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.

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.

Detection of early infarction signs with machine learning-based diagnosis by means of the Alberta Stroke Program Early CT score (ASPECTS) in the clinical routine.

PURPOSE: New software solutions emerged to support radiologists in image interpretation in acute ischemic stroke. This study aimed to validate the performance of computer-aided assessment of the Alberta Stroke Program Early CT score (ASPECTS) for detecting signs of early infarction. METHODS: ASPECT scores were assessed in 119 CT scans of patients with acute middle cerebral artery ischemia. Patient collective was differentiated according to (I) normal brain, (II) leukoencephalopathic changes, (III) infarcts, and (IV) atypical parenchymal defects (multiple sclerosis, etc.). ASPECTS assessments were automatically provided by the software package e-ASPECTS (Brainomix®, UK) (A). Subsequently, three neuroradiologists (B), (C), and (D) examined independently 2380 brain regions. Interrater comparison was performed with the definite infarct core as reference standard after best medical care (thrombolysis and/or thrombectomy). RESULTS: Interrater comparison revealed higher correlation coefficient of (B) 0.71, (C) 0.76, and of (D) 0.80 with definite infarct core compared to (A) 0.59 for ASPECTS assessment in the acute ischemic stroke setting. While (B), (C), and (D) showed a significant correlation for individual patient groups (I), (II), (III), and (IV), except for (D) (II), (A) was not significant in patient groups with pre-existing changes (II), (III), and (IV). The following sensitivities, specificities, PPV, NPV, and accuracies given in percent were achieved: (A) 83, 57, 55, 82, and 67; (B) 74, 76, 69, 83, and 77; (C) 80.8, 85.2, 76, 84, and 80; (D) 63, 90.7, 82, 79, and 80, respectively. CONCLUSION: For ASPECTS assessment, the examined software may provide valid data in case of normal brain. It may enhance the work of neuroradiologists in clinical decision making. A final human check for plausibility is needed, particularly in patient groups with pre-existing cerebral changes.

[Invasive stroke treatment - Study results and clinical routine : Lost in translation?]. / Invasive Schlaganfallbehandlung - Studienergebnisse und klinische Routine : Lost in translation?

OBJECTIVE: How can the overwhelmingly positive results of the five randomized thrombectomy trials published in 2015 be transferred to the clinical routine? MATERIAL AND METHODS: Analysis of trial-specific characteristics with regard to implementation of mechanical thrombectomy into clinical routine. RESULTS: Stroke patients with symptomatic proximal artery occlusion are principally eligible for mechanical thrombectomy; however, the stroke patients included in the thrombectomy trials are not representative of all stroke patients. They were carefully selected according to clinical and imaging criteria as well as to the time window from symptom onset. Furthermore, they were treated in highly selected specialized stroke centers. Analysis of the five trials and the Catalan population-based SONIIA registry revealed that the observed number needed to treat (NNT) of 5 to reach a modified Rankin scale (mRS) score of 0-2 only applies to approximately 1 % of all stroke patients. The NNT for the remaining patients who are principally eligible for thrombectomy requires further study. Currently, centralization seems to be useful to facilitate mechanical thrombectomy in routine care leading to several problems that have to be dealt with in particular regions. Secondary transport to thrombectomy centers plays a major role in this context and has to be provided with highest priority. CONCLUSION: Only careful analysis of study results and the background circumstances will enable adequate organization and successful practical implementation of this highly effective therapy in the clinical routine. Regional conditions have to be considered and will be crucial in this context.

[Cerebrovascular complications of immunologically mediated heparin-induced thrombocytopenia]. / Zerebrovaskuläre Komplikationen der Heparininduzierten Thrombozytopenie Typ II (HIT-II).

Immunologically mediated heparin-induced thrombocytopenia (HIT) is a thrombotic disease caused by antibodies occurring after heparin exposure. Thrombocytopenia occurs within a few days after heparin exposure, about half of HIT-patients develop venous or arterial thrombotic complications. Neurological complications of HIT are mainly ischaemic stroke and sinus vein thrombosis. To ensure the primary clinical diagnosis functional and immunological assays for antibody detection are available. The probability for the occurrence of HIT depends on the nature of heparin employed (LMWH vs. UFH) and individual patient characteristics such as gender and primary disease (medical vs. surgical patients). In the case of suspected HIT heparin administration should be discontinued immediately and replaced by an alternative anticoagulation to prevent the expansion or development of further thrombotic complications. Herein we report a case of a patient suffering from HIT-associated embolic cerebral ischaemic stroke.

Waiting for platelet counts causes unsubstantiated delay of thrombolysis therapy.

BACKGROUND: Platelet counts (PCs) <100,000/µl are considered as a contraindication for intravenous thrombolysis (IVT). While US guidelines recommend IVT initiation before the availability of clotting tests, the guidelines of the European Stroke Organization give no such practical advice. We aimed to assess the incidence of thrombocytopenia in IVT patients, outcome after thrombolysis in affected patients and the time gained by initiating treatment prior to availability of PC results. METHODS: All patients with thrombocytopenia were identified in our prospectively acquired thrombolysis database. Baseline demographic data, intracerebral hemorrhage rates as well as functional outcome were assessed. The median time between initiation of thrombolysis and availability of PCs was calculated. RESULTS: Of 625 IVT patients, 3 (0.5%) had thrombocytopenia at stroke onset. None of them developed intracerebral hemorrhage (ICH) or died during the follow-up. Waiting for PCs would have delayed treatment in 72.4% of the patients, with a median hypothetical delay of 22 min (interquartile range: 11-41 min). CONCLUSIONS: To date, there are no sufficient data to evaluate the ICH risk in thrombocytopenic patients. However, thrombocytopenia is rare in IVT patients. Thus, generally waiting for PC results prior to initiation of IVT is not warranted. Avoiding this significant delay yields shorter door-to-needle times and potentially more effective treatment.

The potential of neurosonography in neurological emergency and intensive care medicine: monitoring of increased intracranial pressure, brain death diagnostics, and cerebral autoregulation­ part 2.

Transcranial B-mode sonography is an easy to use bedside imaging modality to monitor significant changes of the brain parenchyma such as in malignant middle cerebral infarction or intracerebral hemorrhage. The elevation of intracranial pressure can be followed with various neurosonographical techniques: Measurements of the ventricular width, midline shift, arterial resistance, and optic nerve sheath diameter. They should be viewed as complementary to each other and to other imaging modalities. Repeated cCT and MRI may be avoided in unstable patients by bedside neurosonography in the hands of an experienced physician. Monitoring of evolving hydrocephalus using serial measurements of the third and lateral ventricles can be used to guide therapeutic decisions such as the removal of a ventricular drainage. The cessation of cerebral blood flow in the case of intracranial pressure exceeding systemic arterial pressure is an important part of brain death diagnostics. Early demonstration of a sufficient temporal bone window is needed in patients in whom brain death may be expected. Cerebrovascular autoregulation is an integer component of the brain's blood supply and is compromised in a variety of neurological diseases. In neurological/neurosurgical patients in the intensive care unit, its assessment allows for extended neuromonitoring and control of therapeutic procedures.

[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.

[Management of intracerebral hemorrhage: can we still learn something?]. / Management intrazerebraler Blutungen : Lernen wir dazu?

Intracerebral hemorrhage (ICH) is the most devastating form of stroke. It affects approximately 2 million people worldwide every year and is a major cause of mortality and morbidity. Despite the focus of intensive scientific research on ICH for decades there is still no proven treatment strategy for this disease. Advances in knowledge on the underlying pathomechanisms of ICH and the clinical impact have contributed to the development of novel treatment approaches. Currently, surgical treatment, aggressive blood pressure management and intraventricular fibrinolysis in patients with additional severe intraventricular hemorrhage are being investigated in large scale phase III clinical trials.

[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.

Intravenous thrombolysis in posterior cerebral artery infarctions.

BACKGROUND: Approximately 5-10% of all acute ischemic strokes (AIS) occur in the territory of the posterior cerebral artery (PCA). Little is known about intravenous thrombolysis (IVT) in this infarct subgroup in terms of outcome and intracerebral hemorrhage rates. The aim of our study was to evaluate differences between supratentorial PCA infarcts and anterior circulation infarcts regarding baseline characteristics, stroke severity, outcome, safety and clinical findings, which would implicate a change in the existing thrombolysis practice in patients with PCA stroke. METHODS: All patients with AIS in the supratentorial PCA territory receiving IVT between 01/2006 and 01/2010 were selected from the Erlangen Thrombolysis Database (group 1, n = 21). They were compared to all IVT patients with strokes in other supratentorial vascular territories over the same period of time (group 2, n = 398). Baseline demographic data, as well as clinical and laboratory findings were analyzed. The outcome was assessed using the modified Rankin Scale at 3 months. RESULTS: Only serum glucose levels at baseline (110.5 ± 36.1 vs. 127.2 ± 48.2 mg/dl; p = 0.036) and the baseline National Institutes of Health Stroke Scale score (median 6.5 vs. 9; p = 0.016) were significantly lower in group 1 compared to group 2. Favorable clinical outcome (57.1 vs. 48.6%; p = 0.445) and intracerebral hemorrhage rates (4.8 vs. 4%; p = 1.000) were comparable in both groups. CONCLUSIONS: No substantial differences were found between supratentorial PCA and anterior circulation infarcts. Our data on safety and efficacy support the present common thrombolysis practice in supratentorial PCA infarct patients, though an indication for IVT should rather be based on the existence of functionally disabling deficit than merely on the National Institutes of Health Stroke Scale.

Off-label thrombolysis for acute ischemic stroke: rate, clinical outcome and safety are influenced by the definition of 'minor stroke'.

BACKGROUND: Several contraindications for intravenous thrombolysis are not based on controlled trials. Specialized stroke centers often apply less restrictive criteria. The aim of our study was to analyze how many patients at our institution receive off-label thrombolysis. In addition, clinical outcome and safety data were compared to those from patients treated on-label, and the influence of different definitions of 'minor stroke' were examined. METHODS: Consecutive thrombolysis patients treated between January 2006 and January 2010 were included. Patients treated off-label were compared to patients given on-label therapy according to the European license. Since no specified definition for 'minor neurological deficit' exists in the license, two distinct definitions were considered off-label, i.e. National Institutes of Health Stroke Scale score (NIHSSS) <1 (definition 1) and NIHSSS ≤4 (definition 2). RESULTS: Of a total of 422 patients, 232 (55%) were treated off-label. The most prevalent off-label criteria (OLCs) were the following: age >80 years (n = 113), minor stroke (definition 1, n = 3; definition 2, n = 84), elevated blood pressure necessitating aggressive treatment (n = 75), time window >3 h (n = 71) and major surgery or trauma within the preceding 3 months (n = 20). In group comparisons, off-label patients had an overall worse outcome using definition 1 for minor stroke, while there was no difference when definition 2 was applied. In multivariate analysis, off-label therapy (definition 1) in general and age >80 years were independent predictors of poor outcome. None of the contraindications were associated with an increased bleeding risk. CONCLUSIONS: Off-label therapy is frequently applied at our center and is not associated with higher complication rates. Overall outcome of off-label treatment largely depends on the definition used for minor stroke. Besides age >80 years, a known poor prognostic factor, no other specific OLC was associated with poor outcome. Our data suggest that the criteria in the European license may be too restrictive.

[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.

Evolution of stroke diagnosis in the emergency room--a prospective observational study.

BACKGROUND: Access to acute neurological care is limited. Especially in nonurban areas, and owing to uncertainties in diagnosing stroke, non-neurologists often misinterpret stroke symptoms. We evaluated the profile of patients with suspected stroke and the accuracy of the admission diagnosis 'stroke' in the setting of a specialized neurological emergency department in a nonurban region. METHODS: In this prospective observational study, (1) data from all 4,174 patients with the discharge diagnosis 'stroke' and (2) data from 1,800 consecutive patients (3 cohorts per year over 3 years) with the admission diagnosis 'stroke' were included over a 3-year period. RESULTS: The positive predictive value of the admission diagnosis 'stroke' was 0.34; the negative predictive value was 0.97. The rate of misdiagnosis significantly correlated with age and time from symptom onset to presentation. During the study period, the proportion of patients with the admission diagnosis 'stroke' admitted early after symptom onset increased from 19.9 to 27.8% within 3 h and from 26.4 to 32.7% within 4.5 h, respectively. Thrombolysis rates increased (from 9.4 to 15.4%). CONCLUSION: The uncertainties in interpreting stroke symptoms and the lack of facilities for treating emergency stroke in nonurban areas may be outweighed by offering access to a specialized neurological emergency room, thus rectifying any misinterpretation of stroke symptoms and shortening in-hospital time windows for treatment. Still, the rate of misdiagnosis is high, requiring expensive resources, despite the constant flow of information to the public. Therefore, more prospective data comparing different emergency room settings are needed which focus in particular on patients with the admission diagnosis 'stroke'.

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.