Showing papers in "Stroke in 2018"

First Pass Effect: A New Measure for Stroke Thrombectomy Devices.

Abstract: Background and Purpose—In acute ischemic stroke, fast and complete recanalization of the occluded vessel is associated with improved outcomes. We describe a novel measure for newer generation devic...

Diagnosis of Cerebral Amyloid Angiopathy: Evolution of the Boston Criteria.

Abstract: The history of how to diagnosis cerebral amyloid angiopathy (CAA) tells the story of the disease itself. CAA is defined by histopathology—deposition of β-amyloid in the cerebrovasculature—and through the 1980s the disorder was only diagnosed in patients with available brain tissue from hematoma evacuation, biopsy, or most commonly postmortem examination. Introduction of the imaging-based Boston criteria for diagnosis of CAA in the 1990s allowed a diagnosis of probable CAA in living patients with no available brain tissue and substantially moved the field from the pathologist’s realm to the clinicians. The Boston criteria for CAA have become the basis for clinical decision-making as well as a rapidly growing body of literature investigating the disease’s clinical manifestations, phenotypic spectrum, progression, and potential for disease-modifying therapy. The history of CAA diagnostic criteria also illustrates broader issues for other major central nervous system diseases. If the brain were as accessible to direct tissue examination during life as the blood or even the liver, diagnosis and staging of brain disorders such as cerebral small-vessel or neurodegenerative disease would be relatively straightforward and the state of clinical trials would presumably be more advanced. Given the relative inaccessibility of brain tissue, however, diagnostic approaches have needed to rely on indirect but nonetheless powerful methods such as magnetic resonance imaging (MRI). The current article will review the evolution and application of the Boston criteria, how the criteria have contributed to the search for CAA biomarkers, and future directions in this still evolving field.

Thrombus Neutrophil Extracellular Traps Content Impair tPA-Induced Thrombolysis in Acute Ischemic Stroke.

Abstract: Background and Purpose—Neutrophil Extracellular Traps (NETs) are DNA extracellular networks decorated with histones and granular proteins produced by activated neutrophils. NETs have been identifie...

Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients

Abstract: Background and Purpose— This ARISTOPHANES study (Anticoagulants for Reduction in Stroke: Observational Pooled Analysis on Health Outcomes and Experience of Patients) used multiple data sources to c...

2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke.

Abstract: Given the seismic changes we have seen in stroke care over the past 5 years, the stroke community has been eagerly anticipating the 2018 updated Acute Ischemic Stroke Guideline.1 This comprehensive document defines state-of-the-art acute stroke management. We highlight a few selected areas of change relevant to stroke systems of care, imaging, thrombectomy eligibility, postprocedure management, and secondary prevention. Most current stroke systems of care are designed to have Emergency Medical Services transport suspected stroke patients to the closest stroke center, regardless of its infrastructure and subspecialty expertise. Unlike intravenous alteplase, the successful delivery of mechanical thrombectomy requires specialized services unavailable at most hospitals. An important area of future study will be if there is a benefit to bypassing a closer hospital without thrombectomy capabilities to transport patients directly in the field to a Comprehensive Stroke Center, where thrombectomy can be performed more expeditiously. As the authors …

Accuracy of Prediction Instruments for Diagnosing Large Vessel Occlusion in Individuals With Suspected Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke.

Abstract: Introduction—Endovascular thrombectomy is a highly efficacious treatment for large vessel occlusion (LVO). LVO prediction instruments, based on stroke signs and symptoms, have been proposed to iden...

Human Neural Stem Cell Extracellular Vesicles Improve Recovery in a Porcine Model of Ischemic Stroke.

Abstract: Background and Purpose— Recent work from our group suggests that human neural stem cell–derived extracellular vesicle (NSC EV) treatment improves both tissue and sensorimotor function in a preclinical thromboembolic mouse model of stroke. In this study, NSC EVs were evaluated in a pig ischemic stroke model, where clinically relevant end points were used to assess recovery in a more translational large animal model. Methods— Ischemic stroke was induced by permanent middle cerebral artery occlusion (MCAO), and either NSC EV or PBS treatment was administered intravenously at 2, 14, and 24 hours post-MCAO. NSC EV effects on tissue level recovery were evaluated via magnetic resonance imaging at 1 and 84 days post-MCAO. Effects on functional recovery were also assessed through longitudinal behavior and gait analysis testing. Results— NSC EV treatment was neuroprotective and led to significant improvements at the tissue and functional levels in stroked pigs. NSC EV treatment eliminated intracranial hemorrhage in ischemic lesions in NSC EV pigs (0 of 7) versus control pigs (7 of 8). NSC EV–treated pigs exhibited a significant decrease in cerebral lesion volume and decreased brain swelling relative to control pigs 1-day post-MCAO. NSC EVs significantly reduced edema in treated pigs relative to control pigs, as assessed by improved diffusivity through apparent diffusion coefficient maps. NSC EVs preserved white matter integrity with increased corpus callosum fractional anisotropy values 84 days post-MCAO. Behavior and mobility improvements paralleled structural changes as NSC EV–treated pigs exhibited improved outcomes, including increased exploratory behavior and faster restoration of spatiotemporal gait parameters. Conclusions— This study demonstrated for the first time that in a large animal model novel NSC EVs significantly improved neural tissue preservation and functional levels post-MCAO, suggesting NSC EVs may be a paradigm changing stroke therapeutic.

Selective NLRP3 (Pyrin Domain-Containing Protein 3) Inflammasome Inhibitor Reduces Brain Injury After Intracerebral Hemorrhage.

Abstract: Background and Purpose— Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. As a key component of the innate immune system, the NOD-like receptor (NLR) family, NLRP3 (pyrin domain–containing protein 3) inflammasome, when activated after ICH, promotes neuroinflammation and brain edema. MCC950 is a potent, selective, small-molecule NLRP3 inhibitor that blocks NLRP3 activation at nanomolar concentrations. Here, we examined the effect of MCC950 on brain injury and inflammation in 2 models of ICH in mice. Methods— In mice with ICH induced by injection of autologous blood or bacterial collagenase, we determined the therapeutic potential of MCC950 and its mechanisms of neuroprotection. Results— MCC950 reduced IL-1β (interleukin-1β) production and attenuated neurodeficits and perihematomal brain edema after ICH induction by injection of either autologous blood or collagenase. In mice with autologous blood-induced ICH, the protection of MCC950 was associated with reduced leukocyte infiltration into the brain and microglial production of IL-6. MCC950 improved blood–brain barrier integrity and diminished cell death. Notably, the protective effect of MCC950 was abolished in mice depleted of either microglia or Gr-1 + myeloid cells. Conclusions— These results indicate that the NLRP3 inflammasome inhibitor, MCC950, attenuates brain injury and inflammation after ICH. Hence, NLRP3 inflammasome inhibition is a potential therapy for ICH that warrants further investigation.

Late Window Paradox.

Abstract: The mantra of acute stroke therapy, time is brain is a call to arms that motivates both the public and medical practitioners to treat stroke as a time-critical emergency. Countless articles have documented inexorable declines in favorable clinical outcomes associated with delayed administration of thrombolytic or endovascular therapies. Therefore, one would naturally anticipate that the benefits of endovascular therapy would be markedly more modest if treatment is delayed many hours beyond the guideline-recommended 6-hour therapeutic window. How then do we explain the remarkably robust results of DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) and DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo), 2 recently published trials of endovascular therapy initiated up to 16 to 24 hours after patients were last known well? DAWN randomized patients at a median of 12.5 hours from onset and documented the largest absolute increase in functional independence ever reported in any acute stroke treatment trial, 35.5%.1 DEFUSE 3 randomized patients at a median of 11 hours after onset and documented a 28% increase in functional independence and an additional 20% absolute reduction in death or severe disability, which represents the largest reduction in mortality/severe disability ever achieved.2 By comparison, the pooled analysis of 5 modern early window thrombectomy trials (HERMES [Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials]) revealed an absolute increase in functional independence of 19.5% and a reduction in mortality/severe disability of 11%3 (Figure 1). Both early and late window studies included patients of similar ages, baseline National Institutes of Health Stroke Scale scores, and vessel occlusion sites. Patients were treated with the same modern thrombectomy devices and reperfusion was achieved in similar proportions of patients in the endovascular arms of the …

Prediction of Tissue Outcome and Assessment of Treatment Effect in Acute Ischemic Stroke Using Deep Learning.

Abstract: Background and Purpose— Treatment options for patients with acute ischemic stroke depend on the volume of salvageable tissue. This volume assessment is currently based on fixed thresholds and single imagine modalities, limiting accuracy. We wish to develop and validate a predictive model capable of automatically identifying and combining acute imaging features to accurately predict final lesion volume. Methods— Using acute magnetic resonance imaging, we developed and trained a deep convolutional neural network (CNN deep ) to predict final imaging outcome. A total of 222 patients were included, of which 187 were treated with rtPA (recombinant tissue-type plasminogen activator). The performance of CNN deep was compared with a shallow CNN based on the perfusion-weighted imaging biomarker Tmax (CNN Tmax ), a shallow CNN based on a combination of 9 different biomarkers (CNN shallow ), a generalized linear model, and thresholding of the diffusion-weighted imaging biomarker apparent diffusion coefficient (ADC) at 600×10 −6 mm 2 /s (ADC thres ). To assess whether CNN deep is capable of differentiating outcomes of ±intravenous rtPA, patients not receiving intravenous rtPA were included to train CNN deep, −rtpa to access a treatment effect. The networks’ performances were evaluated using visual inspection, area under the receiver operating characteristic curve (AUC), and contrast. Results— CNN deep yields significantly better performance in predicting final outcome (AUC=0.88±0.12) than generalized linear model (AUC=0.78±0.12; P =0.005), CNN Tmax (AUC=0.72±0.14; P thres (AUC=0.66±0.13; P shallow (AUC=0.85±0.11; P =0.063). Measured by contrast, CNN deep improves the predictions significantly, showing superiority to all other methods ( P ≤0.003). CNN deep also seems to be able to differentiate outcomes based on treatment strategy with the volume of final infarct being significantly different ( P =0.048). Conclusions— The considerable prediction improvement accuracy over current state of the art increases the potential for automated decision support in providing recommendations for personalized treatment plans.

Modified Thrombolysis in Cerebral Infarction 2C/Thrombolysis in Cerebral Infarction 3 Reperfusion Should Be the Aim of Mechanical Thrombectomy: Insights From the ASTER Trial (Contact Aspiration Versus Stent Retriever for Successful Revascularization)

Abstract: Background and Purpose— Although successful reperfusion is usually defined as a modified Thrombolysis in Cerebral Infarction (mTICI) 2B or 3 at the end of the procedure, studies have shown that mTICI 2B patients had poorer functional outcomes than TICI 3 patients. An mTICI 2C category has been recently introduced for patients with near-complete perfusion except for slow flow in a few distal cortical vessels or presence of small distal cortical emboli after mechanical thrombectomy. The purpose of this study was to evaluate the difference in functional outcome between patients achieving successful reperfusion (ie, mTICI 2B, mTICI 2C, and TICI 3 scores). Methods— Ancillary study from the ASTER (Contact Aspiration Versus Stent Retriever for Successful Revascularization) prospective multicenter blinded end point trial. Reperfusion results are reported as the mTICI score, including the mTICI 2C grade. Primary outcome was the percentage of patients with favorable outcome defined as a 90-day modified Rankin Scale score of 0 to 2. Results— Two hundred ninety patients with successful reperfusion (mTICI ≥2B), harboring ischemic stroke secondary to occlusion of the anterior circulation within 6 hours of onset of symptoms, undergoing mechanical thrombectomy by contact aspiration or stent retriever were included. Favorable outcome (pre-specified as primary outcome of this ancillary study) did not differ significantly between the 3 reperfusion grades, with a similar positive effect of 2C (odds ratio, 1.71; 95% confidence interval, 0.98–3.00) and 3 (odds ratio, 1.73; 95% confidence interval, 0.88–3.41) grades compared with 2B grade. After combining grades 2C and 3, patients had a significantly higher rate of favorable outcome than patients with 2B (odds ratio, 1.72; 95% confidence interval, 1.01–2.90; P =0.043). Favorable outcome rate decreased with increasing onset-to-reperfusion time, with no significant interaction between mTICI 2C/3 grade and onset-to-reperfusion time on favorable outcome. Conclusions— Combining mTICI 2C and TICI 3 grades helps to determine a subgroup of patients achieving better functional outcomes than mTICI 2B patients. Achieving mTICI 2C/3 reperfusion should be the new aim of mechanical thrombectomy for anterior circulation LVO.

Letter by Trinh-Duc et al Regarding Article, "2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association".

Abstract: We read with interest the article by Powers et al.1 In their guidelines, the authors recommend to primary stroke centers (PSCs) to establish hand-off and transfer protocols for endovascular intervention. However, such a transfer (Drip ‘n Ship) is frequently not possible for a PSC located far away from the closest comprehensive stroke center. Such Drip ‘n Ship shortage likely contributes to the low number of eligible patients (4%), who may benefit from endovascular thrombectomy.2 Our PSC is located at more than 100 km from the closest comprehensive stroke center, and our mobile intensive care unit service facilities are just sufficient to supply local needs. The use of nonmedicalized interhospital transfer could help solving the Drip ‘n Ship shortage issues. To our knowledge, no …

Successful Reperfusion With Intravenous Thrombolysis Preceding Mechanical Thrombectomy in Large-Vessel Occlusions

Abstract: Background and Purpose— Although current guidelines advocate pretreatment with intravenous thrombolysis (IVT) in all eligible patients with acute ischemic stroke with large-vessel occlusion before mechanical thrombectomy, there are observational data questioning the efficacy of this approach. One of the main arguments in favor of IVT pretreatment is the potential for tissue-type plasminogen activator–induced successful reperfusion (SR) before the onset of endovascular procedure. Methods— We performed a systematic review and meta-analysis of randomized controlled clinical trials and observational cohorts providing rates of SR with IVT in patients with large-vessel occlusion before the initiation of mechanical thrombectomy. We also performed subgroup analyses according to study type (randomized controlled clinical trials versus observational) and according to the inclusion per protocol of patients with tandem (intracranial/extracranial) occlusions. Results— We identified 13 eligible studies (7 randomized controlled clinical trials and 6 observational cohorts), including 1561 patients with acute ischemic stroke (median National Institutes of Health Stroke Scale score, 17) with large-vessel occlusion. SR following IVT and before mechanical thrombectomy was documented in 11% (95% confidence interval, 7%–16%), with no difference among cohorts derived from randomized controlled clinical trials and observational studies. There was significant heterogeneity across included studies both in the overall analysis and among subgroups (I 2 >84%; P for Cochran Q, P for subgroup differences, 0.003). Conclusions— Pretreatment with systemic thrombolysis in patients with large-vessel occlusion eligible for mechanical thrombectomy results in SR in 1 of 10 cases, negating the need for additional endovascular reperfusion. Tandem occlusions seem to be the least responsive to IVT pretreatment.

High Neutrophil-to-Lymphocyte Ratio Predicts Stroke-Associated Pneumonia

Abstract: Background and Purpose- Although there are a variety of risk factors and predictive models for stroke-associated pneumonia (SAP), more objective and easily accessible markers are still needed. In this study, we evaluated the relationship between the neutrophil-to-lymphocyte ratio (NLR) and SAP in patients with acute ischemic stroke. Methods- We assessed 1317 consecutive patients with acute ischemic stroke. SAP was defined according to the modified Centers for Disease Control and Prevention criteria. The severity of pneumonia was rated using scores from the Pneumonia Severity Index, the quick Sequential Organ Failure Assessment, and the Acute Physiology and Chronic Health Evaluation II. The NLR was calculated after dividing absolute neutrophil counts by absolute lymphocyte counts. Results- Among the total patients, SAP occurred in 112 (9.0%) patients. Using a multivariable analysis, the NLR (adjusted odds ratio=1.55; 95% confidence interval, 1.15-2.11; P=0.005) remained significant after adjusting for confounders. In addition, age, atrial fibrillation, previous stroke history, initial National Institutes of Health Stroke Scale score, and high-sensitivity C-reactive protein were also significant, independent of NLR. The NLR was higher in the severe pneumonia group when it was assessed by Pneumonia Severity Index ( P<0.001), quick Sequential Organ Failure Assessment ( P<0.001), and Acute Physiology and Chronic Health Evaluation II scores ( P=0.004). Furthermore, patients who had SAP had worse clinical outcomes both during hospitalization and after discharge. Conclusions- We demonstrated that a higher NLR predicted SAP in patients with acute ischemic stroke. The NLR may help to identify high-risk patients in time and provide clues for further studies about preventive antibiotic therapy.

SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A Randomized Controlled Phase 2 Trial

Abstract: Background and Purpose— The proinflammatory cytokine IL-1 (interleukin-1) has a deleterious role in cerebral ischemia, which is attenuated by IL-1 receptor antagonist (IL-1Ra). IL-1 induces peripheral inflammatory mediators, such as interleukin-6, which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke. Methods— SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke) was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of subcutaneous IL-1Ra (100 mg administered twice daily for 3 days) in patients presenting within 5 hours of ischemic stroke onset. Randomization was stratified for baseline National Institutes of Health Stroke Scale score and thrombolysis. Measurement of plasma interleukin-6 and other peripheral inflammatory markers was undertaken at 5 time points. The primary outcome was difference in concentration of log(interleukin-6) as area under the curve to day 3. Secondary outcomes included exploratory effect of IL-1Ra on 3-month outcome with the modified Rankin Scale. Results— We recruited 80 patients (mean age, 72 years; median National Institutes of Health Stroke Scale, 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma interleukin-6 ( P P P =0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit. Conclusions— IL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. Subcutaneous IL-1Ra is safe and well tolerated. Further experimental studies are required to investigate efficacy and possible interactions of IL-1Ra with thrombolysis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN74236229

Distribution and Temporal Trends From 1993 to 2015 of Ischemic Stroke Subtypes: A Systematic Review and Meta-Analysis

Abstract: Background and Purpose— Preventive strategies, together with demographic and socioeconomic changes, might have modified the worldwide distribution of ischemic stroke (IS) subtypes. We investigated those changes by means of a systematic review and meta-analysis. Methods— We evaluated all population- and hospital-based studies reporting the distribution of IS etiologic subtypes according to the TOAST criteria (Trial of ORG 10172 in Acute Stroke Treatment). Studies were identified by searching articles indexed on PubMed and Scopus from January 1, 1993, to June 30, 2017. Two independent investigators extracted data and checked them for accuracy. Proportions of each etiologic subtype were pooled according to a random effect meta-analytic model weighted by study size; temporal trends were assessed using a mixed-effect meta-regression model. Results— Sixty-five studies including patients from 1993 to 2015 were finally included. Overall, ISs were attributed to cardioembolism (22%; 95% confidence interval [CI], 20–23); large artery atherosclerosis (23%; 95% CI, 21–25); small artery occlusion (22%; 95% CI, 21–24); other determined cause (3%; 95% CI, 3–3); and undetermined cause (26%; 95% CI, 24–28). Cardioembolism was the leading IS etiologic subtype in whites (28%; 95% CI, 26–29) and large artery atherosclerosis in Asians (33%; 95% CI, 31–36). Meta-regression showed an increasing temporal trend for cardioembolism in whites (2.4% annually, P =0.008) and large artery atherosclerosis in Asians (5.7% annually, P P =0.001); there was considerable heterogeneity across all the analyses. Conclusions— According to our systematic review and meta-analysis, cardioembolism in whites and large artery atherosclerosis in Asians are the leading causes of IS. The heterogeneous distribution of etiologic subtypes of IS may depend on the demographic and socioeconomic characteristics of the different populations. More extensive protocols should be adopted to reduce the persistently relevant proportion of undetermined cause IS.

Induced Hypertension for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial.

Abstract: Background and Purpose-Induced hypertension is widely used to treat delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but a literature review shows that its presumed effectiveness is based on uncontrolled caseseries only. We here report clinical outcome of aneurysmal subarachnoid hemorrhage patients with DCI included in a randomized trial on the effectiveness of induced hypertension. Methods-Aneurysmal subarachnoid hemorrhage patients with clinical symptoms of DCI were randomized to induced hypertension or no induced hypertension. Risk ratios for poor outcome (modified Rankin Scale score >3) at 3 months, with 95% confidence intervals, were calculated and adjusted for age, clinical condition at admission and at time of DCI, and amount of blood on initial computed tomographic scan with Poisson regression analysis. Results-The trial aiming to include 240 patients was ended, based on lack of effect on cerebral perfusion and slow recruitment, when 21 patients had been randomized to induced hypertension, and 20 patients to no hypertension. With induced hypertension, the adjusted risk ratio for poor outcome was 1.0 (95% confidence interval, 0.6-1.8) and the risk ratio for serious adverse events 2.1 (95% confidence interval, 0.9-5.0). Conclusions-Before this trial, the effectiveness of induced hypertension for DCI in aneurysmal subarachnoid hemorrhage patients was unknown because current literature consists only of uncontrolled case series. The results from our premature halted trial do not add any evidence to support induced hypertension and show that this treatment can lead to serious adverse events.

Beyond Large Vessel Occlusion Strokes: Distal Occlusion Thrombectomy.

Abstract: Background and Purpose— Endovascular therapy is the standard of care for the treatment of proximal large vessel occlusion strokes. Its safety and efficacy in the treatment of distal intracranial occlusions has not been well studied. Methods— The data that support the findings of this study are available from the corresponding author on reasonable request. Retrospective review of a prospectively collected endovascular database (2010–2015, n=949) for all patients with distal intracranial occlusions treated endovascularly. Distal occlusions were defined as any segment of the anterior cerebral artery (ACA), posterior cerebral artery, or occlusion at or distal to the middle cerebral artery (MCA)-M3 opercular segment. Results— Distal occlusions were treated in 69 patients. The mean age was 66.7±15.8 and 57% were male. Patients (29 [42%]) received intravenous tPA (tissue-type plasminogen activator). The median preprocedure National Institutes of Health Stroke Scale score was 18 (interquartile range, 13–23). The distal occlusion was the primary treatment location in 45 patients, in 23 patients the distal occlusion was treated as a rescue strategy after successful treatment of a proximal large vessel occlusion strokes, and 1 patient had both primary and rescue treatment. The locations of the primary cases were MCA-M3 (n=21), ACA alone (n=8), ACA with a concomitant MCA-M1 or MCA-M2 (n=10), ACA with a concomitant MCA-M3 (n=3), and posterior cerebral artery (n=3). The locations of the rescue cases were MCA-M3 (n=11), ACA (n=7), posterior cerebral artery (n=4), and both MCA-M3 and ACA (n=1). There was a single patient with primary ACA and MCA-M2 occlusions treated, who then had a rescue MCA-M3 thrombectomy addressed after initial reperfusion. The most common treatment modalities used were stent-retrievers (n=37, 54%), intra-arterial tPA (n=36, 52%), and thromboaspiration (n=31, 45%). Near complete or complete reperfusion of the distal territory (modified Treatment In Cerebral Ischemia [mTICI] 2b-3) was achieved in 57 cases (83%). Three parenchymal hematomas (4%) occurred in the territory of the treated distal occlusion with 2 of these patients also receiving intravenous tPA. At 90 days, 21 patients (30%) had a modified Rankin Scale score of 0 to 2 and 14 (20%) had died. Conclusions— Distal intracranial occlusions can be treated safely and successfully with endovascular therapy. These results need to be corroborated by larger prospective controlled studies.

Surgical Management of Moyamoya Disease.

Abstract: Moyamoya disease (MMD) is a rare cerebrovascular disease which is characterized by bilateral progressive steno-occlusion of basal cerebral arteries with emergence of coexisting abnormal net-like vessels.1 MMD is most frequent in Asian countries with an incidence ≤0.94/100 000, but an increase in incidence has been reported in non-Asian countries with some ethnic differences in disease characteristics.2–4 MMD shows worldwide a bimodal age distribution with a peak each in childhood and adulthood2–4; thus, it is one of the leading causes of stroke in children and young adults. The most frequent initial symptom of MMD adults in Asians and whites is intracranial hemorrhage because of fragile blood vessels and ischemic events, respectively.2,3 Children with MMD worldwide frequently experience ischemic events.2–4 The diagnostic workup includes magnetic resonance angiography or digital subtraction angiography and hemodynamic assessments using (semi) quantitative techniques, such as SPECT or PET.2 Historically, disease severity has been classified by the angiography-based Suzuki classification. This classification, however, neither correlates with disease severity nor allows therapeutic risk stratification and thus, has not been applied in routine clinical setting. As a consequence, the Berlin Moyamoya Grading has been established using standard diagnostic tools: magnetic resonance imaging and functional cerebrovascular assessment of hemodynamic impairment.5 This novel grading system correlates with disease severity and more importantly, allows to stratify the individual risk of surgical therapy. Only recently, the Berlin Moyamoya Grading has been validated on an independent Japanese data set.6 Cerebral hemodynamic impairment and repeat ischemic symptoms have to date been the main indications for treatment.2 However, because asymptomatic moyamoya is a progressive disease with an annual stroke rate of ≤13.3%,7,8 treatment indications for asymptomatic patients are currently revisited by the prospective AMORE trial.8 For …

Minimally Invasive Surgery for Intracerebral Hemorrhage

Abstract: Background and Purpose- Minimally invasive surgery (MIS) for intracerebral hemorrhage (ICH) has been evaluated in numerous clinical trials. Although meta-analyses for this strategy have been performed in the past, recent trials add important information to results of the comparison and permit strategy-specific analyses, including evaluation of endoscopic evacuation and stereotactic thrombolysis. Methods- Major scientific databases including but not limited to Pubmed, the CENTRAL (Cochrane Central Register of Controlled Trials), Embase, Web of Science, Scopus, the ICTRP (International Clinical Trials Registry Platform), the Internet Stroke Center, and the CNKI (Chinese National Knowledge Infrastructure) were searched in October of 2017 for randomized controlled trials of MIS treatment of supratentorial spontaneous ICH. The primary outcome was defined as death or dependence at the end of follow-up, and the secondary outcome was defined as death. Results- The initial search yielded 958 reports, which were reduced to 15 high-quality randomized controlled trials involving 2152 patients. We analyzed odds ratios for MIS overall, endoscopic surgery, and stereotactic thrombolysis compared with conventional treatment, including medical treatment and conventional craniotomy. The odds ratio and CIs of the primary and secondary outcomes were 0.46 (0.36-0.57) and 0.59 (0.45-0.76) for MIS versus conventional treatment; 0.40 (0.25-0.66) and 0.37 (0.20-0.67) for endoscopic surgery versus conventional treatment; 0.47 (0.34-0.65) and 0.76 (0.56-1.04) for stereotactic thrombolysis versus conventional treatment; and 0.44 (0.29-0.67) and 0.56 (0.37-0.84) for MIS versus craniotomy. We also conducted subgroup analyses focusing on time to evacuation for MIS versus conventional treatment and found 0.36 (0.22-0.59) and 0.59 (0.34-1.00) for evacuations performed within 24 hours and 0.49 (0.38-0.63) and 0.57 (0.43-0.76) for evacuations performed within 72 hours. Conclusions- This meta-analysis demonstrates that select patients with supratentorial ICH benefit from MIS over other treatments. This beneficial effect remains true when analyzing specific techniques and evacuation timing subgroups.

Rescue Stenting for Failed Mechanical Thrombectomy in Acute Ischemic Stroke: A Multicenter Experience

Abstract: Background and Purpose— Effective rescue treatment has not yet been suggested in patients with mechanical thrombectomy (MT) failure. This study aimed to test whether rescue stenting (RS) improved clinical outcomes in MT-failed patients. Methods— This is a retrospective analysis of the cohorts of the 16 comprehensive stroke centers between September 2010 and December 2015. We identified the patients who underwent MT but failed to recanalize intracranial internal carotid artery or middle cerebral artery M1 occlusion. Patients were dichotomized into 2 groups: patients with RS and without RS after MT failure. Clinical and laboratory findings and outcomes were compared between the 2 groups. It was tested whether RS is associated with functional outcome. Results— MT failed in 148 (25.0%) of the 591 patients with internal carotid artery or middle cerebral artery M1 occlusion. Of these 148 patients, 48 received RS (RS group) and 100 were left without further treatment (no stenting group). Recanalization was successful in 64.6% (31 of 48 patients) of RS group. Compared with no stenting group, RS group showed a significantly higher rate of good outcome (modified Rankin Scale score, 0–2; 39.6% versus 22.0%; P =0.031) without increasing symptomatic intracranial hemorrhage (16.7% versus 20.0%; P =0.823) or mortality (12.5% versus 19.0%; P =0.360). Of the RS group, patients who had recanalization success had 54.8% of good outcome, which is comparable to that (55.4%) of recanalization success group with MT. RS remained independently associated with good outcome after adjustment of other factors (odds ratio, 3.393; 95% confidence interval, 1.192–9.655; P =0.022). Follow-up vascular imaging was available in the 23 (74.2%) of 31 patients with recanalization success with RS. The stent was patent in 20 (87.0%) of the 23 patients. Glycoprotein IIb/IIIa inhibitor was significantly associated with stent patency but not with symptomatic intracranial hemorrhage. Conclusions— RS was independently associated with good outcomes without increasing symptomatic intracranial hemorrhage or mortality. RS seemed considered in MT-failed internal carotid artery or middle cerebral artery M1 occlusion.

Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study.

Abstract: Background and Purpose— Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR). Methods— Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance–weighted MR was used to obtain the causal estimates. Inverse-variance–weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias. Results— A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04–1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10–1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67–0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes. Conclusions— LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes.

Exosome Therapy for Stroke.

Abstract: Nearly, all cells generate and eject vesicles, and these vesicles constitute major vehicles for intercellular communication. Exosomes, as nanosized vesicles (≈30–100 nm in diameter1), target cell function by delivering proteins, lipids, and nucleic acids. Exosomes are emerging as a valuable source for disease stage–specific information and as fingerprints of disease progression and as potential biomarkers in different pathophysiological states.2–5 However, because exosomes provide a major medium of intercellular communication,6 they likely also impact the treatment of diseases.7,8 Recent reports have highlighted the critical application of exosomes as personalized targeted drug delivery vehicles.6,9 Exosomes harvested from multipotent mesenchymal stromal cells (MSCs) mediate the restorative therapeutic effects of MSCs for stroke.10 Here, we review the biogenesis of exosomes and their molecular composition and role as messengers of intercellular communication and describe using exosomes for treatment of stroke. We also focus on therapeutic effects and underlying mechanisms of action of exosomes as therapeutic vectors for stroke11 but do not discuss the role of exosomes as disease or injury biomarkers. Capitalizing on the function of exosomes as vehicles for intercellular communication in physiological and pathophysiological conditions such as stroke provides a paradigm shift and enormous potential for safe and effective therapeutic approaches for stroke and for other diseases/injury. Exosomes are highly conserved among most eukaryotic organisms, from microorganisms up to mammals.12 Exosomes originate from the endocytic route and are formed by the inward budding of the plasma membrane. The membrane of late endosomes invaginates and forms small vesicles that are pinched off into the endosomal space. The internal intraluminal vesicles with their cargo secreted into the extracellular space are exosomes.13 Exosomes contain conserved proteins, such as CD81, CD63 (membrane-associated proteins like LAMP-3 [lysosome-associated membrane protein 3]), and CD9; Alix …

Anxiety After Stroke: The Importance of Subtyping

Abstract: Background and Purpose— Anxiety after stroke is common and disabling. Stroke trialists have treated anxiety as a homogenous condition, and intervention studies have followed suit, neglecting the different treatment approaches for phobic and generalized anxiety. Using diagnostic psychiatric interviews, we aimed to report the frequency of phobic and generalized anxiety, phobic avoidance, predictors of anxiety, and patient outcomes at 3 months poststroke/transient ischemic attack. Methods— We followed prospectively a cohort of new diagnosis of stroke/transient ischemic attack at 3 months with a telephone semistructured psychiatric interview, Fear Questionnaire, modified Rankin Scale, EuroQol-5D5L, and Work and Social Adjustment Scale. Results— Anxiety disorder was common (any anxiety disorder, 38 of 175 [22%]). Phobic disorder was the predominant anxiety subtype: phobic disorder only, 18 of 175 (10%); phobic and generalized anxiety disorder, 13 of 175 (7%); and generalized anxiety disorder only, 7 of 175 (4%). Participants with anxiety disorder reported higher level of phobic avoidance across all situations on the Fear Questionnaire. Younger age (per decade increase in odds ratio, 0.64; 95% confidence interval, 0.45–0.91) and having previous anxiety/depression (odds ratio, 4.38; 95% confidence interval, 1.94–9.89) were predictors for anxiety poststroke/transient ischemic attack. Participants with anxiety disorder were more dependent (modified Rankin Scale score 3–5, [anxiety] 55% versus [no anxiety] 29%; P P Conclusions— Anxiety after stroke/transient ischemic attack is predominantly phobic and is associated with poorer patient outcomes. Trials of anxiety intervention in stroke should consider the different treatment approaches needed for phobic and generalized anxiety.

Primary Results of the Multicenter ARISE II Study (Analysis of Revascularization in Ischemic Stroke With EmboTrap).

Abstract: Background and Purpose— EmboTrap is a novel stent retriever designed to achieve rapid and substantial flow restoration in acute ischemic stroke secondary to large-vessel occlusions. Here, we evaluated EmboTrap’s safety and efficacy compared with established stent retrievers. Methods— ARISE II (Analysis of Revascularization in Ischemic Stroke With EmboTrap) was a single-arm, prospective, multicenter study, comparing the EmboTrap device to a composite performance goal criterion derived using a Bayesian meta-analysis from the pivotal SWIFT (Solitaire device) and TREVO 2 (Trevo device) trials. Patients at 11 US and 8 European sites were eligible for inclusion if they had large-vessel occlusions and moderate-to-severe neurological deficits within 8 hours of symptom onset. The primary efficacy end point was achievement of modified Thrombolysis in Cerebral Ischemia (mTICI) reperfusion scores of ≥2b within 3 EmboTrap passes as adjudicated by the core laboratory. The primary safety end point was a composite of symptomatic intracerebral hemorrhage and serious adverse device effects. Secondary end points included functional independence (modified Rankin Scale, 0–2) and all-cause mortality at 90 days. Results— Between October 2015 and February 2017, 227 patients were enrolled and treated with the EmboTrap device. The primary efficacy end point (mTICI ≥2b within 3 passes) was achieved in 80.2% (95% confidence interval, 74%–85% versus 56% performance goal criterion; P value, Conclusions— The EmboTrap stent-retriever mechanical thrombectomy device demonstrated high rates of substantial reperfusion and functional independence in patients with acute ischemic stroke secondary to large-vessel occlusions. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02488915.

Eligibility for Endovascular Trial Enrollment in the 6- to 24-Hour Time Window: Analysis of a Single Comprehensive Stroke Center.

Abstract: Background and Purpose— The results of the DAWN trial (Diffusion-Weighted Imaging or Computerized Tomography Perfusion Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) support the benefit of endovascular therapy in patients presenting beyond the 6-hour time window with anterior circulation large vessel occlusions. The impact of these results with respect to additional number of eligible patients in clinical practice remains unknown. Methods— A retrospective review of ischemic stroke admissions to a single DAWN trial-participating comprehensive stroke center was performed during the DAWN enrollment period (November 2014 to February 2017) to identify patients meeting criteria for DAWN and DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke-3) eligibility. Patients presenting beyond 6 hours were further investigated to clarify reasons for trial exclusion. Results— Of the 2667 patients with acute ischemic stroke admitted within the study period, 30% (n=792) presented within the 6- to 24-hour time window, and 47% (n=1242) had a National Institutes of Health Stroke Scale ≥6. Further clinical trial-specific selection criteria were applied based on the presence of large vessel occlusion, baseline modified Rankin Scale score, core infarct, and perfusion imaging (when available). There were 45 patients who met all DAWN trial criteria and 47 to 58 patients who would meet DEFUSE-3 trial criteria. Thirty-three percent of DAWN-eligible patients are DEFUSE-3 ineligible. Conclusions— Of all patients with acute ischemic stroke presenting to a single comprehensive stroke center, 1.7% of patients qualified for DAWN clinical trial enrollment with an additional 0.6% to 1% qualifying for the DEFUSE-3 trial. These data predict an increase in thrombectomy utilization with important implications for comprehensive stroke center resource optimization and stroke systems of care.

Periodontal Disease, Regular Dental Care Use, and Incident Ischemic Stroke

Abstract: Background and Purpose— Periodontal disease is independently associated with cardiovascular disease. Identification of periodontal disease as a risk factor for incident ischemic stroke raises the possibility that regular dental care utilization may reduce the stroke risk. Methods— In the ARIC (Atherosclerosis Risk in Communities) study, pattern of dental visits were classified as regular or episodic dental care users. In the ancillary dental ARIC study, selected subjects from ARIC underwent fullmouth periodontal measurements collected at 6 sites per tooth and classified into 7 periodontal profile classes (PPCs). Results— In the ARIC study 10 362 stroke-free participants, 584 participants had incident ischemic strokes over a 15-year period. In the dental ARIC study, 6736 dentate subjects were assessed for periodontal disease status using PPC with a total of 299 incident ischemic strokes over the 15-year period. The 7 levels of PPC showed a trend toward an increased stroke risk (χ 2 trend P Conclusions— We confirm an independent association between periodontal disease and incident stroke risk, particularly cardioembolic and thrombotic stroke subtype. Further, we report that regular dental care utilization may lower this risk for stroke.

Vagus Nerve Stimulation Enhances Stable Plasticity and Generalization of Stroke Recovery

Abstract: Background and Purpose— Chronic impairment of the arm and hand is a common consequence of stroke. Animal and human studies indicate that brief bursts of vagus nerve stimulation (VNS) in conjunction with rehabilitative training improve recovery of motor function after stroke. In this study, we tested whether VNS could promote generalization, long-lasting recovery, and structural plasticity in motor networks. Methods— Rats were trained on a fully automated, quantitative task that measures forelimb supination. On task proficiency, unilateral cortical and subcortical ischemic lesions were administered. One week after ischemic lesion, rats were randomly assigned to receive 6 weeks of rehabilitative training on the supination task with or without VNS. Rats then underwent 4 weeks of testing on a task assessing forelimb strength to test generalization of recovery. Finally, the durability of VNS benefits was tested on the supination task 2 months after the cessation of VNS. After the conclusion of behavioral testing, viral tracing was performed to assess synaptic connectivity in motor networks. Results— VNS enhances plasticity in corticospinal motor networks to increase synaptic connectivity to musculature of the rehabilitated forelimb. Adding VNS more than doubled the benefit of rehabilitative training, and the improvements lasted months after the end of VNS. Pairing VNS with supination training also significantly improved performance on a similar, but untrained task that emphasized volitional forelimb strength, suggesting generalization of forelimb recovery. Conclusions— This study provides the first evidence that VNS paired with rehabilitative training after stroke (1) doubles long-lasting recovery on a complex task involving forelimb supination, (2) doubles recovery on a simple motor task that was not paired with VNS, and (3) enhances structural plasticity in motor networks.

Mechanical Thrombectomy in Patients With Milder Strokes and Large Vessel Occlusions.

Abstract: Background and Purpose- We aimed to describe the safety and efficacy of immediate mechanical thrombectomy (MT) in patients with large vessel occlusions and low National Institutes of Health Stroke Scale (NIHSS) versus best medical management. Methods- Patients from prospectively collected databases of 6 international comprehensive stroke centers with large vessel occlusions (distal intracranial internal carotid, middle cerebral artery-M1 and M2 segments, or basilar artery with or without tandem occlusions) and NIHSS 0 to 5 were identified and divided into 2 groups for analysis: immediate MT or initial best medical management which included rescue MT after neurological deterioration (best medical management-MT). Uni- and multivariate analyses and patient-level matching for age, baseline NIHSS, and occlusion site were performed to compare baseline and outcome variables across the 2 groups. The primary outcome was defined as good outcome (modified Rankin Scale score, 0-2) at day 90. Safety outcome was symptomatic intracranial hemorrhage as defined by the ECASS (European Cooperative Acute Stroke Study) II and mortality at day 90. Results- Compared with best medical management-MT (n=220), patients with immediate MT (n=80) were younger (65.3±13.5 versus 69.5±14.1; P=0.021), had more often atrial fibrillation (44.8% versus 28.2%; P=0.012), higher baseline NIHSS (4, 0-5 versus 3, 0-5; P=0.005), higher Alberta Stroke Program Early CT Score (10, 7-10 versus 10, 5-10; P=0.023), more middle cerebral artery-M1, and less middle cerebral artery-M2 (41.3% versus 21.9% and 28.8% versus 49.3%; P=0.016) occlusions. The adjusted odds ratio for good outcome was 3.1 (95% CI, 1.4-6.9) favoring immediate MT. In the matched analysis, there was a 14.4% absolute difference in good outcome (84.4% versus 70.1%; P=0.03) at day 90 favoring immediate MT. There were no safety concerns. Conclusions- Our retrospective, pilot analysis suggests that immediate thrombectomy in large vessel occlusions patients with low NIHSS on presentation may be safe and has the potential to result in improved outcomes. Randomized clinical trials are warranted to establish the optimal management for this patient population.

Serum Trimethylamine N-Oxide Concentration Is Positively Associated With First Stroke in Hypertensive Patients.

Abstract: Background and Purpose— Trimethylamine N-oxide (TMAO)—a gut derived metabolite—has been shown to be atherogenic. It remains unknown whether TMAO is associated with the risk of first stroke. We aime...