•The response of astrocytes to injury is a major determinant of the outcome after stroke.•In the acute phase, reactive astrocytes are neuroprotective.•In the post-acute and chronic phase, astrocytes ...act as both positive and negative regulators of neural plasticity.•Modulation of astrocyte function at this later stage appears as an attractive strategy to improve functional outcome.•Astrocyte intermediate filament (nanofilament) proteins may represent the right target for this objective, and the complement system may be at least one of the suitable bullets to hit it.
Stroke is an acute insult to the central nervous system (CNS) that triggers a sequence of responses in the acute, subacute as well as later stages, with prominent involvement of astrocytes. Astrocyte activation and reactive gliosis in the acute stage of stroke limit the tissue damage and contribute to the restoration of homeostasis. Astrocytes also control many aspects of neural plasticity that is the basis for functional recovery. Here, we discuss the concept of intermediate filaments (nanofilaments) and the complement system as two handles on the astrocyte responses to injury that both present attractive opportunities for novel treatment strategies modulating astrocyte functions and reactive gliosis.
Ischemic stroke is a devastating disease with a complex pathophysiology. Animal modeling of ischemic stroke serves as an indispensable tool first to investigate mechanisms of ischemic cerebral ...injury, secondly to develop novel antiischemic regimens. Most of the stroke models are carried on rodents. Each model has its particular strengths and weaknesses. Mimicking all aspects of human stroke in one animal model is not possible since ischemic stroke is itself a very heterogeneous disorder. Experimental ischemic stroke models contribute to our understanding of the events occurring in ischemic and reperfused brain. Major approaches developed to treat acute ischemic stroke fall into two categories, thrombolysis and neuroprotection. Trials aimed to evaluate effectiveness of recombinant tissue-type plasminogen activator in longer time windows with finer selection of patients based on magnetic resonance imaging tools and trials of novel recanalization methods are ongoing. Despite the failure of most neuroprotective drugs during the last two decades, there are good chances to soon have effective neuroprotectives with the help of improved preclinical testing and clinical trial design. In this article, we focus on various rodent animal models, pathogenic mechanisms, and promising therapeutic approaches of ischemic stroke.
Both stroke and obesity show an increasing incidence worldwide. While obesity is an established risk factor for stroke, its influence on outcome in ischemic stroke is less clear. Many studies suggest ...a better prognosis in obese patients after stroke ("obesity paradox"). This review aims at assessing the clinical outcomes of obese patients after stroke by performing a systematic literature search.
The reviewers searched MEDLINE from inception to December 2015. Studies were eligible if they included outcome comparisons in stroke patients with allocation to body weight.
Twenty-five studies (299'750 patients) were included and none was randomised. Ten of 12 studies (162'921 patients) reported significantly less mortality rates in stroke patients with higher BMI values. Seven of 9 studies (92'718 patients) ascertained a favorable effect of excess body weight on non-fatal outcomes (good clinical outcome, recurrence of vascular events). Six studies (85'042 patients) indicated contradictory results after intravenous thrombolysis (IVT), however. Several methodological limitations were observed in major part of studies (observational study design, inaccuracy of BMI in reflecting obesity, lacking body weight measurement, selection bias, survival bias).
Most observational data indicate a survival benefit of obese patients after stroke, but a number of methodological concerns exist. No obesity paradox was observed in patients after IVT. There is a need for well-designed randomized controlled trials assessing the effects of weight reduction on stroke risk in obese patients.
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 endpointssICH (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 adjOR1.97–6.98) 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.
Cerebral venous thrombosis (CVT) affects mainly working-aged individuals. Functional recovery after CVT is generally considered good with about 3/4 of patients achieving short-term independence. ...However, vascular events, long-term functional outcome, and employment after CVT remain poorly investigated. We identified consecutive adult CVT patients treated at the Helsinki University Hospital (1987–2013) and invited them to a follow-up visit. Each clinical examination was combined with interview. We also recorded recurrent venous thromboembolism (VTE) and hemorrhagic events during follow-up and antithrombotic medication use. A modified Rankin Scale (mRS) served to assess functional outcome. Logistic regression served to identify independent factors associated with unemployment and functional recovery. Of the 195 patients identified, 21 died, 9 declined to participate, and 4 were excluded from the study. Thus, 161 patients (106 women) underwent an examination after a median of 39 months (interquartile range 14–95). VTE (one of which was CVT) occurred in 9 (6 %) patients, and severe hemorrhagic events in 10 (6 %). Functional outcome was good, with 84 % scoring 0–1 on the mRS; 42 % reported residual symptoms. Altogether, 91 (57 %) patients were employed. After adjusting for age and sex, a National Institutes of Health Stroke Scale score >2 at admission and low education level, associated with both unfavorable functional outcome and unemployment. Long-term functional outcome after CVT may appear good if measured with mRS, but patients often have residual symptoms and are frequently unable to return to their previous work.
Summary Spontaneous intracranial artery dissection is an uncommon and probably underdiagnosed cause of stroke that is defined by the occurrence of a haematoma in the wall of an intracranial artery. ...Patients can present with headache, ischaemic stroke, subarachnoid haemorrhage, or symptoms associated with mass effect, mostly on the brainstem. Although intracranial artery dissection is less common than cervical artery dissection in adults of European ethnic origin, intracranial artery dissection is reportedly more common in children and in Asian populations. Risk factors and mechanisms are poorly understood, and diagnosis is challenging because characteristic imaging features can be difficult to detect in view of the small size of intracranial arteries. Therefore, multimodal follow-up imaging is often needed to confirm the diagnosis. Treatment of intracranial artery dissections is empirical in the absence of data from randomised controlled trials. Most patients with subarachnoid haemorrhage undergo surgical or endovascular treatment to prevent rebleeding, whereas patients with intracranial artery dissection and cerebral ischaemia are treated with antithrombotics. Prognosis seems worse in patients with subarachnoid haemorrhage than in those without.
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; 8.1–12.0mmol/l 145–216mg/dl = 1; >12.0mmol/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. ANN NEUROL 2012;
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.
The original version of this consensus statement on mechanical thrombectomy was approved at the European Stroke Organisation (ESO)-Karolinska Stroke Update conference in Stockholm, 16–18 November ...2014. The statement has later, during 2015, been updated with new clinical trials data in accordance with a decision made at the conference. Revisions have been made at a face-to-face meeting during the ESO Winter School in Berne in February, through email exchanges and the final version has then been approved by each society. The recommendations are identical to the original version with evidence level upgraded by 20 February 2015 and confirmed by 15 May 2015. The purpose of the ESO-Karolinska Stroke Update meetings is to provide updates on recent stroke therapy research and to discuss how the results may be implemented into clinical routine. Selected topics are discussed at consensus sessions, for which a consensus statement is prepared and discussed by the participants at the meeting. The statements are advisory to the ESO guidelines committee. This consensus statement includes recommendations on mechanical thrombectomy after acute stroke. The statement is supported by ESO, European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), and European Academy of Neurology (EAN).
OBJECTIVETo discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study.
METHODSThe study comprised 6,165 patients with ischemic stroke from 12 ...studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0–2 vs 3–6 and 0–1 vs 2–6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10.
RESULTSWe identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0–2 vs 3–6, p = 5.3 × 10). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1).
CONCLUSIONSIn this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.
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