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.

[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.

[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.

[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.

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.

[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.

[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.

Safety and outcome after thrombolysis in stroke patients with mild symptoms.

BACKGROUND: Thrombolytic therapy is frequently withheld in patients with minor stroke symptoms. However, recent studies demonstrate that a substantial proportion of these patients dies or remains permanently disabled because of underestimation of symptom severity at baseline or secondary deterioration. We aimed to assess the safety and outcome of thrombolysis therapy in patients with minor but disabling stroke symptoms. METHODS: 32 patients presenting with mild symptoms were treated with intravenous recombinant tissue-type plasminogen activator between April 2006 and April 2008. Data were extracted from a prospectively collected database. Baseline demographic data, and clinical, laboratory and imaging findings were analyzed. Outcome was assessed using the modified Rankin Scale (mRS) score at 3 months and was dichotomized into favorable (mRS 0-1) versus unfavorable (mRS 2-6). RESULTS: In the majority of patients, the left hemisphere was affected, with aphasia representing the most common symptom leading to treatment decision. The frequency of perfusion lesion (46%) and vessel occlusion (35%) at baseline was high but had no effect on the outcome at 3 months in our series of treated patients. Outcome was favorable in 94% of patients, and 47% recovered without any persisting symptom. Only one asymptomatic and no symptomatic hemorrhage was observed. CONCLUSION: Our data support current guidelines and international licenses which give no lower National Institutes of Health Stroke Scale (NIHSS) limit for intravenous thrombolysis (IVT). Considering the accumulating evidence that the natural course in patients with mild symptoms is not as favorable as often assumed and taking the low risk of bleeding in those patients into account, patients with mild but disabling symptoms should be treated with IVT regardless of their baseline NIHSS score.

[Patient selection for thrombolysis using perfusion and diffusion MRI. An overview]. / Patientenauswahl zur Thrombolyse mittels Perfusions- und Diffusions-MRT. Aktuelle Datenlage.

Multiparametric MRI including diffusion and perfusion imaging provides information on the extent of irreversibly damaged ischemic and/or critically hypoperfused tissue. Magnetic resonance angiography provides additional information on vessel status. The concept of perfusion-diffusion mismatch allows the estimation of tissue at risk of infarction which might be salvaged by timely reperfusion. In large case series and nonrandomized cohort studies, perfusion-diffusion mismatch-based thrombolysis was performed not less than 3 h after symptom onset with excellent safety and signs of good efficacy. However no randomised controlled trial has confirmed this to date. Recent studies improved the understanding of the mismatch concept and identified reperfusion unequivocally as an important predictor of the clinical response to thrombolysis. At the moment MRI-based thrombolysis can be performed after 3 h based on individual benefit:risk assessment in experienced stroke centers.

[Malignant hyperthermia and its differential diagnosis]. / Maligne Hyperthermie und deren Differenzialdiagnosen.

Hyperthermia affects almost all endogenous regulatory systems, where especially cardiovascular and central nervous system interactions can result in life threatening complications. This review illustrates signs and symptoms, pathophysiology and therapeutic options of the three most common hyperthermic syndromes in neurology: malignant hyperthermia, serotonine-syndrom and malignant neuroleptic syndrome. The aim of this contribution is to enable the reader to make the differential diagnosis of these three disease entities. Furthermore the association of other specific myopathies and hyperthermia syndromes is discussed.

Influence of intraventricular fibrinolytic therapy with rt-PA on the long-term outcome of treated patients with spontaneous basal ganglia hemorrhage: a case-control study.

Over the recent years, fibrinolytic agents have been tested for intraventricular clot fibrinolysis (IVF). Compared with patients who did not receive IVF, administration of rt-PA induces rapid resorption of intraventricular blood and normalization of cerebrospinal fluid (CSF) circulation resulting in a reduced 30-day mortality and beneficial short-term outcome after 3 months. Our objective was to analyze possible influences of IVF on the long-term outcome after 12 months. Based on a prospective data base, patients with ganglionic supratentorial hematoma with additional intraventricular hemorrhage and occlusive hydrocephalus (n = 135) were isolated. Twenty-seven patients received IVF. To design a case-control study, we carefully matched 22 controls without IVF with regard to hematoma volume, Graeb score, Glasgow Coma Scale on admission and age (five patients remained unmatchable). We determined clinical and imaging parameters by reviewing the medical records and CT scans of all included patients. Outcome after 12 months was evaluated using the modified Rankin scale (mRS). One multivariate regression analysis was performed to determine predisposing factors for outcome. IVF significantly reduced Graeb score during treatment (eight on admission, three after IVF, one prior to discharge in the treated group versus 8/6/2 in patients without IVF). In patients with IVF requirement, a second external ventricular drainage (EVD) and a ventriculoperitoneal (VP) shunt were reduced (P = 0.08) and the incidence of a lumbar drainage was significantly higher (P < 0.01), whilst the overall time of extra-corporal CSF drainage was comparable. EVD associated complications were equal in both groups. Overall long-term outcome was poor but no significant differences were found between patients with and without IVF (mRS 4-6: 12/22 (54%) in patients with and 13/22 (59%) in patients without IVF; P = 0.81). The five excluded patients with IVF were similar to the 22 included ones with respect to imaging findings and outcome. The multivariate analysis revealed age and baseline hematoma volume, but not IVF to significantly impact the outcome. In accordance with previous studies, IVF hastened clot lysis and reduced the need for repeated EVD exchanges and permanent shunting. However, despite these advantages, IVF did not influence long-term outcome after 12 months. The results of the prospective randomized trial (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) need to be awaited.

Serial diffusion and perfusion MRI analysis of the perihemorrhagic zone in a rat ICH model.

OBJECTIVES: Cerebral ischemia has been proposed as a contributing mechanism to secondary neuronal injury after intracranial hemorrhage (ICH). We aimed to examine perihemorrhagic changes with an animal experimental MRI study using a stroke-MRI protocol. In a subset of animals the feasibility and effects of stereotactic hematoma evacuation was investigated. METHODS: An MRI compatible setup for rats was established using a double injection model. ICH was stereotactically placed into the right basal ganglia of 49 Wistar rats. Coronal T2-WI, T2*-WI, DWI and PWI were generated with a 2.35T animal MRI scanner at 3 time points. Clot volumes, normalized ADC and relative MTT values were analysed in 3 hematoma regions (periphery, outer rim, healthy ipsilateral tissue) in all sequences. RESULTS: There were no perihemorrhagic ADC decreases consistent with ischemic cytotoxic edema but a mild vasogenic edema surrounding the ICH could be observed. This improved partially with evacuation. Reduced perfusion was seen in the periphery and outer rim. This disappeared with lysis and evacuation of the clot. CONCLUSION: No evidence for the existence of a perihemorrhagic ischemic area was found. But, reversible perfusion reduction in this model indicates that early evacuation may help reducing secondary neuronal changes.

Thrombolytic therapy for acute ischaemic stroke in octogenarians: selection by magnetic resonance imaging improves safety but does not improve outcome.

BACKGROUND: Owing to the fear of an increased bleeding risk, thrombolytic therapy is withheld from many patients with acute stroke > 80 years of age. OBJECTIVE: To analyse the risk for symptomatic intracranial haemorrhage (sICH), morbidity and mortality after thrombolytic therapy in octogenarians focusing, in particular, on whether patients selected using magnetic resonance imaging (MRI) had a better risk:benefit ratio. METHODS: The prospectively collected single-centre data of all patients treated with systemic thrombolytic therapy for acute ischaemic stroke since 1998 (n = 468) were reviewed, and patients > or = 80 years (n = 90) were compared with those aged < 80 years (n = 378). In addition, the group of octogenarians was analysed with respect to initial imaging modality. RESULTS: The overall rate of sICH in the octogenarians was 6.9%, compared with 5.3% in younger patients (p = 0.61). In older patients selected by computed tomography, the rate of sICH was 9.4%; no patient selected by MRI had sICH (p = 0.10). Mortality in the octogenarians selected by computed tomography was 29.7% after 3 months as compared with 26.9% in the patients selected by MRI (p = 1.0). 20.3% of the octogenarians selected by computed tomography and 15.4% of those selected by MRI had a favourable outcome (modified Rankin scale < or = 1) after 3 months (p = 0.77). CONCLUSION: Compared with younger patients, octogenarians do not have an increased risk of sICH. The use of MRI to select octogenarians for thrombolytic therapy seemed to decrease the risk of sICH, but did not influence the overall outcome after 3 months.

EFNS guideline on neuroimaging in acute stroke. Report of an EFNS task force.

Neuroimaging techniques are necessary for the evaluation of stroke, one of the leading causes of death and neurological impairment in developed countries. The multiplicity of techniques available has increased the complexity of decision making for physicians. We performed a comprehensive review of the literature in English for the period 1965-2005 and critically assessed the relevant publications. The members of the panel reviewed and corrected an initial draft, until a consensus was reached on recommendations stratified according to the European Federation of Neurological Societies (EFNS) criteria. Non-contrast computed tomography (CT) scan is the established imaging procedure for the initial evaluation of stroke patients. However, magnetic resonance imaging (MRI) has a higher sensitivity than CT for the demonstration of infarcted or ischemic areas and depicts well acute and chronic intracerebral hemorrhage. Perfusion and diffusion MRI together with MR angiography (MRA) are very helpful for the acute evaluation of patients with ischemic stroke. MRI and MRA are the recommended techniques for screening cerebral aneurysms and for the diagnosis of cerebral venous thrombosis and arterial dissection. For the non-invasive study of extracranial vessels, MRA is less portable and more expensive than ultrasonography but it has higher sensitivity and specificity for carotid stenosis. Transcranial Doppler is very useful for monitoring arterial reperfusion after thrombolysis, for the diagnosis of intracranial stenosis and of right-to-left shunts, and for monitoring vasospasm after subarachnoid hemorrhage. Currently, single photon emission computed tomography and positron emission tomography have a more limited role in the evaluation of the acute stroke patient.