Effect of Remote Ischemic Conditioning in Ischemic Stroke Subtypes: A Post Hoc Subgroup Analysis From the RESIST Trial.

BACKGROUND: Remote ischemic conditioning (RIC) is a simple and noninvasive procedure that has proved to be safe and feasible in numerous smaller clinical trials. Mixed results have been found in recent large randomized controlled trials. This is a post hoc subgroup analysis of the RESIST trial (Remote Ischemic Conditioning in Patients With Acute Stroke), investigating the effect of RIC in different acute ischemic stroke etiologies, and whether an effect was modified by treatment adherence. METHODS: Eligible patients were adults (aged ≥18 years), independent in activities of daily living, who had prehospital stroke symptoms with a duration of less than 4 hours. They were randomized to RIC or sham. The RIC treatment protocol consisted of 5 cycles with 5 minutes of cuff inflation alternating with 5 minutes with a deflated cuff. Acceptable treatment adherence was defined as when at least 80% of planned RIC cycles were received. The analysis was performed using the entire range (shift analysis) of the modified Rankin Scale (ordinal logistic regression). RESULTS: A total of 698 had acute ischemic stroke, 253 (36%) were women, and the median (interquartile range) age was 73 (63-80) years. Median (interquartile range) overall adherence to RIC/sham was 91% (68%-100%). In patients with a stroke due to cerebral small vessel disease, who were adherent to treatment, RIC was associated with improved functional outcome, and the odds ratio for a shift to a lower score on the modified Rankin Scale was 2.54 (1.03-6.25); P=0.042. The association remained significant after adjusting for potential confounders. No significant associations were found with other stroke etiologies, and the overall test for interaction was not statistically significant (χ2, 4.33, P=0.23). CONCLUSIONS: In patients with acute ischemic stroke due to cerebral small vessel disease, who maintained good treatment adherence, RIC was associated with improved functional outcomes at 90 days. These results should only serve as a hypothesis-generating for future trials. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481777.

Diagnostic yield of computed tomography angiography in patients presenting with spontaneous intracerebral hemorrhage.

BACKGROUND: Hypertension and cerebral amyloid angiopathy are the most common causes of spontaneous intracerebral hemorrhage (ICH); however, these conditions do not imply macrovascular pathology. Still, computed tomography (CT) angiography (CTA) is often performed in the acute phase in patients with ICH. PURPOSE: To assess the diagnostic yield of CTA in the detection of secondary etiology in consecutive patients with spontaneous ICH. MATERIAL AND METHODS: We performed a retrospective analysis of data from a prospective single-center cohort study of 203 patients presenting with spontaneous ICH admitted to a comprehensive stroke center over a two-year period (15 October 2016 to 15 October 2018). The underlying vascular pathology was assessed using CTA. RESULTS: CTA was performed in addition to non-contrast CT and/or magnetic resonance imaging (MRI). Vascular pathology was found in 11 of 203 (5.4%) patients and included arteriovenous malformations (n=4), aneurysms (n=4), vasospasms (n=1), cerebral venous thrombosis (n=1), and other vascular malformations (n=1). In eight cases, the finding was deemed symptomatic. Patients with vascular pathology on CTA more often had lobar located hemorrhages (63.6% vs. 36.4%, P = 0.049). Numerically, patients with vascular pathology were younger, had smaller hematoma volumes, and lower mortality. CONCLUSION: Underlying macrovascular pathology was detected on CTA in only approximately 1 of 20 consecutive patients with ICH. The patients with vascular pathology more often had a hemorrhage with a lobar location and young age and the present study is supportive of a risk-based stratification approach in performing CTA.

Transport Strategy in Patients With Suspected Acute Large Vessel Occlusion Stroke: TRIAGE-STROKE, a Randomized Clinical Trial.

BACKGROUND: When patients with acute ischemic stroke present with suspected large vessel occlusion in the catchment area of a primary stroke center (PSC), the benefit of direct transport to a comprehensive stroke center (CSC) has been suggested. Equipoise remains between transport strategies and the best transport strategy is not well established. METHODS: We conducted a national investigator-driven, multicenter, randomized, assessor-blinded clinical trial. Patients eligible for intravenous thrombolysis (IVT) who were suspected for large vessel occlusion were randomized 1:1 to admission to the nearest PSC (prioritizing IVT) or direct CSC admission (prioritizing endovascular therapy). The primary outcome was functional improvement at day 90 for all patients with acute ischemic stroke, measured as shift towards a lower score on the modified Rankin Scale score. RESULTS: From September 2018 to May 2022, we enrolled 171 patients of whom 104 had acute ischemic stroke. The trial was halted before full recruitment. Baseline characteristics were well balanced. Primary analysis of shift in modified Rankin Scale (ordinal logistic regression) revealed an odds ratio for functional improvement at day 90 of 1.42 (95% CI, 0.72-2.82, P=0.31). Onset to groin time for patients with large vessel occlusion was 35 minutes (P=0.007) shorter when patients were transported to a CSC first, whereas onset to needle (IVT) was 30 minutes (P=0.012) shorter when patients were transported to PSC first. IVT was administered in 67% of patients in the PSC group versus 78% in the CSC group and EVT was performed in 53% versus 63% of the patients, respectively. CONCLUSIONS: This trial investigated the benefit of bypassing PSC. We included only IVT-eligible patients presenting <4 hours from onset and with suspected large vessel occlusion. Lack of power prevented the results from showing effect on functional outcome for patients going directly to CSC. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03542188.

Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial.

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: A Randomized Placebo-Controlled Trial.

BACKGROUND AND PURPOSE: Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. METHODS: The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. RESULTS: Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). CONCLUSIONS: This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

Plasma neurofilament light chain is associated with mortality after spontaneous intracerebral hemorrhage.

Background Neurofilament light chain (NfL) is a neuron-specific biomarker with prognostic ability in several types of central nervous system injuries. This study investigates if plasma NfL (pNfL) is elevated early after spontaneous intracerebral hemorrhage (ICH) and whether such elevation reflects disease severity and day-30 outcome. Methods pNfL was quantified by single molecule array analysis in 103 reference subjects (RS) and in samples from 37 patients with ICH obtained on admission to hospital and at 24-h follow-up. The primary outcome was day-30 mortality. Clinical status on admission was evaluated by standardized scoring systems. Results Median pNfL among RS was 9.6 (interquartile range [IQR] 6.2) pg/mL. Upon admission, ICH patients had pNfL of 19.8 (IQR 30.7) pg/mL increasing to 35.9 (IQR 44.5) pg/mL at 24 h (all, p < 0.001). On admission, pNfL was higher among ICH non-survivors than survivors (119.2 [IQR 152.6] pg/mL vs. 15.7 [IQR 19.6] pg/mL, p < 0.01) and this difference was observed also on 24 h follow-up (195.1 [IQR 73.9] pg/mL vs. 31.3 [IQR 27.8] pg/mL, p < 0.01). The area under the receiver operating characteristic curve (ROC AUC) for discrimination of day-30 mortality was significant on admission (AUC = 0.83, 95% confidence interval [CI]: 0.56-1.0) and increased on 24-h follow-up (AUC = 0.93, 95% CI: 0.84-1.0). The odds ratio (OR) for death, by each quartile increase in pNfL was significant both on admission (OR = 4.52, 95% CI: 1.32-15.48) and after 24-h follow-up (OR = 9.52, 95% CI: 1.26-71.74). Conclusions PNfL is associated with day-30 mortality after spontaneous ICH when early after the ictus.

Coagulation Profile after Spontaneous Intracerebral Hemorrhage: A Cohort Study.

BACKGROUND: Intracerebral hemorrhage (ICH) causes death or disability and the incidence increases with age. Knowledge of acute hemostatic function in patients with ICH without anticoagulant and antiplatelet therapy is sparse. Increased knowledge of the coagulation profile in the acute phase of ICH could improve acute treatment and recovery. We investigated coagulation at admission and changes in coagulation during the first 24hours after symptom onset. METHODS: Enrolled were 41 ICH patients without anticoagulant or antiplatelet therapy admitted to Aarhus University Hospital, Denmark. Blood samples were collected at admission, 6, and 24hours after symptom onset. Thromboelastometry (ROTEM), thrombin generation, and thrombin-antithrombin (TAT) complex were analyzed. Clinical outcome was evaluated using the National Institute of Health Stroke Scale, the Modified Rankin Score, and mortality. RESULTS: At admission, compared with healthy individuals, ICH patients had increased maximum clot firmness (EXTEM P < .0001; INTEM P < .0001; FIBTEM P < .0001), increased platelet maximum clot elasticity (P < .0001) in ROTEM, higher peak thrombin (P < .0001) and endogenous thrombin potential (P = .01) in thrombin generation, and elevated TAT complex levels. During 24hours after significantly, while thrombin generation showed decreased peak thrombin (P < .0001) and endogenous thrombin potential (P < .0001). Coagulation test results did not differ between patients when stratified according to clinical outcome. CONCLUSIONS: ICH patients without anticoagulant or antiplatelet therapy demonstrated activated coagulation at admission and within 24hours after symptom onset.

Does b1000-b0 Mismatch Challenge Diffusion-Weighted Imaging-Fluid Attenuated Inversion Recovery Mismatch in Stroke?

BACKGROUND AND PURPOSE: Our aim was to explore whether the mismatch in lesion visibility between b1000 and b0 images is an alternative to mismatch between diffusion-weighted imaging and fluid-attenuated inversion recovery imaging as a surrogate marker of stroke age. METHODS: We analyzed patients from the European multicenter I-KNOW database. Independent readers assessed the visibility of ischemic lesions of the anterior circulation on b0 and fluid-attenuated inversion recovery imaging images. The signal-intensity ratio for b0 and fluid-attenuated inversion recovery imaging images was also measured from the segmented stroke lesion volume on b1000 images. RESULTS: This study included 112 patients (68 men; mean age, 67.4 years) with stroke onset within (n=85) or longer than (n=27) 4.5 hours. b1000-b0 mismatch identified patients within 4.5 hours of stroke onset with moderate sensitivity (72.9%; 95% confidence interval [CI], 63.5-82.4) and specificity (70.4%; 95% CI, 53.2-87.6), high positive predictive value (88.6%; 95% CI, 81.1-96.0), and low negative predictive value (45.2%; 95% CI, 30.2-60.3). Global comparison of b1000-b0 mismatch with diffusion-weighted imaging-fluid-attenuated inversion recovery imaging mismatch (considered the imaging gold standard) indicated high sensitivity (85.9%; 95% CI, 78.2-93.6), specificity (91.2%; 95% CI, 76.3-98.1), and positive predictive value (96.7%; 95% CI, 88.0-99.1) and moderate negative predictive value (73.8%; 95% CI, 60.5-87.1) of this new approach. b0 signal-intensity ratio (r=0.251; 95% CI, 0.069-0.417; P=0.008) was significantly although weakly correlated with delay between stroke onset and magnetic resonance imaging. CONCLUSIONS: b1000-b0 mismatch may identify patients with ischemic stroke of the within 4.5 hours of onset with high positive predictive value, perhaps constituting an alternative imaging tissue clock.

MRI Assessment of Ischemic Lesion Evolution within White and Gray Matter.

BACKGROUND: In acute ischemic stroke (AIS), gray matter (GM) and white matter (WM) have different vulnerabilities to ischemia. Thus, we compared the evolution of ischemic lesions within WM and GM using MRI. METHODS: From a European multicenter prospective database (I-KNOW), available T1-weighted images were identified for 50 patients presenting with an anterior AIS and a perfusion weighted imaging (PWI)/diffusion weighted imaging (DWI) mismatch ratio of 1.2 or more. Six lesion compartments were outlined: initial DWI (b = 1,000 s/mm2) lesion, initial PWI-DWI mismatch (Tmax >4 s and DWI-negative), final infarct mapped on 1-month fluid-attenuated inversion recovery (FLAIR) imaging, lesion growth between acute DWI and 1-month FLAIR, DWI lesion reversal at 1 month and salvaged mismatch. The WM and GM were segmented on T1-weighted images, and all images were co-registered within subjects to the baseline MRI. WM and GM proportions were calculated for each compartment. RESULTS: Fifty patients were eligible for the study. Median delay between symptom onset and baseline MRI was 140 min. The percentage of WM was significantly greater in the following compartments: initial mismatch (52.5 vs. 47.5%, p = 0.003), final infarct (56.7 vs. 43.3%, p < 0.001) and lesion growth (58.9 vs. 41.2%, p < 0.001). No significant difference was found between GM and WM percentages within the initial DWI lesion, DWI reversal and salvaged mismatch compartments. CONCLUSIONS: Ischemic lesions may extend preferentially within the WM. Specific therapeutic strategies targeting WM ischemic processes may deserve further investigation.

Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: a randomized trial.

BACKGROUND AND PURPOSE: Remote ischemic preconditioning is neuroprotective in models of acute cerebral ischemia. We tested the effect of prehospital rPerC as an adjunct to treatment with intravenous alteplase in patients with acute ischemic stroke. METHODS: Open-label blinded outcome proof-of-concept study of prehospital, paramedic-administered rPerC at a 1:1 ratio in consecutive patients with suspected acute stroke. After neurological examination and MRI, patients with verified stroke receiving alteplase treatment were included and received MRI at 24 hours and 1 month and clinical re-examination after 3 months. The primary end point was penumbral salvage, defined as the volume of the perfusion-diffusion mismatch not progressing to infarction after 1 month. RESULTS: Four hundred forty-three patients were randomized after provisional consent, 247 received rPerC and 196 received standard treatment. Patients with a nonstroke diagnosis (n=105) were excluded from further examinations. The remaining patients had transient ischemic attack (n=58), acute ischemic stroke (n=240), or hemorrhagic stroke (n=37). Transient ischemic attack was more frequent (P=0.006), and National Institutes of Health Stroke Scale score on admission was lower (P=0.016) in the intervention group compared with controls. Penumbral salvage, final infarct size at 1 month, infarct growth between baseline and 1 month, and clinical outcome after 3 months did not differ among groups. After adjustment for baseline perfusion and diffusion lesion severity, voxelwise analysis showed that rPerC reduced tissue risk of infarction (P=0.0003). CONCLUSIONS: Although the overall results were neutral, a tissue survival analysis suggests that prehospital rPerC may have immediate neuroprotective effects. Future clinical trials should take such immediate effects, and their duration, into account. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00975962.

Very low cerebral blood volume predicts parenchymal hematoma in acute ischemic stroke.

BACKGROUND AND PURPOSE: Parenchymal hematoma (PH) may worsen the outcome of patients with stroke. The aim of our study was to confirm the relationship between the volume of very low cerebral blood volume (CBV) and PH using a European multicenter database (I-KNOW). A secondary objective was to explore the impact of early reperfusion and recanalization. METHODS: The volume of cerebral tissue with CBV≤2.5th percentile of the normal hemisphere was calculated within the acute diffusion-weighted imaging lesion. Hemorrhagic transformation was assessed on day 2 MRI according to the European Cooperative Acute Stroke Study II criteria. Recanalization and reperfusion were assessed on 3-hour follow-up MRI. RESULTS: Of the 110 patients, hemorrhagic transformation occurred in 59 patients, including 7 PH. In univariate analysis, the acute National Institutes of Health Stroke Scale score (P=0.002), acute diffusion-weighted imaging lesion volume (P=0.02), and thrombolysis (P=0.03), but not very low CBV (P=0.52), were associated with hemorrhagic transformation. The volume of very low CBV was the only predictor of PH (P=0.007). Early reperfusion and recanalization had no influence on either hemorrhagic transformation or PH. CONCLUSION: Very low CBV was the only independent predictor of PH in patients with acute stroke.

Acute stroke: automatic perfusion lesion outlining using level sets.

PURPOSE: To develop a user-independent algorithm for the delineation of hypoperfused tissue on perfusion-weighted images and evaluate its performance relative to a standard threshold method in simulated data, as well as in acute stroke patients. MATERIALS AND METHODS: The study was approved by the local ethics committee, and patients gave written informed consent prior to their inclusion in the study. The algorithm identifies hypoperfused tissue in mean transit time maps by simultaneously minimizing the mean square error between individual and mean perfusion values inside and outside a smooth boundary. In 14 acute stroke patients, volumetric agreement between automated outlines and manual outlines determined in consensus among four neuroradiologists was assessed with Bland-Altman analysis, while spatial agreement was quantified by using lesion overlap relative to mean lesion volume (Dice coefficient). Performance improvement relative to a standard threshold approach was tested with the Wilcoxon signed rank test. RESULTS: The mean difference in lesion volume between automated outlines and manual outlines was -9.0 mL ± 44.5 (standard deviation). The lowest mean volume difference for the threshold approach was -25.8 mL ± 88.2. A significantly higher Dice coefficient was observed with the algorithm (0.71; interquartile range [IQR], 0.42-0.75) compared with the threshold approach (0.50; IQR, 0.27- 0.57; P , .001). The corresponding agreement among experts was 0.79 (IQR, 0.69-0.83). CONCLUSION: The perfusion lesions outlined by the automated algorithm agreed well with those defined manually in consensus by four experts and were superior to those obtained by using the standard threshold approach. This user-independent algorithm may improve the assessment of perfusion images as part of acute stroke treatment. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13121622/-/DC1.

Inter-Rater Agreement on Cincinnati Prehospital Stroke Scale (CPSS) and Prehospital Acute Stroke Severity Scale (PASS) Between EMS Providers, Neurology Residents and Neurology Consultants.

Objective: To examine the agreement between emergency medical service (EMS) providers, neurology residents and neurology consultants, using the Cincinnati Prehospital Stroke Scale (CPSS) and the Prehospital Acute Stroke Severity Scale (PASS). Methods: Patients with stroke, transient ischemic attack (TIA) and stroke mimic were included upon primary stroke admission or during rehabilitation. Patients were included from June 2018 to September 2019. Video recordings were made of patients being assessed with CPSS and PASS. The recordings were later presented to the healthcare professionals. To determine relative and absolute interrater reliability in terms of inter-rater agreement (IRA), we used generalisability theory. Group-level agreement was determined against a gold standard and presented as an area under the curve (AUC). The gold standard was a consensus agreement between two neurology consultants. Results: A total of 120 patient recordings were assessed by 30 EMS providers, two neurology residents and two neurology consultants. Using the CPSS and the PASS, a total of 1,800 assessments were completed by EMS providers, 240 by neurology residents and 240 by neurology consultants. The overall relative and absolute IRA for all items combined from the CPSS and PASS score was 0.84 (95% CI 0.80; 0.87) and 0.81 (95% CI 0.77; 0.85), respectively. Using the CPSS, the agreement on a group-level resulted in AUCs of 0.83 (95% CI 0.78; 0.88) for the EMS providers and 0.86 (95% CI 0.82; 0.90) for the neurology residents when compared with the gold standard. Using the PASS, the AUC was 0.82 (95% CI 0.77; 0.87) for the EMS providers and 0.88 (95% CI 0.84; 0.93) for the neurology residents. Conclusion: The high relative and absolute inter-rater agreement underpins a high robustness/generalisability of the two scales. A high agreement exists across individual raters and different groups of healthcare professionals supporting widespread applicability of the stroke scales.

Infarction of 'non-core-non-penumbral' tissue after stroke: multivariate modelling of clinical impact.

There is considerable intersubject variability in early neurological course after anterior circulation stroke, yet the pathophysiology underlying this variability is not fully understood. Here, we hypothesize that, although not predicted by current pathophysiological models, infarction of 'non-core-non-penumbral' (i.e. clinically silent) brain tissue may nevertheless occur, and negatively influence clinical course over and above the established positive impact of penumbral salvage. In order to test this hypothesis, non-core-non-penumbral tissue was identified in two independent prospectively recruited cohorts, using computed tomography perfusion, and magnetic resonance perfusion- and diffusion-weighted imaging, respectively. Follow-up structural magnetic resonance imaging was obtained about 1 month later in all patients to map the final infarct. The volumes of both the acutely silent but eventually infarcted tissue, and the eventually non-infarcted penumbra, were determined by performing voxel-wise analysis of the acute and follow-up image sets, using previously validated perfusion thresholds. Early neurological course was expressed as change in National Institutes of Health Stroke Scale scores between the acute and 1-month assessments, relative to the acute score. The relationship between the acutely silent but eventually infarcted tissue volume and early neurological course was tested using a multivariate regression model that included the volume of non-infarcted penumbra. Thirty-four and 58 patients were recruited in the computed tomography perfusion and magnetic resonance perfusion cohorts, respectively (mean onset-to-imaging time: 136 and 156 min; 27 and 42 patients received intravenous thrombolysis, respectively). Infarction of acutely silent tissue was identified in most patients in both cohorts. Although its volume (median 0.2 and 2 ml, respectively) was much smaller than that of salvaged penumbra (59.3 and 93 ml, respectively), it was substantial in ∼10% of patients. As expected, salvaged penumbra strongly positively influenced early neurological course. Even after correcting for the latter effect in the multivariate model, infarction of acutely silent tissue independently negatively influenced early neurological course in both cohorts (P=0.018 and 0.031, respectively). This is the first systematic study to document infarction of acutely silent tissue after anterior circulation stroke, and to show that it affects a sizeable fraction of patients and has the predicted negative impact on clinical course. These findings were replicated in two independent cohorts, regardless of the perfusion imaging modality used. Preventing infarction of the tissue not initially at risk should have direct clinical benefit.

Perfusion Changes in Acute Stroke Treated with Theophylline as an Add-on to Thrombolysis : A Randomized Clinical Trial Subgroup Analysis.

PURPOSE: Theophylline has been suggested to have a neuroprotective effect in ischemic stroke; however, results from animal stroke models and clinical trials in humans are controversial. The aim of this study was to assess the effect of theophylline on the cerebral perfusion with multiparametric magnetic resonance imaging (MRI). METHODS: The relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative mean transit time (rMTT) in the infarct core, penumbra, and unaffected tissue were measured using multi-parametric MRI at baseline and 3­h follow-up in patients treated with theophylline or placebo as an add-on to thrombolytic therapy. RESULTS: No significant differences in mean rCBF, rCBV, and rMTT was found in the penumbra and unaffected tissue between the theophylline group and the control group between baseline and 3­h follow-up. In the infarct core, mean rCBV increased on average by 0.05 in the theophylline group and decreased by 0.14 in the control group (p < 0.04). Mean rCBF and mean rMTT in the infarct core were similar between the two treatment groups. CONCLUSION: The results indicate that theophylline does not change the perfusion in potentially salvageable penumbral tissue but only affects the rCBV in the infarct core. In contrast to the penumbra, the infarct core is unlikely to be salvageable, which might explain why theophylline failed in clinical trials.

Predicting infarction within the diffusion-weighted imaging lesion: does the mean transit time have added value?

BACKGROUND AND PURPOSE: There is ample evidence that in anterior circulation stroke, the diffusion-weighted imaging (DWI) lesion may escape infarction and thus is not a reliable infarct predictor. In this study, we assessed the predictive value of the mean transit time (MTT) for final infarction within the DWI lesion, first in patients scanned back-to-back with 15O-positron emission tomography and MR (DWI and perfusion-weighted imaging; "Cambridge sample") within 7 to 21 hours of clinical onset, then in a large sample of patients with anterior circulation stroke receiving DWI and perfusion-weighted imaging within 12 hours (85% within 6 hours; "I-KNOW sample"). METHODS: Both samples underwent structural MRI at approximately 1 month to map final infarcts. For both imaging modalities, MTT was calculated as cerebral blood volume/cerebral blood flow. After image coregistration and matrix resampling, the MTT values between voxels of interest that later infarcted or not were compared separately within and outside DWI lesions (DWI+ and DWI-, respectively) both within and across patients. In the I-KNOW sample, receiver operating characteristic curves were calculated for these voxel of interest populations and areas under the curve and optimal thresholds calculated. RESULTS: In the Cambridge data set (n=4), there was good concordance between predictive values of MTT (positron emission tomography) and MTT (perfusion-weighted imaging) for both DWI+ and DWI- voxels of interest indicating adequate reliability of MTT (perfusion-weighted imaging) for this purpose. In the I-KNOW data set (N=42), the MTT significantly added to the DWI lesion to predict infarction in both DWI- and DWI+ voxels of interest with areas under the curve approximately 0.78 and 0.64 (both P<0.001) and optimal thresholds approximately 8 seconds and 11 seconds, respectively. CONCLUSIONS: Despite the relatively small samples, this study suggests that adding MTT (perfusion-weighted imaging) may improve infarct prediction not only as already known outside, but also within, DWI lesions.

Machine Learning-Based Prediction of Brain Tissue Infarction in Patients With Acute Ischemic Stroke Treated With Theophylline as an Add-On to Thrombolytic Therapy: A Randomized Clinical Trial Subgroup Analysis.

Background and Purpose: The theophylline in acute ischemic stroke trial investigated the neuroprotective effect of theophylline as an add-on to thrombolytic therapy in patients with acute ischemic stroke. The aim of this pre-planned subgroup analysis was to use predictive modeling to virtually test for differences in the follow-up lesion volumes. Materials and Methods: A subgroup of 52 patients from the theophylline in acute ischemic stroke trial with multi-parametric MRI data acquired at baseline and at 24-h follow-up were analyzed. A machine learning model using voxel-by-voxel information from diffusion- and perfusion-weighted MRI and clinical parameters was used to predict the infarct volume for each individual patient and both treatment arms. After training of the two predictive models, two virtual lesion outcomes were available for each patient, one lesion predicted for theophylline treatment and one lesion predicted for placebo treatment. Results: The mean predicted volume of follow-up lesions was 11.4 ml (standard deviation 18.7) for patients virtually treated with theophylline and 11.2 ml (standard deviation 17.3) for patients virtually treated with placebo (p = 0.86). Conclusions: The predicted follow-up brain lesions for each patient were not significantly different for patients virtually treated with theophylline or placebo, as an add-on to thrombolytic therapy. Thus, this study confirmed the lack of neuroprotective effect of theophylline shown in the main clinical trial and is contrary to the results from preclinical stroke models.

A multicentre, randomised, sham-controlled trial on REmote iSchemic conditioning In patients with acute STroke (RESIST) - Rationale and study design.

RATIONALE: Remote ischaemic conditioning, applied in the prehospital setting and continued in-hospital, may improve functional outcome in patients with acute ischaemic stroke and intracerebral haemorrhage. AIMS: To evaluate whether combined remote ischaemic per- and postconditioning can improve long-term functional outcome in acute ischaemic stroke and intracerebral haemorrhage patients. METHODS AND DESIGN: Danish multicentre, prospective, randomised, patient-assessor blinded, sham-controlled study. Adult patients with a putative stroke identified prehospital with symptom duration <4 h, who are independent in daily activities will be randomised 1:1 to remote ischaemic conditioning or Sham-remote ischaemic conditioning. The treatment protocol will be five cycles, each consisting of 5 min with a blood pressure cuff inflation and 5 min with a deflated cuff placed on the upper extremity. The cuff pressure for remote ischaemic conditioning will be 200 mmHg-285 mmHg according to the individual systolic blood pressure and 20 mmHg sham-remote ischaemic conditioning during inflation. The study is approved as an acute study and consent is waived in the acute phase.Sample size estimation: For a 7% increased odds for a beneficial shift on the modified Rankin Scale at a significance level of 5% and power of 90%, 1000 patients with a target diagnosis of acute ischaemic stroke and intracerebral haemorrhage and a total of 1500 patients with a prehospital presumed stroke will be included.Study outcomes: The primary outcome will be the modified Rankin Scale score measured at three-month follow-up (analysed using ordinal logistic regression). ClinicalTrials.gov Identifier: NCT03481777.

Comparison of 10 perfusion MRI parameters in 97 sub-6-hour stroke patients using voxel-based receiver operating characteristics analysis.

BACKGROUND AND PURPOSE: Perfusion-weighted imaging can predict infarct growth in acute stroke and potentially be used to select patients with tissue at risk for reperfusion therapies. However, the lack of consensus and evidence on how to best create PWI maps that reflect tissue at risk challenges comparisons of results and acute decision-making in trials. Deconvolution using an arterial input function has been hypothesized to generate maps of a more quantitative nature and with better prognostic value than simpler summary measures such as time-to-peak or the first moment of the concentration time curve. We sought to compare 10 different perfusion parameters by their ability to predict tissue infarction in acute ischemic stroke. METHODS: In a retrospective analysis of 97 patients with acute stroke studied within 6 hours from symptom onset, we used receiver operating characteristics in a voxel-based analysis to compare 10 perfusion parameters: time-to-peak, first moment, cerebral blood volume and flow, and 6 variants of time to peak of the residue function and mean transit time maps. Subanalysis assessed the effect of reperfusion on outcome prediction. RESULTS: The most predictive maps were the summary measures first moment and time-to-peak. First moment was significantly more predictive than time to peak of the residue function and local arterial input function-based methods (P<0.05), but not significantly better than conventional mean transit time maps. CONCLUSIONS: Results indicated that if a single map type was to be used to predict infarction, first moment maps performed at least as well as deconvolved measures. Deconvolution decouples delay from tissue perfusion; we speculate this negatively impacts infarct prediction.

Interrater agreement for final infarct MRI lesion delineation.

BACKGROUND AND PURPOSE: Lesion volume measured on follow-up magnetic resonance imaging (MRI) is commonly used as an outcome parameter in clinical stroke trials. However, few studies have evaluated the optimal sequence choice and the interrater reliability of this outcome measure. The objective of this study was to quantify the geometric interrater agreement for lesion delineation of chronic infarcts on T2-weighted and fluid-attenuated inverse recovery (FLAIR) MRI. METHODS: In a retrospective study of 14 patients, lesions on 90-day follow-up FLAIR and T2 fast spin echo MRI were outlined by 9 independent, blinded, experienced neuroradiologists. Voxel-wise interrater agreement was measured as (1) the volume of the intersection of individual rater's lesion outlines relative to the mean lesion volume (overlap ratio) and (2) the Hausdorff distance between the lesion markings. RESULTS: Mean patient age was 64.4 years (range, 45 to 79). Lesion volumes on FLAIR were, on average, 2.5 mL greater than were T2 volumes (median; P<0.001). We found considerable differences between raters' lesion markings, but interrater agreement was consistently better on FLAIR than on T2 images, as measured by a greater overlap ratio (P<0.0001) and a smaller Hausdorff distance (P<0.0001) on FLAIR than on T2. CONCLUSIONS: FLAIR should be used to quantify follow-up infarct size to minimize interrater variability. Our study suggests that imaging analysis performed by 1 or a few trained readers may be preferred. Future studies should address objective and preferably automated criteria for final lesion delineation.