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.

Outcomes Following Adherence to a Randomized Stroke Trial Protocol.

This secondary analysis of a randomized clinical trial assesses whether compliance with the study protocol is associated with a better functional outcome even among participants in the sham-control group.

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.

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.

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.

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.

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.

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.

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.

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.

Effects of centralizing acute stroke services: A prospective cohort study.

OBJECTIVE: To investigate the effects of centralizing the acute stroke services in the Central Denmark Region (CDR). METHODS: The CDR (1.3 million inhabitants) centralized acute stroke care from 6 to 2 designated acute stroke units with 7-day outpatient clinics. We performed a prospective "before-and-after" cohort study comparing all strokes from the CDR with strokes in the rest of Denmark to discover underlying general trends, adopting a difference-in-differences approach. The population comprised 22,141 stroke cases hospitalized from May 2011 to April 2012 and May 2013 to April 2014. RESULTS: Centralization was associated with a significant reduction in length of acute hospital stay from a median of 5 to 2 days with a length-of-stay ratio of 0.53 (95% confidence interval 0.38-0.75, data adjusted) with no corresponding change seen in the rest of Denmark. Similarly, centralization led to a significant increase in strokes with same-day admission (mainly outpatients), whereas this remained unchanged in the rest of Denmark. We observed a significant improvement in quality of care captured in 11 process performance measures in both the CDR and the rest of Denmark. Centralization was associated with a nonsignificant increase in thrombolysis rate. We observed a slight increase in readmissions at day 30, but this was not significantly different from the general trend. Mortality at days 30 and 365 remained unchanged, as in the rest of Denmark. CONCLUSIONS: Centralizing acute stroke care in the CDR significantly reduced the length of acute hospital stay without compromising quality. Readmissions and mortality stayed comparable to the rest of Denmark.

Transit time homogenization in ischemic stroke - A novel biomarker of penumbral microvascular failure?

Cerebral ischemia causes widespread capillary no-flow in animal studies. The extent of microvascular impairment in human stroke, however, is unclear. We examined how acute intra-voxel transit time characteristics and subsequent recanalization affect tissue outcome on follow-up MRI in a historic cohort of 126 acute ischemic stroke patients. Based on perfusion-weighted MRI data, we characterized voxel-wise transit times in terms of their mean transit time (MTT), standard deviation (capillary transit time heterogeneity - CTH), and the CTH:MTT ratio (relative transit time heterogeneity), which is expected to remain constant during changes in perfusion pressure in a microvasculature consisting of passive, compliant vessels. To aid data interpretation, we also developed a computational model that relates graded microvascular failure to changes in these parameters. In perfusion-diffusion mismatch tissue, prolonged mean transit time (>5 seconds) and very low cerebral blood flow (≤6 mL/100 mL/min) was associated with high risk of infarction, largely independent of recanalization status. In the remaining mismatch region, low relative transit time heterogeneity predicted subsequent infarction if recanalization was not achieved. Our model suggested that transit time homogenization represents capillary no-flow. Consistent with this notion, low relative transit time heterogeneity values were associated with lower cerebral blood volume. We speculate that low RTH may represent a novel biomarker of penumbral microvascular failure.

[Dissection of the cervical arteries]. / Dissektion af halskar.

Dissection of the cervical arteries is an important cause of stroke in young adults. A haematoma in the wall of the cervical vessel leads to stenosis or occlusion and thereby risk of stroke. The most frequent local symptoms in carotid-artery dissection are head- and neck pain accompanied by Horner's syndrome, while typical symptoms in vertebral-artery dissection are pain in the back of the neck and head. The mural haematoma is best visualized by magnetic resonance imaging. Antithrombotic versus anticoagulation treatment to prevent stroke have recently shown to be equally effective.

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.

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.

Sequential MR Assessment of the Susceptibility Vessel Sign and Arterial Occlusion in Acute Stroke.

PURPOSE: Susceptibility vessel sign (SVS) may likely influence recanalization after thrombolysis. We assessed, through the European sequential MRI database "I-KNOW," the relationship between the presence of SVS on T2-weighted gradient echo imaging, its angiographic counterpart on magnetic resonance angiography and its subsequent impact on recanalization after thrombolysis. MATERIALS AND METHODS: Initial clinical and MRI characteristics and early follow up were analyzed in acute ischemic stroke patients treated with rt-Pa within 4.5 hours. Patients underwent multimodal MRI at admission. Sequential imaging performed 3 hours, 2 days and 1 month later allowed the analysis of SVS changes and recanalization. RESULTS: Fifty patients were included in the study. SVS was observed in 54% of cases at admission. SVS was still present in 46% patients at 3 hours, 16% at 2 days, and 0% at 1 month. It was an independent predictor of no recanalization after thrombolysis (P = .04). After 3 hours, SVS disappeared in only 4 cases, and was not linked with recanalization on MRA. Conversely, when SVS persisted, a partial or complete recanalization was observed in 9 and 6 cases, respectively. CONCLUSIONS: SVS is a predictor of lower recanalization rate. Its disappearance is not necessarily correlated with recanalization.

Theophylline as an add-on to thrombolytic therapy in acute ischaemic stroke (TEA-Stroke): A randomized, double-blinded, placebo-controlled, two-centre phase II study.

INTRODUCTION: Early reperfusion of brain tissue at risk of injury (penumbra salvage) is crucial in treating acute ischaemic stroke. Neuroprotective agents may extend the time window for the reperfusion. The vasoactive agent theophylline redistributes the perfusion to ischaemic brain tissue and thus reduces brain damage, brain tissue oedema and mortality in animal stroke models. Furthermore, treatment with theophylline has been shown to result in considerable and rapid clinical improvement, albeit only temporary, in some stroke patients.We hypothesize that treatment with theophylline will improve the collateral supply in acute ischaemic brain tissue and thus facilitate reperfusion despite proximal vessel occlusion. The primary study objective is to evaluate whether theophylline is safe and efficient in acute ischaemic stroke patients as an add-on to thrombolytic therapy. METHODS: The TEA-Stroke Trial is a two-centre, proof of concept phase II clinical study with a randomized, double-blinded, placebo-controlled design. One hundred and twenty patients with acute ischaemic stroke and significant perfusion-diffusion mismatch, as determined by magnetic resonance imaging, are randomized 1:1 to either theophylline or placebo as an add-on to standard thrombolytic therapy. STUDY OUTCOME: The dual primary outcome measures include penumbra salvage (penumbral tissue not developing into infarcted tissue) and clinical improvement at the 24-h follow-up. DISCUSSION: Results from studies of theophylline in stroke animal models, clinical case series and randomized clinical trials are controversial. A Cochrane analysis from 2004 concluded that there was not enough evidence to assess whether theophylline is safe and improves outcomes in patients with acute ischaemic stroke. The TEA-Stroke Trial will clarify whether theophylline as an add-on to standard thrombolytic therapy improves penumbra salvage with a reduced risk of reperfusion damage, reduced final infarct size, and improved clinical outcome.

Endovascular Treatment of Basilar Artery Thrombosis Secondary to Bilateral Vertebral Artery Dissection with Symptom Onset Following Cervical Spine Manipulation Therapy.

BACKGROUND: Vertebral artery (VA) dissection (VAD) has been described following neck injury and can be associated with stroke, but the causal association with cervical spine manipulation therapy (cSMT) is controversial. The standard treatment for VAD is antithrombotic medical therapy. To highlight the considerations of an endovascular approach to VAD, we present a critical case of bilateral VAD causing embolic occlusion of the basilar artery (BA) in a patient with symptom debut following cSMT. CASE REPORT: A 37-year-old woman presented with acute onset of neurological symptoms immediately following cSMT in a chiropractic facility. Acute magnetic resonance imaging (MRI) showed ischemic lesions in the right cerebellar hemisphere and occlusion of the cranial part of the BA. Angiography depicted bilateral VAD. Symptoms remitted after endovascular therapy, which included dilatation of the left VA and extraction of thrombus from the BA. After 6 months, the patient had minor sensory and cognitive deficits. CONCLUSIONS: In severe cases, VAD may be complicated by BA thrombosis, and this case highlights the importance of a fast diagnostic approach and advanced intravascular procedure to obtain good long-term neurological outcome. Furthermore, this case underlines the need to suspect VAD in patients presenting with neurological symptoms following cSMT.

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.