Endothelial receptor proteins in acute venous thrombosis and delayed thrombus resolution in cerebral sinus vein thrombosis.

BACKGROUND AND PURPOSE: Cerebral sinus venous thrombosis (CSVT) is a rare but life-threatening disease and its diagnosis remains challenging. Blood biomarkers, including D-Dimer are currently not recommended in guidelines. Soluble endothelial receptor proteins (sICAM-1, sPECAM-1 and sVCAM-1) have been shown to be promising diagnostic biomarkers in deep vein thrombosis (DVT) and pulmonary embolism (PE). Therefore, we examined endothelial receptor proteins as potential biomarkers for detecting CSVT. METHODS: In this bi-centre, prospective study, we quantified D-Dimer as well as sICAM-1, sPECAM-1 and sVCAM-1 in plasma of patients with clinically suspected CSVT managed in the neurological emergency department (ED) of a tertiary care hospital. All patients underwent cerebral magnetic resonance imaging (MRI) and were followed up after 3, 6 and 12 months to detect thrombus resolution. RESULTS: Twenty-four out of 75 (32%) patients with clinically suspected CSVT presenting with headache to the ED were diagnosed with acute CSVT. These patients had a mean age of 45 ± 16 years and 78% were female. In patients with CSVT, mean baseline D-dimer (p < 0.001) and sPECAM-1 (p < 0.001) were significantly higher compared to patients without CSVT. The combination of D-Dimer and sPECAM-1 yielded the best ROC-AUC (0.994; < 0.001) with a negative predictive value of 95.7% and a positive predictive value of 95.5%. In addition, higher baseline sPECAM-1 levels (> 198 ng/ml) on admission were associated with delayed venous thrombus resolution at 3 months (AUC = 0.83). CONCLUSION: sPECAM-1 in combination with D-Dimer should be used to improve the diagnostic accuracy of acute CSVT and sPECAM-1 may predict long-term outcome of CSVT. Confirmatory results are needed in other settings in order to show their value in the management concept of CSVT patients.

Effect of concomitant usage of alteplase and mechanical thrombectomy for M1 middle cerebral artery occlusion on clinical outcome: a retrospective analysis of 457 patients from two centers.

Introduction: Endovascular thrombectomy (EVT) and concomitant usage of intravenous alteplase (alteplase) in large vessel occlusion stroke may produce unwanted excess intracerebral hemorrhage (ICH). Whether this applies specifically to isolated occlusion of the M1 segment of the middle cerebral artery (MCA) is unknown. Methods: A retrospective study from two tertiary thrombectomy centers. ICH was determined according to Heidelberg Bleeding Classification (HBC). Factors associated with the occurrence of ICH in EVT alone vs. EVT with alteplase were evaluated using logistic regression analysis. Factors related to the clinical outcome as determined with a modified Rankin scale (mRS) were investigated with univariate and adjusted multivariate logistic regression analysis. The interaction between clinical variables and the usage of alteplase on the occurrence of ICH was evaluated. Results: Any ICH occurred in 156/457 (34.1%) patients Class 1a bleeding in 37 (8.1%), type 2 in 45 (9.8%) Class 1c in 22 (4.8%), Class 2 in 25 (5.5%), and Class 3 (extraparenchymal) in 27 (5.9%). ICH occurred in similar frequency between alteplase-treated patients vs. EVT alone (85/262 [32%] vs. 71/195 [36%]; OR 1.19 (95% CI 0.81-1.76). After adjustment, odds for clinical outcome were lower in ICH patients (OR 0.44 [95% CI 0.25-0.74]), p = 0.002). Higher ICH rate was associated with more EVT steps (p for interaction -0.005), and usage of only stent-retriever (p for interaction =0.005). Conclusion: Utilization of alteplase alongside EVT for MCA M1 occlusion did not result in excessive ICH occurrences or clinical deterioration.

Thrombus migration in emergent M1 middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Thrombus migration (TM) is a well-established phenomenon in patients with intracranial vessel occlusion, particularly in those who receive alteplase. However, the relationship between TM, reperfusion success, and clinic-radiological outcomes is still being determined. This study aimed to describe the various outcomes in the event of TM in patients with M1 middle cerebral artery (M1 MCA) occlusion. MATERIALS AND METHODS: The study involved a retrospective analysis of patients undergoing endovascular thrombectomy (EVT) due to M1 MCA occlusion from two tertiary centers between January 2015 and December 2020. The proximal positions of thrombi were measured using a curve tool on CT or MR angiography before EVT. Subsequently, measurements were taken on angiographic imaging. Patients were grouped based on the amount of difference between the two measurements: growth (≤ - 10 mm), stability (> -10 mm and ≤ 10 mm), migration (> 10 mm), and resolution. RESULTS: A total of 463 patients (266 [57%] females, median 76 [interquartile range IQR: 65-83] years) were analyzed. Of them, 106 (22.8%) expressed any degree of TM. In multivariate ordinal regression analysis, the alteplase was significantly associated with TM (t = 2.192, p = 0.028), as was the greater interval from first imaging to angiography (t = 2.574, p = 0.010). In multivariate logistical regression analysis, the good clinical outcome measured by the modified Rankin scale (0-2) was not associated with TM status. CONCLUSIONS: Thrombus migration within the M1 MCA segment occurs in almost a quarter of patients, is associated with alteplase administration, and is mainly irrelevant to radiological and clinical outcome.

Risk of stroke in patients with prior VKA or DOAC: A population-based real-world registry analysis.

INTRODUCTION: To date, risk assessment of suffering ischemic and hemorrhagic stroke in individuals under oral anticoagulation (OAC) is limited to hospital-based cohorts and patients with atrial fibrillation. PATIENTS AND METHODS: Through the combination of three individual datasets, (1) the population-based Tyrolean Stroke Pathway database, prospectively documenting all (unselected) stroke patients in the entire federal state of the Tyrol and (2) nation-wide prescription data, detailing each reimbursed prescription in Austria as well as (3) the Austrian Stroke Unit Registry, a nation-wide registry comprising data on all patients admitted to any of the 38 stroke units in Austria, we assessed risk of stroke in patients with prior oral anticoagulation and compared characteristics of patients taking direct oral anticoagulants and Vitamin-K-Antagonists. RESULTS: In Austria, oral anticoagulant prescription reimbursements increased from 292,475 in 2015 to 389,407 in 2021. In the Tyrol, prior oral anticoagulation treatment was evident in 586 of 3861 (15.2%) patients with ischemic and 131 of 523 (25.0%) with hemorrhagic stroke, with 20% and 35% of those stroke patients respectively having prior oral anticoagulation due to other indications than non-valvular atrial fibrillation. Considering prescription rates, treatment with direct oral anticoagulants was associated with a reduced stroke risk compared to Vitamin-K-Antagonists, especially in ischemic (1.05% vs 0.62%; RR 0.59, p < 0.001) but also in hemorrhagic stroke, even if less pronounced (0.21% vs 0.14%; RR 0.68, p = 0.06). In Austria, prior intake of direct oral anticoagulants was associated with lower risk of suffering acute large vessel occlusion stroke (RR 0.79, p = 0.003). DISCUSSION AND CONCLUSIONS: One in seven patients suffering ischemic and one in four suffering hemorrhagic stroke had prior oral anticoagulation treatment. Both ischemic and hemorrhagic strokes are less frequent in those with direct oral anticoagulant intake compared to those taking Vitamin-K-Antagonists. Establishment of clear standard operating procedures on how to best care for acute stroke patients with oral anticoagulation is essential.

Endovascular stroke therapy outside core working hours in a nationwide stroke system.

BACKGROUND: Endovascular therapy (EVT) has been established as a major component in the acute treatment of large vessel occlusion stroke. However, it is unclear whether outcome and other treatment-related factors differ if patients are treated within or outside core working hours. METHODS: We analyzed data from the prospective nationwide Austrian Stroke Unit Registry capturing all consecutive stroke patients treated with EVT between 2016 and 2020. Patients were trichotomized according to the time of groin puncture into treatment within regular working hours (08:00-13:59), afternoon/evening (14:00-21:59) and night-time (22:00-07:59). Additionally, we analyzed 12 EVT treatment windows with equal patient numbers. Main outcome variables included favorable outcome (modified Rankin Scale scores of 0-2) 3 months post-stroke as well as procedural time metrics, recanalization status and complications. RESULTS: We analyzed 2916 patients (median age 74 years, 50.7% female) who underwent EVT. Patients treated within core working hours more frequently had a favorable outcome (42.6% vs 36.1% treated in the afternoon/evening vs 35.8% treated at night-time; p=0.007). Similar results were found when analyzing 12 treatment windows. All these differences remained significant in multivariable analysis adjusting for outcome-relevant co-factors. Onset-to-recanalization time was considerably longer outside core working hours, which was mainly explained by longer door-to-groin time (p<0.001). There was no difference in the number of passes, recanalization status, groin-to-recanalization time and EVT-related complications. CONCLUSIONS: The findings of delayed intrahospital EVT workflows and worse functional outcomes outside core working hours in this nationwide registry are relevant for optimization of stroke care, and might be applicable to other countries with similar settings.

Dabigatran in Cerebral Sinus Vein Thrombosis and Thrombophilia.

BACKGROUND AND PURPOSE: Thrombophilic gene alterations are a major risk factor for cerebral sinus vein thrombosis (CSVT). Up to 30% of all patients with cerebral sinus vein thrombosis (CSVT) are found to have thrombophilic defects such as prothrombin mutation (PTM) or factor V Leiden (FVL). Their repercussions on the plasma levels of dabigatran etexilate are unclear. In this prospective case-control study, we aimed to investigate whether thrombophilia in CSVT has an influence on dabigatran peak-plasma levels. METHODS: We monitored 10 patients over 12 months with acute CSVT, genetic thrombophilia with off-label use of dabigatran etexilate 150 mg twice a day and measured dabigatran peak-plasma levels and radiological outcome. We also monitored patients without genetic thrombophilia with dabigatran etexilate 150 mg twice a day and compared the efficiency and dabigatran peak-plasma levels. RESULTS: Patients with homozygote PTM had significantly lower dabigatran peak concentration compared to patients with FVL or the control group (23 ± 4.2 vs. 152.3 ± 27.5 and 159.6 ± 63.08; p-value ≤ 0.05) There was no significant difference in dabigatran etexilate plasma levels between the heterozygote PTM group compared to patients with FVL or the control group (p = 0.29). There was no correlation between dabigatran peak concentration and delayed thrombus dissolution. CONCLUSIONS: Dabigatran peak concentration was stable in patients with heterozygote FVL and heterozygote PTM, but not in homozygote PTM, compared to controls. Genetic screening for thrombophilia in patients after CSVT may be useful to make patient tailored therapeutic decisions regarding oral anticoagulation and may decrease thrombotic events.

Value of ultrasound fusion imaging in detecting vascular cerebral white matter pathology.

BACKGROUND: Transcranial sonography is beside magnetic resonance imaging (MRI) and computed tomography, a well-established imaging method for evaluation of brain parenchyma and already implicated in various neurological disorders as bed-side investigation possibility in clinical routine. The aim of this study was the qualitative assessment detecting vascular white matter hyperintensities (WMHs), with ultrasound fusion-imaging technique (UFI) and to find the optimal location for their visualization in accordance to the grade of WMHs and to possibly providing a standardized protocol for clinical use. RESULTS: 29 patients with WMHs of variable degree quantified according to Fazekas grading scale (n = 13 I; n = 9 II; n = 7 III) and 11 subjects with normal findings on MRI were identified for further analysis. Ultrasound images were analyzed to a standardized protocol and predefined anatomical landmarks. UFI could visualize the MRI-verified WMHs in 147 of 161 localizations (91%). The overall ultrasound detection rate of WMHs increased with higher degree of WMHs burden (I:85%, II:94%, III:97%). The highest sensitivity was achieved at the contralateral central part (CPc) (97%) of the lateral ventricle. The inter-rater analysis between 2 independent raters, who were blinded to the patient's diagnosis and assessed only the B-mode ultrasound images, indicated an 86% agreement with an overall moderate strength of agreement (κ: 0.489, p < 0.0005) for all localizations. The highest accordance within raters was shown at the CPc; 92% (κ: 0.645, p < 0.0005). CONCLUSIONS: This explorative study describes prospectively the ultrasound detection of periventricular vascular WMHs based on MRI lesions using UFI. Transcranial ultrasound (TCS) could serve as an additional screening opportunity for the detection of incidental WMLs during routine TCS investigations to initiate early vascular risk factor modification in primary prevention.

Protocol for the Exercise, Cancer and Cognition - The ECCO-Study: A Randomized Controlled Trial of Simultaneous Exercise During Neo-/Adjuvant Chemotherapy in Breast Cancer Patients and Its Effects on Neurocognition.

Introduction: Epidemiological studies show that increased physical activity is linked to a lower risk of breast cancer and mortality. As a result, physical activity can significantly improve patients' quality of life (QOL) both during and after therapy.Many breast cancer patients demonstrate a decrease in cognitive capacity, referred to as the symptom-complex cancer related cognitive impairment (CRCI). Most frequently reported impairments are mild to moderate deficits in processing speed, attention, memory, and executive functions. Cognitive symptoms persist for months or even years, following medical treatment in roughly 35% of afflicted people, impairing everyday functioning, limiting the ability to return to work, and lowering the overall QOL. Recent studies point toward a key role of inflammatory pathways in the CRCI genesis. Attention to physical activity as a potential supportive care option is therefore increasing. However, evidence for the positive effects of exercise on preventing CRCI is still lacking. Patients and Methods: Against this background, the prospective, two-arm, 1:1 randomized, controlled trial investigates the influence of first line chemotherapy accompanied by exercise training on preventing CRCI in 126 patients with breast cancer at the local University Hospital. The study will evaluate biomarkers and secondary assessments suspected to be involved in the pathogenesis of CRCI in addition to objective (primary outcome) and subjective cognitive function. CRCI is believed to be connected to either functional and/or morphological hippocampal damage due to chemotherapy. Thus, cerebral magnetic resonance imaging (MRI) and hippocampal volume measurements are performed. Furthermore, a specific neuropsychological test battery for breast cancer patients has been developed to detect early signs of cognitive impairments in patients and to be integrated into practice. Discussion: This study will explore how a long-term supervised exercise intervention program might prevent CRCI, enables optimization of supportive care and objectifies limits of psychological and physical resilience in breast cancer patients during and after chemotherapy treatment. Trial Registration: ClinicalTrials.gov: Identifier: NCT04789187. Registered on 09 March 2021.

Caregiver burden in patients with behavioural variant frontotemporal dementia and non-fluent variant and semantic variant primary progressive aphasia.

Studies on caregiver burden in patients with frontotemporal lobar degeneration are rare, differ methodologically and show variable results. Single center longitudinal pilot study on caregiver burden and potential risk factors in patients with behavioural variant frontotemporal dementia (bvFTD) and semantic (svPPA) and non-fluent variants (nfvPPA) primary progressive aphasia. Forty-six bvFTD, nine svPPA, and six nfvPPA patients and caring relatives were analysed for up to 2 years using the Mini-Mental State Examination as global measure for cognitive performance, Frontal Assessment Battery (frontal lobe functions), Frontal Behavioural Inventory (personality and behaviour), Neuropsychiatric Inventory (dementia-related neuropsychiatric symptoms), Barthel Index and Lawton IADL Scale (basic and instrumental activities of daily living), the Caregiver Strain Index (CSI), and in most participants also the Zarit Burden Interview (ZBI). CSI baseline sum scores were highest in bvFTD (mean ± SD 5.5 ± 3.4, median 5, IQR 6), intermediate in svPPA (2.9 ± 2.3; 3; 3.5) and low in nfvPPA (1.6 ± 2.1; 1; 2). Similar differences of caregiver burden were found using the ZBI. During follow-up, CSI and ZBI sum scores deteriorated in svPPA, not in bvFTD and nfvPPA, and correlated significantly with personality and behaviour, neuropsychiatric symptoms, caregiver age, and instrumental, but not basic activities of daily living, Mini-Mental State Examination scores or frontal lobe functions. This study reveals differences in caregiver burden in variants of frontotemporal lobar degeneration. Caregivers should be systematically asked for caregiver burden from the time of the diagnosis to provide comprehensive support in time.

Autotitrating Bilevel Positive Airway Pressure in Large Vessel Steno-Occlusive Stroke Patients With Suspected Sleep Apnea: A Multicenter Randomized Controlled Study.

Background: We hypothesized that autotitrating bilevel positive airway pressure (auto-BPAP) favorably affects short-term clinical outcomes in hyperacute ischemic stroke. Methods: In a multicenter, randomized, controlled trial patients with large vessel steno-occlusive stroke and clinically suspected sleep apnea were allocated to auto-BPAP or standard stroke care alone. Auto-BPAP was initiated within 24 h from stroke onset and performed over 48 h during diurnal and nocturnal sleep. Sleep apnea was assessed using cardiorespiratory polygraphy. Primary endpoint was early neurological improvement on National Institutes of Health Stroke Scale (NIHSS) score at 72 h. Safety and tolerability of BPAP, functional independence [modified Rankin Scale (mRS) 0-2], stroke recurrence, and mortality at 90 days were assessed. Results: Due to low recruitment, the trial was prematurely stopped after 24 patients had been randomized (auto-BPAP, n = 14; control, n = 10): median baseline NIHSS 13 (5.5-18), 88% large vessel occlusion, and 12% large vessel stenosis. Polygraphy confirmed sleep apnea in 64% of auto-BPAP and 88% of control patients (p = 0.34). Adherence to auto-BPAP was achieved by 9 of the 14 (64%) patients. Between auto-BPAP and control patients, no differences were observed in early neurological improvement (median NIHSS change: -2.0, IQR = 7 points vs. -0.5, IQR = 3 points), 90 days functional independence (21 vs. 30%, p = 0.67), stroke recurrence (0 vs. 20%, p = 0.16), and death (14 vs. 20%, p = 1.0). No safety concerns were identified. Conclusions: In this prematurely terminated trial, auto-BPAP was safe but did not show an effect on short-term clinical outcomes in selected ischemic stroke patients. Its tolerability, however, may be limited in hyperacute stroke care and needs to be improved before larger trials are conducted. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT01812993.

C-REGS 2 - Design and methodology of a high-quality comparative effectiveness observational trial.

The main aim of this study is to systematically record Cerebrolysin treatment modalities and concomitant medication, according to local standards, in patients with moderate to severe neurological deficits after acute ischemic stroke and to assess the impact of these parameters on therapy outcome during early rehabilitation (day 21) and on day 90. An open observational treatment design based on the principles of high-quality comparative effectiveness research (HQCER) has been chosen to capture the therapies as applied in real-world clinical practice. HQCER opens a new horizon for strengthening the validity of the results from observational trials, thereby enhancing the associated level of evidence. Rigorous pre-specification of analytical procedures and tight risk-based centralized monitoring were additional measures to improve the impact of the observational approach. The value for real-world studies has become obvious, and such studies based on comparative effectiveness designs supplement the classical study designs by enabling the inclusion of larger proband numbers and more statistical reliability for practical use.

Blood pressure excursions in acute ischemic stroke patients treated with intravenous thrombolysis.

OBJECTIVE: To investigate the association of blood pressure BP excursions, defined as greater than 185 SBP or greater than 105 DBP, with the probability of intracranial hemorrhage (ICH) and worse functional outcomes in patients with acute ischemic stroke (AIS) treated with tissue plasminogen activator (tPA). METHODS: We performed a post hoc analysis of the CLOTBUST-ER trial. Serial BP measurements were conducted using automated cuff recording according to the recommended BP protocol guidelines for tPA administration. The outcomes were prespecified efficacy and safety endpoints of CLOTBUST-ER. RESULTS: The mean number of serial BP recordings per patient was 37. Of the 674 patients, 227 (34%) had at least one BP excursion (>185/105 mmHg) during the first 24 h following tPA-bolus. The majority of BP excursions (46%) occurred within the first 75 min from tPA-bolus. Patients with at least one BP excursion in the first 24 h following tPA bolus had significantly lower rates of independent functional outcome at 90 days (31 vs. 40.1%, P = 0.028). The total number of BP excursions was associated with decreased odds of 24-h clinical recovery (OR = 0.88, 95% CI:0.80-0.96), 24-h neurological improvement (OR = 0.87, 95% CI: 0.81-0.94), 7-day functional improvement (common OR = 0.92, 95% CI: 0.87-0.97), 90-day functional improvement (common OR = 0.94, 95% CI: 0.88-0.98) and 90-day independent functional outcome (OR = 0.90, 95% CI: 0.82-0.98) in analyses adjusted for potential confounders. DBP excursions were independently associated with increased odds of any intracranial hemorrhage (OR = 1.26, 95% CI: 1.04-1.53). CONCLUSION: BP excursions above guideline thresholds during the first 24 h following tPA administration for AIS are common and are independently associated with adverse clinical outcomes.

Ultrasound Examination of the Pupil - A New Tool for the Neuro-Ophthalmological Assessment.

BACKGROUND: Pupil examination represents a diagnostic and prognostic test in the management of several neurological diseases. Infrared video pupillometry (IVP) is the gold standard, since it is not routinely available, a noninvasive bedside ultrasound assessment has been proposed as an alternative. The aim of this study was to assess the feasibility and reproducibility of ultrasound pupillometry (UP) in comparison with IVP. MATERIALS AND METHODS: 81 subjects (43 men and 38 women, mean age: 52 ±â€Š20 years and 49 ±â€Š19 years, respectively) with no history of neurophthalmologic disease were enrolled. UP was performed with a 12-MHz linear probe according to current guidelines for orbital insonation. Light and painful stimuli were applied to test pupillary light reflex (PLR) and ciliospinal reflex (CR). In 30 of these subjects IVP examination was performed additionally to obtain intra-observer and inter-observer agreement. RESULTS: Increasing age was associated with a decreased pupillary diameter (PD) at rest, after PLR and CR (R -0.728, p < 0.01, R -0.643, p < 0.01, R 0.674, p < 0.001 respectively), while no association was noticed with time to constriction/dilation. UP measurements were reproducible (rate of inter- and intra-observer agreement: R 0.979, p < 0.01, R 0.946, p < 0.01 respectively) and concordant with IVP (PLR R 0.831, p < 0.01; CR R 0.879, p < 0.01). CONCLUSION: According to our study, ultrasound pupillometry is a feasible and reliable technique for bedside pupillary function assessment, and is a good alternative to infrared video pupillometry. Moreover, it represents the only way for functional pupillary assessment in patients with periorbital hematoma.

Pharyngeal electrical stimulation for neurogenic dysphagia following stroke, traumatic brain injury or other causes: Main results from the PHADER cohort study.

BACKGROUND: Neurogenic dysphagia is common and has no definitive treatment. We assessed whether pharyngeal electrical stimulation (PES) is associated with reduced dysphagia. METHODS: The PHAryngeal electrical stimulation for treatment of neurogenic Dysphagia European Registry (PHADER) was a prospective single-arm observational cohort study. Participants were recruited with neurogenic dysphagia (comprising five groups - stroke not needing ventilation; stroke needing ventilation; ventilation acquired; traumatic brain injury; other neurological causes). PES was administered once daily for three days. The primary outcome was the validated dysphagia severity rating scale (DSRS, score best-worst 0-12) at 3 months. FINDINGS: Of 255 enrolled patients from 14 centres in Austria, Germany and UK, 10 failed screening. At baseline, mean (standard deviation) or median [interquartile range]: age 68 (14) years, male 71%, DSRS 11·4 (1·7), time from onset to treatment 32 [44] days; age, time and DSRS differed between diagnostic groups. Insertion of PES catheters was successfully inserted in 239/245 (98%) participants, and was typically easy taking 11·8 min. 9 participants withdrew before the end of treatment. DSRS improved significantly in all dysphagia groups, difference in means (95% confidence intervals, CI) from 0 to 3 months: stroke (n = 79) -6·7 (-7·8, -5·5), ventilated stroke (n = 98) -6·5 (-7·6, -5·5); ventilation acquired (n = 35) -6·6 (-8·4, -4·8); traumatic brain injury (n = 24) -4·5 (-6·6, -2·4). The results for DSRS were mirrored for instrumentally assessed penetration aspiration scale scores. DSRS improved in both supratentorial and infratentorial stroke, with no difference between them (p = 0·32). In previously ventilated participants with tracheotomy, DSRS improved more in participants who could be decannulated (n = 66) -7·5 (-8·6, -6·5) versus not decannulated (n = 33) -2·1 (-3·2, -1·0) (p<0·001). 74 serious adverse events (SAE) occurred in 60 participants with pneumonia (9·2%) the most frequent SAE. INTERPRETATION: In patients with neurogenic dysphagia, PES was safe and associated with reduced measures of dysphagia and penetration/aspiration. FUNDING: Phagenesis Ltd.

Enhancing and accelerating stroke treatment in Eastern European region: Methods and achievement of the ESO EAST program.

INTRODUCTION: Despite the availability of prevention and therapies of stroke, their implementation in clinical practice, even of low-cost ones, remains poor. In 2015, the European Stroke Organisation (ESO) initiated the ESO Enhancing and Accelerating Stroke Treatment (EAST) program, which aims to improve stroke care quality, primarily in Eastern Europe. Here, we describe its methods and milestones. PATIENTS AND METHODS: The ESO EAST program is using an implementation strategy based on a 'detecting-understanding-reducing disparities' conceptual framework: stroke care quality is first measured (after developing a platform for data collection), gaps are identified in the current service delivery, and ultimately feedback is provided to participating hospitals, followed by the application of interventions to reduce disparities. The ESO EAST program is carried out by establishing a stroke quality registry, stroke management infrastructure, and creating education and training opportunities for healthcare professionals. RESULTS: Program management and leadership infrastructure has been established in 19 countries (Country Representatives in 22 countries, National Steering Committee in 19 countries). A software platform for data collection and analysis: Registry of Stroke Care Quality was developed, and launched in 2016, and has been used to collect data from over 90,000 patients from >750 hospitals and 56 countries between September 2016 and May 2019. Training in thrombolysis, nursing and research skills has been initiated. DISCUSSION: ESO EAST is the first pan-Eastern European (and beyond) multifaceted quality improvement intervention putting evidence-informed policies into practice. Continuous monitoring of stroke care quality allows hospital-to-hospital and country-to-country benchmarking and identification of the gaps and needs in health care.

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke.

BACKGROUND: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. METHODS: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. RESULTS: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06-0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89-1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0-2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01-2.31; p = 0.04). CONCLUSION: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies.

Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial.

BACKGROUND: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. METHODS: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. FINDINGS: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77-1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80-1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79-1·60; p=0·53). INTERPRETATION: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. FUNDING: Cerevast Therapeutics.

Is Functional Outcome Different in Posterior and Anterior Circulation Stroke?

Background and Purpose- Posterior circulation stroke (PCS) account for 20% of all ischemic strokes. There is limited evidence whether functional outcome of PCS is comparable to that of anterior circulation stroke (ACS). We aimed to analyze whether 3-month functional outcome is different in PCS and ACS. Methods- Patients with acute ischemic stroke prospectively enrolled within the Austrian Stroke Unit Registry were stratified by infarct localization according to the Oxfordshire Community Stroke Project Classification. Propensity score matching was used to control for covariate imbalances and to match patients with PCS and ACS. Patients were matched for stroke severity, recombinant tissue-type plasminogen activator treatment, and demographic and vascular risk factors. Main outcomes were the distribution of modified Rankin Scale after 3 months and multiple proportional odds models to estimate the influence of the infarct localization on the functional outcome. Results- From a total of 90 484 patients enrolled within the Austrian Stroke Unit Registry, 9208 (4604 PCS/4604 ACS) were matched, of those 954 (477 in each group) were treated with recombinant tissue-type plasminogen activator. We detected a significant shift towards better 3-month functional outcome in patients with ACS compared with PCS (odds ratio [OR], 1.19; 95% CI, 1.1-1.28; P<0.0001). In particular, functional outcome was worse in PCS with onset-to-door-time >270 minutes (OR, 1.34; 95% CI, 1.17-1.54; P<0.0001) and in PCS with unknown onset-to-door-time (OR, 1.26; 95% CI, 1.13-1.42; P<0.0001); however, we did not detect any difference in functional outcome between ACS and PCS in patients with an onset-to-door-time ≤270 minutes (1-180 minutes: OR, 0.92, 95% CI, 0.78-1.09, P=0.3554; 181-270 minutes: OR, 1.04, 95% CI, 0.79-1.37, P=0.7689). In patients treated with recombinant tissue-type plasminogen activator, functional outcome was not significantly different between PCS and ACS. Conclusions- PCS was associated with worse outcome compared with ACS in patients arriving later than 4.5 hours at hospital or in those with unknown onset of symptoms. Our results urge for implementation of symptoms found in the posterior circulation into preclinical patient-triage tools.

Pharyngeal electrical stimulation for early decannulation in tracheotomised patients with neurogenic dysphagia after stroke (PHAST-TRAC): a prospective, single-blinded, randomised trial.

BACKGROUND: Dysphagia after stroke is common, especially in severely affected patients who have had a tracheotomy. In a pilot trial, pharyngeal electrical stimulation (PES) improved swallowing function in this group of patients. We aimed to replicate and extend this single-centre experience. METHODS: We did a prospective, single-blind, randomised controlled trial across nine sites (seven acute care hospitals, two rehabilitation facilities) in Germany, Austria, and Italy. Patients with recent stroke who required tracheotomy were randomly assigned to receive 3 days of either PES or sham treatment (1:1). All patients had the stimulation catheter inserted; sham treatment was applied by connecting the PES base station to a simulator box instead of the catheter. Randomisation was done via a computerised interactive system (stratified by site) in blocks of four patients per site. Patients and investigators applying PES were not masked. The primary endpoint was assessed by a separate investigator at each site who was masked to treatment assignment. The primary outcome was readiness for decannulation 24-72 h after treatment, assessed using fibreoptic endoscopic evaluation of swallowing and based on a standardised protocol, including absence of massive pooling of saliva, presence of one or more spontaneous swallows, and presence of at least minimum laryngeal sensation. We planned a sequential statistical analysis of superiority for the primary endpoint. Interim analyses were to be done after primary outcome data were available for 50 patients (futility), 70 patients, and every additional ten patients thereafter, up to 140 patients. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN18137204. FINDINGS: From May 29, 2015, to July 5, 2017, of 81 patients assessed, 69 patients from nine sites were randomly assigned to receive PES (n=35) or sham (n=34) treatment. Median onset to randomisation time was 28 days (IQR 19-41; PES 28 [20-49]; sham 28 [18-40]). The Independent Data and Safety Monitoring Board recommended that the trial was stopped early for efficacy after 70 patients had been recruited and primary endpoint data for 69 patients were available. This decision was approved by the steering committee. More patients were ready for decannulation in the PES group (17 [49%] of 35 patients) than in the sham group (three [9%] of 34 patients; odds ratio [OR] 7·00 [95% CI 2·41-19·88]; p=0·0008). Adverse events were reported in 24 (69%) patients in the PES group and 24 (71%) patients in the sham group. The number of patients with at least one serious adverse event did not differ between the groups (ten [29%] patients in the PES group vs eight [23%] patients in the sham group; OR 1·30 [0·44-3·83]; p=0·7851). Seven (20%) patients in the PES group and three (9%) patients in the sham group died during the study period (OR 2·58 [0·61-10·97]; p=0·3059). None of the deaths or serious adverse events were judged to be related to PES. INTERPRETATION: In patients with stroke and subsequent tracheotomy, PES increased the proportion of patients who were ready for decannulation in this study population, many of whom received PES within a month of their stroke. Future trials should confirm whether PES is beneficial in tracheotomised patients who receive stimulation similarly early after stroke and explore its effects in other cohorts. FUNDING: Phagenesis Ltd.

Caregiving and Caregiver Burden in Dementia Home Care: Results from the Prospective Dementia Registry (PRODEM) of the Austrian Alzheimer Society.

BACKGROUND: Comprehensive studies on caregiver burden (CB) of persons caring for dementia patients differ methodologically and show variable results. OBJECTIVE: Analysis of known and hypothesized factors of CB in home care of dementia patients. METHODS: Multicenter longitudinal study comprising 585 persons caring mostly for Alzheimer's disease patients (age median 77.25 years, Mini-Mental State Examination raw score median 23) using the Zarit Caregiver Burden Interview (CBI). Known patient-related determinants of CB were studied, such as dementia severity (Clinical Dementia Rating, CDR), neuropsychological deficits (CERAD-Plus), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), disability (Disability Assessment for Dementia, DAD), dependency (Dependency Scale, DS), and moreover, unclarified potential factors (age, sex, education of patients; age, sex, occupational status of the caregivers; family relationship). Psychological and somatic effects of CB were analyzed (factor analysis). RESULTS: Caregiver age was median 61. Female caregivers prevailed (67.8%). Median CBI sum score (CBIss) was 16 at baseline. After two years, CBIss was 22 and 37% of the caregivers reported mild to moderate (CBIss 21-40), 16.8% moderate to severe or severe (≥41), and 46.2% absent to little CB (CBIss ≤ 20). CB correlated positively with NPI, CDR, DS scores, disability (DAD), years of education of the patients, and proximity of patient and caregiver sex (female), and negatively with caregiver age. Caregivers reported restrictions of time, health problems, and negative emotions. CONCLUSION: The findings are applicable to identify persons at risk for substantial CB and its consequences. There is demand for personal, psychological, and medical support of caregivers and increasing male participation.