[Survey regarding the treatment of malignant middle cerebral artery infarction in German hospitals]. / Umfragestudie zur Behandlung des malignen Mediainfarkts an deutschen Kliniken.

BACKGROUND: There are a variety of intensive care therapies in the treatment of malignant middle cerebral artery infarction (MMI) besides hemicraniectomy (HC), the only treatment with proven efficacy. It is, however, not known how HC and conservative treatments are utilized in German hospitals, Furthermore, data on the care-situation of patients with MMI in Germany is scarce. METHODS: An anonymous questionnaire was sent to 297 neurological and 133 neurosurgical hospitals in Germany. RESULTS: The Response rate was 24,7%. Most respondents indicated personal experience in the treatment of MMI (83,3%). HC is usually performed early on site (83,3%). Indication to HC is confirmed on a high level of hierarchy and profession using clinical and radiological criteria in 78,2% of hospitals. Inherent standardized treatment protocols are established in 70,8% of hospitals. Patients are treated on an intensive care unit in 74,5% of hospitals after DHC and in 42,5% of hospitals under non-surgical treatment. Intracranial pressure monitoring is not performed on a regular basis. Differing opinions were observed concerning diagnosis and treatment of MMI without recognizable consensus. CONCLUSION: Basically, structural requirements for the treatment of MMI exist in the participating hospitals. Heterogeneity in the treatment of MMI is striking. The implementation of treatment protocols and adherence to guidelines are desirable steps to optimize treatment.

[Intensive care therapy of space-occupying large hemispheric infarction. Summary of the NCS/DGNI guidelines]. / Intensivtherapie des raumfordernden ischämischen Hemisphäreninfarkts. Zusammenfassung der NCS/DGNI-Leitlinie.

Large hemispheric infarction (LHI), synonymously called malignant middle cerebral artery (MCA) infarction, is a severe neurological disease with a high mortality and morbidity. Treating physicians as well as relatives are often faced with few and low quality data when attempting to apply optimal treatment to these patients and make decisions. While current stroke treatment guidelines focus on risk factors, prevention and acute management, they include only limited recommendations concerning intensive care management of LHI. The Neurocritical Care Society (NCS) and the German Society for Neurocritical and Emergency Medicine (DGNI) organized an interdisciplinary consensus conference on intensive care management of LHI to meet this demand. European and American experts in neurology, neurocritical care, neurosurgery, neuroradiology and neuroanesthesiology were selected based on their expertise and research focus. Subgroups for several main topics elaborated a number of central clinical questions concerning this topic and evaluated the quality of the currently available data according to the grading of recommendation assessment, development and evaluation (GRADE) guideline system. Subsequently, evidence-based recommendations were compiled after weighing the advantages against the disadvantages of certain management options. This is a commented abridged version of the results of the consensus conference.

[Current registry studies of acute ischemic stroke]. / Aktuelle Registerstudien beim akuten ischämischen Schlaganfall.

Study registries offer the opportunity to evaluate the effects of new therapies or to observe the consequences of new treatments in clinical practice. The SITS-MOST registry confirmed the validity of findings from randomized trials on intravenous thrombolysis concerning safety and efficacy in the clinical routine. Current study registries concerning new interventional thrombectomy techniques suggest a high recanalization rate; however, the clinical benefit can only be evaluated in randomized, controlled trials. Similarly, the experiences of the BASICS registry on basilar artery occlusion have led to the initiation of a controlled trial. The benefit of hemicraniectomy in malignant middle cerebral artery infarction has been demonstrated by the pooled analysis of three randomized trials. Numerous relevant aspects are currently documented in the DESTINY-R registry. Finally, the recently started RASUNOA registry examines diagnostic and therapeutic aspects of ischemic and hemorrhagic stroke occurring during therapy with new oral anticoagulants.

Patient outcomes in historical comparators compared with randomised-controlled trials.

BACKGROUND: Decompressive hemicraniectomy for malignant middle cerebral artery infarction has long been controversial. Recently, data from randomised-controlled trials have shown that the procedure is life-saving and improves outcome. However, these randomised-controlled trials were difficult to conduct, because of ethical considerations due to high mortality in control groups. While the use of historical comparators may not be ideal for phase III efficacy trials, these data may be useful to inform the selection of trial populations. We sought to replicate the findings of the DESTINY trial of decompressive surgery in malignant middle cerebral artery infarction using the Virtual International Stroke Trials Archive, to determine whether historical comparators could be used as an alternative to control groups in situations where randomised-controlled trials are infeasible or regarded as unethical due to the high mortality under conservative treatment. METHODS: We extracted data on patients from Virtual International Stroke Trials Archive who displayed signs of malignant middle cerebral artery infarction (baseline National Institutes of Health Stroke Scale> or =20, LOC1A score of > or =1 on the National Institutes of Health Stroke Scale at baseline, lesion volume > or =145 cm(3)). We used a chi(2)-test and logistic regression (adjusting for baseline National Institutes of Health Stroke Scale) to compare the functional outcomes (modified Rankin scores and Barthel index) at the last available follow-up assessment between the DESTINY surgical and the Virtual International Stroke Trials Archive comparator groups. We assessed 90-day survival rates using a Kaplan-Meier analysis and Cox proportional hazards modelling (adjusting for the baseline National Institutes of Health Stroke Scale score). RESULTS: Fewer patients in the Virtual International Stroke Trials Archive comparator group (n=6/32, 19% with a 90-day follow-up) achieved a good functional outcome by mRS at the final follow-up, when compared with the DESTINY surgical group (n=8/17, 47% with a 6-month follow-up; chi(2)-test, P=0.04). This difference persisted after adjusting for baseline National Institutes of Health Stroke Scale (logistic regression, P=0.04), but not when accounting for patient age (P=0.66). Analysis of Barthel index at the final follow-up revealed no significant difference between the two groups (chi(2)-test, P=0.07), although a trend towards a better outcome in the DESTINY group was observed. In contrast with the findings of the DESTINY trial, we found no significant difference in 90-day survival rates between the surgical (88%) and the Virtual International Stroke Trials Archive (72%) comparator groups (Cox proportional hazards model, P=0.24). CONCLUSION: The beneficial effects of decompressive hemicraniectomy on survival were not confirmed using a historical comparator dataset. Our observations might be due to the fact that patients with malignant middle cerebral artery infarction are usually excluded from clinical trials of drug efficacy, and patients identified from Virtual International Stroke Trials Archive may not have been truly representative of patients with malignant middle cerebral artery infarction. This mismatch could be rectified through recruitment of population-based studies and stroke registries to Virtual International Stroke Trials Archive to increase the number of patients eligible for entry into the comparator patient data pool.

[Acute stroke therapy. Current developments]. / Akuttherapie des Schlaganfalls. Was gibt es Neues?

This article covers three major topics of acute stroke therapy: extension of the time window for thrombolysis with desmoteplase, decompressive surgery after malignant middle cerebral artery infarction, and the effect of hemostatic therapy with recombinant activated factor VII (rFVIIa) in patients with spontaneous primary intracerebral hemorrhage. Thrombolytic therapy with recombinant tissue or tissue-type plasminogen activator is still the only approved acute stroke therapy within a 3-h time window. Imaging-based patient selection seems to help extending this time window. After promising results of two phase II trials with the thrombolytic agent desmoteplase in an extended time window after acute ischemic stroke, the DIAS-II study was reconducted in Europe, North America, and Australia as a phase III trial. First results of the included 186 patients are shown. Surprisingly, patients treated with desmoteplase had no better outcome than placebo-treated patients, and there was increased mortality in the high-dose group. Among all stroke subtypes, space-occupying malignant middle cerebral artery is one with the poorest prognosis. Most patients die within a few days due to the development of massive brain edema, despite maximum intensive care. Decompressive hemicraniectomy represents a much more effective therapy for the treatment of local brain swelling. However, until recently this method was highly controversial. Here we present the results of the randomized trials published in 2007 and discuss their relevance for acute therapy. Hematoma growth occurs within 4 h in one third of patients who suffer from intracerebral hemorrhage. Prospective, placebo-controlled, multicenter trials have shown that intravenous application of rFVIIa reduces volume increase. We present preliminary results of the latest phase III trial (FAST: recombinant factor VIIa in acute hemorrhagic stroke), which tried to find whether the hemostatic effect will translate into clinical effect.

Diagnostic performance of spectroscopic and perfusion MRI for distinction of brain tumors.

OBJECTIVE: To assess the value of spectroscopic and perfusion MRI for glioma grading and for distinguishing glioblastomas from metastases and from CNS lymphomas. METHODS: The authors examined 79 consecutive patients with first detection of a brain neoplasm on nonenhanced CT scans and no therapy prior to evaluation. Spectroscopic MRI; arterial spin-labeling MRI for measuring cerebral blood flow (CBF); first-pass dynamic, susceptibility-weighted, contrast-enhanced MRI for measuring cerebral blood volume; and T1-weighted dynamic contrast-enhanced MRI were performed. Receiver operating characteristic analysis was performed, and optimum thresholds for tumor classification and glioma grading were determined. RESULTS: Perfusion MRI had a higher diagnostic performance than spectroscopic MRI. Because of a significantly higher tumor blood flow in glioblastomas compared with CNS lymphomas, a threshold value of 1.2 for CBF provided sensitivity of 97%, specificity of 80%, positive predictive value (PPV) of 94%, and negative predictive value (NPV) of 89%. Because CBF was significantly higher in peritumoral nonenhancing T2-hyperintense regions of glioblastomas compared with metastases, a threshold value of 0.5 for CBF provided sensitivity, specificity, PPV, and NPV of 100%, 71%, 94%, and 100%. Glioblastomas had the highest tumor blood flow values among all other glioma grades. For discrimination of glioblastomas from grade 3 gliomas, sensitivity was 97%, specificity was 50%, PPV was 84%, and NPV was 86% (CBF threshold value of 1.4), and for discrimination of glioblastomas from grade 2 gliomas, sensitivity was 94%, specificity was 78%, PPV was 94%, and NPV was 78% (CBF threshold value of 1.6). CONCLUSION: Perfusion MRI is predictive in distinguishing glioblastomas from metastases, CNS lymphomas and other gliomas vs MRI and magnetic resonance spectroscopy.

[The value of platelet inhibitors in the secondary prophylaxis of stroke -- a review]. / Stellenwert von Thrombozyten-Aggregationshemmern in der Sekundärprävention des ischämischen Schlaganfalls.

INTRODUCTION: The goal of secondary prophylaxis following cerebral ischemia is a long lasting inhibition of thrombogenesis to prevent recurrent stroke or other vascular events. Platelet inhibitors (PI) according to meta-analyses lead to a relative risk reduction (RRR) of 22 % for vascular events after stroke. The aim of this article is a summary and critical review of all relevant studies and meta-analyses for secondary prevention of stroke and to give a differentiated therapeutic recommendation. METHODS: We performed a careful and extensive review of the present literature for PI in the secondary prevention of stroke. Next to the classic meta-analyses such as the Antiplatelet Trialists' analysis, the relevant single trials (e. g. CATS, TASS, ESPS 2, CURE, CAPRIE) as well as meta-analyses and post hoc analyses of these studies are summarized and interpreted. Therapeutic recommendations are in consistence with the recommendations and guidelines of national (DGN), European (EUSI) and international (AHA/ASA) Groups/Associations. Also, the present literature was searched for new information with regard to side effects and pharmacological interactions and introduced into the review. CONCLUSIONS: ASA reduces the RR after TIA/stroke by approximately 13 % and has the same efficacy with less side effects in lower dosages (50 - 325 mg/Tag). Ticlopidine is a reserve drug due to its unfavorable side effect profile (neutropenia, TTP). Clopidogrel is better than ASA (RRR 8.7 %) for vascular patients in preventing another vascular event (stroke, MI, vascular death). This effect is pronounced in patients at high risk for atherothrombotic events such as previous MI, cardiac surgery, or diabetes. Dipyridamole+ASA is better than ASA in patients with TIA/stroke (in indirect comparison also than Clopidogrel) for the secondary prevention of recurrent stroke (RRR 23 %), but not for the prevention of other vascular events. Therefore, Clopidogrel should be primarily given to patients with a high vascular risk (one or more cardiovascular risk factors) or to patients with ASA intolerance. Dipyridamole/ASA should be primarily given to TIA/stroke patients with a lower cardiovascular comorbidity. Studies for the combination of Clopidogrel/ASA (MATCH, CHARISMA) and for the comparison of both combinations (PRoFESS) are underway. At present, the combination of clopidogrel and ASA for cerebrovascular prevention should only be given within controlled studies or as an individual treatment with an accordingly acquired informed consent.

Induction of interleukin-6 by depolarization of neurons.

Interleukin-6 (IL-6) has neuromodulatory and neuroprotective effects in vivo. It is expressed in glial cells and neurons both under physiological conditions and in various neurological diseases. Although the expression of IL-6 in glia has been intensely investigated, little is known about the regulation of IL-6 production by neurons. Therefore, we investigated the regulation of IL-6 expression in neurons. Membrane depolarization raised IL-6 mRNA accumulation in primary cortical cells and the PC-12 cell line. In vivo, IL-6 mRNA in the brain increased significantly after epileptic seizures. To investigate IL-6 gene transcription, PC-12 cells were transfected with reporter gene constructs containing the human IL-6 promoter. Membrane depolarization raised IL-6 transcription twofold to fourfold. This increase could be blocked by lowering extracellular Ca(2+) levels or by inhibiting L-type Ca(2+) channels or Ca(2+)/calmodulin-dependent protein kinases. Internal mutations in various elements of the IL-6 promoter revealed the glucocorticoid response element (GRE) 2 to be a depolarization-responsive element. Although the GRE2 bound the glucocorticoid receptor (GR) and was stimulated by dexamethasone, the GR was not responsible for the effect of membrane depolarization because a consensus GRE did not mediate stimulation by membrane depolarization. Instead, another yet undefined factor that binds to the IL-6 GRE2 may mediate the response to membrane depolarization. These data demonstrate that the expression of IL-6 in neurons is regulated by membrane depolarization and suggest a novel Ca(2+)-responsive promoter element. Through this mechanism, IL-6 may function as a neuromodulator induced by neuronal activity.