GFAP point-of-care measurement for prehospital diagnosis of intracranial hemorrhage in acute coma.

BACKGROUND: Prehospital triage and treatment of patients with acute coma is challenging for rescue services, as the underlying pathological conditions are highly heterogenous. Recently, glial fibrillary acidic protein (GFAP) has been identified as a biomarker of intracranial hemorrhage. The aim of this prospective study was to test whether prehospital GFAP measurements on a point-of-care device have the potential to rapidly differentiate intracranial hemorrhage from other causes of acute coma. METHODS: This study was conducted at the RKH Klinikum Ludwigsburg, a tertiary care hospital in the northern vicinity of Stuttgart, Germany. Patients who were admitted to the emergency department with the prehospital diagnosis of acute coma (Glasgow Coma Scale scores between 3 and 8) were enrolled prospectively. Blood samples were collected in the prehospital phase. Plasma GFAP measurements were performed on the i-STAT Alinity® (Abbott) device (duration of analysis 15 min) shortly after hospital admission. RESULTS: 143 patients were enrolled (mean age 65 ± 20 years, 42.7% female). GFAP plasma concentrations were strongly elevated in patients with intracranial hemorrhage (n = 51) compared to all other coma etiologies (3352 pg/mL [IQR 613-10001] vs. 43 pg/mL [IQR 29-91.25], p < 0.001). When using an optimal cut-off value of 101 pg/mL, sensitivity for identifying intracranial hemorrhage was 94.1% (specificity 78.9%, positive predictive value 71.6%, negative predictive value 95.9%). In-hospital mortality risk was associated with prehospital GFAP values. CONCLUSION: Increased GFAP plasma concentrations in patients with acute coma identify intracranial hemorrhage with high diagnostic accuracy. Prehospital GFAP measurements on a point-of-care platform allow rapid stratification according to the underlying cause of coma by rescue services. This could have major impact on triage and management of these critically ill patients.

Outcome of glioblastoma patients after intensive care unit admission with invasive mechanical ventilation: a multicenter analysis.

PURPOSE: Patients with glioblastoma are exposed to severe symptoms and organs failures (e.g., coma or acute respiratory failure), that may require intensive care unit (ICU) admission and invasive mechanical ventilation (IMV). However, only limited data are available concerning the prognosis of patients with glioblastoma receiving IMV. We sought to describe the reasons for ICU admission, and outcomes of patients with glioblastoma requiring IMV for unplanned critical complications. METHODS: In this retrospective analysis, four certified interdisciplinary brain tumor centers performed a retrospective review of their electronic data systems. All patients with glioblastoma admitted to an in-house ICU and receiving IMV between January 2015 and December 2019 were included. Clinical and prognostic factors as well as relevant outcome parameters were evaluated by group comparisons and Kaplan Meier survival curves. RESULTS: We identified 33 glioblastoma patients with a duration of IMV of 9.2 ± 9.4 days. Main reasons for ICU admission were infection (n = 12; 34.3%) including 3 cases of Pneumocystis jirovecii pneumonia, status epilepticus (31.4%) and elevated intracranial pressure (22.9%). In-hospital mortality reached 60.6%. Younger age, low number of IMV days, better Karnofsky Performance Status Scale before admission and elevated intracranial pressure as cause of ICU admission were associated with positive prognostic outcome. CONCLUSION: We conclude that less than 50% of patients with glioblastoma have a favorable short-term outcome when unplanned ICU treatment with IMV is required. Our data mandate a careful therapy guidance and frequent reassessment of goals during ICU stay.

Diagnostic performance of Glial Fibrillary Acidic Protein and Prehospital Stroke Scale for identification of stroke and stroke subtypes in an unselected patient cohort with symptom onset < 4.5 h.

INTRODUCTION: Rapid identification and treatment of stroke is crucial for the outcome of the patient. We aimed to determine the performance of glial fibrillary acidic protein (GFAP) independently and in combination with the Prehospital Stroke Score (PreSS) for identification and differentiation of acute stroke within 4.5 h after symptom onset. PATIENTS AND METHODS: Clinical data and serum samples were collected from the Treat-Norwegian Acute Stroke Prehospital Project (Treat-NASPP). Patients with suspected stroke and symptoms lasting ≤ 4.5 h had blood samples collected and were evaluated with the National Institutes of Health Stroke Scale prospectively. In this sub study, NIHSS was retrospectively translated into PreSS and GFAP was measured using the sensitive single molecule array (SIMOA). RESULTS: A total of 299 patients with suspected stroke were recruited from Treat-NASPP and included in this study (44% acute ischemic stroke (AIS), 10% intracranial hemorrhage (ICrH), 7% transient ischemic attack (TIA), and 38% stroke mimics). ICrH was identified with a cross-fold validated area under the receiver-operating characteristic curve (AUC) of 0.73 (95% CI 0.62-0.84). A decision tree with PreSS and GFAP combined, first identified patients with a low probability of stroke. Subsequently, GFAP detected patients with ICrH with a 25.0% sensitivity (95% CI 11.5-43.4) and 100.0% specificity (95% CI 98.6-100.0). Lastly, patients with large-vessel occlusion (LVO) were detected with a 55.6% sensitivity (95% CI 35.3-74.5) and 82.4% specificity (95% CI 77.3-86.7). CONCLUSION: In unselected patients with suspected stroke, GFAP alone identified ICrH. Combined in a decision tree, GFAP and PreSS identified subgroups with high proportions of stroke mimics, ICrH, LVO, and AIS (non-LVO strokes).

Differential expression of CD8 defines phenotypically distinct cytotoxic T cells in cancer and multiple sclerosis.

BACKGROUND: Cytotoxic T lymphocytes take on a leading role in many immune-related diseases. They function as key effector immune cells fighting cancer cells, but they are also considerably involved in autoimmune diseases. Common to both situations, CD8+ T cells need to adapt their metabolism and effector function to the harsh and nutrient-deprived conditions of the disease-associated microenvironment. METHODS: We used an in vitro starvation as well as rapamycin treatment protocol mimicking nutrient deprivation to generate CD8Low versus CD8High T cells and performed FACS-Sorting followed by transcriptomic profiling of the cytotoxic T cell subsets. Prominent markers identified in the CD8Low versus the CD8High T cells were then used to investigate the presence of these cell subsets in immune-related human diseases. Employing cancer tissue microarrays and PhenOptics multispectral imaging as well as flow cytometry, we studied these CD8+ T cell subsets in cancer and relapsing-remitting multiple sclerosis patients. RESULTS: Starvation induced a decreased expression of CD8, yielding a CD8Low T cell subpopulation with an altered transcriptomic signature and reduced effector function. CD8Low T cell showed enhanced ST2L and IL6ST (CD130) expression compared to CD8High T cells which expressed elevated KLRD1 (CD94) and granzyme B levels within the tumour microenvironment (TME). Spatial analysis revealed the presence of CD8High T cells in close proximity to tumour cells, while the CD8Low T cells resided at the tumour boundaries. Importantly, the number of tumour-infiltrating CD8Low T lymphocytes correlated with a poor prognosis as well as with enhanced cancer progression in human mammary carcinoma. We also found a reduced frequency of CD8Low T lymphocytes in a cohort of relapse (disease active) multiple sclerosis patients compared to healthy subjects during immune cell starvation in vitro. CONCLUSIONS: In summary, our data show that functionally distinct cytotoxic T lymphocytes can be identified based on their expression of CD8. Indicating a more general role in CD8 T cell immunity, these cells may play opposing roles in the TME, and also in the pathophysiology of autoimmune diseases such as multiple sclerosis.

Decline in the number of patients with meningitis in German hospitals during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVES: In 2020, a wide range of hygiene measures was implemented to mitigate infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In consequence, pulmonary infections due to other respiratory pathogens also decreased. Here, we evaluated the number of bacterial and viral meningitis and encephalitis cases during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: In a multicentre retrospective analysis of data from January 2016 until December 2020, numbers of patients diagnosed with bacterial meningitis and other types of CNS infections (such as viral meningitis and encephalitis) at 26 German hospitals were studied. Furthermore, the number of common meningitis-preceding ear-nose-throat infections (sinusitis, mastoiditis and otitis media) was evaluated. RESULTS: Compared to the previous years, the total number of patients diagnosed with pneumococcal meningitis was reduced (n = 64 patients/year in 2020 vs. n = 87 to 120 patients/year between 2016 and 2019, all p < 0.05). Additionally, the total number of patients diagnosed with otolaryngological infections was significantly lower (n = 1181 patients/year in 2020 vs. n = 1525 to 1754 patients/year between 2016 and 2019, all p < 0.001). We also observed a decline in viral meningitis and especially enterovirus meningitis (n = 25 patients/year in 2020 vs. n = 97 to 181 patients/year between 2016 and 2019, all p < 0.001). DISCUSSION: This multicentre retrospective analysis demonstrates a decline in the number of patients treated for viral and pneumococcal meningitis as well as otolaryngological infections in 2020 compared to previous years. Since the latter often precedes pneumococcal meningitis, this may point to the significance of the direct spread of pneumococci from an otolaryngological focus such as mastoiditis to the brain as one important pathophysiological route in the development of pneumococcal meningitis.

Role of S100B Serum Concentration as a Surrogate Outcome Parameter After Mechanical Thrombectomy.

BACKGROUND AND OBJECTIVES: To establish serum concentration of protein S100B as an objective biomarker surrogate for astroglial tissue damage after mechanical thrombectomy in patients with acute ischemic stroke. METHODS: This prospective 2-center study recruited patients with acute middle cerebral artery infarctions caused by large vessel occlusion treated with mechanical thrombectomy. Blood samples were collected at day 2 after intervention and analyzed for S100B serum concentrations using ELISA techniques. Infarct size was determined on follow-up brain imaging and functional outcome according to modified Rankin Scale (mRS) was assessed at 90 days. RESULTS: A total of 171 patients were included (mean age ± SD: 70 ± 14 years, 42% female). S100B levels correlated with infarct size. Median S100B concentrations at day 2 after intervention were lower in patients with favorable outcome (mRS score 0-1) at 90 days compared to patients with unfavorable outcome (mRS score 2-6) (median 0.10 µg/L [interquartile range 0.07-0.14] vs 0.20 µg/L [0.11-0.48], p < 0.001). Younger age (odds ratio [OR] 1.120 [confidence interval (CI) 1.068-1.174]; p < 0.001), lower National Institutes of Health Stroke Scale score 24 hours after symptom onset (OR 1.232 [CI 1.106-1.372]; p < 0.001), and lower S100B serum concentrations (OR 1.364 [CI 1.105-1.683]; p = 0.004) were independently associated with a favorable outcome. S100B was able to eliminate the lateralization bias associated with the use of mRS for functional outcome assessment at 90 days after stroke. DISCUSSION: S100B serum concentrations after mechanical thrombectomy indicate the extent of ischemic tissue damage. This can be assessed rapidly, independent of brain imaging and clinical outcome scales. Following prospective validation in further studies, this may provide an objective surrogate outcome measure both in clinical routine and interventional trials. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that S100B 2 days following mechanical thrombectomy for acute ischemic stroke accurately distinguishes favorable from unfavorable functional outcome.

Isoflurane in (Super-) Refractory Status Epilepticus: A Multicenter Evaluation.

BACKGROUND: We aimed to determine the association between seizure termination and side effects of isoflurane for the treatment of refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) in neurointensive care units (neuro-ICUs). METHODS: This was a multicenter retrospective study of patients with RSE/SRSE treated with isoflurane for status epilepticus termination admitted to the neuro-ICUs of nine German university centers during 2011-2018. RESULTS: We identified 45 patients who received isoflurane for the treatment of RSE/SRSE. During isoflurane treatment, electroencephalograms showed no epileptiform discharges in 33 of 41 (80%) patients, and burst suppression pattern was achieved in 29 of 41 patients (71%). RSE/SRSE was finally terminated after treatment with isoflurane in 23 of 45 patients (51%) for the entire group and in 13 of 45 patients (29%) without additional therapy. Lengths of stay in the hospital and in the neuro-ICU were significantly extended in cases of ongoing status epilepticus under isoflurane treatment (p = 0.01 for length of stay in the hospital, p = 0.049 for length in the neuro-ICU). During isoflurane treatment, side effects were reported in 40 of 45 patients (89%) and mainly included hypotension (n = 40, 89%) and/or infection (n = 20, 44%). Whether side effects occurred did not affect the outcome at discharge. Of 22 patients with follow-up magnetic resonance imaging, 2 patients (9%) showed progressive magnetic resonance imaging alterations that were considered to be potentially associated with RSE/SRSE itself or with isoflurane therapy. CONCLUSIONS: Isoflurane was associated with a good effect in stopping RSE/SRSE. Nevertheless, establishing remission remained difficult. Side effects were common but without effect on the outcome at discharge.

Proteomics-Based Approach to Identify Novel Blood Biomarker Candidates for Differentiating Intracerebral Hemorrhage From Ischemic Stroke-A Pilot Study.

Background: A reliable distinction between ischemic stroke (IS) and intracerebral hemorrhage (ICH) is required for diagnosis-specific treatment and effective secondary prevention in patients with stroke. However, in resource-limited settings brain imaging, which is the current diagnostic gold standard for this purpose, is not always available in time. Hence, an easily accessible and broadly applicable blood biomarker-based diagnostic test differing stroke subtypes would be desirable. Using an explorative proteomics approach, this pilot study aimed to identify novel blood biomarker candidates for distinguishing IS from ICH. Material and Methods: Plasma samples from patients with IS and ICH were drawn during hospitalization and were analyzed by using liquid chromatography/mass spectrometry. Proteins were identified using the human reference proteome database UniProtKB, and label-free quantification (LFQ) data were further analyzed using bioinformatic tools. Results: Plasma specimens of three patients with IS and four patients with ICH with a median National Institute of Health Stroke Scale (NIHSS) of 12 [interquartile range (IQR) 10.5-18.5] as well as serum samples from two healthy volunteers were analyzed. Among 495 identified protein groups, a total of 368 protein groups exhibited enough data points to be entered into quantitative analysis. Of the remaining 22 top-listed proteins, a significant difference between IS and ICH was found for Carboxypeptidase N subunit 2 (CPN2), Coagulation factor XII (FXII), Plasminogen, Mannan-binding lectin serine protease 1, Serum amyloid P-component, Paraoxonase 1, Carbonic anhydrase 1, Fibulin-1, and Granulins. Discussion: In this exploratory proteomics-based pilot study, nine candidate biomarkers for differentiation of IS and ICH were identified. The proteins belong to the immune system, the coagulation cascade, and the apoptosis system, respectively. Further investigations in larger cohorts of patients with stroke using additional biochemical analysis methods, such as ELISA or Western Blotting are now necessary to validate these markers, and to characterize diagnostic accuracy with regard to the development of a point-of-care-system for use in resource-limited areas.

Ischemic Lesion Location Based on the ASPECT Score for Risk Assessment of Neurogenic Dysphagia.

Dysphagia is common in patients with middle cerebral artery (MCA) infarctions and associated with malnutrition, pneumonia, and mortality. Besides bedside screening tools, brain imaging findings may help to timely identify patients with swallowing disorders. We investigated whether the Alberta stroke program early CT score (ASPECTS) allows for the correlation of distinct ischemic lesion patterns with dysphagia. We prospectively examined 113 consecutive patients with acute MCA infarctions. Fiberoptic endoscopic evaluation of swallowing (FEES) was performed within 24 h after admission for validation of dysphagia. Brain imaging (CT or MRI) was rated for ischemic changes according to the ASPECT score. 62 patients (54.9%) had FEES-proven dysphagia. In left hemispheric strokes, the strongest associations between the ASPECTS sectors and dysphagia were found for the lentiform nucleus (odds ratio 0.113 [CI 0.028-0.433; p = 0.001), the insula (0.275 [0.102-0.742]; p = 0.011), and the frontal operculum (0.280 [CI 0.094-0.834]; p = 0.022). A combination of two or even all three of these sectors together increased relative dysphagia frequency up to 100%. For right hemispheric strokes, only non-significant associations were found which were strongest for the insula region. The distribution of early ischemic changes in the MCA territory according to ASPECTS may be used as risk indicator of neurogenic dysphagia in MCA infarction, particularly when the left hemisphere is affected. However, due to the exploratory nature of this research, external validation studies of these findings are warranted in future.

Comparing Programming Sessions of Vim-DBS.

Background: Essential Tremor (ET) is a progressive neurological disorder characterized by postural and kinetic tremor most commonly affecting the hands and arms. Medically intractable ET can be treated by deep brain stimulation (DBS) of the ventral intermediate nucleus of thalamus (VIM). We investigated whether the location of the effective contact (most tremor suppression with at least side effects) in VIM-DBS for ET changes over time, indicating a distinct mechanism of loss of efficacy that goes beyond progression of tremor severity, or a mere reduction of DBS efficacy. Methods: We performed programming sessions in 10 patients who underwent bilateral vim-DBS surgery between 2009 and 2017 at our department. In addition to the intraoperative (T1) and first clinical programming session (T2) a third programming session (T3) was performed to assess the effect- and side effect threshold (minimum voltage at which a tremor suppression or side effects occurred). Additionally, we compared the choice of the effective contact between T1 and T2 which might be affected by a surgical induced "brain shift." Discussion: Over a time span of about 4 years VIM-DBS in ET showed continuous efficacy in tremor suppression during stim-ON compared to stim-OFF. Compared to immediate postoperative programming sessions in ET-patients with DBS, long-term evaluation showed no relevant change in the choice of contact with respect to side effects and efficacy. In the majority of the cases the active contact at T2 did not correspond to the most effective intraoperative stimulation site T1, which might be explained by a brain-shift due to cerebral spinal fluid loss after neurosurgical procedure.

Diagnostic Accuracy of Glial Fibrillary Acidic Protein and Ubiquitin Carboxy-Terminal Hydrolase-L1 Serum Concentrations for Differentiating Acute Intracerebral Hemorrhage from Ischemic Stroke.

BACKGROUND: Biomarkers indicative of intracerebral hemorrhage (ICH) may help triage acute stroke patients in the pre-hospital phase. We hypothesized that serum concentration of glial fibrillary acidic protein (GFAP) in combination with ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), measured by a rapid bio-assay, could be used to distinguish ICH from ischemic stroke. METHODS: This prospective two-center study recruited patients with a clinical diagnosis of acute stroke both in the pre-hospital phase and at hospital admission (within 4 and 6 h after symptom onset, respectively). Blood samples were analyzed for concentrations of GFAP and UCH-L1 using ELISA techniques. The reference standard was the diagnosis of ICH, ischemic stroke, or stroke mimicking condition achieved after clinical workup including brain imaging. RESULTS: A total of 251 patients were included (mean age [± SD] 72 ± 15 years; 5 ICH, 23 ischemic strokes and 14 stroke mimics in the pre-hospital part; and 59 ICH, 148 ischemic strokes and 2 stroke mimics in the in-hospital part). Mean delay (± SD) from symptom onset to blood withdrawal was 130 ± 79 min for the pre-hospital patients and 136 ± 86 min for the in-hospital patients. Both GFAP and UCH-L1 serum concentrations were higher in patients having ICH as compared to other diagnoses (GFAP: median 330 ng/L [interquartile range 64-7060, range 8-56,100] vs. 27.5 ng/L [14-57.25, 0-781], p < 0.001; UCH-L1: 401 ng/L [265-764, 133-1812] vs. 338 ng/L [213-549.5, 0-2950], p = 0.025). Area-under-the-curve values were 0.866 (95% CI 0.809-0.924, p < 0.001) for GFAP, and 0.590 (0.511-0.670, p = 0.033) for UCH-L1. Regarding overall diagnostic accuracy, UCH-L1 did not add significantly to the performance of GFAP. CONCLUSIONS: GFAP may differentiate ICH from ischemic stroke and stroke mimics. A point-of-care test to distinguish between ischemic and hemorrhagic strokes might facilitate triage to different treatment pathways or locations, or be used to select patients for trials of ultra-early interventions.

Beta adrenoceptor blockade ameliorates impaired glucose tolerance and alterations of the cerebral ceramide metabolism in an experimental model of ischemic stroke.

BACKGROUND: Sphingolipids are versatile signaling molecules derived from membrane lipids of eukaryotic cells. Ceramides regulate cellular processes such as proliferation, differentiation and apoptosis and are involved in cellular stress responses. Experimental evidence suggests a pivotal role of sphingolipids in the pathogenesis of cardiovascular diseases, including ischemic stroke. A neuroprotective effect has been shown for beta-adrenergic antagonists in rodent stroke models and supported by observational clinical data. However, the exact underlying pathophysiological mechanisms are still under investigation. We aimed to examine the influence of propranolol on the ceramide metabolism in the stroke-affected brain. METHODS: Mice were subjected to 60 or 180 min transient middle cerebral artery occlusion (tMCAO) and infarct size, functional neurological deficits, glucose tolerance, and brain ceramide levels were assessed after 12, 24, and 72 h to evaluate whether the latter two processes occur in a similar time frame. Next, we assessed the effects of propranolol (10 mg/kg bw) at 0, 4 and 8 h after tMCAO and FTY720 (fingolimod; 1 mg/kg) on infarct size, functional outcome, immune cell counts and brain ceramide levels at 24 h after 60 min tMCAO. RESULTS: We found a temporal coincidence between stroke-associated impaired glucose tolerance and brain ceramide accumulation. Whereas propranolol reduced ischemic lesion size, improved functional outcome and reduced brain ceramide accumulation without an effect on circulating immune cells, FTY720 showed the known neuroprotective effect and strong reduction of circulating immune cells without affecting brain ceramide accumulation. CONCLUSIONS: Propranolol ameliorates both stroke-associated impairment of glucose tolerance and brain ceramide accumulation which are temporally linked, strengthening the evidence for a role of the sympathetic nervous system in regulating post-stroke glucose metabolism and its metabolic consequences in the brain.

Predictors of Dysphagia in Acute Pontine Infarction.

BACKGROUND AND PURPOSE: Little is known about the frequency and the clinical characteristics of neurogenic dysphagia in pontine strokes. In this study, we sought to identify predictors for dysphagia in a cohort of patients with isolated pontine infarctions. METHODS: We included all patients admitted to our department between 2008 and 2014 having an acute (<48 hours after symptom onset) ischemic stroke in the pons, as documented by means of diffusion-weighted magnetic resonance imaging. Precise infarct localization was stratified according to established vascular territories. The presence of dysphagia was the primary end point of the study and was assessed by a Speech-Language Pathologist according to defined criteria. RESULTS: The study recruited 59 patients, 14 with and 45 without dysphagia. Median (interquartile range) stroke severity (in terms of National Institutes of Health Stroke Scale values) was higher in the dysphagic group as compared with patients without dysphagia (8.5 [6-12] versus 2 [1-5]; P<0.001). Infarct localization in the upper part of the pons (78.6% versus 33.3%; P=0.004) and in the anterolateral vascular territory (78.6% versus 31.1%; P=0.002) occurred more often in the dysphagic group. In a multivariate model, age, infarct volume, and National Institutes of Health Stroke Scale value were independent predictors of dysphagia. CONCLUSIONS: Dysphagia occurs frequently in patients with isolated pontine infarctions. Clinical and imaging predictors of dysphagia may help to provide optimal screening, to prevent complications and to improve long-term prognosis.

Reliability of infarct volumetry: Its relevance and the improvement by a software-assisted approach.

Despite the efficacy of neuroprotective approaches in animal models of stroke, their translation has so far failed from bench to bedside. One reason is presumed to be a low quality of preclinical study design, leading to bias and a low a priori power. In this study, we propose that the key read-out of experimental stroke studies, the volume of the ischemic damage as commonly measured by free-handed planimetry of TTC-stained brain sections, is subject to an unrecognized low inter-rater and test-retest reliability with strong implications for statistical power and bias. As an alternative approach, we suggest a simple, open-source, software-assisted method, taking advantage of automatic-thresholding techniques. The validity and the improvement of reliability by an automated method to tMCAO infarct volumetry are demonstrated. In addition, we show the probable consequences of increased reliability for precision, p-values, effect inflation, and power calculation, exemplified by a systematic analysis of experimental stroke studies published in the year 2015. Our study reveals an underappreciated quality problem in translational stroke research and suggests that software-assisted infarct volumetry might help to improve reproducibility and therefore the robustness of bench to bedside translation.

Glial Fibrillary Acidic Protein Serum Levels Distinguish between Intracerebral Hemorrhage and Cerebral Ischemia in the Early Phase of Stroke.

BACKGROUND: Recent studies have suggested that glial fibrillary acidic protein (GFAP) serum concentrations distinguish between intracerebral hemorrhage (ICH) and ischemic stroke (IS) shortly after symptom onset. In this prospective multicenter trial we validated GFAP in an independent patient cohort and assessed the quantitative relationship between GFAP release, bleeding size, and localization. METHODS: We included patients with a persistent neurological deficit (NIH Stroke Scale ≥4) suggestive of stroke within 6 h of symptom onset. Blood samples were drawn at hospital admission. GFAP serum concentrations were measured using an electrochemiluminometric immunoassay. Primary endpoint was the final diagnosis established at hospital discharge (ICH, IS, or stroke mimic). RESULTS: 202 patients were included (45 with ICH, 146 with IS, 11 stroke mimics). GFAP concentrations were significantly higher in ICH than in IS patients [median (interquartile range) 0.16 µg/L (0.04-3.27) vs 0.01 µg/L (0.01-0.01), P <0.001]. A GFAP cutoff of 0.03 µg/L provided a sensitivity of 77.8% and a specificity of 94.2% in distinguishing ICH from IS and stroke mimics [ROC analysis area under the curve 0.872 (95% CI, 0.802-0.942), P <0.001]. GFAP serum concentrations were positively correlated with ICH volume. Lobar ICH volumes were larger and thus associated with higher GFAP concentrations as compared to deep ICH. CONCLUSIONS: Serum GFAP was confirmed to be a biomarker indicating ICH in patients presenting with acute stroke symptoms. Very small ICH may be missed owing to less tissue destruction.

Adherence to oral anticoagulant therapy in secondary stroke prevention - impact of the novel oral anticoagulants.

BACKGROUND: Oral anticoagulant therapy (OAT) potently prevents strokes in patients with atrial fibrillation. Vitamin K antagonists (VKA) have been the standard of care for long-term OAT for decades, but non-VKA oral anticoagulants (NOAC) have recently been approved for this indication, and raised many questions, among them their influence on medication adherence. We assessed adherence to VKA and NOAC in secondary stroke prevention. METHODS: All patients treated from October 2011 to September 2012 for ischemic stroke or transient ischemic attack with a subsequent indication for OAT, at three academic hospitals were entered into a prospective registry, and baseline data and antithrombotic treatment at discharge were recorded. At the 1-year follow-up, we assessed the adherence to different OAT strategies and patients' adherence to their respective OAT. We noted OAT changes, reasons to change treatment, and factors that influence persistence to the prescribed OAT. RESULTS: In patients discharged on OAT, we achieved a fatality corrected response rate of 73.3% (n=209). A total of 92% of these patients received OAT at the 1-year follow-up. We observed good adherence to both VKA and NOAC (VKA, 80.9%; NOAC, 74.8%; P=0.243) with a statistically nonsignificant tendency toward a weaker adherence to dabigatran. Disability at 1-year follow-up was an independent predictor of lower adherence to any OAT after multivariate analysis, whereas the choice of OAT did not have a relevant influence. CONCLUSION: One-year adherence to OAT after stroke is strong (>90%) and patients who switch therapy most commonly switch toward another OAT. The 1-year adherence rates to VKA and NOAC in secondary stroke prevention do not differ significantly between both therapeutic strategies.

Perioperative cerebral ischemia promote infiltrative recurrence in glioblastoma.

BACKGROUND: Hypoxia is a key driver for infiltrative growth in experimental gliomas. It has remained elusive whether tumor hypoxia in glioblastoma patients contributes to distant or diffuse recurrences. We therefore investigated the influence of perioperative cerebral ischemia on patterns of progression in glioblastoma patients. METHODS: We retrospectively screened MRI scans of 245 patients with newly diagnosed glioblastoma undergoing resection for perioperative ischemia near the resection cavity. 46 showed relevant ischemia nearby the resection cavity. A control cohort without perioperative ischemia was generated by a 1:1 matching using an algorithm based on gender, age and adjuvant treatment. Both cohorts were analyzed for patterns of progression by a blinded neuroradiologist. RESULTS: The percentage of diffuse or distant recurrences at first relapse was significantly higher in the cohort with perioperative ischemia (61.1%) compared to the control cohort (19.4%). The results of the control cohort matched well with historical data. The change in patterns of progression was not associated with a difference in survival. CONCLUSIONS: This study reveals an unrecognized association of perioperative cerebral ischemia with distant or diffuse recurrence in glioblastoma. It is the first clinical study supporting the concept that hypoxia is a key driver of infiltrative tumor growth in glioblastoma patients.

Prescription frequency and predictors for the use of novel direct oral anticoagulants for secondary stroke prevention in the first year after their marketing in Europe--a multicentric evaluation.

BACKGROUND: Direct oral anticoagulants (DOAC) are alternatives to the use of vitamin K antagonists (VKA) as oral anticoagulant therapies to prevent stroke in patients with atrial fibrillation. AIMS: We assembled a representative secondary prevention cohort from four tertiary care stroke centers to identify factors that independently influence therapeutic decision making 1) not to anticoagulate with either VKA or DOAC and 2) to use DOAC if the patient appears suitable for oral anticoagulant therapy. METHODS: We identified all patients discharged with the diagnoses 'ischemic stroke' (ICD-10 code I63) or 'transient ischemic attack' (G45) in combination with 'atrial fibrillation' (I48) during 1 year. We performed binary logistic regression analyses to identify factors independently influencing the aforementioned decisions. RESULTS: Our cohort comprised 758 patients. At discharge from the stroke service, 374 patients (49·3%) received oral anticoagulant therapy. Older age, severe stroke, poor recovery in the acute phase, and higher serum creatinine were independent factors to withhold oral anticoagulant therapy, whereas prior oral anticoagulant therapy favored the decision to anticoagulate. Among patients who were anticoagulated, prescription was balanced for VKA (50·3%) and DOAC (49·7%). Renal function and prior oral anticoagulant therapies were the most important factors in this decision. CONCLUSIONS: Shortly after their marketing, DOAC are used as frequently as VKA for secondary stroke prevention in patients with atrial fibrillation. The decision between VKA and DOAC is mainly determined by the patient's renal function and the absence or presence of prior oral anticoagulant therapy.

mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy.

A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.

The gap between trial data and clinical practice -- an analysis of case reports on bleeding complications occurring under dabigatran and rivaroxaban anticoagulation.

BACKGROUND: The novel direct oral anticoagulants (NOA), dabigatran (a thrombin inhibitor), rivaroxaban and apixaban (factor Xa inhibitors) have shown at least noninferiority compared to warfarin concerning the prevention of stroke and systemic embolism as well as the risk of hemorrhagic complications in large phase III trials in patients with atrial fibrillation (AF). These results have been obtained under regular monitoring of side effects and reinforcement of medication adherence in carefully controlled clinical trials. To what extent they translate into clinical practice is a matter of ongoing research. While postmarketing registers, most prominently the GLORIA-AF registry, are currently recruiting and will not report data for several years, we aimed at extracting risk factors for hemorrhagic complications under NOA from all available case reports and single case series published to date. METHODS: To identify risk factors which increase the risk of hemorrhage under NOA, we performed a PubMed search for both dabigatran and rivaroxaban, as well as three search terms for hemorrhagic complications. The cases of hemorrhagic complications were analyzed for the presence of the following four factors: 'prescriber errors', 'unfavorable comedications', 'renal impairment' and 'prescription of NOA in the frail elderly'. RESULTS AND DISCUSSION: We found a discrepancy in the frequency of case reports on hemorrhagic complications to the disadvantage of dabigatran which can hardly be attributed to the earlier marketing time of dabigatran alone. As risk factors, we identified prescriber errors, impaired renal function, comedication with antiplatelet drugs or p-glycoprotein inhibitors, old age and low body weight. Strikingly, the majority of the bleeding complications reported in this compilation of case reports showed at least one and in most cases several risk factors. CONCLUSIONS: We should, therefore, carefully select our patients for treatment with the NOA with an emphasis on age, body weight, renal function and comedications and follow them faithfully concerning their medication adherence and eventual side effects.