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Background: To emphasize treatment speed for time-sensitive conditions, emergency medicine has developed not only the concept of the golden hour, but also the platinum half-hour. Patients with acute stroke treated within the first half-hour of onset have not been previously characterized. Methods: In this cohort study, we analyzed patients enrolled in the FAST-MAG (Field Administration of Stroke Therapy–Magnesium) trial, testing paramedic prehospital start of neuroprotective agent ≤2 hours of onset. The features of all acute cerebral ischemia, and intracranial hemorrhage patients with treatment starting at ≤30 m of last known well were compared with later-treated patients. Results: Among 1680 patients, 203 (12.1%) received study agents within 30 minutes of last known well. Among platinum half-hour patients, median onset-to-treatment time was 28 minutes (interquartile range, 25–30), and final diagnoses were acute cerebral ischemia in 71.8% (ischemic stroke, 61.5%, TIA 10.3%); intracranial hemorrhage in 26.1%; and mimic in 2.5%. Clinical features among platinum half-hour patients were largely similar to later-treated patients and included age 69 (interquartile range, 57–79), 44.8% women, prehospital Los Angeles Motor Scale median 4 (3–5), and early-postarrival National Institutes of Health Stroke Scale deficit 8 (interquartile range, 3–18). Platinum half-hour acute cerebral ischemia patients did have more severe prehospital motor deficits and younger age; platinum half-hour intracranial hemorrhage patients had more severe motor deficits, were more often female, and less often of Hispanic ethnicity. Outcomes at 3 m in platinum half-hour patients were comparable to later-treated patients and included freedom-from-disability (modified Rankin Scale score, 0–1) in 35.5%, functional independence (modified Rankin Scale score, 0–2) in 53.2%, and mortality in 17.7%. Conclusions: Prehospital initiation permits treatment start within the platinum half-hour after last known well in a substantial proportion of acute ischemic and hemorrhagic stroke patients, accounting for more than 1 in 10 enrolled in a multicenter trial. Hyperacute platinum half-hour patients were largely similar to later-treated patients and are an attainable target for treatment in prehospital stroke trials.

BackgroundTargeted eloquence-based tissue reperfusion within the primary motor cortex may have a differential effect on disability as compared with traditional volume-based (thrombolysis in cerebral infarction, TICI) reperfusion after endovascular thrombectomy (EVT) in the setting of acute ischemic stroke (AIS).MethodsWe explored the impact of eloquent reperfusion (ER) within primary motor cortex (PMC) on clinical outcome (modified Rankin Scale, mRS) in AIS patients undergoing EVT. ER-PMC was defined as presence of flow on final digital subtraction angiography (DSA) within four main cortical branches, supplying the PMC (middle cerebral artery (MCA) – precentral, central, postcentral; anterior cerebral artery (ACA) – medial frontal branch arising from callosomarginal or pericallosal arteries) and graded as absent (0), partial (1), and complete (2). Prospectively collected data from two centers were analyzed. Multivariate analysis was conducted to assess the impact of ER-PMC on 90-day disability (mRS) among patients with anterior circulation occlusion who achieved partial reperfusion (TICI 2a and 2b).ResultsAmong the 125 patients who met the study criteria, ER-PMC distribution was: absent (0) in 19/125 (15.2%); partial (1) in 52/125 (41.6%), and complete (2) in 54/125 (43.2%). TICI 2b was achieved in 102/125 (81.6%) and ER-PMC was substantially higher in those patients (PConclusionsEloquent PMC-tissue reperfusion is a key determinant of functional outcome, with a greater impact than volume-based (TICI) degree of partial reperfusion alone. PMC-targeted revascularization among patients with partial reperfusion may further diminish post-stroke disability after EVT.

Background Intracranial atherosclerotic disease (ICAD) is one of the most challenging stroke etiologies, with frequent recurrences despite optimized medical management. Encephaloduroarteriosynangiosis (EDAS) is an indirect revascularization method that produces extra-cranial collaterals to intracranial vessels. We present the results of a phase-II trial of EDAS in intracranial atherosclerotic disease patients. Aims To evaluate the feasibility, safety, and preliminary efficacy of EDAS in intracranial atherosclerotic disease patients. Methods ERSIAS was a prospective objective-performance-criterion trial of EDAS plus intensive medical management (IMM) in intracranial atherosclerotic disease (ICAD) patients failing medical treatment. Primary endpoint was any stroke/death within 30-days post-surgery or stroke in the territory of the qualifying artery beyond 30 days. The primary analysis compared event rates through one year with an objective-performance-criterion based on a 10% reduction from the 20% rate in the intensive medical management arm of the stenting versus aggressive medical management for preventing recurrent stroke in intracranial stenosis trial (SAMMPRIS) in patients with poor collaterals. Event rates through two years were compared with propensity-score-matched (PSM) medically treated patients from SAMMPRIS and the carotid occlusion surgery study (COSS). Results During a median follow-up of 24.5 months, 5 (9.6%) of 52 patients had a primary endpoint event. The primary endpoint rate at one year met the threshold for nonfutility and advancement to phase III (Conclusion ERSIAS phase II provides evidence of safety and strong signals of efficacy of EDAS-plus-intensive medical management, supporting advancement to a seamless phase-IIb/III trial. Clinical Trial Registration URL: https://www.clinicaltrials.gov.NCT01819597 .

Developing neurons must meet core molecular, cellular, and temporal requirements to ensure the correct formation of synapses, resulting in functional circuits. However, because of the vast diversity in neuronal class and function, it is unclear whether or not all neurons use the same organizational mechanisms to form synaptic connections and achieve functional and morphologic maturation. Moreover, it remains unknown whether neurons united in a common goal and comprising the same sensory circuit develop on similar timescales and use identical molecular approaches to ensure the formation of the correct number of synapses. To begin to answer these questions, we took advantage of theDrosophilaantennal lobe (AL), a model olfactory circuit with remarkable genetic access and synapse-level resolution. Using tissue-specific genetic labeling of active zones, we performed a quantitative analysis of synapse formation in multiple classes of neurons of both sexes throughout development and adulthood. We found that olfactory receptor neurons (ORNs), projection neurons (PNs), and local interneurons (LNs) each have unique time courses of synaptic development, addition, and refinement, demonstrating that each class follows a distinct developmental program. This raised the possibility that these classes may also have distinct molecular requirements for synapse formation. We genetically altered neuronal activity in each neuronal subtype and observed differing effects on synapse number based on the neuronal class examined. Silencing neuronal activity in ORNs, PNs, and LNs impaired synaptic development but only in ORNs did enhancing neuronal activity influence synapse formation. ORNs and LNs demonstrated similar impairment of synaptic development with enhanced activity of a master kinase, GSK-3β, suggesting that neuronal activity and GSK-3β kinase activity function in a common pathway. ORNs also, however, demonstrated impaired synaptic development with GSK-3β loss-of-function, suggesting additional activity-independent roles in development. Ultimately, our results suggest that the requirements for synaptic development are not uniform across all neuronal classes with considerable diversity existing in both their developmental time frames and molecular requirements. These findings provide novel insights into the mechanisms of synaptic development and lay the foundation for future work determining their underlying etiologies.SIGNIFICANCE STATEMENTDistinct olfactory neuron classes inDrosophiladevelop a mature synaptic complement over unique timelines and using distinct activity-dependent and molecular programs, despite having the same generalized goal of olfactory sensation.

Developing neurons must meet core molecular, cellular, and temporal requirements to ensure the correct formation of synapses, resulting in functional circuits. However, because of the vast diversity in neuronal class and function, it is unclear whether or not all neurons use the same organizational mechanisms to form synaptic connections and achieve functional and morphological maturation. Moreover, it remains unknown if neurons united in a common goal and comprising the same sensory circuit develop on similar timescales and using identical molecular approaches to ensure the formation of the correct number of synapses. To begin to answer these questions, we took advantage of the Drosophila antennal lobe, a model olfactory circuit with remarkable genetic access and synapse-level resolution. Using tissue-specific genetic labeling of active zones, we performed a quantitative analysis of synapse formation in multiple classes of neurons throughout development and adulthood. We found that olfactory receptor neurons (ORNs), projection neurons (PNs), and local interneurons (LNs) each have unique time-courses of synaptic development, addition, and refinement, demonstrating that each class follows a distinct developmental program. This raised the possibility that these classes may also have distinct molecular requirements for synapse formation. We genetically altered neuronal activity in each neuronal subtype and observed differing effects on synapse number based on the neuronal class examined. Silencing neuronal activity in ORNs, PNs, and LNs impaired synaptic development but only in ORNs did enhancing neuronal activity influence synapse formation. ORNs and LNs demonstrated similar impairment of synaptic development with enhanced activity of a master kinase, GSK-3β, suggesting that neuronal activity and GSK-3β kinase activity function in a common pathway. ORNs also, however, demonstrated impaired synaptic development with GSK-3β loss-of-function, suggesting additional activity-independent roles in development. Ultimately, our results suggest that the requirements for synaptic development are not uniform across all neuronal classes with considerable diversity existing in both their developmental timeframes and molecular requirements. These findings provide novel insights into the mechanisms of synaptic development and lay the foundation for future work determining their underlying etiologies.

Background: Prehospital automated large vessel occlusion (LVO) detection in Mobile Stroke Units (MSUs) could accelerate identification and treatment of patients with LVO acute ischemic stroke. Here, we evaluate the performance of a machine learning (ML) model on CT angiograms (CTAs) obtained from 2 MSUs to detect LVO. Methods: Patients evaluated on MSUs in Houston and Los Angeles with out-of-hospital CTAs were identified. Anterior circulation LVO was defined as an occlusion of the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or anterior cerebral artery vessels and determined by an expert human reader. A ML model to detect LVO was trained and tested on independent data sets consisting of in-hospital CTAs and then tested on MSU CTA images. Model performance was determined using area under the receiver-operator curve statistics. Results: Among 68 patients with out-of-hospital MSU CTAs, 40% had an LVO. The most common occlusion location was the middle cerebral artery M1 segment (59%), followed by the internal carotid artery (30%), and middle cerebral artery M2 (11%). Median time from last known well to CTA imaging was 88.0 (interquartile range, 59.5–196.0) minutes. After training on 870 in-hospital CTAs, the ML model performed well in identifying LVO in a separate in-hospital data set of 441 images with area under receiver-operator curve of 0.84 (95% CI, 0.80–0.87). ML algorithm analysis time was under 1 minute. The performance of the ML model on the MSU CTA images was comparable with area under receiver-operator curve 0.80 (95% CI, 0.71–0.89). There was no significant difference in performance between the Houston and Los Angeles MSU CTA cohorts. Conclusions: In this study of patients evaluated on MSUs in 2 cities, a ML algorithm was able to accurately and rapidly detect LVO using prehospital CTA acquisitions.

ATP-binding cassette (ABC) multidrug transporters are large, polytopic membrane proteins that exhibit astonishing promiscuity for their transport substrates. These transporters unidirectionally efflux thousands of structurally and functionally distinct compounds. To preclude the reentry of xenobiotic molecules via the drug-binding pocket, these proteins contain a highly conserved molecular gate, essentially allowing the transporters to function as molecular diodes. However, the structure-function relationship of these conserved gates and gating regions are not well characterized. In this study, we combine recent single-molecule, cryo-EM data with genetic and biochemical analyses of residues in the gating region of the yeast multidrug transporter Pdr5, the founding member of a large group of clinically relevant asymmetric ABC efflux pumps. Unlike the symmetric ABCG2 efflux gate, the Pdr5 counterpart is highly asymmetric, with only four (instead of six) residues comprising the gate proper. However, other residues in the near vicinity are essential for the gating activity. Furthermore, we demonstrate that residues in the gate and in the gating regions have multiple functions. For example, we show that Ile-685 and Val-1372 are required not only for successful efflux but also for allosteric inhibition of Pdr5 ATPase activity. Our investigations reveal that the gating region residues of Pdr5, and possibly other ABCG transporters, play a role not only in molecular gating but also in allosteric regulation, conformational switching, and protein folding.

Background and Purpose: Clot fragmentation and distal embolization during endovascular thrombectomy for acute ischemic stroke may produce emboli downstream of the target occlusion or in previously uninvolved territories. Susceptibility-weighted magnetic resonance imaging can identify both emboli to distal territories (EDT) and new territories (ENT) as new susceptibility vessel signs (SVS). Diffusion-weighted imaging (DWI) can identify infarcts in new territories (INT). Methods: We studied consecutive acute ischemic stroke patients undergoing magnetic resonance imaging before and after thrombectomy. Frequency, predictors, and outcomes of EDT and ENT detected on gradient-recalled echo imaging (EDT-SVS and ENT-SVS) and INT detected on DWI (INT-DWI) were analyzed. Results: Among 50 thrombectomy-treated acute ischemic stroke patients meeting study criteria, mean age was 70 (±16) years, 44% were women, and presenting National Institutes of Health Stroke Scale score 15 (interquartile range, 8–19). Overall, 21 of 50 (42%) patients showed periprocedural embolic events, including 10 of 50 (20%) with new EDT-SVS, 10 of 50 (20%) with INT-DWI, and 1 of 50 (2%) with both. No patient showed ENT-SVS. On multivariate analysis, model-selected predictors of EDT-SVS were lower initial diastolic blood pressure (odds ratio, 1.09 [95% CI, 1.02–1.16]), alteplase pretreatment (odds ratio, 5.54 [95% CI, 0.94–32.49]), and atrial fibrillation (odds ratio, 7.38 [95% CI, 1.02–53.32]). Classification tree analysis identified pretreatment target occlusion SVS as an additional predictor. On univariate analysis, INT-DWI was less common with internal carotid artery (5%), intermediate with middle cerebral artery (25%), and highest with vertebrobasilar (57%) target occlusions ( P =0.02). EDT-SVS was not associated with imaging/functional outcomes, but INT-DWI was associated with reduced radiological hemorrhagic transformation (0% versus 54%; P Conclusions: Among acute ischemic stroke patients treated with thrombectomy, imaging evidence of distal emboli, including EDT-SVS beyond the target occlusion and INT-DWI in novel territories, occur in about 2 in every 5 cases. Predictors of EDT-SVS are pretreatment intravenous fibrinolysis, potentially disrupting thrombus structural integrity; atrial fibrillation, possibly reflecting larger target thrombus burden; lower diastolic blood pressure, suggestive of impaired embolic washout; and pretreatment target occlusion SVS sign, indicating erythrocyte-rich, friable target thrombus.

An emerging feature of neurodegenerative disease is synaptic dysfunction and loss, leading to the suggestion that mechanisms required for synaptic maturation may be linked to disease. Synaptic maturation requires the transmission of signals between nascent synaptic sites and the nucleus, but how these signals are generated is not well understood. We posit that proteolytic cleavage of receptors, which enables their translocation to the nucleus, may be a shared molecular mechanism between the events that promote synaptic maturation and those linked to later-onset disorders of the nervous system, including neurodegenerative disease. Here we show during synaptic development, that cleavage of synaptic maturation molecules requires γ-secretase, a protein complex linked to Alzheimer’s Disease, a devastating neurodegenerative condition, is required for postsynaptic maturation. In the absence of γ-secretase,Drosophilaneuromuscular synapses fail to appropriately recruit postsynaptic scaffolding and cytoskeletal proteins, and mutant larvae display behavioral deficits. At the NMJ, γ-secretase promotes synaptic maturation through the cleavage of the Wnt receptor Fz2, and the subsequent entry of its C-terminus into the nucleus. A developmental synaptic role for γ-secretase is also conserved in both theDrosophilacentral nervous system and mammalian cortical neuron dendrites. Finally, we found that similar maturation defects are evident in fly models for ALS, Alzheimer’s, Huntington’s, and Parkinson’s Diseases. The previously unknown, but conserved, role for γ-secretase coupled with its well-known role in neurodegenerative disease suggest that neurodevelopmental defects may be common to diverse neurodegenerative disease models.

Background Because “time is brain,” acute stroke trials are migrating to the prehospital setting. The impact upon enrollment in post-arrival trials of earlier recruitment in a prehospital trial requires delineation. Methods We analyzed all patients recruited into acute and prevention stroke trials during an 8-year period when an academic medical center (AMC) was participating in a prehospital treatment trial – the NIH Field Administration of Stroke Treatment – Magnesium (FAST-MAG) study. Results During the study period, in addition to FAST-MAG, the AMC participated in 33 post-arrival stroke trials: 27 for acute cerebral ischemia, one for intracerebral hemorrhage, and 5 secondary prevention trials. Throughout the study period, the AMC was recruiting for at least 3 concurrent post-arrival acute trials. Among 199 patients enrolled in acute stroke trials, 98 (49%) were in FAST-MAG and 101 (51%) in concurrent, post-arrival acute trials. Among FAST-MAG patients, 67% were not eligible for any concurrent acute, post-arrival trial. Of 134 patients eligible for post-arrival acute trials, 101 (76%) were enrolled in post-arrival trials and 32 (24%) in FAST-MAG. Leading reasons FAST-MAG patients were ineligible for post-arrival acute trials were: NIHSS too low (23.4%), intracranial hemorrhage (17.9%), IV tPA used in standard management (9.0%), NIHSS too high (7.1%), and age too high (5.2%). Conclusions A prehospital hyperacute stroke trial with wide entry criteria reduced only modestly, by one-fourth, enrollment into concurrently active, post-arrival stroke trials. Simultaneous performance of prehospital and post-arrival acute and secondary prevention stroke trials in research networks is feasible.

SUMMARY Adenosine-to-inosine RNA editing, catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes, alters RNA sequences from those encoded by DNA. These editing events are dynamically regulated, but few trans regulators of ADARs are known in vivo. Here, we screen RNA-binding proteins for roles in editing regulation with knockdown experiments in the Drosophila brain. We identify zinc-finger protein at 72D (Zn72D) as a regulator of editing levels at a majority of editing sites in the brain. Zn72D both regulates ADAR protein levels and interacts with ADAR in an RNA-dependent fashion, and similar to ADAR, Zn72D is necessary to maintain proper neuromuscular junction architecture and fly mobility. Furthermore, Zn72D’s regulatory role in RNA editing is conserved because the mammalian homolog of Zn72D, Zfr, regulates editing in mouse primary neurons. The broad and conserved regulation of ADAR editing by Zn72D in neurons sustains critically important editing events., Graphical Abstract, In Brief Sapiro et al. identify Drosophila Zn72D as an influential regulator of neuronal A-to-I RNA editing and synaptic morphology. Zn72D regulates ADAR levels and editing at a large subset of editing sites, providing insight into the maintenance of critical tissue-specific RNA editing events.

This article reviews the basic tenets of a clinical approach to effective immunotherapy of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). Although one randomized controlled study in early MCI patients by fish-derived omega-3 fatty acids (ω-3) showed slowing of disease progression, large clinical trials with different products have failed to show cognitive effects. Macrophages of healthy subjects phagocytize and degrade amyloid-β1-42 (Aβ) in the brain tissues, whereas macrophages of patients with AD and MCI are functionally defective. ω-3 and ω-3-derived specialized proresolving mediators (SPMs), such as resolvin D1, have powerful biochemical and immunological effects, which may repair the functions of MCI patients' macrophages in the brain's clearance of Aβ. Unfortunately, ω-3 products on the market have a variable quality. Nutritional supplementation with a combination drink called Smartfish with an emulsion of ω-3 and other fatty acids, antioxidants, 1,25-dihydroxy vitamin D3, and resveratrol improved the innate immune system of MCI patients by modulation of macrophage type to the pro-phagocytic M1-M2 type with an effective unfolded protein response against endoplasmic reticulum stress. Some MCI patients maintained their initial cognitive status for three years on Smartfish supplementation. Future randomized clinical trials should investigate the immune effects of ω-3, 1,25-dihydroxy vitamin D3, and SPMs on macrophage type, function, and biochemistry in parallel with cognitive effects.

Background and Purpose— Prehospital scales have been developed to identify patients with acute cerebral ischemia (ACI) because of large vessel occlusion (LVO) for direct routing to Comprehensive Stroke Centers (CSCs), but few have been validated in the prehospital setting, and their impact on routing of patients with intracranial hemorrhage has not been delineated. The purpose of this study was to validate the Los Angeles Motor Scale (LAMS) for LVO and CSC-appropriate (LVO ACI and intracranial hemorrhage patients) recognition and compare the LAMS to other scales. Methods— The performance of the LAMS, administered prehospital by paramedics to consecutive ambulance trial patients, was assessed in identifying (1) LVOs among all patients with ACI and (2) CSC-appropriate patients among all suspected strokes. Additionally, the LAMS administered postarrival was compared concurrently with 6 other scales proposed for paramedic use and the full National Institutes of Health Stroke Scale. Results— Among 94 patients, age was 70 (±13) and 49% female. Final diagnoses were ACI in 76% (because of LVO in 48% and non-LVO in 28%), intracranial hemorrhage in 19%, and neurovascular mimic in 5%. The LAMS administered by paramedics in the field performed moderately well in identifying LVO among patients with ACI (C statistic, 0.79; accuracy, 0.72) and CSC-appropriate among all suspected stroke transports (C statistic, 0.80; accuracy, 0.72). When concurrently performed in the emergency department postarrival, the LAMS showed comparable or better accuracy versus the 7 comparator scales, for LVO among ACI (accuracies LAMS, 0.70; other scales, 0.62–0.68) and CSC-appropriate (accuracies LAMS, 0.73; other scales, 0.56–0.73). Conclusions— The LAMS performed in the field by paramedics identifies LVO and CSC-appropriate patients with good accuracy. The LAMS performs comparably or better than more extended prehospital scales and the full National Institutes of Health Stroke Scale.

Introduction: Emboli retrieved from stroke patients undergoing mechanical thrombectomy vastly differ in histopathologic appearance, likely reflecting varying etiologies of stroke. We investigated whether clot components correlated with clinical features and thrombectomy outcomes. Methods: Retrieved thrombi from endovascular thrombectomy in consecutive AIS-LVO patients at 2 academic medical centers were fixed in formalin and sections stained by hematoxylin and eosin. The RBC, WBC and fibrin percentages of the clot were quantified by a neuropathologist blinded to the clinical details. We evaluated the association of these clot components, patient demographic and clinical features, with TICI score (both ordinal and dichotomized at 2c), AOL score, number of thrombectomy passes, and first-pass substantial recanalization (≥TICI 2b result on the first thrombectomy device pass). Non-parametric values were computed via Spearman correlation and pairwise interaction of clinical features was analyzed by ordinal logistic regression. Results: Among the 75 analyzed patients, mean age was 71.4 (SD 17.7), 50.7% were female and presenting NIHSS mean was 16.1 (SD 7.6). Devices employed were stent retrievers in 71% of patients, aspiration in 10%, and both stent retrievers and aspiration in 19%. Number of passes per procedure was mean 2.16 (SD 1.21). Substantial reperfusion (TICI 2B-3) was achieved in 88% and excellent reperfusion (TICI 2C-3) in 44%. In retrieved thrombi, mean RBC% was 44.8% (SD 31.9) and mean fibrin% was 49.8% (SD 31.4). Rates of first-pass substantial reperfusion, final substantial reperfusion, and final excellent reperfusion were homogenous across wide ranges of retrieved thrombus RBC% and fibrin% in correlation analysis. Conclusion: RBC and fibrin composition range widely among retrieved thrombi causing acute ischemic stroke. Current generation thrombectomy devices perform well across a broad range of clot compositions.

Background: Mobile Stroke Units (MSUs) are capable of rapid initiation of intravenous thrombolysis and have the potential to improve acute stroke patient routing by providing conclusive imaging diagnosis of LVO (arterial sequences) and intracranial hemorrhage (parenchymal/extraparenchymal sequences). However, the incremental increase in diagnostic accuracy and effect on patient disposition have not been well delineated. Methods: Consecutive transports in a regionally-deployed MSU from September 2017-August 2019) were analyzed, comparing patient routing that would have occurred under standard ambulance protocols to routing and process outcomes after CT/CTA MSU imaging. Standard ambulance regional routing policy was direct to nearest PSC if Los Angeles Motor Scale (LAMS) 0-3 and direct to nearest CSC within 30m if LAMS 4-5. Results: Among 83 MSU transports, final diagnosis was acute cerebral ischemia in 68% and intracranial hemorrhage in 10%. Among 57 acute cerebral ischemia patients, Los Angeles Motor Scale (LAMS) score was 0-3 in 65% and 4-5 in 35%. All (100%) of patients with ICA/M1 occlusions had LAMS score 4-5. However, among patients with expanded range endovascular target occlusions (M2, basilar), LAMS scores were 0-3 in 56%, and MSU imaging permitted improved routing. Among 8 intracranial hemorrhage patients (2 IPH, 5 SDH, 1 SAH), MSU imaging permitted improved direct-to-CSC routing in the 62% of patients with LAMS scores 0-3. Among all MSU admissions, 15% (13) were rerouted based solely upon in-vehicle imaging, including 7% for radiographically proven endovascularly treatable occlusion, 7% for neurosurgical/NICU intracranial hemorrhage care, and 1% for neurosurgical tumor care. Transport times for re-routed patients was median 12 minutes, compared to closest stroke center median 6 minutes. Conclusion: More than 1 in 7 MSU evaluations result in improved routing of comprehensive stroke center-appropriate patients directly to a CSC facility, including AIS patients potentially eligible for thrombectomy, intracranial hemorrhage patients, and acutely-presenting brain tumor patients. In addition to speeding start of intravenous thrombolysis, MSUs can substantially improve timely access to CSC care.

Background: Circadian variations in stroke onset provide critical information for allocation of prehospital and hospital resources in clinical care and clinical trials. Studies of stroke circadian timing have had conflicting findings, and understanding would benefit from analysis confined to patients with defined onset in waking and clearly distinguished ischemic and hemorrhagic stroke subtypes. Methods: We analyzed all patients enrolled in the NIH FAST-MAG phase 3 trial of field-initiated neuroprotective agent in patients with hyperacute stroke within 2h of onset (last known well). Onset times were analyzed in 1h time blocks throughout the 24h day-night cycle. Patient demographic and clinical features, medical history, imaging characteristics, and stroke deficit severity were evaluated for association with onset times. Results: Among 1632 patients, final diagnoses were acute cerebral ischemia in 76.2% and intracranial hemorrhage in 23.7%. Hourly circadian variation in onset is shown in the Figure. Acute cerebral ischemia (ACI) had a unimodal distribution with peak onset at midday (12:00-12:59); intracerebral hemorrhage (ICH) a bimodal distribution with peaks at mid-morning (08:00-08:59) and early evening (18:00-18:59). Events were markedly reduced in early morning, with only 3.4% starting in the 25% of the day between 00:00-05:59. The proportion of events that were hemorrhagic was higher in the first 8h of the day (00:00-07:59) than the remaining 16h, 33.3% vs 22.5%, p=0.006. Both among ACI and ICH patients, vascular risk factors, presenting deficit severity, and initial brain imaging findings were fairly homogenous throughout all day-night time periods. Conclusion: There is marked, more than 10-fold, circadian variation in onset of acute cerebrovascular disease, and circadian variation in the ratio of ischemic to hemorrhagic neurovascular events. These findings can inform resource planning for regional systems of acute stroke care.

Background: As hemorrhagic and ischemic strokes progress, acute stroke therapy is time dependent. To emphasize treatment speed for time-sensitive conditions, emergency medicine has developed not only the concept of the “golden hour,” but also the “platinum thirty”. Acute stroke patients treated within the first half-hour of onset have not been previously characterized. Methods: We analyzed all patients with acute stroke symptoms enrolled in the multicenter NIH-funded FAST-MAG trial, testing paramedic prehospital start of neuroprotective agent within 2h of onset. The frequency, demographic, clinical, and outcome features of patients with treatment start within the platinum 30m were compared with later treated patients. Results: Among the 1700 enrolled patients, 180 (10.6%) received study agent within 30 minutes of last known well (LKW). In these platinum-30 patients, final diagnoses were: acute cerebral ischemia in 70.0% (ischemic stroke 59.4%, TIA 10.6%); intracranial hemorrhage in 26.7%; and mimic in 2.8%, similar to the overall study population. Mean age was 68.3 (±13.2) years, 46.1% were women, initial deficit in the field on the Los Angeles Motor Scale was mean 4.1 (±1.2) and early-post-arrival NIHSS deficit was 11.3 (±10.5). Time from LKW to 911 call was median 4m (IQR 2-6); from LKW to paramedic evaluation 10m (IQR 7-12); from LKW to study drug start 27m (IQR 25-29); and from LKW to ED arrival 36m (IQR 31-41). Outcomes at 3 months included freedom from disability (mRS 0-1) in 35.0%, functional independence (mRS 0-2) in 53.3%, and mortality in 17.2%. Demographic, medical history, presenting deficit severity, and 3m outcomes among the platinum-30 patients were largely similar to the 1415 patients treated between 31-120m after onset. Conclusions: Paramedic prehospital initiation of neuroprotection study agent permits treatment start within the platinum first 30 minutes in a substantial proportion of acute ischemic and hemorrhagic stroke patients, accounting for more than 1 in 10 patients enrolled in a multicenter trial. Hyperacute

Background: Intracranial atherosclerotic disease (ICAD) is one of the most challenging stroke etiologies, with frequent recurrences despite optimized medical management. Encephaloduroarteriosynangiosis (EDAS) is an indirect revascularization method that produces collaterals from the extracranial circulation into cerebral hypoperfused areas. We present the results of a phase-II trial of EDAS in patients with ICAD failing medical management. Methods: ERSIAS was a prospective objective performance criterion (OPC) trial of EDAS plus intensive medical management (IMM) in patients with symptomatic ICAD despite optimized medical management, and poor angiographic collaterals. The primary endpoint was any stroke or death within 30 days postsurgery or stroke in the territory of the qualifying artery beyond 30 days. The primary analysis compared event rates through one year with the OPC of 10·1%, based on a 10% reduction from the 20·1% rate in the IMM arm of SAMMPRIS trial. The event rates through two years were compared with propensity-score-matched (PSM) medically treated patients from the SAMPPRIS and COSS trials. Secondary endpoints included functional neurological outcome and angiographic neovascularization. Findings: Fifty-two patients underwent EDAS-plus-IMM. The median age was 52 years (IQR=38·3-65·8), and 32 were females (61·5%). The primary endpoint rate at one year was 9·6%, lower than the OPC of 10·1% (p=0·07), meeting the p

Background and Purpose— The Los Angeles Motor Scale (LAMS) is a 3-item, 0- to 10-point motor stroke-deficit scale developed for prehospital use. We assessed the convergent, divergent, and predictive validity of the LAMS when performed by paramedics in the field at multiple sites in a large and diverse geographic region. Methods— We analyzed early assessment and outcome data prospectively gathered in the FAST-MAG trial (Field Administration of Stroke Therapy–Magnesium phase 3) among patients with acute cerebrovascular disease (cerebral ischemia and intracranial hemorrhage) within 2 hours of onset, transported by 315 ambulances to 60 receiving hospitals. Results— Among 1632 acute cerebrovascular disease patients (age 70±13 years, male 57.5%), time from onset to prehospital LAMS was median 30 minutes (interquartile range 20–50), onset to early postarrival (EPA) LAMS was 145 minutes (interquartile range 119–180), and onset to EPA National Institutes of Health Stroke Scale was 150 minutes (interquartile range 120–180). Between the prehospital and EPA assessments, LAMS scores were stable in 40.5%, improved in 37.6%, and worsened in 21.9%. In tests of convergent validity, against the EPA National Institutes of Health Stroke Scale, correlations were r =0.49 for the prehospital LAMS and r =0.89 for the EPA LAMS. Prehospital LAMS scores did diverge from the prehospital Glasgow Coma Scale, r =−0.22. Predictive accuracy (adjusted C statistics) for nondisabled 3-month outcome was as follows: prehospital LAMS, 0.76 (95% confidence interval 0.74–0.78); EPA LAMS, 0.85 (95% confidence interval 0.83–0.87); and EPA National Institutes of Health Stroke Scale, 0.87 (95% confidence interval 0.85–0.88). Conclusions— In this multicenter, prospective, prehospital study, the LAMS showed good to excellent convergent, divergent, and predictive validity, further establishing it as a validated instrument to characterize stroke severity in the field.

Background: Prior studies have suggested race-ethnic differences in functional outcome, mortality, and use of comfort care after stroke, but have been limited by analysis of single stroke subtypes, lack of 3-month outcomes, and uncertainty whether delayed access to acute care was moderating response patterns. Methods: We analyzed all patients with final diagnoses of acute cerebral ischemia or intracranial hemorrhage enrolled within 2 hours of onset in the multicenter, prehospital NIH FAST-MAG trial. Self- or family-reported race-ethnicity was analyzed for relation to presenting stroke features, stroke subtype, and 3-month outcome. Results: Among 1616 hyperacute cerebrovascular disease patients (76.4% acute cerebral ischemia, 23.6% intracranial hemorrhage), race-ethnic frequencies were: white, non-Hispanic (W) - 55.5%, Hispanic (H) - 23.1%, Black (B) - 13.6%, Asian (A) - 8.4%. Ischemic vs hemorrhagic stroke differed by race-ethnicity, with hemorrhagic strokes more common in Hispanics (34.0%) and Asians (28.1%), compared with Whites (19.8%) and Blacks (17.8%), p = 0.0001. Age at time of stroke was highest in Whites (mean 73.1), vs H (65.5), B (63.5), A (66.9); and presenting severity (NIHSS) highest in A (mean 13.5) and H (12.7), vs W (10.7) and B (10.8). A greater dimorphic spread in 3 month outcomes was seen in W than in the other race-ethnic groups: Whites had more excellent (mRS 0-1) 3 month outcomes - W- 42.2%, B- 35.0%, H -28.4%, A-28.0%, p = 0.002; but Whites also had higher mortality by 3m - W-18.2%, A- 15.6%, H-13.0%, B-10.6%, p = 0.007. The race-ethnic difference in mortality was driven by hemorrhagic rather than ischemic strokes: ICH mortality - W-41.7%, A-19.4%, H-19.0%, B-18.2%; IS mortality: A-14.4%, W-13.5%, H-10.5%, B-9.4%. Conclusions: In this multicenter study of acute cerebrovascular disease in a diverse US region, notable race-ethnic differences included higher frequencies of hemorrhagic vs ischemic stroke among Hispanics and Asians; and more excellent, but also more fatal, 3 month outcomes among Whites. These patterns likely distinct different race-ethnic risk factor profiles shaping incident stroke type, as well as divergent sociocultural influences upon robust rehabilitation care and comfort care measures.

Introduction: Among all stroke patients, intracranial hemorrhage (ICH) patients activate the 911 system sooner than cerebral ischemia (CI) patients. However, the temporal profiles of EMS alarm and response among hyperacute patients who may be enrolled in prehospital treatment trials has not been well delineated. Methods: We analyzed all final diagnosis acute cerebrovascular disease patients enrolled in the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial, in 315 ambulances transporting to 60 receiving stroke centers. Results: Among 1632 hyperacute cerebrovascular disease patients, final diagnosis was ICH in 23.7% and CI in 76.3%. Compared with CI patients, ICH patients were younger (65.3 vs 70.9, p < 0.001), less often female (33.3% vs 45.3%, p Conclusion: Speed of prehospital care is swift among hyperacute cerebrovascular disease patients, including 911 calls at 15 minutes after last known well, paramedic arrival on patient 6 minutes after 911 activation, and ED arrival 39 minutes after 911 activation. In the hyperacute window, ICH patients call 911 only slightly faster than ACI patients, and subsequent prehospital intervals of care are similar. In a busy metropolitan region, national alarm-to-on patient time targets were achieved in more than three-quarters of patients.

Background Pivotal clinical trials suggest that intravenous (IV) recombinant tissue plasminogen activator (rt-PA) benefits stroke patients regardless of the underlying etiology. Paradoxical strokes, presumed to be caused by fibrin-rich clots originating in the venous circulation, may respond better to fibrinolysis than other ischemic stroke subtypes. In this study, we compared the response with IV rt-PA in paradoxical stroke patients and other stroke subtypes. Methods In total, 486 patients treated with IV rt-PA at a single institution were retrospectively reviewed. Adjudication of stroke mechanism was based on chart review. Five major stroke mechanisms—cardioembolic, artery-to-artery emboli, lacunar, cryptogenic, and paradoxical—were identified by final diagnosis from chart reviews. Mimics, undefined etiology, and defined etiology not falling into the major mechanisms were excluded. Analysis of variance and general linear model were used to assess the differences between groups. Results A total of 323 patients were analyzed. We found significant differences in clinical outcome between stroke mechanisms, including discharge National Institutes of Health Stroke Scale (NIHSS) ( P = .007), discharge Rankin ( P = .011), discharge disposition ( P = .000), and infarct volume ( P = .007). Post hoc analysis showed that cardioembolic patients had the worst outcomes (discharge NIHSS score 11.12 ± 12.26), whereas paradoxical strokes had the best outcomes (discharge NIHSS score 3.67 ± 4.90), but these did not approach statistical significance. However, regression analysis showed that 4 variables—congestive heart failure, admission NIHSS, age, and mean infarct volume—rather than stroke mechanism were the true predictors of poor outcome. Conclusions Paradoxical strokes had better outcomes after IV fibrinolysis than other ischemic stroke subtypes, but this difference is attributable to younger age and milder stroke severity on presentation.

Background: Informed consent options for acute stroke randomized trials include self-consent from patients with retained competency, proxy consent from a legally authorized representative (LAR), and exception from informed consent in emergency circumstances (EFIC). Mechanisms other than self-consent trespass upon the ethical principle of autonomy (respect for persons), and should be used only if self-consent alone would bias the patient population. Methods: We analyzed acute stroke patients enrolled within 2h of symptom onset in the NIH Phase 3 Field Administration of Stroke Therapy - Magnesium (FAST-MAG) trial, comparing entry characteristics and outcomes with different consent mechanisms. Results: Among 1700 patients, median time from onset to study entry was 45 min (IQR 35-62). Overall, 60% of patients were competent and provided self-consent, 39% noncompetent and enrolled by proxy consent from an on-scene LAR, and 1% noncompetent enrolled using EFIC/delayed consent. Compared to self-consented patients, proxy-consented patients were: older, 73.8 vs 66.5, p Conclusions: Proxy-informed consent patients differ systematically from self-consent patients, with older age, more comorbidities, more severe deficits, and worse long term outcomes. To ensure that acute stroke trial cohorts are representative of the general stroke population, it is important that enrollment mechanisms include proxy and/or deferred consent.

Background: Stroke evolution after hospital arrival is well characterized for acute cerebral ischemia and intracranial hemorrhage. But with the advent of patient routing to designated stroke centers, and of prehospital stroke therapeutic trials, it is important to characterize stroke evolution in the earliest, prehospital moments of onset. Initial studies have prehospital evolution using serial Glasgow Coma Scale (GCS) assessment; however, GCS assesses level of consciousness rather than focal deficits. Methods: In the NIH FAST-MAG trial database, we analyzed patient deficit evolution from time of first paramedic assessment to early post-arrival assessment in the ED, using serial scores on the GCS, serial scores on the Los Angeles Motor Scale (LAMS) (a prehospital stroke deficit measure), and the Paramedic Global Impression of Change (PGIC) score, a 5 point Likert paramedic-clinician score. Results: Among 1632 acute, EMS-transported neurovascular disease patients, 1,245 (76.3%) had a final diagnosis of acute cerebral ischemia and 387 (23.7%) of acute intracranial hemorrhage. Time of paramedic initial assessment was median 23 mins (IQR 14-41) after onset and time of early ED assessment 58 mins (IQR 46-78). Considering score changes by 2 or more as salient, overall the LAMS and GCS indicated approximately equal frequencies of prehospital deterioration (LAMS 11.1%, GCS 12.0%), but the LAMS indicated higher frequencies of prehospital improvement (LAMS 24.5% vs GCS 5.7%, p Conclusions: Focal deficit scales are superior to the GCS in characterizing prehospital stroke evolution. Change in neurologic status occurs in more than one-third of acute stroke patients during transport and the early ED, with improvement more common in acute cerebral ischemia and deterioration more common in ICH.

Introduction: The specific protein composition of stroke-causing emboli is unknown. Because ischemic stroke has a varied etiology, it is possible that the composition of the thrombus from which an embolus originated will have distinctive molecular characteristics reflective of the underlying pathophysiology. In this study, we used mass spectrometry to evaluate the protein composition of retrieved emboli from patients with differing stroke etiologies and correlated the protein levels to serum predictors of atherosclerosis. Methods: Emboli from 20 consecutive acute stroke patients were retrieved by embolectomy during routine stroke care. Thrombus proteins were extracted, digested and multidimentional fractionation of peptides was performed. Fractionated peptides underwent nano-liquid chromatography with tandem mass spectrometry. Spectra were searched using Mascot software in which results with p Results: Demographics: 55% had atrial fibrillation, 20% had significant proximal vessel atherosclerosis, 10% were cryptogenic, and three had other identified etiologies (left ventricular thrombus, dissection, endocarditis). Eighty-one common proteins (eg hemoglobin, fibrin, actin) were found in all 20 emboli. Serum LDL levels correlated with Septin-2 (r s =0.78, p=0.028), Phosphoglycerate Kinase 1 (r s =0.75, p=0.036), Integrin Alpha-M (r s =0.68, p=0.033) and Glucose-6-phosphate dehydrogenase (r s =0.63, p=0.05). Septin-7 levels inversely correlated to ESR (r s = -0.84, p=0.01). No significant protein correlations to A1C were found. Conclusion: To our knowledge, this study is the first mass spectrometry analysis of thrombi retrieved from acute stroke patients and the first to correlate the thrombus proteome to clinical features of the patient. Notably, we found proteins associated with inflammation (eg Integrin Alpha–M) in emboli from patients with high LDL. Although these findings are tempered by a small sample size, we provide preliminary support for the feasibility of utilizing proteomic analysis of emboli to discover proteins that may be used as markers for stroke etiology.

Background: Clinical trials of stroke therapies require accurate documentation of last known well time (LKWT) to account for injury accumulation prior to treatment start. For prehospital studies, this requirement is particularly challenging, as paramedic-determined and final-determined LKWTs in routine practice are concordant (within 15 mins) in only half of cases. We sought to determine the accuracy of LKWT obtained in the field by a two-tier enrollment system of study-trained paramedics and cellphone-connected physician-investigators. Methods: Paramedics screened consecutive transports for participation in the NIH Field Administration of Stroke Therapy-Magnesium (FAST-MAG) clinical trial. Paramedic screening criteria included LKWT Results: A total of 4458 post-screening enrollment calls were made by paramedics from January 2005 to December 2012 of which 539 (12%) were determined by physician-instigators to have inaccurate LKWT leading to non-enrollment. Of the remaining 3919 calls, 1700 led to enrollments in the study and 2219 were not enrolled for a reason other than inaccurate LKWT. Among enrolled cases, exact congruence between prehospital and post-arrival LKWTs occurred 72% (n=1220), concordance within 15 minutes in 87%, within 30 minutes in 93%, and within 1 hour in 97%. Among enrolled cases, final-determined LKWT was within the study entry window of 2h in 96.3%. Conclusions: A 2-tiered system of paramedic screening followed by physician-investigator cellphone assessment led to high congruence between prehospital-determined and post-arrival-determined of LKWT. This system can be used in future trials of prehospital, paramedic-in initiated stroke therapy when accuracy of LKWT is important for intervention evaluation.

Background and Purpose— Novel methods are needed to reduce the disparity of Hispanic enrollment in stroke clinical trials. Prehospital enrollment using a dedicated Spanish language line may help overcome this bias. Methods— Subjects or legally authorized representatives provided information on race and ethnicity for all cases enrolled in the FAST-MAG clinical trial (Field Administration of Stroke Therapy-Magnesium), a prehospital phase 3 randomized study of intravenous magnesium for neuroprotection. One of 2 in-ambulance cell phones (in English or Spanish) was used to obtain informed content in the field. We describe the yield and characteristics of subjects enrolled via Spanish line. Results— There were 1700 subjects enrolled from 2005 to 2012, of which 402 (24%) identified as Hispanic ethnicity. Study racial makeup was 1325 (78%) white, 219 (13%) black, and 139 (8%) Asian. The dedicated Spanish line was used for 195 (12%) enrollments. Spanish-line enrollments were younger (65 versus 70 years old; P P P Conclusions— The use of a dedicated Spanish language enrollment line allowed for greater enrollment of Hispanics, a population with significantly different baseline characteristics. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00059332.

A practical diagnostic test is needed for early Alzheimer's disease (AD) detection. Immunosignaturing, a technology that employs antibody binding to a random-sequence peptide microarray, generates profiles that distinguish transgenic mice engineered with familial AD mutations (APPswe/PSEN1-dE9) from non-transgenic littermates. It can also detect an AD-like signature in humans. Here, we assess the changes in the immunosignature at different time points of the disease in mice and humans. We also evaluate the accuracy of the late-stage signature as a test to discriminate between young mice with familial AD mutations from non-transgenic littermates. Plasma samples from AD patients were assayed 3–12 months apart, while APPswe/PSEN1-dE9 and non-transgenic controls supplied plasma at monthly intervals until they reached 15 months of age. Microarrays with 10,000 random-sequence peptides were used to compare antibody binding patterns. These patterns gradually changed over the life-span of mice. Strong, characteristic signatures were observed in transgenic mice at early, mid and late stages, but these profiles had minimal overlap. The signature of young transgenic mice had an error rate of 18% at classifying plasma samples from late-stage transgenic mice. Conversely, the late-stage transgenic mice signature discriminated between young transgenic mice and littermates with an error rate of 21%. Less distinctive profiles were recognizable throughout the transgenic mice lifespan, being detectable as early as 2 months. The human signature had minimal change on short-term follow-up. Our results call for a reappraisal of the way incipient AD is studied, as biomarkers seen in late-stages of the disease may not be relevant in earlier stages.

A previously healthy 49-year-old woman experienced left arm paresthesias. Over the next few weeks, the paresthesias progressed to all extremities. Initial laboratory studies were unrevealing; the patient's progressive weakness and numbness continued. An MRI brain was consistent with an unspecified demyelinating disease affecting the cortical white matter and cervical spine. Lumbar puncture revealed normal cell count and differential, with negative culture, gram stain, and oligoclonal bands. She was then diagnosed clinically with multiple sclerosis (MS) and treated with teriflunomide. She soon developed skin and joint pain, intractable hiccups for 22 days, early satiety, and urinary incontinence. Repeat MRI again showed demyelinating lesions, this time in her thoracic spine. Her treatment was changed to glatiramer acetate.

Background and Purpose— Paramedic use of fixed-size lumen, gravity-controlled tubing to initiate intravenous infusions in the field may allow rapid start of neuroprotective therapy for acute stroke. In a large, multicenter trial, we evaluated its efficacy in attaining target serum levels of candidate neuroprotective agent magnesium sulfate and the relation of achieved magnesium levels to outcome. Methods— The FAST-MAG phase 3 trial (Field Administration of Stroke Therapy – Magnesium) randomized 1700 patients within 2 hours of onset to paramedic-initiated, a 15-minute loading intravenous infusion of magnesium or placebo followed by a 24-hour maintenance dose. The drug delivery strategy included fixed-size lumen, gravity-controlled tubing for field drug administration, and a shrink-wrapped ambulance kit containing both the randomized field loading and hospital maintenance doses for seamless continuation. Results— Among patient randomized to active treatment, magnesium levels in the first 72 hours were assessed 987 times in 572 patients. Mean patient age was 70 years (SD±14 years), and 45% were women. During the 24-hour period of active infusion, mean achieved serum level was 3.91 (±0.8), consistent with trial target. Mg levels were increased by older age, female sex, lower weight, height, body mass index, and estimated glomerular filtration rate, and higher blood urea nitrogen, hemoglobin, and higher hematocrit. Adjusted odds for clinical outcomes did not differ by achieved Mg level, including disability at 90 days, symptomatic hemorrhage, or death. Conclusions— Paramedic infusion initiation using gravity-controlled tubing permits rapid achievement of target serum levels of potential neuroprotective agents. The absence of association of clinical outcomes with achieved magnesium levels provides further evidence that magnesium is not biologically neuroprotective in acute stroke.

Many patients with stroke-mimicking conditions receive treatment with intravenous fibrinolysis (IVF), a treatment associated with potentially serious complications. We sought to determine if any clinical or radiographic characteristics can help predict stroke mimics among IVF candidates.This retrospective study was carried out at a single institution. Patients treated with intravenous recombinant tissue plasminogen activator (rt-PA; n = 193) were divided into 3 categories: acute ischemic stroke (n = 142), aborted stroke (n = 21), and stroke mimics (n = 30). Analysis of variance and the chi-square test were used to assess differences, while logistic regression models were computed to predict groups.Mimics treated with rt-PA did not experience complications (intracranial bleeding, systemic hemorrhage, or angioedema), and had better neurologic and functional outcomes than stroke patients (P.05). Several variables helped differentiate strokes from mimics, including atherosclerosis on computed tomographic angiography (odds ratio [OR] 23.6; 95% confidence interval [CI] 8.4-66.2), atrial fibrillation (OR 11.4; 95% CI 1.5-86.3), age50 years (OR 7.2; 95% CI 2.8-18.5), and focal weakness (OR 4.15; 95% CI 1.75-9.8). Other variables decreased chances of stroke: migraine history (OR 0.05; 95% CI 0.01-0.4), epilepsy (OR 0.13; 95% CI 0.02-0.8), paresthesia (OR 0.1; 95% CI 0.04-0.3), and precordialgia (OR 0.045; 95% CI 0.002-0.9). A regression model using focal weakness, computed tomographic angiography findings, and precordialgia had a 90.2% predictive accuracy.IVF has low complication rates in stroke mimics. Certain clinical characteristics appear predictive of stroke mimics, particularly normal computed tomographic angiography. If confirmed, this may help prevent giving IVF to patients without stroke.

Objetivo: describir las características sociales, demográficas y los componentes de educación, salud y empleo de la población con algún tipo de limitación de la ciudad de Medellín, 2008. Materiales y Métodos: estudio descriptivo transversal, con fuente de información secundaria de 4283 personas con algún tipo de limitación (sensorial, física, mental o del habla) registradas en la Encuesta de Calidad de Vida 2008. El análisis fue univariado y bivariado según sexo y comuna, se acompañó con pruebas estadísticas. Resultados: de las personas con algún tipo de limitación, el 53,2% eran mujeres, con 46 años en promedio, el 84,5% están afiliados a salud, el 26,2% están incapacitados permanentemente para trabajar y el 78% de las personas con algún tipo de limitación no recibió ingresos de ningún tipo en el año 2008. La limitación más prevalente fue la sensorial (48,6%), seguida de la física (39,3%), mental (26,3%) y del habla (14,4%). Estas últimas presentaron un 38,4% de analfabetismo y el 35% de los limitados físicos presentó deserción escolar. Conclusiones: se evidenció una relación directamente proporcional entre la edad y la presencia de algún tipo de discapacidad; adicional a esto, existen factores económicos, educativos y de salud que deterioran su calidad de vida y aumentan su vulnerabilidad.Objetivo: descrever as características sociais demográficas e os componentes de educação, saúde e emprego da povoação com algum tipo de limitação da cidade de Medellín, 2008. Materiais e Métodos: pesquisa descritiva transversal, com fonte de informação secundaria de 4283 pessoas com algum tipo de limitação (Sensorial, física, mental o de falar) registrado na Enquete de Qualidade de Vida 2008. O analise foi uni- variado e bivariado segundo sexo e comuna, acompanhou se testes estadísticos. Resultados: das pessoas com algum tipo de limitação, o 53,2% foram mulheres, com 46 anos em meia, o 84,5% estão afiliados a saúde, o 26,2% são deficientes físicos permanentes para trabalhar e o 78% das pessoas com algum tipo de deficiência física não recebeu ingressos de nenhum tipo no ano 2008. A deficiência física mais prevalente foi a sensorial (48,6%), seguida da física (39,3%), mental (26,3%) e do fala (14,4%). Esta ultima apresentou um 38,4% de analfabetismo e o 35% dos limitados físicos apresentou deserção escolar. Conclusões: evidenciou se uma relação diretamente proporcional entre idade e a presença de algum de tipo de deficiência; adicional a isto, existem fatores econômicos, educativos e de saúde que deterioraram sua qualidade de vida e aumentam sua vulnerabilidade.Objective: To describe the social, demographic characteristics and the education, health, and employment components of people with some kind of limitation in the city of Medellin, 2008. Materials and Methods: descriptive transversal study with secondary data source of 4,283 people with some type of limitation (sensory, physical, mental or speech) recorded in the 2008 Quality of Life Survey. The univariate and bivariate analysis was carried out by sex and district, and it was accompanied by statistical tests. Results: of those people with some kind of limitation, 53.2% were women, 46 years old average, 84.5% are part of the health system, 26.2% are permanently disabled to work and 78% of these people with some kind of limitation did not receive any income in 2008. The most prevalent limitation was the sensory limitation (48.6%), followed by physical limitation (39.3%), mental limitation (26.3%) and speech limitation (14.4%). These last ones showed a 38.4% illiteracy and 35% of the physically limited presented school dropout. Conclusions: A direct relationship between age and the presence of a disability was evident. In addition to this there is economical, educational and health factors deteriorate their quality of life and increase their vulnerability.

Background: There is limited experience in the community with intravenous tissue plasminogen activator (rt-PA) administered 3 to 4.5 hours after acute ischemic stroke (AIS) onset. Many patients do not meet entry criteria of pivotal clinical trials because of severe stroke, age >80, severe hypertension (sHTN), or history of previous stroke and diabetes. Whether rt-PA benefits these patients is unclear. Thus, we investigated the outcomes of stroke patients treated with rt-PA with or without these adverse clinical characteristics. Methods: Chart review of patients with AIS treated with intravenous rt-PA at a single institution. Outcomes at discharge were compared between patients with severe stroke, age >80, sHTN, or previous stroke/diabetes and those without these characteristics. Good outcome was defined as modified Rankin score (mRS) of 0 to 1. Analysis of variance and t tests were used to compare the outcomes. Results: Of the 118 cases analyzed, 103 (87%) were treated ≤3 hours and 15 (13%) between 3 and 4.5 hours. Sixty-three (53%) patients had severe stroke, age >80, sHTN, or previous stroke/diabetes, whereas 55 (47%) did not. Compared to controls, patients with these adverse characteristics were less likely to have good outcomes (35% vs 56%, p = .02). No patients treated within the 3- to 4.5-hour window experienced symptomatic intracranial hemorrhage (sICH). Eight patients treated between 3 and 4.5 hours had severe stroke, age >80, sHTN, or previous stroke/diabetes. Of these, 6 had poor outcomes. Conclusions: In a highly selected group of patients treated with intravenous rt-PA, lack of adherence to current guidelines did not improve stroke outcomes. This was related to more severe strokes at baseline, not sICH. Prospective studies of this patient group are needed.

Background: Endovascular recanalization therapies are an increasingly employed treatment strategy in acute cerebral ischemia. The determinants of the final clinical outcome after endovascular treatment have been understudied. We investigated the effects of hyperlipidemia and statins on acute ischemic stroke outcomes after endovascular procedures. Methods: An inquiry of a prospectively maintained stroke registry was conducted. Endovascular procedures were performed using recombinant tissue plasminogen activator, prourokinase or the Merci device within 12 hours after symptom onset. The analyzed outcomes were revascularization, hemorrhage and excellent functional outcome (Rankin score of 0–1 at 3 months). The analyses included χ2 and Wilcoxon rank sum, logistic regression (for multivariate analyses with binary outcomes) and linear regression (for continuous outcomes). Significance was set at p < 0.05. Results: We included 142 patients, 80% treated with intra-arterial fibrinolysis, 22% with percutaneous mechanical embolectomy and 27% treated with intravenous fibrinolysis prior to endovascular intervention. Age (OR = 0.956, 95% CI = 0.927–0.986, p = 0.0041), National Institutes of Health Stroke Scale (NIHSS) score on admission (OR = 0.881, 95% CI = 0.812–0.957, p = 0.0025) and history of hyperlipidemia (OR = 0.284, 95% CI = 0.08–0.99, p = 0.0478) were negatively associated with excellent functional outcome at 3 months. Every 50 mg/dl increment in the total cholesterol level resulted in 64% decrease in the odds of excellent functional outcome (OR = 0.36, 95% CI = 0.447–0.882, p = 0.0253). History of hyperlipidemia decreased the likelihood of neurological improvement (p = 0.0462) and was associated with a higher NIHSS score at 7 days or discharge. Statin use was related to an average 6.5-unit NIHSS decrease at discharge (p = 0.0168). Statins were not associated with increased frequency of recanalization or symptomatic intracerebral hemorrhage. Conclusions: History of hyperlipidemia may have a negative impact on the outcomes of acute ischemic stroke treated with intra-arterial fibrinolysis or percutaneous mechanical embolectomy. Statin use before and after these procedures may be related to better neurological outcomes. Larger prospective studies are needed to endorse these findings.

Objective: The purpose of this study was to identify circulating angiogenic factor profiles associated to success or failure of intensive medical treatment in ICAS patients. Methods: Prospective observational study of circulating angiogenic factors in 72 patients with ICAS treated medically. Twenty-one pro and antiangiogenic factors were isolated from plasma in patients with intracranial arterial stenosis greater than 70% due to ICAS. Patients were followed for 6 months and mRS were collected. Failure to medical management was defined as presence of TIA or stroke within 30 days of presentation. Levels of angiogenic factors were determined by plasma multiplex sandwich ELISA. Samples were run in duplicate with variation coefficient lower than 20%. Angiogenic profiles (APs) were defined using Principal Component Analysis (PCA). Seven profiles were selected (Eigenvalue greater than 1.0). A logistic regression model was built for the outcome variable medical management failure/success using the 7 APs as predictors. An ordinal logistic regression model was built to predict the outcome variable mRS at 6 months using age, gender, baseline mRS and APs as predictors. Results: Seventy-two patients with ICAS were included. Mean age was 61.8 (SD 12.3)yrs. There were 53% females. The predominant region of stenosis was the MCA. Of the 7 APs defined by PCA, the regression model identified AP-4 as significantly associated to failure of medical management (P=0.02). AP-4 was characterized by high levels of HGF and the anti-angiogenic factors VEGFR1, Endostatin, Angiostatin, VEGFR3, and TSP2. In the long-term follow up, AP-4 was positively associated with mRS, independently of baseline mRS and age (P=0.002). Conclusion: In this extensive prospective study of angiogenic factors in patients with ICAS, a profile characterized by elevation of HGF and several circulating anti-angiogenic factors was strongly associated with failure to medical management and poor outcomes at 6 months.

Objective: To evaluate the hypothesis that circulating pro and antiangiogenic profiles predict the degree of angiographic neovascularization in patients undergoing EDAS for the treatment of symptomatic ICAS. Methods: This is a prospective observational study of circulating angiogenic factors in patients with arterial stenosis greater than 70% due to ICAS. All patients received intensive medical management. Patients with persistent symptoms underwent in addition EDAS revascularization. Twenty-one angiogenic factors were analyzed in serum samples collected at baseline, before surgery, using multiplex ELISA. All samples were run in duplicate and accepted as valid if the intersample variability was less than 20%. Patients have angiographic follow up 6 months after EDAS and a Neovascularization Index (NI) based on Perren grades and ASITN collaterals were calculated. Angiogenic profiles (APs) were defined using Principal Component Analysis (PCA). Seven profiles were selected for each time-point (Eigenvalue greater than 1.0). A regression model was built for the outcome variable NI using as predictor variables age, smoking history diabetes, and the 7 APs. Forward stepwise modeling with minimum BIC stopping rule was used to select the best fitted model. Results: Fifteen patients were enrolled. Mean age was 62.1 ± 12.3, 75% were females. The regression model demonstrated significant associations of age, diabetes and the AP 1-6 with the NI. Whole model P=0.023, Rsquare=0.93. The solution of the regression formula for the significant AP components revealed a strong negative association of the antiangiogenic factors endostatin and angiostatin (regression parameters -1.8 and -4.5, respectively, p=0.02). At 6 months follow up no patients had suffer strokes. Conclusion: In this prospective study of angiogenic factors in patients with ICAS undergoing EDAS revascularization, we have found that baseline levels of the antiangiogenic factors endostatin and angiostatin are significantly negatively associated to the degree of postoperative revascularization at 6 months. This finding supports the concept that neutralization of antiangiogenic factors may serve as a new pharmacological target to treat cerebral ischemia in patients with ICAS.

Objective: VEGFA isoforms 165a and 165b are pro and antiangiogenic, respectively. We aimed to evaluate the effects of IMM and EDAS in the VEGFA165a/b ratio in patients with ICAS. Methods: This is a prospective observational study of VEGFA165a and b in patients with stenosis greater than 70% due to ICAS. All patients received IMM. Patients with persistent symptoms underwent EDAS while maintaining IMM. Serum samples were collected at baseline, 1 week, 1, 3, and 6 months. VEGFA isoforms were quantified using multiplex sandwich ELISA. All samples were run in duplicate and accepted as valid if the intersample variability was less than 20%. A mixed model was built for the outcome variable VEGFA165a/b ratio using the predictor variables timepoint, treatment, and the interaction of time and treatment. The restricted maximum likelihood method was used to fit the model with random effects to account for the repeated measurements and intersubject variability. Results: A total of 72 patients were enrolled, of which 58 had IMM alone and 14 had EDAS. Mean age was 61.8 ± 12.3, 53% were females. The regression model demonstrated that there were no significant differences in the VEGFA165a/b ratio at baseline and 1 month after enrollment. Significant differences in VEGFA165a/b ratio were found at one week with higher levels in the surgical group (EDAS: 0.46 ± 0.22, IMM: 0.24 ± 0.07, p=0.03) and at 3 and 6 months with higher levels in the IMM group (3m: EDAS: 0.29 ± 0.14, IMM: 0.45 ± 0.20, p=0.03, 6m: EDAS:0.19 ± 0.11, IMM 0.37 ± 0.19 p=0.01). Conclusion: While the surgical event may well explain the early elevation of the VEGFA165a/b ratio one week after surgery, the elevation of a proangiogenic profile by the 3rd and 6th month in the IMM group is relevant. None of the patients in the IMM or EDAS groups had strokes at the last 6 months follow-up, and the peak (early for EDAS and at 3 and 6 months for IMM) of the VEGFA165a/b ratio may indicate a protective effect, averting stroke.