Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Moyamoya disease in Southeast Asians: genetic and autopsy data, new cases, systematic review, and meta-analysis of all patients from the literature.

BACKGROUND: Moyamoya disease (MMD) is a rare disorder causing ischemic and hemorrhagic juvenile stroke. It is associated with the founder susceptibility variant p.R4810K in the RNF213 gene in East Asia. Our aim was to enhance understanding of MMD in so far poorly characterized Southeast Asians and exploring differences with Caucasian Europeans. METHODS: By retrospective analysis of medical records and systematic database search on PubMed for all published cases, we identified Southeast Asian patients with MMD. We extracted and pooled proportions using fixed-effects models. Our own cohort was tested for the East Asian RNF213 founder variant p.R4810K. One of our Southeast Asian patients underwent post-mortem histopathological examination. RESULTS: The study cohort comprised 32 Southeast Asians. Mean age at onset in the entire cohort was 32.5 ± 20.3 years (n = 24), 43.4 ± 8.7 years in patients admitted to our center (n = 11), and 23.4 ± 22.4 years in patients from the international literature (n = 13). Female-to-male ratio was 1.6:1. MMD predominantly affected bilateral anterior intracranial vessels. Cerebral ischemia outnumbered transient ischemic attacks (TIAs) and intracranial hemorrhage. TIAs, arterial hypertension and obesity were significantly less frequent in Southeast Asian patients compared to Caucasian Europeans. p.R4810K was absent in all examined Southeast Asians despite of typical histopathological signs of MMD in one autopsy case. CONCLUSION: Clinical and histopathological manifestations of MMD in Southeast Asians are similar to those in Caucasian Europeans. The genotype of MMD in Southeast Asians differs from that of most East Asian patients.

Progression of initially unilateral Moyamoya angiopathy in Caucasian Europeans.

BACKGROUND: Moyamoya angiopathy (MMA) is a rare cause of stroke in Caucasians, but it is much more frequent in East Asia. Since 2021, diagnostic criteria not only comprise bilateral, but also unilateral MMA. Hitherto, progression of unilateral MMA has predominantly been described in East Asians. Our study aimed to analyze the occurrence and characteristics of progression of initially unilateral MMA in Caucasian Europeans. METHODS: By retrospective analysis of medical records of 200 European Caucasians with MMA, admitted to our German center between 2010 and 2022, cases of unilateral MMA and its progression, i.e. progressive ipsi- or novel contralateral arterial stenosis, during follow-up were identified. Kruskal Wallis Test and Fisher's Exact Test were used to identify statistically significant differences between progressive and stable patients concerning demographic, clinical, laboratory, and radiographic features. RESULTS: Our cohort comprised 63 patients with initially unilateral MMA. Fourteen (22.2%) had an ipsi- (n = 3, 21.4%) or contralateral (n = 11, 78.6%) progression. Mean age of patients with progressive MMA at symptom onset was 32 ± 14.1 years. The ratio of women to men in this subgroup was 2.5:1. Mean follow-up period was 5.4 ± 3.7 years, mean age at progression was 39.9 ± 12.7 years. Mean time interval between penultimate follow-up and progression was 4.8 ± 4.5 years. Patients with progression showed affection of the posterior cerebral artery (p = 0.009) and suffered from vertigo (p = 0.009) significantly more often. CONCLUSION: Unilateral MMA progresses in a substantial proportion in European Caucasians. Long-term follow-up is required due to potential late progression with consecutive symptoms and the need for bypass surgery.

Time course of neuroinflammation after human stroke - a pilot study using co-registered PET and MRI.

BACKGROUND: Microglial activation contributes to both inflammatory damage and repair in experimental ischemic stroke. However, because of the logistical challenges, there have been few clinical imaging studies directly describing inflammatory activation and its resolution after stroke. The purpose of our pilot study was to describe the spatio-temporal profile of brain inflammation after stroke using 18kD translocator protein (TSPO) positron emission tomography (PET) with magnetic resonance (MR) co-registration in the subacute and chronic stage after stroke. METHODS: Three patients underwent magnetic resonance imaging (MRI) and PET scans with TSPO ligand [11C]PBR28 15 ± 3 and 90 ± 7 days after an ischaemic stroke. Regions of interest (ROI) were defined on MRI images and applied to the dynamic PET data to derive regional time-activity curves. Regional uptake was quantified as standardised uptake values (SUV) over 60 to 90 min post-injection. ROI analysis was applied to identify binding in the infarct, and in frontal, temporal, parietal, and occipital lobes and cerebellum excluding the infarcted area. RESULTS: The mean age of participants was 56 ± 20.4 years and mean infarct volume was 17.9 ± 18.1 ml. [11C]PBR28 showed increased tracer signal in the infarcted area compared to non-infarcted areas of the brain in the subacute phase of stroke (Patient 1 SUV 1.81; Patient 2 SUV 1.15; Patient 3 SUV 1.64). [11C]PBR28 uptake returned to the level of non-infarcted areas at 90 days Patient 1 SUV 0.99; Patient 3 SUV 0.80). No additional upregulation was detected elsewhere at either time point. CONCLUSIONS: The neuroinflammatory reaction after ischaemic stroke is limited in time and circumscribed in space suggesting that post-ischaemic inflammation is tightly controlled but regulatory mechanisms.

How relevant are cerebral white matter lesions in the D313Y variant of the α-galactosidase A gene? Neurological, cardiological, laboratory, and MRI data of 21 patients within a follow-up of 3 years.

BACKGROUND: Fabry disease is an inherited metabolic disorder with various symptoms. Neurological manifestations are small fiber neuropathy, cerebral white matter lesions (WML), megadolicho basilar artery, and stroke. The relevance of the D313Y variant in the galactosidase alpha gene is controversially discussed. OBJECTIVES: We aimed at elucidating the implications of this differential diagnosis of multiple sclerosis (MS), focussing on the analysis of WML over time and correlations with other markers. METHODS: We reviewed retrospectively the clinical, laboratory, and magnetic resonance imaging data of 21 carriers of the D313Y variant at a single German outpatient clinic for MS between 2004 and 2021. RESULTS: In our cohort (15 females, 6 males), mean age at diagnosis was 44.1 ± 16.3 years, and mean follow-up duration was 3.1 ± 3.9 years. WML were rated on both, the Fazekas scale and the age-related white matter changes rating scale, and were of variable interindividual extent. Follow-up imaging showed virtually no progress. WML did not correlate with the severity of clinical findings or lysoGb3 levels. Symptomatic carriers of the variant are characterized by an almost complete lack of internal organ manifestations and laboratory findings, usually associated with Fabry disease. CONCLUSION: WML in carriers of the D313Y variant do not seem to be suitable for assessing or predicting the (para-) clinical status. Concerning MS patients, the variant and its clinical signs can be a differential diagnosis, but also a co-factor. Imaging and cerebrospinal fluid findings facilitate the distinction between both entities.

Microembolic signals and antiplatelet therapy in Moyamoya angiopathy.

BACKGROUND: Embolism as a cause of stroke is widely neglected in Moyamoya angiopathy (MMA), and recommendations for use of antiplatelet therapy (APT) vary. We examined the presence of microembolic signals (MES) during transcranial Doppler (TCD) monitoring and assessed the effects of APT on the occurrence of MES in MMA. PATIENTS AND METHODS: We retrospectively analysed patients with MMA treated at our centre between 2011 and 2021. TCD was performed at first presentation and at most visits, while number of visits varied between individual patients. TCD was performed for 30 min bilaterally. Patient demographics, vascular risk factors, and antiplatelet treatment were collected from each clinic visit and ischemic and haemorrhagic episodes were captured as recorded during follow-up visits. RESULTS: 209 patients were included in the analysis (mean age 38.7 ± 15.3, 28% male). 21 patients with 27 MES-positive TCD examinations were identified (10%). Patient characteristics were similar in MES-positive and MES-negative groups. However, recent ischemic events were detected at a significantly higher rate in MES-positive patients (42.9% vs 4.8%, p < 0.001). After MES detection, change of antiplatelet drug regime was performed, leading to loss of MES in all cases. Dual APT was preferably used in the MES-positive group (p < 0.001) but no significant difference of haemorrhage during follow-up-visits was observed. Reduction of APT before bypass-surgery triggered MES in four patients. CONCLUSION: APT is required in patients with MMA. MES monitoring may help to identify risk patients in need of intensified APT.

Evaluating Rates of Recurrent Ischemic Stroke Among Young Adults With Embolic Stroke of Undetermined Source: The Young ESUS Longitudinal Cohort Study.

Importance: Cryptogenic strokes constitute approximately 40% of ischemic strokes in young adults, and most meet criteria for the embolic stroke of undetermined source (ESUS). Two randomized clinical trials, NAVIGATE ESUS and RESPECT ESUS, showed a high rate of stroke recurrence in older adults with ESUS but the prognosis and prognostic factors among younger individuals with ESUS is uncertain. Objective: To determine rates of and factors associated with recurrent ischemic stroke and death and new-onset atrial fibrillation (AF) among young adults. Design, Setting, and Participants: This multicenter longitudinal cohort study with enrollment from October 2017 to October 2019 and a mean follow-up period of 12 months ending in October 2020 included 41 stroke research centers in 13 countries. Consecutive patients 50 years and younger with a diagnosis of ESUS were included. Of 576 screened, 535 participants were enrolled after 1 withdrew consent, 41 were found to be ineligible, and 2 were excluded for other reasons. The final follow-up visit was completed by 520 patients. Main Outcomes and Measures: Recurrent ischemic stroke and/or death, recurrent ischemic stroke, and prevalence of patent foramen ovale (PFO). Results: The mean (SD) age of participants was 40.4 (7.3) years, and 297 (56%) participants were male. The most frequent vascular risk factors were tobacco use (240 patients [45%]), hypertension (118 patients [22%]), and dyslipidemia (109 patients [20%]). PFO was detected in 177 participants (50%) who had transthoracic echocardiograms with bubble studies. Following initial ESUS, 468 participants (88%) were receiving antiplatelet therapy, and 52 (10%) received anticoagulation. The recurrent ischemic stroke and death rate was 2.19 per 100 patient-years, and the ischemic stroke recurrence rate was 1.9 per 100 patient-years. Of the recurrent strokes, 9 (64%) were ESUS, 2 (14%) were cardioembolic, and 3 (21%) were of other determined cause. AF was detected in 15 participants (2.8%; 95% CI, 1.6-4.6). In multivariate analysis, the following were associated with recurrent ischemic stroke: history of stroke or transient ischemic attack (hazard ratio, 5.3; 95% CI, 1.8-15), presence of diabetes (hazard ratio, 4.4; 95% CI, 1.5-13), and history of coronary artery disease (hazard ratio, 10; 95% CI, 4.8-22). Conclusions and Relevance: In this large cohort of young adult patients with ESUS, there was a relatively low rate of subsequent ischemic stroke and a low frequency of new-onset AF. Most recurrent strokes also met the criteria for ESUS, suggesting the need for future studies to improve our understanding of the underlying stroke mechanism in this population.

Potential Embolic Sources and Outcomes in Embolic Stroke of Undetermined Source in the NAVIGATE-ESUS Trial.

Background and Purpose- Emboli in embolic stroke of undetermined source (ESUS) may originate from various potential embolic sources (PES), some of which may respond better to anticoagulation, whereas others to antiplatelets. We analyzed whether rivaroxaban is associated with reduction of recurrent stroke compared with aspirin in patients with ESUS across different PES and by number of PES. Methods- We assessed the presence/absence of each PES (atrial cardiopathy, atrial fibrillation, arterial atherosclerosis, left ventricular dysfunction, cardiac valvulopathy, patent foramen ovale, cancer) in NAVIGATE-ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) participants. Prevalence of each PES, as well as treatment effect and risk of event for each PES were determined. Results by number of PES were also determined. The outcomes were ischemic stroke, all-cause mortality, cardiovascular mortality, and myocardial infarction. Results- In 7213 patients (38% women, mean age 67years) followed for a median of 11 months, the 3 most prevalent PES were atrial cardiopathy (37%), left ventricular disease (36%), and arterial atherosclerosis (29%). Forty-one percent of all patients had multiple PES, with 15% having ≥3 PES. None or a single PES was present in 23% and 36%, respectively. Recurrent ischemic stroke risk was similar for rivaroxaban- and aspirin-assigned patients for each PES, except for those with cardiac valvular disease which was marginally higher in rivaroxaban-assigned patients (hazard ratio, 1.8 [95% CI, 1.0-3.0]). All-cause mortality risks were similar across treatment groups for each PES while too few myocardial infarctions and cardiovascular deaths occurred for meaningful assessment. Increasing number of PES was not associated with increased stroke recurrence nor all-cause mortality, and outcomes did not vary between rivaroxaban- and aspirin-assigned patients by number of PES. Conclusions- A large proportion of patients with ESUS had multiple PES which could explain the neutral results of NAVIGATE-ESUS. Recurrence rates between rivaroxaban- and aspirin-assigned patients were similar across the spectrum of PES. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02313909.

Predictors of Recurrent Ischemic Stroke in Patients with Embolic Strokes of Undetermined Source and Effects of Rivaroxaban Versus Aspirin According to Risk Status: The NAVIGATE ESUS Trial.

BACKGROUND: Embolic stroke of undetermined source (ESUS) identifies patients with cryptogenic ischemic stroke presumed due to embolism from several unidentified sources. Among patients with recent ESUS, we sought to determine independent predictors of recurrent ischemic stroke during treatment with aspirin or rivaroxaban and to assess the relative effects of these treatments according to risk. METHODS: Exploratory analyses of 7213 participants in the NAVIGATE ESUS international trial who were randomized to aspirin 100 mg/day or rivaroxaban 15 mg/day and followed for a median of 11 months, during which time there were 309 first recurrent ischemic strokes (4.6% per year). Baseline features were correlated with recurrent stroke by multivariate analysis. RESULTS: The 7 independent predictors of recurrent stroke were stroke or transient ischemic attack (TIA) prior to the qualifying stroke (hazard ratio [HR] 2.03 95% confidence internal [CI] 1.58-2.60), current tobacco user (HR 1.62, 95% CI 1.24-2.12), age (HR 1.02 per year increase, 95%CI 1.01-1.03), diabetes (HR 1.28, 95% CI 1.01-1.64), multiple acute infarcts on neuroimaging (HR 1.49, 95% CI 1.09-2.02), aspirin use prior to qualifying stroke (HR 1.34, 95% CI 1.02-1.70), and time from qualifying stroke to randomization (HR .98, 95% CI .97-.99). The rate of recurrent stroke rate was 2.6% per year for participants without any of these risk factors, and increased by an average of 45% for each independent predictor (P < .001). There were no significant interactions between treatment effects and independent stroke predictors or stroke risk status. CONCLUSIONS: In this large cohort of ESUS patients, several features including prior stroke or TIA, advanced age, current tobacco user, multiple acute infarcts on neuroimaging, and diabetes independently identified those with an increased risk of ischemic stroke recurrence. The relative effects of rivaroxaban and aspirin were similar across the spectrum of independent stroke predictors and recurrent stroke risk status.

Experimental ischaemic stroke induces transient cardiac atrophy and dysfunction.

BACKGROUND: Stroke can lead to cardiac dysfunction in patients, but the mechanisms underlying the interaction between the injured brain and the heart are poorly understood. The objective of the study is to investigate the effects of experimental murine stroke on cardiac function and molecular signalling in the heart. METHODS AND RESULTS: Mice were subjected to filament-induced left middle cerebral artery occlusion for 30 or 60 min or sham surgery and underwent repetitive micro-echocardiography. Left ventricular contractility was reduced early (24-72 h) but not late (2 months) after brain ischaemia. Cardiac dysfunction was accompanied by a release of high-sensitive cardiac troponin (hsTNT (ng/ml): d1: 7.0 ± 1.0 vs. 25.0 ± 3.2*; d3: 7.3 ± 1.1 vs. 52.2 ± 16.7*; d14: 5.7 ± 0.8 vs. 5.2 ± 0.3; sham vs. 60 min. MCAO; mean ± SEM; *p < 0.05); reduced heart weight (heart weight/tibia length ratio: d1: 6.9 ± 0.2 vs. 6.4 ± 0.1*; d3: 6.7 ± 0.2 vs. 5.8 ± 0.1*; d14: 6.7 ± 0.2 vs. 6.4 ± 03; sham vs. 60 min. MCAO; mean ± SEM; *p < 0.05); resulting from cardiomyocyte atrophy (cardiomyocyte size: d1: 12.8% ± 0.002**; d3: 13.5% ± 0.002**; 14d: 6.3% ± 0.003*; 60 min. MCAO vs. sham; mean ± SEM; **p < 0.01; *p < 0.05), accompanied by increased atrogin-1 and the E3 ubiquitin ligase murf-1. Net norepinephrine but not synthesis was increased, suggesting a reduced norepinephrine release or an increase of norepinephrine re-uptake, resulting in a functional denervation. Transcriptome analysis in cardiac tissue identified the transcription factor peroxisome proliferator-activated receptor gamma as a potential mediator of stroke-induced transcriptional dysregulation involved in cardiac atrophy. CONCLUSIONS: Stroke induces a complex molecular response in the heart muscle with immediate but transient cardiac atrophy and dysfunction.

Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial.

BACKGROUND: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS. AIMS: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. METHODS: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus. RESULTS: Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe. CONCLUSIONS: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research.

Management of Spontaneous Intracerebral Hemorrhage.

PURPOSE OF REVIEW: We review the current evidence for medical and surgical treatments of spontaneous intracerebral hemorrhage (ICH). RECENT FINDINGS: Therapy with hemostatic agents (e.g. factor VIIa and tranexamic acid) if started early after bleeding onset may reduce hematoma expansion, but their clinical effectiveness has not been shown. Rapid anticoagulation reversal with prothrombin concentrates (PCC) plus vitamin K is the first choice in vitamin K antagonist-related ICH. In ICH related to dabigatran, anticoagulation can be rapidly reversed with idarucizumab. PCC are recommended for ICH related to FXa inhibitors, whereas specific reversal agents are not yet approved. While awaiting ongoing trials studying minimally invasive approaches or hemicraniectomy, the role of surgery in ICH remains to be defined. Therapies targeting downstream molecular cascades in order to prevent secondary neuronal damage are promising, but the complexity and multi-phased nature of ICH pathophysiology is challenging. Finally, in addition to blood pressure control, antithrombotic prevention after ICH has to consider the risk of recurrent bleeding as well as the risk of ischemic events. Treatment of acute ICH remains challenging, and many promising interventions for acute ICH await further evidence from trials.

Outcome of intracerebral hemorrhage associated with different oral anticoagulants.

OBJECTIVE: In an international collaborative multicenter pooled analysis, we compared mortality, functional outcome, intracerebral hemorrhage (ICH) volume, and hematoma expansion (HE) between non-vitamin K antagonist oral anticoagulation-related ICH (NOAC-ICH) and vitamin K antagonist-associated ICH (VKA-ICH). METHODS: We compared all-cause mortality within 90 days for NOAC-ICH and VKA-ICH using a Cox proportional hazards model adjusted for age; sex; baseline Glasgow Coma Scale score, ICH location, and log volume; intraventricular hemorrhage volume; and intracranial surgery. We addressed heterogeneity using a shared frailty term. Good functional outcome was defined as discharge modified Rankin Scale score ≤2 and investigated in multivariable logistic regression. ICH volume was measured by ABC/2 or a semiautomated planimetric method. HE was defined as an ICH volume increase >33% or >6 mL from baseline within 72 hours. RESULTS: We included 500 patients (97 NOAC-ICH and 403 VKA-ICH). Median baseline ICH volume was 14.4 mL (interquartile range [IQR] 3.6-38.4) for NOAC-ICH vs 10.6 mL (IQR 4.0-27.9) for VKA-ICH (p = 0.78). We did not find any difference between NOAC-ICH and VKA-ICH for all-cause mortality within 90 days (33% for NOAC-ICH vs 31% for VKA-ICH [p = 0.64]; adjusted Cox hazard ratio (for NOAC-ICH vs VKA-ICH) 0.93 [95% confidence interval (CI) 0.52-1.64] [p = 0.79]), the rate of HE (NOAC-ICH n = 29/48 [40%] vs VKA-ICH n = 93/140 [34%] [p = 0.45]), or functional outcome at hospital discharge (NOAC-ICH vs VKA-ICH odds ratio 0.47; 95% CI 0.18-1.19 [p = 0.11]). CONCLUSIONS: In our international collaborative multicenter pooled analysis, baseline ICH volume, hematoma expansion, 90-day mortality, and functional outcome were similar following NOAC-ICH and VKA-ICH.

A Mouse Model of Post-Stroke Pneumonia Induced by Intra-Tracheal Inoculation with Streptococcus pneumoniae.

BACKGROUND: Stroke-induced immunodeficiency increases the risk of infectious complications, which adversely affects neurological outcome. Among those, pneumonia affects as many as one third of stroke patients and is the main contributor to mortality in the post-acute phase of stroke. Experimental findings on post-stroke susceptibility to spontaneous pneumonia in mice are contradictory. Here, we established a mouse model inducing standardized bacterial pneumonia and characterized the impaired pulmonary cellular and humoral immune responses after experimental stroke. METHODS: Bacterial pneumonia was induced by intra-tracheal inoculation with Streptococcus pneumoniae at different time points after transient middle cerebral artery occlusion (MCAO). Bacterial counts in lungs and blood, histological changes, and cytokine production in the lungs were assessed. Furthermore, we investigated the effect of pneumonia on stroke outcome. RESULTS: Intra-tracheal inoculation resulted in reproducible pneumonia and bacteraemia, and demonstrated post-stroke susceptibility to streptococcal pneumonia developing with a delay of at least 24 h after MCAO. Higher bacterial counts in mice infected 3 days after stroke induction correlated with reduced neutrophil and macrophage infiltration in the lungs and lower levels of pro-inflammatory cytokines in the broncho-alveolar lavage compared to sham-operated animals. Pneumonia increased mortality without affecting brain-infiltrating leukocytes. CONCLUSIONS: In this standardized mouse model of post-stroke pneumonia, we describe attenuated leukocyte infiltration and cytokine production in response to bacterial infection in the lungs that has a profound effect on outcome.

Changes in electrocorticographic beta frequency components precede spreading depolarization in patients with acute brain injury.

OBJECTIVE: Spreading depolarization (SD) occurs after traumatic brain injury, subarachnoid hemorrhage, malignant hemispheric stroke and intracranial hemorrhage. SD has been associated with secondary brain injury, which can be reduced by ketamine. In this present study frequency bands of electrocorticographic (ECoG) recordings were investigated with regards to SDs. METHODS: A total of 43 patients after acute brain injury were included in this retrospective and explorative study. Relative delta 0.5-4Hz, theta 4-8Hz, alpha 8-13Hz and beta 13-40Hz bands were analyzed with regards to SD occurrence and analgesic and sedative administration. Higher frequencies, including gamma 40-70Hz, fast gamma 70-100Hz and high frequency oscillations 100-200Hz were analyzed in a subset of patients with a sampling rate of up to 400Hz. RESULTS: A close association of relative beta frequency and SD was found. Relative beta frequency was suppressed up to two hours prior to SD when compared to hours with no SD. This finding was partially explained by administration of ketamine. Even after removal of all patient data during administration of ketamine, SDs occurred predominantly during times with low relative beta frequency in a patient-independent analysis. CONCLUSION: Suppression of beta frequency by ketamine or without ketamine is associated with low SD counts. SIGNIFICANCE: Alteration of beta frequency might help to predict occurrence of SDs in acutely brain injured patients.

DAMP signaling is a key pathway inducing immune modulation after brain injury.

Acute brain lesions induce profound alterations of the peripheral immune response comprising the opposing phenomena of early immune activation and subsequent immunosuppression. The mechanisms underlying this brain-immune signaling are largely unknown. We used animal models for experimental brain ischemia as a paradigm of acute brain lesions and additionally investigated a large cohort of stroke patients. We analyzed release of HMGB1 isoforms by mass spectrometry and investigated its inflammatory potency and signaling pathways by immunological in vivo and in vitro techniques. Features of the complex behavioral sickness behavior syndrome were characterized by homecage behavior analysis. HMGB1 downstream signaling, particularly with RAGE, was studied in various transgenic animal models and by pharmacological blockade. Our results indicate that the cytokine-inducing, fully reduced isoform of HMGB1 was released from the ischemic brain in the hyperacute phase of stroke in mice and patients. Cytokines secreted in the periphery in response to brain injury induced sickness behavior, which could be abrogated by inhibition of the HMGB1-RAGE pathway or direct cytokine neutralization. Subsequently, HMGB1-release induced bone marrow egress and splenic proliferation of bone marrow-derived suppressor cells, inhibiting the adaptive immune responses in vivo and vitro. Furthermore, HMGB1-RAGE signaling resulted in functional exhaustion of mature monocytes and lymphopenia, the hallmarks of immune suppression after extensive ischemia. This study introduces the HMGB1-RAGE-mediated pathway as a key mechanism explaining the complex postischemic brain-immune interactions.