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Background: Lipid droplets (LD), lipid-storing organelles containing neutral lipids like glycerolipids and cholesterol, are increasingly accepted as hallmarks of inflammation. The nuclear paraspeckle assembly transcript 1 (NEAT1), a long non-coding RNA with over 200 nucleotides, exerts an indispensable impact on regulating both LD agglomeration and autophagy in multiple neurological disorders. However, knowledge as to how NEAT1 modulates the formation of LD and associated signaling pathways is limited., Methods: In this study, primary microglia were isolated from newborn mice and exposed to oxygen-glucose-deprivation/reoxygenation (OGD/R). To further explore NEAT1-dependent mechanisms, an antisense oligonucleotide (ASO) was adopted to silence NEAT1 under in vitro conditions. Studying NEAT1-dependent interactions with regard to autophagy and LD agglomeration under hypoxic conditions, the inhibitor and activator of autophagy 3-methyladenine (3-MA) and rapamycin (RAPA) were used, respectively. In a preclinical stroke model, mice received intraventricular injections of ASO NEAT1 or control vectors in order to yield NEAT1 knockdown. Analysis of readout parameters included qRT-PCR, immunofluorescence, western blot assays, and behavioral tests., Results: Microglia exposed to OGD/R displayed a temporal pattern of NEAT1 expression, peaking at four hours of hypoxia followed by six hours of reoxygenation. After effectively silencing NEAT1, LD formation and autophagy-related proteins were significantly repressed in hypoxic microglia. Stimulating autophagy in ASO NEAT1 microglia under OGD/R conditions by means of RAPA reversed the downregulation of LD agglomeration and perilipin 2 (PLIN2) expression. On the contrary, application of 3-MA promoted repression of both LD agglomeration and expression of the LD-associated protein PLIN2. Under in vivo conditions, NEAT1 was significantly increased in mice at 24 h post-stroke. Knockdown of NEAT1 significantly alleviated LD agglomeration and inhibited autophagy, resulting in improved cerebral perfusion, reduced brain injury and increased neurological recovery., Conclusion: NEAT1 is a key player of LD agglomeration and autophagy stimulation, and NEAT1 knockdown provides a promising therapeutic value against stroke., (© 2024. The Author(s).)

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein predominantly expressed in microglia within the central nervous system (CNS). TREM2 regulates multiple microglial functions, including lipid metabolism, immune reaction, inflammation, and microglial phagocytosis. Recent studies have found that TREM2 is highly expressed in activated microglia after ischemic stroke. However, the role of TREM2 in the pathologic response after stroke remains unclear. Herein, TREM2-deficient microglia exhibit an impaired phagocytosis rate and cholesteryl ester (CE) accumulation, leading to lipid droplet formation and upregulation of Perilipin-2 (PLIN2) expression after hypoxia. Knockdown of TREM2 results in increased lipid synthesis (PLIN2, SOAT1) and decreased cholesterol clearance and lipid hydrolysis (LIPA, ApoE, ABCA1, NECH1, and NPC2), further impacting microglial phenotypes. In these lipid droplet-rich microglia, the TGF-β1/Smad2/3 signaling pathway is downregulated, driving microglia towards a pro-inflammatory phenotype. Meanwhile, in a neuron-microglia co-culture system under hypoxic conditions, we found that microglia lost their protective effect against neuronal injury and apoptosis when TREM2 was knocked down. Under in vivo conditions, TREM2 knockdown mice express lower TGF-β1 expression levels and a lower number of anti-inflammatory M2 phenotype microglia, resulting in increased cerebral infarct size, exacerbated neuronal apoptosis, and aggravated neuronal impairment. Our work suggests that TREM2 attenuates stroke-induced neuroinflammation by modulating the TGF-β1/Smad2/3 signaling pathway. TREM2 may play a direct role in the regulation of inflammation and also exert an influence on the post-ischemic inflammation and the stroke pathology progression via regulation of lipid metabolism processes. Thus, underscoring the therapeutic potential of TREM2 agonists in ischemic stroke and making TREM2 an attractive new clinical target for the treatment of ischemic stroke and other inflammation-related diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

H ypoxia triggers reactive microglial inflammation and lipid droplet (LD) accumulation under stroke conditions, although the mutual interactions between these two processes are insufficiently understood. Hence, the involvement of transforming growth factor (TGF)-β1 in inflammation and LD accumulation in cultured microglia exposed to hypoxia were analyzed herein. Primary microglia were exposed to oxygen-glucose deprivation (OGD) injury and lipopolysaccharide (LPS) stimulation. For analyzing the role of TGF-β1 patterns under such conditions, a TGF-β1 siRNA and an exogenous recombinant TGF-β1 protein were employed. Further studies applied Triacsin C, an inhibitor of LD formation, in order to directly assess the impact of LD formation on the modulation of inflammation. To assess mutual microglia-to-neuron interactions, a co-culture model of these cells was established. Upon OGD exposure, microglial TGF-β1 levels were significantly increased, whereas LPS stimulation yielded decreased levels. Elevating TGF-β1 expression proved highly effective in suppressing inflammation and reducing LD accumulation in microglia exposed to LPS. Conversely, inhibition of TGF-β1 led to the promotion of microglial cell inflammation and an increase in LD accumulation in microglia exposed to OGD. Employing the LD formation inhibitor Triacsin C, in turn, polarized microglia towards an anti-inflammatory phenotype. Such modulation of both microglial TGF-β1 and LD levels significantly affected the resistance of co-cultured neurons. This study provides novel insights by demonstrating that TGF-β1 plays a protective role against microglia-mediated neuroinflammation through the suppression of LD accumulation. These findings offer a fresh perspective on stroke treatment, suggesting the potential of targeting this pathway for therapeutic interventions.

Various preclinical stroke models have demonstrated the neuroprotective effects of extracellular vesicles (EVs) obtained from several types of cells, including neurons, astrocytes, microglia, neuronal progenitor cells, bone marrow stem cells, and mesenchymal stem cells. EVs interfere with key mechanisms in stroke pathophysiology such as cell death, neuroinflammation, autophagy, and angiogenesis. The mode of action and efficacy depend on the specific EV content, including miRNAs, proteins, and lipids, which can be modified through (I) bioengineering methods, (II) choice of source cells, and (III) modification of the source cell environment. Indeed, modifying the environment by preconditioning the EV-secreting cells with oxygen-glucose deprivation or medium modification revealed superior neuroprotective effects in stroke models. Although the concept of preconditioned EVs is relatively novel, it holds promise for the future treatment of ischemic stroke. Here, we give a brief overview about the main mechanisms of EV-induced neuroprotection and discuss the current status of preconditioning concepts for EV-treatment of ischemic stroke., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Stroke stimulates reactive astrogliosis, aquaporin 4 (AQP4) depolarization and neuroinflammation. Preconditioned extracellular vesicles (EVs) from microglia exposed to hypoxia, in turn, reduce poststroke brain injury. Nevertheless, the underlying mechanisms of such effects are elusive, especially with regards to inflammation, AQP4 polarization, and cerebrospinal fluid (CSF) flow. Methods: Primary microglia and astrocytes were exposed to oxygen-glucose deprivation (OGD) injury. For analyzing the role of AQP4 expression patterns under hypoxic conditions, a co-culture model of astrocytes and microglia was established. Further studies applied a stroke model, where some mice also received an intracisternal tracer infusion of rhodamine B. As such, these in vivo studies involved the analysis of AQP4 polarization, CSF flow, astrogliosis, and neuroinflammation as well as ischemia-induced brain injury. Results: Preconditioned EVs decreased periinfarct AQP4 depolarization, brain edema, astrogliosis, and inflammation in stroke mice. Likewise, EVs promoted postischemic CSF flow and cerebral blood perfusion, and neurological recovery. Under in vitro conditions, hypoxia stimulated M2 microglia polarization, whereas EVs augmented M2 microglia polarization and repressed M1 microglia polarization even further. In line with this, astrocytes displayed upregulated AQP4 clustering and proinflammatory cytokine levels when exposed to OGD, which was reversed by preconditioned EVs. Reduced AQP4 depolarization due to EVs, however, was not a consequence of unspecific inflammatory regulation, since LPS-induced inflammation in co-culture models of astrocytes and microglia did not result in altered AQP4 expression patterns in astrocytes. Conclusions: These findings show that hypoxic microglia may participate in protecting against stroke-induced brain damage by regulating poststroke inflammation, astrogliosis, AQP4 depolarization, and CSF flow due to EV release., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: Recent studies postulate a high prognostic value of the Alberta Stroke Programme Early CT Score (ASPECTS) applied on non-contrast whole-brain flat-detector CT (FDCT) after successful endovascular treatment (EVT). The aim of this study was the evaluation of long-term patient outcome after endovascular treatment using postinterventional FDCT., Methods: Using a local database (Stroke Research Consortium in Northern Bavaria, STAMINA), 517 patients with successful endovascular treatment (modified Thrombolysis in Cerebral Infarction (mTICI) ≥ 2B) due to acute ischaemic stroke (AIS) and large vessel occlusion (LVO) of the anterior circulation were recruited retrospectively. In all cases, non-contrast FDCT after EVT was analysed with special focus at ASPECTS. These results were correlated with the functional outcome in long-term (modified Rankin Scale (mRS) shift from pre-stroke to 90 days after discharge)., Results: A significant difference in FDCT-ASPECTS compared to the subgroup of favourable vs. unfavourable outcome (Δ mRS) (median ASPECTS 10 (10-9) vs. median ASPECTS 9 (10-7); p = 0,001) could be demonstrated. Multivariable regression analysis revealed FDCT-ASPECTS (OR 0.234, 95% CI - 0.102-0.008, p = 0.022) along with the NHISS at admission (OR 0.169, 95% CI 0.003-0.018, p = 0.008) as independent factors for a favourable outcome. Cut-off point for a favourable outcome (Δ mRS) was identified at an ASPECTS ≥ 8 (sensitivity 90.6%, specificity 35%)., Conclusion: For patients with LVO and successful EVT, FDCT-ASPECTS was found to be highly reliable in predicting long-term outcome., (© 2022. The Author(s).)

Importance: It is uncertain whether thrombectomy is associated with benefits in patients with prestroke disability., Objective: To evaluate the use of thrombectomy for patients with large vessel occlusion and prestroke disability., Design, Setting, and Participants: This cohort study included patients with large vessel occlusion stroke and prestroke disability (modified Rankin Scale score, 3 or 4) admitted to a single tertiary care center between January 1, 2006, and June 30, 2019 (controls: 2006-2015; thrombectomy: 2015-2019). Follow-up was conducted at 90 days. Data analysis was performed from November 1 to December 31, 2021., Exposures: Use of thrombectomy vs no thrombectomy., Main Outcomes and Measures: The primary outcome was functional recovery at 90 days defined as clinical recovery to the functional status before stroke onset. Secondary outcomes included functional dependency, mortality, early neurologic improvement, and recanalization., Results: Among 205 patients (149 women [72.7%]; median age, 82 years [IQR, 75-87 years]), 102 individuals (49.8%) received thrombectomy and 103 (50.2%) were controls. Thrombectomy was significantly associated with functional recovery (thrombectomy, 20 [19.6%]; controls, 8 [7.8%]; adjusted difference, 9.4%; 95% CI, 2.2% to 16.7%; P = .005). Secondary outcomes showed differences in mortality, early neurologic improvement, and recanalization in favor of thrombectomy treatment. The rate of functional dependency did not differ significantly between the 2 groups (adjusted difference, 8.9%; 95% CI, -2.5% to 20.2%; P = .13). The rate of functional recovery after thrombectomy was 44.0% for patients with early neurologic improvement, 29.4% for patients with small infarct volume (<50 mL), and 7.0% for patients with neither of these parameters., Conclusions and Relevance: Findings of this study suggest that selected patients with prestroke disability may benefit from thrombectomy. However, the thrombectomy-associated increase in functional recovery was small. Therefore, routine use of thrombectomy may not be beneficial among patients with a large ischemic core and infarct volumes less than 50 mL may be necessary to obtain functional recovery. Patients with higher chances of functional recovery are also at an increased risk of survival with substantial disability, indicating potential harms from the intervention; further studies are needed.

Objective: This study determined the effect of amantadine treatment on consciousness in patients with non-traumatic brain injury., Methods: We pooled individual patient data of five single-centre observational studies to determine the effect of amantadine treatment among patients with ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, community-acquired bacterial meningitis and status epilepticus, admitted between January 2012 and December 2015 and ventilated ≥7 days. Patient selection and multivariable regression modelling were used to adjust for differences in intergroup comparison and for parameters associated with consciousness. Improvement of consciousness 5 days after treatment initiation was defined as primary outcome. Secondary outcomes included Glasgow Coma Scale (GCS) at day 5 and GCS at day 10, rate of ICU delirium, epileptic seizures and all-cause mortality at 90 days., Results: Overall, 84 of 294 (28.6%) eligible patients received amantadine. Amantadine treatment was associated with improvement of consciousness at day 5 (amantadine: 86.9% vs control: 54.0%; absolute difference: 32.9 (20.0-44.2); adjusted OR (aOR): 5.71 (2.50-13.05), p<0.001). Secondary outcomes showed differences in GCS 5 days (9 (8-11) vs 6 (3-9), p<0.001) and GCS 10 days (10(8-11) vs 9(6-11),p=0.003) after treatment initiation. There were no significant differences regarding all-cause mortality (aOR: 0.89 (0.44-1.82), p=0.758) and ICU delirium (aOR: 1.39 (0.58-3.31), p=0.462). Rate of epileptic seizures after initiation of amantadine treatment was numerically higher in the amantadine group (amantadine: 10.7% vs control: 3.0%; absolute difference: 7.7 (0.3-16.4); aOR: 3.68 (0.86-15.71), p=0.079)., Conclusions: Amantadine treatment is associated with improved consciousness among patients with different types of non-traumatic brain injury in this observational cohort analysis. Epileptic seizures should be considered as potential side effects and randomised controlled trials are needed to confirm these findings., Competing Interests: Competing interests: JBK reports personal fees from Bayer, personal fees from Bristol-Myers Squibb & Pfizer, personal fees from Sanofi, and personal fees from Boehringer Ingelheim outside the submitted work. BK reports personal fees from Bayer, personal fees from Bristol-Myers Squibb & Pfizer and personal fees from Medtronic outside the submitted work. HBH reports personal fees from Boehringer Ingelheim, personal fees from Bayer AG, personal fees from Daiichi Sankyo, grants and personal fees from Novartis, grants and personal fees from Portola Pharmaceuticals, grants and personal fees from Union Chimique Belge Pharma, and grants and personal fees from Medtronic outside the submitted work. MIS reports grants from IZKF and Marohn Foundation., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Several automated computed tomography perfusion software applications have been developed to provide support in the definition of ischemic core and penumbra in acute ischemic stroke. However, the degree of interchangeability between software packages is not yet clear. Our study aimed to evaluate 2 commonly used automated perfusion software applications (Syngo.via and RAPID) for the indication of ischemic core with respect to the follow-up infarct volume (FIV) after successful recanalization and with consideration of the clinical impact., Methods: Retrospectively, 154 patients with large vessel occlusion of the middle cerebral artery or the internal carotid artery, who underwent endovascular therapy with a consequent Thrombolysis in Cerebral Infarction 3 result within 2 hours after computed tomography perfusion, were included. Computed tomography perfusion core volumes were assessed with both software applications with different thresholds for relative cerebral blood flow (rCBF). The results were compared with the FIV on computed tomography within 24 to 36 hours after recanalization. Bland-Altman was applied to display the levels of agreement and to evaluate systematic differences., Results: Highest correlation between ischemic core volume and FIV without significant differences was found at a threshold of rCBF<38% for the RAPID software ( r =0.89, P <0.001) and rCBF<25% for the Syngo software ( r =0.87, P <0.001). Bland-Altman analysis revealed best agreement in these settings. In the vendor default settings (rCBF<30% for RAPID and rCBF<20% for Syngo) correlation between ischemic core volume and FIV was also high (RAPID: r =0.88, Syngo: r =0.86, P <0.001), but mean differences were significant ( P <0.001). The risk of critical overestimation of the FIV was higher with rCBF<38% (RAPID) and rCBF<25% (Syngo) than in the default settings., Conclusions: By adjusting the rCBF thresholds, comparable results with reliable information on the FIV after complete recanalization can be obtained both with the RAPID and Syngo software. Keeping the software specific default settings means being more inclusive in patient selection, but forgo the highest possible accuracy in the estimation of the FIV.

Background: Data regarding the influence of concomitant parenchymatous hematoma (PH) on long-term outcomes in patients with atraumatic subarachnoid hemorrhage (SAH) are scarce. Further, it is not established if these patients benefit from surgical intervention., Aim: The aim of this study was to determine the influence of concomitant PH in SAH patients on functional long-term outcome, and whether these patients may benefit from surgical hematoma evacuation., Methods: Over a 5-year period, all consecutive patients with SAH treated at the Departments of Neurology, Neuroradiology, and Neurosurgery, at the University Hospital Erlangen (Germany) were recorded. In addition to the clinical and imaging characteristics of SAH, we documented the presence, location, and volume of PH as well as treatment parameters. Outcome assessment at 12 months included functional outcome (modified Rankin scale (mRS), favorable = 0-2), health-related quality of life, and long-term complications. For outcome analysis, a propensity score matching (ratio 1:1, caliper 0.1) was performed to compare SAH patients with and without PH. Sub-analyses were performed regarding PH treatment (surgical evacuation vs. conservative)., Results: A total of 494 patients with atraumatic SAH were available. Eighty-five (17.2%) had PH on initial imaging. SAH patients with PH had a worse clinical condition on admission and had a greater extent of subarachnoid/intraventricular hemorrhage. Median PH volume was 11.0 ml (5.4-31.8) with largest volumes observed in patients with ruptured middle cerebral artery (MCA)-aneurysm (31.7 ml (16.3-43.2)). After propensity-score matching (PSM), patients with PH had worse functional outcomes at 12 months (modified Rankin scale (mRS) 0-2: PH 31.8% vs. ØPH57.7% p < 0.001), and a lower rate of self-reported health compared to patients without PH (EQ-5D VAS: PH 50(30-70) vs. ØPH 80(65-95); p < 0.001). In PH patients, surgical evacuation was associated with a higher rate of favorable outcome at 12 months compared to those treated conservatively (surgery 14/28 (50.0%) vs. conservative 14/57 (24.6%); adjusted odds-ratio (OR; 95%CI): 1.34 (1.08-1.66); p = 0.001), irrespective of aneurysm location. Subgroup-analysis revealed positive associations of surgical hematoma evacuation with outcome in subgroups with larger PH volumes (>10 ml; OR (95%CI): 1.39 (1.09-1.79)), frontal PH location (OR 1.59 (1.14-2.23)), and early surgery (within 600 min after onset; OR 1.42 (1.03-1.94))., Conclusions: Concomitant PH occurs frequently in patients with SAH and is associated with functional impairment after 1 year. Surgical evacuation of PH may improve outcomes in these patients, irrespective of aneurysm-location.

Aims: This study determined the influence of age on bleeding characteristics and clinical outcomes in primary spontaneous (non-OAC), vitamin K antagonist-related (VKA-) and non-vitamin K antagonist oral anticoagulant-related (NOAC-) ICH., Methods: Pooled individual patient data of multicenter cohort studies were analyzed by logistic regression modelling and propensity-score-matching (PSM) to explore the influence of advanced age on clinical outcomes among non-OAC-, VKA-, and NOAC-ICH. Primary outcome measure was functional outcome at three months assessed by the modified Rankin Scale, dichotomized into favorable (mRS = 0-3) and unfavorable (mRS = 4-6) functional outcome. Secondary outcome measures included mortality, hematoma characteristics, and frequency of invasive interventions., Results: In VKA-ICH 33.5% (670/2001), in NOAC-ICH 44.2% (69/156) and in non-OAC-ICH 25.2% (254/1009) of the patients were ≥80 years. After adjustment for treatment interventions and relevant parameters, elderly ICH patients comprised worse functional outcome at three months (adjusted odds ratio (aOR) in VKA-ICH: 1.49 (1.21-1.84); p < 0.001; NOAC-ICH: 2.01 (0.95-4.26); p = 0.069; non-OAC-ICH: 3.54 (2.50-5.03); p < 0.001). Anticoagulation was significantly associated with worse functional outcome below the age of 70 years, (aOR: 2.38 (1.78-3.16); p < 0.001), but not in patients of ≥70 years (aOR: 1.21 (0.89-1.65); p = 0.217). The differences in initial ICH volume and extent of ICH enlargement between OAC-ICH and non-OAC-ICH gradually decreased with increasing patient age., Conclusions: As compared to elderly ICH-patients, in patients <70 years OAC-ICH showed worse clinical outcomes compared to non-OAC-ICH because of larger baseline ICH-volumes and extent of hematoma enlargement. Treatment strategies aiming at neutralizing altered coagulation should be aware of these findings.

Introduction: The number of patients with left ventricular assist devices (LVAD) is rapidly growing in industrialized countries. While cerebrovascular events comprise a significant complication, data on stroke etiology, clinical management and functional outcome are scarce., Methods: Consecutive LVAD patients with ischemic or hemorrhagic stroke receiving treatment at an university stroke center between 2010 and 2018 were included into an institutional registry. Clinical characteristics, causes, management and functional outcome of stroke occurring within this cohort are reported. Acceptable functional outcome was defined as mRS 0-3., Results: N = 30 acute strokes occurred in 20 patients (77% ischemic, 23% hemorrhagic, mean age 57 ± 13 years, 10% female, 8 patients (40%) had more than one event). 87% of all events happened with non-pulsatile devices, on average 9 (IQR 3-22) months after the implantation. All patients used oral anticoagulation with a Vitamin-K antagonist in combination with anti-platelets. The international normalized ratio (INR)-values were outside the therapeutic range in 39% of ischemic strokes and in 57% of hemorrhagic strokes. Ischemic strokes were predominantly of cardioembolic origin (92%) and of mild to moderate clinical severity (median NIHSS 6 (IQR 4-10). None qualified to receive intravenous thrombolysis or intra-arterial endovascular therapy. 61% of IS-patients showed an acceptable functional outcome after three months. 4/7 patients with hemorrhagic stroke received immediate reversal of anticoagulation without any thrombotic complications., Conclusion: The majority of LVAD patients with ischemic stroke had an acceptable functional outcome after three months. Future clinical research is warranted to improve therapeutic strategies for acute care and stroke prevention., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: This study aims to assess the number of patients with acute ischemic cerebrovascular events seeking in-patient medical emergency care since the implementation of social distancing measures in the coronavirus disease 2019 (COVID-19) pandemic., Methods: In this retrospective multicenter study, data on the number of hospital admissions due to acute ischemic stroke or transient ischemic attack and numbers of reperfusion therapies performed in weeks 1 to 15 of 2020 and 2019 were collected in 4 German academic stroke centers. Poisson regression was used to test for a change in admission rates before and after the implementation of extensive social distancing measures in week 12 of 2020. The analysis of anonymized regional mobility data allowed for correlations between changes in public mobility as measured by the number and length of trips taken and hospital admission for stroke/transient ischemic attack., Results: Only little variation of admission rates was observed before and after week 11 in 2019 and between the weeks 1 and 11 of 2019 and 2020. However, reflecting the impact of the COVID-19 pandemic, a significant decrease in the number of admissions for transient ischemic attack was observed (-85%, -46%, -42%) in 3 of 4 centers, while in 2 of 4 centers, stroke admission rates decreased significantly by 40% and 46% after week 12 in 2020. A relevant effect on reperfusion therapies was found for 1 center only (thrombolysis, -60%; thrombectomy, -61%). Positive correlations between number of ischemic events and mobility measures in the corresponding cities were identified for 3 of 4 centers., Conclusions: These data demonstrate and quantify decreasing hospital admissions due to ischemic cerebrovascular events and suggest that this may be a consequence of social distancing measures, in particular because hospital resources for acute stroke care were not limited during this period. Hence, raising public awareness is necessary to avoid serious healthcare and economic consequences of undiagnosed and untreated strokes and transient ischemic attacks.

Background: The most recent years have significantly expanded knowledge regarding risks and benefits of resuming oral anticoagulation (OAC) after intracerebral hemorrhage (ICH). No randomized data is yet available, though several large observational studies and meta-analyses have investigated the impact of resuming OAC on thromboembolic versus hemorrhagic complications in these high-risk patients after ICH., Aims: The present review will summarize the most important studies conducted over the last years and will focus on relevant factors help guiding on decision-making on whether to start OAC after ICH., Summary of Review: Several important factors (demographic, co-morbidities, clinical characteristics) need to be considered before individual decision-making for or against OAC is employed. Existing observational data suggest that patients after ICH with indication for long-term oral anticoagulation benefit from OAC given significant reductions of thromboembolic events without significantly increasing bleeding complications. Studies even suggest that thereby also clinical outcomes may be improved. Prospective trials currently recruiting patients will clarify whether OAC after ICH - or left atrial appendage closure as a meaningful alternative - is of clinical net-benefit., Conclusions: Large sized and well-executed investigations (moderate quality of evidence) are showing that OAC resumption after ICH decreases thromboembolic complications and long-term mortality without significantly increasing bleeding complications. Further, data suggest that resumption may be safer in non-lobar ICH compared to lobar ICH, but overall, thoughtful selection, strict blood pressure control, and precise communication are paramount before starting a patient on OAC after ICH.

Background and Purpose: In patients with acute ischemic stroke and large vessel occlusion, the prognosis has improved tremendously since the implementation of endovascular thrombectomy (EVT). The effect of EVT on the incidence of malignant middle cerebral artery infarctions (MMI) has not been studied before., Methods: ESTIMATE, a multicenter retrospective study, evaluates data of ischemic stroke patients with occlusion in the anterior circulation in the years of 2007-2015 comparing three treatment options (no therapy; IV-TPA; IV-TPA plus EVT or EVT only). Primary endpoint of the study was the incidence of MMI on follow-up imaging and mortality rates. Secondary endpoints were functional outcome, further clinical and imaging data. Logistic and Cox-regression models with a propensity score weighting approach were applied to evaluate differences between treatment groups., Results: In 2161 patients over 9 years, EVT reduced the MMI rates significantly: patients without acute stroke treatment had increased odds for MMI of 1.57 [95% confidence interval (CI) 1.49-1.65]. In contrast, after treatment with IV-TPA, only we observed an OR of 0.88 (95% CI 0.83-0.94, p < 0.001), and after EVT an OR of 0.80 (95% CI 0.76-0.85, p < 0.001). This was more pronounced in larger pretreatment infarctions (ASPECTS < 5, p < 0.01). IV-TPA also lowers the MMI rates but not to the same extent. EVT-treated patients had increased survival rates (p < 0.05) and the best functional outcome at discharge., Conclusions: The findings of this study illustrate that occurrence of MMI and mortality rates was significantly reduced in patients treated with EVT.

Background and Purpose- Whether to resume oral anticoagulation treatment after intracerebral hemorrhage (ICH) remains an unresolved question. Previous studies focused primarily on recurrent stroke after ICH. We sought to investigate the association between cardioembolic stroke risk, oral anticoagulation therapy resumption, and functional recovery among ICH survivors in the absence of recurrent stroke. Methods- We conducted a joint analysis of 3 observational studies: (1) the multicenter RETRACE study (German-Wide Multicenter Analysis of Oral Anticoagulation Associated Intracerebral Hemorrhage); (2) the Massachusetts General Hospital ICH study (n=166); and (3) the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage; n=131). We included 941 survivors of ICH in the setting of active oral anticoagulation therapy for prevention of cardioembolic stroke because of nonvalvular atrial fibrillation and without evidence of ischemic stroke and recurrent ICH at 1 year from the index event. We created univariable and multivariable models to explore associations between cardioembolic stroke risk (based on CHA 2 DS 2 -VASc scores) and functional recovery after ICH, defined as achieving modified Rankin Scale score of ≤3 at 1 year for participants with modified Rankin Scale score of >3 at discharge. Results- In multivariable analyses, the CHA 2 DS 2 -VASc score was associated with a decreased likelihood of functional recovery (odds ratio, 0.83 per 1 point increase; 95% CI, 0.79-0.86) at 1 year. Anticoagulation resumption was independently associated with a higher likelihood of recovery, regardless of CHA 2 DS 2 -VASc score (odds ratio, 1.89; 95% CI, 1.32-2.70). We found an interaction between CHA 2 DS 2 -VASc score and anticoagulation resumption in terms of association with increased likelihood of functional recovery (interaction P=0.011). Conclusions- Increasing cardioembolic stroke risk is associated with a decreased likelihood of functional recovery at 1 year after ICH, but this association was weaker among participants resuming oral anticoagulation therapy. These findings support, including recovery metrics, in future studies of anticoagulation resumption after ICH.

Objective: Oral anticoagulation treatment (OAT) resumption is a therapeutic dilemma in intracerebral hemorrhage (ICH) care, particularly for lobar hemorrhages related to amyloid angiopathy. We sought to determine whether OAT resumption after ICH is associated with long-term outcome, accounting for ICH location (ie, lobar vs nonlobar)., Methods: We meta-analyzed individual patient data from: (1) the multicenter RETRACE study (n = 542), (2) a U.S.-based single-center ICH study (n = 261), and (3) the Ethnic/Racial Variations of Intracerebral Hemorrhage study (n = 209). We determined whether, within 1 year from ICH, OAT resumption was associated with: (1) mortality, (2) favorable functional outcome (modified Rankin Scale = 0-3), and (3) stroke incidence. We separately analyzed nonlobar and lobar ICH cases using propensity score matching and Cox regression models., Results: We included 1,012 OAT-related ICH survivors (633 nonlobar and 379 lobar). Among nonlobar ICH survivors, 178/633 (28%) resumed OAT, whereas 86/379 (23%) lobar ICH survivors did. In multivariate analyses, OAT resumption after nonlobar ICH was associated with decreased mortality (hazard ratio [HR] = 0.25, 95% confidence interval [CI] = 0.14-0.44, p < 0.0001) and improved functional outcome (HR = 4.22, 95% CI = 2.57-6.94, p < 0.0001). OAT resumption after lobar ICH was also associated with decreased mortality (HR = 0.29, 95% CI = 0.17-0.45, p < 0.0001) and favorable functional outcome (HR = 4.08, 95% CI = 2.48-6.72, p < 0.0001). Furthermore, OAT resumption was associated with decreased all-cause stroke incidence in both lobar and nonlobar ICH (both p < 0.01)., Interpretation: These results suggest novel evidence of an association between OAT resumption and outcome following ICH, regardless of hematoma location. These findings support conducting randomized trials to explore risks and benefits of OAT resumption after ICH. Ann Neurol 2017;82:755-765., (© 2017 American Neurological Association.)

Objective: To perform a systematic review and meta-analysis of studies reporting recurrent intracranial hemorrhage (ICH) and ischemic stroke (IS) in ICH survivors with atrial fibrillation (AF) during long-term follow-up., Methods: A comprehensive literature search including MEDLINE, EMBASE, Cochrane library, clinical trials registry was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We considered studies capturing outcome events (ICH recurrence and IS) for ≥3 months and treatment exposure to vitamin K antagonists (VKAs), antiplatelet agents (APAs), or no antithrombotic medication (no-ATM). Corresponding authors provided aggregate data for IS and ICH recurrence rate between 6 weeks after the event and 1 year of follow-up for each treatment exposure. Meta-analyses of pooled rate ratios (RRs) were conducted with the inverse variance method., Results: Seventeen articles met inclusion criteria. Seven observational studies enrolling 2,452 patients were included in the meta-analysis. Pooled RR estimates for IS were lower for VKAs compared to APAs (RR = 0.45, 95% confidence interval [CI] 0.27-0.74, p = 0.002) and no-ATM (RR = 0.47, 95% CI 0.29-0.77, p = 0.002). Pooled RR estimates for ICH recurrence were not significantly increased across treatment groups (VKA vs APA: RR = 1.34, 95% CI 0.79-2.30, p = 0.28; VKA vs no-ATM: RR = 0.93, 95% CI 0.45-1.90, p = 0.84)., Conclusions: In observational studies, anticoagulation with VKA is associated with a lower rate of IS than APA or no-ATM without increasing ICH recurrence significantly. A randomized controlled trial is needed to determine the net clinical benefit of anticoagulation in ICH survivors with AF., (© 2017 American Academy of Neurology.)

Background There is conflicting evidence about the influence of sex on outcome after spontaneous intracerebral hemorrhage (sICH) and the majority of the research focused on mortality and short-term outcome only. We investigated sex differences in long-term functional outcome after sICH. Methods We used data from a prospective hospital registry and included all consecutive patients with ICH admitted to our institution between January 2006 and July 2014. Functional outcome was assessed by modified Rankin Scale evaluated 3 and 12 months after ICH. We explored the influence of sex on long-term functional outcome using multivariable regression models and additionally by means of propensity score matching. Results We analyzed 823 patients, of whom 380 (46%) women. Women were on average three years older (p < 0.001), men had more often deep hematomas (p = 0.01). Unadjusted mortality rates were significantly increased in women at three months (42% vs. 35%; odds ratio (OR): 1.35; 95% confidence interval (CI): 1.02-1.80). After adjusting for baseline prognostic factors there were no differences between men and women in short- and long-term mortality (OR = 1.01; 95% CI = 0.66-1.54 and OR = 1.04; 95%CI = 0.69-1.57, respectively) and short- and long-term unfavorable outcome (OR = 1.02; 95%CI = 0.67-1.55 and OR = 0.96; 95% CI = 0.62-1.48, respectively). Conclusion We found no sex-related differences in long-term functional outcome in patients with sICH. The apparently worse functional outcome in women can be explained by differences in age.

Background: Data on clinical characteristics and outcome of patients with intracerebral hemorrhage (ICH) and concomitant systemic cancer disease are very limited., Methods: Nine hundred and seventy three consecutive primary ICH patients were analyzed using our prospective institutional registry over a period of 9 years (2006-2014). We compared clinical and radiological parameters as well as outcome - scored using the modified Rankin Scale (mRS) and analyzed in a dichotomized fashion as favorable outcome (mRS = 0-3) and unfavorable outcome (mRS = 4-6) - of ICH patients with and without cancer. Relevant imbalances in baseline clinical and radiological characteristics were adjusted using propensity score (PS) matching., Results: Prevalence of systemic cancer among patients with ICH was 8.5% (83/973). ICH patients with cancer were older (77 [70-82] vs. 72 [63-80] years; p = 0.002), had more often prior renal dysfunction (19/83 [22.9%] vs.107/890 [12.0%]; p = 0.005), and smaller hemorrhage volumes (10.1 [4.8-24.3] vs. 15.3 [5.4-42.9] mL; p = 0.017). After PS-matching there were no significant differences neither in mortality nor in functional outcome both at 3 months (mortality: 33/81 [40.7%] vs. 55/158 [34.8%]; p = 0.368; mRS = 0-3: 28/81 [34.6%] vs. 52/158 [32.9%]; p = 0.797) and 12 months (mortality: 39/78 [50.0%] vs. 70/150 [46.7%]; p = 0.633; mRS = 0-3: 25/78 [32.1%] vs. 53/150 [35.3%]; p = 0.620) among patients with and without concomitant systemic cancer. ICH volume tended to be highest in patients with hematooncologic malignancy and smallest in urothelial cancer., Conclusions: Patients with ICH and concomitant systemic cancer on average are older; however, they show smaller ICH volumes compared to patients without cancer. Yet, mortality and functional outcome is not different in ICH patients with and without cancer. Thus, the clinical history or the de novo diagnosis of concomitant malignancies in ICH patients should not lead to unjustified treatment restrictions., (© 2017 S. Karger AG, Basel.)

Background: Direct oral anticoagulants (DOACs) are increasingly used for secondary prevention of cardioembolic stroke. While DOACs are associated with a long-term reduced risk of intracranial hemorrhage compared to vitamin K antagonists, pivotal trials avoided the very early period after stroke and few data exist on early initiation of DOAC therapy post stroke., Methods: We retrospectively analyzed data from our prospective database of all consecutive transient ischemic attack (TIA) or ischemic stroke patients with atrial fibrillation treated with DOACs during hospital stay. As per our institutional treatment algorithm for patients with cardioembolic ischemia DOACs are started immediately in TIA and minor stroke (group 1), within days 3-5 in patients with infarcts affecting one third or less of the middle cerebral artery, the anterior cerebral artery, or the posterior cerebral artery territories (group 2) as well as in infratentorial stroke (group 3) and after 1-2 weeks in patients with large infarcts (>⅓MCA territory, group 4). We investigated baseline characteristics, time to initiation of DOAC therapy after symptom onset, and hemorrhagic complications., Results: In 243 included patients, administration of DOAC was initiated 40.5 hours (interquartile range [IQR] 23.0-65.5) after stroke onset in group 1 (n = 41) and after 76.7 hours (IQR 48.0-134.0), 108.4 hours (IQR 67.3-176.4), and 161.8 hours (IQR 153.9-593.8) in groups 2-4 (n = 170, 28, and 4), respectively. Two cases of asymptomatic intracranial hemorrhage (.8%) and 1 case of symptomatic intracranial hemorrhage (.4%) were observed, both in group 2., Conclusions: No severe safety issues were observed in early initiation of DOACs for secondary prevention after acute stroke in our in-patient cohort., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Early repolarization pattern (ER) gained attention as a risk factor for ventricular arrhythmia and sudden cardiac death in the general population. While electrocardiographic abnormalities are frequent findings in stroke patients, data on ER pattern in this population are lacking., Methods: We assessed the prevalence of ER pattern in consecutive acute stroke patients at a tertiary stroke center. Functional outcome after 90 days was analyzed to determine the effect of an ER pattern on mortality. Multivariate logistic regression analysis was used to identify factors associated with an ER pattern., Results: Out of 1141 consecutive stroke patients 771 patients remained for analysis after application of exclusion criteria. ER was observed in 62 (8.04%) patients. ER was more prevalent among subjects with intracerebral and subarachnoidal hemorrhage (13.0%) than among patients with ischemic stroke (7.0%; p = 0.024). Multiple regression analysis revealed QRS-duration (OR 0.972 95% CI 0.950-0.994, p = 0.012), QT-duration (OR 1.009, 95% CI 1.004-1.014, p = 0.001) and mechanical ventilation on admission (OR 0.320, 95% CI 0.136-0.752, p = 0.009) as independent predictors for ER. Overall ER on admission was not associated with increased mortality at 3-month follow-up (ER 11.3% vs. non-ER 9.2%; p = 0.582)., Conclusions: ER is frequently found among patients with acute cerebrovascular events and is more prevalent in patients with hemorrhagic compared to ischemic events. Our study yields no evidence that ER is associated with worse outcome or mortality after stroke.

Background: Patients with ischemic stroke caused by atrial fibrillation (AF) have a high risk of recurrence without adequate secondary prevention with oral anticoagulation (OAC). We investigated adherence to OAC in the first year after introduction of direct oral anticoagulants., Methods: In 284 appropriate patients, the rate of anticoagulation (AC) at discharge, adherence at 90 days and 1 year, changes between substances, and predictors for adherence to AC were analyzed. Functional outcome was assessed using the modified Rankin Scale score., Results: AC was initiated in 70.3% of survivors before discharge. In these patients, only 8.6% and 9.9% discontinued AC after 90 days and 1 year, respectively. In 22.1%, AC was recommended but not started before discharge. Only 53.2% of them received AC at 90 days, increasing to 67.5% at 1 year. A total of 7.6% of patients were deemed unsuitable for AC, none of them subsequently received AC. Overall, 85.4% of patients suitable for AC were treated at 1-year follow-up. No independent predictors for withholding AC were identified. Switching of medication occurred in only a minority of patients within the first year., Conclusions: AC is feasible in more than 90% patients with acute ischemic stroke and AF. When initiated during the acute hospital stay, AC is discontinued in only a minority of patients. However, if AC is recommended but not started during initial hospitalization the rate of AC treatment at 90 days and 1 year is much lower. Therefore, AC should be initiated within the acute hospital stay whenever possible., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Using ferric chloride (FeCl3) to induce experimental superior sagittal sinus (SSS) thrombosis might interfere with magnetic resonance imaging (MRI)-assisted visualization and evaluation of the thrombus, the brain parenchyma, and the quality of the occlusion. The aim of this study was to investigate whether aluminum chloride (AlCl3)-induced thrombosis of the SSS has comparable properties to those of FeCl3 without causing artifacts in MRI. SSS thrombosis was induced in 14 male Wistar rats by exposure of the SSS and subsequent topical application of a filter paper strip soaked in AlCl3 (n = 7) or FeCl3 (n = 7) over a period of 15 min. The animals with AlCl3-induced SSS thrombosis showed a constant and complete occlusion with in histological analysis large thrombi. Blood flow measurements indicated a significant reduction on the first and seventh postoperative day compared to preoperative measurements. MRI enabled visualization and subsequent evaluation of the thrombus and the surrounding parenchyma. In comparison, FeCl3-induced SSS thrombosis could not be evaluated by MRI due to artifacts caused by the paramagnetic properties and increased susceptibility of FeCl3. The occluded sinus and the surrounding area appeared hypointense. The quality of SSS occlusion by AlCl3 was comparable to that of FeCl3. AlCl3 therefore represents a significant alternative substance in experimental SSS thrombosis ideally suited for studies using MRI. [ABSTRACT FROM AUTHOR]

Background: Spontaneous intracerebral hemorrhage (ICH) is a frequent cerebrovascular disorder and still associated with high mortality and poor clinical outcomes. The purpose of this review was to update a 15-year-old former meta-analysis on randomized clinical trials (RCTs) addressing the question of whether ICH patients treated with dexamethasone have better outcomes than controls. Methods: The electronic databases PubMed, SCOPUS, and Cochrane as well as web platforms on current clinical trials were searched for the years 1970–2020 without constriction on language. Data were extracted and outcomes were pooled for conventional and cumulative meta-analysis using a commercial software program (www.Meta-Analysis.com). Results: Finally, 7 RCTs were identified and analyzed including 248 participants in the dexamethasone groups and 242 in the control groups. Five studies showed a high risk of bias. The overall relative risk (RR) for death was 1.32 (95% confidence interval [CI] 0.99–1.76; p = 0.06) and did not differ significantly between the 2 groups. After exclusion of studies with high risk of bias, the RR for death was 1.37 (95% CI 0.54–3.42; p = 0.51). The RR for poor outcome did not differ significantly between the 2 groups analyzed for all included studies (RR = 0.69; 95% CI 0.47–1; p = 0.05) and after exclusion of studies with high risk of bias (RR = 0.7; 95% CI 0.45–1.08; p = 0.11). The RR for complications did not differ significantly including all studies (RR = 1.29; 95% CI 0.77–2.17; p = 0.34) and after exclusion of studies with high risk of bias (RR = 1.27; 95% CI 0.18–8.89; p = 0.81). The cumulative statistics delivered no other results; however, it pointed out fewer complications over time in the dexamethasone group. Conclusion: Clear evidence of a beneficial or negative effect of dexamethasone is still lacking. Modern RCTs or observational studies with propensity design are necessary to evaluate the efficacy and safety of treatment with dexamethasone in patients with ICH. [ABSTRACT FROM AUTHOR]

Background: The influence of prior nicotine or alcohol use (legal drug use [LDU]) on outcome measures after intracerebral hemorrhage (ICH) is insufficiently established. We investigated drug-specific associations with (1) neuroradiologic and clinical parameters and (2) functional long-term outcome after ICH.Methods: This observational cohort study analyzed consecutive spontaneous patients with ICH (n = 554) from our prospective institutional registry over a 5-year study period (January 2010 to December 2014). We compared no-LDU patients with LDU patients, and patients using only nicotine, only alcohol, or both. To account for baseline imbalances, we reanalyzed cohorts after propensity score matching.Results: Prevalence of prior LDU was 197 of 554 (35.6%), comprising 94 of 554 (17.0%) with only nicotine use, 33 of 554 (6.0%) with only alcohol use, and 70 of 554 (12.6%) with alcohol and nicotine use. LDU patients were younger (65 [56-73] versus 75 [67-82], P <.01), less often female (n = 61 of 197 [31.0%] versus n = 188 of 357 [52.7%], P <.01), had more often prior myocardial infarction (n = 29 of 197 [14.7%] versus n = 24 of 357 [6.7%], P <.01), and in-hospital complications (sepsis or systemic inflammatory response syndrome: n = 95 of 197 [48.2%] versus n = 98 of 357 [27.5%], P <.01; pneumonia: n = 89 of 197 [45.2%] versus n = 110 of 357 [30.8%], P <.01). Except for an increased risk of pneumonia (odds ratio 2.22, confidence interval [1.04-4.75], P = .04) in patients using both nicotine and alcohol, we detected no significant differences upon reanalysis after propensity score matching of neuroradiologic or clinical parameters, complications, or long-term outcome between patients with and without LDU (mortality: n = 48 of 150 [32.0%] versus n = 45 of 150 [30.0%], P = .71; favorable outcome [modified Rankin Scale 0-3]: n = 56 of 150 [37.3%] versus n = 53 of 150 [35.3%], P = .72).Conclusions: Prior nicotine use, alcohol use, and their combination were associated with significant differences in baseline characteristics. However, adjusting for unevenly balanced baseline parameters revealed no differences in functional long-term outcome after ICH. [ABSTRACT FROM AUTHOR]

Background: Clostridium septicum is a rare cause of meningitis and brain abscess in children and adults. Gas production by the pathogen can lead to pneumocephalus and the overall mortality rate of Clostridium septicum CNS infection is as high as 74%. The most common entry site of the pathogen is the gastrointestinal tract. Case presentation: We describe a 74-year-old man who presented with a left-sided cerebral infarction in the middle cerebral artery territory. In addition the patient showed signs of Systemic Inflammatory Response Syndrome and Disseminated Intravascular Coagulation. Examination of blood cultures and cerebrospinal fluid led to the diagnosis of sepsis and meningitis caused by Clostridium septicum. Despite appropriate antibiotic therapy the condition of the patient deteriorated rapidly and he died on day 2 after admission. Autopsy revealed a previously unknown adenocarcinoma of the colon ascendens as entry site of the pathogen. Conclusion: Clostridium septicum should be considered as potential pathogen in patients with sepsis and meningitis. Gram stain morphology in conjunction with severe sepsis can rapidly point into the direction of this pathogen. CNS infections manifest either as meningoencephalitis/cerebritis or as brain abscess. Entry site of the pathogen is almost uniquely the gastrointestinal tract. In adults more than 50% suffer from colorectal carcinoma, therefore survivors of Clostridium septicum infections should be examined for underlying occult colorectal malignancy. [ABSTRACT FROM AUTHOR]