Bart J. Emmer

Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial

IMPORTANCE Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known. OBJECTIVE To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT. DESIGN, SETTING, AND PARTICIPANTS The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015. MAIN OUTCOMES AND MEASURES Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion. RESULTS Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours. CONCLUSION AND RELEVANCE For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion. TRIAL REGISTRATION trialregister.nl Identifier: NTR1804.

Collateral Status on Baseline Computed Tomographic Angiography and Intra-Arterial Treatment Effect in Patients with Proximal Anterior Circulation Stroke

Background and Purpose— Recent randomized trials have proven the benefit of intra-arterial treatment (IAT) with retrievable stents in acute ischemic stroke. Patients with poor or absent collaterals (preexistent anastomoses to maintain blood flow in case of a primary vessel occlusion) may gain less clinical benefit from IAT. In this post hoc analysis, we aimed to assess whether the effect of IAT was modified by collateral status on baseline computed tomographic angiography in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN). Methods— MR CLEAN was a multicenter, randomized trial of IAT versus no IAT. Primary outcome was the modified Rankin Scale at 90 days. The primary effect parameter was the adjusted common odds ratio for a shift in direction of a better outcome on the modified Rankin Scale. Collaterals were graded from 0 (absent) to 3 (good). We used multivariable ordinal logistic regression analysis with interaction terms to estimate treatment effect modification by collateral status. Results— We found a significant modification of treatment effect by collaterals (P=0.038). The strongest benefit (adjusted common odds ratio 3.2 [95% confidence intervals 1.7–6.2]) was found in patients with good collaterals (grade 3). The adjusted common odds ratio was 1.6 [95% confidence intervals 1.0–2.7] for moderate collaterals (grade 2), 1.2 [95% confidence intervals 0.7–2.3] for poor collaterals (grade 1), and 1.0 [95% confidence intervals 0.1–8.7] for patients with absent collaterals (grade 0). Conclusions— In MR CLEAN, baseline computed tomographic angiography collateral status modified the treatment effect. The benefit of IAT was greatest in patients with good collaterals on baseline computed tomographic angiography. Treatment benefit appeared less and may be absent in patients with absent or poor collaterals. Clinical Trial Registration— URL: http://www.trialregister.nl and http://www.controlled-trials.com. Unique identifier: (NTR)1804 and ISRCTN10888758, respectively.

Baseline Blood Pressure Effect on the Benefit and Safety of Intra-Arterial Treatment in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands).

Background and Purpose— High blood pressure (BP) is associated with poor outcome and the occurrence of symptomatic intracranial hemorrhage in acute ischemic stroke. Whether BP influences the benefit or safety of intra-arterial treatment (IAT) is not known. We aimed to assess the relation of BP with functional outcome, occurrence of symptomatic intracranial hemorrhage and effect of IAT. Methods— This is a post hoc analysis of the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands). BP was measured at baseline, before IAT or stroke unit admission. We estimated the association of baseline BP with the score on the modified Rankin Scale at 90 days and safety parameters with ordinal and logistic regression analysis. Effect of BP on the effect of IAT was tested with multiplicative interaction terms. Results— Systolic BP (SBP) had the best correlation with functional outcome. This correlation was U-shaped; both low and high baseline SBP were associated with poor functional outcome. Higher SBP was associated with symptomatic intracranial hemorrhage (adjusted odds ratio, 1.25 for every 10 mm Hg higher SBP [95% confidence interval, 1.09–1.44]). Between SBP and IAT, there was no interaction for functional outcome, symptomatic intracranial hemorrhage, or other safety parameters; the absolute benefit of IAT was evident for the whole SBP range. The same was found for diastolic BP. Conclusions— BP does not affect the benefit or safety of IAT in patients with acute ischemic stroke caused by proximal intracranial vessel occlusion. Our data provide no arguments to withhold or delay IAT based on BP. Clinical Trial Registration— URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758.

Selection of patients for intra-arterial treatment for acute ischaemic stroke: development and validation of a clinical decision tool in two randomised trials

Objective To improve the selection of patients with acute ischaemic stroke for intra-arterial treatment using a clinical decision tool to predict individual treatment benefit. Design Multivariable regression modelling with data from two randomised controlled clinical trials. Setting 16 hospitals in the Netherlands (derivation cohort) and 58 hospitals in the United States, Canada, Australia, and Europe (validation cohort). Participants 500 patients from the Multicenter Randomised Clinical Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands trial (derivation cohort) and 260 patients with intracranial occlusion from the Interventional Management of Stroke III trial (validation cohort). Main outcome measures The primary outcome was the modified Rankin Scale (mRS) score at 90 days after stroke. We constructed an ordinal logistic regression model to predict outcome and treatment benefit, defined as the difference between the predicted probability of good functional outcome (mRS score 0-2) with and without intra-arterial treatment. Results 11 baseline clinical and radiological characteristics were included in the model. The externally validated C statistic was 0.69 (95% confidence interval 0.64 to 0.73) for the ordinal model and 0.73 (0.67 to 0.79) for the prediction of good functional outcome, indicating moderate discriminative ability. The mean predicted treatment benefit varied between patients in the combined derivation and validation cohort from −2.3% to 24.3%. There was benefit of intra-arterial treatment predicted for some individual patients from groups in which no treatment effect was found in previous subgroup analyses, such as those with no or poor collaterals. Conclusion The proposed clinical decision tool combines multiple baseline clinical and radiological characteristics and shows large variations in treatment benefit between patients. The tool is clinically useful as it aids in distinguishing between individual patients who may experience benefit from intra-arterial treatment for acute ischaemic stroke and those who will not. Trial registration clinicaltrials.gov NCT00359424 (IMS III) and isrctn.com ISRCTN10888758 (MR CLEAN).

Changes in white matter microstructure suggest an inflammatory origin of neuropsychiatric systemic lupus erythematosus

To assess white matter (WM) and gray matter (GM) magnetization transfer ratio histogram peak heights (MTR‐HPHs) in different subsets of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) who have unremarkable findings on 3T magnetic resonance imaging of the brain and to evaluate whether these values could be used to highlight different clinically suspected underlying pathogenic processes or identify the clinical NPSLE status or whether they could be associated with a specific NPSLE syndrome.

Association Between Vascular Anatomy and Posterior Communicating Artery Aneurysms

OBJECTIVE Hemodynamic stress, conditioned by the geometry and morphology of the vessel trees, plays an important role in the formation of intracranial aneurysms. The aim of this study was to identify image-based location-specific morphologic parameters that are associated with posterior communicating artery (PCoA) aneurysms. METHODS Morphologic parameters obtained from computed tomography angiography of 56 patients with PCoA aneurysms and 23 control patients were evaluated with 3D Slicer, an open-source image analysis software, to generate 3-dimensional models of the aneurysms and surrounding vasculature. Segment lengths, diameters, and vessel-to-vessel angles were examined. To control for genetic and clinical risk factors, the unaffected contralateral side of patients with unilateral PCoA aneurysms was used as a control group for internal carotid artery (ICA)-related parameters. A separate control group with visible PCoAs and aneurysms elsewhere was used as a control group for PCoA-related parameters. RESULTS Internal carotid artery-related parameters were not statistically different between the PCoA aneurysm and control groups. Univariate and multivariate subgroup analysis for patients with visualized PCoAs demonstrated that a larger PCoA diameter was significantly associated with the presence of a PCoA aneurysm (odds ratio = 12.1, 95% confidence interval = 1.3-17.1, P = 0.04) after adjusting for other morphologic parameters. CONCLUSIONS Larger PCoA diameters are associated with the presence of PCoA aneurysms. These parameters may provide objective metrics to assess aneurysm formation and growth risk stratification in high-risk patients.

Thrombectomy in posterior circulation stroke through persistent primitive trigeminal artery: A case report.

We describe a case of intra-arterial treatment (IAT) of acute posterior circulation occlusion in a patient with a persistent primitive trigeminal artery (PPTA). The patient presented with an acute left sided hemiparesis and loss of consciousness (Glasgow coma score of 5). Computed tomography angiography showed an acute occlusion of the right internal carotid artery (ICA), the PPTA, distal basilar artery (BA), right posterior cerebral artery (PCA), and right superior cerebellar artery (SCA). Stent-retriever assisted thrombectomy was not considered possible through the hypoplastic proximal BA. After passage of the proximal ICA occlusion, the right PCA and SCA were recanalized through the PPTA, with a single thrombectomy procedure. Ten days after intervention patient was discharged scoring optimal EMV with only a mild facial and left hand paresis remaining. PPTA is a persistent embryological carotid–basilar connection. Knowledge of existing (embryonic) variants in neurovascular anatomy is essential when planning and performing acute neurointerventional procedures.

Conscious sedation or local anesthesia during endovascular treatment for acute ischemic stroke

Objective To investigate the effect of conscious sedation (CS) on functional outcome and complication rates after intra-arterial treatment (IAT) for acute ischemic stroke (AIS) compared to the use of local anesthesia (LA) at the puncture site only. Methods Patients undergoing IAT for AIS with CS or LA in the Erasmus University Medical Center from March 2014 to June 2016 were included for analysis. The primary outcome was the score on the ordinal modified Rankin Scale (mRS). We compared CS to LA by ordinal logistic regression with covariate adjustment using propensity scoring. Results In 146 AIS patients treated with IAT, use of CS was associated with a shift towards worse mRS scores (odds ratio [OR] 0.4 [95% confidence interval (CI) 0.2–0.7]) compared to LA. Mortality after 90 days was higher in the CS group compared to the LA group (OR 2.3 [95% CI 1.0–5.2]). No differences between groups were noted with regard to procedure duration (8 minutes, β = 6.3 [95% CI −7.4 to 20.0]) or occurrence of procedure-related complications (OR 1.3 [95% CI 0.6–2.7]). Conclusion CS was associated with poor functional outcome and increased mortality rates compared to LA. Furthermore, CS did not reduce duration of intervention or interventional complications. CS during IAT for AIS is of no benefit if LA is considered safe. Classification of evidence This study provides Class II evidence, because of nonrandom allocation, that for patients with AIS undergoing IAT, LA rather than CS improves functional outcome.

Imaging stent–thrombus interaction in mechanical thrombectomy

A 52-year-old man had a right M1 occlusion, treated with mechanical intra-arterial therapy. After 5 minutes of intra-arterial embedding, the stentriever containing thrombus was retrieved, rinsed, and fixed for microscopy. MicroCT scanning electron and light microscopy was performed on the stentriever to assess stent–thrombus interaction (figure). Twenty-three sites of interaction between thrombus and stentriever were analyzed. Interaction was not mechanical at 12 of these sites. We observed fibrin cross-bridges connecting thrombus to stent wires. Fibrin also created smooth covers overlying erythrocyte-rich areas. Light microscopy further showed thrombus interspersed with leukocytes, consisting of fibrin- and platelet-rich areas coalescing around the stent wire.

Quantitative Analysis of Geometry and Lateral Symmetry of Proximal Middle Cerebral Artery

BACKGROUND The purpose of our work is to quantitatively assess clinically relevant geometric properties of proximal middle cerebral arteries (pMCA), to investigate the degree of their lateral symmetry, and to evaluate whether the pMCA can be modeled by using state-of-the-art deformable image registration of the ipsi- and contralateral hemispheres. METHODS Individual pMCA segments were identified, quantified, and statistically evaluated on a set of 55 publicly available magnetic resonance angiography time-of-flight images. Rigid and deformable image registrations were used for geometric alignment of the ipsi- and contralateral hemispheres. Lateral symmetry of relevant geometric properties was evaluated before and after the image registration. RESULTS No significant lateral differences regarding tortuosity and diameters of contralateral M1 segments of pMCA were identified. Regarding the length of M1 segment, 44% of all subjects could be considered laterally symmetrical. Dominant M2 segment was identified in 30% of men and 9% of women in both brain hemispheres. Deformable image registration performed significantly better (P < .01) than rigid registration with regard to distances between the ipsi- and the contralateral centerlines of M1 segments (1.5 ± 1.1 mm versus 2.8 ± 1.2 mm respectively) and between the M1 and the anterior cerebral artery (ACA) branching points (1.6 ± 1.4 mm after deformable registration). CONCLUSIONS Although natural lateral variation of the length of M1 may not allow for sufficient modeling of the complete pMCA, deformable image registration of the contralateral brain hemisphere to the ipsilateral hemisphere is feasible for localization of ACA-M1 branching point and for modeling 71 ± 23% of M1 segment.