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Objective: Parenchymal hematoma (PH) following intravenous thrombolysis (IVT) in ischemic stroke can occur either within the ischemic area (iPH) or as a remote PH (rPH). The latter could be, at least partly, related to cerebral amyloid angiopathy, which belongs to the continuum of cerebral small vessel disease. We hypothesized that cerebral white matter lesions (WMLs)-an imaging surrogate of small vessel disease-are associated with a higher rate of rPH., Methods: We analyzed 2,485 consecutive patients treated with IVT at the Helsinki University Hospital. Blennow rating scale of 5 to 6 points on baseline computed tomographic head scans was considered as severe WMLs. An rPH was defined as hemorrhage that-contrary to iPH-appears in brain regions without visible ischemic damage and is clinically not related to the symptomatic acute lesion site. The associations between severe WMLs and pure rPH versus no PH, pure iPH versus no PH, and pure rPH versus pure iPH were studied in multivariate logistic regression models., Results: rPHs were mostly (74%) located in lobar regions. After adjustments, the presence of severe WMLs was associated with pure rPH (odds ratio [OR] = 6.79, 95% confidence interval [CI] = 2.57-17.94) but not with pure iPH (OR = 1.45, 95% CI = 0.83-2.53) when compared to patients with no PH. In direct comparison of pure rPH with pure iPH, severe cerebral WMLs were further associated with higher iPH rates (OR = 3.60, 95% CI = 1.06-12.19)., Interpretation: Severe cerebral WMLs were associated with post-thrombolytic rPH but not with iPH within the ischemic area. Ann Neurol 2016;80:593-599., (© 2016 American Neurological Association.)

Background and Aims: Basilar artery occlusion is a most devastating form of stroke, and the current practice is to reverse it with revascularization therapies. Pharmacological thrombolysis, intravenous or intraarterial, has been adjuncted or replaced with invasive, endovascular thrombectomy procedures. The preferred approach remains unknown and many recanalizations are futile with no clinical benefit. We sought to determine reasons for futility and weigh the existing reports to find whether endovascular mechanical interventions provide superior outcomes over pharmacological thrombolysis alone., Methods: After analyzing systematically the reports of outcomes produced by variable basilar artery occlusion recanalization protocols, information was retrieved and reconciled from 15 reports published from year 2005 comprising 803 patients in 17 cohorts. In the largest single-center cohort (162, Helsinki), predictors of futile recanalization (three-month modified Rankin Scale score 4 to 6) were determined., Results: Good outcome was reported by mechanical approaches either alone or on demand more frequently than by pharmacological, intravenous or intraarterial thrombolysis protocols (35.5% versus 24.4%, p < 0.001), accompanied by higher recanalization rates (84.1% versus 70.9%, p < 0.001). Along with superior recanalization rate at 91%, good outcome was reached by primary thrombectomy in 36% at the cost of substantial futile recanalization rate at 60%, which was lower when using modern stentrievers only (52.8%). In the Helsinki cohort, the single most significant predictor was extensive baseline ischemia, increasing the odds of futility 20-fold (95%CI 4.39-92.29, p < 0.001). Other attributes of futility were ventilation support and history of atrial fibrillation or previous stroke., Conclusions: Endovascular mechanical approaches have been reported to provide superior outcomes over pharmacological thrombolysis in basilar artery occlusion. Stricter patient selection, most notably to exclude victims of already extended ischemia, would assist in translating excellent recanalization rates into improved clinical outcomes and more acceptable futility rates., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Lindsberg, Silvennoinen, Salonen list no disclosures. Sairanen and Nagel received travel expenses to a scientific conference with the support of from Boehringer Ingelheim Pharmaceuticals Inc. Nagel has received counseling fees from Brainomix Ltd.

Basilar artery occlusion (BAO) is one of the most devastating forms of stroke and few patients have good outcomes without recanalization. Most centers apply recanalization therapies for BAO up to 12-24 hours after symptom onset, which is a substantially longer time window than the 4.5 hours used in anterior circulation stroke. In this speculative synthesis, we discuss recent advances in BAO treatment in order to understand why and under which circumstances longer symptom duration might not necrotize the brainstem and turn therapeutic attempts futile. We raise the possibility that distinct features of the posterior circulation, e.g., highly developed, persistent collateral arterial network, reverse filling of the distal basilar artery, and delicate plasma flow siding the clot, might sustain brittle patency of brainstem perforators in the face of stepwise growth of the thrombus. Meanwhile, the tissue clock characterizing the rapid necrosis of a typical anterior circulation penumbra will not start. During this perilous time period, recanalization at any point would salvage the brainstem from eventual necrosis caused by imminent reinforcement and further building up of the clot., (© 2015 American Academy of Neurology.)

Objective: To determine whether higher neutrophil counts before IV recombinant tissue plasminogen activator (rtPA) administration in ischemic stroke (IS) patients are associated with symptomatic intracerebral hemorrhages (sICH) and worse outcomes at 3 months., Methods: Blood samples for leukocyte, neutrophil, and lymphocyte counts were drawn before IV rtPA administration in IS patients included in the cohorts of Lille and Helsinki. The primary endpoint was sICH (European Cooperative Acute Stroke-II definition). Secondary endpoints were death and excellent (modified Rankin Scale [mRS] score 0-1 or equal to prestroke mRS) and good (mRS score 0-2 or equal to prestroke mRS) outcomes at 3 months., Results: We included 846 patients (median age 71 years; 50.8% men). The neutrophil count and neutrophil to lymphocyte ratio (NLR) were independently associated with the 4 endpoints: sICH (adjusted odds ratio [adjOR] for an increase of 1,000 neutrophils = 1.21 and adjOR 1.11, respectively), death (adjOR 1.16 and adjOR 1.08), and excellent (adjOR 0.87 and adjOR 0.85) and good (adjOR 0.86 and adjOR 0.91) outcomes. The total leukocyte count was not associated with any of the 4 endpoints. The best discriminating factor for sICH was NLR ≥4.80 (sensitivity 66.7%, specificity 71.3%, likelihood ratio 2.32). Patients with NLR ≥4.80 had a 3.71-fold increased risk for sICH (95% confidence interval adjOR: 1.97-6.98) compared to patients with NLR <4.80., Conclusions: Higher neutrophil counts and NLR are independently associated with sICH and worse outcome at 3 months. The identification of mediators of this effect could provide new targets for neuroprotection in patients treated by rtPA., (© 2015 American Academy of Neurology.)

Background and Purpose: Cerebral white matter lesions (WMLs), a surrogate for small-vessel disease, are common in patients with stroke and may be related to an increased intracranial bleeding risk after intravenous thrombolysis in acute ischemic stroke. We aimed to investigate the risk of symptomatic intracerebral hemorrhage (sICH) in the presence of WMLs in a large cohort of ischemic stroke patients treated with intravenous thrombolysis., Methods: We included 2485 consecutive patients treated with intravenous thrombolysis at the Helsinki University Central Hospital. WMLs were scored according to 4 previously published computed tomography visual rating scales from all baseline head scans. A sICH was classified according to the European Cooperative Acute Stroke Study II criteria. The associations of sICH with nominal, ordinal, and continuous variables were analyzed in a univariate binary regression model and adjusted in multivariate binary regression models., Results: In univariate and multivariate regression analyses, all 4 tested visual WML rating scales (as continuous variables or dichotomized at different cutoff points) were associated with increased risk of sICH. In binary analyses, WML doubled the bleeding risk: the odds ratios of all 4 visual rating scales ranged from 2.22 (95% confidence interval, 1.49-3.30) to 2.70 (1.87-3.90) in univariable and from 2.00 (1.26-3.16) to 2.62 (1.71-4.02) in multivariable analyses. The multivariable-adjusted odds ratio for the association of high load of WMLs with remote parenchymal hemorrhage was 4.11 (2.38-7.10)., Conclusions: WMLs visible on computed tomography are associated with a more than doubled risk of sICH in patients treated with intravenous thrombolysis for acute ischemic stroke., (© 2015 American Heart Association, Inc.)

Background: Intraventricular hemorrhage is a severe subtype of intracerebral hemorrhage associated with high mortality and poor outcome., Aim: We analyzed various intraventricular hemorrhage scores at baseline to find common parameters associated with increased mortality., Methods: Consecutive intracerebral hemorrhage patients treated in Helsinki University Central Hospital during 2005-2010 were included in the Helsinki Intracerebral Hemorrhage Study registry and analyzed for three-month mortality., Results: After excluding lost-to-follow-up patients, 967 intracerebral hemorrhage patients were included, out of whom 398 (41%) had intraventricular hemorrhage. Intraventricular hemorrhage patients, compared with nonintraventricular hemorrhage patients, had lower baseline Glasgow Coma Scale [median 12 (IQR 6-15) vs. 15 (13-15); P < 0.001] and higher National Institutes of Health Stroke Scale [18 (10-27) vs. 7 (3-14); P < 0.001] scores; larger intracerebral hemorrhage volumes [17 ml (7.2-42) vs. 6.8 (2.4-18); P < 0.001] and more often hydrocephalus (51% vs. 9%; P < 0.001); and higher mortality rates (54% vs. 18%; P < 0.001). In multivariable analysis, the presence of intraventricular hemorrhage was independently associated with mortality [OR 2.05 (95% CI 1.36-3.09)] when adjusted for well-known prognostic factors of intracerebral hemorrhage, i.e. age, gender, baseline National Institutes of Health Stroke Scale, intracerebral hemorrhage volume, infratentorial location, and etiology., Conclusions: The presence of intraventricular hemorrhage was independently associated with increased mortality, and all the intraventricular hemorrhage scores were strong predictors of three-month mortality., (© 2015 World Stroke Organization.)

Background and Purpose: Compared with other stroke causes, small-vessel disease is associated with better 3-month outcomes in patients with acute ischemic stroke treated with intravenous thrombolysis. Another question is the impact of coexisting cerebral white matter lesions (WMLs; a surrogate marker of small-vessel disease) on outcome, which was addressed in the current study., Methods: We analyzed 2485 consecutive intravenous thrombolysis-treated patients at the Helsinki University Central Hospital, 2001 to 2014. WMLs were scored according to 4 previously published computed tomographic visual rating scales from all baseline head scans. The inter-rater agreement was calculated. The primary outcome measure was shift analysis, and the secondary examined all possible binary cutoffs in the modified Rankin Scale at 3 months. The associations of modified Rankin Scale with nominal, ordinal, and continuous variables were analyzed in univariate and adjusted in multivariate binary and ordinal regression (shift analysis) models., Results: In univariate and multivariate regression analyses, all 4 tested visual WML rating scales (as continuous variables, or dichotomized at different cutoff points) were associated with worse outcome at all binary levels and in shift analyses of the modified Rankin Scale. After adjusting for confounders, the statistically strongest association in shift analyses remained for the Blennow scale dichotomized at >3 points, reflecting at least moderate WMLs (odds ratio, 1.90; 95% confidence interval, 1.48-2.44)., Conclusions: WMLs on admission computed tomographic scan are independently associated with worse outcome in intravenous thrombolysis-treated patients with stroke., (© 2015 American Heart Association, Inc.)

Cerebral amyloid angiopathy (CAA) predisposes to symptomatic intracerebral hemorrhage (sICH) after combined thrombolytic and anticoagulant treatment of acute myocardial infarction. However, the role of CAA in stroke thrombolysis has not been established. Here, we describe a confirmed case of CAA-related hemorrhage in a patient receiving thrombolysis for acute ischemic stroke. On autopsy, immunohistochemistry revealed amyloid-β positive staining in thickened cortical and meningeal arteries at sites of hemorrhage. Further research is urgently needed to determine the hemorrhage risk related to CAA in stroke thrombolysis and develop better diagnostic tools to identify CAA in the emergency room., (© 2014 Japanese Society of Neuropathology.)

Background and Purpose: Seizures are a common complication of intracerebral hemorrhage (ICH). We developed a novel tool to quantify this risk in individual patients., Methods: Retrospective analysis of the observational Helsinki ICH Study (n=993; median follow-up, 2.7 years) and the Lille Prognosis of InTra-Cerebral Hemorrhage (n=325; 2.2 years) cohorts of consecutive ICH patients admitted between 2004 and 2010. Helsinki ICH Study patients' province-wide electronic records were evaluated for early seizures occurring within 7 days of ICH and among 7-day survivors (n=764) for late seizures (LSs) occurring >7 days from ICH. A Cox regression model estimating risk of LSs was used to derive a prognostic score, validated in the Prognosis of InTra-Cerebral Hemorrhage cohort., Results: Of the Helsinki ICH Study patients, 109 (11.0%) had early seizures within 7 days of ICH. Among the 7-day survivors, 70 (9.2%) patients developed LSs. The cumulative risk of LSs was 7.1%, 10.0%, 10.2%, 11.0%, and 11.8% at 1 to 5 years after ICH, respectively. We created the CAVE score (0-4 points) to estimate the risk of LSs, with 1 point for each of cortical involvement, age<65 years, volume>10 mL, and early seizures within 7 days of ICH. The risk of LSs was 0.6%, 3.6%, 9.8%, 34.8%, and 46.2% for CAVE scores 0 to 4, respectively. The c-statistic was 0.81 (0.76-0.86) and 0.69 (0.59-0.78) in the validation cohort., Conclusions: One in 10 patients will develop seizures after ICH. The risk of this adverse outcome can be estimated by a simple score based on baseline variables., (© 2014 American Heart Association, Inc.)

Background and Purpose: In middle cerebral artery occlusion, probability of recanalization after intravenous tissue-type plasminogen activator thrombolysis (IVT) was reported to drop <1% for thrombi exceeding 8 mm. We aimed to evaluate the effect of thrombus length and location on success of recanalization after IVT in basilar artery occlusion., Methods: We evaluated 164 consecutive patients with angiography-proven basilar artery occlusion and available thrombus length. We excluded 24 patients who underwent endovascular treatment. All included patients (n=140) received IVT. Thrombolysis in myocardial infarction 2 to 3 was considered as successful recanalization., Results: Of the 140 included patients, 37 (26.4%) lacked post-treatment angiography, mostly because of early death. Of the remaining 103 patients, those with recanalization had shorter thrombi (median, 5.5 mm and mean, 9.7 mm) when compared with those with nonrecanalized (median, 15.0 mm and mean, 16.6 mm; P<0.001). Thrombi shorter than 10 mm had 70% to 80% probability of recanalization, whereas 10 to 20 mm, 20 to 30 mm, and >30 mm long thrombi had probabilities of 50% to 70%, 30% to 50%, and 20% to 30%, respectively. Patients with thrombi <10 mm (n=52) and recanalization had more frequently top-of-the basilar (92.5%) and less frequently caudal or midbasilar (7.5%) clot location (P=0.01). In multivariable analysis, thrombus length was independently associated with recanalization (P=0.001). Their relationship remained linear across all lengths., Conclusions: Although recanalization of basilar artery occlusion with IVT depends on thrombus length, its probability even in patients with thrombi >30 mm (20%-30%) was substantially higher than minimal recanalization of middle cerebral artery thrombi exceeding 8 mm. There was no threshold length, beyond which basilar artery occlusion recanalization with IVT could ad hoc be deemed hopeless., (© 2014 American Heart Association, Inc.)

Background and Purpose: It is unclear whether blood lipid profiles and statin use before intracerebral hemorrhage (ICH) are associated with its outcome., Methods: The Helsinki ICH Study, a single-center observational registry of consecutive ICH patients, was used to study the associations between premorbid statin use, baseline lipid levels, and clinical outcome., Results: The registry includes 964 ICH patients. Statin users (n=187; 19%) were significantly older, had more frequent comorbidities and medication, lower lipid levels, and higher admission Glasgow Coma Scale compared with nonusers. Modified Rankin Scale at discharge or mortality did not differ between statin users and nonusers. Compared with survivors, significantly lower total cholesterol and low-density lipoprotein cholesterol levels were observed in patients who died in hospital (median, 4.1 mmol/L [interquartile range, 3.6-4.4] versus 4.5 [3.8-5.1]; P<0.01; 1.9 mmol/L [1.4-2.5] versus 2.4 [1.8-3.0]; P<0.001, respectively), at 3 or 12 months. After adjusting for known ICH prognostic factors based on univariate analysis that is, age, National Institutes of Health Stroke Scale, Glasgow Coma Scale, ICH volume, and intraventricular location, lower low-density lipoprotein levels were independently associated with in-hospital mortality (odds ratio, 0.54 [95% confidence interval, 0.31-0.93]; P=0.028)., Conclusions: Premorbid statin use did not affect the outcome of ICH, but lower low-density lipoprotein levels were associated with higher in-hospital mortality.

Background: Thrombolysis of ischemic stroke patients presenting with mild symptoms is controversial., Aim: We aimed to describe the clinical outcome and frequency of infarcts and symptomatic intracerebral hemorrhages on follow-up imaging of such thrombolysis-treated patients., Methods: Our cohort included 1398 consecutive ischemic stroke patients treated with intravenous thrombolysis at the Helsinki University Central Hospital, years 1995-2010. We analyzed the patients according to baseline National Institutes of Health Stroke Scale: ≤2, 3-4, 5-6, and >6. In our institution, visualization of an artery occlusion or perfusion deficit is required for thrombolysis with National Institutes of Health Stroke Scale ≤ 2. We used univariate and multivariable methods to describe the cohort and study associations between the variables. Excellent three-month outcome was defined as modified Rankin Scale 0-1., Results: Fifty-eight (4·1%) patients were treated with National Institutes of Health Stroke Scale ≤ 2, another 194 (13·6%) with 3-4 points, and 236 (16·5%) with 5-6 points. With National Institutes of Health Stroke Scale ≤ 2, 45 (78%) of the patients had excellent three-month outcome, achieved in 116 (59%) patients with National Institutes of Health Stroke Scale 3-4, in 130 (55%) with National Institutes of Health Stroke Scale 5-6, and in 241 (26%) with National Institutes of Health Stroke Scale > 6. Frequencies of symptomatic intracerebral hemorrhage (European Cooperative Acute Stroke Study-2) were 0%, 2·6%, 2·1%, and 8·1%, and visible infarcts on follow-up imaging 48%, 43%, 48%, and 74%, respectively. In patients with baseline National Institutes of Health Stroke Scale ≤ 6, poor outcome was associated with previous stroke, diabetes, elevated admission blood glucose, and development of intracerebral hemorrhage., Conclusions: Half of patients presenting with National Institutes of Health Stroke Scale 0-6 developed an infarction despite thrombolysis, and 40% had poor outcome, which was associated with glucose metabolism and hemorrhagic complications. Managing thrombolysis candidates with mild symptoms warrants individual consideration often supported by multimodal imaging., (© 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.)

Objective: To evaluate the impact of extensive baseline ischemic changes on functional outcome after thrombolysis of basilar artery occlusion (BAO), and to study the effect of time to treatment in the absence of such findings., Methods: We prospectively evaluated 184 consecutive patients with angiography-proven BAO. The majority of patients received intravenous alteplase and concomitant full-dose heparin. Extensive baseline ischemia was defined as posterior circulation Acute Stroke Prognosis Early CT score (pc-ASPECTS) < 8. Onset-to-treatment time (OTT) was evaluated both as a continuous and as a categorical variable (0-6 hours, 6-12 hours, 12-24 hours, and 24-48 hours). Successful recanalization means thrombolysis in myocardial infarction (TIMI) = 2 to 3. Symptomatic intracranial hemorrhage (sICH) was evaluated with National Institute of Neurological Disorders and Stroke, European Cooperative Acute Stroke Study II, and Safe Implementation of Thrombolysis in Stroke criteria. Poor 3-month outcome was defined as modified Rankin Scale score of 3 to 6., Results: The majority (96%) of patients with baseline pc-ASPECTS < 8 had poor 3-month outcome, and a similar number (94%) was observed in those of them with confirmed recanalization (51.5%). In contrast, half of the patients with pc-ASPECTS ≥ 8 and successful recanalization (73.2%) achieved good outcome. In these patients, OTT was associated with poor outcome neither as a continuous nor as a categorical variable. Factors independently associated with poor outcome were greater age and baseline National Institutes of Health Stroke Scale, lack of recanalization, history of atrial fibrillation, and sICH. In the model including the whole cohort (patients with any pc-ASPECTS), pc-ASPECTS < 8 was independently associated with poor outcome (odds ratio = 5.83, 95% confidence interval = 1.09-31.07)., Interpretation: In the absence of extensive baseline ischemia, recanalization of BAO up to 48 hours was seldom futile and produced good outcomes in 50% of patients, which was independent of time to treatment., (© 2013 American Neurological Association.)

Acute basilar artery occlusion is a neurological emergency that almost invariably leads to death or severe disability if not recanalized. Therapeutic recanalization is attempted using thrombolytic therapy either intravenously alone or by bridging it to on-demand, endovascular procedures. Due to often demanding differential diagnosis, angiographic evidence of basilar artery occlusion is necessary before treatment decisions. The etiology is often cardioembolism or vertebrobasilar thromboembolism due to atherothrombotic disease, or vertebral artery dissection in less than one in ten cases. Different therapeutic approaches have not been compared in randomized controlled trials. The selection of recanalization therapies thus builds on empirical knowledge and availability of vascular interventional services in the local setting.

Basilar artery occlusion (BAO) is associated with high mortality (85-95%) if recanalization does not occur. Evidence of the efficacy of different therapy protocols of intravenous thrombolysis (IVT) or intraarterial thrombolysis (IAT) and/or mechanical endovascular treatment is based on retrospective or prospective patient cohorts, since randomized controlled trials (RCTs) do not exist. Roughly a third of BAO patients reach independent outcome following thrombolysis. From those in whom recanalization occurs, about half will reach independence. In noninvasive and endovascular protocols, recanalization of BAO is reached in 60-85% of the patients. While invasive endovascular approaches afford greater recanalization rates, they have not been proven superior to IVT in terms of functional outcome. Meaningful survival after BAO requires rapid access to thrombolysis. "Bridging" protocols have been introduced where rescue therapies such as endovascular thrombolysis and on-demand mechanical thrombectomy or angioplasty are used. Multimodal imaging techniques should be used to choose the best therapeutic option individually., (© 2012 New York Academy of Sciences.)

Objectives: The benefits of prophylactic carotid endarterectomy (CEA) together with best medical treatment (BMT) are well-established. Early initiation of proper medical treatment reduces the risk of new strokes as waiting periods for CEA operation can be considerably long. We investigated: (1) preoperative medical treatment of CEA patients at our hospital and (2) how well the present medical treatment coheres with national and international secondary prevention guidelines and other CEA cohorts., Methods: A retrospective study cohort of 135 consecutive patients planned for CEA in a tertiary center because of symptomatic (n = 100) or asymptomatic (n = 35) carotid artery stenosis during a 14-month period (2007-2008)., Results: One hundred and twenty-six of 135 (93.3%) patients received antiplatelet therapy at the time of surgery, 125/135 (92.6%) were on statin, and 121/135 (89.6%) used antihypertensive medications. Ten of the 100 symptomatic patients had recurrence or progression in their ischemic symptoms while waiting for the operation, with a median time of 8.5 days (range 1-30 days)., Discussion: Carotid artery stenosis patients are considered high-risk patients regardless of symptomatology. The high proportion of medication use exceeds the use in the past proof-of-concept randomized controlled trials on the benefit of CEA+BMT over BMT. Nevertheless, there is room for improvement.

Objective: A study was undertaken to develop a score for assessing risk for symptomatic intracranial hemorrhage (sICH) in ischemic stroke patients treated with intravenous (IV) thrombolysis., Methods: The derivation cohort comprised 974 ischemic stroke patients treated (1995-2008) with IV thrombolysis at the Helsinki University Central Hospital. The predictive value of parameters associated with sICH (European Cooperative Acute Stroke Study II) was evaluated, and we developed our score according to the magnitude of logistic regression coefficients. We calculated absolute risks and likelihood ratios of sICH per increasing score points. The score was validated in 828 patients from 3 Swiss cohorts (Lausanne, Basel, and Geneva). Performance of the score was tested with area under a receiver operating characteristic curve (AUC-ROC)., Results: Our SEDAN score (0 to 6 points) comprises baseline blood Sugar (glucose; 8.1-12.0 mmol/l [145-216 mg/dl] = 1; >12.0 mmol/l [>216 mg/dl] = 2), Early infarct signs (yes = 1) and (hyper)Dense cerebral artery sign (yes = 1) on admission computed tomography scan, Age (>75 years = 1), and NIH Stroke Scale on admission (≥10 = 1). Absolute risk for sICH in the derivation cohort was: 1.4%, 2.9%, 8.5%, 12.2%, 21.7%, and 33.3% for 0, 1, 2, 3, 4, and 5 score points, respectively. In the validation cohort, absolute risks were similar (1.0%, 3.5%, 5.1%, 9.2%, 16.9%, and 27.8%, respectively). AUC-ROC was 0.77 (0.71-0.83; p < 0.001)., Interpretation: Our SEDAN score reliably assessed risk for sICH in IV thrombolysis-treated patients with anterior- and posterior circulation ischemic stroke, and it can support clinical decision making in high-risk patients. External validation of the score supports its generalization., (Copyright © 2012 American Neurological Association.)

Background: A part of ischemic stroke patients score 0 on the National Institutes of Health Stroke Scale (NIHSS) within 24 h following thrombolysis. Their clinical characteristics and long-term outcome are poorly studied. We report a single-center assessment of such patients., Methods: The cohort comprises 874 consecutive patients from the Helsinki Stroke Thrombolysis Registry, out of whom 113 scored 0 on 24-hour NIHSS. We analyzed their baseline demographic, clinical and radiological characteristics and 3-month outcome (modified Rankin Scale, mRS). Associations between the study parameters were tested by multivariate analysis., Results: Patients with a 24-hour NIHSS score = 0 (n = 113) were younger than the rest of the population (n = 761; median: 65.6 vs. 71.5 years; p < 0.001), their NIHSS score on admission was lower (median: 5 vs. 10; p < 0.001), as was their glucose level (median: 6.2 vs. 6.7 mmol/l; p = 0.02). The onset-to-treatment time was similar in both groups (median: 120 vs. 115 min; p = 0.89). Patients with a 24-hour NIHSS score = 0 more often achieved an excellent outcome (mRS scores: 0-1; 81 vs. 31%; p < 0.001) and had lower mortality (1.8 vs. 11.8%; p < 0.01). One third of these patients had a brain infarction visible on 24-hour imaging. Lower baseline NIHSS score and younger age were independently associated with 24-hour NIHSS score = 0, which, in turn, was independently associated with excellent 3-month outcome., Conclusions: Patients with an NIHSS score = 0 at 24 h following thrombolysis are younger, have milder symptoms and have a lower glucose level on admission. They achieve more often excellent outcome and lower mortality. Still, 8% of them required help in daily activities or were dead at 3 months (mRS scores: 3-6)., (Copyright © 2010 S. Karger AG, Basel.)

Background: Treating hyperglycemia in acute ischemic stroke may be beneficial, but knowledge on its prognostic value and optimal target glucose levels is scarce. We investigated the dynamics of glucose levels and the association of hyperglycemia with outcomes on admission and within 48 h after thrombolysis., Methods: We included 851 consecutive patients with acute ischemic stroke treated with intravenous thrombolysis in the Helsinki University Central Hospital during 1998-2008. Outcome measures were unfavorable 3- month outcome (3-6 on the modified Rankin Scale), death, and symptomatic intracerebral hemorrhage (sICH) according to NINDS criteria. Hyperglycemia was defined as a blood glucose level of ≥8.0 mmol/l. Four groups were identified based on (a) admission and (b) peak glucose levels 48 h after thrombolysis: (1) persistent normoglycemia (baseline plus 48-hour normoglycemia), (2) baseline hyperglycemia (48-hour normoglycemia), (3) 48-hour hyperglycemia (baseline normoglycemia), and (4) persistent hyperglycemia (baseline plus 48-hour hyperglycemia)., Results: 480 (56.4%) of our patients (median age 70 years; onset-to-needle time 199 min; National Institutes of Health Stroke Scale score 9), had persistent normoglycemia, 59 (6.9%) had baseline hyperglycemia, 175 (20.6%) had 48-hour hyperglycemia, while persistent hyperglycemia appeared in 137 (16.1%) patients. Persistent and 48-hour hyperglycemia independently predicted unfavorable outcome [odds ratio (OR) = 2.33, 95% confidence interval (CI) = 1.41-3.86, and OR = 2.17, 95% CI = 1.30-3.38, respectively], death (OR = 6.63, 95% CI = 3.25-13.54, and OR = 3.13, 95% CI = 1.56-6.27, respectively), and sICH (OR = 3.02, 95% CI = 1.68-5.43, and OR = 1.89, 95% CI = 1.04-3.43, respectively), whereas baseline hyperglycemia did not., Conclusions: Hyperglycemia (≥8.0 mmol/l) during 48 h after intravenous thrombolysis of ischemic stroke is strongly associated with unfavorable outcome, sICH, and death., (Copyright © 2010 S. Karger AG, Basel.)

Background and Purpose: Numerous contraindications included in the license of alteplase, most of which are not based on scientific evidence, restrict the portion of patients with acute ischemic stroke eligible for treatment with alteplase. We studied whether off-label thrombolysis was associated with poorer outcome or increased rates of symptomatic intracerebral hemorrhage compared with on-label use., Methods: All consecutive patients with stroke treated with intravenous thrombolysis from 1995 to 2008 at the Helsinki University Central Hospital were registered (n=1104). After excluding basilar artery occlusions (n=119), the study population included 985 patients. Clinical outcome (modified Rankin Scale 0 to 2 versus 3 to 6) and symptomatic intracerebral hemorrhage according to 3 earlier published criteria were analyzed with a logistic regression model adjusting for 21 baseline variables., Results: One or more license contraindications to thrombolysis was present in 51% of our patients (n=499). The most common of these were age >80 years (n=159), mild stroke National Institutes of Health Stroke Scale score <5 (n=129), use of intravenous antihypertensives prior to treatment (n=112), symptom-to-needle time >3 hours (n=95), blood pressure >185/110 mm Hg (n=47), and oral anticoagulation (n=39). Age >80 years was the only contraindication independently associated with poor outcome (OR, 2.18; 95% CI, 1.27 to 3.73) in the multivariate model. None of the contraindications were associated with an increased risk of symptomatic intracerebral hemorrhage., Conclusions: Off-license thrombolysis was not associated with poorer clinical outcome, except for age >80 years, nor with increased rates of symptomatic intracerebral hemorrhage. The current extensive list of contraindications should be re-evaluated when data from ongoing randomized trials and observational studies become available.

A TIA (Transient Ischemic Attack) is a sudden onset transient cerebral or retinal ischemic symptom. The definition of TIA has evolved from a time-based (< 24 hours) towards tissue-based. This requires brain scanning either with a computer tomography or magnetic resonance imaging. The benefit of urgent etiological work-up and immediate start of secondary preventive medications has been shown in two independent open studies, in which eight out of ten ischemic strokes could be prevented after a TIA. The risk of ischemic stroke is highest in the two days following a TIA. This puts a huge demand on both the patients and their doctors in the recognition of a TIA. The patient needs to be referred on an emergency basis to a specialized centre with adequate investigational facilities.

Apoptotic cell death contributes to neuronal loss in the penumbral region of brain infarction. Activated caspase-3 (ACA-3) cleaves proteins including poly(ADP-ribose) polymerase-1 (PARP-1) important in DNA repair, thus promoting apoptosis. Overactivation of PARP-1 depletes NAD(+) and ATP, resulting in necrosis. These cell death phenomena have been investigated mostly in experimental animals. We studied an autopsy cohort of 13 fatal ischemic stroke cases (symptoms 15 h to 18 days) and 2 controls by immunohistochemical techniques. The number of PARP-1 immunoreactive neurons was highest in the periinfarct area. Nuclear PARP-1 correlated with increasing neuronal necrosis (P = 0.013). Cytoplasmic PARP-1 correlated with TUNEL in periinfarct and core areas (P = 0.01). Cytoplasmic cleaved PARP-1 was inversely correlated with increasing necrotic damage (P = 0.001). PAR-polymers were detected in neurons confirming enzymatic activity of PARP-1. Cytoplasmic ACA-3 correlated with death receptor Fas (r (s) = 0.48; P = 0.005). In conclusion, the confirmation of the same pathways of cell death than previously described in experimental animal models encourages neuroprotective treatments acting on these mediators also in human stroke.

Background: We examined the hypothesis that endothelial denudation in advanced carotid plaques (CPs) occurs by increased apoptosis of endothelial cells (ECs) using scanning electron microscopy (SEM) as well as markers of cellular proliferation and apoptosis in advanced symptomatic CPs (SCPs) and asymptomatic CPs (ACPs)., Methods: 93 consecutive patients underwent carotid endarterectomy. Five additional specimens were studied by SEM. We performed TUNEL assays, and immunostaining against Fas receptor (FasR), Fas ligand (FasL), activated caspase 3 (ACA3) and Ki-67., Results: SEM revealed morphological changes consistent with EC detachment. Surprisingly, ACA3 positivity was more pronounced on the endothelium of ACPs (4.6 +/- 0.7% of total EC count) than on SCPs (3.3 +/- 0.7%, p = 0.049), and was found to correlate positively with nuclear Ki-67 expression (r(s) = 0.275, p = 0.040). FasL expression was significantly increased on the endothelium of SCPs compared with ACPs (66.4 +/- 4.4 vs. 53.9 +/- 4.5%, p = 0.047)., Conclusions: Absence of increased positivity of apoptotic markers dismisses apoptosis as a dominant mechanism underlying endothelial detachment of SCPs. Rather, increased ACA3 with co-expression of Ki-67 in ACPs might suggest that renewal of endothelium by active cell turnover may contribute to clinically silent evolution of plaques with preserved EC integrity. These observations may assist in designing novel therapies to prevent endothelial decay and symptom generation in advanced carotid artery disease., (Copyright 2007 S. Karger AG, Basel.)

The concept of the therapeutic window of opportunity in ischemic neuronal injury and understanding the necessity of well organized stroke services revolutionized the management of acute ischemic stroke during the last years of the second millennium. Thrombolysis with IV rt-PA within 3 hours from the onset of symptoms is an established therapy for selected patients. The challenge of stroke therapy at the outset of this millennium is how to translate basic pathophysiologic evidence of ischemic neuronal injury into novel neuroprotective therapies either independently or combined with thrombolysis. Great hopes are placed in identification of pivotal molecular events in ischemic brain tissue and design of effective pharmacological interventions to target them. Aggressive, invasive procedures are also being developed and therapies such as intra-arterial clot lysis, hemicraniectomy and mild hypothermia may improve the bleakest outcomes associated with the most severe forms of ischemic stroke, but their role must be rigorously evaluated. There is, however, no need to wait for future breakthroughs. The existing evidence strongly implies that good care of patients with stroke starts with organization of the entire stroke chain; from the prehospital scene, through the emergency room, to the stroke unit. Without structured stroke services no pharmacological or intervening therapy is likely to improve the outcome of the patient with a stroke.

Cyclooxygenase (COX) catalyzes synthesis of prostanoids after liberation of arachidonic acid, an important biochemical sequela of cerebral ischemia that aggravates brain injury. We investigated expression of inducible COX-2 in infarcted human brains (symptom duration, 15 hours to 18 days) and found that COX-2 protein was present in both neuronal and glial cells throughout the brain in accord with infarct topography and duration. These results emphasize the global yet temporally regulated nature of COX-2 induction during focal ischemia in humans, clearly different from the circumscribed acute expression reported in experimental animal models. We speculate that early induction of COX-2 may fuel tissue damage through prostanoids and free radicals, and delayed induction in remote brain areas may promote reconstitutive processes in the face of tissue scarring and remodeling of the surviving neural networks.

The mRNA expression of the proinflammatory cytokine interleukin-1beta (IL-1beta) has been shown to be induced in neural elements during ischemia. It is not clear which cells generate the IL-1beta mRNA and eventually synthesize IL-1 protein and which cells respond to this signaling by producing IL-1 receptors during ischemia. To clarify this question, rats were subjected to global ischemia by bilateral carotid occlusion and hypotension for 20 minutes, followed by reperfusion for 2 hours (n = 7), 8 hours (n = 7), or 24 hours (n = 7). Cryostat sections were hybridized using antisense oligonucleotide probes (30 dimer). Multiple cell markers were used in immunohistochemical staining to identify the cells expressing IL-1beta and IL-1R protein. The sham animals (n = 5) showed no or only a weak expression of IL-1R or IL-1beta mRNA. The number of IL-1beta mRNA-expressing cells was significantly increased by 2 hours of reperfusion in several brain areas including cortex (12-fold compared with sham) and caudate-putamen (14-fold), and was maximally increased in most hippocampal regions by 8 hours of reperfusion (mean +/- SD of positive cells/field versus sham equivalent being 37.9 +/- 12.3 versus 4.0 +/- 3.3; 30.6 +/- 9.0 versus 3.1 +/- 2.3; 41.3 +/- 17.5 versus 2.9 +/- 1.9; in CA1; CA2; CA3/CA4 regions of the hippocampus, respectively). IL-1beta mRNA signal was also intensified in the white matter areas. Changes in IL-1R mRNA were seen in the hippocampus (after 2 hours CA1: 16-fold; CA2: 17-fold; DG: 24-fold increase; and CA3/CA4: 10-fold increase after 8 hours), and the expression was prolonged especially in CA1 and CA2 regions up to 24 hours of reperfusion. The major cellular source of IL-1beta protein was glia (astrocytes, oligodendrocytes, microglia, and scattered perivascular macrophages/monocytes), while neurons and sporadic microvascular endothelia showed IL-1R immunoreactivity. The data suggest that neurons in discrete areas vulnerable for selective neuronal death, and possibly the vascular endothelium, are target cells for ischemia-induced glial IL-1beta production.