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Objective: To evaluate the effect of intensive rehabilitation on the modified Rankin Scale (mRS), a measure of activities limitation commonly used in acute stroke studies, and to define the specific changes in body structure/function (motor impairment) most related to mRS gains., Methods: Patients were enrolled >90 days poststroke. Each was evaluated before and 30 days after a 6-week course of daily rehabilitation targeting the arm. Activity gains, measured using the mRS, were examined and compared to body structure/function gains, measured using the Fugl-Meyer (FM) motor scale. Additional analyses examined whether activity gains were more strongly related to specific body structure/function gains., Results: At baseline (160 ± 48 days poststroke), patients (n = 77) had median mRS score of 3 (interquartile range, 2-3), decreasing to 2 [2-3] 30 days posttherapy ( p < 0.0001). Similarly, the proportion of patients with mRS score ≤2 increased from 46.8% at baseline to 66.2% at 30 days posttherapy ( p = 0.015). These findings were accounted for by the mRS score decreasing in 24 (31.2%) patients. Patients with a treatment-related mRS score improvement, compared to those without, had similar overall motor gains (change in total FM score, p = 0.63). In exploratory analysis, improvement in several specific motor impairments, such as finger flexion and wrist circumduction, was significantly associated with higher likelihood of mRS decrease., Conclusions: Intensive arm motor therapy is associated with improved mRS in a substantial fraction (31.2%) of patients. Exploratory analysis suggests specific motor impairments that might underlie this finding and may be optimal targets for rehabilitation therapies that aim to reduce activities limitations., Clinical Trial: Clinicaltrials.gov identifier: NCT02360488., Classification of Evidence: This study provides Class III evidence that for patients >90 days poststroke with persistent arm motor deficits, intensive arm motor therapy improved mRS in a substantial fraction (31.2%) of patients., (© 2021 American Academy of Neurology.)

Importance: Many patients receive suboptimal rehabilitation therapy doses after stroke owing to limited access to therapists and difficulty with transportation, and their knowledge about stroke is often limited. Telehealth can potentially address these issues., Objectives: To determine whether treatment targeting arm movement delivered via a home-based telerehabilitation (TR) system has comparable efficacy with dose-matched, intensity-matched therapy delivered in a traditional in-clinic (IC) setting, and to examine whether this system has comparable efficacy for providing stroke education., Design, Setting, and Participants: In this randomized, assessor-blinded, noninferiority trial across 11 US sites, 124 patients who had experienced stroke 4 to 36 weeks prior and had arm motor deficits (Fugl-Meyer [FM] score, 22-56 of 66) were enrolled between September 18, 2015, and December 28, 2017, to receive telerehabilitation therapy in the home (TR group) or therapy at an outpatient rehabilitation therapy clinic (IC group). Primary efficacy analysis used the intent-to-treat population., Interventions: Participants received 36 sessions (70 minutes each) of arm motor therapy plus stroke education, with therapy intensity, duration, and frequency matched across groups., Main Outcomes and Measures: Change in FM score from baseline to 4 weeks after end of therapy and change in stroke knowledge from baseline to end of therapy., Results: A total of 124 participants (34 women and 90 men) had a mean (SD) age of 61 (14) years, a mean (SD) baseline FM score of 43 (8) points, and were enrolled a mean (SD) of 18.7 (8.9) weeks after experiencing a stroke. Among those treated, patients in the IC group were adherent to 33.6 of the 36 therapy sessions (93.3%) and patients in the TR group were adherent to 35.4 of the 36 assigned therapy sessions (98.3%). Patients in the IC group had a mean (SD) FM score change of 8.36 (7.04) points from baseline to 30 days after therapy (P < .001), while those in the TR group had a mean (SD) change of 7.86 (6.68) points (P < .001). The covariate-adjusted mean FM score change was 0.06 (95% CI, -2.14 to 2.26) points higher in the TR group (P = .96). The noninferiority margin was 2.47 and fell outside the 95% CI, indicating that TR is not inferior to IC therapy. Motor gains remained significant when patients enrolled early (<90 days) or late (≥90 days) after stroke were examined separately., Conclusions and Relevance: Activity-based training produced substantial gains in arm motor function regardless of whether it was provided via home-based telerehabilitation or traditional in-clinic rehabilitation. The findings of this study suggest that telerehabilitation has the potential to substantially increase access to rehabilitation therapy on a large scale., Trial Registration: ClinicalTrials.gov identifier: NCT02360488.

Background: Examination of linked data on patient outcomes and cost of care may help identify areas where stroke care can be improved. We report on the association between variations in stroke severity, patient outcomes, cost, and treatment patterns observed over the acute hospital stay and through the 12-month follow-up for subjects receiving endovascular therapy compared to intravenous tissue plasminogen activator alone in the IMS (Interventional Management of Stroke) III Trial., Methods and Results: Prospective data collected for a prespecified economic analysis of the trial were used. Data included hospital billing records for the initial stroke admission and subsequent detailed resource use after the acute hospitalization collected at 3, 6, 9, and 12 months. Cost of follow-up care varied 6-fold for patients in the lowest (0-1) and highest (20+) National Institutes of Health Stroke Scale category at 5 days, and by modified Rankin Scale at 3 months. The kind of resources used postdischarge also varied between treatment groups. Incremental short-term cost-effectiveness ratios varied greatly when treatments were compared for patient subgroups. Patient subgroups predefined by stroke severity had incremental cost-effectiveness ratios of $97 303/quality-adjusted life year (severe stroke) and $3 187 805/quality-adjusted life year (moderately severe stroke)., Conclusions: Detailed economic and resource utilization data from IMS III provide powerful evidence for the large effect that patient outcome has on the economic value of medical and endovascular reperfusion therapies. These data can be used to inform process improvements for stroke care and to estimate the cost-effectiveness of endovascular therapy in the US health system for stroke intervention trials., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Registration number: NCT00359424., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background and Purpose: We assessed the effect of endovascular treatment in acute ischemic stroke patients with severe neurological deficit (National Institutes of Health Stroke Scale score, ≥20) after a prespecified analysis plan., Methods: The pooled analysis of the Interventional Management of Stroke III (IMS III) and Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trials included participants with an National Institutes of Health Stroke Scale score of ≥20 before intravenous tissue-type plasminogen activator (tPA) treatment (IMS III) or randomization (MR CLEAN) who were treated with intravenous tPA ≤3 hours of stroke onset. Our hypothesis was that participants with severe stroke randomized to endovascular therapy after intravenous tPA would have improved 90-day outcome (distribution of modified Rankin Scale scores), when compared with those who received intravenous tPA alone., Results: Among 342 participants in the pooled analysis (194 from IMS III and 148 from MR CLEAN), an ordinal logistic regression model showed that the endovascular group had superior 90-day outcome compared with the intravenous tPA group (adjusted odds ratio, 1.78; 95% confidence interval, 1.20-2.66). In the logistic regression model of the dichotomous outcome (modified Rankin Scale score, 0-2, or functional independence), the endovascular group had superior outcomes (adjusted odds ratio, 1.97; 95% confidence interval, 1.09-3.56). Functional independence (modified Rankin Scale score, ≤2) at 90 days was 25% in the endovascular group when compared with 14% in the intravenous tPA group., Conclusions: Endovascular therapy after intravenous tPA within 3 hours of symptom onset improves functional outcome at 90 days after severe ischemic stroke., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424 (IMS III) and ISRCTN10888758 (MR CLEAN)., (© 2015 American Heart Association, Inc.)

Background: Interventional Management of Stroke III did not show that combining IV recombinant tissue plasminogen activator (rt-PA) with endovascular therapies (EVTs) is better than IV rt-PA alone., Objective: To report efficacy and safety results for EVT of intracranial internal carotid artery (ICA) and middle cerebral artery trunk (M1) occlusion., Methods: Five revascularization methods for persistent occlusions after IV rt-PA treatment were evaluated for prespecified primary and secondary endpoints, after accounting for differences in key baselines variables using propensity scores. Revascularization was scored using the arterial occlusive lesion (AOL) and the modified Thrombolysis in Cerebral Ischemia (mTICI) scores., Results: EVT of 200 subjects with intracranial ICA or M1 occlusion resulted in 81.5% AOL 2-3 recanalization, in addition to 76% mTICI 2-3 and 42.5% mTICI 2b-3 reperfusion. Adverse events included symptomatic intracranial hemorrhage (SICH) (8.0%), vessel perforations (1.5%), and new emboli (14.9%). EVT techniques used were standard microcatheter n=51; EKOS n=14; Merci n=77; Penumbra n=39; Solitaire n=4; multiple n=15. Good clinical outcome was associated with both TICI 2-3 and TICI 2b-3 reperfusion. Neither modified Rankin scale (mRS) 0-2 (28.5%), nor 90-day mortality (28.5%), nor asymptomatic ICH (36.0%) differed among revascularization methods after propensity score adjustment for subjects with intracranial ICA or M1 occlusion., Conclusions: Good clinical outcome was associated with good reperfusion for ICA and M1 occlusion. No significant differences in efficacy or safety among revascularization methods were demonstrated after adjustment. Lack of high-quality reperfusion, adverse events, and prolonged time to treatment contributed to lower-than-expected mRS 0-2 outcomes and study futility compared with IV rt-PA., Trial Registration Number: NCT00359424., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Purpose: General anesthesia (GA) for endovascular therapy (EVT) of acute ischemic stroke may be associated with worse outcomes., Methods: The Interventional Management of Stroke III trial randomized patients within 3 hours of acute ischemic stroke onset to intravenous tissue-type plasminogen activator±EVT. GA use within 7 hours of stroke onset was recorded per protocol. Good outcome was defined as 90-day modified Rankin Scale ≤2. A multivariable analysis adjusting for dichotomized National Institutes of Health Stroke Scale (NIHSS; 8-19 versus ≥20), age, and time from onset to groin puncture was performed., Results: Four hundred thirty-four patients were randomized to EVT, 269 (62%) were treated under local anesthesia and 147 (33.9%) under GA; 18 (4%) were undetermined. The 2 groups were comparable except for median baseline NIHSS (16 local anesthesia versus 18 GA; P<0.0001). The GA group was less likely to achieve a good outcome (adjusted relative risk, 0.68; confidence interval, 0.52-0.90; P=0.0056) and had increased in-hospital mortality (adjusted relative risk, 2.84; confidence interval, 1.65-4.91; P=0.0002). Those with medically indicated GA had worse outcomes (adjusted relative risk, 0.49; confidence interval, 0.30-0.81; P=0.005) and increased mortality (relative risk, 3.93; confidence interval, 2.18-7.10; P<0.0001) with a trend for higher mortality with routine GA. There was no significant difference in the adjusted risks of subarachnoid hemorrhage (P=0.32) or symptomatic intracerebral hemorrhage (P=0.37)., Conclusions: GA was associated with worse neurological outcomes and increased mortality in the EVT arm; this was primarily true among patients with medical indications for GA. Relative risk estimates, though not statistically significant, suggest reduced risk for subarachnoid hemorrhage and symptomatic intracerebral hemorrhage under local anesthesia. Although the reasons for these associations are not clear, these data support the use of local anesthesia when possible during EVT., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424., (© 2015 American Heart Association, Inc.)

Background and Purpose: Randomized trials have indicated a benefit for endovascular therapy in appropriately selected stroke patients at 3 months, but data regarding outcomes at 12 months are currently lacking., Methods: We compared functional and quality-of-life outcomes at 12 months overall and by stroke severity in stroke patients treated with intravenous tissue-type plasminogen activator followed by endovascular treatment as compared with intravenous tissue-type plasminogen activator alone in the Interventional Management of Stroke III Trial. The key outcome measures were a modified Rankin Scale score ≤2 (functional independence) and the Euro-QoL EQ-5D, a health-related quality-of-life measure., Results: 656 subjects with moderate-to-severe stroke (National Institutes of Health Stroke Scale ≥8) were enrolled at 58 centers in the United States (41 sites), Canada (7), Australia (4), and Europe (6). There was an interaction between treatment group and stroke severity in the repeated measures analysis of modified Rankin Scale ≤2 outcome (P=0.039). In the 204 participants with severe stroke (National Institutes of Health Stroke Scale ≥20), a greater proportion of the endovascular group had a modified Rankin Scale ≤2 (32.5%) at 12 months as compared with the intravenous tissue-type plasminogen activator group (18.6%, P=0.037); no difference was seen for the 452 participants with moderately severe strokes (55.6% versus 57.7%). In participants with severe stroke, the endovascular group had 35.2 (95% confidence interval: 2.1, 73.3) more quality-adjusted-days over 12 months as compared with intravenous tissue-type plasminogen activator alone., Conclusions: Endovascular therapy improves functional outcome and health-related quality-of-life at 12 months after severe ischemic stroke., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424., (© 2015 American Heart Association, Inc.)

Background and Purpose: We explored changes in the patient population and practice of endovascular therapy during the course of the Interventional Management of Stroke (IMS) III Trial., Methods: Changes in baseline characteristics, use of baseline CT angiography, treatment times and specifics, and outcomes were compared between the first 4 protocols and the fifth and final protocol., Results: Compared with subjects treated in the first 4 protocol versions (n=610), subjects treated in fifth and final protocol (n=46) were older (75 versus 68 years, P<0.0002) and less likely to have a pretreatment Rankin of 0 (76% versus 89%, P=0.01), were more likely to have a pretreatment CT angiography (65% versus 45%, P=0.009), had quicker median times in the endovascular arm from onset to start of intra-arterial therapy (209 versus 250 minutes, P=0.002) and to reperfusion (269 versus 344 minutes, P<0.0001), had a higher mean dose of total tissue-type plasminogen activator in the endovascular arm (74.0 versus 63.7 mg, P<0.0001), and were less likely to receive intra-arterial tissue-type plasminogen activator as part of the endovascular procedure (16% versus 44%, P=0.015). There were no significant differences in functional and safety outcomes between subjects treated in the 2 treatments arms in either the first 4 protocols or fifth protocol although the small sample size in the fifth protocol provided limited power., Conclusions: Endovascular technology and diagnostic approaches to acute stroke patients changed substantially during the IMS III Trial. Efforts to decrease the time to delivery of endovascular therapy were successful., (© 2014 American Heart Association, Inc.)

Background: The IMS III trial did not show a clinical benefit of endovascular treatment compared with intravenous alteplase (recombinant tissue plasminogen activator) alone for moderate or severe ischaemic strokes. Late reperfusion of tissue that was no longer salvageable could be one explanation, as suggested by previous exploratory studies that showed an association between time to reperfusion and good clinical outcome. We sought to validate this association in a preplanned analysis of data from the IMS III trial., Methods: We used data for patients with complete proximal arterial occlusions in the anterior circulation who received endovascular treatment and achieved angiographic reperfusion (score on Thrombolysis in Cerebral Infarction scale of grade 2-3) during the endovascular procedure (within 7 h of symptom onset). We used logistic regression to model good clinical outcome (defined as a modified Rankin Scale score of 0-2 at 3 months) as a function of the time to reperfusion. We prespecified variables to be considered for adjustment, including age, baseline National Institutes of Health Stroke Scale score, sex, and baseline blood glucose concentration., Findings: Of 240 patients who were otherwise eligible for inclusion in our analysis, 182 (76%) achieved angiographic reperfusion. Mean time from symptom onset to reperfusion (ie, procedure end) was 325 min (SD 52). Increased time to reperfusion was associated with a decreased likelihood of good clinical outcome (unadjusted relative risk for every 30-min delay 0·85 [95% CI 0·77-0·94]; adjusted relative risk 0·88 [0·80-0·98])., Interpretation: Delays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. Rapid reperfusion could be crucial for the success of future acute endovascular trials., Funding: US National Institutes of Health and National Institute of Neurological Disorders and Stroke., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain., Methods: We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability)., Results: The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8-19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83)., Conclusions: The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.).

Background and Purpose: A positive correlation between large parenchymal hematoma (PH) volume and large CT lesion volume in subjects treated with intravenous (IV) recombinant tissue plasminogen activator (rtPA) as well as placebo controls was identified in the European Cooperative Acute Stroke Study II (ECASS II). A study was undertaken to examine the relationship between PH volume and total lesion volume (including both cerebral infarction and hemorrhage) in subjects with symptomatic parenchymal hematoma (sPH) treated with combined IV and intra-arterial (IA) rtPA in the Interventional Management of Stroke (IMS) studies., Methods: Hematoma and lesion volumes were measured planimetrically and by the ABC/2 method in 105 subjects from IMS studies I and II following combined IV and IA rtPA treatment. PH type 1 or 2 was determined by dichotomizing at >30% of lesion volume. Hematoma and lesion volumes for both symptomatic PH1 (sPH1) and PH2 (sPH2) types were compared using both measurement methods. Both sPH types were compared for baseline NIH Stroke Score, baseline Alberta Stroke Program Early CT score and treatment revascularization score based on the planimetric volume method., Results: The volume of sPH1 and sPH2 did not differ by either method of measurement. Subjects with sPH2 had a lower lesion volume compared with all PH1 (p=0.004) and sPH1 (p=0.02) by both methods. The ABC/2 method overestimated PH volume by 55±33% and lesion volume by 34±22% for sPH compared with the planimetric method., Conclusions: In IMS I and II, hemorrhages in subjects with sPH2 were similar in volume to those in subjects with sPH1 and were associated with a smaller rather than a larger total lesion volume compared with other PH in the setting of combined IV/IA therapy. The use of PH2 as a sole surrogate for sPH in studies of stroke treatment may underestimate the incidence of clinically significant hemorrhage.

Rationale: The Interventional Management of Stroke (IMS) I and II pilot trials demonstrated that the combined intravenous (i.v.) and intraarterial (i.a.) approach to recanalization may be more effective than standard i.v. rt-PA (Activase) alone for moderate-to-large National Institutes of Health Stroke Scale (NIHSS>or=10) strokes, and with a similar safety profile., Aims: The primary objective of this NIH-funded, Phase III, randomized, multicenter, open-label clinical trial is to determine whether a combined i.v./i.a. approach to recanalization is superior to standard i.v. rt-PA alone when initiated within 3 h of acute ischemic stroke onset. The IMS III trial will develop and maintain a network of interventional centers to test the safety, feasibility, and potential efficacy of new FDA-approved catheter devices as part of a combined i.v./i.a. approach to recanalization as the IMS III study progresses. A secondary objective of the IMS III trial is to determine the cost-effectiveness of the combined i.v./i.a. approach as compared with standard i.v. rt-PA. Trial enrollment began in July of 2006., Design: A projected 900 subjects with moderate-to-large (NIHSS>or=10) ischemic strokes between ages 18 and 80 will be enrolled over the next 5 years at 40-plus centers in the United States and Canada. Patients must have i.v. treatment initiated within 3 h of stroke onset in both arms. Subjects will be randomized in a 2 : 1 ratio with more subjects enrolled in the combined i.v./i.a. group. The i.v. rt-PA alone group will receive the standard full dose [0.9 mg/kg, 90 mg maximum (10% as bolus)] of rt-PA intravenously over an hour. The combined i.v./i.a. group will receive a lower dose of i.v. rt-PA ( approximately 0.6 mg/kg, 60 mg maximum) over 40 min, followed by immediate angiography. If a treatable thrombus is not demonstrated, no i.a. therapy will be administered. If an appropriate thrombus is identified, treatment will continue with either the Concentric Merci thrombus-removal device, infusion of rt-PA and delivery of low-intensity ultrasound at the site of the occlusion via the EKOS Micro-Infusion Catheter, or infusion of rt-PA via a standard microcatheter. If i.a. rt-Pa therapy is the chosen strategy, a maximum of 22 mg of i.a. rt-PA may be given. The choice of i.a. strategy will be made by the treating neurointerventionalist. The i.a. treatment must begin within 5 h and be completed within 7 h of stroke onset., Study Outcomes: The primary outcome measure is a favorable clinical outcome, defined as a modified Rankin Scale Score of 0-2 at 3 months. The primary safety measure is mortality at 3 months and symptomatic ICH within the 24 h of randomization.

Background and Purpose: Anterior cerebral artery (ACA) emboli may occur before or during fibrinolytic revascularization of middle cerebral artery (MCA) and internal carotid artery (ICA) T occlusions. We sought to determine the incidence and effect of baseline and new embolic ACA occlusions in the Interventional Management of Stroke (IMS) studies., Materials and Methods: Case report forms, pretreatment and posttreatment arteriograms, and CTs from 142 subjects entered into IMS I & II were reviewed to identify subjects with baseline ACA occlusion, new ACA emboli occurring during fibrinolysis, subsequent CT-demonstrated infarction in the ACA distribution, and to evaluate global and lower extremity motor clinical outcome., Results: During M1/M2 thrombolysis procedures, new ACA embolus occurred in 1 of 60 (1.7%) subjects. Baseline distal emboli were identified in 3 of 20 (15%) T occlusions before intra-arterial (IA) treatment, and new posttreatment distal ACA emboli were identified in 3 subjects. At 24 hours, 8 (32%) T occlusions demonstrated CT-ACA infarct, typically of small volume. Infarcts were less common following sonography microcatheter-assisted thrombolysis compared with standard microcatheter thrombolysis (P = .05). Lower extremity weakness was present in 9 of 10 subjects with ACA embolus/infarct at 24 hours. The modified Rankin 0 to 2 outcomes were achieved in 4 of 25 (16%) subjects with T occlusion overall, but in 0 of 10 subjects with distal ACA emboli or ACA CT infarcts (P = .07)., Conclusions: With IV/IA recombinant tissue plasminogen activator treatment for MCA emboli, new ACA emboli are uncommon events. Distal ACA emboli during T-occlusion thrombolysis are not uncommon, typically lead to small ACA-distribution infarcts, and may limit neurologic recovery.

Ischemic brain and peripheral white blood cells release cytokines, chemokines and other molecules that activate the peripheral white blood cells after stroke. To assess gene expression in these peripheral white blood cells, whole blood was examined using oligonucleotide microarrays in 15 patients at 2.4+/-0.5, 5 and 24 h after onset of ischemic stroke and compared with control blood samples. The 2.4-h blood samples were drawn before patients were treated either with tissue-type plasminogen activator (tPA) alone or with tPA plus Eptifibatide (the Combination approach to Lysis utilizing Eptifibatide And Recombinant tPA trial). Most genes induced in whole blood at 2 to 3 h were also induced at 5 and 24 h. Separate studies showed that the genes induced at 2 to 24 h after stroke were expressed mainly by polymorphonuclear leukocytes and to a lesser degree by monocytes. These genes included: matrix metalloproteinase 9; S100 calcium-binding proteins P, A12 and A9; coagulation factor V; arginase I; carbonic anhydrase IV; lymphocyte antigen 96 (cluster of differentiation (CD)96); monocarboxylic acid transporter (6); ets-2 (erythroblastosis virus E26 oncogene homolog 2); homeobox gene Hox 1.11; cytoskeleton-associated protein 4; N-formylpeptide receptor; ribonuclease-2; N-acetylneuraminate pyruvate lyase; BCL6; glycogen phosphorylase. The fold change of these genes varied from 1.6 to 6.8 and these 18 genes correctly classified 10/15 patients at 2.4 h, 13/15 patients at 5 h and 15/15 patients at 24 h after stroke. These data provide insights into the inflammatory responses after stroke in humans, and should be helpful in diagnosis, understanding etiology and pathogenesis, and guiding acute treatment and development of new treatments for stroke.

Despite recent advances in stroke treatment and prevention, identifying effective educational interventions for "at-risk" groups that will help reduce their stroke risk and improve the speed of seeking treatment remains of paramount importance. The purpose of this pilot study was to determine whether a brief educational intervention, tailored to the patient's stage of readiness to change, could affect the initiation and achievement of stroke risk-reducing behaviors for this at-risk population. The study also explored potential demographic and medical confounders that could influence behavioral and knowledge goal achievement. Three groups of 20 participants, each with multiple risk factors for stroke, from a family practice clinic were randomly assigned to a control, simple-advice, or brief intervention group. The majority of the participants were African American with a mean age of 68 years. Selected findings showed (a) significant differences in the number of newly initiated stroke-risk-reduction behaviors and stroke knowledge among the three groups and (b) significant positive correlations between the action stage of readiness to change and the initiation and achievement of the new stroke-risk-reduction behaviors. Although results supported the usefulness of the brief intervention model to reduce modifiable stroke-risk factors and increase stroke knowledge, the necessity of additional longitudinal research that refines the targeting of interventions for diverse racial, cultural, and age groups was acknowledged.

Background and Purpose: Little is known about the relationship between perihematomal edema in spontaneous intracerebral hemorrhage (ICH) and outcome. The purpose of this study was to determine whether absolute or relative edema volume (edema volume divided by hematoma volume) predicts mortality or functional outcome in patients with hyperacute spontaneous ICH. We hypothesized that increasing baseline relative edema volume is associated with greater probability of poor functional outcome., Methods: This was a secondary analysis of a prospective, population-based study of hematoma growth in 142 patients with spontaneous ICH. Patients were imaged within 3 hours of onset, then 1 and 20 hours later. Our primary analysis excluded patients with anticoagulant use (n=7), underlying aneurysm/vascular malformation (n=9), trauma (n=1), incomplete data (n=20), infratentorial ICH (n=17), intraventricular extension (n=38), and no consent (n=2). We analyzed whether associations existed between baseline edema volumes or other clinical/radiological variables and either 12-week modified Rankin Scale score >2 or 30-day mortality. Secondary analyses used 20-hour CT scan data, all patients with supratentorial ICH, and 12-week Barthel Index score <85., Results: By multivariable logistic regression analysis, baseline relative edema was the strongest independent predictor of functional outcome and was associated with lesser odds of poor 3-month functional outcome (odds ratio, 0.09 per 1.0-unit [100%] increase; 95% CI, 0.01 to 0.64; P=0.016) and 12-week Barthel Index score <85 (odds ratio, 0.12; 95% CI, 0.02 to 0.91; P=0.039) but did not predict mortality. Secondary analyses confirmed this result. Absolute edema volume predicted neither mortality nor functional outcome., Conclusions: Relative edema is strongly predictive of functional outcome in patients with hyperacute supratentorial spontaneous ICH without intraventricular extension.

Background and Purpose: The natural history of perihematomal edema in human hyperacute spontaneous intracerebral hemorrhage (ICH) has not been well described., Methods: This study was a secondary analysis of a previously reported prospective, population-based study of hematoma growth in 142 patients with spontaneous ICH. Patients were first imaged within 3 hours of onset, then 1 and 20 hours later. We excluded patients with anticoagulant use (n=7), underlying aneurysm/vascular malformation (n=9), trauma (n=1), incomplete data (n=20), infratentorial ICH (n=17), and no consent (n=2), leaving an overall study population of 86 patients. From this overall group we further excluded patients with intraventricular extension (n=38), subsequent surgery (n=5), or death (n=2) before 20-hour postbaseline CT. This second, "restricted" analysis group of 41 patients was relatively devoid of clinical or radiological variables likely to confound edema measurement. Absolute and relative edema volumes (edema volume divided by hematoma volume) were descriptively summarized. Correlations between baseline edema volumes and relevant clinical and radiological variables were then performed., Results: Overall, median absolute edema volume increased from 6.93 to 14.4 cm(3) during the first 24 hours after ICH, and median relative edema volume increased from 0.47 to 0.81. In the restricted group, median absolute edema volume was 7.4 cm(3) at baseline and 11.0 cm(3) at 24 hours after ICH, and median relative edema volume increased from 0.55 to 0.81. Baseline relative edema volume was significantly negatively correlated with subsequent change in relative edema volume from baseline to 20-hour CT (r=0.57, P=0.0002) but was not significantly correlated with other clinical and radiological variables, including hematoma volume or change in hematoma volume., Conclusions: Perihematomal edema volume increases by approximately 75% during the first 24 hours after hyperacute spontaneous ICH. Patients with the least amounts of baseline relative edema volume were most likely to develop significant additional amounts of edema during the first 24 hours after spontaneous ICH.

Background and Purpose: Follow-up imaging data from stroke patients without angiographically apparent arterial occlusions at symptom onset are lacking. We reviewed our Emergency Management of Stroke (EMS) trial experience to determine the clinical and imaging outcomes of patients with ischemic stroke who showed no arterial occlusion on angiograms obtained within 4 hours of symptom onset., Methods: All patients in this report were participants in the EMS trial that was designed to address the safety and potential efficacy of combined IV and intraarterial thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke., Results: Thirty-five patients were randomized to receive either IV rt-PA (n = 17) or placebo (n = 18), followed by cerebral angiography. No symptomatic arterial occlusion was evident in 10 (29%) of the 34 patients. Eight (80%) of 10 patients without angiographically apparent clot within 4 hours of symptom onset had a new cerebral infarction confirmed on follow-up brain imaging. The median 72-hour infarction volume was 2.4 cc (range, 1-30 cc). Four of the 10 "no-clot" patients had a favorable 3-month outcome as assessed by Barthel Index (score, 95 or 100) and modified Rankin Scale (score, 0 or 1). The six remaining patients had 3-month Rankin Scale scores of 1 (Barthel of 90), 2, 3, 4, or 5., Conclusion: Acute ischemic stroke patients with a neurologic deficit but a negative angiogram during the first 4 hours after symptom onset usually develop image-documented cerebral infarction, and approximately half suffer from long-term functional disability. The two most likely explanations for negative angiograms are very early irreversible ischemic damage despite recanalization or ongoing ischemia secondary to clot in non-visible penetrating arterioles or in the microvasculature.

The stroke patient is acutely ill within minutes of symptom onset. Typically, he or she is awake and thus requires a focal neurologic exam to evaluate vision, movement, sensation and language. With the advent of acute stroke treatments that need to be rapidly implemented, it is critical that the nurse be able to assess patients and relay the information accurately and efficiently to other members of the health care team. Performing and documenting the awake stroke exam in the most efficient and useful manner is key to the nursing care of the stroke patient. The National Institutes of Health Stroke Scale (NIHSS) is a systematic assessment tool designed to measure the neurologic deficits most often seen with acute stroke patients. Originally designed as a research tool, it is a nonlinear ordinal scale, with possible scores ranging form 0-42. Exam performance has been timed to take 5-8 minutes. Use of the NIHSS includes documentation of neurologic status and outcome, data collection for planning safe nursing care and standardization of information exchanges between nurse caregivers and other health care professionals.

In the National Institutes of Neurologic Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rt-PA) stroke trial, the primary adverse events monitored were intracranial hemorrhage (ICH), systemic bleeding, death and new stroke. Nurses caring for the study patients noted these adverse events and other complications. In addition to what is known about acute ischemic stroke (AIS), the NINDS trial provides further information for optimal care of this specific group of patients. The complications found in this trial require expert nursing care to monitor, prevent and intervene, making clinical decisions relevant to the patients needs. The critical decision-making process must be grounded in knowledge of acute stroke physiology and thrombolysis.

Stroke is a leading cause of death and disability among Americans. The recent US Food and Drug Administration approval of recombinant tissue plasminogen activator (rt-PA, Activase) for the treatment of acute ischemic stroke offers the first proven therapy to reverse or ameliorate stroke symptoms. rt-PA is thought to restore circulation in the patient with acute ischemic stroke by dissolving an occluding thrombus or embolus. A basic understanding of cerebral circulation and the mechanism by which stroke compromises brain tissue is fundamental to appreciating this new therapy. The importance of prompt stroke diagnosis and treatment cannot be underestimated.

With the approval of rt-PA therapy for ischemic stroke, stroke care has acutely transitioned from focusing on rehabilitative services to emergency services. This treatment, which must be initiated within the first three hours after the onset of stroke symptoms, requires reorganization of current management approaches. Developing a Code Stroke Team facilitates this process and helps to identify potential thrombolysis candidates. A pathway to deliver rapid care begins with 911 notification and transport, emergency department triage and procedures, and moves through the initiation of thrombolytic therapy. We call this pathway "Code Stroke".

Patients delay in responding to stroke as an emergency in part because they have deficient information about the disease and treatment. Healthcare providers may also have a lack of information about stroke assessment and management, which could attribute to delays in patient care. In order to provide early, rapid stroke treatment in eligible persons, the public and the healthcare community must be informed. Information on stroke risk, symptoms and treatment should be provided to those likely to experience stroke, the general public and the emergency and medical communities who may witness and intervene when stroke occurs. Programs developed at the eight centers of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA stroke trial provide a sampling of approaches that increase awareness in these groups. Lessons learned include: 1. Program planning should start with a community needs assessment. 2. A variety of strategies can be applied to meet the community needs and resources. 3. Educational principles and models should be utilized in planning effective programs. 4. The message must be simple: "Stroke is an emergency. Time is brain".

Treatment with tissue plasminogen activator (rt-PA) for acute stroke requires intensive care of the patient. The risk of thrombolytic therapy and the need for rapid interventions make it clear that the nursing role during this time is crucial. Nurses should be familiar with safe dosage and administration of rt-PA for stroke, which is clearly different than administration of rt-PA for myocardial infarction. Furthermore, thrombolytic stroke treatment must be accompanied by intensive neurological monitoring to observe for complications. Intracerebral hemorrhage is usually accompanied by an acute change in neurological status and vital sign instability. Intensive monitoring of neurologic condition, vital signs, cardiac status and other standard critical care practices must be initiated immediately to optimize patient outcome.

Ischemic stroke remains a significant problem in the United States. Complex intracellular metabolic events occur leading to cell death. A search for treatments to prevent this ischemic process continues. Thrombolytic agents, recently developed and tested, may lessen the disabling effects of stroke.

Purpose: To determine the relationship between the hyperdense middle cerebral artery sign (HMCAS) and neurologic deficit, as evidenced by the National Institutes of Health (NIH) stroke scale score, and to determine the relationship of the HMCAS and the NIH stroke scale score to arteriographic findings after thrombolytic therapy., Methods: Fifty-five patients with acute ischemic stroke were rated on the NIH stroke scale, were examined with CT, and were treated with intravenous alteplase within 90 minutes of symptom onset. Presence of the HMCAS was determined on the baseline CT scan by a neuroradiologist blinded to the patient's neurologic deficit. Patients with the HMCAS were compared with those without HMCAS with regard to baseline NIH stroke scale score, 2-hour NIH stroke scale score, findings at posttreatment arteriography, 3-month residual neurologic deficit, and 3-month ischemia volumes as evidenced on CT scans., Results: Eighteen patients (33%) had the HMCAS. These patients had a median baseline NIH stroke scale score of 19.5 compared with a median score of 10 for the patients lacking the HMCAS sign. At 3 months, one (6%) of the HMCAS-positive patients was completely improved neurologically compared with 17 (47%) of the HMCAS-negative patients. Restricting analysis to those patients with a stroke scale score of 10 or greater (n = 37), 18 HMCAS-positive patients showed less early neurologic improvement, were less likely to be completely improved at 3 months, and had larger infarcts compared with the 19 HMCAS-negative patients. Compared with the HMCAS-positive and HMCAS-negative patients with a stroke scale score of 10 or greater, patients with a stroke scale score of less than 10 had fewer occlusive changes of the internal carotid and middle cerebral arteries on posttreatment arteriograms and had a better neurologic recovery at 3 months., Conclusion: The presence of the HMCAS on CT scans obtained within 90 minutes of stroke onset is associated with a major neurologic deficit, and in this study it predicted a poor clinical and radiologic outcome after intravenous thrombolytic therapy. However, a major neurologic deficit, defined as a stroke scale score of 10 or more, was better than a positive HMCAS as a predictor of poor neurologic outcome after thrombolytic therapy. Patients with a low stroke scale score (< 10) may benefit from ultraearly intravenous alteplase therapy.

Background and Purpose: Early thrombolytic therapy with recombinant tissue-type plasminogen activator is a theoretically attractive approach to the treatment of acute focal cerebral ischemia. In preparation for a larger multicenter trial, three centers piloted a protocol for a randomized, double-blind, placebo-controlled trial of intravenous recombinant tissue-type plasminogen activator begun within 3 hours of the onset of symptoms of acute stroke to test its feasibility and to explore trends., Methods: Eligible patients had pretreatment computed tomographic scanning, gave informed consent, and began treatment with either 0.85 mg/kg recombinant tissue-type plasminogen activator or placebo as soon as possible, but no later than 180 minutes after stroke onset. Patients were stratified by whether treatment was begun within 90 minutes or 91 to 180 minutes from onset. The primary end point was the proportion of patients in each group who improved by 4 or more points on the National Institutes of Health Stroke Scale at 24 hours, as determined by a separate blinded evaluator., Results: Twenty-seven patients were randomized: 20 (10 recombinant tissue-type plasminogen activator, 10 placebo) within 90 minutes, and 7 (4 recombinant tissue-type plasminogen activator, 3 placebo) from 91 to 180 minutes. Median baseline Stroke Scale scores were 16 (minimum = 5, maximum = 26) for the recombinant tissue-type plasminogen activator-treated group and 11 (minimum = 3, maximum = 21) for the control subjects in the group treated within 90 minutes. Six patients treated with recombinant tissue-type plasminogen activator within 90 minutes improved by 4 or more points at 24 hours compared with 1 patient in the placebo group (P < .05, Fisher's Exact Test). Two patients in each group in the 91- to 180-minute arm improved. One fatal intracerebral hemorrhage occurred in the placebo group., Conclusions: A randomized, double-blind, placebo-controlled trial of recombinant tissue-type plasminogen activator very early in acute stroke is feasible. Preliminary observations suggest that recombinant tissue-type plasminogen activator treatment within 90 minutes may be associated with early neurological improvement. Larger studies are needed so that the potentially serious short-term risks of this treatment can be assessed in relation to meaningful long-term benefit.

Purpose: To determine the prevalence of the hyperdense middle cerebral artery sign (HMCAS) in an acute stroke population (treated with intravenous tissue plasminogen activator (tPA) within 90 minutes of stroke onset); to correlate the presence/absence of the sign with arteriographic findings; and to correlate the HMCAS with the volume of subsequent infarction., Patients and Methods: 55 patients with acute ischemic stroke underwent CT to exclude cerebral hemorrhage and were then treated with intravenous tPA. The neuroradiologist, blinded to the clinical and arteriographic data, sought the HMCAS on the initial and subsequent scans., Results: The HMCAS was detected by CT in 19 of 55 (34.5%) patients (one false positive). Arteriograms in 14 of the 18 true positive patients confirmed the CT-predicted middle cerebral artery segment in 12. The 18 patients developed infarcts larger than patients not exhibiting the sign (132 cc vs 52 cc, P less than .002)., Conclusion: The HMCAS does predict middle cerebral artery occlusion and subsequent development of a large infarct.

The authors evaluate eight patients with intracerebral hemorrhage (ICH) who underwent computerized tomography (CT) within 2 1/2 hours after symptom onset and then again several hours later. The second CT scan was performed within 12 hours after onset for seven of the patients and 100 hours after onset for the eighth patient. In four patients, the second CT scan was obtained prospectively. The mean percentage of increase in the volume of hemorrhage between the first and second CT scans was 107% (range 1% to 338%). In each of the six patients with a greater than 40% increase in hemorrhage volume, neurological deterioration occurred soon after the first CT. A systolic blood pressure of 195 mm Hg or greater was recorded during the first 6 hours in five of the same six patients. The data from this study indicate that, in ICH, bleeding may continue after the 1st hour post-hemorrhage, particularly in patients with early clinical deterioration.

The standard of care for acute thromboembolic stroke is changing rapidly with the advent of new pharmacologic therapies. The deterioration of focal cerebral ischemia to infarction can be lessened with timely restoration of cerebral blood flow. As pharmacologic therapy of acute stroke evolves, emergency physicians will increasingly facilitate its implementation. The purpose of this study was to elucidate those factors significantly affecting the acute stroke patient's emergency department (ED) evaluation time. The pretreatment ED evaluations of 20 patients entered in an ongoing trial of a fibrinolytic agent (ancrod) for acute ischemic stroke were reviewed. Pretreatment screening factors included the assessment of hematologic status, concurrent illness, and potential neoplastic disease or cerebral hemorrhage as the etiology for the neurological deficit. The following factors had a statistically significant effect on pretreatment evaluation time (range, 2.6 to 11.4 hours) by multiple linear regression analysis: time from arrival until bleeding time completed (P less than .005), time from arrangement of computed head tomography until its completion (P less than .05), chosen site of treatment (ED v neurological step-down unit; P less than .005), order of patient entry (P less than .01), and time from arrival until completion of fibrinogen level assay (P less than .05). These results emphasize the need to coordinate and streamline the clinical evaluation process. The use of the ED as the site of treatment, abbreviating the time until pharmacologic therapy, has not been previously documented. Expedient completion of an evaluation compatible with safe pharmacologic therapy of acute ischemic stroke will dictate the time of definitive therapy. These results should assist other institutions considering rapid pharmacologic therapy for acute ischemic stroke.

Ancrod has been used in Europe for over 15 years for peripheral vascular disease, deep vein thrombosis, and central retinal venous thrombosis, and in patients at risk for thromboembolism. In a double-blind, randomized, placebo-controlled study at University Hospitals in Cincinnati, 20 acute cerebral infarction patients received a series of IV infusions of ancrod (ten) or placebo (ten) for seven days. Early fibrinolysis with a small decrease in fibrinogen was observed, and d-dimers were elevated at four hours, indicating early clot lysis. At three months, patients with moderate to severe strokes (less than 40 on the Scandinavian Stroke Scale) in the ancrod group showed average improvement by a factor of 3 over the placebo group. No bleeding, abnormal laboratory results, or deaths occurred, but ancrod was discontinued in one patient who had seizures. As a result of this study, a double-blind multicenter international clinical trial to further assess the safety and effectiveness of ancrod is being planned.