Pulse pressure variability is associated with unfavorable outcomes in acute ischaemic stroke patients treated with intravenous thrombolysis.

BACKGROUND AND PURPOSE: Blood pressure (BP) variability has been associated with worse neurological outcomes in acute ischaemic stroke (AIS) patients receiving treatment with intravenous thrombolysis (IVT). However, no study to date has investigated whether pulse pressure (PP) variability may be a superior indicator of the total cardiovascular risk, as measured by clinical outcomes. METHODS: Pulse pressure variability was calculated from 24-h PP measurements following tissue plasminogen activator bolus in AIS patients enrolled in the Combined Lysis of Thrombus using Ultrasound and Systemic Tissue Plasminogen Activator for Emergent Revascularization (CLOTBUST-ER) trial. The outcomes of interest were the pre-specified efficacy and safety end-points of CLOTBUST-ER. All associations were adjusted for potential confounders in multivariable regression models. RESULTS: Data from 674 participants was analyzed. PP variability was identified as the BP parameter with the most parsimonious fit in multivariable models of all outcomes, and was independently associated (P < 0.001) with lower likelihood of both 24-h neurological improvement and 90-day independent functional outcome. PP variability was also independently related to increased odds of any intracranial bleeding (P = 0.011) and 90-day mortality (P < 0.001). Every 5-mmHg increase in the 24-h PP variability was independently associated with a 36% decrease in the likelihood of 90-day independent functional outcome (adjusted odds ratio 0.64, 95% confidence interval 0.52-0.80) and a 60% increase in the odds of 90-day mortality (adjusted odds ratio 1.60, 95% confidence interval 1.23-2.07). PP variability was not associated with symptomatic intracranial bleeding at either 24 or 36 h after IVT administration. CONCLUSIONS: Increased PP variability appears to be independently associated with adverse short-term and long-term functional outcomes of AIS patients treated with IVT.

Intravenous thrombolysis for large vessel or distal occlusions presenting with mild stroke severity.

BACKGROUND AND PURPOSE: We investigated the effectiveness of intravenous thrombolysis (IVT) in acute ischaemic stroke (AIS) patients with large vessel or distal occlusions and mild neurological deficits, defined as National Institutes of Health Stroke Scale scores < 6 points. METHODS: The primary efficacy outcome was 3-month functional independence (FI) [modified Rankin Scale (mRS) scores 0-2] that was compared between patients with and without IVT treatment. Other efficacy outcomes of interest included 3-month favorable functional outcome (mRS scores 0-1) and mRS score distribution at discharge and at 3 months. The safety outcomes comprised all-cause 3-month mortality, symptomatic intracranial hemorrhage (ICH), asymptomatic ICH and severe systemic bleeding. RESULTS: We evaluated 336 AIS patients with large vessel or distal occlusions and mild stroke severity (mean age 63 ± 15 years, 45% women). Patients treated with IVT (n = 162) had higher FI (85.6% vs. 74.8%, P = 0.027) with lower mRS scores at hospital discharge (P = 0.034) compared with the remaining patients. No differences were detected in any of the safety outcomes including symptomatic ICH, asymptomatic ICH, severe systemic bleeding and 3-month mortality. IVT was associated with higher likelihood of 3-month FI [odds ratio (OR), 2.19; 95% confidence intervals (CI), 1.09-4.42], 3-month favorable functional outcome (OR, 1.99; 95% CI, 1.10-3.57), functional improvement at discharge [common OR (per 1-point decrease in mRS score), 2.94; 95% CI, 1.67-5.26)] and at 3 months (common OR, 1.72; 95% CI, 1.06-2.86) on multivariable logistic regression models adjusting for potential confounders, including mechanical thrombectomy. CONCLUSIONS: Intravenous thrombolysis is independently associated with higher odds of improved discharge and 3-month functional outcomes in AIS patients with large vessel or distal occlusions and mild stroke severity. IVT appears not to increase the risk of systemic or symptomatic intracranial bleeding.

Fatal oral anticoagulant-related intracranial hemorrhage: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Intracranial hemorrhage (ICH) is the most feared complication in patients treated with oral anticoagulants due to non-valvular atrial fibrillation. Non-vitamin K oral anticoagulants (NOACs) reduce the risk of ICH compared with vitamin K antagonists (VKAs). We performed a systematic review and meta-analysis to evaluate the risk of fatal NOAC-related ICH compared with VKA-related ICH. METHODS: We calculated the corresponding risk ratios (RRs) in each included study to express the relative risk of fatal ICH amongst all patients receiving oral anticoagulation with either NOACs or VKAs. We additionally evaluated the mortality rates in NOAC-related ICH in patients treated with and without NOAC-specific reversal agents (idarucizumab and factor Xa inhibitors antidote). Case fatality was evaluated at 30-90 days following symptom onset. RESULTS: Our literature search identified six eligible studies (four randomized controlled trials and two open-label trials of NOAC-specific reversal agents). In pairwise analyses, NOACs were found to have a lower risk of fatal ICH compared with VKAs [RR, 0.46; 95% confidence interval (CI), 0.36-0.58] with no heterogeneity (I2 = 0%) across included randomized controlled trials. However, the case fatality rate was similar in NOAC-related and VKA-related (RR, 1.00; 95% CI, 0.84-1.19) ICH with no evidence of heterogeneity (I2 = 0%). In the indirect analysis, the case fatality rate of NOAC-related ICH in patients treated with specific reversal agents was lower compared with the remainder of the patients [17% (95% CI, 11-24%) vs. 41% (95% CI, 34-49%); P < 0.001]. CONCLUSIONS: Non-vitamin K oral anticoagulants halve the risk of fatal ICH in patients with non-valvular atrial fibrillation compared with VKAs, whereas indirect comparisons indicate that NOAC-specific reversal agents may be associated with a lower case fatality rate in NOAC-related ICH.

[Spontaneous intracranial hypotension and Marfan syndrome]. / Spontanes Liquorunterdrucksyndrom und Marfan-Syndrom.

Spontaneous intracranial hypotension is the most common complication in patients undergoing a lumbar puncture. A much rarer entity is headaches attributed to spontaneous (or idiopathic) low cerebrospinal fluid (CSF) pressure but the combination with a connective tissue disorder is even rarer. The first case of a patient with spontaneous intracranial hypotension and genetically established Marfan syndrome was published in 1995. This article describes the cases of two female patients who presented with postural headache. Magnetic resonance imaging revealed multiple leakages of CSF and both patients had a genetically confirmed diagnosis of Marfan syndrome. The initial symptomatic treatment did not result in a significant relief of the headaches. Epidural blood patching was performed and the intervention was successful in both patients. Finally, the most important epidemiological, diagnostic and pathophysiological aspects are demonstrated and the therapeutic procedures are presented.

[Consideration of guidelines, recommendations and quality indicators for treatment of stroke in the dataset "Emergency Department" of DIVI]. / Berücksichtigung von Leitlinien, Empfehlungen und Qualitätsindikatoren zur Schlaganfalltherapie im Datensatz Notaufnahme der DIVI.

BACKGROUND: The dataset "Emergency Department" of the German Interdisciplinary Association of Critical Care and Emergency Medicine (DIVI) has been developed during several expert meetings. Its goal is an all-encompassing documentation of the early clinical treatment of patients in emergency departments. Using the example of the index disease acute ischemic stroke (stroke), the aim was to analyze how far this approach has been fulfilled. MATERIAL AND METHODS: In this study German, European and US American guidelines were used to analyze the extent of coverage of the datasets on current emergency department guidelines and recommendations from professional societies. In addition, it was examined whether the dataset includes recommended quality indicators (QI) for quality management (QM) and in a third step it was examined to what extent national provisions for billing are included. In each case a differentiation was made whether the respective rationale was primary, i.e. directly apparent or whether it was merely secondarily depicted by expertise. In the evaluation an additional differentiation was made between the level of recommendations and further quality relevant criteria. RESULTS: The modular design of the emergency department dataset comprising 676 data fields is briefly described. A total of 401 individual fields, divided into basic documentation, monitoring and specific neurological documentation of the treatment of stroke patients were considered. For 247 data fields a rationale was found. Partially overlapping, 78.9 % of 214 medical recommendations in 3 guidelines and 85.8 % of the 106 identified quality indicators were primarily covered. Of the 67 requirements for billing of performance of services, 55.5 % are primarily part of the emergency department dataset. Through appropriate expertise and documentation by a board certified neurologist, the results can be improved to almost 100 %. CONCLUSION: The index disease stroke illustrates that the emergency department dataset of the DIVI covers medical guidelines, especially 100 % of the German guidelines with a grade of recommendation. All necessary information to document the specialized stroke treatment procedure in the German diagnosis-related groups (DRG) system is also covered. The dataset is also suitable as a documentation tool of quality management, for example, to participate in the registry of the German Stroke Society (ADSR). Best results are obtained if the dataset is applied by a physician specialized in the treatment of patients with stroke (e.g. board certified neurologist). Finally the results show that changes in medical guidelines and recommendations for quality management as well as billing-relevant content should be implemented in the development of datasets for documentation to avoid duplicate documentation.

Reduced mortality and severe disability rates in the SENTIS trial.

BACKGROUND AND PURPOSE: The Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke trial showed a trend for reduced all-cause mortality and positive secondary safety end point outcomes. We present further analyses of the mortality and severe disability data from the Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke trial. MATERIALS AND METHODS: The Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke trial was a multicenter, randomized, controlled trial that evaluated the safety and effectiveness of the NeuroFlo catheter in patients with stroke. The current analysis was performed on the as-treated population. All-cause and stroke-related mortality rates at 90 days were compared between groups, and logistic regression models were fit to obtain ORs and 95% CIs for the treated versus not-treated groups. We categorized death-associated serious adverse events as neurologic versus non-neurologic events and performed multiple logistic regression analyses. We analyzed severe disability and mortality by outcomes of the mRS. Patient allocation was gathered by use of a poststudy survey. RESULTS: All-cause mortality trended in favor of treated patients (11.5% versus 16.1%; P = .079) and stroke-related mortality was significantly reduced in treated patients (7.5% versus 14.2%; P = .009). Logistic regression analysis for freedom from stroke-related mortality favored treatment (OR, 2.41; 95% CI, 1.22, 4.77; P = .012). Treated patients had numerically fewer neurologic causes of stroke-related deaths (52.9% versus 73.0%; P = .214). Among the 90-day survivors, nominally fewer treated patients were severely disabled (mRS 5) (5.6% versus 7.5%; OR, 1.72; 95% CI, 0.72, 4.14; P = .223). Differences in allocation of care did not account for the reduced mortality rates. CONCLUSIONS: There were consistent reductions in all-cause and stroke-related mortality in the NeuroFlo-treated patients. This reduction in mortality did not result in an increase in severe disability.

Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban.

Dabigatran, apixaban, and rivaroxaban have been approved for primary and secondary stroke prevention in patients with atrial fibrillation. However, questions have arisen about how to manage emergency situations, such as when thrombolysis would be required for acute ischemic stroke or for the managing intracranial or gastrointestinal bleedings. We summarize the current literature and provide recommendations for the management of these situations. Peak plasma levels of the direct oral anticoagulants (DOACs) apixaban, dabigatran, or rivaroxaban are observed about 2-4 h after intake. Elimination of dabigatran is mainly dependent on renal function. Consequently, if renal function is impaired, there is a risk of drug accumulation that is highest for dabigatran followed by rivaroxaban and then apixaban and thus dosing recommendations are different. To date, no bedside tests are available that reliably assess the anticoagulatory effect of DOACs, nor are specific antidotes available. We recommend performing the following tests if DOAC intake is unknown: dabigatran-associated bleeding risk is minimized or can be neglected if thrombin time, Hemoclot test, or Ecarin clotting time is normal. Apixaban and rivaroxaban effects can be ruled out if findings from the anti-factor Xa activity test are normal. High plasma levels of DOAC are also mostly excluded if PTT and PTZ are normal four or more hours after DOAC intake. However, normal values of global coagulation tests are not sufficient if thrombolysis is indicated for treating acute stroke. The decision for or against thrombolysis is an individual decision; in these cases, thrombolysis use is off-label. In case of bleeding, prothrombin complex concentrates seems to be the most plausible treatment. For severe gastrointestinal bleeding with life-threatening blood loss, the bleeding source needs to be identified and treated by invasive measures. Use of procoagulant drugs (antifibrinolytics) might also be considered. However, there is very limited clinical experience with these products in conjunction with DOAC.

[FEES in the stroke unit: recommendations for implementation in the clinical routine]. / FEES auf der Stroke-Unit : Empfehlungen zur Umsetzung im klinischen Alltag.

Dysphagia occurs in about 50 % of patients with acute stroke, is strongly related to early complications, such as aspiration pneumonia and is a major cause of increased morbidity and mortality in acute stroke. Flexible endoscopic evaluation of swallowing (FEES) has proven to be an easy to use, non-invasive tool for assessment of dysphagia in acute stroke, significantly adding accuracy to the clinical evaluation of dysphagia. With respect to the growing use of FEES in German stroke units this article summarizes recommendations for implementation and execution.A 3-step process is recommended to acquire the relevant knowledge and skills for carrying out FEES. After a systematic training (first step), swallowing endoscopy should be done under close supervision (second step) which is then followed by independent practice coupled with indirect supervision (third step). In principle, FEES should adopt a team approach involving both neurologists and speech language pathologists (SLP) or alternatively speech therapists. The allocation of responsibilities between these two professions should be kept flexible and should be adjusted to the individual level of education. Reducing the role of the SLP to mere assistance work in particular should be avoided. To enhance interprofessional communication and to allow for a smooth and efficient workflow, endoscopic grading of stroke-related dysphagia should adopt a standardized score that also includes protective and rehabilitative measures as well as nutritional recommendations. A major task for the future is to develop an educational curriculum for FEES that takes the specific needs of stroke unit care into account and is applicable to both physicians and SLPs.

[Industry-funded therapy studies: what is in the pipeline?]. / Industriegeförderte Therapiestudien : Was ist in der Pipeline?

Several acute stroke trials are underway or have been recently completed. Among the latter are the ICTUS trial and the IST-3 trial. Several other approaches are being tested for thrombolytic therapy among them modern imaging-based patient selection and new thrombolytic agents, such as desmoteplase and tenecteplase. Other strategies include neuroprotection and neurorestoration, biophysical approaches, such as near infrared laser therapy, hemodynamic augmentation and sphenopalatine ganglion stimulation. Mechanical thrombectomy is practiced in many centers although randomized trials are pending and the IMS-3 trial was stopped. This overview will cover the very recently completed and currently recruiting acute ischemic stroke trials.

[Near-infrared laser treatment of acute stroke: from bench to bedside]. / Nah-Infrarot-Lasertherapie beim akuten Schlaganfall : From bench to bedside.

Near-infrared laser therapy (NIRLT) as a transcranial laser therapy (TLT) is currently being investigated as a neuroreparatory and neuroprotective treatment for acute ischemic stroke patients in a pivotal phase III trial (NEST-3). In this review we cover the theoretical background, experimental studies, translational research and the clinical trial program.

Safety and feasibility of NeuroFlo use in eight- to 24-hour ischemic stroke patients.

BACKGROUND: Acute treatment of ischemic stroke patients presenting more than eight-hours after symptom onset remains limited and largely unproven. Partial aortic occlusion using the NeuroFlo catheter can augment cerebral perfusion in animals. We investigated the safety and feasibility of employing this novel catheter to treat ischemic stroke patients eight-hours to 24 h following symptom onset. METHODS: A multicenter, single-arm trial enrolled ischemic stroke patients at nine international academic medical centers. Eligibility included age 18-85 years old, National Institutes of Health stroke scale (NIHSS) score between four and 20, within eight-hours to 24 h after symptom onset, and perfusion-diffusion mismatch confirmed by magnetic resonance imaging. The primary outcome was all adverse events occurring from baseline to 30 days posttreatment. Secondary outcomes included stroke severity on neurological indices through 90 days. This study is registered with ClinicalTrials.gov, number NCT00436592. RESULTS: A total of 26 patients were enrolled. Of these, 25 received treatment (one excluded due to aortic morphology); five (20%) died. Favorable neurological outcome at 90 days (modified Rankin score 0-2 vs. 3-6) was associated with lower baseline NIHSS (P < 0·001) and with longer duration from symptom discovery to treatment. There were no symptomatic intracranial hemorrhages or parenchymal hematomas. Asymptomatic intracranial hemorrhage was visible on computed tomography in 32% and only on microbleed in another 20%. CONCLUSIONS: Partial aortic occlusion using the NeuroFlo catheter, a novel collateral therapeutic strategy, appears safe and feasible in stroke patients eight-hours to 24 h after symptom onset.

[Difficult decisions in stroke therapy]. / Grenzentscheidungen in der Schlaganfalltherapie.

In numerous situations stroke physicians face a lack of evidence during their daily practice. In this report the authors address some of the difficult treatment decisions encountered in acute therapy and secondary prevention. Examples include off-label thrombolysis and prevention in high-risk situations. The available data from trials and registries are discussed, and personal views and recommendations are expressed.

Characteristics and outcome of patients with early complete neurological recovery after thrombolysis for acute ischemic stroke.

BACKGROUND: Recombinant tissue plasminogen activator (rt-PA) is the only approved specific therapy for acute ischemic stroke. This study analyzes demographic and clinical characteristics of patients with early complete neurological recovery after thrombolysis. METHODS: Data of 320 consecutive patients treated with rt-PA within 3 h of stroke onset at our facility between April 2006 and March 2009 were extracted from our prospective institutional stroke and thrombolysis database. Baseline demographic parameters, risk factors, clinical characteristics as well as neuroradiologic findings of patients with complete recovery 24 h after treatment and at hospital discharge were analyzed. Outcome was evaluated using the modified Rankin Scale at 90 days. RESULTS: Thirty patients (9.4%) were asymptomatic 24 h after thrombolysis and 70 (22%) at hospital discharge. Patients with complete recovery were younger, more often male, had milder stroke symptoms, less often cardioembolic strokes, fewer bleeding complications and more often normal follow-up imaging. In addition, in-hospital time was shorter and these patients retained a better functional outcome at 90 days. Only 1 patient who had completely recovered at hospital discharge died during the follow-up time. In multivariate regression analysis, only the National Institute of Health Stroke Score (NIHSS) on admission was predictive for complete recovery at both examined time points. CONCLUSION: Rapid complete recovery can be achieved in up to a fifth of acute stroke patients treated with thrombolysis. These patients are younger and have milder strokes, less often with cardioembolic origin. Better outcome and lower mortality are sustained at 3 months.

Evidence-based guideline: The role of diffusion and perfusion MRI for the diagnosis of acute ischemic stroke: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: To assess the evidence for the use of diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) in the diagnosis of patients with acute ischemic stroke. METHODS: We systematically analyzed the literature from 1966 to January 2008 to address the diagnostic and prognostic value of DWI and PWI. RESULTS AND RECOMMENDATIONS: DWI is established as useful and should be considered more useful than noncontrast CT for the diagnosis of acute ischemic stroke within 12 hours of symptom onset. DWI should be performed for the most accurate diagnosis of acute ischemic stroke (Level A); however, the sensitivity of DWI for the diagnosis of ischemic stroke in a general sample of patients with possible acute stroke is not perfect. The diagnostic accuracy of DWI in evaluating cerebral hemorrhage is outside the scope of this guideline. On the basis of Class II and III evidence, baseline DWI volumes probably predict baseline stroke severity in anterior territory stroke (Level B) but possibly do not in vertebrobasilar artery territory stroke (Level C). Baseline DWI lesion volumes probably predict (final) infarct volumes (Level B) and possibly predict early and late clinical outcome measures (Level C). Baseline PWI volumes predict to a lesser degree the baseline stroke severity compared with DWI (Level C). There is insufficient evidence to support or refute the value of PWI in diagnosing acute ischemic stroke (Level U).

Feasibility and safety of magnetic resonance imaging-based thrombolysis in patients with stroke on awakening: initial single-centre experience.

BACKGROUND: Up to 25% of all acute ischaemic strokes occur during sleep. Because of the unclear time window, patients with stroke on awakening are usually not considered for acute therapy and excluded from most acute treatment trials. AIM: To evaluate the feasibility of magnetic resonance imaging-based intravenous thrombolysis in patients with stroke on awakening in a routine clinical setting. METHODS: Forty-five patients with stroke on awakening clinically qualifying for intravenous thrombolysis and presenting within 6 h after symptom recognition were admitted to our institution between October 2006 and May 2008. Following an institutional protocol, patients received magnetic resonance imaging as a first-line imaging modality and were offered mismatch-based thrombolysis whenever possible. Baseline demographic data, clinical, laboratory and imaging findings were analysed. Outcome was assessed using the modified Rankin Scale score at 3 months. RESULTS: Magnetic resonance imaging screening was feasible in 43/45 patients (96%). After screening, 10 patients (22%) were treated with intravenous thrombolysis. There were no differences between treated and untreated patients regarding cardiovascular risk factors, stroke aetiology, previous prophylactic treatment and symptom recognition to door time or door to imaging time. Outcome was comparable in both groups despite a trend towards more severe strokes in the intravenous thrombolysis group. Only one asymptomatic and no symptomatic haemorrhage were observed. CONCLUSION: Our data demonstrate that magnetic resonance imaging-based thrombolysis is feasible and possibly safe in patients with stroke on awakening (SOA). Randomised clinical trials for patients with stroke on awakening are needed to further test the safety and efficacy of intravenous thrombolysis in this patient group. The results of our study may help to initiate and design such studies.

[Wake up stroke: Overview on diagnostic and therapeutic options for ischemic stroke on awakening]. / "Wake-up Stroke": Ubersicht zu diagnostischen und therapeutischen Optionen des aus dem Schlaf heraus aufgetretenen ischämischen Schlaganfalls.

Up to 25 % of all acute ischemic strokes (AIS) occur during sleep with the patients or relatives becoming aware of their neurological deficits as they wake up. Because of the unclear time of stroke onset patients with stroke on awakening are usually not considered for acute therapies and excluded from most treatment trials. We give an overview of the published data regarding ischemic wake up strokes (WUS). In particular we focused on baseline characteristics, imaging methods and therapy strategies. Comparing WUS patients and patients with known stroke onset there were no major differences found regarding patient characteristics, etiology, clinical and radiological characteristics. Even though there is no existing gold standard multiparametric neuroimaging (CT; MRI) appears to be helpful for decision making whether to treat a WUS patient with thrombolysis or not. Especially multiparametric MRI which proved to be safe in patients within an extended time window might serve as an adequate diagnostic tool. The results of first pilot studies analyzing treatment of WUS demonstrate that a substantial number of these patients can be treated with IV thrombolysis (IVT) successfully. Large randomized, controlled, prospective clinical trials for patients with WUS are needed to test safety and efficacy of IVT and to evaluate the assumed benefit of multiparametric neuroimaging techniques in this patient group. The results of first pilot studies may be instrumental to help plan and design such trials.