. In our opinion,
endovascular SyNC treatment represents the most
promising treatment option for SyNC, since it allows for
targeted elimination of the embolic source, with few
systemic side effects and without the need for general
anesthesia. However, currently available carotid devices
are designed to treat stenotic lesions, and thus are
not optimally designed for SyNC. Developing a device
specifically tailored to SyNC could be an important step
towards establishing endovascular SyNC treatment
in clinical practice. In this review, we provide an
overview of the current state of evidence with regard
to epidemiological, clinical and imaging features of
SyNC, propose a SyNC definition based on imaging and
clinical features, and outline a possible pathway towards
evidence-­based SyNC therapies, with a special focus on
endovascular SyNC treatment.
Background
Acute ischemic stroke (AIS) etiology is most often
classified using the 1993 Trial of Org 10 172 in
Acute Stroke Treatment (TOAST) criteria.1 Large
artery atherosclerosis, defined as arterio-­
arterial
embolism from plaques in the aorta or supra-­aortic
branches, accounts for almost one out of four
cases of AIS. The TOAST criteria only consider
carotid artery plaques to be a source of stroke if
a stenosis >50% is present. Patients with strokes
caused by non-­ stenotic carotid artery plaques
(<50% luminal narrowing) fall under the cate-
gory of ‘embolic stroke of undetermined source’.
The 50% stenosis degree cut-­off was also used in
Ospel JM, et al. J NeuroIntervent Surg 2024;16:418–424. doi:10.1136/jnis-2022-020005
the landmark carotid endarterectomy trials2–4 (the
North American Symptomatic Carotid Endarter-
ectomy Trial (NASCET) and the European Carotid
Surgery Trial (ECST)), thereby finding its way into
guidelines and clinical practice. Since revasculariza-
tion of high-­degree stenotic carotids has become
the standard of care, stroke imaging has natu-
rally prioritized identification of these high-­grade
(>50%) stenoses over other plaque characteristics
indicative of increased stroke risk. However, in
recent years it has become apparent that symp-
tomatic non-­ stenotic carotid disease (SyNC) is a
common and under-­recognized stroke etiology.5 6
While the overall stroke risk in non-­stenotic carotid
plaques is on average lower compared with stenotic
plaques, advanced imaging methods have allowed
for identification of numerous high-­ risk plaque
features such as intraplaque hemorrhage7 that, as
compared with the absence of high-­risk features,
are associated with increased stroke risk in non-­
stenotic plaques, such as intraplaque hemorrhage.7
Patients with non-­ stenotic but vulnerable carotid
plaques seem to still carry a substantially increased
risk for arterio-­ arterial embolic stroke.7 8 In this
review, we provide an overview of epidemiolog-
ical, clinical and imaging features of SyNC, propose
an SyNC definition, summarize scientific evidence
and current practice patterns with regard to SyNC
treatment strategies, and discuss future directions of
SyNC management.
Systematic literature search
We searched the MEDLINE/PubMed electronic
database using the search terms ‘non-­ stenotic’,
‘vulnerable’, ‘hot’, ‘low’, ‘stenosis/stenotic’, ‘high’,
‘risk’, ‘carotid’, ‘plaque/s’, ‘disease/s/d’. We included
original research studies, case reports, reviews and
meta-­analyses that (1) included patients with SyNC
(defined as ≤70% stenosis), (2) reported cerebro-
vascular outcomes, (3) were published in the English
language, and (4) were published in the year 2010
or later. Bibliographies of identified manuscripts
were screened for additional relevant studies. The
literature search is up-­to-­date as of December 24,
2022. The search yielded 242 results, of which 17
studies of original data (original research articles
and case reviews) and 12 reviews were included
after abstract and full-­text screening. Online supple-
mental figure 1 shows a flow chart of included and
excluded studies. Online supplemental tables 1 and
   1 of 8
 Vascular neurology
2 provide an overview of the studies/case reports and review
articles that were identified during the literature search. Of note,
we have focused this article and hence also the literature search
on atherosclerotic lesions and therefore excluded carotid webs,
which are a separate entity with a different pathophysiology that
has been comprehensively summarized elsewhere.9
SyNC definition
It may seem obvious that non-­stenotic or mildly stenotic plaques
(<50-­70% luminal narrowing) can nevertheless be a source of
arterio-­ arterial embolic strokes. However, in the presence of
other, competing stroke etiologies, such as atrial fibrillation
or small vessel disease, it is hard to determine the source of
stroke with certainty. Thus, care needs to be taken to consider
competing stroke sources when deciding whether a stroke
patient suffers from SyNC. Interestingly, five out of the 17 (29%)
identified original research studies and five of the 12 (42%)
identified review avoided to define ‘SyNC’ precisely (online
supplemental tables 1 and 2). The most commonly chosen
stenosis threshold to define SyNC was <50%, and one study
used an additional lower threshold of 30%, with SyNC being
defined as 30–49% carotid stenosis. Two studies chose <70%
stenosis for their SyNC definition.10 11 Additional criteria that
were used included the presence of intraplaque hemorrhage8 or
plaque thickness >3 mm.12 Four studies used more comprehen-
sive definitions that incorporate morphological plaque features
(stenosis degree and high-­risk plaque features), clinical character-
istics (competing stroke sources) and/or brain imaging findings
(evidence of one or multiple strokes in the ipsilateral internal
carotid artery territory).5 13–15 The latter points are critical, since
imaging assessment of the carotid lesion itself always needs to be
reviewed in the context of the brain imaging findings and clinical
symptoms; without evidence of one or ideally several infarcts of
the ipsilateral internal carotid artery territory, a definite diag-
nosis of SyNC cannot be made (table 1). Although transcranial
Doppler sonography could be primarily used for brain imaging
in SyNC assessment, as it is able to detect intracranial emboli,
CT and MRI are less operator-­dependent and more often used
in the acute stroke setting. We personally believe that diffusion-­
weighted MRI should be the preferred brain imaging modality
whenever possible since its sensitivity for acute infarcts is higher
compared with all other modalities. Based on the combination
of carotid lesion imaging characteristics, clinical characteristics
and brain imaging findings, patients can be stratified in a prob-
abilistic manner into ‘definite’, ‘probable’, and ‘possible’ SyNC
cases. Since definite proof is impossible to obtain, we suggest
adhering to such a probabilistic approach in which the following
factors are weighed against each other (see also figure 1).
1. Plaque morphology: Certain high-­risk features, most nota-
bly intraplaque hemorrhage, but also plaque ulceration and
irregular plaque surface, among others, are known to be
associated with an increased stroke risk, especially in non-­
stenotic carotid plaques. The presence of such high-­ risk
features in a non-­stenotic carotid plaque increases the likeli-
hood of this plaque being the source of stroke. The same is
true for a non-­stenotic plaque that is changing in morpholo-
gy, since this change may be the result of instability and active
embolization.
2. Brain imaging: Presence of infarcts, especially concomitant
acute/subacute and new infarcts, in the ipsilateral internal
carotid artery territory are highly suggestive of an arterio-­
arterial embolic source in the internal carotid artery. This is
especially true if there are no visible infarcts in other vascular
territories. Of note, the internal carotid artery territory is
2 of 8
J NeuroIntervent Surg: first published as 10.1136/jnis-2022-020005 on 17 April 2023. Downloaded from http://jnis.bmj.com/ on March 14, 2024 by luiz mattos. Protected by copyright.
Table 1 Working definition for symptomatic non-­stenotic carotid
disease5
If no other stroke causes are present (ESUS based on current definition): Definite
all of the following SyNC
 1) Non-­stenotic (<50%) carotid plaque with high risk features and
changing morphology (on at least two exams at any time point,
detected on ultrasound, DSA, CTA or MRI)
 2) Imaging findings* consistent with recurrent embolic stroke(s)
confined to the corresponding ICA territory† (co-­existing old and new
strokes or new stroke/s compared to previous exam with pre-­existing
strokes)
 3) Absence of acute or chronic infarcts in other vascular territories
If no other stroke causes are present (ESUS based on current definition): Probable
all of the following SyNC
 1) Non-­stenotic (<50%) carotid plaque with high risk features
(detected on ultrasound, DSA, CTA or MRI)
 2) Imaging findings* consistent with acute embolic stroke(s) confined
to the corresponding ICA territory†
 3) Absence of acute or chronic infarcts in other vascular territories
In presence of a potential cardiac cause: all of the following‡
 1) Non-­stenotic (<50%) carotid plaque with high risk features and
changing morphology (on at least two exams at any time point,
detected on ultrasound, DSA, CTA or MRI)
 2) Imaging findings* consistent with acute embolic stroke(s) confined
to the corresponding ICA territory†
 3) Absence of acute or chronic infarcts in other vascular territories
In presence of a potential cardiac cause: all of the following‡
 1) Non-­stenotic (<50%) carotid plaque with high risk features
(detected on ultrasound, DSA, CTA or MRI)
 2) Imaging findings* consistent with recurrent embolic stroke(s)
confined to the corresponding ICA territory† (co-­existing old and new
strokes or new stroke/s compared to baseline exam with pre-­existing
strokes)
 3) Absence of acute or chronic infarcts in other vascular territories
In presence of a potential cardiac cause: all of the following‡ Possible
SyNC
 1) Non-­stenotic (<50%) carotid plaque with high risk features
(detected on ultrasound, DSA, CTA or MRI)
 2) Imaging findings* consistent with acute embolic stroke(s) confined
to the corresponding ICA territory†
*DWI positive lesions on MRI (preferred imaging modality) or hypodense lesions on
NCCT with acute/subacute morphology
†Ipsilateral posterior cerebral artery and/or contralateral anterior cerebral artery
territory infarcts are compatible with the definition of SyNC in the presence of a
dominant posterior communicating artery/anterior communicating artery and a
hypoplastic corresponding P1 segment and/or contralateral A1 segment (see also
online supplemental figure 2).
‡Presence of an ipsilateral intracranial atherosclerotic disease that can explain the
strokes is an exclusion criterion.
CTA, CT angiography; DSA, digital subtraction angiography; DWI, diffusion-­
weighted imaging; ESUS, embolic stroke of undetermined source; ICA, internal
carotid artery; NCCT, non-­contrast CT; SyNC, symptomatic non-­stenotic carotid
disease.
variable based on the presence and caliber of the anterior and
posterior communicating arteries. For example, the ipsilat-
eral anterior cerebral artery territory is normally part of the
internal carotid artery territory, except for cases in which the
ipsilateral A1 segment is absent (online supplemental figure
2).16–18
3. Absence of competing stroke etiologies: the likelihood of
SyNC increases if an extensive stroke work-­up, including
24-­hour electrocardiogram, medium and long-­term cardiac
Ospel JM, et al. J NeuroIntervent Surg 2024;16:418–424. doi:10.1136/jnis-2022-020005

Figure 1 Multidimensional probabilistic framework for a symptomatic non-­stenotic carotid disease (SyNC) definition. Red indicates high likelihood
of SyNC, green indicates low likelihood of SyNC. The likelihood of SyNC depends on three main ‘dimensions': (1) carotid plaque morphology (ie,
presence of high-­risk plaque features), (2) brain imaging (ie, evidence of acute/subacute or old infarcts in the ipsilateral internal carotid artery
territory), and (3) presence of competing, alternative etiologies (eg, atrial fibrillation). Information from these three factors needs to be synthesized
when determining the likelihood of SyNC. ICA, internal carotid artery.
monitoring, echocardiogram, and vasculitis work-­up, is oth-
erwise negative.
As mentioned before, these three ‘dimensions’ need to be
weighed against each other when deciding about a potential
SyNC case. We therefore propose a probabilistic SyNC defi-
nition based on these considerations that has been previously
described by our group. In short, we suggest classifying cases
as ‘definite SyNC’ if they show evidence of recurrent ipsilat-
eral stroke exclusively in the internal carotid artery territory,
an ipsilateral SyNC lesion with high-­risk features and changing
morphology (suggesting active embolization), as well as absence
of other stroke causes. If these criteria are only partially met,
we suggest classifying the case either as ‘probable’ or ‘possible’
SyNC5 (table 1). Certainly, clear-­cut ‘definite’ SyNC cases will be
the exception and, most of the time, one will encounter patients
who reside somewhere along the spectrum of ‘possible’ to ‘prob-
able’ SyNC.
Clinical features of SyNC
Currently, is not entirely clear whether and how clinical char-
acteristics of SyNC patients differ from AIS patients with other
stroke etiologies. Embolic stroke of undetermined source (ESUS)
patients are on average younger and present with milder symp-
toms compared with other stroke etiologies.19–21 Since SyNC
patients so far have been classified as ESUS, it is possible that
the aforementioned characteristics apply to the SyNC popula-
tion as well, but this is uncertain. The included SyNC studies
report mean ages at stroke onset from 63 to 78 years (online
supplemental table 1), which is very similar when compared with
other common stroke etiologies such as small vessel disease and
cardioembolic strokes. Additionally, SyNC may be associated
with a general pro-­inflammatory vascular state, characterized
by increased fluorodeoxyglucose (FDG) uptake not only of the
SyNC lesion but also other vessels, including the contralateral
carotid artery.13 Indeed, carotid atherosclerotic lesions are associ-
ated with increased C-­reactive protein (CRP), a systemic inflam-
matory marker, and the combination of carotid atherosclerosis
and increased CRP is not only associated with strokes but also
myocardial infarction,22 further supporting the hypothesis that
SyNC may simply be a manifestation of a systemic inflammatory
process. Thus, one could consider routinely obtaining CRP levels
in SyNC patients to evaluate systemic inflammatory activity.
Other clinical factors that may play a role in carotid plaque
formation and instability, and thus also SyNC pathogenesis, need
to be explored in further detail. For example, it is possible that
low vitamin D levels predispose to intraplaque hemorrhage,23
but this needs to be confirmed in additional studies.
Ospel JM, et al. J NeuroIntervent Surg 2024;16:418–424. doi:10.1136/jnis-2022-020005
Vascular neurology
J NeuroIntervent Surg: first published as 10.1136/jnis-2022-020005 on 17 April 2023. Downloaded from http://jnis.bmj.com/ on March 14, 2024 by luiz mattos. Protected by copyright.
Imaging of SyNC
Since the definition of SyNC relies both on imaging findings of
the carotid lesion itself as well as brain imaging findings, both
should be undertaken when SyNC is suspected.
As for brain imaging, only a few of the included studies specif-
ically reported brain imaging findings as part of SyNC.13 14 24
Nevertheless, in order to establish a causal relationship, evidence
of infarcts in the ipsilateral internal carotid artery territory is
crucial, while infarcts in other territories would speak against
SyNC. One caveat is that the internal carotid artery territory is
variable depending on the circle of Willis configuration (online
supplemental figure 2). Possible imaging modalities to show
evidence of recent or past ischemia would be non-­contrast CT
and MRI. A non-­contrast CT could show evidence of larger
ischemic events. MRI is by far the more sensitive modality,
when including both diffusion-­weighted imaging to detect acute
infarcts and fluid attenuated inversion recovery (FLAIR) or T2
sequences to detect subacute and old infarcts. The situation is
much more complex when it comes to imaging of the carotid
lesion itself. Several plaque features have been described to be
indicators of ‘vulnerable’ non-­stenotic lesions that are prone to
embolization.
Degree of stenosis
The degree of stenosis as per the NASCET criteria2 3 can be
assessed on most imaging modalities, most commonly, CT angi-
ography (CTA), ultrasound and MRI/MR angiography. It is well-­
known that stenotic carotid plaques carry a higher risk of stroke
than non-­stenotic (<50%) plaques. Even within the group of
non-­stenotic plaques, it seems that a higher degree of stenosis
is associated with ipsilateral stroke.10 12 Thus, the degree of
stenosis seems to be an important imaging marker, even within
the non-­stenotic plaque subgroup. In other words, it seems that,
given that all other plaque features are equal, a carotid plaque
with 40% stenosis yields a higher stroke risk as compared with a
plaque with 10% stenosis.
MRI markers: intraplaque hemorrhage
Intra-­plaque hemorrhage (figure 2) is the most well-­ studied
imaging marker in the setting of SyNC, and it has a clear, strong
association with ipsilateral internal carotid artery territory
strokes, irrespective of the degree of luminal narrowing.8 14 25 26
Not surprisingly, intraplaque hemorrhage was mentioned as a
high-­risk feature in almost every included study (online supple-
mental tables 1 and 2). Assessing for intraplaque hemorrhage
requires a non-­contrast fat-­saturated T1 image, which does not
require any specialized MR equipment and only takes 3–5 min to
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 Vascular neurology

J NeuroIntervent Surg: first published as 10.1136/jnis-2022-020005 on 17 April 2023. Downloaded from http://jnis.bmj.com/ on March 14, 2024 by luiz mattos. Protected by copyright.
Figure 2 Exemplary MRI and CT plaque features of symptomatic non-­stenotic carotid disease from different patients. (A) Non-­stenotic plaque with
intraplaque hemorrhage (black asterisk), seen as a hyperintense signal on non-­contrast T1 fat-­saturated sequence. The vessel lumen is denoted by
the white asterisk. (B) Non-­stenotic plaque with thick, continuous fibrous cap (contrast-­enhancing plaque membrane denoted by white arrows, vessel
lumen denoted by white asterisk). These more stable plaques are less likely to rupture. (C) Non-­stenotic plaque with irregular, ruptured fibrous cap
(discontinuous plaque membrane denoted by white arrows, vessel lumen denoted by white asterisk). These unstable plaques are more likely rupture
and embolize. (D) Irregular, predominantly non-­calcified hypodense plaque with irregular surface. (E) Exclusively non-­calcified (‘soft’) hypodense
plaque. (F) Plaque with irregular surface and fissure-­like extension of the lumen into the plaque substance (ulceration; black arrow). (G) Exclusively
calcified plaque. These plaques are considered to be stable and less likely to cause distal embolism. (H) Very small but irregular non-­calcified plaque
with undulating plaque surface.

acquire. Nevertheless, since acute stroke imaging is CT-­based in CT markers

the vast majority of hospitals, assessing intraplaque hemorrhage
is not necessarily part of the routine stroke work-­up in most
centers.
Other MRI markers
Other high-­risk MRI imaging markers include lipid-­rich necrotic
core, ulceration, ruptured fibrous cap, and possibly various
quantitative fibrin, lipid and calcific component measures26 (see
figure 2 for exemplary findings). However, the evidence, partic-
ularly for quantitative measurements, is sparse and different
studies used different software packages and variable definitions
to identify and quantify those components. Besides investigating
the association of these individual plaque components with
stroke risk, many authors have classified plaques using the Amer-
ican Heart Association (AHA) classification.13 27 28 This classifi-
cation has originally been established to describe coronary artery
plaques and uses histological criteria to group arterial plaques,
whereby the higher groups (AHA type IV–VI plaques) are asso-
ciated with a higher risk of arterio-­arterial embolism. Although
compelling in theory, this nomenclature is problematic in the
sense that imaging findings do not translate 1:1 into histolog-
ical correlates, and it is therefore hard to know the histolog-
ical composition and architecture of a plaque without actually
obtaining histological proof. In clinical practice, we therefore
suggest a pragmatic approach for now when performing plaque
MRI, that is, assessing for intraplaque hemorrhage, plaque ulcer-
ation and irregularity, without quantifying plaque components
or applying any detailed classification.
4 of 8
In theory, using a CT-­based marker for SyNC assessment would
be ideal, since non-­contrast CT of the head and CTA of the head
and neck are routinely performed in all patients with suspected
AIS. Several CT-­based imaging markers have been suggested,
including plaque thickness (both as a continuous variable and
thickness ≥3 mm),6 7 12 29 plaque ulceration/irregularity, and
non-­calcified and hypodense plaques (figure 2). However, the
association of these features with ipsilateral strokes is weak, and
many studies could not show a significant association at all.6 15
This may be related to the relatively low tissue contrast of CTA,
which makes accurate distinction of different plaque compo-
nents close to impossible. Some authors have also attempted to
quantify histological plaque components based on differences in
density,30 but such attempts are still experimental and suffer from
the same limitations mentioned in the previous section. Limited
spatial resolution and resulting volume averaging artifacts consti-
tute additional problems. In other words, CTA should not be
the primary assessment modality for SyNC. If a high-­risk carotid
plaque feature is seen on CTA in the appropriate context, then
the suspicion of SyNC can certainly be raised, but the absence of
such features on CTA should not lead us to conclude that SyNC
is not present.
Ultrasound
Although carotid ultrasound is usually also not part of the acute
stroke work-­up, ultrasound has the advantages of being rela-
tively inexpensive, widely available, and radiation-­free. Perhaps
Ospel JM, et al. J NeuroIntervent Surg 2024;16:418–424. doi:10.1136/jnis-2022-020005

the greatest disadvantage is the high inter-­operator variability.
High-­risk ultrasound features reported in the identified studies
include degree of stenosis, intraplaque hemorrhage, lipid-­rich
necrotic core, as well as both echolucency/high echogenicity
and low echogenicity, although no quantitative thresholds were
provided by the authors31 (online supplemental table 1). One
review discussed the potential advantages of contrast-­enhanced
ultrasound,24 which is, however, not routinely used in most
centers.
Positron emission tomography
A number of studies used positron emission tomography (PET)
to assess for metabolic activity of carotid lesions.10 12 32 Interest-
ingly, in addition to FDG-­uptake being higher in complicated
(AHA type VI) lesions compared with lower-­grade AHA lesions,
the authors also found that patients with type VI lesions show
increased uptake in the contralateral carotid artery. They hypoth-
esized that this could indicate a possible systemic inflammatory
process as an underlying etiology in patients with complicated
plaques.13
Other modalities such as digital subtraction angiography
and optical coherence tomography have also been discussed,33
although no robust SyNC imaging markers for these modalities
exist at this point. Of note, despite increasing evidence on the
importance of carotid plaque features other than the degree of
stenosis, they are often not commented on in radiology reports.
In a retrospective evaluation of 651 CTA reports in a large
comprehensive stroke center in the USA, the degree of carotid
stenosis was explicitly mentioned in >98%, but the presence or
absence of most other high risk features were reported in <20%,
and <1% explicitly mentioned whether there was a carotid lesion
that could increase stroke risk.34 These data suggest that many
non-­stenotic high risk lesions may go unnoticed, and increasing
awareness among the diagnostic neuroradiology community
could substantially help in detecting SyNC cases and recognizing
them as such early on. Online supplemental table 3 provides an
‘SyNC checklist‘ for radiologists that can be used when assessing
carotid CT/MR angiographies.
Risk of stroke in SyNC patients
What is the risk of future stroke in patients with SyNC? Since
many studies did not use a clear SyNC definition, one can only
provide rough estimates on future stroke risk. Probably the most
thorough, comprehensive study that was conducted on this
question is the prospective, longitudinal multicenter Plaque-­At-­
Risk (PARISK) cohort study that included patients with recent
transient ischemic attack (TIA) or minor stroke and ipsilateral
carotid plaques causing <70% stenosis.11 During 5.1 years
follow-­up, 37/238 (16%) patients suffered a recurrent stroke
or TIA, with MRI evidence of new infarcts in 19/238 (8%)
patients.11 Intraplaque hemorrhage and total plaque volume
(both assessed on MRI) were associated with recurrent ipsilat-
eral stroke or TIA, with hazard ratios of 2.12 (95% CI 1.02
to 4.44) and 1.07 (95% CI 1.00 to 1.15) per 100 µL increase,
respectively. Although the stenosis threshold used in PARISK
(<70%) is different from the one used by most studies and
ourselves (<50%), most (73%) PARISK patients showed very
mild stenosis with <30% luminal narrowing. Thus, the PARISK
findings will likely apply to patients with <50% plaques as well.
In contrast to PARISK, the majority of studies that we identified
during the literature search are cross-­sectional in nature, that is,
patients with AIS/TIA were imaged, and ipsilateral (and contra-
lateral) carotid plaque features were reported. For instance, a
single center study by Larson et al performed routine carotid
Ospel JM, et al. J NeuroIntervent Surg 2024;16:418–424. doi:10.1136/jnis-2022-020005
Vascular neurology
J NeuroIntervent Surg: first published as 10.1136/jnis-2022-020005 on 17 April 2023. Downloaded from http://jnis.bmj.com/ on March 14, 2024 by luiz mattos. Protected by copyright.
plaque imaging on 123 consecutive ESUS patients,35 whereby 31
patients (25.2%) had an ipsilateral hemorrhagic plaque versus
five patients (4.1%) on the side contralateral to the stroke. The
recurrent stroke risk in the ipsilateral intraplaque hemorrhage
group was 16.7% compared with 2.4% in the non-­intraplaque
hemorrhage group, and the overall rate of recurrent ipsilateral
stroke was 9.5%/year. Although numerous other studies also
suggest that SyNC-­type lesions are found more often ipsilat-
eral to the stroke,6 15 29 causality still needs to be confirmed in
prospective, longitudinal studies.
One important caveat with regard to non-­stenotic lesions and
their association with ipsilateral stroke is that the non-­stenotic
plaque morphology at the time of imaging may be a result of
embolization, and the initial plaque may in fact have been a
stenotic one. Since serial imaging prior, during and after the
stroke/TIA is neither ethical nor feasible, this possibility cannot
be entirely excluded.
Potential SyNC treatment options
The treatment for SyNC needs to be approached differently
from the treatment for high-­grade carotid stenosis, because the
risk of future stroke is lower in SyNC; this has to be taken into
account when balancing treatment risks and potential benefits.
Overall, it seems that a more cautious approach in SyNC would
be reasonable, given the better natural history of the disease.
Medical management
Some studies have suggested intensive medical treatment, for
example, with rivaroxaban plus aspirin, dual antiplatelet agents
or high-­dose statins as a potential SyNC treatment,7 24 36 the
primary goal being to influence plaque remodelling in a posi-
tive way and stabilize ‘vulnerable’ plaques. Evidence for such
therapeutic regimens is hitherto largely missing. The ongoing
randomized Colchicine for prevention of vascular inflammation
in non-­cardioembolic stroke (CONVINCE) trial investigates the
efficacy of low-­dose colchicine to reduce non-­ cardioembolic
strokes,37 which may be an interesting treatment option to
counteract the inflammatory component of SyNC. There are
also novel treatments under investigation, for example, C-­117,
a compound that may potentially reduce non-­stenotic carotid
plaque burden based on the results of one randomized trial.38
Surgical management (carotid endarterectomy)
Carotid endarterectomy (CEA), although commonly performed
for high-­grade carotid stenosis, is hardly ever used to treat SyNC,
because it is an invasive surgical procedure which requires general
anesthesia and temporary ligation of the carotid artery and, as
with any surgery, carries some perioperative risks. Although few
studies have reported successful CEA for SyNC,14 39 routine CEA
is hardly justified, given the lack of guideline-­based SyNC treat-
ment recommendations, and the perceived ‘benign’ course of
SyNC compared with high-­grade carotid stenosis.
Interventional management (carotid artery stenting)
Based on the above considerations, carotid artery stenting (CAS)
may be a valid alternative to CEA in SyNC patients. However,
the lack of randomized evidence (which in turn, has resulted in
a lack of guideline-­based treatment recommendations) applies
to CAS as well, and for the time being there are no robust data
to suggest superiority of either CEA, CAS or aggressive medical
management. Furthermore, currently available stents used for
CAS are intended for more severely stenotic vessel segments and
have a high radial force, which comes at the cost of vessel wall
5 of 8
 Vascular neurology
Figure 3 Steps towards successful evidence-­based symptomatic non-­stenotic carotid disease (SyNC) treatment. First, observational studies should
be conducted to better characterize the natural history of SyNC. These data will serve as a comparator for future intervention trials. In parallel,
development of an endovascular SyNC treatment device can be initiated. Second, in vitro testing and preliminary in vivo testing in animal studies, and
later on, first in-­human studies, will be performed. Once the safety of the device has been proven, a randomized trial can be initiated. On completion
of the trial or slightly before that, registries of treated SyNC patients should be initiated to capture long-­term outcomes, and any potentially occurring
late unexpected adverse events.
stretching and micro-­injuries. To achieve this high radial force,
dense wire meshes encompassing the full stent circumference
(360°) are used. This high metal density results in a large throm-
bogenic surface area exposed in the vessel and requires lifelong
antiplatelet therapy to prevent platelet adhesion and in-­stent
thrombosis. The high circumferential metal coverage of current
carotid stents also renders subsequent CEA impossible because
the dense wire mesh cannot be cut by a surgical scalpel.
Lastly, the pores of currently used stents are relatively large,
and allow small plaque fragments to migrate into the vessel
lumen, increasing the risk of periprocedural embolic strokes.
Proximal and distal protection devices are available to minimize
that risk, although they cannot completely prevent distal embo-
lization, and earlier reviews suggest no significant differences in
periprocedural strokes and death with versus without protection
devices.40 41
Endovascular SyNC treatment: how to move
forward?
Despite the above-­mentioned issues, we personally believe that
of all treatment options, endovascular treatment is the most
promising option. Several challenges need to be overcome first:
more (prospective) knowledge about the ‘natural history’ of
SyNC should be gathered, the role of systemic inflammatory
conditions in SyNC patients should be further investigated,
and robust evidence for all three treatment options needs
to be created. The neurointerventional community seems to
agree with this approach: in a multinational web-­based survey
(ESCAPE ALICE: EndovaSCular TreAtment Preference Evalua-
tion at the Advanced Live Interventional Course of Essen),42 43
we asked 248 neurointerventionalists from 48 countries how
they see the future of SyNC treatment. The majority of physi-
cians thought that essential prerequisites to successful interven-
tional SyNC treatment are (1) a standard definition for SyNC,
and (2) a standardized imaging protocol (online supplemental
figure 3A,B). Two thirds believed that now is the time for a
randomized trial comparing medical versus interventional versus
surgical SyNC therapy, while 23% believed that, first, better data
on the natural history of non-­stenotic carotid plaques are needed
(online supplemental figure 3D). With regard to potential endo-
vascular SyNC treatment devices, four out of five physicians
thought that an uncovered stent is preferable to a covered device
(online supplemental figure 3C). Self-­expanding properties and
appropriate mesh design with small pores were thought to be the
most critical features of an endovascular SyNC treatment device,
while a strong outward force was considered the least desirable
of all provided answer options (online supplemental figure 3D).
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Indeed, SyNC is by definition non-­stenotic, and thus it is not
necessary to widen the vessel lumen by applying an outward
force. In fact, only focal coverage by the stent material at the
site of the plaque is needed to eliminate the embolic lesion. Not
only would focal metal coverage reduce the thrombogenic risks,
it would also allow for subsequent CEA because the device could
be cut at the site of minimal metal coverage. Further design
specifications, such as anti-­inflammatory coating or a resorbable
material for temporary plaque stabilization, could be considered
as well. Figure 3 outlines a suggested timeline for establishing
endovascular SyNC treatment in clinical practice. Of note, these
considerations are purely speculative at this point and, currently,
no such SyNC treatment device exists.
Conclusion
SyNC is an under-­ researched and under-­ reported source of
stroke. Although it is well known that certain imaging modal-
ities, each having their advantages and disadvantages, can
identify non-­stenotic carotid plaques associated with increased
stroke risk, most studies are cross-­sectional in nature and only
little prospective data are available. Furthermore, SyNC defini-
tions vary between studies, and many neuroradiologists seem to
be unaware of the stroke risks associated with certain carotid
plaque features, and hence do not comment on them in their
reports. Given the high recurrent stroke risk in SyNC patients
with approximately one out of seven patients suffering a repeat
stroke or TIA,11 the neuroradiology community should be sensi-
tized for SyNC, and a consensus on a standardized SyNC defi-
nition that includes plaque and brain imaging findings, as well
as clinical features, should be prioritized. Next, observational
studies need to be conducted to determine the natural history of
SyNC and the risk of stroke recurrence. These data can serve as
a baseline and comparator for randomized controlled trials that
may be conducted after endovascular SyNC devices have been
tested and validated. While we acknowledge that such trials will
be challenging to conduct, we believe they are feasible and are
critical to guide the medical care of SyNC patients, for whom no
good treatment currently exists. To ensure that potential short-­
term benefits from any treatment found by trials translate into
long-­term benefits in clinical practice, randomized controlled
trials should be followed by registries for long-­term follow-­up.
Such registries, although they may be subject to enrollment bias,
could complement randomized trials and may provide a more
realistic picture of SyNC treatment benefits in clinical routine as
opposed to the highly standardized clinical trial setting. These
steps will hopefully soon lead to increased recognition and
targeted treatment of SyNC.
Ospel JM, et al. J NeuroIntervent Surg 2024;16:418–424. doi:10.1136/jnis-2022-020005

Twitter Aravind Ganesh @draravindganesh
Contributors JO, MK: Conceptualization, literature search, drafting and critical
revision of the manuscript and figures. MG: Conceptualization, critical revision of the
manuscript and figures. WB: drafting of the figures, critical revision of the manuscript
and figures. Remaining authors: critical revision of the manuscript and figures.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests JO is a consultant for NICOLab and Chief Scientific Officer
of Collavidence. AG has received grants from the Canadian Institutes of Health
Research, Canadian Cardiovascular Society, Alberta Innovates, Camps Alberta
Neuroscience, Government of Canada – INOVAIT program, Government of Canada
– New Frontiers in Research Fund, Microvention, Alzheimer Society of Canada, Heart
and Stroke Foundation of Canada, Panmure House. He has also received consulting
fees from MD Anlaytics, MyMedicalPanel, Figure 1, CTC Communications Corp,
Atheneum, DeepBench, Research on Mind, Creative Research Designs, AlphaSights,
42mr. He has further received honoraria from Figure 1, Alexion, Biogen, Servier
Canada and travel support from American Academy of Neurology, Association
of Indian Neurologists in America, American Heart Association, University of
Calgary. He has patent US 17/317,771 filed. He is member of the editorial board
of Neurology:Clinical Practice, Neurology, Stroke, Frontiers in Neurology, and owns
stock options in SnapDx, ​TheRounds.​com, Collavidence Inc. DFK holds grants from
Cerenovus, Insera Therapeutics, Medtronic, Microvention, Balt, Monarch Biosciences,
Brainomix, MiVi, Stryker, and royalties from Medtronic. He holds patents on balloon
guide technology, is a data safety monitoring board member of NoNO Inc and
Vesalio, holds stock options from Nested Knowledge LLC, Superior Medical Experts
LLC, Marblehead Medical LLC, Conway Medical LLC, Monarch Biosciences and is
an investor in Piraeus Medical. He uses Brainomix software.WB holds licenses from
Medtronic and for a Balloon Guide Catheter Technology, has received consulting
fees from Medtronic, Stryker, Imperative Care, Microvention, MIVI Neurovascular,
Cerenovus, Asahi, Balt, payments for lectures from Cerenovus and Asahi, patents
planned for Balloon Guide Catheter technology and Kyphoplasty technology, is
a consulting medical director for MIVI Neurovascular, Chief Medical Officer of
Marblehead Medical LLC, Editor in Chief of Interventional Neuroradiology, Board
Member of Piraeus Medical, Executive Committee Member of WFITN, and holds stock
options of Piraeus Medical, Nested Knowledge, Sonoris Medical, MIVI Neurovascular,
Superior Medical Experts. MG holds grants from NoNo Inc, Medtronic, Cerenovus,
royalties from GE Healthcare and Microvention, consulting fees from Microvention,
Medtronic, Stryker, Mentice, and stock options from Circle Neurovascular.
Patient consent for publication Not applicable.
Ethics approval Not applicable.
Provenance and peer review Commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
been peer-­reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
ORCID iDs
Manon Kappelhof http://orcid.org/0000-0001-5250-8955
Aravind Ganesh http://orcid.org/0000-0001-5520-2070
Waleed Brinjikji http://orcid.org/0000-0001-5271-5524
Mayank Goyal http://orcid.org/0000-0001-9060-2109
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