Intensive heart rhythm monitoring to decrease ischemic stroke and systemic embolism-the Find-AF 2 study-rationale and design.

BACKGROUND: Atrial fibrillation (AF) is one of the most frequent causes of stroke. Several randomized trials have shown that prolonged monitoring increases the detection of AF, but the effect on reducing recurrent cardioembolism, ie, ischemic stroke and systemic embolism, remains unknown. We aim to evaluate whether a risk-adapted, intensified heart rhythm monitoring with consequent guideline conform treatment, which implies initiation of oral anticoagulation (OAC), leads to a reduction of recurrent cardioembolism. METHODS: Find-AF 2 is a randomized, controlled, open-label parallel multicenter trial with blinded endpoint assessment. 5,200 patients ≥ 60 years of age with symptomatic ischemic stroke within the last 30 days and without known AF will be included at 52 study centers with a specialized stroke unit in Germany. Patients without AF in an additional 24-hour Holter ECG after the qualifying event will be randomized in a 1:1 fashion to either enhanced, prolonged and intensified ECG-monitoring (intervention arm) or standard of care monitoring (control arm). In the intervention arm, patients with a high risk of underlying AF will receive continuous rhythm monitoring using an implantable cardiac monitor (ICM) whereas those without high risk of underlying AF will receive repeated 7-day Holter ECGs. The duration of rhythm monitoring within the control arm is up to the discretion of the participating centers and is allowed for up to 7 days. Patients will be followed for at least 24 months. The primary efficacy endpoint is the time until recurrent ischemic stroke or systemic embolism occur. CONCLUSIONS: The Find-AF 2 trial aims to demonstrate that enhanced, prolonged and intensified rhythm monitoring results in a more effective prevention of recurrent ischemic stroke and systemic embolism compared to usual care.

Project DECIDE, part II: decision-making places for people with dementia in Alzheimer's disease: supporting advance decision-making by improving person-environment fit.

BACKGROUND: The UN Convention on the Rights of Persons with Disabilities, and the reformed guardianship law in Germany, require that persons with a disability, including people with dementia in Alzheimer's disease (PwAD), are supported in making self-determined decisions. This support is achieved through communication. While content-related communication is a deficit of PwAD, relational aspects of communication are a resource. Research in supported decision-making (SDM) has investigated the effectiveness of different content-related support strategies for PwAD but has only succeeded in improving understanding, which, although one criterion of capacity to consent, is not sufficient to ensure overall capacity to consent. The aim of the 'spatial intervention study' of the DECIDE project is to examine an innovative resource-oriented SDM approach that focuses on relational aspects. We hypothesise that talking to PwAD in their familiar home setting (as opposed to a clinical setting) will reduce the complexity of the decision-making process and enhance overall capacity to consent. METHODS: People with a suspected or confirmed diagnosis of dementia in Alzheimer's disease will be recruited from two memory clinics (N = 80). We will use a randomised crossover design to investigate the intervention effect of the decision-making place on capacity to consent. Besides reasoning capacity, which is part of overall capacity to consent and will be the primary outcome, various secondary outcomes (e.g., other aspects of capacity to consent, subjective task complexity, decisional conflict) and suspected moderating or mediating variables (e.g., meaning of home, demographic characteristics) will be assessed. DISCUSSION: The results of the study will be used to develop a new SDM strategy that is based on relational resources for PwAD. If a change in location achieves the anticipated improvement in capacity to consent, future research should focus on implementing this SDM strategy in a cost-effective manner in clinical practice. TRIAL REGISTRATION: DRKS00030799 .

Project DECIDE, part 1: increasing the amount of valid advance directives in people with Alzheimer's disease by offering advance care planning-a prospective double-arm intervention study.

BACKGROUND: Everybody has the right to decide whether to receive specific medical treatment or not and to provide their free, prior and informed consent to do so. As dementia progresses, people with Alzheimer's dementia (PwAD) can lose their capacity to provide informed consent to complex medical treatment. When the capacity to consent is lost, the autonomy of the affected person can only be guaranteed when an interpretable and valid advance directive exists. Advance directives are not yet common in Germany, and their validity is often questionable. Once the dementia diagnosis has been made, it is assumed to be too late to write an advance directive. One approach used to support the completion of advance directives is 'Respecting Choices'®-an internationally recognised, evidence-based model of Advance Care Planning (ACP), which, until now, has not been evaluated for the target group of PwAD. This study's aims include (a) to investigate the proportion of valid advance directives in a memory clinic population of persons with suspected AD, (b) to determine the predictors of valid advance directives, and (c) to examine whether the offer of ACP can increase the proportion of valid advance directives in PwAD. METHOD: We intend to recruit at least N = 250 participants from two memory clinics in 50 consecutive weeks. Of these, the first 25 weeks constitute the baseline phase (no offer of ACP), the following 25 weeks constitute the intervention phase (offer of ACP). The existence and validity of an advance directive will be assessed twice (before and after the memory clinic appointment). Moreover, potential predictors of valid advance directives are assessed. DISCUSSION: The results of this study will enhance the development of consent procedures for advance directives of PwAD based on the ACP/Respecting Choices (R) approach. Therefore, this project contributes towards increasing the autonomy and inclusion of PwAD and the widespread acceptance of valid advance directives in PwAD. Trial Registration DRKS, DRKS00026691, registered 15th of October 2021, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00026691.

Cardiac metastasis causes paradoxical malignant embolism.

BACKGROUND: Embolic events play an important role in clinical everyday practice. Malignant arterial embolism is a rare nevertheless often fatal entity for cardiac, cerebral or systemic ischemia, requiring immediate diagnosis and treatment. CASE: This is a case report of a 65 years-old female, suffering from pulmonal adenocarcinoma, who was hospitalized due to neurological deficits caused by an acute ischemic stroke, followed by anterior myocardial infarction within 3 days. Diagnostic work-up revealed metastasis of the pulmonal adenocarcinoma in the right atrium and a patent foramen ovale. Histopathological examination of the coronary embolus verified paradoxical arterial embolism of the pulmonal adenocarcinoma into a coronary vessel and consequently cerebral arteries. CONCLUSION: The present case underlines the need for (i), consideration of malignant embolism, (ii) histopathological examination of the embolus to determine its etiology, and (iii) interdisciplinary discussion of individual therapeutic and prevention strategies in cancer patients with cerebral, cardiac or systemic embolic events.

Report of a fulminant anti-pan-neurofascin-associated neuropathy responsive to rituximab and bortezomib.

Inflammatory neuropathies with pathogenic involvement of the nodes of Ranvier through autoantibodies have been increasingly characterized in the past years. The so-called anti-pan-NF-associated neuropathies caused by the simultaneous existence of anti-Neurofascin-186/-140 and -155-antibodies are extremely rare and cause life-threatening symptoms. Therapeutic strategies are needed as symptoms may be life-threatening and may not respond to standard first-line CIDP treatment. We report a case of a 52-year-old male with a rare anti-pan-neurofascin (NF) (-155, -186/-140)-associated neuropathy. The initial presentation was subacute with mild paresthesia leading to a fulminant "locked-in"-like syndrome requiring mechanical ventilation within the first eight weeks despite treatment with intravenous immunoglobulins. Nerve conduction studies revealed non-excitable nerves with acute spontaneous activity in electromyography. High titers of anti-Neurofascin-155, -186/-140-antibodies were detected in serum and cerebrospinal fluid. A combination of aggressive immunotherapy consisting of intravenous immunoglobulins, plasma exchange, rituximab and bortezomib resulted in clinical improvement with ambulation and non-detectable anti-neurofascin-antibodies within the following 3 months. The follow-up nerve conduction studies showed normalized amplitudes of the peripheral nerves with signs of reinnervation in electromyography. We conclude that an early aggressive immunotherapy consisting of a combination of rituximab and bortezomib could be considered as a therapeutic option for anti-pan-NF-associated neuropathies.

Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion.

Background and Purpose: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra. Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume >15 mL and ratio >1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient <620 10−6 mm2/s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function. Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P=1.7×10−13; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P<1.0×10−4; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P=7.1×10−3; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P=1.5×10−3; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P=0.099; n=26). Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov; Unique identifier: NCT00927836.

Imaging Markers of Brain Frailty and Outcome in Patients With Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Functional outcome after stroke may be related to preexisting brain health. Several imaging markers of brain frailty have been described including brain atrophy and markers of small vessel disease. We investigated the association of these imaging markers with functional outcome after acute ischemic stroke. METHODS: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial (AX200 in Ischemic Stroke Trial), a randomized controlled clinical trial of granulocyte colony-stimulating factor versus placebo. We assessed the ratio of brain parenchymal volume to total intracerebral volumes (ie, the brain parenchymal fraction) and total brain volumes from routine baseline magnetic resonance imaging data obtained within 9 hours of symptom onset using the unified segmentation algorithm in SPM12. Enlarged perivascular spaces, white matter hyperintensities, lacunes, as well as a small vessel disease burden, were rated visually. Functional outcomes (modified Rankin Scale score) at day 90 were determined. Logistic regression was used to test associations between brain imaging features and functional outcomes. RESULTS: We enrolled 259 patients with a mean age of 69±12 years and 46 % were female. Increased brain parenchymal fraction was associated with higher odds of excellent outcome (odds ratio per percent increase, 1.078 [95% CI, 1.008-1.153]). Total brain volumes and small vessel disease burden were not associated with functional outcome. An interaction between brain parenchymal fraction and large vessel occlusion on excellent outcome was not observed. CONCLUSIONS: Global brain health, as assessed by brain parenchymal fraction on magnetic resonance imaging, is associated with excellent functional outcome after ischemic stroke. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00927836.

Early Brain Volume Changes After Stroke: Subgroup Analysis From the AXIS-2 Trial.

BACKGROUND AND PURPOSE: The evolution of total brain volume early after stroke is not well understood. We investigated the associations between age and imaging features and brain volume change in the first month after stroke. METHODS: We retrospectively studied patients with acute ischemic stroke enrolled in the AXIS-2 trial. Total brain volume change from hyperacute MRI data to the first month after stroke was assessed using unified segmentation in SPM12. We hypothesized that age, ischemic brain lesion size, and white matter (WM) changes were associated with larger brain volume change. Enlarged perivascular spaces (EPVSs) and white matter hyperintensities (WMHs) were rated visually and the presence of lacunes was assessed. RESULTS: We enrolled 173 patients with a mean age of 67 ± 11 years, 44% were women. There was a median 6 ml decrease in volume (25th percentile -1 ml to 75th percentile 21 ml) over time, equivalent to a median 0.5% (interquartile range [IQR], -0.07%-1.4%), decrease in brain volume. Age was associated with larger brain volume loss (per 10 years of age, 5 ml 95% CI 2-8 ml). Baseline diffusion weighted imaging (DWI) lesion volume was not associated with greater volume loss per 10 ml of lesion volume, change by 0 ml (95% CI -0.1 to 0.1 ml). Increasing Fazekas scores of deep WMH were associated with greater tissue loss (5 ml, 95% CI 1-10 ml). CONCLUSIONS: Total brain volume changes in a heterogenous fashion after stroke. Volume loss occurs over 1 month after stroke and is associated with age and deep WM disease. We did not find evidence that more severe strokes lead to increased early tissue loss.

[Healthcare of the future-Insights and strategy for (dementia) health services research]. / Gesundheitsversorgung der Zukunft ­ Erkenntnisse und Strategie der (Demenz­)Versorgungsforschung.

BACKGROUND: Due to the demographic change healthcare for older people is becoming more important. A key strategic document for the near future is the national dementia strategy (NDS), which defines four fields of action including promoting excellent research on dementia. The NDS will guide and influence the further development of dementia healthcare research in the coming years. OBJECTIVE: The current research on specific NDS topics is presented and an outlook on expected developments is given. MATERIAL AND METHODS: This article provides a narrative review in which concepts and examples for selected sections of the NDS are presented: funding and promotion of healthcare research, development of evidence-based prevention and healthcare concepts and transfer into routine care, support for people with dementia (PwD) and their caregiver, cross-sectoral networking, participation in dementia research and networks in healthcare research. These were analyzed with respect to future developments and concretized based on current healthcare and promotion models. RESULTS: Insights are given into the healthcare concept of dementia care management, rethinking regional healthcare models such as medicine and e­health. The innovation fund and research practice networks are described as examples of current structural methods of evidence-based design of future healthcare. CONCLUSION: The NDS represents an ambitious agenda with very comprehensive goals and topics for the improvement of healthcare for PwD and will probably significantly influence healthcare research and thus healthcare in the future. Overarching, mutually influencing and strengthening components on the way to improvement of the situation for PwD and the healthcare system are translation, participation and networking in research.

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases.

BACKGROUND: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. AIMS: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. METHODS: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. RESULTS: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0-3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. CONCLUSION: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source.

BACKGROUND: Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. METHODS: We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. RESULTS: A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. CONCLUSIONS: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.).

Development and validation of a score to detect paroxysmal atrial fibrillation after stroke.

OBJECTIVE: Prolonged monitoring times (72 hours) are recommended to detect paroxysmal atrial fibrillation (pAF) after ischemic stroke but this is not yet clinical practice; therefore, an individual patient selection for prolonged ECG monitoring might increase the diagnostic yield of pAF in a resource-saving manner. METHODS: We used individual patient data from 3 prospective studies (ntotal = 1,556) performing prolonged Holter-ECG monitoring (at least 72 hours) and centralized data evaluation after TIA or stroke in patients with sinus rhythm. Based on the TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis) guideline, a clinical score was developed on one cohort, internally validated by bootstrapping, and externally validated on 2 other studies. RESULTS: pAF was detected in 77 of 1,556 patients (4.9%) during 72 hours of Holter monitoring. After logistic regression analysis with variable selection, age and the qualifying stroke event (categorized as stroke severity with NIH Stroke Scale [NIHSS] score ≤5 [odds ratio 2.4 vs TIA; 95% confidence interval 0.8-6.9, p = 0.112] or stroke with NIHSS score >5 [odds ratio 7.2 vs TIA; 95% confidence interval 2.4-21.8, p < 0.001]) were found to be predictive for the detection of pAF within 72 hours of Holter monitoring and included in the final score (Age: 0.76 points/year, Stroke Severity NIHSS ≤5 = 9 points, NIHSS >5 = 21 points; to Find AF [AS5F]). The high-risk group defined by AS5F is characterized by a predicted risk between 5.2% and 40.8% for detection of pAF with a number needed to screen of 3 for the highest observed AS5F points within the study population. Regarding the low number of outcomes before generalization of AS5F, the results need replication. CONCLUSION: The AS5F score can select patients for prolonged ECG monitoring after ischemic stroke to detect pAF. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that the AS5F score accurately identifies patients with ischemic stroke at a higher risk of pAF.

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany - A national case collection.

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran that reverses its anticoagulant effects within minutes. It may exhibit the potential for patients under dabigatran therapy suffering ischemic stroke to regain eligibility for thrombolysis with rt-PA and may inhibit lesion growth in patients with intracerebral hemorrhage on dabigatran. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January to August 2016 were used. Results Thirty-one patients presenting with signs of stroke received idarucizumab in 22 stroke centers. Nineteen patients treated with dabigatran presented with ischemic stroke and 12 patients suffered from intracranial bleeding. In patients receiving rt-PA thrombolysis following idarucizumab, 79% benefitted from i.v. thrombolysis with a median improvement of five points in NIHSS. No bleeding complications occurred. Hematoma growth was observed in 2 out of 12 patients with intracranial hemorrhage. The outcome was favorable with a median NIHSS improvement of 5.5 points and mRS 0-3 in 67%. Overall, mortality was low with 6.5% (one patient in each group). Conclusion Administration of rt-PA after reversing dabigatran activity with idarucizumab in case of ischemic stroke is feasible, easy to manage, effective, and appears to be safe. In dabigatran-associated intracranial hemorrhage, idarucizumab has the potential to prevent hematoma growth and improve outcome. Idarucizumab represents a new therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage.

Predictors of and attitudes toward counseling about SUDEP and other epilepsy risk factors among Austrian, German, and Swiss neurologists and neuropediatricians.

OBJECTIVE: To examine the attitudes toward counseling about sudden unexpected death in epilepsy (SUDEP) and other epilepsy risk factors among Austrian, German, and Swiss neurologists and neuropediatricians, and to determine factors associated with not discussing SUDEP. METHODS: Questionnaires were sent to approximately 5,000 neurologists and neuropediatricians in 2014 regarding respondents' demographics, their working environments, and how often they discussed SUDEP, suicidal ideations on anticonvulsive medication, driving restrictions, and risks in daily life activities. RESULTS: In total, 519 surveys were completed (respondents' mean age: 45.5 years, 41.6% female, 66.9% adult neurologists, 31.0% neuropediatricians). A minority of 2.7% reported that they counseled all of their patients on SUDEP, 8.7% counseled most of the time (50-90%), 20.8% sometimes (10-49%), 44.5% rarely (1-9%), and 23.3% reported not counseling about SUDEP at all. In contrast, 92.9% reported that they counseled all patients about driving restrictions and 81.5% about risks in daily life activities. Suicidal ideations were discussed in 59.0% for some and in 3.3% for all patients, whereas 35.1% of respondents reported never discussing suicidal ideations. Independent predictors of not discussing SUDEP were no additional epilepsy training, no or uncertain SUDEP cases in the past, <10 years in practice, <25 epilepsy patients seen per quarter, and the opinion of a lack of consequences in SUDEP prevention. The opinion that SUDEP is a risk factor in particular patient groups and the attitude that all risks should be discussed predicted counseling on SUDEP. SIGNIFICANCE: Our findings show a discrepancy between guidelines and practice regarding the discussion of premature mortality due to SUDEP or suicidality. Both are not discussed at all by a substantial proportion of neurologists and neuropediatricians. This is in contrast to ubiquitous education about driving restrictions. Dissemination of knowledge among physicians about potential preventive strategies might increase the likelihood of discussion. Clinical practice guidelines are welcomed by the majority of physicians in this process.

Association between the perfusion/diffusion and diffusion/FLAIR mismatch: data from the AXIS2 trial.

The perfusion-/diffusion-weighted imaging (PWI/DWI) mismatch and the diffusion/fluid attenuated inversion recovery (DWI/FLAIR) mismatch are magnetic resonance imaging (MRI) markers of evolving brain ischemia. We examined whether the DWI/FLAIR mismatch was independently associated with the PWI/DWI mismatch. Furthermore, we determined whether the presence of the DWI/FLAIR mismatch in patients with the PWI/DWI mismatch would provide additional information regarding last seen normal time (LTM). We used data from the 'AX200 for ischemic stroke' trial (AXIS 2 study NCT00927836). We studied the association between the presence of the DWI/FLAIR and PWI/DWI mismatch, baseline National Institute of Health Stroke Scale (NIHSS), age, ischemic-core volume, gender, intravenous (IV) tissue plasminogen activator (tPA), and perfusion-mismatch volume in univariate analysis. Significant variables (P<0.05) were added into the final multivariate model. We analyzed 197 patients. Seventy-two (37%) had both the PWI/DWI and the DWI/FLAIR mismatch. Patients with the double mismatch pattern had a shorter LTM than patients with the PWI/DWI mismatch alone (Median difference 90 minutes, P<0.01). Multivariate analysis confirmed the independent association between the two mismatch patterns (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.2 to 5.4). Our study implies that the DWI/FLAIR mismatch and PWI/DWI mismatch are strongly associated, independent from LTM. Furthermore, in the presence of the PWI/DWI mismatch, the DWI/FLAIR pattern indicates a shorter LTM. This could have implications in selecting patients for reperfusion therapy.

Improved detection of silent atrial fibrillation using 72-hour Holter ECG in patients with ischemic stroke: a prospective multicenter cohort study.

BACKGROUND AND PURPOSE: Adequate diagnosis of atrial fibrillation (AF), including paroxysmal AF, is an important part of stroke workup. Prolonged ECG monitoring may improve the detection of paroxysmal, previously undiagnosed AF (unknown AF). Therefore, we evaluated systematic 72-hour Holter ECG monitoring to detect unknown AF for the workup of patients with stroke. METHODS: Unselected survivors of a stroke or transient ischemic attack (TIA) without known AF were enrolled in a prospective, multicenter cohort study of 72-hour Holter ECG monitoring in 9 German secondary and tertiary stroke centers between May 2010 and January 2011. In addition to standardized workup of stroke pathogenesis according to the German Stroke Unit protocol, all patients underwent 72-hour Holter ECG monitoring directly after admission. All ECGs were centrally analyzed by 2 independent observers. We determined the proportion of unknown AF and compared the detection rates of 72- and 24-hour monitoring. RESULTS: A total of 1135 patients were enrolled (mean age, 67 years [SD, 13.1 years], 45% women, 29% TIA). Unknown AF was detected in 49 out of 1135 patients (4.3%, [95% confidence interval, 3.4-5.2%]) by 72-hour ECG monitoring. Unknown AF was diagnosed in 29 patients (2.6%) within the first 24 hours of ECG monitoring, and in 20 more patients only by 72 hours of ECG monitoring. The number needed to screen by 72-hour ECG was 55 patients (95% confidence interval [35-123]) for each additional AF diagnosis. Patients with unknown AF were significantly older and had more often a history of previous stroke. Patients with unknown AF were equally distributed within categories of pathogenesis according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. CONCLUSIONS: In unselected survivors of stroke or TIA, 72-hour ECG monitoring is feasible and improves the detection rate of silent paroxysmal AF.

Granulocyte colony-stimulating factor in patients with acute ischemic stroke: results of the AX200 for Ischemic Stroke trial.

BACKGROUND AND PURPOSE: Granulocyte colony-stimulating factor (G-CSF; AX200; Filgrastim) is a stroke drug candidate with excellent preclinical evidence for efficacy. A previous phase IIa dose-escalation study suggested potential efficacy in humans. The present large phase IIb trial was powered to detect clinical efficacy in acute ischemic stroke patients. METHODS: G-CSF (135 µg/kg body weight intravenous over 72 hours) was tested against placebo in 328 patients in a multinational, multicenter, randomized, and placebo-controlled trial (NCT00927836; www.clinicaltrial.gov). Main inclusion criteria were ≤9-hour time window after stroke onset, infarct localization in the middle cerebral artery territory, baseline National Institutes of Health Stroke Scale score range of 6 to 22, and baseline diffusion-weighted imaging lesion size ≥15 mL. Primary and secondary end points were the modified Rankin scale score and the National Institutes of Health Stroke Scale score at day 90, respectively. Data were analyzed using a prespecified model that adjusted for age, National Institutes of Health Stroke Scale score at baseline, and initial infarct volume (diffusion-weighted imaging). RESULTS: G-CSF treatment failed to meet the primary and secondary end points of the trial. For additional end points such as mortality, Barthel index, or infarct size at day 30, G-CSF did not show efficacy either. There was, however, a trend for reduced infarct growth in the G-CSF group. G-CSF showed the expected peripheral pharmacokinetic and pharmacodynamic profiles, with a strong increase in leukocytes and monocytes. In parallel, the cytokine profile showed a significant decrease of interleukin-1. CONCLUSIONS: G-CSF, a novel and promising drug candidate with a comprehensive preclinical and clinical package, did not provide any significant benefit with respect to either clinical outcome or imaging biomarkers. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836.

Standardized prehospital treatment of stroke.

BACKGROUND: The lack of standardized pre-hospital treatment is a weak link in the care of acute stroke patients. METHODS: Selective review of the literature on acute stroke, with consideration of current guidelines in Germany and other countries (DGN, ESO, AHA/ASA). RESULTS: The mandatory, immediate transfer of acute stroke patients to a specialized stroke unit is supported by high-level evidence. Simple, sensitive screening tests for the diagnosis of stroke are available that can be performed in the field by trained non-physician emergency medical personnel. With regard to pre-hospital treatment, adequate scientific evidence supports cardiopulmonary stabilization, as well as oxygen supplementation if there are signs of hypoxemia. The patient's neurological findings, time of onset of symptoms, current medications, and past medical and surgical history must all be precisely and thoroughly documented. The receiving hospital must be informed of the patient's impending arrival as early as possible, particularly in cases where recanalizing procedures are still a therapeutic option. Treatment with aspirin or heparin must not be started in situ, i.e. without prior cerebral imaging. CONCLUSION: In the pre-hospital phase of stroke care delivery, the goal of a high capture rate can best be achieved through the use of appropriate diagnostic tests with maximal sensitivity. Patients with suspected acute stroke should be given the highest priority for transfer to a specialized stroke unit. Optimal pre-hospital care requires the smoothly functioning cooperation of all professionals involved, from the triaging and nursing personnel to the paramedics, dispatchers, emergency physicians in the field, and admitting physicians in the hospital.