Abstract
BACKGROUND:
Prevalence and contribution of intracranial and extracranial arterial stenosis to stroke risk were assessed prospectively in children and young adults with sickle cell disease (SCD).
METHODS:
In this cross-sectional study, children and young adults (mean = 19.4 years) with SCD underwent neurological exam, brain MRI, and MRA of the head and neck. Two neuroradiologists independently recorded infarcts and arterial stenosis. Clinical features and stroke outcomes were compared between participants with and without stenosis and between children and young adults. Logistic regression analysis assessed the association of variables of interest with overt stroke and silent cerebral infarct (SCI).
RESULTS:
Of 167 participants (79 children and 88 young adults), 20 (12.0%) had intracranial stenosis, all in the anterior circulation, and nine had concurrent extracranial stenosis. No participants had isolated extracranial stenosis. Participants with intracranial stenosis were more likely than those without stenosis to have an overt stroke (70% vs. 5%, p<.001) or SCI (95% vs. 35%, p<.001). Logistic regression analysis indicated that intracranial stenosis was strongly associated with overt stroke when compared to participants with SCI alone and strongly associated with SCI when compared to participants with normal brain MRI; male sex and age were also significant predictors of SCI.
CONCLUSIONS:
Intracranial stenosis was strongly associated with both overt stroke and SCI; prevalence of intracranial stenosis was similar to prior estimates in SCD. Extracranial stenosis without concurrent intracranial stenosis did not occur and thus could not be evaluated as an independent risk factor for stroke.
Keywords: stenosis, stroke, sickle cell disease
Introduction
Stroke is a well-known complication of sickle cell disease (SCD) that leads to significant morbidity and mortality in both children and adults.1 Without primary stroke prevention, approximately 11% of patients with the most severe form of SCD, sickle cell anemia (SCA), will have an overt, clinically apparent stroke based on history, neurological exam, and neuroimaging by age 20 years, and up to 24% will have a stroke by age 45 years.2 Without standard secondary stroke prevention with regular blood transfusion therapy, approximately 67% of those with initial stroke will have a second stroke.3 More common than strokes are silent cerebral infarcts (SCI), characterized by radiographic evidence of infarct without overt neurological symptoms. The prevalence of SCI in the SCD population reaches 25% by age 6 years4, 39% by age 18 years5, and 53% by age 30 years.6 Furthermore, these SCIs are often progressive, conferring a 14-fold increase in the risk of subsequent overt stroke.7 The long-term impact of stroke and SCI events can be devastating, ranging from cognitive decline to permanent neurological deficits or death.
While there are many well-described risk factors for stroke in SCD, the contribution of vascular stenosis in both intracranial and extracranial vessels is not adequately understood. Intracranial stenosis has a prevalence of 10–15% of individuals with SCD.8,9 The presence of progressive cerebral vasculopathy confers a high rate of stroke recurrence, with a decreased interval between the first stroke and subsequent strokes.10 Extracranial angiography of the neck is not routinely performed in SCD. Thus, less is known regarding the role and prevalence of extracranial stenosis, though it has been theorized to explain strokes that occur in children with SCD without any detectable intracranial stenosis.11
Screening protocols to detect extracranial stenosis in patients with SCD have been proposed.11,12,13 Transcranial Doppler (TCD) ultrasound of the intracranial proximal middle cerebral and distal internal carotid arteries is an effective screening tool in children with SCA. Elevated TCD cerebral blood flow velocity in these vessels portends stroke risk in children and may prompt the initiation of regular blood transfusion therapy for primary stroke prevention.14 Parallel screening has been suggested via submandibular ultrasound to further detect stroke risk by identifying potential extracranial internal carotid artery stenosis in children.15 However, isolated extracranial stenosis seems to be rare in SCD11, 16 and the clinical utility of this proposed screening has not been validated in a second cohort or applied widely in clinical care.
Aims
The goal of this work was to quantify the prevalence and impact of intracranial and extracranial stenosis in children and young adults with SCD. We tested two hypotheses: i) that magnetic resonance angiography (MRA)-defined intracranial stenosis is associated with stroke or SCI in this population and ii) that MRA-defined extracranial stenosis is independently associated with stroke or SCI.
Methods
Participants
Children and young adults ages 6 to 40 years with SCD defined as hemoglobin (Hb) SS or HbSβ0 Thalassemia were recruited sequentially from comprehensive SCD clinics at an academic medical center and a community health clinic from 2014 to 2019. Volunteers provided informed, written consent or parental consent and participant assent if under 18 years-of-age. The Institutional Review Board approved this study.
Protocol
In this cross-sectional study, detailed medical history, standardized neurological exam, hemoglobin and hematocrit via venipuncture, and non-contrast neuroimaging were obtained. No participant had acute or subacute stroke or infarcts at the time of study data collection. Participants were at their clinical baseline. When possible, research visits were paired with routine clinic appointments for participant convenience. A standard protocol was performed including: 3.0 Tesla MRI of the brain with 3D T1-weighted imaging, axial T2-weighted imaging, T2-weighted axial and coronal FLuid Attenuated Inversion Recovery (FLAIR) imaging, intracranial time-of-flight MRA, and neck time-of-flight MRA. MRA of the neck was deferred in participants who had difficulty remaining still for the 45-minute scan duration.
Images were read separately by two blinded neuroradiologists to identify the presence of intracranial or extracranial arterial stenosis >50% of vessel diameter (>50% stenosis was chosen based on prior SCD literature8, 10), moyamoya syndrome, and infarcts. Infarcts were defined as lesions at least 3mm in one dimension and visible in two planes on T2-weighted FLAIR images according to established MRI criteria from the Silent Infarct Transfusion trial.17 Infarcts were categorized as overt or silent based on clinical history and neurological examination.18 Discrepancies in radiology findings were resolved by consensus of the two neuroradiologists.
Statistical analysis
Descriptive statistics included mean, standard deviation, and median for continuous variables and percent for categorical variables. Differences in continuous variables were calculated using an independent samples t-test or a Mann-Whitney U test with two-sided p-values. Differences in categorical variables were assessed using a χ2 test or a Fisher’s exact test with two-sided p-values. Two separate multivariable logistic regression analyses were completed with variables selected based on biological plausibility for their relationships to the outcomes of overt stroke and SCI: intracranial stenosis, age, sex, BMI, and hemoglobin. Odds ratios, p-values, and 95% confidence intervals were reported. Statistical analysis was performed using Stata 16.0.
Results
Prevalence of stenosis and stroke
Of 186 total participants, MRA of the head with diagnostic quality was obtained in 167 participants; 33 participants did not complete an adequate MRA of the neck (Figure 1). Further analysis included 167 participants. Intracranial stenosis was present in 20 participants (12.0%), and all stenoses were in the anterior circulation including the intracranial internal carotid artery or its major branches, the middle cerebral and/or anterior cerebral arteries. Of these 20 participants, 19 had MRA of the neck of diagnostic quality; nine of these participants (5.4% of total or 6.7% with MRA neck) had extracranial stenosis in addition to their intracranial stenosis. No participants had isolated extracranial stenosis.
Figure 1. Flow diagram for vascular imaging and stenosis outcomes.
Diagram shows numbers of participants that received relevant vascular imaging studies (head and/or neck magnetic resonance angiography, MRA) and presence and absence of stenosis.
Overall, 76 participants (45.5%) had experienced either an SCI or overt stroke at the time of the study. Overt ischemic strokes had occurred in 22 participants (13.2%) and SCI in 71 (42.5%), with 17 participants (10.2%) experiencing both overt stroke and SCI (Table 1), similar to prior estimates in the SCD population.2,4,5,6
Table 1.
Summary statistics for all study participants and participants with vs. without intracranial stenosis
| All participants | Intracranial stenosis present | No intracranial stenosis present | p-value | |
|---|---|---|---|---|
| N | 167 | 20 | 147 | |
| Age, years | 19.4± 9.1 (18.5) | 23.3± 9.0 (22.0) | 18.9 ± 9.0 (17.5) | .039* |
| Children <18 years | 79 (47.3%) | 5/79 (6.3%) | 74/79 (93.7%) | .033* |
| Sex, male | 78 (46.7%) | 10 (50.0%) | 68 (46.3%) | .753 |
| Moyamoya | 14 (8.4%) | 14 (70%) | 0 | N/A |
| Normal MRI | 91 (54.5%) | 0 | 91 (61.9%) | <.001* |
| Overt stroke† | 22 (13.2%) | 14 (70.0%) | 8 (5.4%) | <.001* |
| Silent cerebral infarct (SCI)† | 71 (42.5%) | 19 (95%) | 52 (35.4%) | <.001* |
| Both overt stroke and SCI† | 17 (10.2%) | 13 (65%) | 4 (2.7%) | <.001* |
| Smoker, ever | 16 (9.6%) | 0 | 16 (10.9%) | .222 |
| Diabetes | 2 (1.2%) | 0 | 2 (1.4%) | .774 |
| Hypertension | 16 (9.6%) | 3 (15.0%) | 13 (8.8%) | .413 |
| BMI, kg/m2 | 20.9± 4.6 (20.5) | 22.5 ± 4.5 (22.3) | 20.6± 4.6 (20.5) | .093 |
| Hemoglobin, g/dl | 8.9± 1.4 (9.1) | 8.8 ± 1.3 (9.0) | 8.9 ± 1.4 (9.1) | .576 |
| Hematocrit, % | 25.7± 3.9 (25.0) | 25.4 ± 3.6 (25.5) | 25.8 ± 3.9 (25) | .649 |
Mean ± standard deviation (SD) with median in parentheses for continuous variables, and number of participants with percent (%) of group in parentheses for categorical variables.
= statistical significance, two-sided p<.05.
Some participants had both overt stroke and SCI, so the groups overlap.
Given that all participants with extracranial stenosis (n=9) also had intracranial stenosis, extracranial stenosis could not be considered separately in terms of stroke risk. Participants with intracranial stenosis were compared to the group of participants without intracranial stenosis (Table 1). All participants with intracranial stenosis had experienced either an overt stroke or SCI, compared to 38.1% of participants without stenosis (p<.001). Overt strokes occurred in 70% of participants with stenosis, compared to 5.4% of participants without stenosis (p<.001). SCI occurred in 95.0% of participants with stenosis, compared to 35.4% of participants without stenosis (p<.001). Thus, participants with intracranial stenosis were more likely to experience all stroke outcomes than participants without intracranial stenosis. While eight participants without stenosis did experience an overt stroke (Supplementary Table), no participants with normal brain MRI (no overt or silent infarcts) had intracranial stenosis.
Among the group with intracranial stenosis, we also compared the 9 participants who had concurrent extracranial stenosis on MRA of the neck with the 10 participants who had no extracranial stenosis (intracranial stenosis only). These groups were not significantly different in any demographic variables or stroke outcomes (Table 2).
Table 2.
Summary statistics for participants with both intracranial and extracranial stenosis vs. patients with intracranial stenosis alone
| Intracranial and extracranial stenosis | Intracranial stenosis only | p-value | |
|---|---|---|---|
| n | 9 | 10 | |
| Age, years | 25.7 ± 9.5 (24.6) | 22.9 ± 7.4 (22.0) | .447 |
| Children <18 years | 1 (11.1%) | 3 (30%) | .582 |
| Sex, male | 5 (55.6%) | 4 (40%) | .656 |
| Moyamoya | 8 (88.9%) | 6 (60%) | .303 |
| Normal MRI | 0 | 0 | N/A |
| Overt stroke | 7 (77.8%) | 7 (70%) | 1.000 |
| SCI | 9 (100%) | 9 (90%) | 1.000 |
| Both overt stroke and SCI | 7 (77.8%) | 7 (70%) | 1.000 |
| Smoker, ever | 0 | 0 | N/A |
| Diabetes | 0 | 0 | N/A |
| Hypertension | 2 (22.2%) | 1 (10%) | .582 |
| Chronic transfusions | 7 (77.8%) | 7 (70%) | 1.00 |
| Hydroxyurea | 2 (22.2%) | 3 (30%) | 1.00 |
| BMI, kg/m2 | 22.4 ± 4.0 (22.1) | 23.1± 4.9 (23.0) | .720 |
| Hemoglobin, g/dl | 8.8 ± 1.4 (9.3) | 8.8 ± 1.4 (9.0) | .951 |
| Hematocrit, % | 25.4 ± 3.9 (26.0) | 25.4 ± 3.8 (26.0) | .982 |
Mean ± standard deviation (SD) with median in parentheses for continuous variables, and number of participants with percent (%) of group in parentheses for categorical variables
The MRAs of the participants with both intracranial and extracranial stenosis largely reveal a continuous, long-segment stenosis extending from the extracranial to the intracranial portion of the internal carotid artery rather than the separate areas of focal narrowing typically seen in cases of isolated intracranial stenosis in SCD. These participants also had a high burden of both overt and silent bilateral infarcts. Figure 2 shows representative examples of intracranial and extracranial stenosis from three young adult participants.
Figure 2. Representative examples of intracranial stenosis and extracranial stenosis with diffuse smooth vessel narrowing in sickle cell disease.
Panel (A) 32-year-old female with right intracranial internal carotid artery (ICA) severe stenosis seen on head magnetic resonance angiography (MRA) maximum intensity projection (MIP) and axial MRA head; neck MRA MIP demonstrates the long-segment stenosis extending continuously from the extracranial ICA to the intracranial ICA and tiny extracranial ICA is seen on axial MRA neck. Panel (B) 34-year-old male with similar but less severe intracranial and extracranial ICA stenosis as patient (A). Panel (C) 39-year-old female with right middle cerebral artery (MCA) stenosis seen on head MRA MIP, ICA is not visible on MIP due to near occlusion, and intracranial ICA stenosis seen on axial MRA head. Neck MIP and axial MRA show longitudinal and cross-sectional smooth narrowing of the extracranial ICA.
Young adults were more likely than children to have stenosis and strokes
Stenosis was present in 17.0% (15 of 88) of adult participants and 6.3% (5 of 79) of children (p=.025). Adults were significantly more likely than children to have overt strokes (18.2% vs. 7.6%, p=.043) and SCIs (52.3% vs. 31.6%, p=.007). Adults were also more likely than children to have moyamoya-type vasculopathy (13.6% vs. 2.5%, p=.007), to smoke (18.2% vs. 0%, p<.001), or have hypertension (15.9% vs. 2.5%, p=.003), and had significantly higher BMI (23.1 kg/m2 vs. 18.1 kg/m2, p<.001) (Table 3).
Table 3.
Summary statistics for pediatric vs. adult participants
| Children | Adults | p-value | |
|---|---|---|---|
| n | 79 | 88 | |
| Age, years | 11.3 ± 3.5 (11.0) | 26.7 ± 5.7 (27.0) | <.001* |
| Stenosis present | 5 (6.3%) | 15 (17.0%) | .025* |
| Sex, male | 32 (40.5%) | 46 (52.3%) | .128 |
| Moyamoya | 2 (2.5%) | 12 (13.6%) | .007* |
| Normal MRI | 52 (65.8%) | 39 (44.3%) | .005* |
| Overt stroke, all | 6 (7.6%) | 16 (18.2%) | .043* |
| Ischemic overt stroke | 5 (6.3%) | 15 (17.0%) | .054 |
| Hemorrhagic overt stroke | 1 (1.3%) | 1 (1.1%) | 1.0 |
| SCI | 25 (31.6%) | 46 (52.3%) | .007* |
| Both overt stroke and SCI | 4 (5.1%) | 13 (14.8%) | .038* |
| Smoker, ever | 0 | 16 (18.2%) | <.001* |
| Diabetes | 1 (1.3%) | 1 (1.1%) | .939 |
| Hypertension | 2 (2.5%) | 14 (15.9%) | .003* |
| BMI, kg/m2 | 18.3 ± 4.2 (17.9) | 23.1± 3.6 (22.8) | <.001* |
| Chronic transfusions | 18 (22.8%) | 23 (26.1%) | .615 |
| Hydroxyurea | 56 (70.9%) | 57 (64.8%) | .399 |
| Hemoglobin, g/dl | 9.0 ± 1.3 (8.9) | 8.9 ± 1.4 (9.1) | .720 |
| Hematocrit, % | 25.7 ± 3.7 (25.0) | 25.7 ± 4.1 (25.0) | .974 |
Mean ± standard deviation (SD) with median in parentheses for continuous variables.
= statistical significance, two-sided p<.05.
Intracranial stenosis is strongly associated with overt stroke and SCI in regression models
Intracranial stenosis is strongly associated with overt stroke. The first logistic regression model included only the 76 participants who experienced overt stroke or SCI. No participants with normal brain MRI had intracranial stenosis, so they were not included. In this multivariable regression model, when compared to SCI as the reference group, intracranial stenosis was the only significant predictor of overt stroke (OR 14.54, 95% CI [4.01, 52.71]) (Table 4).
Table 4.
Multivariable logistic regression analyses for overt stroke compared to those with only SCI, and for SCI compared to those without any stroke
| Odds Ratio | 95% confidence interval | p-value | |
|---|---|---|---|
| Overt stroke, n=22 (reference group SCI, n=54) | |||
| Intracranial Stenosis | 14.54 | 4.01, 52.71 | <.001* |
| Sex, male | 0.42 | 0.12, 1.51 | .185 |
| Age | 0.99 | 0.91, 1.09 | .866 |
| BMI | 1.02 | 0.85, 1.22 | .843 |
| Hemoglobin | 0.88 | 0.54, 1.43 | .602 |
| Silent cerebral infarct, n=54 (reference group no stroke, n=91) | |||
| Intracranial Stenosis | Omitted† | ||
| Sex, male | 2.16 | 1.03, 4.51 | .004* |
| Age | 1.08 | 1.02, 1.14 | .041* |
| BMI | 0.91 | 0.82, 1.02 | .092 |
| Hemoglobin | 0.98 | 0.75, 1.28 | .877 |
= statistical significance, p<.05.
every participant with stenosis in this model had a SCI so this variable is omitted from this model.
Intracranial stenosis is also strongly associated with SCI. The second logistic regression model included the 54 participants who experienced SCI (those with both overt stroke and SCI were excluded) and the 91 participants with normal MRI as the reference group. All participants with intracranial stenosis that were included in this group (n=6) had SCI while none of the 91 participants with normal MRI had intracranial stenosis; thus, intracranial stenosis could not be included in the multivariable regression model. Regardless, since 100% of the subgroup of participants with intracranial stenosis without overt stroke had SCI, stenosis is clearly a strong predictor of SCI. Male sex (OR 2.16, 95% CI [1.03, 4.51]) and age (OR 1.08, 95% CI [1.02, 1.14]) were also associated with SCI.
Discussion
In individuals with SCD, intracranial arterial stenosis is a strong predictor of overt stroke and SCI, while extracranial arterial stenosis does not provide additional independent information on stroke risk. The prevalence of intracranial stenosis in this population of young adults and children with SCD was 12%, similar to prior estimates of 10–15%.8,9 Extracranial stenosis was present in 6.7% of the sample, but only in participants who also had concurrent intracranial stenosis. Importantly, no participants in this study had isolated extracranial stenosis. A 2010 study by Deane et al.11 similarly found a 5.4% prevalence of extracranial stenosis in a population of 236 children with SCA, based on carotid Doppler ultrasound assessment of peak systolic velocities in the extracranial internal carotid artery, not anatomic imaging with MRA. This increased velocity, presumed to represent extracranial stenosis, was strongly associated with overt clinical stroke. Six out of eight participants with extracranial stenosis in this study also had evidence of intracranial arteriopathy while two (0.8% of total) had isolated extracranial stenosis.11 A 2015 French study12 assessed a sample of 189 overt stroke-free children with SCA with both carotid Doppler ultrasound and non-contrast MRA head and neck. Stenosis was defined on MRA as a mild “at least 20% decrease in the lumen of middle cerebral artery, anterior cerebral artery, intracranial ICA or extracranial ICA.” With this more inclusive definition of stenosis, intracranial stenosis was reported in 12.7% of the sample and extracranial stenosis in 12.2%. Interestingly, only two young children in the French study had both intracranial and extracranial stenosis; 11.1% of the sample had isolated extracranial stenosis, which was a significant independent risk factor for SCI.
Adult arterial ischemic stroke literature considers extracranial stenosis in cervical vessels >70% to be hemodynamically significant, warranting consideration of aggressive treatment even when asymptomatic, while stenosis 50–69% is considered to be moderate, and stenosis <50% is mild and typically clinically insignificant.19 Similarly, clinical trials for intracranial stenosis treatments have used intracranial stenosis >50% for medical therapy20 and >70% for trials that have involved stenting.21 In our cohort, >50% stenosis was used to conform with prior SCD literature;8,10,22 however, all but one of 9 participants with extracranial stenosis had stenosis >70% of vessel diameter. Pathology in SCD of continuous, long-segment stenosis extending from the extracranial to the intracranial internal carotid artery appears quite different than focal cervical stenosis seen in older adults without SCD with extracranial carotid stenosis related to atherosclerosis.
In addition to there being no participants in this study with isolated extracranial stenosis, there were no significant differences in demographic variables, stroke outcomes, or treatments between the participants with and without extracranial stenosis. This suggests that the process of extracranial stenosis development is not independent from that of intracranial stenosis development in SCD. Additional proposed screening protocols to specifically detect extracranial stenosis may be an unnecessary use of time and resources with little added clinical utility, as existing screening for intracranial stenosis should be sufficient to detect at-risk patients. However, in some cases of acute ischemic stroke in SCD, MRA neck may still be useful to detect non-SCD related etiologies of stroke such as cervical artery dissection.13
Disease modifying therapy may have an impact on the development of stenosis. Of our 20 study participants with intracranial stenosis only 14 of 20 were on chronic transfusion therapy at the time of our study. All participants were offered transfusions. However, six stopped transfusions against medical advice and were transitioned to less burdensome oral hydroxyurea. This was more common in adults (five of six participants who declined ongoing transfusions were adults). The older age of our cohort and potentially fewer patients with on disease modifying therapy could be why we found more concurrent intracranial and extracranial stenosis than Bernaudin et al.5
Strengths of this study include prospective enrollment, detailed adjudication of neuroimaging, and inclusion of both children and adults. Limitations include the modest sample size and cross-sectional design. Clinical TCD data was only available for 8 of 20 participants with intracranial stenosis due to older age or care established at our center after stroke had occurred, thus TCD to screen for stroke risk was unnecessary. The lack of complete TCD data paired with MRA data limits comparison with other cohorts that have shown that intracranial stenosis is rare in children with normal TCD.22 Extracranial vessels were not assessed in 33 participants who did not complete an adequate neck MRA (Figure 1), however, intracranial stenosis was clearly the more important risk factor for stroke and SCI. Insight into the prevalence and significance of vascular stenosis and stroke outcomes in the SCD population are important for informing screening and treatment protocols. Based on this study, screening angiography protocols to specifically detect extracranial stenosis may have limited clinical utility in children and young adults with SCD.
Intracranial stenosis was the strongest predictor of stroke studied in this cohort; other modifiable risk factors studied were not significant. While intracranial stenosis is clearly an important risk factor, strokes also occur in individuals without stenosis (Supplementary Table), perhaps implicating other pathophysiology like impaired cerebral hemodynamics or severe anemia. Exact mechanisms of diffuse arteriopathy in SCD are not well understood, highlighting the need for future studies in this area, perhaps with the goal of describing vessel wall abnormalities. Longitudinal studies will also help understand whether more aggressive stroke prevention treatments in younger children with SCD will result in reduced frequency of intracranial stenosis in young adults.
Supplementary Material
Supplemental Table: Eight participants without stenosis who had overt strokes
Acknowledgements:
This work was supported by the National Institutes of Health NIH 1R01NS096127, K24-HL147017, and the American Heart Association: AHA #14CSA20380466
Declarations of Interests:
No disclosures relevant to this work.
L. Jordan receives research support from the National Institutes of Health (NINDS, NHLBI, and NIDDK). She has served as a consultant for blue bird bio.
M. Donahue receives research support from the American Heart Association, National Institutes of Health (NINDS, NIA, and NINR), and Lipedema Foundation. He also receives research-related support from Philips Healthcare, and consulting or advisory board payments from Global Blood Therapeutics, bluebird bio, and Pfizer.
M. R. DeBaun and his institution are the sponsors of 2 externally funded research investigator-initiated projects. Global Blood Therapeutics (GBT) is providing funding for the cost of the clinical studies but will not be a cosponsor of either study. M.R.D. is not receiving any compensation for the conduct of these 2 investigator-initiated observational studies. He is a member of the GBT advisory board for a proposed randomized controlled trial for which he receives compensation, and he is the chairperson of a steering committee for an industry supported phase 2 trial (SPARTAN) for prevention of priapism in SCD.
Footnotes
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Associated Data
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Supplementary Materials
Supplemental Table: Eight participants without stenosis who had overt strokes