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Stroke Mechanisms in Symptomatic Intracranial Atherosclerotic Disease

Classification and Clinical Implications
Originally publishedhttps://doi.org/10.1161/STROKEAHA.119.025732Stroke. 2019;50:2692–2699

Abstract

Background and Purpose—

In patients with symptomatic intracranial atherosclerotic stenosis, identifying the underlying stroke mechanisms may inform secondary prevention. We aimed to propose reproducible classification criteria for stroke mechanisms based on routine neuroimaging in symptomatic intracranial atherosclerotic stenosis and explore their clinical implications.

Methods—

We recruited patients with acute ischemic stroke attributed to 50% to 99% intracranial atherosclerotic stenosis in anterior circulation from 2 centers. Two investigators independently classified probable stroke mechanisms as parent artery atherosclerosis occluding penetrating artery, artery-to-artery embolism, hypoperfusion, and mixed mechanisms, with prespecified criteria based on infarct topography and magnetic resonance/computed tomography angiography. These stroke mechanisms were correlated with features of the patients at baseline and recurrent ischemic stroke in the same territory or relevant transient ischemic attack within 1 year.

Results—

Among 153 patients recruited, the most common stroke mechanisms were isolated hypoperfusion (35.3%) and mixed mechanism of artery-to-artery embolism and hypoperfusion (37.3%) that was associated with higher incidence of dyslipidemia (P=0.045) and hypertension (P=0.033) than patients with other stroke mechanisms. The proposed criteria showed substantial to excellent intrarater and interrater reproducibilities (κ, 0.791–0.908). Overall, 31 patients received interventional treatment of the diseased intracranial artery; 122 received medical treatment, among whom a mixed mechanism of artery-to-artery embolism and hypoperfusion at baseline was associated with higher risk of ischemic stroke in the same territory within 1 year (24.4% versus 7.8%; hazard ratio, 3.40; 95% CI, 1.25–9.20; log-rank P=0.010) than other mechanisms combined.

Conclusions—

Artery-to-artery embolism and hypoperfusion commonly coexist in ischemic stroke attributed to intracranial atherosclerotic stenosis, which may be associated with higher risk of stroke relapse.

Introduction

Intracranial atherosclerotic stenosis (ICAS) is a common cause of ischemic stroke worldwide,1 with a higher prevalence in Asians.2 Ischemic stroke caused by ICAS faces a high risk of recurrence despite optimal medical treatment,3,4 which might lie in the less-than-ideal recognition of underlying stroke mechanisms and lack of individualized treatment for strokes of different mechanisms.

Ischemic strokes caused by ICAS with different mechanisms may need different management strategies in blood pressure control,5 antiplatelet therapy, and statins therapy.3,6 For instance, those with an ischemic stroke caused by hypoperfusion distal to a tight stenosis may not benefit as much as other patients from stringent blood pressure–lowering therapy.5 Those with artery-to-artery (AA) embolism may benefit more from short-term dual antiplatelet treatment and intensive statin treatment.6 Another study indicated that among patients with single small subcortical infarctions, those with parent artery atherosclerosis (that might have caused occlusion of perforators and thus the infarction) had higher prevalence of atherosclerosis indicators and lower prevalence of leukoaraiosis and microbleeds than single small subcortical infarctions without parent artery atherosclerosis.7 These previous studies investigating the clinical implications of stroke mechanisms in symptomatic ICAS (sICAS) patients usually focused on a certain stroke mechanism, whereas data are scarce regarding the clinical correlates and the impact of different mechanisms on risk of recurrence and functional outcomes, and on patients’ response to medical or interventional treatment, in sICAS patients. Lack of a simple-to-use system based on widely available imaging modalities to classify the stroke mechanisms has prevented large-scale studies in this area.

It would be ideal to define stroke mechanisms in ICAS-related stroke by comprehensive imaging workup, for example, employing transcranial Doppler microemboli monitoring, computed tomography (CT)/magnetic resonance (MR) perfusion imaging, and high-resolution MR imaging (MRI), for the assessment of cerebral hemodynamics, perfusion, and plaque characteristics, in addition to routine brain MRI and MR/CT angiography (MRA/CTA). But it is not generalizable to apply all these advanced imaging exams in sICAS patients in large-scale studies or in clinical practice. Therefore, in this study, we proposed criteria for classifying probable stroke mechanisms in sICAS patients based on routine brain MRI and MRA/CTA. We examined the intrarater and interrater reproducibilities of the criteria and associated the stroke mechanisms with clinical features and outcomes of the patients.

Methods

Study Design and Subjects

The data that support the findings of this study are available from the corresponding author on reasonable request. This was a substudy of a multicenter cohort study to investigate cerebral hemodynamics in patients with sICAS.8 The study was approved by local institutional review board, and all patients provided informed consents. We screened and retrospectively analyzed patients in the cohort study who were admitted to Prince of Wales Hospital, Hong Kong and the First Affiliated Hospital of Zhengzhou University, Zhengzhou, between November 2006 and December 2016, with the following criteria: (1) adult ischemic stroke patients admitted within 7 days of ictus; (2) the patient underwent MRI with diffusion-weighted imaging (DWI) sequence within 14 days of ictus, and cerebral MRA or CTA exam within 1 month; (3) the ischemic stroke was attributed to 50% to 99% atherosclerotic stenosis of intracranial portion of internal carotid artery or middle cerebral artery (MCA) stem as revealed by MRA or CTA. The relevance of ICAS and the index stroke was determined by experienced neurologists. We excluded patients with an index ischemic stroke attributed to nonatherosclerotic intracranial stenosis (eg, Moyamoya disease, vasculitis, or dissection), total occlusion of an intracranial artery, restenosis within a stented artery, or tandem stenosis of extra and intracranial arteries; patients with potential cardioembolic source (eg, atrial fibrillation); patients with interventional (angioplasty with or without stenting) or surgical procedures (direct or indirect bypass surgery, carotid endarterectomy) of intra and extracranial arteries within the month before the index stroke.

For eligible patients, we collected the demographics, cardiovascular risk factors, blood pressure at admission, results of laboratory tests during hospitalization. We determined the location and severity of stenosis of culprit ICAS on MRA or CTA if either available or on CTA if both available. All patients (in the cohort) received optimal medical treatment in accordance with up-to-date guidelines,9 except that some patients would receive interventional treatment of the culprit ICAS lesion when enrolled in a randomized clinical trial for medical treatment with or without adjunctive interventional treatment. Medical treatment for the patients included antiplatelet therapy in all those without contraindications and cardiovascular risk factor management.9 All patients were followed up for 1 year: patients at Prince of Wales Hospital were followed up at 1, 3, 6, 9, and 12 months at neurological outpatient clinic for clinical events and to ensure their compliance to secondary stroke prevention strategies; patients at the other hospital were followed up at neurological outpatient clinic or by telephone at 1 year. All patients were analyzed for the baseline characteristics including the stroke mechanisms, whereas those receiving interventional treatment (angioplasty with/without stenting therapy) of the culprit ICAS lesion for the index stroke were excluded from the analyses of the associations between the initial stroke mechanisms and the outcomes.

The primary outcome was recurrent ischemic stroke in the same territory (SIT) of the diseased intracranial artery of interest within 1 year. The secondary outcome was a composite of SIT and transient ischemic attack (TIA) that was probably relevant to the same territory within 1 year. A recurrent ischemic stroke or TIA and the relevance to the same territory were determined according to newly developed neurological deficits and presence of new infarct(s) confirmed with brain CT or MRI upon recurrence. A neurologist would determine the occurrence of an outcome event based on the duration and features of newly developed neurological deficits when there was no brain imaging available upon a suspected recurrent event. Uncertainty in determining an outcome event was resolved by agreement between investigators.

Classification of Probable Stroke Mechanisms in sICAS Patients Based on Routine MRI-DWI and MRA/CTA

We classified the probable stroke mechanisms in sICAS patients as (1) parent artery atherosclerosis occluding penetrating artery, (2) AA embolism, (3) hypoperfusion, and (4) mixed mechanisms, based on Chinese Ischemic Stroke Subclassification system and other previous studies on stroke mechanisms in ICAS.10,11 We assessed the topology of ischemic lesions in DWI and the location and severity of intracranial stenosis in MRA or CTA; the degree of stenosis was assessed with the WASID (Warfarin-Aspirin Symptomatic Intracranial Disease) method.12 Detailed classification criteria are shown below. Figure 1 shows examples of different ischemic lesion patterns indicating different stroke mechanisms.

Figure 1.

Figure 1. Ischemic lesion patterns indicating different stroke mechanisms in 4 patients with symptomatic intracranial atherosclerotic stenosis. A, An isolated acute infarction in penetrating artery territory indicating probable parent artery atherosclerosis occluding penetrating artery. B, Territorial infarction indicating probable artery-to-artery embolism. C, Chain-like internal borderzone infarctions indicting probable hypoperfusion. D, Multiple cortical infarctions in D1 and D2, and wedge-shaped external borderzone infarctions in D2 and D3 indicating probable mixed mechanism of artery-to-artery embolism and hypoperfusion.

Parent Artery Atherosclerosis Occluding Penetrating Artery

There was ≥50% stenosis of the index intracranial artery and an isolated acute infarct in penetrating artery territory adjacent to the stenosed artery.11,13 In the anterior circulation, the proximal portion or orifice of a perforating artery is more likely to be occluded by parent artery atherosclerosis, so the infarct usually extends to the lowest portion of the basal ganglia.7

AA Embolism

There was single or multiple small cortical infarct(s) with or without subcortical infarcts; or wedge-shaped infarct(s) lying completely within the expected territory of an artery, involving the cortical and subcortical regions supplied by the index diseased intracranial artery (also known as territorial infarcts)14,15 but not involving borderzone areas.11

Hypoperfusion

There was single or multiple infarct(s) in the borderzone (or watershed) areas.11 Borderzone areas include external cortical borderzones and internal subcortical borderzones.16,17 External cortical borderzones refer to the regions between the cortical territories of anterior cerebral artery and MCA or between anterior cerebral artery and posterior cerebral artery; infarcts in these areas are usually wedge-shaped or ovoid.18 The internal borderzones refer to the white matter along and above the lateral ventricles between the deep and the superficial supplying territories of MCA or between the superficial territories of MCA and anterior cerebral artery. Internal borderzone infarcts may appear as confluent or partial infarcts.17 Confluent infarcts along the internal borderzone are usually large and cigar-shaped; partial internal borderzone infarcts may include ≥3 lesions, each with a diameter of ≥3 mm, in a linear fashion paralleling to the lateral ventricle in the centrum semiovale or corona radiata—sometimes referred to as rosary- or chain-like infarcts.17,19

Mixed Mechanisms

Coexistence of 2 or 3 mechanisms as described above.

Intrarater and Interrater Reproducibilities of Stroke Mechanism Classification

To assess the intrarater reproducibility of the classification criteria, 1 investigator (X. Feng) classified probable stroke mechanisms in all cases twice, with at least 30 days apart in the 2 assessments in each case. To assess the interrater reproducibility, 2 investigators (X. Feng and K.L. Chan) independently classified stroke mechanisms in all cases.

Statistical Analyses

We presented demographics and other baseline characteristics with numbers (%) for categorical variables and medians (interquartile ranges) for continuous variables. Intrarater and interrater reproducibilities of the classification system were assessed with the percentages of cases with agreement and the Cohen κ statistic. The stroke mechanisms were analyzed as 4 categories as described above; as 3 categories—parent artery atherosclerosis occluding penetrating artery, AA embolism, or hypoperfusion, without considering coexistence of other accompanying mechanism(s); or as mixed mechanism of AA embolism + hypoperfusion versus other mechanisms. κ values >0.80, 0.60 to 0.80, 0.40 to 0.60, or <0.40 were considered as excellent, substantial, moderate, or poor agreement, respectively.

Pearson χ2 tests or Fisher exact tests were used to detect the differences in categorical variables and Wilcoxon rank-sum tests for continuous variables, between 2 independent groups. We plotted the associations between stroke mechanisms and the primary and secondary outcomes using Kaplan-Meier curves. Hazard ratios (HRs) and 95% CIs were calculated in log-rank tests. Patients with less common stroke mechanisms were combined in such analyses to compare with those with more common stroke mechanisms. The level of statistical significance was P<0.05 (2-sided). All statistical analyses were performed using the SPSS statistical package version 22.0 (SPSS, Inc, Chicago, IL).

Results

Patients’ Characteristics

Overall, 153 patients were analyzed in the current study: 112 from Hong Kong and 41 from Zhengzhou. All of the patients had both MRA and CTA, so we determined the location and severity of culprit ICAS lesions on CTA in all patients. Among these patients, 33 had an sICAS in intracranial internal carotid artery, 112 in MCA, and 8 had ICAS lesions across intracranial internal carotid artery and proximal MCA. Table 1 shows baseline characteristics of the patients, with high prevalence of vascular risk factors, especially dyslipidemia (56.2%) and hypertension (66.7%).

Table 1. Baseline Characteristics of Patients With Different Mechanisms of the Index Stroke at Baseline*

CharacteristicsAll (n=153)Mechanism A+H (n=57)Other Mechanisms (n=96)P Values
Age, y62 (53–70)60 (49–69)63 (56–71)0.062
Male109 (71.2)42 (73.7)67 (69.8)0.607
SBP, mm Hg153 (135–170)149 (135–167)155 (138–171)0.144
DBP, mm Hg83 (76–94)83 (78–92)82 (74–95)0.967
Cardiovascular risk factors
 Smoker74 (48.4)28 (49.1)46 (47.9)0.885
 History of dyslipidemia86 (56.2)38 (66.7)48 (50.0)0.045
 History of hypertension102 (66.7)44 (77.2)58 (60.4)0.033
 History of diabetes mellitus59 (38.6)26 (45.6)33 (34.4)0.167
 History of ischemic heart disease6 (3.9)4 (7.0)2 (2.1)0.132
 History of stroke/TIA17 (11.1)6 (10.5)11 (11.5)0.859
Laboratory test results
 Fasting Glucose, mmol/L5.7 (5.1–7.5)6.0 (5.1–8.7)5.6 (5.1–7.2)0.144
 HbA1c, mmol/L6.3 (5.6–7.5)6.3 (5.7–7.9)6.2 (5.6–7.0)0.501
 Triglyceride, mmol/L1.4 (1.1–2.0)1.5 (1.2–2.2)1.4 (1.0–2.0)0.331
 HDL, mmol/L1.1 (0.9–1.3)1.1 (0.9–1.2)1.1 (0.9–1.4)0.408
 LDL, mmol/L3.3 (2.3–4.0)3.4 (2.3–4.1)3.0 (2.3–3.9)0.346
Severity of stenosis in culprit ICAS, %68.0 (56.0–76.0)68.0 (58.0–76.0)67.5 (55.0–76.0)0.817
 50–6983 (54.2)32 (56.1)51 (53.1)0.914
 70–8946 (30.1)16 (28.1)30 (31.3)
 ≥9024 (15.7)9 (15.8)15 (15.6)

DBP indicates diastolic blood pressure; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein cholesterol; ICAS, intracranial atherosclerotic stenosis; IQR, interquartile range; LDL, low-density lipoprotein cholesterol; Mechanism A+H indicates mixed mechanism of artery-to-artery embolism and hypoperfusion; SBP, systolic blood pressure; and TIA, transient ischemic attack.

*Values are described with medians (IQRs) or n (%).

Reproducibility of the Stroke Mechanism Classification Criteria

Classification of probable stroke mechanisms agreed in 89.5% (137/153) patients between assessments by 1 investigator (X. Feng) in 2 separate occasions and in 85.0% (130/153) patients between assessments by 2 independent investigators (X. Feng and K.L. Chan; Tables I and II in the online-only Data Supplement).

The intrarater reproducibility was excellent (κ, 0.853; 95% CI, 0.785–0.920), and the interrater reproducibility was substantial (κ, 0.791; 95% CI, 0.713–0.869), when classifying the stroke mechanisms into 4 categories (Table 2). When defining existence of the 3 mechanisms without considering coexistence of other accompanying mechanisms, the intrarater and interrater reproducibilities were substantial to excellent (κ, 0.795–0.908) for each mechanism (Table 2).

Table 2. Intrarater and Interrater Reproducibilities of Stroke Mechanism Classification

κ (95% CI)
Intrarater reproducibility
 Overall (4 categories)0.853 (0.785–0.920)
 Existence of each mechanism
  P0.865 (0.760–0.970)
  A0.908 (0.842–0.975)
  H0.825 (0.721–0.929)
Interrater reproducibility
 Overall (4 categories)0.791 (0.713–0.869)
 Existence of each mechanism
  P0.834 (0.723–0.945)
  A0.856 (0.774–0.938)
  H0.795 (0.690–0.900)

A indicates artery-to-artery embolism; H, hypoperfusion; and P, parent artery atherosclerosis occluding penetrating artery.

Associations Between Stroke Mechanisms and Baseline Characteristics

Among all 153 cases, the most common stroke mechanisms were mixed mechanism of AA embolism + hypoperfusion (37.3%) and isolated hypoperfusion (35.3%). More of patients with AA embolism + hypoperfusion as the baseline stroke mechanism had a history of dyslipidemia (P=0.045) and hypertension (P=0.033) than those with other mechanisms (Table 1). Among all the patients recruited, 31 patients received angioplasty/stenting therapy of the culprit intracranial artery for the index stroke, and 122 patients received medical treatment alone. There was no significant difference in the initial stroke mechanisms between them (P>0.05, Table III in the online-only Data Supplement).

Associations Between Stroke Mechanisms and Risks of Recurrent Stroke/TIA in Medically Treated Patients

Among the 122 patients who received medical treatment alone, 17 (13.9%) had a primary outcome (SIT within 1 year). There was no significant difference in baseline characteristics between patients with and without a primary outcome except for the history of hypertension and history of stroke/TIA (Table 3).

Table 3. Baseline Characteristics of Patients With or Without the Primary or Secondary Outcomes*

CharacteristicsPrimary OutcomeSecondary Outcome
No (n=105)Yes (n=17)P ValuesNo (n=101)Yes (n=21)P Values
Age, y62 (52–70)61 (54–72)0.89163 (53–70)60 (51–69)0.482
Male75 (71.4)9 (52.9)0.12772 (71.3)12 (57.1)0.203
SBP, mm Hg151 (135–171)150 (136–163)0.663150 (135–171)153 (136–163)0.803
DBP, mm Hg84 (76–95)80 (70–90)0.28684 (76–96)80 (75–90)0.263
Cardiovascular risk factors
 Smoker53 (50.5)5 (29.4)0.10752 (51.5)6 (28.6)0.056
 History of dyslipidemia55 (52.4)10 (58.8)0.62152 (51.5)13 (61.9)0.384
 History of hypertension66 (62.9)15 (88.2)0.04064 (63.4)17 (81.0)0.121
 History of diabetes mellitus38 (36.2)7 (41.2)0.69337 (36.6)8 (38.1)0.899
 History of ischemic heart disease4 (3.8)1 (5.9)0.7104 (4.0)1 (4.8)0.876
 History of stroke/TIA11 (10.5)5 (29.4)0.04811 (10.9)5 (23.8)0.136
Laboratory test results
 Fasting Glucose, mmol/L5.6 (5.0–7.4)6.4 (5.3–7.6)0.4525.6 (5.0–7.5)6.0 (5.3–7.6)0.554
 HbA1c, mmol/L6.1 (5.6–7.4)6.6 (5.7–7.5)0.4206.1 (5.6–7.4)6.5 (5.6–7.1)0.577
 Triglyceride, mmol/L1.5 (1.1–2.0)1.3 (1.0–2.0)0.6761.5 (1.1–2.0)1.3 (1.0–2.0)0.774
 HDL, mmol/L1.1 (1.0–1.3)1.0 (0.8–1.3)0.2741.1 (1.0–1.3)1.1 (0.9–1.4)0.931
 LDL, mmol/L3.2 (2.3–3.9)2.6 (1.9–3.5)0.0603.2 (2.3–3.9)2.6 (1.9–3.5)0.086
Severity of stenosis in culprit ICAS, %68.0 (55.0–77.0)70.0 (67.0–76.0)0.10668.0 (55.0–77.0)70.0 (65.0–76.0)0.231
 50–6955 (52.4)6 (35.3)0.42053 (52.5)8 (38.1)0.460
 70–8933 (31.4)7 (41.2)31 (30.7)9 (42.9)
 ≥9017 (16.2)4 (23.5)17 (16.8)4 (19.0)

Primary outcome denotes SIT within 1 y; secondary outcomes denotes SIT, or probably relevant TIA within 1 y. DBP indicates diastolic blood pressure; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein cholesterol; ICAS, intracranial atherosclerotic stenosis; IQR, interquartile range; LDL, low-density lipoprotein cholesterol; SBP, systolic blood pressure; SIT, ischemic stroke in the same territory; and TIA, transient ischemic attack.

*Values are described with medians (IQRs) or n (%).

Among the 17 patients with a primary outcome, the probable mechanisms of the index strokes at baseline were AA embolism in 1, hypoperfusion in 5, and mixed mechanism of AA embolism + hypoperfusion in 11 patients. Twenty-one patients had a secondary outcome (SIT or probably relevant TIA within 1 year); the probable mechanisms of the index strokes at baseline were AA embolism in 2, hypoperfusion in 6, and mixed mechanism of AA embolism + hypoperfusion in 13 patients.

Because of the small numbers of cases with certain stroke mechanisms, we plotted Kaplan-Meier curves of the probabilities of the outcomes in 3 groups of patients: those with baseline stroke mechanisms of hypoperfusion (n=46), AA embolism + hypoperfusion (n=45), and all other circumstances (n=31) and in 2 groups of patients: those with the mixed mechanism of AA embolism + hypoperfusion for the baseline stroke (n=45) and otherwise (n=77).

Patients with mixed mechanism of AA embolism + hypoperfusion for the baseline stroke were at a significantly higher risk of the primary outcome (24.4% versus 7.8%; HR, 3.40; 95% CI, 1.25–9.20; P=0.010) than those with other stroke mechanisms combined (Figure 2A). The risk of the primary outcome in patients with mixed mechanism of AA embolism + hypoperfusion was significantly higher than that in those with a baseline stroke mechanism other than hypoperfusion or AA embolism + hypoperfusion (24.4% versus 3.2%; HR, 8.50; 95% CI, 2.51–28.82; P=0.013) and also tended to be higher than that in those with hypoperfusion as the baseline stroke mechanism (24.4% versus 10.9%; HR, 2.42; 95% CI, 0.80–7.37; P=0.087; Figure 2B). Similar results were revealed in Kaplan-Meier curves for the secondary outcome (Figure 2C and 2D).

Figure 2.

Figure 2. Cumulative probabilities of primary outcome (ischemic stroke in the same territory [SIT] within 1 y) and secondary outcomes (SIT or probably relevant transient ischemic attack within 1 y) by different stroke mechanisms at baseline. A, Patients with mixed mechanism of artery-to-artery (AA) embolism + hypoperfusion for the baseline stroke were at a significantly higher risk of the primary outcome (24.4% vs 7.8%; hazard ratio [HR], 3.40; 95% CI, 1.25–9.20; P=0.010) than those with other baseline stroke mechanisms. B, The risk of the primary outcome in patients with mixed mechanism of AA embolism + hypoperfusion was significantly higher than that in those with a baseline stroke mechanism other than hypoperfusion or AA embolism + hypoperfusion (24.4% vs 3.2%; HR, 8.50; 95% CI, 2.51–28.82; P=0.013) and also tended to be higher than that of those with hypoperfusion as the baseline stroke mechanism (24.4% vs 10.9%; HR, 2.42; 95% CI, 0.80–7.37; P=0.087). C/D, Similar trends for the analyses for the secondary outcome.

Discussion

In the current study, we proposed criteria for classifying probable mechanisms of stroke attributed to ICAS (parent artery atherosclerosis occluding penetrating artery, AA embolism, hypoperfusion, and mixed mechanisms), based on routine imaging exams (MRI-DWI and MRA/CTA). We demonstrated substantial to excellent intrarater and interrater reproducibilities of the classification criteria and correlated the stroke mechanisms with clinical features and outcomes of the patients. Patients with ICAS-related stroke caused by mixed mechanism of AA embolism and hypoperfusion were more likely to have a history of dyslipidemia and hypertension and more likely to have recurrent SIT or relevant TIA within 1 year, compared with other stroke mechanisms.

As mentioned above, patients with ischemic stroke caused by ICAS with different mechanisms may benefit from different management strategies. Impaired perfusion distal to a symptomatic ICAS lesion might modify the relationship between blood pressure and stroke risk in affected patients.5,20 Intensive blood pressure control (eg, <130/80 mm Hg) may increase the risk of recurrent stroke in patients with symptomatic extra or intracranial stenosis with impaired perfusion.5,20 However, it was indicated in the subgroup analysis of the CHANCE trial (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) that patients with ischemic stroke caused by AA embolism may benefit from more intensive antiplatelet and statins therapy.6 The risk of recurrent stroke in patients with multiple infarctions was up to 18.8% at 3 months with aspirin therapy versus 10.1% with clopidogrel plus aspirin therapy for 3 weeks and clopidogrel for days 22 to 90 (HR, 0.5; 95% CI, 0.30–0.96; P=0.04).6 Therefore, for further investigations of more effective secondary prevention of sICAS patients, it is important to understand the stroke mechanisms. Before conducting large-scale investigations or incorporating data from different institutions on this topic, it is a prerequisite to establish a reliable classification system that could be widely applied based on routine brain imaging exams in clinical practice.

Although the theories in probable stroke mechanisms in ICAS have been proposed and discussed for years,21 relevant data were limited. In previous relevant studies, stroke subtypes were usually grouped by the number and location of DWI lesions.6,14,22 Chinese Ischemic Stroke Subclassification was among the first ischemic stroke classification systems that consider not only the cause of ischemic stroke but also the underlying mechanisms of large artery atherosclerosis stroke.11 Classification of stroke cause by Chinese Ischemic Stroke Subclassification has been reported to be reproducible in minor stroke patients.23 However, little is known of its reproducibility in classifying large artery atherosclerosis stroke mechanisms. In this study, we further detailed the classification criteria for stroke mechanisms in sICAS patients solely based on MR brain and MR/CT vessel imaging that are widely used in clinical practice and proved the interrater and intrarater reproducibilities. Although in the present study, all patients had both MRA and CTA exams and the location and severity of culprit ICAS lesions were defined on CTA, the proposed criteria would also be applicable when there is either MRA or CTA, rather than both available, which is more common in clinical practice. Thus, the classification criteria could be used in large-scale studies in the future, for better understanding of the stroke mechanisms in sICAS and the clinical relevance.

As detailed above, we classified stroke mechanisms in sICAS into 4 categories. Among the subjects, the most common probable mechanisms were isolated hypoperfusion, and coexistence of AA embolism and hypoperfusion, which is in agreement with previous studies in ICAS patients—there were more borderzone infarcts in patients with ICAS than those with extracranial internal carotid artery stenosis24; and combined small pial or scattered multiple cortical infarcts with borderzone infarcts were commonly seen in those with sICAS in the anterior circulation.25 Moreover, we found that more patients with the baseline stroke mechanism of AA embolism + hypoperfusion had a history of dyslipidemia and hypertension than those with other stroke mechanisms. Dyslipidemia is a risk factor for the presence of vulnerable plaques,26 which may increase the risk of plaque rupture and subsequent AA embolism. Hypertension has been reported to be associated with poor leptomeningeal collateral status in acute ischemic stroke patients27; in patients with ICAS with reduced antegrade flow to the relevant territory, downstream perfusion may be prolonged or impaired given inadequate collateral compensation. In addition, there may be continuous elevated wall shear stress upon the plaques that may increase plaque vulnerability and the risk of plaque rupture, by inducing endothelial dysfunction, weakening the plaque surface, and increasing the necrotic core, which may aggravate plaque vulnerability and eventually lead to plaque rupture.8,28 These inferences may partly explain the association between hypertension and the stroke mechanism of AA embolism + hypoperfusion in sICAS in the current study.

DWI lesion patterns in the MCA territory have been reported to be a strong and independent predictor for the risk of recurrent stroke and functional outcome. The recurrence rates were lower in patients with deep infarcts than those with superficial infarcts and other cortical infarcts and internal borderzone infarcts.22 Post hoc analysis of the SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) also showed that in 70% to 99% sICAS patients, borderzone infarcts and impaired collateral flow identified a subgroup of patients with particularly high risk of recurrent stroke despite medical treatment.29 In the current cohort, we found that patients with mixed mechanism of AA embolism and hypoperfusion had a higher risk of recurrent SIT within 1 year. AA embolism and hypoperfusion often coexist in patients with atherosclerotic lesions severely narrowing the cerebral arterial lumen.30 An atherosclerotic plaque protruding into the lumen could block cerebral blood flow and lead to hypoperfusion in the distal area; meanwhile, elevated mechanical forces by accelerated blood flow could regulate relevant cellular and molecular pathways that the atherosclerotic plaque may remodel to a more vulnerable phenotype and result in distal embolism.28 Additionally, impaired clearance (washout) of emboli might be an important link between hypoperfusion, AA embolism, and ischemic stroke; hypoperfusion may aggregate the subsequence of AA embolism and result in more infarct lesions.21,31 Future studies are needed to further reveal the interactions between hypoperfusion, AA embolism, and risk of ischemic stroke and infarct patterns in the presence of ICAS.

This study had limitations. First, the sample size was relatively small that we combined some of the subgroups in statistical analyses for the associations between stroke mechanisms and outcomes, and the small numbers of primary/secondary outcomes did not allow multivariate analyses that could take into account possible confounding factors for the independent associations between initial stroke mechanisms and the outcomes, for instance, certain vascular risk factors and treatment strategies. Second, with retrospective analyses of prospectively collected data from a cohort study, there might be bias in patient selection. Third, we only recruited patients with anterior-circulation stroke, whereas future relevant studies are needed in strokes attributed to ICAS in the posterior circulation. Last but not least, although classification criteria for stroke mechanisms in sICAS based on clinically routine imaging exams would be generalizable in large-scale studies, such criteria need validation with more advanced imaging workups and validation in multicenter studies with a larger number of raters in the near future.

Conclusions

The proposed criteria for classifying probable mechanisms of ICAS-related stroke based on routine MRI and MR/CT vessel imaging were reproducible. AA embolism and hypoperfusion are common mechanisms of stroke attributed to ICAS, which often coexist. Patients with ICAS-related stroke caused by mixed mechanism of AA embolism and hypoperfusion possess a higher risk of recurrent ischemic stroke, who may need more stringent medical treatment or other treatment strategies that warrants further investigations. When validated with more advanced imaging workups, the classification criteria for stroke mechanisms in sICAS in the current study could be generalizable in larger-scale and multicenter relevant studies. Subsequent studies in this area will facilitate better understanding of stroke mechanisms in sICAS and inform more individualized and more effective secondary stroke prevention in affected patients.

Footnotes

Presented in part at the European Stroke Organisation Conference, Milan, Italy, May 22–24, 2019.

The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.119.025732.

Correspondence to Xinyi Leng, PhD, Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Shatin, Hong Kong SAR, China, Email or Thomas W Leung, MD, Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China, Email

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