Protocol of the Berlin Long-term Observation of Vascular Events (BeLOVE): a prospective cohort study with deep phenotyping and long-term follow up of cardiovascular high-risk patients.

INTRODUCTION: The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations. METHODS AND ANALYSIS: A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after ~90 days and includes assessments of the patient's medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including 'OMICs' technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes. ETHICS AND DISSEMINATION: The study was approved by the Charité-Universitätsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations. STUDY REGISTRATION: First study phase: Approved WHO primary register: German Clinical Trials Register: https://drks.de/search/de/trial/DRKS00016852; WHO International Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/ DRKS00023323. Recruitment started on January 1, 2021.

Prospective collection of blood plasma samples to identify potential biomarkers for the prehospital stroke diagnosis (ProGrEss-Bio): study protocol for a multicenter prospective observational study.

Introduction: Intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) are well-established, evidence-based, time-critical therapies that reduce morbidity and mortality in acute ischemic stroke (AIS) patients. The exclusion of intracerebral hemorrhage (ICH) is mandatory and has been performed by cerebral imaging to date. Mobile stroke units (MSUs) have been shown to improve functional outcomes by bringing cerebral imaging and IVT directly to the patient, but they have limited coverage. Blood biomarkers clearly distinguishing between AIS, ICH, and stroke mimics (SM) could provide an alternative to cerebral imaging if concentration changes are detectable in the hyperacute phase after stroke with high diagnostic accuracy. In this study, we will take blood samples in a prehospital setting to evaluate potential biomarkers. The study was registered in the German Clinical Trials Register (https://drks.de/search/de) with the identifier DRKS00023063. Methods and analysis: We plan a prospective, observational study involving 300 patients with suspected stroke and symptom onset of ≤4.5 h before the collection of biomarkers. Study participants will be recruited from three sites in Berlin, Germany during MSU deployments. The focus of the study is the collection of blood samples from participants at the prehospital scene and from participants with AIS or ICH at a second-time point. All samples will be analyzed using targeted and untargeted analytical approaches. Study-related information about participants, including medical information and discharge diagnoses from the subsequent treating hospital, will be collected and documented in an electronic case report form (eCRF). Discussion: This study will evaluate whether a single blood biomarker or a combination of biomarkers can distinguish patients with AIS and ICH from patients with stroke and SM in the early phase after symptom onset in the prehospital setting. In addition, the kinetics of blood biomarkers in AIS and ICH patients will be investigated. Our goal is to evaluate new ways to reliably diagnose stroke in the prehospital setting and thus accelerate the application of evidence-based therapies to stroke patients.

A Managed Care System with Telemedicine Support for Neurological Emergencies.

OBJECTIVES: Telemedicine is frequently used to provide remote neurological expertise for acute stroke workup and was associated with better functional outcomes when combined with a stroke unit system-of-care. We investigated whether such system-of-care yields additional benefits when implemented on top of neurological competence already available onsite. METHODS: Quality improvement measures were implemented within a "hub-and-spoke" teleneurology network in 11 hospitals already provided with onsite or telestroke expertise. Measures included dedicated units for neurological emergencies, standardization of procedures, multiprofessional training, and quality-of-care monitoring. Intervention effects were investigated in a controlled study enrolling patients insured at 3 participating statutory health insurances diagnosed with acute stroke or other neurological emergencies. Outcomes during the intervention period between November 2017 and February 2020 were compared with those pre-intervention between October 2014 and March 2017. To control for temporal trends, we compared outcomes of patients with respective diagnoses in 11 hospitals of the same region. Primary outcome was the composite of up-to-90-day death, new disability with the need of ambulatory or nursing home care, expressed by adjusted hazard ratio (aHR). RESULTS: We included 1,418 patients post-implementation (55% female, mean age 76.7 ± 12.8 year) and 2,306 patients pre-implementation (56%, 75.8 ± 13.0 year, respectively). The primary outcome occurred in 479/1,418 (33.8%) patients post-implementation and in 829/2,306 (35.9%) pre-implementation. The aHR for the primary outcome was 0.89 (95% confidence interval [CI]: 0.79-0.99, p = 0.04) with no improvement seen in non-participating hospitals between post- versus pre-implementation periods (aHR 1.04; 95% CI: 0.95-1.15). INTERPRETATION: Implementation of a multicomponent system-of-care was associated with a lower risk of poor outcomes. ANN NEUROL 2023;93:511-521.

Effect of Mobile Stroke Unit Dispatch in all Patients with Acute Stroke or TIA.

OBJECTIVE: To determine the effect of additional mobile stroke unit (MSU) dispatch on functional outcomes among the full spectrum of stroke patients, regardless of subtype or potential contraindications to reperfusion therapies. METHODS: We used data from the nonrandomized Berlin-based B_PROUD study (02/2017 to 05/2019), in which MSUs were dispatched based solely on availability, and the linked B-SPATIAL stroke registry. All patients with final stroke or transient ischemic attack (TIA) diagnoses were eligible. The intervention under study was the additional dispatch of an MSU, an emergency physician-staffed ambulance equipped to provide prehospital imaging and thrombolytic treatment, compared to conventional ambulance alone. The primary outcome was the 3-month modified Rankin Scale (mRS) score, and the co-primary outcome was a 3-tiered disability scale. We identified confounders using directed acyclic graphs and obtained adjusted effect estimates using inverse probability of treatment weighting. RESULTS: MSUs were dispatched to 1,125 patients (mean age: 74 years, 46.5% female), while for 1,141 patients only conventional ambulances were dispatched (75 years, 49.9% female). After confounding adjustment, MSU dispatch was associated with more favorable 3-month mRS scores (common odds ratio [cOR] = 0.82; 95% confidence interval [CI]: 0.71-0.94). No statistically significant association was found with the co-primary outcome (cOR = 0.86; 9% CI: 0.72-1.01) or 7-day mortality (OR = 0.94; 95% CI: 0.59-1.48). INTERPRETATION: When considering the entire population of stroke/TIA patients, MSU dispatch improved 3-month functional outcomes without evidence of compromised safety. Our results are relevant for decision-makers since stroke subtype and treatment eligibility are unknown at time of dispatch. ANN NEUROL 2023;93:50-63.

Associations of clonal hematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke.

Clonal hematopoiesis (CH) is common among older people and is associated with an increased risk of atherosclerosis, inflammation, and shorter overall survival. Age and inflammation are major risk factors for ischemic stroke, yet the association of CH with risk of secondary vascular events and death is unknown. We investigated CH in peripheral blood DNA from 581 patients with first-ever ischemic stroke from the Prospective Cohort With Incident Stroke-Berlin study using error-corrected targeted sequencing. The primary composite end point (CEP) consisted of recurrent stroke, myocardial infarction, and all-cause mortality. A total of 348 somatic mutations with a variant allele frequency ≥1% were identified in 236 of 581 patients (41%). CH was associated with large-artery atherosclerosis stroke (P = .01) and white matter lesion (P < .001). CH-positive patients showed increased levels of proinflammatory cytokines, such as interleukin-6 (IL-6), interferon gamma, high-sensitivity C-reactive protein, and vascular cell adhesion molecule 1. CH-positive patients had a higher risk for the primary CEP (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.04-2.31; P = .03), which was more pronounced in patients with larger clones. CH clone size remained an independent risk factor (HR, 1.30; 95% CI, 1.04-1.62; P = .022) in multivariable Cox regression. Although our data show that, in particular, larger and TET2- or PPM1D-mutated clones are associated with increased risk of recurrent vascular events and death, this risk is partially mitigated by a common germline variant of the IL-6 receptor (IL-6R p.D358A). The CH mutation profile is accompanied by a proinflammatory profile, opening new avenues for preventive precision medicine approaches to resolve the self-perpetuating cycle of inflammation and clonal expansion.

Optimization of sensitivity and specificity of a biomarker-based blood test (LVOCheck-Opti): A protocol for a multicenter prospective observational study of patients suspected of having a stroke.

Introduction: Acute ischemic stroke (AIS) is a time-critical medical emergency. For patients with large-vessel occlusions (LVO), mechanical thrombectomy (MT) is the gold-standard treatment. Mobile Stroke Units (MSUs) provide on-site diagnostic capabilities via computed tomography (CT) and have been shown to improve functional outcomes in stroke patients, but are cost-efficient only in urban areas. Blood biomarkers have recently emerged as possible alternative to cerebral imaging for LVO diagnosis. Prehospital LVO diagnosis offers the potential to transport patients directly to centers that have MT treatment available. In this study, we assess the accuracy of combining two biomarkers, HFABP and NT-proBNP, with clinical indicators to detect LVO using ultra-early prehospital blood samples. The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00030399). Methods and analysis: We plan a multicenter prospective observational study with 800 patients with suspected stroke enrolled within 24 h of symptom onset. Study participants will be recruited at three sites (MSUs) in Berlin, Germany. Blood-samples will be taken pre-hospitally at the scene and tested for HFABP and NT-proBNP levels. Additional clinical data and information on final diagnosis will be collected and documented in an electronic case report form (eCRF). Sensitivity and specificity of the combination will be calculated through iterative permutation-response calculations. Discussion: This study aims to evaluate the diagnostic capabilities of a combination of the biomarkers HFABP and NT-proBNP in LVO prediction. In contrast to most other biomarker studies to date, by employing MSUs as study centers, ultra-early levels of biomarkers can be analyzed. Point-of-care LVO detection in suspected stroke could lead to faster treatment in both urban and rural settings and thus improve functional outcomes on a broader scale. Clinical trial registration: Deutsches Register klinischer Studien https://drks.de/search/de/trial/DRKS00030399, DRKS00030399.

Patient-Centered Outcomes in a Randomized Trial Investigating a Multimodal Prevention Program After Transient Ischemic Attack or Minor Stroke: The INSPiRE-TMS Trial.

BACKGROUND: The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes. METHODS: In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up. RESULTS: Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5-43.5); 36.1 after 2 years (95% CI, 13.1-59.7) and 29.6 (95% CI, 2.0-57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03-1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96-1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95-1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up. CONCLUSIONS: Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01586702.

Comparison of Mobile Stroke Unit With Usual Care for Acute Ischemic Stroke Management: A Systematic Review and Meta-analysis.

IMPORTANCE: So far, uncertainty remains as to whether there is sufficient cumulative evidence that mobile stroke unit (MSU; specialized ambulance equipped with computed tomography scanner, point-of-care laboratory, and neurological expertise) use leads to better functional outcomes compared with usual care. OBJECTIVE: To determine with a systematic review and meta-analysis of the literature whether MSU use is associated with better functional outcomes in patients with acute ischemic stroke (AIS). DATA SOURCES: MEDLINE, Cochrane Library, and Embase from 1960 to 2021. STUDY SELECTION: Studies comparing MSU deployment and usual care for patients with suspected stroke were eligible for analysis, excluding case series and case-control studies. DATA EXTRACTION AND SYNTHESIS: Independent data extraction by 2 observers, following the PRISMA and MOOSE reporting guidelines. The risk of bias in each study was determined using the ROBINS-I and RoB2 tools. In the case of articles with partially overlapping study populations, unpublished disentangled results were obtained. Data were pooled in random-effects meta-analyses. MAIN OUTCOMES AND MEASURES: The primary outcome was excellent outcome as measured with the modified Rankin Scale (mRS; score of 0 to 1 at 90 days). RESULTS: Compared with usual care, MSU use was associated with excellent outcome (adjusted odds ratio [OR], 1.64; 95% CI, 1.27-2.13; P < .001; 5 studies; n = 3228), reduced disability over the full range of the mRS (adjusted common OR, 1.39; 95% CI, 1.14-1.70; P = .001; 3 studies; n = 1563), good outcome (mRS score of 0 to 2: crude OR, 1.25; 95% CI, 1.09-1.44; P = .001; 6 studies; n = 3266), shorter onset-to-intravenous thrombolysis (IVT) times (median reduction, 31 minutes [95% CI, 23-39]; P < .001; 13 studies; n = 3322), delivery of IVT (crude OR, 1.83; 95% CI, 1.58-2.12; P < .001; 7 studies; n = 4790), and IVT within 60 minutes of symptom onset (crude OR, 7.71; 95% CI, 4.17-14.25; P < .001; 8 studies; n = 3351). MSU use was not associated with an increased risk of all-cause mortality at 7 days or at 90 days or with higher proportions of symptomatic intracranial hemorrhage after IVT. CONCLUSIONS AND RELEVANCE: Compared with usual care, MSU use was associated with an approximately 65% increase in the odds of excellent outcome and a 30-minute reduction in onset-to-IVT times, without safety concerns. These results should help guideline writing committees and policy makers.

Time-to-care metrics in patients with interhospital transfer for mechanical thrombectomy in north-east Germany: Primary telestroke centers in rural areas vs. primary stroke centers in a metropolitan area.

Background: Mechanical thrombectomy (MT) is highly effective in large vessel occlusion (LVO) stroke. In north-east Germany, many rural hospitals do not have continuous neurological expertise onsite and secondary transport to MT capable comprehensive stroke centers (CSC) is necessary. In metropolitan areas, small hospitals often have neurology departments, but cannot perform MT. Thus, interhospital transport to CSCs is also required. Here, we compare time-to-care metrics and outcomes in patients receiving MT after interhospital transfer from primary stroke centers (PCSs) to CSCs in rural vs. metropolitan areas. Methods: Patients from ten rural telestroke centers (RTCs) and nine CSCs participated in this study under the quality assurance registry for thrombectomies of the Acute Neurological care in North-east Germany with TeleMedicine (ANNOTeM) telestroke network. For the metropolitan area, we included patients admitted to 13 hospitals without thrombectomy capabilities (metropolitan primary stroke centers, MPSCs) and transferred to two CSCs. We compared groups regarding baseline variables, time-to-care metrics, clinical, and technical outcomes. Results: Between October 2018 and June 2022, 50 patients were transferred from RTCs within the ANNOTeM network and 42 from MPSCs within the Berlin metropolitan area. RTC patients were older (77 vs. 72 yrs, p = 0.05) and had more severe strokes (NIHSS 17 vs. 10 pts., p < 0.01). In patients with intravenous thrombolysis (IVT; 34.0 and 40.5%, respectively), time from arrival at the primary stroke center to start of IVT was longer in RTCs (65 vs. 37 min, p < 0.01). However, RTC patients significantly quicker underwent groin puncture at CSCs (door-to-groin time: 42 vs. 60 min, p < 0.01). Despite longer transport distances from RTCs to CSCs (55 vs. 22 km, p < 0.001), there was no significant difference of times between arrival at the PSC and groin puncture (210 vs. 208 min, p = 0.96). In adjusted analyses, there was no significant difference in clinical and technical outcomes. Conclusion: Despite considerable differences in the setting of stroke treatment in rural and metropolitan areas, overall time-to-care metrics were similar. Targets of process improvement should be door-to-needle times in RTCs, transfer organization, and door-to-groin times in CSCs wherever such process times are above best-practice models.

Cardiac Troponin and Recurrent Major Vascular Events after Minor Stroke or Transient Ischemic Attack.

OBJECTIVE: This study was undertaken to investigate whether high-sensitivity cardiac troponin T (hs-cTnT) is associated with major adverse cardiovascular events (MACE) in patients with minor stroke or transient ischemic attack (TIA), and whether this association differs after risk stratification based on the Age, Blood Pressure, Clinical Features, Duration of Symptoms, Diabetes (ABCD2 ) score. METHODS: INSPiRE-TMS was a randomized controlled trial allocating patients with minor stroke or TIA to an intensified support program or conventional care. In this post hoc analysis, participants were categorized using hs-cTnT levels (5th generation; Roche Diagnostics, Manheim, Germany; 99th percentile upper reference limit [URL] = 14ng/l). Vascular risk was stratified using the ABCD2 score (lower risk = 0-5 vs higher risk = 6-7). Cox proportional hazard regression was performed using covariate adjustment and propensity score matching (PSM) for the association between hs-cTnT and MACE (stroke/nonfatal coronary event/vascular death). RESULTS: Among 889 patients (mean age = 70 years, 37% female), MACE occurred in 153 patients (17.2%) during a mean follow-up of 3.2 years. hs-cTnT was associated with MACE (9.3%/yr, >URL vs 4.4%/yr, ≤URL, adjusted hazard ratio [HR] = 1.63 [95% confidence interval (CI) = 1.13-2.35], adjusted HR [Q4 vs Q1 ] = 2.57 [95% CI = 1.35-4.97], adjusted HR [log-transformed] = 2.31 [95% CI = 1.37-3.89]). This association remained after PSM (adjusted HR = 1.76 [95% CI = 1.14-2.72]). There was a significant interaction between hs-cTnT and ABCD2 category for MACE occurrence (pinteraction  = 0.04). In the lower risk category, MACE rate was 9.5%/yr in patients with hs-cTnT > URL, which was higher than in those ≤URL (3.8%/yr) and similar to the overall rate in the higher risk category. INTERPRETATION: hs-cTnT levels are associated with incident MACE within 3 years after minor stroke or TIA and may help to identify high-risk individuals otherwise deemed at lower risk based on the ABCD2 score. If confirmed in independent validation studies, this might warrant intensified secondary prevention measures and cardiac diagnostics in stroke patients with elevated hs-cTnT. ANN NEUROL 2021;90:901-912.

Association Between Dispatch of Mobile Stroke Units and Functional Outcomes Among Patients With Acute Ischemic Stroke in Berlin.

Importance: Effects of thrombolysis in acute ischemic stroke are time-dependent. Ambulances that can administer thrombolysis (mobile stroke units [MSUs]) before arriving at the hospital have been shown to reduce time to treatment. Objective: To determine whether dispatch of MSUs is associated with better clinical outcomes for patients with acute ischemic stroke. Design, Setting, and Participants: This prospective, nonrandomized, controlled intervention study was conducted in Berlin, Germany, from February 1, 2017, to October 30, 2019. If an emergency call prompted suspicion of stroke, both a conventional ambulance and an MSU, when available, were dispatched. Functional outcomes of patients with final diagnosis of acute cerebral ischemia who were eligible for thrombolysis or thrombectomy were compared based on the initial dispatch (both MSU and conventional ambulance or conventional ambulance only). Exposure: Simultaneous dispatch of an MSU (computed tomographic scanning with or without angiography, point-of-care laboratory testing, and thrombolysis capabilities on board) and a conventional ambulance (n = 749) vs conventional ambulance alone (n = 794). Main Outcomes and Measures: The primary outcome was the distribution of modified Rankin Scale (mRS) scores (a disability score ranging from 0, no neurological deficits, to 6, death) at 3 months. The coprimary outcome was a 3-tier disability scale at 3 months (none to moderate disability; severe disability; death) with tier assignment based on mRS scores if available or place of residence if mRS scores were not available. Common odds ratios (ORs) were used to quantify the association between exposure and outcome; values less than 1.00 indicated a favorable shift in the mRS distribution and lower odds of higher levels of disability. Results: Of the 1543 patients (mean age, 74 years; 723 women [47%]) included in the adjusted primary analysis, 1337 (87%) had available mRS scores (primary outcome) and 1506 patients (98%) had available the 3-tier disability scale assessment (coprimary outcome). Patients with an MSU dispatched had lower median mRS scores at month 3 (1; interquartile range [IQR], 0-3) than did patients without an MSU dispatched (2; IQR, 0-3; common OR for worse mRS, 0.71; 95% CI, 0.58-0.86; P < .001). Similarly, patients with an MSU dispatched had lower 3-month coprimary disability scores: 586 patients (80.3%) had none to moderate disability; 92 (12.6%) had severe disability; and 52 (7.1%) had died vs patients without an MSU dispatched: 605 (78.0%) had none to moderate disability; 103 (13.3%) had severe disability; and 68 (8.8%) had died (common OR for worse functional outcome, 0.73, 95% CI, 0.54-0.99; P = .04). Conclusions and Relevance: In this prospective, nonrandomized, controlled intervention study of patients with acute ischemic stroke in Berlin, Germany, the dispatch of mobile stroke units, compared with conventional ambulances alone, was significantly associated with lower global disability at 3 months. Clinical trials in other regions are warranted.

Probability assessment of intracerebral hemorrhage in prehospital emergency patients.

BACKGROUND: Routing of patients with intracerebral hemorrhage (ICH) and acute ischemic stroke (AIS) to the most appropriate hospital is challenging for emergency medical services particularly when specific treatment options are only provided by specialized hospitals and determination of the exact diagnosis is difficult. We aimed to develop a prehospital score - called prehospital-intracerebral hemorrhage score (ph-ICH score) - to assist in discriminating between both conditions. METHODS: The ph-ICH score was developed with data from patients treated aboard a mobile stroke unit in Berlin, Germany, between 2011 and 2013 (derivation cohort) and in 2018 (validation cohort). Diagnosis of ICH or AIS was established using clinical data and neuroradiological cerebral imaging. Diagnostic accuracy was measured with significance testing, Cohen's d and receiver-operating-characteristics. RESULTS: We analyzed 416 patients (32 ICH, 224 AIS, 41 transient ischemic attack, 119 stroke mimic) in the derivation cohort and 285 patients (33 ICH and 252 AIS) in the validation cohort. Systolic blood pressure, level of consciousness and severity of neurological deficits (i. e. certain items of the National Institutes of Health Stroke Scale) were used to calculate the ph-ICH score that showed higher values in the ICH compared to the AIS group (derivation cohort: 1.8 ± 1.2 vs. 1.0 ± 0.9 points; validation cohort: 1.8 ± 0.9 vs. 0.8 ± 0.7 points; d = 0.9 and 1.4, both p < 0.01). Receiver-operating-characteristics showed fair and good accuracy with an area under the curve of 0.71 for the derivation and 0.81 for the validation cohort. CONCLUSIONS: The ph-ICH score can assist medical personnel in the field to assess the likelihood of ICH and AIS in emergency patients.

Stroke Admissions, Stroke Severity, and Treatment Rates in Urban and Rural Areas During the COVID-19 Pandemic.

Background: Many regions worldwide reported a decline of stroke admissions during the early phase of the coronavirus disease 2019 (COVID-19) pandemic. It remains unclear whether urban and rural regions experienced similar declines and whether deviations from historical admission numbers were more pronounced among specific age, stroke severity or treatment groups. Methods: We used registry datasets from (a) nine acute stroke hospitals in Berlin, and (b) nine hospitals from a rural TeleNeurology network in Northeastern Germany for primary analysis of 3-week-rolling average of stroke/TIA admissions before and during the COVID-19 pandemic. We compared course of stroke admission numbers with regional cumulative severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) infections. In secondary analyses, we used emergency department logs of the Berlin Charité University hospital to investigate changes in age, stroke severity, and thrombolysis/thrombectomy frequencies during the early regional Sars-CoV-2 spread (March and April 2020) and compared them with preceding years. Results: Compared to past years, stroke admissions decreased by 20% in urban and 20-25% in rural hospitals. Deviations from historical averages were observable starting in early March and peaked when numbers of regional Sars-CoV-2 infections were still low. At the same time, average admission stroke severity and proportions of moderate/severe strokes (NIHSS >5) were 20 and 20-40% higher, respectively. There were no relevant deviations observed in proportions of younger patients (<65 years), proportions of patients with thrombolysis, or number of thrombectomy procedures. Stroke admissions at Charité subsequently rebounded and reached near-normal levels after 4 weeks when the number of new Sars-CoV-2 infections started to decrease. Conclusions: During the early pandemic, deviations of stroke-related admissions from historical averages were observed in both urban and rural regions of Northeastern Germany and appear to have been mainly driven by avoidance of admissions of mildly affected stroke patients.

A support programme for secondary prevention in patients with transient ischaemic attack and minor stroke (INSPiRE-TMS): an open-label, randomised controlled trial.

BACKGROUND: Patients with recent stroke or transient ischaemic attack are at high risk for a further vascular event, possibly leading to permanent disability or death. Although evidence-based treatments for secondary prevention are available, many patients do not achieve recommended behavioural modifications and pharmaceutical prevention targets in the long-term. We aimed to investigate whether a support programme for enhanced secondary prevention can reduce the frequency of recurrent vascular events. METHODS: INSPiRE-TMS was an open-label, multicentre, international randomised controlled trial done at seven German hospitals with acute stroke units and a Danish stroke centre. Patients with non-disabling stroke or transient ischaemic attack within 2 weeks from study enrolment and at least one modifiable risk factor (ie, arterial hypertension, diabetes, atrial fibrillation, or smoking) were included. Computerised randomisation was used to allocate patients (1:1) either to the support programme in addition to conventional care or to conventional care alone. The support programme used feedback and motivational interviewing strategies with eight outpatient visits over 2 years aiming to improve adherence to secondary prevention targets. The primary outcome was the composite of major vascular events consisting of stroke, acute coronary syndrome, and vascular death, assessed in the intention-to-treat population (all patients who underwent randomisation, did not withdraw study participation, and had at least one follow-up). Outcomes were assessed at annual follow-ups using time-to-first-event analysis. All-cause death was monitored as a safety outcome. This trial is registered with ClinicalTrials.gov, NCT01586702. FINDINGS: From Aug 22, 2011, to Oct 30, 2017, we enrolled 2098 patients. Of those, 1048 (50·0%) were randomly assigned to the support programme group and 1050 (50·0%) patients were assigned to the conventional care group. 1030 (98·3%) patients in the support group and 1042 (99·2%) patients in the conventional care group were included in the intention-to-treat analysis. The mean age of analysed participants was 67·4 years and 700 (34%) were women. After a mean follow-up of 3·6 years, the primary outcome of major vascular events had occurred in 163 (15·8%) of 1030 patients of the support programme group and in 175 (16·8%) of 1042 patients of the conventional care group (hazard ratio [HR] 0·92, 95% CI 0·75-1·14). Total major vascular event numbers were 209 for the support programme group and 225 for the conventional care group (incidence rate ratio 0·93, 95% CI 0·77-1·12; p=0·46) and all-cause death occurred in 73 (7·1%) patients in the support programme group and 85 (8·2%) patients in the conventional care group (HR 0·85, 0·62-1·17). More patients in the support programme group achieved secondary prevention targets (eg, in 1-year-follow-up 52% vs 42% [p<0·0001] for blood pressure, 62% vs 54% [p=0·0010] for LDL, 33% vs 19% [p<0·0001] for physical activity, and 51% vs 34% [p=0·0010] for smoking cessation). INTERPRETATION: Provision of an intensified secondary prevention programme in patients with non-disabling stroke or transient ischaemic attack was associated with improved achievement of secondary prevention targets but did not lead to a significantly lower rate of major vascular events. Further research is needed to investigate the effects of support programmes in selected patients who do not achieve secondary prevention targets soon after discharge. FUNDING: German Federal Ministry of Education and Research, Pfizer, and German Stroke Foundation.

Predictive value of acute EEG measurements for seizures and epilepsy after stroke using a dry cap electrode EEG system - Study design and proof of concept.

The development of seizures is a common complication in patients with stroke. A recent study suggests that electroencephalography (EEG) could be useful to predict the occurrence of seizures after stroke. However, EEG is not routinely performed in the follow-up after stroke. We present the design and proof of concept of a large prospective cohort study in which we seek to evaluate the predictive usefulness of a single dry cap EEG measurement in the acute phase after stroke or transient ischemic attack (TIA) with respect to the development of poststroke epilepsy (PSE). In patients with ischemic stroke (IS), TIA, or intracerebral hemorrhage (ICH), an acute EEG measurement using a dry cap electrode EEG (dEEG) system is performed within 7 days of symptom onset. Electroencephalography data will be analyzed quantitatively and qualitatively looking for background asymmetry, different band power ratios, and epileptiform activity. The development of seizures will be assessed repeatedly during the first 2 years after stroke or TIA using a validated questionnaire. Results from the pilot phase of 11 patients showed that the dry cap EEG measurements in patients with acute stroke and TIA are feasible. In comparison with conventional EEG, a higher proportion of noise and artifacts was detected. This article is part of the Special Issue "Seizure & Stroke".

Quantitative and Qualitative EEG as a Prediction Tool for Outcome and Complications in Acute Stroke Patients.

Currently, the relevance of EEG measurements in acute stroke patients is considered low in clinical practice. However, recent studies on the predictive value of EEG measurements after stroke for various outcomes may increase the role of EEG in patients with stroke. We aimed to review the current literature on the utility of EEG measurements after stroke as a tool to predict outcome and complications, focusing on studies in which the EEG measurement was performed in the acute phase after the event and in which long-term outcome measures were reported. In our literature review, we identified 4 different outcome measures (functional outcome, mortality, development of post-stroke cognitive decline, and development of post-stroke epilepsy) where studies on the utility of acute EEG measurements exist. There is a large body of evidence for the prediction of functional outcome, in which a multitude of associated quantitative and qualitative EEG parameters are described. In contrast, only few studies focus on mortality as outcome parameter. We found studies of high methodical quality on the prediction of post-stroke cognitive decline, though the number of patients in these studies often was small. The role of EEG as a prediction tool for seizures and epilepsy after stroke could increase after a recently published study, especially if its result can be incorporated into already existing post-stroke epilepsy prediction tools. In summary, EEG is useful for the prediction of functional outcome, mortality, development of post-stroke cognitive decline and epilepsy, even though there is a discrepancy between the large amount of studies on EEG in acute stroke patients and its underuse in clinical practice.

Telemedicine in Prehospital Acute Stroke Care.

Background Mobile stroke units ( MSU s), equipped with an integrated computed tomography scanner, can shorten time to thrombolytic treatment and may improve outcome in patients with acute ischemic stroke. Original (German) MSU s are staffed by neurologists trained as emergency physicians, but patient assessment and treatment decisions by a remote neurologist may offer an alternative to neurologists aboard MSU . Methods and Results Remote neurologists examined and assessed emergency patients treated aboard the MSU in Berlin, Germany. Audiovisual quality was rated by the remote neurologist from 1 (excellent) to 6 (insufficient), and duration of video examinations was assessed. We analyzed interrater reliability of diagnoses, scores on the National Institutes of Health Stroke Scale and treatment decisions (intravenous thrombolysis) between the MSU neurologist and the remote neurologist. We included 90 of 103 emergency assessments (13 patients were excluded because of either failed connection, technical problems, clinical worsening during teleconsultation, or missing data in documentation) in this study. The remote neurologist rated audiovisual quality with a median grade for audio quality of 3 (satisfactory) and for video quality of 2 (good). Mean time for completion of teleconsultations was about 19±5 minutes. The interrater reliabilities between the onboard and remote neurologist were high for diagnoses (Cohen's κ=0.86), National Institutes of Health Stroke Scale sum scores (intraclass correlation coefficient, 0.87) and treatment decisions (16 treatment decisions agreed versus 2 disagreed; Cohen's κ=0.93). Conclusions Remote assessment and treatment decisions of emergency patients are technically feasible with satisfactory audiovisual quality. Agreement on diagnoses, neurological examinations, and treatment decisions between onboard and remote neurologists was high.

Evaluation of a score for the prehospital distinction between cerebrovascular disease and stroke mimic patients.

BACKGROUND: Patients with a sudden onset of focal neurological deficits consistent with stroke, who turn out to have alternative conditions, have been labeled stroke mimics. AIMS: We assessed a recently validated telemedicine-based stroke mimic score (TeleStroke mimic score; TM-score) and individual patient characteristics with regard to its discriminative value between cerebrovascular disease and stroke mimic patients in the in-person, pre-hospital setting. METHODS: We evaluated patients cared for in a mobile stroke unit in Berlin, Germany. We investigated whether the TM-score (comprising six parameters), Face Arm Speech Time test, and individual patient characteristics were able to differentiate cerebrovascular disease from stroke mimic patients. RESULTS: We included 423 patients (299 (70.7%) cerebrovascular disease and 124 (29.3%) stroke mimic) in the final analysis. A TM-score > 30 indicated a high probability of a cerebrovascular disease and a score ≤15 of a stroke mimic. The TM-score performed well to identify stroke mimics (area under the curve of 0.74 under receiver-operating characteristic curve analysis). The cerebrovascular disease patients were older (74.8 vs. 69.8 years, p = 0.001), had more often severe strokes (NIHSS > 14 25.8% vs. 11.3%, p = 0.001), presented more often with weakness of the face (70.9% vs. 42.7%, p = 0.001) or arm (60.9% vs. 33.9%, p = 0.001), dysarthria (59.5% vs. 40.3%, p < 0.001), history of atrial fibrillation (38.1% vs. 21.0%, p = 0.001), arterial hypertension (78.9% vs. 53.2%, p < 0.001), and less often with seizure (0.7% vs. 21.0%, p < 0.001). CONCLUSIONS: The TM-score and certain patient characteristics can help paramedics and emergency physicians in the field to identify stroke mimic patients and select the most appropriate hospital destination.