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Patients with low ASPECTS can still benefit from EVT.
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CBV index may be a prognostic predictor of patients with low ASPECTS.
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Higher CBV index is associated with better outcomes.
Abstract
Introduction
To evaluate the predictors for efficacy and safety of patients with acute ischemic stroke (AIS) and Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) ＜6 undergoing endovascular therapy (EVT).
Methods
This study retrospectively analyzed consecutive patients presented between December 2020 and December 2021 with large vessel occlusions (LVO) within the anterior circulation and an ASPECTS ＜6, followed by EVT. The efficacy outcome was 90-day functional independence, defined as modified Rankin Scale (mRS) score 0–3. The primary safety outcome was symptomatic intracranial hemorrhage (sICH). Secondary safety outcomes included 90-day all-cause mortality and 24-hour any ICH.
Results
A total of 22 patients were included. The percentage of patients with mRS 0–3 at 90 days was 36.4% (8/22). The occurrence of sICH was 22.7% (5/22). The occurrence of any ICH was 45.5% (10/22). The 90-day all-cause mortality was 36.4% (8/22). Median (interquartile range, IQR) cerebral blood volume (CBV) index was 0.5 (0.4–0.7). CBV index in mRS 0–3 group (n = 8) was higher than mRS 4–5 group (n = 14) (P＜0.05). There was no significant difference of age, gender, comorbidities, baseline National Institutes of Health Stroke Scale (NIHSS) score, mismatch ratio, CBV index, interval between stroke onset and re-perfusion, good re-perfusion rate between sICH group (n = 5) and non-sICH group (n = 17).
Conclusions
AIS patients with low ASPECTS can still benefit from EVT and gain good functional outcome, especial those had higher CBV index on pre-EVT computed tomography perfusion (CTP). Further studies with larger sample size are needed to validate our findings.
China Stroke Statistics 2019: A Report From the National Center for Healthcare Quality Management in Neurological Diseases, China National Clinical Research Center for Neurological Diseases, the Chinese Stroke Association, National Center for Chronic and Non-communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention and Institute for Global Neuroscience and Stroke Collaborations.
]. Establishing re-perfusion with intravenous thrombolysis or endovascular therapy (EVT) is the effective treatment for AIS. EVT has been recommended for patients with large vessel occlusion and National Institutes of Health Stroke Scale (NIHSS) score of ≥ 6, Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) of ≥ 6 [
Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.
]. However, for those patients with ASPECTS ＜6, the efficacy and safety of EVT is not conclusive. One meta-analysis demonstrated a significant proportion of this subset of patients still achieved good functional outcomes at 90 days and a trend in higher symptomatic intracranial hemorrhage (sICH) among low ASPECTS patients undergoing EVT [
]. More recently, one randomized controlled trial (RCT) from Japan showed that patients with large cerebral infarction had better functional outcomes with EVT than with medical care alone but had more intracranial hemorrhages [
]. Thus, in terms of individuals with low ASPECTS, who may achieve good functional outcome and who may develop intracranial hemorrhage, deserves further study. For this purpose, we conducted this retrospective study to explore predictors for efficacy and safety of low ASPECTS patients undergoing EVT.
2. Methods
2.1 Patients
Patients presented between December 2020 and December 2021 with large vessel occlusions (LVO) within the anterior circulation on computed tomographic angiography (CTA) and an ASPECTS 0–5 on computed tomography perfusion (CTP), followed by EVT were retrospectively analyzed. Patients met the following criteria were selected for EVT: (1) Acute ischemic stroke with occlusion of an anterior circulation artery (intracranial internal carotid artery [ICA], anterior cerebral artery segment 1 [A1], middle cerebral artery segment 1 [M1] and/or middle cerebral artery segment 2 [M2]) confirmed by CTA; (2) Witnessed symptom onset within 24 h; (3) Mismatch between deficit and infarct on CTP; (4) Absence of intracranial hemorrhage; (5) Specific request for therapy by family members. This study was approved by the Ethical Review Board.
2.2 Endovascular therapy
General anesthesia was used for all patients. Intervention modalities included manual aspiration, stent-retriever thrombectomy, or both were applied based on the condition of individual patient.
2.3 Data collection
Demographic variables including age, sex, baseline NIHSS score, site of occlusion, median interval between time of stroke onset and time of re-perfusion, and degree of recanalization, which was assessed by the modified Thrombolysis in Cerebral Infarction (mTICI) scale, were collected. A single pass/use of device, mTICI 2b/3 recanalization, and no use of rescue therapy was defined as first-pass effect (FPE) [
]. Medical comorbidities including hypertension, diabetes mellitus, atrial fibrillation were obtained from the patient’s clinical history. Diabetes mellitus was defined as treated or presently diagnosed according to the 1999 World Health Organization criteria (fasting blood glucose of ≥ 7.0 mmol/L, or 2-hour oral glucose tolerance test glucose of ≥ 11.1 mmol/L) or a history of hyperglycemia managed by insulin, oral hypoglycemic agents, or diet. We defined hypertension as persistent systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, a clear history of hypertension on medication, or both.
Non-contrast computed tomography (NCCT), CTA, and CTP scan were performed on a 256-slice multidetector CT scanner (Revolution, GE Healthcare, USA) according to our institutional stroke imaging protocol for patients with AIS. After excluding hemorrhagic stroke through NCCT, CTA was performed. CTP was performed in patients with AIS with stroke onset time > 6 h or with unclear time. CTP was postprocessed using Rapid processing of Perfusion and Diffusion (RAPID) software (iSchemaView, San Mateo, CA, USA). CTP parameters from RAPID included ASPECTS, cerebral blood flow (CBF), cerebral blood volume (CBV), time to maximum of the residue function (Tmax). Volume of infarction core was defined as volume of brain tissue with CBF＜30%; Hypoperfusion volume was identified as tissue with a Tmax value > 6 s. Mismatch ratio (mismatch between hypoperfusion and infarction core) was defined as volume of Tmax >6 s/volume of CBF＜30%. CBV index was defined as the average CBV in Tm > 6 s region compared to the average CBV in normal brain tissue [
The efficacy outcome was 90-day functional independence, defined as modified Rankin Scale (mRS) score 0–3. The primary safety outcome was sICH, which was defined according to the second European-Australasian Acute Stroke Study (ECASS II) as presence of intracranial hemorrhage and a four-point neurological deterioration on the NIHSS within 24 hours [
Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators.
]. Secondary safety outcomes included all-cause mortality within 90 days of treatment and any intracranial hemorrhage within 24 hours.
2.5 Statistical analysis
The χ2 test or Fisher exact test was used for comparing categorical variables and the Mann Whitney U test was used to compare continuous variables. P<0.05 was defined as a significant difference. All statistical analyses were performed using SPSS 20.0.
3. Results
Between December 2020 and December 2021, there were 239 patients who were admitted to the hospital for endovascular treatment, and we included 22 patients who completed CTP examination and showed ASPECTS < 6. Median (interquartile range, IQR) mismatch ratio was 2.15 (1.525–2.6); Median (IQR) CBV index was 0.5 (0.4–0.7). All the patients completed follow-up in March 2022 and were included in the primary analyses. The mean age of the patients was 65.95 ± 12.99 (39–85) years and 10/22 (45.5%) were men. Median (IQR) baseline NIHSS score was 15 (13–17.25). 8/22 (36.4%) of all the patients had hypertension, 4/22 (18.2%) had diabetes, and 11/22 (50.0%) had atrial fibrillation.
Occlusions of the internal carotid artery occurred in 13/22 (59.1%) of the patients; occlusions of the A1 segment of the anterior cerebral artery occurred in 1/22 (4.5%) of the patients; occlusions of the M1 segment of the middle cerebral artery occurred in 10/22 (45.5%); occlusions of the M2 segment of the middle cerebral artery occurred in 4/22 (18.2%); tandem lesions occurred in approximately 5/22 (22.7%) of the patients.
All patients underwent direct thrombectomy: one patient treated with only aspiration, 11 patients treated with only stent-retriever; 10 patients treated with aspiration combined with stent-retriever. Median interval between time of stroke onset and time of re-perfusion was 600 (465.0–817.5) minutes. The rate of FPE was 18.2% of patients (4/22). 14/22 (63.6%) of the patients had a mTICI re-perfusion grade of 3, among which 4 patients were one pass; 4/22 (18.2%) of the patients had a mTICI re-perfusion grade of 2b; 2/22 (9.1%) of the patients had a mTICI re-perfusion grade of 2a. The percentage of patients with mRS 0–3 at 90 days was 36.4% (8/22). The percentage of patients with mRS 0–2 was 18.2% (4/22). As shown in Fig. 1 and Fig. 2, two patients were diagnosed as AIS with ASPECTS＜6, and received thrombectomy directly. Both gained mRS 0–3 at 90 days. The occurrence of sICH within 24 hours was 22.7% (5/22). The occurrence of any intracranial hemorrhage within 24 hours was 45.5% (10/22). The 90-day all cause mortality was 36.4% (8/22).
Fig. 1A 39-year old patient presented with sudden headache and left limbs weakness for 13 h. The time from onset to recanalization was 960 min; mRS score was 3 at 3 months. A and B: Preoperative CTP showed ASPECTS 0 (A), infarct core 320 ml, and the CBV index 0.4 (B); C: Preoperative CTA showed complete disppearance of common carotid artery and internal carotid artery, compensatory development of right middle cerebral artery; D: Emergency DSA showed thrombosis with occlusion in middle segment of common carotid artery. E: Post-EVT mTICI was 3.
Fig. 2A 42-year old patient presented with right limbs weakness for 10 h. The time from onset to recanalization was 930 min; mRS score was 2 at 3 months. A and B: Preoperative CTP showed ASPECTS 3 (A), infarct core 74 ml, and the CBV index 0.6 (B); C: Preoperative CTA showed that distal site of left middle cerebral artery M1 segment was poorly developed; D: Emergency DSA showed occlusion of left middle cerebral artery M1 segment. E: Post-EVT mTICI was 3.
To explore the potential predictors for efficacy, we divided the patients into mRS 0–3 group (n = 8) and mRS 4–5 group (n = 14). Demographic characteristics, comorbidities, baseline NIHSS, CTP perfusion parameters, and postoperative indicators were compared between the two groups. Results (Table 1) showed that CBV index in mRS 0–3 group was higher than mRS 4–5 group, the difference between the two groups was statistically significant (P＜0.05).
Table 1Association between baseline, procedural, outcome characteristics and mRS.
mRS 0–3 (n = 8)
mRS 4–5 (n = 14)
P-value
Age, years
64.00 ± 16.41
67.07 ± 11.13
0.61
Male, n (%)
6 (75.0%)
4 (28.6%)
0.07
Hypertension, n (%)
3 (37.5%)
5 (35.7%)
1.00
Diabetes, n (%)
2 (25.0%)
2 (14.3%)
0.60
Atrial fibrillation, n (%)
4 (50.0%)
7 (50.0%)
1.00
Baseline NIHSS, Median (IQR)
15.0 (11.0–15.0)
14.5 (13.0–22.5)
0.63
Mismatch ratio, Median (IQR)
2.6 (2.0–3.7)
1.7 (1.4–2.45)
0.057
CBV index, Median (IQR)
0.65 (0.5–0.8)
0.45 (0.375–0.525)
0.026
Interval between stroke onset and re-perfusion, minutes, Median (IQR)
555.0 (390.0–952.5)
600.0 (510.0–780.0)
0.72
Good re-perfusion (2b-3), n (%)
8 (100.0%)
10 (71.4%)
0.25
FPE, n (%)
2 (25.0%)
2 (14.3%)
0.60
sICH, n (%)
0 (0.0%)
5 (35.7%)
0.12
Any ICH, n (%)
2 (25.0%)
8 (57.1%)
0.20
NIHSS, National Institutes of Health Stroke Scale; IQR, interquartile range; FPE, first-pass effect; sICH, symptomatic intracranial hemorrhage; mRS, modified Rankin Scale; CBV, cerebral blood volume.
To explore the potential predictors for safety, we divided the patients into sICH group (n = 5) and non-sICH group (n = 17). There was no significant difference of age, gender, comorbidities, baseline NIHSS, mismatch ratio, CBV index, interval between stroke onset and re-perfusion, good re-perfusion rate between the two group (Table 2).
Table 2Association between baseline, procedural, outcome characteristics and sICH.
sICH (n = 5)
Non-sICH (n = 17)
P-value
Age, years
65.40 ± 11.63
66.11 ± 13.69
0.92
Male, n (%)
3 (60.0%)
7 (41.2%)
0.62
Hypertension, n (%)
1 (20.0%)
7 (41.2%)
0.61
Diabetes, n (%)
1 (20.0%)
3 (17.6%)
1.00
Atrial fibrillation, n (%)
2 (40.0%)
9 (52.9%)
1.00
Baseline NIHSS, Median (IQR)
15.0 (14.5–19.0)
14.0 (12.5–16.5)
0.25
Mismatch ratio, Median (IQR)
1.5 (1.25–3.4)
2.4 (1.6–2.6)
0.21
CBV index, Median (IQR)
0.4 (0.25–0.55)
0.5 (0.4–0.75)
0.094
Interval between stroke onset and re-perfusion, minutes, Median (IQR)
600.0 (510.0–870.0)
600.0 (480.0–892.5)
0.74
Good re-perfusion (2b-3), n (%)
4 (80.0%)
14 (82.4%)
1.00
FPE, n (%)
1 (20.0%)
3 (17.6%)
1.00
NIHSS, National Institutes of Health Stroke Scale; IQR, interquartile range; mRS, modified Rankin Scale; CBV, cerebral blood volume; FPE, first-pass effect.
Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.
]. However, for those patients with ASPECTS ＜6, the efficacy and safety of EVT is still controversial. The present study retrospectively analyzed the patients with ASPECTS ＜6 to explore who may be more suitable for endovascular treatment. Our study showed that CBV index was higher in patients with mRS 0–3 than those with mRS 4–5, suggesting that the CBV index may be served as a screening indicator.
For patients with low ASPECTS, the percentage of patients with a score of 0 to 3 on the modified Rankin scale at 90 days from our study was 36.4% (8/22), which was similar to the recent RCT that 31.0% achieved mRS 0–3 [
]. With respect to who may gain function independence, one previous study showed that lower age, lower baseline NIHSS score, and successful recanalization (mTICI 2b/3) were predictors of independence after thrombectomy [
]. Another study showed that patients < 65 years of age have better rates of functional independence and lower rates of mortality compared with patients > 75 years of age [
Impact of Age and Alberta Stroke Program Early Computed Tomography Score 0 to 5 on Mechanical Thrombectomy Outcomes: Analysis From the STRATIS Registry.
]. However, age, baseline NIHSS and successful recanalization did not differ from each other between mRS 0–3 group and mRS 4–5.
The CBV index, which is defined as the relative cerebral blood volume in the Tmax > 6 s region has been reported to be associated with collateral circulation. Higher CBV index reflects improved blood flow and favorable collaterals. In patients with internal carotid artery (ICA) or proximal MCA occlusions, CBV index was a surrogate of collateral blood flow status [
]. Our study showed that in patients with low ASPECTS, CBV index was higher in patients with mRS 0–3 than those with mRS 4–5. Our results further strengthen the association between collateral circulation and outcomes of patients treated with EVT. Those patients with low ASPECTS and higher CBV index would benefit from EVT.
In terms of sICH, the occurrence rate in patients after endovascular thrombectomy was reported to be about 6% [
]. Much higher occurrence rate was shown in our study that in patients with low ASPECTS after EVT the occurrence rate of sICH was 22.7%. With respect to predictors of sICH, one single-center retrospective study with 528 patients showed that lower baseline ASPECTS and lower degree of re-perfusion was predictor of Sich [
]; another randomized trial showed that in patients with acute ischemic stroke after endovascular thrombectomy, the independent predictors of sICH were baseline NIHSS score and glucose level at hospital arrival [
]. However, in our study, no significant factors was shown to be associated with the occurrence of sICH, including degree of re-perfusion and baseline NIHSS score.
Our study had several limitations. Firstly, our study was retrospective study design, which may not have accounted for some confounders. Secondly, the sample size was relatively small, which limit the regression analysis to explore the impact of demographic characteristics, comorbidities, baseline NIHSS, CTP parameters, and postoperative indicators on patient outcomes.
5. Conclusion
Our results suggest that AIS patients with low ASPECTS can still benefit from EVT and can gain good functional outcome, especial those had higher CBV index on pre-EVT CTP. However, the risk of sICH is also higher in patients with low ASPECTS, and no predictors have been identified based on the results of our study. Given the limitations of this study, further studies with larger sample size are needed to explore predictors for efficacy and safety of low ASPECTS patients undergoing EVT.
6. Contributors
YNW and GFQ were responsible for the conception and design of the study. LBH and WDZ analyzed the data collected by ZQ and CXD. YS and WDZ interpreted the data. LBH and WJH drafted the manuscript. All authors revised and approved the final manuscript, and are accountable for the accuracy and integrity of the work.
7. Provenance and peer review
Not commissioned; externally peer reviewed.
8. Ethics approval
This study involves human participants and was approved by the Ethical Review Board of Sichuan Provincial People's Hospital.
9. Data availability statement
Data are available on reasonable request
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.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
Wang Y.-J.
Li Z.-X.
Gu H.-Q.
Zhai Y.i.
Jiang Y.
Zhao X.-Q.
et al.
China Stroke Statistics 2019: A Report From the National Center for Healthcare Quality Management in Neurological Diseases, China National Clinical Research Center for Neurological Diseases, the Chinese Stroke Association, National Center for Chronic and Non-communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention and Institute for Global Neuroscience and Stroke Collaborations.
Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.
Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators.
Impact of Age and Alberta Stroke Program Early Computed Tomography Score 0 to 5 on Mechanical Thrombectomy Outcomes: Analysis From the STRATIS Registry.
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