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Several brain imaging markers have been studied in the development of post-stroke depression (PSD) and post-stroke apathy (PSA), but inconsistent associations have been reported. This systematic review and meta-analysis aims to provide a comprehensive and up-to-date evaluation of imaging markers associated with PSD and PSA. Databases (Medline, Embase, PsycINFO, CINAHL, and Cochrane Database of Systematic Reviews) were searched from inception to July 21, 2016. Observational studies describing imaging markers of PSD and PSA were included. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to examine the association between PSD or PSA and stroke lesion laterality, type, and location, also stratified by study phase (acute, post-acute, chronic). Other imaging markers were reviewed qualitatively. The search retrieved 4502 studies, of which 149 studies were included in the review and 86 studies in the meta-analyses. PSD in the post-acute stroke phase was significantly associated with frontal (OR 1.72, 95% CI 1.34-2.19) and basal ganglia lesions (OR 2.25, 95% CI 1.33-3.84). Hemorrhagic stroke related to higher odds for PSA in the acute phase (OR 2.58, 95% CI 1.18-5.65), whereas ischemic stroke related to higher odds for PSA in the post-acute phase (OR 0.20, 95% CI 0.06-0.69). Frequency of PSD and PSA is modestly associated with stroke type and location and is dependent on stroke phase. These findings have to be taken into consideration for stroke rehabilitation programs, as this could prevent stroke patients from developing PSD and PSA, resulting in better clinical outcome.

Several brain imaging markers have been studied in the development of post-stroke depression (PSD) and post-stroke apathy (PSA), but inconsistent associations have been reported. This systematic review and meta-analysis aims to provide a comprehensive and up-to-date evaluation of imaging markers associated with PSD and PSA. Databases (Medline, Embase, PsycINFO, CINAHL, and Cochrane Database of Systematic Reviews) were searched from inception to July 21, 2016. Observational studies describing imaging markers of PSD and PSA were included. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to examine the association between PSD or PSA and stroke lesion laterality, type, and location, also stratified by study phase (acute, post-acute, chronic). Other imaging markers were reviewed qualitatively. The search retrieved 4502 studies, of which 149 studies were included in the review and 86 studies in the meta-analyses. PSD in the post-acute stroke phase was significantly associated with frontal (OR 1.72, 95% CI 1.34–2.19) and basal ganglia lesions (OR 2.25, 95% CI 1.33–3.84). Hemorrhagic stroke related to higher odds for PSA in the acute phase (OR 2.58, 95% CI 1.18–5.65), whereas ischemic stroke related to higher odds for PSA in the post-acute phase (OR 0.20, 95% CI 0.06–0.69). Frequency of PSD and PSA is modestly associated with stroke type and location and is dependent on stroke phase. These findings have to be taken into consideration for stroke rehabilitation programs, as this could prevent stroke patients from developing PSD and PSA, resulting in better clinical outcome. Electronic supplementary material The online version of this article (doi:10.1007/s11065-017-9356-2) contains supplementary material, which is available to authorized users.

Background and Purpose— Increasing thrombus length (TL) impedes recanalization after intravenous (IV) thrombolysis. We sought to determine whether the clinical benefit of aspiration thrombectomy relative to IV r-tPA (recombinant tissue-type plasminogen activator) may be greater at longer TL. Methods— THERAPY was a randomized trial of aspiration thrombectomy plus IV r-tPA versus IV r-tPA alone in large-vessel stroke patients with prospective TL measurement ≥8 mm. In this post hoc study, we evaluated the association of TL with trial end points and potential endovascular treatment effect, using univariate, multivariable, and multiplicative interaction analyses. Results— TL data were available for all 108 patients (28% internal carotid artery, 62% M1, and 10% M2). Median TL was 14.0 mm (interquartile range, 9.7–19.5 mm). Longer TL was associated with worse outcome (90-day modified Rankin Scale score: odds ratio, 1.24 per 5-mm TL increment; 95% confidence interval, 1.04–1.52; P =0.02), even after adjusting for key outcome predictors (adjusted P =0.004). Longer TL was also associated with more serious adverse events (adjusted P =0.01), more symptomatic hemorrhages (adjusted P =0.03), and increased mortality (adjusted P =0.01). No significant relationship was observed between TL and angiographic reperfusion (modified thrombolysis in cerebral ischemia 2b-3), but greater TL was associated with longer endovascular procedural times (ρ=0.36; P =0.045). Increasing TL was associated with greater aspiration thrombectomy treatment effect (interaction term P =0.03). This might be related to a potentially stronger adverse effect of increasing TL on 90-day modified Rankin Scale for patients treated with IV r-tPA (ρ=0.39; P =0.01) compared with intra-arterial therapy (ρ=0.20; P =0.165). Conclusions— Ischemic stroke patients with longer symptomatic thrombi have worse 90-day clinical outcomes but may have a greater relative benefit of aspiration thrombectomy over IV r-tPA alone. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01429350.

Background and Purpose— Identification of salvageable penumbra tissue by dynamic susceptibility contrast magnetic resonance imaging is a valuable tool for acute stroke patient stratification for treatment. However, prior studies have not attempted to combine the different perfusion maps into a predictive model. In this study, we established a multiparametric perfusion imaging model and cross-validated it using positron emission tomography perfusion for detection of penumbral flow. Methods— In a retrospective analysis of 17 subacute stroke patients with consecutive magnetic resonance imaging and H2O15 positron emission tomography scans, perfusion maps of cerebral blood flow, cerebral blood volume, mean transit time, time-to-maximum, and time-to-peak were constructed and combined using a generalized linear model (GLM). Both the GLM maps and the single perfusion maps alone were cross-validated with positron emission tomography-cerebral blood flow scans to predict penumbral flow on a voxel-wise level. Performance was tested by receiver-operating characteristics curve analysis, that is, the area under the curve, and the models’ fits were compared using the likelihood ratio test. Results— The GLM demonstrated significantly improved model fit compared with each of the single perfusion maps ( P Conclusions— Our results support a dynamic susceptibility contrast magnetic resonance imaging–based GLM as an improved model for penumbral flow prediction in stroke patients. With given perfusion maps, this model is a straightforward and observer-independent alternative for therapy stratification.

The theory that oxidative stress (OS) is at the root of several diseases is extremely popular. However, so far, no antioxidant has been recommended or offered by healthcare systems neither has any been approved as therapy by regulatory agencies that base their decisions on evidence-based medicine. This is simply because, so far, despite many preclinical and clinical studies indicating a beneficial effect of antioxidants in many disease conditions, randomised clinical trials have failed to provide the evidence of efficacy required for drug approval. In this review, we discuss the levels of evidence required to claim causality in preclinical research on OS, the weakness of the oversimplification associated with OS theory of disease and the importance of the narrative in its popularity. Finally, from a more translational perspective, we discuss the reasons why antioxidants acting by scavenging ROS might not only prevent their detrimental effects but also interfere with essential signalling roles. We propose that ROS have a complex metabolism and are generated by different enzymes at diverse sites and at different times. Aggregating this plurality of systems into a single theory of disease may not be the best way to develop new drugs, and future research may need to focus on specific oxygen-toxifying pathways rather than on non-specific ROS scavengers. Finally, similarly to what is nowadays required for clinical trials, we recommend making unpublished data available in repositories (open data), as this will allow big data approaches or meta-analyses, without the drawbacks of publication bias.

Introduction: In WAKE-UP (Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke), patients with an acute stroke of unknown onset time were randomized to treatment with intravenous alteplase or placebo, guided by MRI. Methods: In this exploratory post-hoc secondary analysis we compared clinical and imaging data, as well as treatment effects and safety of intravenous thrombolysis between patients with infra- vs. supratentorial stroke. Results: Forty-eight out of 503 randomized patients (9.5%) presented with a stroke involving the cerebellum or brainstem. Patients with infratentorial stroke were younger compared to patients with supratentorial stroke (mean age 60 vs. 66 years), more frequently male (85 vs. 62%), and less severely affected (median NIHSS 4.5 vs. 6.0). There was no heterogeneity for treatment effect between supratentorial (OR 1.67 95% CI 1.11-2.51) and infratentorial (OR 1.31 95% CI 0.41-4.22) sub-groups (test for interaction p = 0.70). In patients with infratentorial stroke, favorable outcome [a score of 0-1 on the modified Rankin scale (mRS) at 90 days] was observed in 12/22 patients (54.5%) in the alteplase group and in 13/25 patients (52.0%) in the placebo group (p = 0.59). The primary safety endpoint (death or mRS 4-6 at day 90) occurred in three patients of the alteplase group (13.6%) and three patients in the placebo group (12.0%); p = 0.74. Discussion: WAKE-UP was underpowered for demonstrating treatment effect in subgroup analyses however, based on our current results, there is no evidence to recommend withholding MRI-guided thrombolysis in patients with unknown onset stroke of infratentorial localization. ispartof: FRONTIERS IN NEUROLOGY vol:10 ispartof: location:Switzerland status: published

Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy.Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05).Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision.Funding: British Heart Foundation.

BACKGROUND AND PURPOSE: Direct aspiration is a recognized technique for revascularization in large-vessel ischemic strokes. There is ongoing debate regarding its efficacy compared with stent retrievers. Every delay in achieving revascularization and a decrease in reperfusion rates reduces the likelihood of patients achieving functional independence. We propose a standardized setup technique for aspiration-first for all anterior circulation thrombectomy procedures for increasing speed and recanalization rates. MATERIALS AND METHODS: We analyzed 127 consecutive patients treated by a standardized approach to thrombectomy with an intention to perform aspiration-first compared with 127 consecutive patients treated with a stent retriever–first approach. Key time metrics evaluated included groin to first angiogram, first angiogram to reperfusion, groin to first reperfusion, and length of the procedure. The degree of successful recanalization (TICI 2b–3) and the number of passes were compared between the 2 groups. RESULTS: In 127 patients who underwent the standardized technique, the median time from groin puncture to first reperfusion was 18 minutes compared with 26 minutes (P < .001). The duration of the procedure was shorter compared with the stent retriever group (26 minutes in the aspiration first group versus 47 minutes, P < .001) and required fewer passes (mean, 2.4 versus 3.1; P < .05). A higher proportion of patients had a TICI score of 2b–3 in the aspiration-first group compared with stent retriever group (96.1% versus 85.8%, P < .005). CONCLUSIONS: Our study highlights the increasing speed and recanalization rates achieved with fewer passes in a standardized approach to thrombectomy with an intention to attempt aspiration-first. Any attempt to reduce revascularization time and increase successful recanalization should be used.

Markku Kaste tutkimusryhmän jäsenenä Background Stroke thrombolysis with alteplase is currently recommended 0-4.5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4.5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis. Methods In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials. gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged =18 years) with ischaemic stroke treated more than 4.5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. Findings We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1.86, 95% CI 1.15-2.99, p=0.011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [

Importance: The rationale for intravenous thrombolysis in patients with lacunar infarcts is debated, since it is hypothesized that the microvascular occlusion underlying lacunar infarcts might not be susceptible to pharmacological reperfusion treatment.Objective: To study the efficacy and safety of intravenous thrombolysis among patients with lacunar infarcts.Design, Setting, and Participants: This exploratory secondary post hoc analysis of the WAKE-UP trial included patients who were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). The WAKE-UP trial was a multicenter, double-blind, placebo-controlled randomized clinical trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time, guided by magnetic resonance imaging. All 503 patients randomized in the WAKE-UP trial were reviewed for lacunar infarcts. Diagnosis of lacunar infarcts was based on magnetic resonance imaging and made by consensus of 2 independent investigators blinded to clinical information.Main Outcomes and Measures: The primary efficacy variable was favorable outcome defined by a score of 0 to 1 on the modified Rankin Scale at 90 days after stroke, adjusted for age and severity of symptoms.Results: Of the 503 patients randomized in the WAKE-UP trial, 108 patients (including 74 men [68.5%]) had imaging-defined lacunar infarcts, whereas 395 patients (including 251 men [63.5%]) had nonlacunar infarcts. Patients with lacunar infarcts were younger than patients with nonlacunar infarcts (mean age [SD], 63 [12] years vs 66 [12] years; P = .003). Of patients with lacunar infarcts, 55 (50.9%) were assigned to treatment with alteplase and 53 (49.1%) to receive placebo. Treatment with alteplase was associated with higher odds of favorable outcome, with no heterogeneity of treatment outcome between lacunar and nonlacunar stroke subtypes. In patients with lacunar strokes, a favorable outcome was observed in 31 of 53 patients (59%) in the alteplase group compared with 24 of 52 patients (46%) in the placebo group (adjusted odds ratio [aOR], 1.67 [95% CI, 0.77-3.64]). There was 1 death and 1 symptomatic intracranial hemorrhage according to Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria in the alteplase group, while no death and no symptomatic intracranial hemorrhage occurred in the placebo group. The distribution of the modified Rankin Scale scores 90 days after stroke also showed a nonsignificant shift toward better outcomes in patients with lacunar infarcts treated with alteplase, with an adjusted common odds ratio of 1.94 (95% CI, 0.95-3.93).Conclusions and Relevance: While the WAKE-UP trial was not powered to demonstrate the efficacy of treatment in subgroups of patients, the results indicate that the association of intravenous alteplase with functional outcome does not differ in patients with imaging-defined lacunar infarcts compared with those experiencing other stroke subtypes.

Cerebrovascular disease involves various medical disorders that obstruct brain blood vessels or deteriorate cerebral circulation, resulting in ischemic or hemorrhagic stroke. Nowadays, platinum coils with or without biological modification have become routine embolization devices to reduce the risk of cerebral aneurysm bleeding. Additionally, many intracranial stents, flow diverters, and stent retrievers have been invented with uniquely designed structures. To accelerate the translation of these devices into clinical usage, an in‐depth understanding of the mechanical and material performance of these metal‐based devices is critical. However, considering the more distal location and tortuous anatomic characteristics of cerebral arteries, present devices still risk failing to arrive at target lesions. Consequently, more flexible endovascular devices and novel designs are under urgent demand to overcome the deficiencies of existing devices. Herein, the pros and cons of the current structural designs are discussed when these devices are applied to the treatment of diseases ranging broadly from hemorrhages to ischemic strokes, in order to encourage further development of such kind of devices and investigation of their use in the clinic. Moreover, novel biodegradable materials and drug elution techniques, and the design, safety, and efficacy of personalized devices for further clinical applications in cerebral vasculature are discussed.

Background Postoperative stroke is a severe complication with a reported 30-day incidence of 0.4%-0.6% after total hip (THA) and knee arthroplasty (TKA). However, most data are based on diagnostic codes and with limited details on perioperative care, including the use of fast-track protocols. We investigated the incidence of and preoperative and postoperative factors for stroke after fast-track THA/TKA. Methods We used an observational study design of elective fast-track THA/TKA patients with prospective collection of comorbidity and complete 90-day follow-up. Medical records were evaluated for events potentially disposing to stroke. Identification of relevant preoperative risk factors was done by multivariable logistic regression. Incidence of stroke was compared with a Danish background population. Results Of 24,862 procedures with a median length of stay of 2 (interquartile range, 2-3) days, we found 27 (0.11%; 95% confidence interval [CI], 0.08%-0.16%) and 43 strokes (0.17%, 95% CI, 0.13%-0.23%) ≤30 and ≤90 days after surgery, respectively. Preoperative risk factors for stroke ≤30 days were age ≥ 85 years (odds ratio [OR], 4.3; 95% CI, 1.1-16.3) and anticoagulant treatment (OR, 3.1; 95% CI, 1.2-7.9). Preoperative anemia was near significant (OR, 2.1; 95% CI, 0.98-4.6, P = .055). Eight strokes ≤30 days were preceded by a cardiovascular event within the second postoperative day. Incidence of stroke after postoperative day 30 was similar to a Danish background population. Conclusion Risk of postoperative stroke in fast-track THA and TKA was low but may be further reduced with increased focus on avoiding perioperative cardiovascular events and in patients with preoperative anticoagulants or anemia.

Introduction: Carotid artery dissection (CAD) and atherosclerotic carotid artery occlusion (ACAO) are major causes of a tandem occlusion in patients with intracranial large vessel occlusion (LVO). Presence of tandem occlusions may hamper intracranial access and potentially increases the risk of procedural complications of endovascular treatment (EVT). Our aim was to assess neurological, functional and technical outcome and complications of EVT for intracranial LVO in patients with CAD in comparison to patients with ACAO and to patients without CAD or ACAO.Methods: We analyzed data of the MR CLEAN trial intervention arm and MR CLEAN Registry, acquired in 16 Dutch EVT-centers. Primary outcome was the change in stroke severity by comparing the National Institute of Health Stroke Scale (NIHSS) score at 24-48 h after treatment vs. baseline. Secondary outcomes included reperfusion rate and symptomatic intracranial hemorrhage (sICH). We compared outcomes and complications between patients with CAD vs. patients with ACAO and patients without CAD or ACAO.Results: In total, we identified 74 (4.7%) patients with CAD, 92 (5.9%) patients with ACAO and 1398 (89.4%) patients without CAD or ACAO. Neurological improvement at short-term after EVT in patients with CAD was significantly better compared to ACAO (raw mean -5 vs. mean -1 NIHSS point; p = 0.03) and did not differ compared to patients without CAD or ACAO (-4 NIHSS points; p = 0.62). Rates of successful reperfusion in patients with CAD (47%) was comparable to patients with ACAO (47%; p = 1.00), but was less often achieved compared to patients without CAD or ACAO (58%; p = 0.08). Occurrence of sICH did not differ significantly between CAD patients (5%) and ACAO (11%; p = 0.33) or without CAD/ACAO (6%; p = 1.00).Conclusion: EVT in patients with intracranial LVO due to CAD results in neurological improvement comparable to patients without tandem occlusions. Therefore, carotid artery dissection by itself should not be a contraindication for endovascular treatment in stroke patients with intracranial large vessel occlusion. Although more challenging endovascular procedures are to be suspected in both patients with CAD or ACAO, accurate distinction between CAD and ACAO might influence clinical decision making as better clinical outcome can be expected in patients with CAD.

Background and Purpose— Previous studies suggest that intracranial carotid artery calcification (ICAC) volume might influence the clinical outcome of patients after endovascular treatment (EVT) for acute ischemic stroke. Importantly, ICAC can be subtyped into a medial or intimal pattern that may differentially influence the effect of EVT in patients with acute ischemic stroke. Methods— All 500 patients included in the MR CLEAN (Multicenter Randomized Clinical trial of Endovascular treatment for acute ischemic stroke in the Netherlands) were evaluated. Volume (mm 3 ) and location pattern (tunica intima or tunica media) of ICAC could be determined on baseline noncontrast computed tomography in 344 patients. Functional outcome at 90 days was assessed with the modified Rankin Scale. Next, we investigated the association of ICAC volume and pattern with functional outcome using adjusted ordinal logistic regression models. Effect modification by EVT was assessed with an interaction term between treatment allocation and ICAC aspect. Results— We found evidence for treatment effect modification by ICAC pattern ( P interaction=0.04). Patients with predominantly medial calcification had better functional outcome with EVT than without this treatment (adjusted common odds ratio, 2.32; 95% CI, 1.23–4.39), but we observed no effect of EVT in patients with predominantly intimal calcifications (adjusted common odds ratio, 0.82; 95% CI, 0.40–1.68). We did not find an association of ICAC volume with functional outcome (adjusted common odds ratio per unit increase ICAC volume 1.01 (95% CI, 0.89–1.13). Moreover, we found no evidence for effect modification by ICAC volume ( P interaction=0.61). Conclusions— The benefit of EVT in acute ischemic stroke patients with a medial calcification pattern is larger than the benefit in patients with an intimal calcification pattern. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR1804. URL: http://www.isrctn.com . Unique identifier: ISRCTN10888758.

Background and Purpose— We compared outcome and complications in patients with stroke treated with intravenous thrombolysis (IVT) who could not live alone without help of another person before stroke (dependent patients) versus independent ones. Methods— In a multicenter IVT-register–based cohort study, we compared previously dependent (prestroke modified Rankin Scale score, 3–5) versus independent (prestroke modified Rankin Scale score, 0–2) patients. Outcome measures were poor 3-month outcome (not reaching at least prestroke modified Rankin Scale [dependent patients]; modified Rankin Scale score of 3–6 [independent patients]), death, and symptomatic intracranial hemorrhage. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (OR [95% confidence interval]) were calculated. Results— Among 7430 IVT-treated patients, 489 (6.6%) were dependent and 6941 (93.4%) were independent. Previous stroke, dementia, heart, and bone diseases were the most common causes of preexisting dependency. Dependent patients were more likely to die (OR unadjusted , 4.55 [3.74–5.53]; OR adjusted , 2.19 [1.70–2.84]). Symptomatic intracranial hemorrhage occurred equally frequent (4.8% versus 4.5%). Poor outcome was more frequent in dependent (60.5%) than in independent (39.6%) patients, but the adjusted ORs were similar (OR adjusted , 0.95 [0.75–1.21]). Among survivors, the proportion of patients with poor outcome did not differ (35.7% versus 31.3%). After adjustment for age and stroke severity, the odds of poor outcome were lower in dependent patients (OR adjusted , 0.64 [0.49–0.84]). Conclusions— IVT-treated stroke patients who were dependent on the daily help of others before stroke carry a higher mortality risk than previously independent patients. The risk of symptomatic intracranial hemorrhage and the likelihood of poor outcome were not independently influenced by previous dependency. Among survivors, poor outcome was avoided at least as effectively in previously dependent patients. Thus, withholding IVT in previously dependent patients might not be justified.

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.

Background and Purpose: Hypertensive vasculopathy and cerebral amyloid angiopathy are the two most common forms of cerebral small vessel disease. Both forms are associated with the development of primary intracerebral hemorrhage, but the pathophysiological mechanisms underlying spontaneous vessel rupture remain unknown. This work constitutes a systematic review on blood-brain barrier dysfunction in the etiology of spontaneous intracerebral hemorrhage due to cerebral small vessel disease.Methods: We searched Medline (1946-2018) and Embase (1974-2018) for animal and human studies reporting on blood-brain barrier dysfunction associated with intracerebral hemorrhage or cerebral microbleeds.Results: Of 26 eligible studies, 10 were animal studies and 16 were in humans. The authors found indications for blood-brain barrier dysfunction in all four animal studies addressing hypertensive vasculopathy-related intracerebral hemorrhage (n = 32 hypertensive animals included in all four studies combined), and in four of six studies on cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 47). Of the studies in humans, five of six studies in patients with cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 117) and seven out of nine studies examining intracerebral hemorrhage with mixed or unspecified underlying etiology (n = 489) found indications for blood-brain barrier dysfunction. One post-mortem study in hypertensive vasculopathy-related intracerebral hemorrhage (n = 82) found no evidence for blood-brain barrier abnormalities.Conclusions: Signs of blood-brain barrier dysfunction were found in 20 out of 26 studies. Blood-brain barrier integrity deserves further investigation with a view to identification of potential treatment targets for spontaneous intracerebral hemorrhage.

Background and Purpose— Prestroke dependence is an exclusion criterion in most trials of endovascular treatment (EVT) for acute ischemic stroke. Little is known about outcomes after EVT in these patients. We compared outcome and safety of EVT between prestroke-dependent and prestroke-independent patients. Methods— We report patients with an anterior circulation occlusion who were included between March 2014 and June 2016 in the MR CLEAN registry (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke)—a prospective, multicenter, observational study for stroke intervention centers in the Netherlands. Prestroke dependence was defined as modified Rankin Scale score of 3 to 5 before onset of current stroke. Primary outcome was favorable outcome at 90 days, defined as modified Rankin Scale of 0 to 2 or not worsening of the modified Rankin Scale score. Secondary outcomes included National Institutes of Health Stroke Scale score post-intervention, reperfusion grade, and safety outcomes. Logistic regression analyses (adjusted for age, baseline National Institutes of Health Stroke Scale score, collaterals, time to EVT, and intravenous thrombolysis before EVT) were used to assess the association between prestroke dependence and outcomes. Results— One thousand four hundred forty-one patients were included in the present study, of whom 157 (11%) were prestroke dependent. Favorable outcome was seen in 27% prestroke-dependent patients, compared with 42% prestroke-independent patients ( P adjusted , 0.90; 95% CI, 0.58–1.39). The occurrence of symptomatic intracranial hemorrhage and ischemic stroke progression was similar in both groups. Conclusions— A substantial proportion of prestroke-dependent patients will reach prestroke modified Rankin Scale scores after EVT, and complication rates are comparable with prestroke-independent patients. Therefore, prestroke-dependent patients should not be routinely excluded from EVT.

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Objective— Cardiovascular disease, including coronary artery disease (CAD) and ischemic stroke, is the leading cause of death worldwide. This Mendelian randomization study uses genetic variants as instruments to investigate whether there is a causal effect of genetically determined platelet count on CAD and ischemic stroke risk. Approach and Results— A genome-wide association study of 166 066 subjects was used to identify instruments and genetic association estimates for platelet count. Genetic association estimates for CAD and ischemic stroke were obtained from genome-wide association studies, including 60 801 CAD cases and 123 504 controls, and 60 341 ischemic stroke cases and 454 450 controls, respectively. The inverse-variance weighted meta-analysis of ratio method Mendelian randomization estimates was the main method used to obtain estimates for the causal effect of genetically determined platelet count on risk of cardiovascular outcomes. We found no significant Mendelian randomization effect of genetically determined platelet count on risk of CAD (odds ratio of CAD per SD unit increase in genetically determined platelet count, 1.01; 95% CI, 0.98–1.04; P =0.60). However, higher genetically determined platelet count was causally associated with an increased risk of ischemic stroke (odds ratio, 1.07; 95% CI, 1.04–1.11; P −5 ), including all major ischemic stroke subtypes. Similar results were obtained in sensitivity analyses more robust to the inclusion of pleiotropic genetic variants. Conclusions— This Mendelian randomization study found evidence that higher genetically determined platelet count is causally associated with higher risk of ischemic stroke.

Background and Purpose— Carotid endarterectomy (CEA) is recommended within 14 days after carotid artery stroke to prevent recurrence. However, the optimal timing of CEA after intravenous thrombolysis (IVT) remains unclear. We studied the safety of CEA after IVT while taking into account both stroke recurrence and CEA-related complications. Methods— Patients who underwent IVT followed by CEA in Helsinki University Hospital 2005 to 2016 were withdrawn from prospectively collected registers. The incidence of stroke recurrence during the time between IVT and CEA, peri/postoperative stroke, hyperperfusion syndrome or drug-resistant high blood pressure, and 3-month outcome measured by modified Rankin Scale was recorded. Stroke patients treated with CEA without preceding IVT were used as controls. Results— Altogether 128 CEAs with preceding IVT and 777 CEAs for stroke without IVT were identified. The median time from IVT to CEA was 9 days (range, 0–349 days; interquartile range, 16). Seven patients (5.5%) underwent CEA within 24 hours, 20 (15.6%) within 48 hours and 87 (68.0%) within 2 weeks from IVT. Stroke recurrence in IVT-CEA patients was 5.5% at median 4 days after IVT (range, 0–8 days). Outcome from CEAs performed within 48 hours from IVT did not differ from CEAs performed later with respect to peri/postoperative ischemic strokes (5.0% and 3.7%), hemorrhagic strokes (5.0% and 1.9%), neck hematomas (5.0% and 8.3%), myocardial infarctions (0.0% and 0.9%), or 3-month modified Rankin Scale. There was a tendency toward higher incidence of hyperperfusion syndrome in the patients operated within 48 hours from IVT (20.0% versus 6.5%; P =0.070). The CEA-related stroke rate was similar to that of the operation without thrombolysis. Only smoking was significantly associated with peri/postoperative stroke (odds ratio, 21.82; 95% confidence interval, 1.08–439.58). Conclusions— Time between IVT and CEA was not associated with CEA-related complications. The high rate of stroke recurrence during the waiting time for CEA underscores the importance of shortening surgery delays.

Background: Delayed hospital arrival remains the main reason for the low rates of thrombolysis in eligible acute ischemic stroke (AIS) patients. The role of socioeconomic and clinical factors for the prehospital delay of AIS remains poor and has never been studied in Portugal. Objectives: Describe the socioeconomic and clinical factors leading to delayed hospital admission of AIS patients eligible to thrombolysis. Methods: A case-control study with a consecutive thrombolyzed AIS patients from 2010 to 2015. Controls were patients who did not receive thrombolysis because of late hospital arrival. Logistic regression with stepwise forward regression analysis was used to identify independent predictors of delayed admission to receive thrombolysis with intravenous tissue-type plasminogen activator (rtPA). Results: Of the 1247 patients admitted with AIS, 76 (6%) arrived on-time and received intravenous rtPA. Controls were 65.8% (146/222) of the total number of patients included in the study. Overall, the mean age was 73 years (+/- 11, 61), a minority were below 60 years, and 43.7% were women. Being beneficiary of social insertion income (odds ratio [OR]: .286; .124-.662, P = .003), not having any telephone contact (OR: .145; .039-.536, .004) or having exclusive landline (.055; .014-.210, < .001) and posterior circulation stroke (OR: .266; .087-.811, P = .020) decreased the likelihood of hospital arrive on-time rtPA. The use of prehospital ambulance services increased (OR: 6.478; 2.751-15.254, P < .001) the odds of ER on-time arrival for thrombolysis. Conclusions: Poverty, lack of stroke awareness, or difficulties in requesting immediate medical help are the main factors implicated in late-hospital admission for thrombolysis in AIS. Stroke awareness campaigns, promotion of activation of national emergency number and stroke code can increase the rate of thrombolysis. info:eu-repo/semantics/publishedVersion

Electrical Impedance Tomography (EIT) is a non-invasive imaging technique, which has the potential to expedite the differentiation of ischaemic or haemorrhagic stroke, decreasing the time to treatment. Whilst demonstrated in simulation, there are currently no suitable imaging or classification methods which can be successfully applied to human stroke data. Development of these complex methods is hindered by a lack of quality Multi-Frequency EIT (MFEIT) data. To address this, MFEIT data were collected from 23 stroke patients, and 10 healthy volunteers, as part of a clinical trial in collaboration with the Hyper Acute Stroke Unit (HASU) at University College London Hospital (UCLH). Data were collected at 17 frequencies between 5 Hz and 2 kHz, with 31 current injections, yielding 930 measurements at each frequency. This dataset is the most comprehensive of its kind and enables combined analysis of MFEIT, Electroencephalography (EEG) and Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) data in stroke patients, which can form the basis of future research into stroke classification. Design Type(s) parallel group design • case control design Measurement Type(s) brain activity measurement • nuclear magnetic resonance assay • Computed Tomography of the Brain with Contrast Technology Type(s) electrical impedance tomography • MRI Scanner • computed tomography scanner Factor Type(s) diagnosis Sample Characteristic(s) Homo sapiens • brain

OBJECTIVE: According to level 2 evidence, earlier evacuation of acute subdural or epidural hematomas necessitating surgery is associated with better outcome. Hence, guidelines recommend performing these procedures immediately. Literature on the extent and causes of prehospital and intrahospital intervals in patients with trauma requiring emergent craniotomies is almost completely lacking. Studies delineating and refining the interval before thrombolytic agent administration in ischemic stroke have dramatically reduced the door-to-needle time. A similar exercise for trauma-to-decompression time might result in comparable reductions. We aim to map intervals in emergent trauma craniotomies in our level 1 trauma center, screen for associated factors, and propose possible ways to reduce these intervals. METHODS: We analyzed patients who were primarily referred (1R; n = 45) and secondarily referred (after computed tomography imaging in a community hospital [2R; n = 22]) to our emergency department (ED) and underwent emergent trauma craniotomies between 2010 and 2016. RESULTS: Median prehospital interval (between emergency call and arrival at the ED) was 42 minutes for 1R patients. Median intrahospital interval (between initial ED arrival and skin incision [SI]) was 140 minutes and 268 minutes for 1R and 2R patients, respectively. In 1R patients, ED-SI interval was positively correlated with Glasgow Coma Scale score (ρ=.49; P < 0.001), but not with age, time of ED arrival, or extended Glasgow Outcome Scale score at 6 months. Based on outlier analysis, we propose prehospital and intrahospital measures to improve performance. CONCLUSIONS: This is the first report on emergency call-SI interval in emergent trauma craniotomy, with a median of 174 minutes and >297 minutes for 1R and 2R patients, respectively, in our center. ispartof: WORLD NEUROSURGERY vol:114 pages:E546-E558 ispartof: location:United States status: published

Background: Christchurch hospital is a tertiary hospital in New Zealand supported by five general neurologists with after-hours services provided mainly by onsite non-neurology medical residents. We assessed the transferrability and impact of the Helsinki Stroke model on stroke thrombolysis door-to-needle time (DNT) in Christchurch hospital. Methods: Key components of the Helsinki Stroke model were implemented first in 2015 with introduction of patient pre-notification and thrombolysis by the computed tomography (CT) suite, followed by implementation of direct transfer to CT on ambulance stretcher in May 2017. Data from the prospective thrombolysis registry which began in 2012 were analyzed for the impact of these interventions on median DNT. Results: Between May and December 2017, 46 patients were treated with alteplase, 25 (54%) patients were treated in-hours (08:00-17:00 non-public holiday weekdays) and 21 (46%) patients were treated after-hours. The in-hours, after-hours, and overall median (interquartile range) DNTs were 34 (28-43), 47 (38-60), and 40 (30-51) minutes. The corresponding times in 2012-2014 prior to interventions were 87 (68-106), 86 (72-116), and 87 (71-112) minutes, representing median DNT reduction of 53, 39, and 47 minutes, respectively (p-values

Background Hyperglycaemia is a frequent complication in acute stroke that has been shown to be independently associated with larger infarct size, haematoma growth, poor clinical outcome and mortality. This Guideline Document presents the European Stroke Organisation (ESO) Guidelines for the management of blood glucose levels in patients with acute ischemic or haemorrhagic stroke. Methods The working group identified related questions and developed its recommendations based on evidence from randomised controlled trials following the standard operating procedure of the ESO. This Guideline Document was reviewed and approved by the European Stroke Organisation Guidelines Committee and the European Stroke Organisation Executive Committee. Results We found low-quality evidence from clinical trials in ischemic or haemorrhagic stroke exploring the use of intravenous insulin aimed to achieve a tight glycaemic control with different glucose level targets and several other sources of heterogeneity. None of these trials neither the meta-analysis of them have demonstrated any significant benefit of tight glycaemic control with intravenous insulin in acute ischemic or haemorrhagic stroke patients on functional outcome or in survival and they have shown an increased risk for hypoglycaemia. Conclusions We suggest against the routine use of tight glycaemic control with intravenous insulin as a means to improve outcomes. The currently available data about the management of glycaemia in patients with acute stroke are limited and the strengths of the recommendations are therefore weak. Nevertheless, this does not prevent that hyperglycaemia in acute stroke patients could be treated as any other hospitalised patient.

Atherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in)stability; proteomic and metabolomics data are to be added to genetic information. 2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; disease mechanism-based biomarkers need to be identified; experimental systems are needed that incorporate whole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation. 3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin–angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet–fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences. 4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis à vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time. 5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia–reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novel modified activated protein C–based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.

Purpose: To assess the degree of cortical vein opacification in patients with internal carotid artery or middle cerebral artery (MCA) stroke and to evaluate the relationship with treatment benefit from intra-arterial therapy (IAT). Materials and Methods: Written informed consent was obtained from all patients in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands. From the trial's database, all patients (recruited from December 2010 until March 2014) with baseline computed tomographic (CT) angiograms were retrospectively included. Enhancement of the vein of Labbe, sphenoparietal sinus, and superficial middle cerebral vein was graded by one neuroradiologist, as follows: 0, not visible; 1, moderate opacification; and 2, full opacification. The sum for the ipsilateral hemisphere was calculated, resulting in the cortical vein opacification score (COVES) (range, 0-6). Primary outcome was the modified Rankin Scale score at 90 days. Association with treatment according to full cortical vein score and different dichotomized cutoff points was estimated with ordinal logistic regression. Interobserver agreement was assessed by two separate observers who reviewed 100 studies each. Results: In total, 397 patients were analyzed. Interaction of the cortical vein score with treatment was significant (P = .044) when dichotomized COVES was 0 versus more than 0. The adjusted odds ratio for shift toward better functional outcome was 1.0 (95% confidence interval [CI]: 0.5, 2.0) for a COVES of 0 (n = 123) and 2.2 (95% CI: 1.6, 4.1) for a COVES greater than 0 (n = 274). The multirater kappa value was 0.73. Conclusion: In this study, patients with acute middle cerebral artery stroke with absence of cortical vein opacification in the affected hemisphere (COVES = 0) appeared to have no benefit from IAT, whereas patients with venous opacification (COVES >0) were shown to benefit from IAT. (C) RSNA, 2017

Background and Purpose— Thrombus characteristics and collateral score are associated with functional outcome in patients with acute ischemic stroke. It has been suggested that they affect each other. The aim of this study is to evaluate the association between clot burden score, thrombus perviousness, and collateral score and to determine whether collateral score influences the association of thrombus characteristics with functional outcome. Methods— Patients with baseline thin-slice noncontrast computed tomography and computed tomographic angiography images from the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands) were included (n=195). Collateral score and clot burden scores were determined on baseline computed tomographic angiography. Thrombus attenuation increase was determined by comparing thrombus density on noncontrast computed tomography and computed tomographic angiography using a semiautomated method. The association of collateral score with clot burden score and thrombus attenuation increase was evaluated with linear regression. Mediation and effect modification analyses were used to assess the influence of collateral score on the association of clot burden score and thrombus attenuation increase with functional outcome. Results— A higher clot burden score (B=0.063; 95% confidence interval, 0.008–0.118) and a higher thrombus attenuation increase (B=0.014; 95% confidence interval, 0.003–0.026) were associated with higher collateral score. Collateral score mediated the association of clot burden score with functional outcome. The association between thrombus attenuation increase and functional outcome was modified by the collateral score, and this association was stronger in patients with moderate and good collaterals. Conclusions— Patients with lower thrombus burden and higher thrombus perviousness scores had higher collateral score. The positive effect of thrombus perviousness on clinical outcome was only present in patients with moderate and high collateral scores. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR1804 and URL: http://www.controlled-trials.com Unique identifier: ISRCTN10888758.

Introduction Mechanical thrombectomy within 6 h after stroke onset improves the outcome in patients with large vessel occlusions. The aim of our study was to establish a model based on diffusion weighted and perfusion weighted imaging to provide an accurate prediction for the 6 h time-window in patients with unknown time of stroke onset. Patients and methods A predictive model was designed based on data from the DEFUSE 2 study and validated in a subgroup of patients with large vessel occlusions from the AXIS 2 trial. Results We constructed the model in 91 patients from DEFUSE 2. The following parameters were independently associated with Discussion After validation in a larger independent dataset the model can be considered to select patients for endovascular treatment in whom stroke onset is unknown. Conclusion In patients with large vessel occlusion and unknown time of stroke onset an automated multivariate imaging model is able to select patients who are likely within the 6 h time-window.

Background The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke differs between the Europe Union and United States. Aims We compared the effects of alteplase in cohorts defined by the current Europe Union or United States marketing approval labels, and by hypothetical revisions of the labels that would remove the Europe Union upper age limit or extend the United States treatment time window to 4.5h. Methods We assessed outcomes in an individual-patient-data meta-analysis of eight randomized trials of intravenous alteplase (0.9mg/kg) versus control for acute ischemic stroke. Outcomes included: excellent outcome (modified Rankin score 0-1) at 3-6 months, the distribution of modified Rankin score, symptomatic intracerebral hemorrhage, and 90-day mortality. Results Alteplase increased the odds of modified Rankin score 0-1 among 2449/6136 (40%) patients who met the current European Union label and 3491 (57%) patients who met the age-revised label (odds ratio 1.42, 95% CI 1.21-1.68 and 1.43, 1.23-1.65, respectively), but not in those outside the age-revised label (1.06, 0.90-1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76-1.25 and 1.01, 0.86-1.19, respectively) but mortality remained higher outside the age-revised label (1.19, 0.99-1.42). Similarly, alteplase increased the odds of modified Rankin score 0-1 among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-h revised approval (odds ratio 1.55, 1.19-2.01 and 1.37, 1.17-1.59, respectively), but not for those outside the 4.5-h revised approval (1.14, 0.97-1.34). By 90 days, no increased mortality remained for the current and 4.5-h revised label cohorts (hazard ratios 0.99, 0.77-1.26 and 1.02, 0.87-1.20, respectively) but mortality remained higher outside the 4.5-h revised approval (1.17, 0.98-1.41). Conclusions An age-revised European Union label or 4.5-h-revised United States label would each increase the number of patients deriving net benefit from alteplase by 90 days after acute ischemic stroke, without excess mortality.

Background Beta-blocker therapy has been suggested to have neuroprotective properties in the setting of acute stroke; however, the evidence is weak and contradictory. We aimed to examine the effects of pre-admission therapy with beta-blockers (BB) on the mortality following spontaneous intracerebral hemorrhage (ICH). Methods Retrospective analysis of the Helsinki ICH Study database. Results A total of 1013 patients with ICH were included in the analysis. Patients taking BB were significantly older, had a higher premorbid mRS score, had more DNR orders, and more comorbidities as atrial fibrillation, hypertension, diabetes mellitus, ischemic heart disease, and heart failure. After adjustment for age, pre-existing comorbidities, and prior use of antithrombotic and antihypertensive medications, no differences in in-hospital mortality (OR 1.1, 95% CI 0.8-1.7), 12-month mortality (OR 1.3, 95% CI 0.9-1.9), and 3-month mortality (OR 1.2, 95% CI 0.8-1.7) emerged. Conclusion Pre-admission use of BB was not associated with mortality after ICH.

Purpose To investigate the prevalence of symptomatic carotid web in patients with acute ischemic stroke due to intracranial large vessel occlusion, to determine the clinical and imaging profile of patients with carotid web as well as their association with ischemic stroke, and to determine the interobserver agreement in the assessment of carotid webs. Materials and Methods All patients (n = 500) of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) in whom the carotid bifurcation could be assessed (n = 443) were included. The presence of a carotid web at the carotid bifurcations was evaluated at computed tomographic (CT) angiography. Demographics, clinical characteristics, and imaging baseline characteristics were presented by descriptive statistics for patients with an identified carotid web. Interobserver agreement in the detection of carotid webs was examined by using kappa statistics. Results Eleven (2.5%) carotid webs were found at the symptomatic side and two (0.5%) carotid webs were found at the asymptomatic side. Ten (91%) patients with a symptomatic carotid web were female. Nine patients with a symptomatic carotid web did not have major risk factors or other causes for ischemic stroke (82%). Fair to good interobserver agreement (κ, 0.72) was observed for diagnosing carotid webs at CT angiography. Conclusion Carotid webs at the symptomatic carotid bifurcation were observed in 2.5% of the patients with acute ischemic stroke due to large vessel occlusion and were mostly diagnosed in female patients with a fair to good interobserver agreement. © RSNA, 2017 Clinical trial registration nos. NTR1804 and ISRCTN10888758 Online supplemental material is available for this article.

BACKGROUND: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. METHODS: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .). ispartof: NEW ENGLAND JOURNAL OF MEDICINE vol:379 issue:7 pages:611-622 ispartof: location:United States status: published

Contains fulltext : 199954.pdf (Publisher’s version ) (Open Access) Background and Purpose: Hypertensive vasculopathy and cerebral amyloid angiopathy are the two most common forms of cerebral small vessel disease. Both forms are associated with the development of primary intracerebral hemorrhage, but the pathophysiological mechanisms underlying spontaneous vessel rupture remain unknown. This work constitutes a systematic review on blood-brain barrier dysfunction in the etiology of spontaneous intracerebral hemorrhage due to cerebral small vessel disease. Methods: We searched Medline (1946-2018) and Embase (1974-2018) for animal and human studies reporting on blood-brain barrier dysfunction associated with intracerebral hemorrhage or cerebral microbleeds. Results: Of 26 eligible studies, 10 were animal studies and 16 were in humans. The authors found indications for blood-brain barrier dysfunction in all four animal studies addressing hypertensive vasculopathy-related intracerebral hemorrhage (n = 32 hypertensive animals included in all four studies combined), and in four of six studies on cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 47). Of the studies in humans, five of six studies in patients with cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 117) and seven out of nine studies examining intracerebral hemorrhage with mixed or unspecified underlying etiology (n = 489) found indications for blood-brain barrier dysfunction. One post-mortem study in hypertensive vasculopathy-related intracerebral hemorrhage (n = 82) found no evidence for blood-brain barrier abnormalities. Conclusions: Signs of blood-brain barrier dysfunction were found in 20 out of 26 studies. Blood-brain barrier integrity deserves further investigation with a view to identification of potential treatment targets for spontaneous intracerebral hemorrhage.

Stroke care has been identified as an area where operations research has great potential. In recent years there has been a small but sustained stream of discrete-event simulation case studies in modelling hyperacute stroke systems. The nature of such case studies has led to a fragmented knowledge base and high entry cost to stroke modelling research. Two common issues have faced researchers in stroke care: understanding the logistics and clinical aspects of stroke care and moving from these findings to an appropriately detailed model. We aim to accelerate studies in this area by introducing a conceptual modelling framework that is domain specific for stroke. A domain specific framework trades-off the wide applicability of a general framework against increased efficiency and reuse to support modelling in the problem domain. This compromise is appropriate when the problem domain is complex, of high value to society, and where the saving in future modelling effort is likely to be greater than the effort to create the framework. We detail the requirements of a domain specific conceptual model and then provide domain specific knowledge to support modellers in gaining an understanding of the problem situation, translating this knowledge into selected model outputs, inputs and content in the case of hyperacute stroke. We illustrate the use of the framework with an example based at a large hospital in the United Kingdom.

Purpose of reviewPerioperative cerebral injury can result in a wide range of clinical consequences from subtle cognitive changes to devastating or fatal strokes. Although the overall incidence of perioperative stroke is low, the large and growing number of aging patients undergoing surgery and anesthesia is placing an increasing number of vulnerable patients at risk. The purpose of this review is to evaluate recent evidence concerning the use of pharmacological and nonpharmacological strategies to protect against perioperative cerebral injury.Recent findingsAlthough a growing body of preclinical literature suggests that anesthetic agents such as barbiturates, volatile anesthetics, and propofol might have neuroprotective properties, clinical evidence of long-term benefit is lacking. Magnesium shows promise, although timing and dosing require clarification. Despite some early promise, there is no strong evidence that erythropoietin is neuroprotective. Remote ischemic preconditioning is the subject of intense study. It is noninvasive, cheap, and reasonably well tolerated and shows promise as a preconditioning neuroprotective intervention. A recent development has been a focus on the potential role of enhanced cardiorespiratory fitness in neuroprotection.The evidence of benefit of current strategies remains sparse. Given the complex pathophysiology of cerebral ischemia and hypoxia, a multimodal approach to neuroprotective strategies seems sensible. The many variables and confounds associated with the clinical setting of patients, their comorbidities and concurrent medications, pose challenges to translate from experimental studies to clinical practice.

BackgroundAutonomic nervous system dysfunction is common after acute stroke and is associated with elevated risk of cardiac arrhythmia and mortality. Heart rate variability and baroreceptor sensitivity have been investigated as parameters of autonomic nervous system dysfunction for the prediction of stroke outcome.SummaryWe performed a systematic literature review on heart rate variability and baroreceptor sensitivity as parameters for autonomic nervous function in acute stroke. Twenty-two studies were included. Associations between heart rate variability or baroreceptor sensitivity and stroke severity, early and late complications, dependency and mortality were reported. However, interpretability of most studies and extrapolation to general stroke population are limited due to many confounding factors such as varying methodology, small sample sizes, survival selection, and exclusion of patients with frequently occurring comorbidities in stroke. Key issues, such as the effect of thrombolytic therapy on autonomic function, autonomic nervous system dysfunction in the hyperacute phase of stroke, and correlation with the risk of recurrent stroke have not been investigated. Also, nonlinear techniques have remained largely unexplored in this domain, in spite of their advantage to provide more solid evaluation in the occurrence of arrhythmia.Key messagesCardiac autonomic dysfunction, represented by reduced heart rate variability or impaired baroreceptor sensitivity, is associated with stroke severity, early and late complications, dependency, and mortality. Large-scale prospective studies applying internationally accepted standards of measures for analysis of heart rate variability and baroreceptor sensitivity are needed in patients with acute stroke.

Purpose of review Perioperative cerebral injury can result in a wide range of clinical consequences from subtle cognitive changes to devastating or fatal strokes. Although the overall incidence of perioperative stroke is low, the large and growing number of aging patients undergoing surgery and anesthesia is placing an increasing number of vulnerable patients at risk. The purpose of this review is to evaluate recent evidence concerning the use of pharmacological and nonpharmacological strategies to protect against perioperative cerebral injury. Recent findings Although a growing body of preclinical literature suggests that anesthetic agents such as barbiturates, volatile anesthetics, and propofol might have neuroprotective properties, clinical evidence of long-term benefit is lacking. Magnesium shows promise, although timing and dosing require clarification. Despite some early promise, there is no strong evidence that erythropoietin is neuroprotective. Remote ischemic preconditioning is the subject of intense study. It is noninvasive, cheap, and reasonably well tolerated and shows promise as a preconditioning neuroprotective intervention. A recent development has been a focus on the potential role of enhanced cardiorespiratory fitness in neuroprotection. The evidence of benefit of current strategies remains sparse. Given the complex pathophysiology of cerebral ischemia and hypoxia, a multimodal approach to neuroprotective strategies seems sensible. The many variables and confounds associated with the clinical setting of patients, their comorbidities and concurrent medications, pose challenges to translate from experimental studies to clinical practice.

Spontaneous intracranial artery dissection is an uncommon and probably underdiagnosed cause of stroke that is defined by the occurrence of a haematoma in the wall of an intracranial artery. Patients can present with headache, ischaemic stroke, subarachnoid haemorrhage, or symptoms associated with mass effect, mostly on the brainstem. Although intracranial artery dissection is less common than cervical artery dissection in adults of European ethnic origin, intracranial artery dissection is reportedly more common in children and in Asian populations. Risk factors and mechanisms are poorly understood, and diagnosis is challenging because characteristic imaging features can be difficult to detect in view of the small size of intracranial arteries. Therefore, multimodal follow-up imaging is often needed to confirm the diagnosis. Treatment of intracranial artery dissections is empirical in the absence of data from randomised controlled trials. Most patients with subarachnoid haemorrhage undergo surgical or endovascular treatment to prevent rebleeding, whereas patients with intracranial artery dissection and cerebral ischaemia are treated with antithrombotics. Prognosis seems worse in patients with subarachnoid haemorrhage than in those without.

Cerebral autoregulation reflects the ability of the brain to keep the cerebral blood flow (CBF) relatively constant despite changes in cerebral perfusion pressure. It is an intrinsic neuroprotective physiological phenomenon often suggested as part of pathophysiological pathways in brain research. However, despite increasing knowledge of this phenomenon for over 50 years, harnessing cerebral autoregulation as a basis for therapy remains an elegant concept rather than a practical reality. This raises the question is it useful to measure at the bedside or is it merely a scientific curiosity that is too complex and has little pragmatic relevance. In this article, we attempt to answer this question by demonstrating how cerebral autoregulation assessment can have prognostic value, indicate pathological states, and potentially even influence therapy with the use of the optimal cerebral perfusion pressure' paradigm. Evidence from the literature is combined with bedside clinical examples to address the following fundamental questions about cerebral autoregulation: What is it? How do we measure it? Why is it important? Can we use it as a basis for therapy?