The role of mast cells in ischemic and hemorrhagic brain injury

Stroke, ischemic or hemorrhagic, belongs among the foremost causes of death and disability worldwide. Massive brain swelling is the leading cause of death in large hemispheric strokes and is only modestly alleviated by available treatment. Thrombolysis with tissue plasminogen activator (TPA) is the only approved therapy in acute ischemic stroke, but fear of TPA-mediated hemorrhage is often a reason for withholding this otherwise beneficial treatment. In addition, recanalization of the occluded artery (spontaneously or with thrombolysis) may cause reperfusion injury by promoting brain edema, hemorrhage, and inflammatory cell infiltration. A dominant event underlying these phenomena seems to be disruption of the blood-brain barrier (BBB). In contrast to ischemic stroke, no widely approved clinical therapy exists for intracerebral hemorrhage (ICH), which is associated with poor outcome mainly due to the mass effect of enlarging hematoma and associated brain swelling. Mast cells (MCs) are perivascularly located resident inflammatory cells which contain potent vasoactive, proteolytic, and fibrinolytic substances in their cytoplasmic granules. Experiments from our laboratory showed MC density and their state of granulation to be altered early following focal transient cerebral ischemia, and degranulating MCs were associated with perivascular edema and hemorrhage. (I) Pharmacological MC stabilization led to significantly reduced ischemic brain swelling (40%) and BBB leakage (50%), whereas pharmacological MC degranulation raised these by 90% and 50%, respectively. Pharmacological MC stabilization also revealed a 40% reduction in neutrophil infiltration. Moreover, genetic MC deficiency was associated with an almost 60% reduction in brain swelling, 50% reduction in BBB leakage, and 50% less neutrophil infiltration, compared with controls. (II) TPA induced MC degranulation in vitro. In vivo experiments with post-ischemic TPA administration demonstrated 70- to 100-fold increases in hemorrhage formation (HF) compared with controls HF. HF was significantly reduced by pharmacological MC stabilization at 3 (95%), 6 (75%), and 24 hours (95%) of follow-up. Genetic MC deficiency again supported the role of MCs, leading to 90% reduction in HF at 6 and 24 hours. Pharmacological MC stabilization and genetic MC deficiency were also associated with significant reduction in brain swelling and in neutrophil infiltration. Importantly, these effects translated into a significantly better neurological outcome and lower mortality after 24 hours. (III) Finally, in ICH experiments, pharmacological MC stabilization resulted in significantly less brain swelling, diminished growth in hematoma volume, better neurological scores, and decreased mortality. Pharmacological MC degranulation produced the opposite effects. Genetic MC deficiency revealed a beneficial effect similar to that found with pharmacological MC stabilization. In sum, the role of MCs in these clinically relevant scenarios is supported by a series of experiments performed both in vitro and in vivo. That not only genetic MC deficiency but also drugs targeting MCs could modulate these parameters (translated into better outcome and decreased mortality), suggests a potential therapeutic approach in a number of highly prevalent cerebral insults in which extensive tissue injury is followed by dangerous brain swelling and inflammatory cell infiltration. Furthermore, these experiments could hint at a novel therapy to improve the safety of thrombolytics, and a potential cellular target for those seeking novel forms of treatment for ICH.Aivoinfarkti on yhdessä sydäninfarktin ja syövän kanssa yleisimpiä kuolinsyitä maailmassa. Aivohalvauspotilaiden kuntoutus on kallista eikä se useinkaan estä työkyvyttömyyttä ja elämänlaadun huonontumista. Valtimotukoksen syntymisen ja sen uudelleen avautumisen (spontaanin tai lääkkeellisen) välinen aikaviive ratkaisee kokonaisvaurion laajuuden, koska verenkierron myöhäinen palautuminen johtaa veri-aivo esteen vaurioon, aivoturvotukseen, verenvuotoon ja tulehdussolujen vasteeseen. Valtimotukoksesta aiheutuneen aivoinfarktin ennuste on viime vuosina huomattavasti parantunut liuotushoidon ansioista. Liuotushoito ei kuitenkaan sovellu kaikille potilaille aivoverenvuodon riskin takia. Tämä riski vaihteli kriteereistä riippuen isoissa tutkimuksissa (n. 2-8 %). Jos aivoinfarkti johtuu primäärisestä aivoverenvuodosta, ennuste on tunnetusti huono ja hoitokeinot lähes olemattomat. Syöttösolut on hyvin tunnettuja soluja mm allergia-sairauksissa. Nämä tiettyjen aivoverisuonten ympärille sijoittuvia soluja sisältävät jyväsissään verisuoniin vaikuttavia, valkuaisaineita pilkkovia, fibriiniä hajoittavia sekä muita välittäjäaineita, jotka vapautuvat syöttösolujen aktivaation johdosta. I) Syöttösolujen aktivaatio (yhdiste 48/80) lisäsi veri-aivo esteen vauriota (50 %), aivoturvotusta (90 %) sekä tulehduksellista reaktiota kun taas aktivaation esto (kromoglikaatti) vähensi nämä vasteet seuraavasti: 50 %, 40 % ja 40 % kontrolliryhmään verrattuna. Lisäksi, syöttösolupuutteisilla rotilla oli, villityyppeihin verrattuna, jopa kromoglikaattihoidettuja parempaa löydöstä. II)Liuotushoidon aine (TPA) aktivoi syöttösoluja in vitro. Aivoiskemian mallissa TPA lisäsi aivoverenvuodon 70 100 kertaa kontrolliryhmään verrattuna. TPA:n aiheuttaman aivoverenvuodon vähensi (n. 90 %) syöttösolujen aktivoinnin estämällä 3, 6 sekä 24 tunnin kohdalla. Syttösolupuutteisilla rotilla oli 90 % vähemmän TPA:n aiheuttamaa aivoverenvuotoa kuin villityypeillä. Syöttösolujen aktivoinnin esto ja syöttösolupuutteisuus ilmeni myös vähentyneenä kuolleisuutena ja parempana neurologisena toipumisena. III) Myös primäärisessä aivojen sisäisessä verenvuodossa syöttösolujen aktivoinnin esto merkittävästi vähensi aivoverenvuodon ja aivoturvotuksen kasvua kun taas syöttösolujen aktivointi aiheutti päinvastaisen muutoksen. Syöttösolupuutteisilla rotilla oli samanlaisia löydöksiä kun kromoglikaattihoidetuilla. Tässäkin tutkimuksessa syöttösolujen aktivoinnin esto ja syöttösolupuutteisuus ilmeni vähentyneenä kuolleisuutena ja parempana neurologisena toipumisena. Tulokset viittaavat vahvasti tärkeään syöttösolujen rooliin veri-aivo esteen vaurion, aivoturvotuksen, tulehduksellisen reaktion, liuotushoidon aiheuttaman aivoverenvuodon sekä primäärisen aivojen sisäisen verenvuodon kasvun ja sen aiheuttaman aivoturvotuksen synnyssä

Quality of life and depression 3 months after intracerebral hemorrhage

Objectives: Quality of life (QoL) after intracerebral hemorrhage (ICH) is poorly known. This study investigated factors affecting QoL and depression after spontaneous ICH. Materials and Methods: This prospective study included patients admitted to Helsinki University Hospital between May 2014 and December 2016. Health-related QoL (HRQoL) at 3 months after ICH was measured using the European Quality of Life Scale (EQ-5D-5L), and the 15D scale. Logistic regression analyses were used to test factors affecting HRQoL. EQ-5D-5L anxiety/depression dimension was used to analyze factors associated with anxiety/depression. Results: Of 277 patients, 220 were alive, and sent QoL questionnaire. The questionnaire was returned by 124 patients. Nonreturners had more severe strokes with admission National Institutes of Health Stroke Scale (NIHSS) 7.8 (IQR 3.0-14.8) versus 5.0 (IQR 2.3-11.0); p = 0.018, and worse outcome assessed as modified Rankin Scale 3-5 at 3 months 59.4% versus 44.4% (p = 0.030). Predictors for lower HRQoL by both scales were higher NIHSS with OR 1.28 (95% CI 1.13-1.46) for EQ-5D-5L, and OR 1.28 (1.15-1.44) for 15D, older age (OR 1.10 [1.03-1.16], and OR 1.09 [1.03-1.15]), and chronic heart failure (OR 18.12 [1.73-189.27], and OR 12.84 [1.31126.32]), respectively. Feeling sad/depressed for more than 2 weeks during the year prior to ICH was predictor for lower EQ-5D-5L (OR 10.64 [2.39-47.28]), and history of ICH for lower 15D utility indexes (OR 11.85 [1.01-138.90]). Prior feelings of sadness/ depression were associated with depression/anxiety at 3 months after ICH with OR 3.62 (1.14-11.45). Conclusions: In this cohort of ICH patients with milder deficits, HRQoL was affected by stroke severity, comorbidities and age. Feelings of depression before ICH had stronger influence on reporting depression/anxiety after ICH than stroke severity-related and outcome parameters. Thus, simple questions on patient's premorbid feelings of sadness/depression could be used to identify patients at risk of depression after ICH for focusing follow-up and treatment.Peer reviewe

Triggering factors in non-traumatic intracerebral hemorrhage

Background: In ischemic stroke and subarachnoid hemorrhage, there are known preceding triggering events that predispose to the stroke by, for example, abruptly raising blood pressure. We explored, whether triggering events can be identified in non-traumatic intracerebral hemorrhage (ICH). Methods: We used structured questionnaires to interview consented patients with ICH treated in a tertiary teaching hospital, between 2014 and 2016. We asked of possible trigger factors, including Valsalva-inducing activity, heavy physical exertion, sexual activity, abrupt change in position, a heavy meal, a sudden change in temperature, exposure to traffic jam, and the combination of the first three (any physical trigger) during the hazard period of 0-2 h prior to ICH. The ratio of the reported trigger during the hazard period was compared to the same 2-h period the previous day (control period) to calculate the relative risks for each factor (case-crossover design). Results: Of our 216 consented ICH patients, 97 (35.0%) could be interviewed for trigger questions. Reasons for not able to provide consistent and reliable responses included lowered level of consciousness, delirium, impaired memory, and aphasia. None of the studied possible triggers alone were more frequent during the hazard period compared to the control period. However, when all physical triggers were combined, we found an association with the triggering event and onset of ICH (risk ratio 1.32, 95% confidence interval 1.01-1.73). Conclusions: Obtaining reliable information on the preceding events before ICH onset was challenging. However, we found that physical triggers as a group were associated with the onset of ICH.Peer reviewe

Prehospital identification of large vessel occlusion using the FAST-ED score

Objectives The prehospital identification of stroke patients with large vessel occlusion (LVO) enables appropriate hospital selection and reduces the onset-to-treatment time. The aim of this study was to investigate whether the Field Assessment Stroke Triage for Emergency Destination (FAST-ED) scale could be reconstructed from existing prehospital patient reports and to compare its performance with neurologist's clinical judgement using the same prehospital data. Materials & Methods All patients transported by ambulance using stroke code on a six-month period were registered for the study. The prehospital patient reports were retrospectively evaluated using the FAST-ED scale by two investigators. The performance of FAST-ED score (>= 4 points) in LVO identification was compared to neurologist's clinical judgement ('LVO or not'). The presence of LVO was verified using computed tomography angiography imaging. Results A total of 610 FAST-ED scores were obtained. The FAST-ED had a sensitivity of 57.8%, specificity of 87.2%, positive predictive value (PPV) of 37.3%, negative predictive value (NPV) of 93.4% and area under curve (AUC) of 0.724. Interclass correlation coefficient for both raters over the entire range of FAST-ED was 0.92 (0.88-0.94). The neurologist's clinical judgement raised sensitivity to 79.4%, NPV to 97.1% and PPV to 45.0% with an AUC of 0.837 (p < .05). Conclusions The existing patient report data could be feasibly used to reconstruct FAST-ED scores to identify LVO. The binary FAST-ED score had a moderate sensitivity and good specificity for prehospital LVO identification. However, the FAST-ED was surpassed by neurologist's clinical judgement which further increased the sensitivity of identification.Peer reviewe

Editorial : Challenges in Posterior Circulation Ischemic Stroke

Non peer reviewe

Clinical frailty and outcome after mechanical thrombectomy for stroke in patients aged > 80 years

Objectives: Data concerning the results of endovascular thrombectomy (EVT) in old patients is still limited. We aimed to investigate the outcomes in thrombectomytreated ischemic stroke patients aged > 80 years, focusing on frailty as a contributing factor. Patients and methods: We performed a single-centre retrospective cohort study with 159 consecutive patients aged > 80 years and treated with EVT for acute ischemic stroke between January 1st 2016 and December 31st 2019. Pre-admission frailty was assessed with the Clinical Frailty Scale (CFS). Patients with CFS > 5 were defined as frail. The main outcome was very poor outcome defined as mRS 46 at three months after EVT. Secondary outcomes were recanalization status, symptomatic intracerebral haemorrhage (sICH), and one-year survival. Finally, we recorded if the patient returned home within 12 months. Results: Very poor outcome was observed in 57.9% of all patients (52.4% in non-frail and 79.4% in frail patients). Rates of recanalization and sICH were comparable in frail and non-frail patients. Of all patients, 46.5% were able to live at home within 1 year after stroke. One-year survival was 59.1% (65.6% in non-frail and 35.3% in frail patients). In logistic regression analysis higher admission NIHSS, not performing thrombolysis, lack of recanalization and higher frailty status were all independently associated with very poor three-month outcome. Factors associated with one-year mortality were male gender, not performing thrombolysis, sICH, and higher frailty status. Conclusion: Almost 60% of studied patients had very poor outcome. Frailty significantly increases the likelihood of very poor outcome and death after EVT-treated stroke.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Peer reviewe

Characteristics and Outcomes of Thrombolysis-Treated Stroke Patients With and Without Saccular Intracranial Aneurysms

Peer reviewe

Aivojen valtimo-laskimoepämuodostumat

English summar

Early versus Late initiation of direct oral Anticoagulants in post-ischaemic stroke patients with atrial fibrillatioN (ELAN) : Protocol for an international, multicentre, randomised-controlled, two-arm, open, assessor-blinded trial

Rationale: Direct oral anticoagulants (DOAC) are highly effective in preventing ischaemic strokes in people with atrial fibrillation (AF). However, it is unclear how soon they should be started after acute ischaemic stroke (AIS). Early initiation may reduce early risk of recurrence but might increase the risk of haemorrhagic complications. Aim: To estimate the safety and efficacy of early initiation of DOACs compared to late guideline-based initiation in people with AIS related to AF. Methods and design: An international, multicentre, randomised (1:1) controlled, two-arm, open, assessor-blinded trial is being conducted. Early treatment is defined as DOAC initiation within 48 h of a minor or moderate stroke, or at day 6-7 following major stroke. Late treatment is defined as DOAC initiation after day 3-4 following minor stroke, after day 6-7 following moderate stroke and after day 12-14 following major stroke. Severity of stroke is defined according to imaging assessment of infarct size. Sample size: ELAN will randomise 2000 participants 1:1 to early versus late initiation of DOACs. This assumes a risk difference of 0.5% favouring the early arm, allowing an upper limit of the 95% confidence interval up to 1.5% based on the Miettinen & Nurminen formula. Outcomes: The primary outcome is a composite of symptomatic intracranial haemorrhage, major extracranial bleeding, recurrent ischaemic stroke, systemic embolism or vascular death at 30 +/- 3 days after randomisation. Secondary outcomes include the individual components of the primary outcome at 30 +/- 3 and 90 +/- 7 days and functional status at 90 +/- 7 days. Discussion: ELAN will estimate whether there is a clinically important difference in safety and efficacy outcomes following early anticoagulation with a DOAC compared to late guideline-based treatment in neuroimaging-selected people with an AIS due to AF.Peer reviewe

Intravenous thrombolysis for suspected ischemic stroke with seizure at onset

Objective Seizure at onset (SaO) has been considered a relative contraindication for intravenous thrombolysis (IVT) in patients with acute ischemic stroke, although this appraisal is not evidence based. Here, we investigated the prognostic significance of SaO in patients treated with IVT for suspected ischemic stroke. Methods In this multicenter, IVT-registry-based study we assessed the association between SaO and symptomatic intracranial hemorrhage (sICH, European Cooperative Acute Stroke Study II definition), 3-month mortality, and 3-month functional outcome on the modified Rankin Scale (mRS) using unadjusted and adjusted logistic regression, coarsened exact matching, and inverse probability weighted analyses. Results Among 10,074 IVT-treated patients, 146 (1.5%) had SaO. SaO patients had significantly higher National Institutes of Health Stroke Scale score and glucose on admission, and more often female sex, prior stroke, and prior functional dependence than non-SaO patients. In unadjusted analysis, they had generally less favorable outcomes. After controlling for confounders in adjusted, matched, and weighted analyses, all associations between SaO and any of the outcomes disappeared, including sICH (odds ratio [OR](unadjusted) = 1.53 [95% confidence interval (CI) = 0.74-3.14], ORadjusted = 0.52 [95% CI = 0.13-2.16], ORmatched = 0.68 [95% CI = 0.15-3.03], ORweighted = 0.95 [95% CI = 0.39-2.32]), mortality (ORunadjusted = 1.49 [95% CI = 1.00-2.24], ORadjusted = 0.98 [95% CI = 0.5-1.92], ORmatched = 1.13 [95% CI = 0.55-2.33], ORweighted = 1.17 [95% CI = 0.73-1.88]), and functional outcome (mRS >= 3/ordinal mRS: ORunadjusted = 1.33 [95% CI = 0.96-1.84]/1.35 [95% CI = 1.01-1.81], ORadjusted = 0.78 [95% CI = 0.45-1.32]/0.78 [95% CI = 0.52-1.16], ORmatched = 0.75 [95% CI = 0.43-1.32]/0.45 [95% CI = 0.10-2.06], ORweighted = 0.87 [95% CI = 0.57-1.34]/1.00 [95% CI = 0.66-1.52]). These results were consistent regardless of whether patients had an eventual diagnosis of ischemic stroke (89/146) or stroke mimic (57/146 SaO patients). Interpretation SaO was not an independent predictor of poor prognosis. Withholding IVT from patients with assumed ischemic stroke presenting with SaO seems unjustified. ANN NEUROL 2019Peer reviewe