Access to thrombolysis for non-resident and resident stroke patients-a registry-based comparative study from Berlin

Objectives Stroke can happen to people away from home. It is unknown whether non-resident and resident stroke patients have equal access to thrombolysis. Materials and methods Consecutive patients cared for by the Stroke Emergency Mobile between 2011 and 2016 after prompting suspicion of acute stroke during the emergency call were included in our registry. Patients were categorized as residents or non-residents based on their main address. Clinical characteristics, thrombolysis rates, and time intervals from symptom onset/last seen well to alarm and to thrombolysis were compared between groups adjusting for age, pre-stroke modified Rankin Scale (mRS) score, and National Institutes of Health Stroke Scale (NIHSS) score. Results Of 4,254 patients for whom a stroke dispatch was activated, 2,451 had ischemic or hemorrhagic strokes, including 73 non-residents. Non-resident stroke patients were younger (median 69.4 vs. 76.6 years, p < 0.001), had less pre-stroke disability (mRS ≥ 2:17.8 vs. 47.5%, p < 0.001) and less severe strokes (median NIHSS 4 vs. 5, p = 0.02). Thrombolysis rates were higher in non-residents (30.9 vs. 22.0% of ischemic stroke patients, p = 0.04) and emergency calls were made faster (symptom onset/last-seen-well-to-alarm time 35 vs. 144 min, p = 0.04). A lower proportion of non-residents had unknown time of symptom onset (21.9 vs. 46.4%, p < 0.001). For patients with known time of symptom onset, thrombolysis rates, and prehospital delays were similar among non-residents and residents. Conclusion In this study, non-resident stroke patients had higher rates of thrombolysis than residents. This may be explained by a lower proportion of patients with unknown time of symptom onset

Smoking Does Not Alter Treatment Effect of Intravenous Thrombolysis in Mild to Moderate Acute Ischemic Stroke—A Dutch String-of-Pearls Institute (PSI) Stroke Study

Background:The smoking-thrombolysis paradox refers to a better outcome in smokers who suffer from acute ischemic stroke (AIS) following treatment with thrombolysis. However, studies on this subject have yielded contradictory results and an interaction analysis of exposure to smoking and thrombolysis in a large, multicenter database is lacking. Methods:Consecutive AIS patients admitted within 12 h of symptom onset between 2009 and 2014 from the prospective, multicenter stroke registry (Dutch String-of-Pearls Stroke Study) were included for this analysis. We performed a generalized linear model for functional outcome 3 months post-stroke depending on risk of the exposure variables (smoking yes/no, thrombolysis yes/no). The following confounders were adjusted for: age, smoking, hypertension, atrial fibrillation, diabetes mellitus, stroke severity, and stroke etiology. Results:Out of 468 patients, 30.6% (N= 143) were smokers and median baseline NIHSS was 3 (interquartile range 1-6). Smoking alone had a crude and adjusted relative risk (RR) of 0.99 (95% CI 0.89-1.10) and 0.96 (95% CI 0.86-1.01) for good outcome (modified Rankin Score <= 2), respectively. A combination of exposure variables (smoking and thrombolysis) did not change the results significantly [crude RR 0.87 (95% CI 0.74-1.03], adjusted RR 1.1 (95%CI 0.90-1.30)]. Smoking alone had an adjusted RR of 1.2 (95% CI 0.6-2.7) for recanalization following thrombolysis (N= 88). Conclusions:In patients with mild to moderate AIS admitted within 12 h of symptom onset, smoking did not modify treatment effect of thrombolysis

Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): multicentre, randomised controlled, endpoint blinded trial

OBJECTIVE: To determine the safety and efficacy of aerobic exercise on activities of daily living in the subacute phase after stroke. DESIGN: Multicentre, randomised controlled, endpoint blinded trial. SETTING: Seven inpatient rehabilitation sites in Germany (2013-17). PARTICIPANTS: 200 adults with subacute stroke (days 5-45 after stroke) with a median National Institutes of Health stroke scale (NIHSS, range 0-42 points, higher values indicating more severe strokes) score of 8 (interquartile range 5-12) were randomly assigned (1:1) to aerobic physical fitness training (n=105) or relaxation sessions (n=95, control group) in addition to standard care. INTERVENTION: Participants received either aerobic, bodyweight supported, treadmill based physical fitness training or relaxation sessions, each for 25 minutes, five times weekly for four weeks, in addition to standard rehabilitation therapy. Investigators and endpoint assessors were masked to treatment assignment. MAIN OUTCOME MEASURES: The primary outcomes were change in maximal walking speed (m/s) in the 10 m walking test and change in Barthel index scores (range 0-100 points, higher scores indicating less disability) three months after stroke compared with baseline. Safety outcomes were recurrent cardiovascular events, including stroke, hospital readmissions, and death within three months after stroke. Efficacy was tested with analysis of covariance for each primary outcome in the full analysis set. Multiple imputation was used to account for missing values. RESULTS: Compared with relaxation, aerobic physical fitness training did not result in a significantly higher mean change in maximal walking speed (adjusted treatment effect 0.1 m/s (95% confidence interval 0.0 to 0.2 m/s), P=0.23) or mean change in Barthel index score (0 (-5 to 5), P=0.99) at three months after stroke. A higher rate of serious adverse events was observed in the aerobic group compared with relaxation group (incidence rate ratio 1.81, 95% confidence interval 0.97 to 3.36). CONCLUSIONS: Among moderately to severely affected adults with subacute stroke, aerobic bodyweight supported, treadmill based physical fitness training was not superior to relaxation sessions for maximal walking speed and Barthel index score but did suggest higher rates of adverse events. These results do not appear to support the use of aerobic bodyweight supported fitness training in people with subacute stroke to improve activities of daily living or maximal walking speed and should be considered in future guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT01953549

Stroke with unknown time of symptom onset: baseline clinical and magnetic resonance imaging data of the first thousand patients in WAKE-UP (efficacy and safety of mri-based thrombolysis in wake-up stroke: a randomized, doubleblind, placebo-controlled trial)

Background and Purpose—We describe clinical and magnetic resonance imaging (MRI) characteristics of stroke patients with unknown time of symptom onset potentially eligible for thrombolysis from a large prospective cohort. Methods—We analyzed baseline data from WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial), an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. MRI judgment included assessment of the mismatch between visibility of the acute ischemic lesion on diffusion-weighted imaging and fluid-attenuated inversion recovery. Results—Of 1005 patients included, diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was present in 479 patients (48.0%). Patients with daytime-unwitnessed stroke (n=138, 13.7%) had a shorter delay between symptom recognition and hospital arrival (1.5 versus 1.8 hours; P=0.002), a higher National Institutes of Stroke Scale score on admission (8 versus 6; P&lt;0.001), and more often aphasia (72.5% versus 34.0%; P&lt;0.001) when compared with stroke patients waking up from nighttime sleep. Frequency of diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was comparable between both groups (43.7% versus 48.7%; P=0.30). Conclusions—Almost half of the patients with unknown time of symptom onset stroke otherwise eligible for thrombolysis had MRI findings making them likely to be within a time window for safe and effective thrombolysis. Patients with daytime onset unwitnessed stroke differ from wake-up stroke patients with regards to clinical characteristics but are comparable in terms of MRI characteristics of lesion age. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01525290. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-005906-32

Clinical characteristics of unknown symptom onset stroke patients with and without diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch

Background: Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) mismatch was suggested to identify stroke patients with unknown time of symptom onset likely to be within the time window for thrombolysis. Aims: We aimed to study clinical characteristics associated with DWI-FLAIR mismatch in patients with unknown onset stroke. Methods: We analyzed baseline MRI and clinical data from patients with acute ischemic stroke proven by DWI from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. Clinical characteristics were compared between patients with and without DWI-FLAIR mismatch. Results: Of 699 patients included, 418 (59.8%) presented with DWI-FLAIR mismatch. A shorter delay between last seen well and symptom recognition (p = 0.0063), a shorter delay between symptom recognition and arrival at hospital (p = 0.0025), and history of atrial fibrillation (p = 0.19) were predictors of DWI-FLAIR mismatch in multivariate analysis. All other characteristics were comparable between groups. Conclusions: There are only minor differences in measured clinical characteristics between unknown symptom onset stroke patients with and without DWI-FLAIR mismatch. DWI-FLAIR mismatch as an indicator of stroke onset within 4.5 h shows no relevant association with commonly collected clinical characteristics of stroke patients

Effect of informed consent on patient characteristics in a stroke thrombolysis trial

Objective: To determine whether the manner of consent, i.e., informed consent by patients themselves or informed consent by proxy, affects clinical characteristics of samples of acute stroke patients enrolled in clinical trials. Methods: We analyzed the manner of obtaining informed consent in the first 1,005 patients from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset running in 6 European countries. Patients providing informed consent by themselves were compared with patients enrolled by proxy consent. Baseline clinical measures were compared between groups. Results: In 359 (35.7%) patients, informed consent was by proxy. Patients with proxy consent were older (median 71 vs 66 years, p &lt; 0.0001) and had a higher frequency of arterial hypertension (58.2% vs 43.4%, p &lt; 0.0001). They showed higher scores on the NIH Stroke Scale (median 11 vs 5, p &lt; 0.0001) and more frequently aphasia (73.7% vs 20.0%, p &lt; 0.0001). The rate of proxy consent varied among countries (p &lt; 0.0001), ranging from 77.1% in Spain to 1.2% in Denmark. Conclusions: Patients recruited by proxy consent were older, had more severe strokes, and had higher prevalence of aphasia than those with capacity to give personal consent. Variations in the manner of consent across countries may influence trial results. Clinicaltrials.gov and Clinicaltrialsregister.eu identifiers: NCT01525290 (clinicaltrials.gov); 2011-005906-32 (clinicaltrialsregister.eu)

Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features

Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of &gt; 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs. Copy-number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in all cases. Furthermore, this molecular DLGNT class can be subdivided into two subgroups [DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2], with all DLGNT-MC-2 additionally displaying a gain of chromosomal arm 1q. Co-deletion of 1p/19q, commonly seen in IDH-mutant oligodendroglioma, was frequently observed in DLGNT, especially in DLGNT-MC-1 cases. Both subgroups also had recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1, adding up to an MAPK/ERK pathway activation identified in 80% of cases. In the DLGNT-MC-1 group, age at diagnosis was significantly lower (median 5 vs 14 years, p &lt; 0.01) and clinical course less aggressive (5-year OS 100, vs 43% in DLGNT-MC-2). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases without typical morphological or radiological characteristics, such as diffuse growth and radiologic leptomeningeal dissemination. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic biomarkers and therapeutic targets, respectively—laying the foundation for future clinical trials with, e.g., MEK inhibitors that may improve the clinical outcome of patients with DLGNT

Gas emission strength and evolution of the molar ratio of BrO/SO2 in the plume of Nyiragongo in comparison to Etna

Airborne and ground-based differential optical absorption spectroscopy observations have been carried out at the volcano Nyiragongo (Democratic Republic of Congo) to measure SO2 and bromine monoxide (BrO) in the plume in March 2004 and June 2007, respectively. Additionally filter pack and multicomponent gas analyzer system (Multi-GAS) measurements were carried out in June 2007. Our measurements provide valuable information on the chemical composition of the volcanic plume emitted from the lava lake of Nyiragongo. The main interest of this study has been to investigate for the first time the bromine emission flux of Nyiragongo (a rift volcano) and the BrO formation in its volcanic plume. Measurement data and results from a numerical model of the evolution of BrO in Nyiragongo volcanic plume are compared with earlier studies of the volcanic plume of Etna (Italy). Even though the bromine flux from Nyiragongo (2.6t/d) is slightly greater than that from Etna (1.9t/d), the BrO/SO2 ratio (maximum 7x10(-5)) is smaller than in the plume of Etna (maximum 2.1x10(-4)). A one-dimensional photochemical model to investigate halogen chemistry in the volcanic plumes of Etna and Nyiragongo was initialized using data from Multi-GAS and filter pack measurements. Model runs showed that the differences in the composition of volcanic volatiles led to a smaller fraction of total bromine being present as BrO in the Nyiragongo plume and to a smaller BrO/SO2 ratio

Evolution of Blood-Brain Barrier Permeability in Subacute Ischemic Stroke and Associations With Serum Biomarkers and Functional Outcome

Background and Purpose: In the setting of acute ischemic stroke, increased blood-brain barrier permeability (BBBP) as a sign of injury is believed to be associated with increased risk of poor outcome. Pre-clinical studies show that selected serum biomarkers including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), matrix metallopeptidases (MMP), and vascular endothelial growth factors (VEGFs) may play a role in BBBP post-stroke. In the subacute phase of stroke, increased BBBP may also be caused by regenerative mechanisms such as vascular remodeling and therefore may improve functional recovery. Our aim was to investigate the evolution of BBBP in ischemic stroke using contrast-enhanced (CE) magnetic resonance imaging (MRI) and to analyze potential associations with blood-derived biomarkers as well as functional recovery in subacute ischemic stroke patients. Methods: This is an exploratory analysis of subacute ischemic stroke patients enrolled in the BAPTISe study nested within the randomized controlled PHYS-STROKE trial (interventions: 4 weeks of aerobic fitness training vs. relaxation). Patients with at least one CE-MRI before (v1) or after (v2) the intervention were eligible for this analysis. The prevalence of increased BBBP was visually assessed on T1-weighted MR-images based on extent of contrast-agent enhancement within the ischemic lesion. The intensity of increased BBBP was assessed semi-quantitatively by normalizing the mean voxel intensity within the region of interest (ROI) to the contralateral hemisphere ("normalized CE-ROI"). Selected serum biomarkers (high-sensitive CRP, IL-6, TNF-alpha, MMP-9, and VEGF) at v1 (before intervention) were analyzed as continuous and dichotomized variables defined by laboratory cut-off levels. Functional outcome was assessed at 6 months after stroke using the modified Rankin Scale (mRS). Results: Ninety-three patients with a median baseline NIHSS of 9 [IQR 6-12] were included into the analysis. The median time to v1 MRI was 30 days [IQR 18-37], and the median lesion volume on v1 MRI was 4 ml [IQR 1.2-23.4]. Seventy patients (80%) had increased BBBP visible on v1 MRI. After the trial intervention, increased BBBP was still detectable in 52 patients (74%) on v2 MRI. The median time to v2 MRI was 56 days [IQR 46-67]. The presence of increased BBBP on v1 MRI was associated with larger lesion volumes and more severe strokes. Aerobic fitness training did not influence the increase of BBBP evaluated at v2. In linear mixed models, the time from stroke onset to MRI was inversely associated with normalized CE-ROI (coefficient -0.002, Standard Error 0.007, p < 0.01). Selected serum biomarkers were not associated with the presence or evolution of increased BBBP. Multivariable regression analysis did not identify the occurrence or evolution of increased BBBP as an independent predictor of favorable functional outcome post-stroke. Conclusion: In patients with moderate-to-severe subacute stroke, three out of four patients demonstrated increased BBB permeability, which decreased over time. The presence of increased BBBP was associated with larger lesion volumes and more severe strokes. We could not detect an association between selected serum biomarkers of inflammation and an increased BBBP in this cohort. No clear association with favorable functional outcome was observed