Time Since Stroke Onset, Quantitative Collateral Score, and Functional Outcome After Endovascular Treatment for Acute Ischemic Stroke

BACKGROUND AND OBJECTIVES: In patients with ischemic stroke undergoing endovascular treatment (EVT), time to treatment and collateral status are important prognostic factors and may be correlated. We aimed to assess the relation between time to CT angiography (CTA) and a quantitatively determined collateral score and to assess whether the collateral score modified the relation between time to recanalization and functional outcome. METHODS: We analyzed data from patients with acute ischemic stroke included in the Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke Registry between 2014 and 2017, who had a carotid terminus or M1 occlusion and were treated with EVT within 6.5 hours of symptom onset. A quantitative collateral score (qCS) was determined from baseline CTA using a validated automated image analysis algorithm. We also determined a 4-point visual collateral score (vCS). Multivariable regression models were used to assess the relations between time to imaging and the qCS and between the time to recanalization and functional outcome (90-day modified Rankin Scale score). An interaction term (time to recanalization × qCS) was entered in the latter model to test whether the qCS modifies this relation. Sensitivity analyses were performed using the vCS. RESULTS: We analyzed 1,813 patients. The median time from symptom onset to CTA was 91 minutes (interquartile range [IQR] 65–150 minutes), and the median qCS was 49% (IQR 25%–78%). Longer time to CTA was not associated with the log-transformed qCS (adjusted β per 30 minutes, 0.002, 95% CI −0.006 to 0.011). Both a higher qCS (adjusted common odds ratio [acOR] per 10% increase: 1.06, 95% CI 1.03–1.09) and shorter time to recanalization (acOR per 30 minutes: 1.17, 95% CI 1.13–1.22) were independently associated with a shift toward better functional outcome. The qCS did not modify the relation between time to recanalization and functional outcome (p for interaction: 0.28). Results from sensitivity analyses using the vCS were similar. DISCUSSION: In the first 6.5 hours of ischemic stroke caused by carotid terminus or M1 occlusion, the collateral status is unaffected by time to imaging, and the benefit of a shorter time to recanalization is independent of baseline collateral status

Cerebral blood flow quantification with multi-delay arterial spin labeling in ischemic stroke and the association with early neurological outcome

Restoring blood flow to brain tissue at risk of infarction is essential for tissue survival and clinical outcome. We used cerebral blood flow (CBF) quantified with multiple post-labeling delay (PLD) pseudocontinuous arterial spin labeling (ASL) MRI after ischemic stroke and assessed the association between CBF and early neurological outcome. We acquired ASL with 7 PLDs at 3.0 T in large vessel occlusion stroke patients at 24 h. We quantified CBF relative to the contralateral hemisphere (rCBF) and defined hyperperfusion as a ≥30% increase and hypoperfusion as a ≥40% decrease in rCBF. We included 44 patients (median age: 70 years, median NIHSS: 13, 40 treated with endovascular thrombectomy) of whom 37 were recanalized. Hyperperfusion in ischemic core occurred in recanalized but not in non-recanalized patients (65.8% vs 0%, p = 0.006). Hypoperfusion occurred only in the latter group (0% vs 85.7%, p < 0.001). In recanalized patients, hyperperfusion was also seen in salvaged penumbra (38.9%). Higher rCBF in ischemic core (aβ, −2.75 [95% CI: −4.11 to −1.40]) and salvaged penumbra (aβ, −5.62 [95% CI: −9.57 to −1.68]) was associated with lower NIHSS scores at 24 h. In conclusion, hyperperfusion frequently occurs in infarcted and salvaged brain tissue following successful recanalization and early neurological outcome is positively associated with the level of reperfusion

Comparison of diffusion weighted imaging b0 with T2*-weighted gradient echo or susceptibility weighted imaging for intracranial hemorrhage detection after reperfusion therapy for ischemic stroke

Purpose: Diffusion-weighted imaging (DWI) b0 may be able to substitute T2*-weighted gradient echo (GRE) or susceptibility-weighted imaging (SWI) in case of comparable detection of intracranial hemorrhage (ICH), thereby reducing MRI examination time. We evaluated the diagnostic accuracy of DWI b0 compared to T2*GRE or SWI for detection of ICH after reperfusion therapy for ischemic stroke. Methods: We pooled 300 follow-up MRI scans acquired within 1 week after reperfusion therapy. Six neuroradiologists each rated DWI images (b0 and b1000; b0 as index test) of 100 patients and, after a minimum of 4 weeks, T2*GRE or SWI images (reference standard) paired with DWI images of the same patients. Readers assessed the presence of ICH (yes/no) and type of ICH according to the Heidelberg Bleeding Classification. We determined the sensitivity and specificity of DWI b0 for detection of any ICH, and the sensitivity for detection of hemorrhagic infarction (HI1 &amp; HI2) and parenchymal hematoma (PH1 &amp; PH2). Results: We analyzed 277 scans of ischemic stroke patients with complete image series and sufficient image quality (median age 65 years [interquartile range, 54–75], 158 [57%] men). For detection of any ICH on DWI b0, the sensitivity was 62% (95% CI: 50–76) and specificity 96% (95% CI: 93–99). The sensitivity of DWI b0 was 52% (95% CI: 28–68) for detection of hemorrhagic infarction and 84% (95% CI: 70–92) for parenchymal hematoma. Conclusion: DWI b0 is inferior for detection of ICH compared to T2*GRE/SWI, especially for smaller and more subtle hemorrhages. Follow-up MRI protocols should include T2*GRE/SWI for detection of ICH after reperfusion therapy.</p

Brain atrophy and endovascular treatment effect in acute ischemic stroke: a secondary analysis of the MR CLEAN trial

Background: Brain atrophy is suggested to impair the potential for functional recovery after acute ischemic stroke. We assessed whether the effect of endovascular treatment is modified by brain atrophy in patients with acute ischemic stroke due to large vessel occlusion. Methods: We used data from MR CLEAN, a multicenter trial including patients with acute ischemic stroke due to anterior circulation large vessel occlusion randomized to endovascular treatment plus medical care (intervention) versus medical care alone (control). We segmented total brain volume (TBV) and intracranial volume (ICV) on baseline non-contrast computed tomography (n = 410). Next, we determined the degree of atrophy as the proportion of brain volume in relation to head size (1 − TBV/ICV) × 100%, analyzed as continuous variable and in tertiles. The primary outcome was a shift towards better functional outcome on the modified Rankin Scale expressed as adjusted common odds ratio. Treatment effect modification was tested using an interaction term between brain atrophy (as continuous variable) and treatment allocation. Results: We found that brain atrophy significantly modified the effect of endovascular treatment on functional outcome (P for interaction = 0.04). Endovascular treatment led to larger shifts towards better functional outcome in the higher compared to the lower range of atrophy (adjusted common odds ratio, 1.86 [95% CI: 0.97–3.56] in the lowest tertile vs. 1.97 [95% CI: 1.03–3.74] in the middle tertile vs. 3.15 [95% CI: 1.59–6.24] in the highest tertile). Conclusion: Benefit of endovascular treatment is larger in the higher compared to the lower range of atrophy, demonstrating that advanced atrophy should not be used as an argument to withhold endovascular treatment

Association of White Matter Lesions and Outcome After Endovascular Stroke Treatment

OBJECTIVE: To investigate the association between white matter lesions (WML) and functional outcome in patients with acute ischemic stroke (AIS) and the modification of the effect of endovascular treatment (EVT) by WML. METHODS: We used data from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trial and assessed severity of WML on baseline noncontrast CT imaging (NCCT; n = 473) according to the Van Swieten Scale. Poststroke functional outcome was assessed with the modified Rankin Scale. We investigated the association of WML with functional outcome using ordinal logistic regression models adjusted for age, sex, and other relevant cardiovascular and prognostic risk factors. In addition, an interaction term between treatment allocation and WML severity was used to assess treatment effect modification by WML. RESULTS: We found an independent negative association between more severe WML and functional outcome (adjusted common odds ratio [acOR] 0.77 [95% confidence interval (CI) 0.66-0.90]). Patients with absent to moderate WML had similar benefit of EVT on functional outcome (acOR 1.93 [95% CI 1.31-2.84]) as patients with severe WML (acOR 1.95 [95% CI 0.90-4.20]). No treatment effect modification of WML was found (p for interaction = 0.85). CONCLUSIONS: WML are associated with poor functional outcome after AIS, but do not modify the effect of EVT. CLASSIFICATION OF EVIDENCE: Prognostic accuracy. This study provides Class II evidence that for patients with AIS, the presence of WML on baseline NCCT is associated with worse functional outcomes

Diagnostic performance of an algorithm for automated collateral scoring on computed tomography angiography

Objectives: Outcome of endovascular treatment in acute ischemic stroke patients depends on collateral circulation to provide blood supply to the ischemic territory. We evaluated the performance of a commercially available algorithm for assessing the collateral score (CS) in acute ischemic stroke patients. Methods: Retrospectively, baseline CTA scans (≤ 3-mm slice thickness) with an intracranial carotid artery (ICA), middle cerebral artery segment M1 or M2 occlusion, from the MR CLEAN Registry (n = 1627) were evaluated. All CTA scans were evaluated for visual CS (0–3) by eight expert radiologists (reference standard). A Web-based AI algorithm quantified the collateral circulation (0–100%) for correctly detected occlusion sides. Agreement between visual CS and categorized automated CS (0: 0%, 1: > 0– ≤ 50%, 2: > 50– < 100%, 3: 100%) was assessed. Area under the curve (AUC) values for classifying patients in having good (CS: 2–3) versus poor (CS: 0–1) collaterals and for predicting functional independence (90-day modified Rankin Scale 0–2) were computed. Influence of CTA acquisition timing after contrast material administration was reported. Results: In the analyzed scans (n = 1024), 59% agreement was found between visual CS and automated CS. An AUC of 0.87 (95% CI: 0.85–0.90) was found for discriminating good versus poor CS. Timing of CTA acquisition did not influence discriminatory performance. AUC for predicting functional independence was 0.66 (95% CI 0.62–0.69) for automated CS, similar to visual CS 0.64 (95% CI 0.61–0.68). Conclusions: The automated CS performs similar to radiologists in determining a good versus poor collateral score and predicting functional independence in acute ischemic stroke patients with a large vessel occlusion. Key Points: • Software for automated quantification of intracerebral collateral circulation on computed tomography angiography performs similar to expert radiologists in determining a good versus poor collateral score. • Software for automated quantification of intracerebral collateral circulation on computed tomography angiography performs similar to expert radiologists in predicting functional independence in acute ischemic stroke patients with a large vessel occlusion. • The timing of computed tomography angiography acquisition after contrast material administration did not influence the performance of automated quantification of the collateral status

Intracranial carotid artery calcification subtype and collaterals in patients undergoing endovascular thrombectomy

Background and aims: Distinct subtypes of intracranial carotid artery calcification (ICAC) have been found (i.e., medial and intimal), which may differentially be associated with the formation of collaterals. We investigated the association of ICAC subtype with collateral status in patients undergoing endovascular thrombectomy (EVT) for ischemic stroke. We further investigated whether ICAC subtype modified the association between collateral status and functional outcome. Methods: We used data from 2701 patients with ischemic stroke undergoing EVT. Presence and subtype of ICAC were assessed on baseline non-contrast CT. Collateral status was assessed on baseline CT angiography using a visual scale from 0 (absent) to 3 (good). We investigated the association of ICAC subtype with collateral status using ordinal and binary logistic regression. Next, we assessed whether ICAC subtype modified the association between collateral status and functional outcome (modified Rankin Scale, 0–6). Results: Compared to patients without ICAC, we found no association of intimal or medial ICAC with collateral status (ordinal variable). When collateral grades were dichotomized (3 versus 0–2), we found that intimal ICAC was significantly associated with good collaterals in comparison to patients without ICAC (aOR, 1.41 [95%CI:1.06–1.89]) or with medial ICAC (aOR, 1.50 [95%CI:1.14–1.97]). The association between higher collateral grade and better functional outcome was significantly modified by ICAC subtype (p for interaction = 0.01). Conclusions: Patients with intimal ICAC are more likely to have good collaterals and benefit more from an extensive collateral circulation in terms of functional outcome after EVT

Diagnostic performance of an algorithm for automated large vessel occlusion detection on CT angiography

BACKGROUND: Machine learning algorithms hold the potential to contribute to fast and accurate detection of large vessel occlusion (LVO) in patients with suspected acute ischemic stroke. We assessed the diagnostic performance of an automated LVO detection algorithm on CT angiography (CTA). METHODS: Data from the MR CLEAN Registry and PRESTO were used including patients with and without LVO. CTA data were analyzed by the algorithm for detection and localization of LVO (intracranial internal carotid artery (ICA)/ICA terminus (ICA-T), M1, or M2). Assessments done by expert neuroradiologists were used as reference. Diagnostic performance was assessed for detection of LVO and per occlusion location by means of sensitivity, specificity, and area under the curve (AUC). RESULTS: We analyzed CTAs of 1110 patients from the MR CLEAN Registry (median age (IQR) 71 years (60-80); 584 men; 1110 with LVO) and of 646 patients from PRESTO (median age (IQR) 73 years (62-82); 358 men; 141 with and 505 without LVO). For detection of LVO, the algorithm yielded a sensitivity of 89% in the MR CLEAN Registry and a sensitivity of 72%, specificity of 78%, and AUC of 0.75 in PRESTO. Sensitivity per occlusion location was 88% for ICA/ICA-T, 94% for M1, and 72% for M2 occlusion in the MR CLEAN Registry, and 80% for ICA/ICA-T, 95% for M1, and 49% for M2 occlusion in PRESTO. CONCLUSION: The algorithm provided a high detection rate for proximal LVO, but performance varied significantly by occlusion location. Detection of M2 occlusion needs further improvement

Interobserver Agreement on Intracranial Hemorrhage on Magnetic Resonance Imaging in Patients With Ischemic Stroke

Background: The Heidelberg Bleeding Classification, developed for computed tomography, is also frequently used to classify intracranial hemorrhage (ICH) on magnetic resonance imaging. Additionally, the presence of any ICH is frequently used as (safety) outcome measure in clinical stroke trials that evaluate acute interventions. We assessed the interobserver agreement on the presence of any ICH and the type of ICH according to the Heidelberg Bleeding Classification on magnetic resonance imaging in patients treated with reperfusion therapy. Methods: We used 300 magnetic resonance imaging scans including susceptibility-weighted imaging or T2∗-weighted gradient echo imaging of ischemic stroke patients within 1 week after reperfusion therapy. Six observers, blinded to clinical characteristics except for suspected location of the infarction, independently rated ICH according to the Heidelberg Bleeding Classification in random pairs. Percent agreement and Cohen's kappa (κ) were estimated for the presence of any ICH (yes/no), and for agreement on the Heidelberg Bleeding Classification class 1 and 2. For the Heidelberg Bleeding Classification class 1 and 2, weighted κ was estimated to take the degree of disagreement into account. Results: In 297 of 300 scans, the quality of scans was sufficient to score ICH. Observers agreed on the presence or absence of any ICH in 264 of 297 scans (88.9%; κ 0.78 [95% CI, 0.71-0.85]). There was agreement on the Heidelberg Bleeding Classification class 1 and 2 and no ICH in class 1 and 2 in 226 of 297 scans (76.1%; κ 0.63 [95% CI, 0.56-0.69]; weighted κ 0.90 [95% CI, 0.87-0.93]). Conclusions: The presence of any ICH can be reliably scored on magnetic resonance imaging and can, therefore, be used as (safety) outcome measure in clinical stroke trials that evaluate acute interventions. Agreement of ICH types according to the Heidelberg Bleeding Classification is substantial and disagreements are small

Dual thrombolytic therapy with mutant pro-urokinase and small bolus alteplase for ischemic stroke (DUMAS): study protocol for a multicenter randomized controlled phase II trial

BACKGROUND: The effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not deplete fibrinogen and lyses fibrin only after induction with alteplase. Therefore, this treatment has the potential to be safer and more efficacious than treatment with alteplase alone. The aim of this study is to assess the safety and efficacy of thrombolytic treatment consisting of a small bolus alteplase followed by m-proUK compared with standard thrombolytic treatment with alteplase in patients presenting with ischemic stroke. METHODS: DUMAS is a multicenter, phase II trial with a prospective randomized open-label blinded end-point (PROBE) design, and an adaptive design for dose optimization. Patients with ischemic stroke, who meet the criteria for treatment with intravenous (IV) alteplase can be included. Patients eligible for endovascular thrombectomy are excluded. Patients are randomly assigned (1:1) to receive a bolus of IV alteplase (5mg) followed by a continuous IV infusion of m-proUK (40 mg/h during 60 min) or usual care with alteplase (0.9 mg/kg). Depending on the results of interim analyses, the dose of m-proUK may be revised to a lower dose (30 mg/h during 60 min) or a higher dose (50 mg/h during 60 min). We aim to include 200 patients with a final diagnosis of ischemic stroke. The primary outcome is any post-intervention intracranial hemorrhage (ICH) on neuroimaging at 24 h according to the Heidelberg Bleeding Classification, analyzed with binary logistic regression. Efficacy outcomes include stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) at 24 h and 5-7 days, score on the modified Rankin scale (mRS) assessed at 30 days, change (pre-treatment vs. post-treatment) in abnormal perfusion volume, and blood biomarkers of thrombolysis at 24 h. Secondary safety endpoints include symptomatic intracranial hemorrhage, death, and major extracranial hemorrhage. This trial will use a deferred consent procedure. DISCUSSION: When dual thrombolytic therapy with a small bolus alteplase and m-proUK shows the anticipated effect on the outcome, this will lead to a 13% absolute reduction in the occurrence of ICH in patients with ischemic stroke. TRIAL REGISTRATION: NL7409 (November 26, 2018)/NCT04256473 (February 5, 2020)