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Neutrophil granulocytes (or polymorphonuclear cells, PMNs) have long been considered as crude killing machines, particularly trained to attack bacterial or fungal pathogens in wounds or infected tissues. That perspective has fundamentally changed over the last decades, as PMNs have been shown to exert a livery exchange between other cells of the innate and adaptive immune system. PMNs do provide major immunomodulatory contribution during acute inflammation and subsequent clearance. Following sterile inflammation like cerebral ischemia, PMNs are among the first hematogenous cells attracted to the ischemic tissue. As inflammation is a crucial component within stroke pathophysiology, several studies regarding the role of PMNs following cerebral ischemia have been carried out. And indeed, recent research suggests a direct connection between PMNs’ influx and brain damage severity. This review highlights the latest research regarding the close interconnection between PMNs and co-working cells following cerebral ischemia. We describe how PMNs are attracted to the site of injury and their tasks within the inflamed brain tissue and the periphery. We further report of new findings regarding the interaction of PMNs with resident microglia, immigrating macrophages and T cells after stroke. Finally, we discuss recent research results from experimental studies in the context with current clinical trials and point out potential new therapeutic applications that could emerge from this new knowledge on the action and interaction of PMNs following cerebral ischemia. [ABSTRACT FROM AUTHOR]

Objective: Approximately 20% of strokes are embolic strokes of undetermined source (ESUS). Undetected atrial fibrillation (AF) remains an important cause. Yet, oral anticoagulation in unselected ESUS patients failed in secondary stroke prevention. Guidance on effective AF detection is lacking. Here, we introduce a novel, non‐invasive AF risk assessment after ESUS. Methods: Catch‐Up ESUS is an investigator‐initiated, observational cohort study conducted between 2018 and 2019 at the Munich University Hospital. Besides clinical characteristics, patients received ≥72 h digital electrocardiogram recordings to generate the rhythm irregularity burden. Uni‐ and multivariable regression models predicted the primary endpoint of incident AF, ascertained by standardized follow‐up including implantable cardiac monitors. Predictors included the novel rhythm irregularity burden constructed from digital electrocardiogram recordings. We independently validated our model in ESUS patients from the University Hospital Tübingen, Germany. Results: A total of 297 ESUS patients were followed for 15.6 ± 7.6 months. Incident AF (46 patients, 15.4%) occurred after a median of 105 days (25th to 75th percentile 31–33 days). Secondary outcomes were recurrent stroke in 7.7% and death in 6.1%. Multivariable‐adjusted analyses identified the rhythm irregularity burden as the strongest AF‐predictor (hazard ratio 3.12, 95% confidence interval 1.62–5.80, p < 0001) while accounting for the known risk factors age, CHA2DS2‐VASc‐Score, and NT‐proBNP. Independent validation confirmed the rhythm irregularity burden as the most significant AF‐predictor (hazard ratio 2.20, 95% confidence interval 1.45–3.33, p < 0001). Interpretation: The novel, non‐invasive, electrocardiogram‐based rhythm irregularity burden may help adjudicating AF risk after ESUS, and subsequently guide AF‐detection after ESUS. Clinical trials need to clarify if high‐AF risk patients benefit from tailored secondary stroke prevention. ANN NEUROL 2023;93:479–488 [ABSTRACT FROM AUTHOR]

Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear aetiology for a period of less than 24 h. Observed psychological, neuroanatomical and hormonal differences between the sexes in episodic memory suggest sex-specific differences in memory disorders such as TGA. The aim of this study was to determine sex-specific differences in cardiovascular risk profiles, recurrences and magnetic resonance imaging (MRI). In total, 372 hospitalised TGA patients between 01/2011 and 10/2021 were retrospectively analysed. Comparisons were made between female and male TGA patients and compared to 216 patients with acute stroke. In our sample, women were overrepresented (61.8%), especially compared to the general population in the 65–74 age category (χ2 = 10.6, p < 0.02). On admission, female TGA patients had significantly higher systolic blood pressure values and a higher degree of cerebral microangiopathy compared to male TGA patients, whereas acute stroke patients did not. No sex-specific differences were observed with respect to recurrences or hippocampal DWI lesions. Our data demonstrate sex-specific differences in TGA. The higher blood pressure on admission and different degree of cerebral microangiopathy in female TGA patients supports the theory of blood pressure dysregulation as a disease trigger. Distinct precipitating events in female and male patients could lead to differences in the severity and duration of blood pressure abnormalities, possibly explaining the higher incidence in female patients. [ABSTRACT FROM AUTHOR]

The global SARS‐CoV‐2 pandemic has contributed to more than 163 million confirmed infections and 3.3 million deaths worldwide. The severity of the pandemic has led to an unprecedented effort to develop multiple effective vaccines. Due to excellent safety and efficacy data from clinical trials, several vaccines were approved. We report a case series of postvaccinal encephalitis in temporal correlation to vaccination with ChAdOx1 nCov‐19. The diagnostic criteria for possible autoimmune encephalitis were fulfilled. Our patients responded well to immunosuppressive therapy with corticosteroids. The incidence has been estimated to be approximately 8 per 10 million vaccine doses. Complication of postvaccinal encephalitis after ChAdOx1 nCoV‐19 vaccination still appear to be very rare, but need to be diagnosed and treated adequately. Large pooled data from observational epidemiologic studies are necessary to verify causality. ANN NEUROL 2021;90:506–511 [ABSTRACT FROM AUTHOR]

MRI findings in COVID-19 encephalitis, especially when suggesting autoimmune encephalopathy may imply therapeutic interventions, such as immunosuppressive therapy. Apart from acute necrotizing encephalopathy (ANE), imaging findings on brain MRI scans in COVID-19 encephalopathy were reported as being unspecific and equivocal. While immunological markers remained unspecific and imaging findings of acute necrotizing encephalitis were absent in our patient, brain MRI disclosed a unique pattern, a.k.a. the claustrum sign. [Extracted from the article]

Regardless of established causalities, we believe that we are obliged as clinical neurologists to report potential complications of ChAdOx1 nCoV-19 vaccination, thus enabling an open discussion and timely diagnosis as well as treatment of similar cases. However, our case series exclusively focused an adenovirus-vectored vaccine, which may impact the side effect potential as well as the immunological mechanisms postvaccination. The cellular immune response showed discrete populations of T cells, natural killer cells, and B cells as early as 7 days after ChAdOx1 nCoV-19 vaccination. [Extracted from the article]

Dear Sirs, Here, we report a case of a 29-year-old male public health care professional, vaccinated with the recombinant adenoviral vector encoding the spike protein antigen of SARS-CoV-2 (ChAdOx1 nCov-19, AstraZeneca) on the 29th of March (day 1). Vein thrombosis On admission, pronounced thrombosis is disclosed within the left transverse and sigmoid sinus, with progressive recanalization on follow-up MRI (arrows). c Plain head CT, displaying left-sided temporal hemorrhage Graph: Fig. [Extracted from the article]

Objective: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions. Methods: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters. Results: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6–46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-d-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention. Conclusions: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient. [ABSTRACT FROM AUTHOR]

A correction to this paper has been published: https://doi.org/10.1007/s00415-021-10634-2 [ABSTRACT FROM AUTHOR]

Abstract: Dopamine plays an important role in learning and memory processes. A deficit of this neurotransmitter as it is apparent in Alzheimer’s disease (AD) may contribute to cognitive decline, a major symptom of AD patients. The aim of this study was to elucidate whether or not stimulation of the dopaminergic system leads to an improvement of cognitive function and reduction of non-cognitive behavioral alterations in a murine model of AD. Transgenic and wild type male mice of the TgCRND8 line were treated either with the dopamine precursor levodopa or vehicle and tested in two learning tasks, the object-recognition task and the Barnes maze test. Additionally 24 h spontaneous behavior in the home cage was analyzed. In both memory tasks wild type mice performed significantly better than transgenics. However, transgenics treated with levodopa showed a significant object recognition memory and improved acquisition of spatial memory in the Barnes maze compared to vehicle treated transgenics. Concerning spontaneous behavior transgenic mice performed much more stereotypies than wild types. However, there was a trend for reduced stereotypies in the levodopa group in the time the drug was active. Neurochemical analysis revealed elevated levels of dopamine in the neostriata and frontal cortices and reduced levels in the hippocampi of transgenic mice compared to wild types. Thus cognitive deficits and stereotypies may be due to changes in the dopaminergic system as they could be ameliorated by levodopa treatment, that might also have a therapeutic significance for AD. [Copyright &y& Elsevier]

Abstract: Several lines of evidence have demonstrated beneficial effects of the hematopoietic factor G-CSF in experimental stroke. A conclusive demonstration of this effect in G-CSF deficient mice is, however, lacking. We therefore investigated the effect of G-CSF deficiency on infarct volumes, functional recovery, mRNA and protein expression of the matrix metalloproteinase 9 (MMP-9) after stroke. Furthermore we tested the efficacy of G-CSF substitution in G-CSF deficient animals to prevent the potential consequences of G-CSF deficiency. In the present study experimental stroke was induced in female non-treated wildtype (wt), G-CSF deficient mice and G-CSF substituted G-CSF deficient mice followed by assessment of infarct volumes, neurological outcome and sensorimotor function. In addition, immunohistochemistry and real-time PCR of the peri-ischemic area were performed. G-CSF deficient mice showed increased infarct volumes, whereas G-CSF substituted mice had a remarkable reduction in lesion size compared to wt mice. These findings are accompanied by an improvement in neurological and sensorimotor function. G-CSF deficiency resulted in an upregulation of MMP-9 in the direct peri-ischemic tissue. Treatment with G-CSF suppressed the upregulation of MMP-9. Taken together, G-CSF deficiency clearly resulted in enlarged infarct volumes, and worsened neurological outcome. G-CSF substitution abolished these negative effects, led to significant reduced lesion volumes, and improved neurological outcome. G-CSF mediated suppression of MMP-9 further demonstrates that endogenous G-CSF plays a significant role in brain protective mechanisms. We have shown for the first time that endogenous G-CSF is required for brain recovery mechanisms after stroke. [Copyright &y& Elsevier]

Abstract: Cerebral ischemia evokes changes in gene expression time-dependently after the ischemic event. Most studies on transcriptional changes following ischemia have centered on relatively early postischemic time points, and detected multiple genes relevant to neuronal cell death. However, functional outcome after ischemia depends critically on adaptations of the postischemic brain. Plasticity may derive from network-inherent changes, or from the formation of new nerve cells in the CNS. We have screened for gene expression changes up to 3 weeks following a limited photothrombotic cortical insult in the rat sensorimotor cortex by using the sensitive restriction-mediated differential display (RMDD) technique. A high number of genes were detected as induced at early or intermediate time points in the ipsi- and contralateral cortex (6 and 48 h). Unexpectedly, at the late time point examined (3 weeks), we still detected 40 genes that were changed in their expression. We further characterized the expression of two genes linked to neurogenesis (nestin and stathmin), and two genes likely involved in reconfiguring neuronal networks (semaphorin VIa and synaptotagmin IV). Conclusively, our data highlight the degree of long-term transcriptional changes in the cortex after ischemia, and provide insight into functional pathways of relevance for compensatory recovery mechanisms in neural networks. [Copyright &y& Elsevier]

Abstract: Since their introduction, atypical neuroleptic agents have been discovered to have some beneficial effects beyond their effectiveness as neuroleptic drugs. Among these initially unexpected effects are their potential effects as mood stabilizers in bipolar disorder and their efficacy in improving long-term outcome in schizophrenia. These effects recently raised the question whether these drugs may also have some neuroprotective effect in the brain. To examine this matter, in this study we evaluated the neuroprotective effect of risperidone after permanent focal cerebral ischemia. Anaesthetized male C57BL/6j mice were submitted to permanent thread occlusion of the middle cerebral artery (MCA). Risperidone (0.1, 1 or 10mg/kg) or vehicle was applied intraperitoneally just after permanent ischemia. Twenty-four hours after permanent ischemia, brain injury was evaluated by triphenyltetrazolium chloride staining (TTC). Risperidone (0.1, 1 and 10mg/kg) showed significant neuroprotection after permanent focal cerebral ischemia. [Copyright &y& Elsevier]

We have previously shown that exogenous application of brain-derived neurotrophic factor (BDNF) reduces infarct volume in the cortical ischemic penumbra after experimental focal ischemia [Stroke 31 (2000) 2212–2217]. Since BDNF is known to modulate the expression and function of various neurotransmitter receptors, we addressed the question whether BDNF may act via modification of postischemic ligand binding to excitatory NMDA and AMPA and/or inhibitory GABAA receptors, respectively. Transient focal cerebral ischemia was induced in male Wistar rats for 2 h using the suture occlusion technique. A period of 30 min after occlusion of the middle cerebral artery, BDNF (300 μg/kg per hour in vehicle; n=5) or vehicle alone (n=5) was continuously infused intravenously for 3 h. Using quantitative receptor autoradiography, postischemic ligand binding of [3H]MK-801, [3H]AMPA and [3H]muscimol was analyzed in the ischemic core, the ischemic cortical penumbra and corresponding regions of the contralateral hemisphere. Transient focal ischemia caused a significant reduction of [3H]muscimol binding to GABAA receptors within the ischemic cortical penumbra of placebo-treated rats. This was largely prevented by exogenous application of BDNF. [3H]MK-801 and [3H]AMPA binding values were also reduced in the cortical penumbra and the corresponding area of the contralateral hemisphere. Our data suggest that the neuroprotective effect of BDNF against ischemic damage in the cortical penumbra may be mediated in part by maintained activity of the inhibitory GABAergic system which likely counteracts glutamate induced excitotoxicity. [Copyright &y& Elsevier]

Endovascular thrombectomy (EVT) is the most effective treatment for acute ischemic stroke caused by large vessel occlusion (LVO). Yet, long-term outcome (LTO) and health-related quality of life (HRQoL) in these patients have rarely been addressed, as opposed to modified Rankin scale (mRS) recordings. We analysed demographic data, treatment and neuroimaging parameters in 694 consecutive stroke patients in a maximum care hospital. In 138 of these patients with respect on receipt of written informed consent, LTO and HRQoL were collected over a period of 48 months after EVT using a standardised telephone survey (median 2.1 years after EVT). Age < 70 years (OR 4.82), lower NIHSS on admission (OR 1.11), NIHSS ≤ 10 after 24 h (OR 11.23) and complete recanalisation (mTICI3) (OR 7.79) were identified as independent predictors of favourable LTO. Occurrence of an infection requiring treatment within the first 72 h was recognised as a negative predictor for good long-term outcome (OR 0.22). Patients with mRS > 2 according to the telephone survey more often had complaints regarding mobility, self-care, and usual activity domains of the HRQoL. Our results underline a sustainable positive effect of effective EVT on the quality of life in LVO stroke. Additionally, predictive parameters of outcome were identified, that may support clinical decision making in LVO stroke., (© 2024. The Author(s).)

Background: Evaluation of outcome after stroke is largely based on assessment of gross function 3 months after stroke onset using scales such as mRS. Cognitive or social functions, level of symptom burden or emotional health are not usually assessed, nor are data available on long-term functional outcomes years after stroke., Methods: Analysis of 1141 patients with AIS treated with IVT from two major German university hospitals between 2017 and 2020. Patient characteristics and short-term outcome were analysed from patient records. Long-term outcome of 228 patients with prior written informed consent was assessed via telephone survey using mRS and PROMs (EQ-5D-5L, EQ-VAS) 2.5 years after stroke., Results: Predictors of excellent to good long-term outcome were younger age, event to door time ≤ 2 h, NIHSS ≤ 6 on admission and NIHSS ≤ 6 after IVT. Stroke recurrence was a negative predictor. Predictors of excellent quality of life at 2.5 years included age < 73 years, lower NIHSS after IVT, absence of hypertension. Quality of life was rated in all dimensions with a medium score of 1 and a medium EQ-VAS of 70, representing the good general health status of this stroke population., Conclusion: Main predictors of an excellent to good long-term outcome and excellent QoL 2.5 years after stroke are younger age, lower NIHSS, and event to door time ≤ 2 h. Research on long-term outcome after disease and treatment is of utmost importance, as it has the ability to reveal the patient true functional outcome and quality of life and to provide information on the status of independence and self-esteem., (© 2023. The Author(s).)

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., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The authors investigated for presence of cognitive impairment after occurrence of bilateral lesions of the genu of the internal capsule (GIC). Clinical and neuropsychological features of unilateral GIC lesions have previously been studied, but the cognitive profile of bilateral lesions of the GIC has not been fully explored., Methods: An investigation was conducted of neurocognitive deficits and computerized tomography MRI findings among 4,200 stroke patients with bilateral GIC involvement who were admitted to the hospital between January 2010 and October 2018., Results: Eight patients with bilateral lesions of the capsular genu were identified and their data analyzed. Overall, behavioral and cognitive dysfunction were characterized by impairment of frontal, memory, and executive functions. Attention and abstraction were present among all eight patients (100%); apathy, abulia, and executive dysfunctions, among seven (87.5%); global mental dysfunction and planning deficits, among six (75.0%); short-term verbal memory deficits and language dysfunctions, among five (62.5%); long-term verbal memory deficits, among four (50.0%); and spatial memory deficits, reading, writing, counting dysfunctions, and anarthria, among two (25.0%). Four of the patients (50.0%) without a history of cognitive disorder showed severe mental deterioration compatible with the clinical picture of dementia. A clinical picture of dementia was still present in these patients 6 months after stroke., Conclusions: Bilateral lesions of the capsular genu appearing either simultaneously or at different times were significantly associated with executive dysfunctions.

Background and Purpose: Surgical decompression of the posterior fossa is often performed in cases with a space-occupying cerebellar infarction to prevent coma and death. In this study, we analyzed our institutional experience with this condition. We specifically attempted to address timing issues and investigated the role of cerebellar necrosectomy using imaging data and conducting volumetric analyses., Methods: We retrospectively studied pertinent clinical and imaging data, including computerized volumetric analyses (preoperative/postoperative infarction volume, necrosectomy volume, and posterior fossa volume), from all 49 patients who underwent posterior fossa decompression surgery for cerebellar infarction in our department from January 2012 to January 2021., Results: Thirty-five (71%) patients had a Glasgow Coma Scale (GCS) of 14-15 at admission vs. only 14 (29%) before vs. 41 (84%) following surgery. Seven (14%) patients had preventive surgery (initial GCS 14-15, preoperative GCS change ≤ 1). Only 18 (37%) patients had an mRS score of 0-3 at discharge. Estimated overall survival was 70.5% at 1 year. Interestingly, 18/20 (90%) surviving cases had a modified Rankin Scale (mRS) outcome of 0-3 (mRS 0-2: 12/20 [60%]) 1 year after surgery. Surgical timing, including preventive surgery and mass effect of the infarct, in the posterior fossa assessed semi-quantitatively (Kirollos grade) and with volumetric parameters that were not predictive of the patients' (functional) outcomes., Conclusion: Posterior fossa decompression for cerebellar infarction is a life-saving procedure, but rapid recovery of the GCS after surgery does not necessarily translate into good functional outcome. Many patients died during follow-up, but long-term mRS outcomes of 4-5 are rare. Surgery should probably aim primarily at pressure relief, and our clinical as well as volumetric data suggest that the impact of removing an infarcted tissue may be limited. It is presumably relatively safe to initially withhold surgery in cases with a GCS of 14-15., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Goulin Lippi Fernandes, Ridwan, Greeve, Schäbitz, Grote and Simon.)

Poststroke recovery processes include restoration or compensation of function, respectively functions initially lost or new functions acquired after an injury. Therapeutic interventions can enhance these processes and/or reduce processes impeding regeneration. Numerous experimental studies suggest great opportunities for such treatments, but the results from recent large clinical trials using neuromodulators such as dopamine and fluoxetine are disappointing. The reasons for this are manifold affecting forward translation of results from animals models into the human situation. This "translational road block" is defined by differences between animals and humans with regard to the genetic and epigenetic background, size and anatomy of the brain, cerebral vascular anatomy, immune system, as well as clinical function and behavior. Backward blockade includes the incompatible adaption of targets and outcomes in clinical trials with regard to prior preclinical findings. For example, the design of clinical recovery trials varies widely and was characterized by the selection of different clinical endpoints, the inclusion a broad spectrum of stroke subtypes and clinical syndromes as well as different time windows for treatment initiation after infarct onset. This review will discuss these aspects based on the results of the recent stroke recovery trials with the goal to contribute to the currently biggest unmet need in stroke research - the development of a recovery enhancing therapy that improves the functional outcome of a chronic stroke patient., Competing Interests: None

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that, especially in the early stages of the disease, is clinically difficult to distinguish from Parkinson's disease (PD). Objective: This study aimed at assessing the use of eye-tracking in head-mounted displays (HMDs) for differentiating PSP and PD. Methods: Saccadic eye movements of 13 patients with PSP, 15 patients with PD, and a group of 16 healthy controls (HCs) were measured. To improve applicability in an inpatient setting and standardize the diagnosis, all the tests were conducted in a HMD. In addition, patients underwent atlas-based volumetric analysis of various brain regions based on high-resolution MRI. Results: Patients with PSP displayed unique abnormalities in vertical saccade velocity and saccade gain, while horizontal saccades were less affected. A novel diagnostic index was derived, multiplying the ratios of vertical to horizontal gain and velocity, allowing segregation of PSP from PD with high sensitivity (10/13, 77%) and specificity (14/15, 93%). As expected, patients with PSP as compared with patients with PD showed regional atrophy in midbrain volume, the midbrain plane, and the midbrain tegmentum plane. In addition, we found for the first time that oculomotor measures (vertical gain, velocity, and the diagnostic index) were correlated significantly to midbrain volume in the PSP group. Conclusions: Assessing eye movements in a HMD provides an easy to apply and highly standardized tool to differentiate PSP of patients from PD and HCs, which will aid in the diagnosis of PSP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Herwig, Agic, Huppertz, Klingebiel, Zuhorn, Schneider, Schäbitz and Rogalewski.)

Although several studies have suggested that anti-inflammatory strategies reduce secondary infarct growth in animal stroke models, clinical studies have not yet demonstrated a clear benefit of immune modulation in patients. Potential reasons include systematic differences of post-ischemic neuroinflammation between humans and rodents. We here performed a systematic review and meta-analysis to summarize and compare the spatial and temporal distribution of immune cell infiltration in human and rodent stroke. Data on spatiotemporal distribution of immune cells (T cells, macrophages, and neutrophils) and infarct volume were extracted. Data from all rodent studies were pooled by means of a random-effect meta-analysis. Overall, 20 human and 188 rodent stroke studies were included in our analyses. In both patients and rodents, the infiltration of macrophages and neutrophils preceded the lymphocytic influx. Macrophages and neutrophils were the predominant immune cells within 72 h after infarction. Although highly heterogeneously across studies, the temporal profile of the poststroke immune response was comparable between patients and rodents. In rodent stroke, the extent of the immune cell infiltration depended on the duration and location of vessel occlusion and on the species. The density of infiltrating immune cells correlated with the infarct volume. In summary, we provide the first systematic analysis and comparison of human and rodent post-ischemic neuroinflammation. Our data suggest that the inflammatory response in rodent stroke models is comparable to that in patients with stroke. However, the overall heterogeneity of the post-ischemic immune response might contribute to the translational failure in stroke research., (© 2021. The Author(s).)

Background: Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear etiology for a period of less than 24 h. TGA occurs as a single event in most cases. Prevalence rates of recurrent TGA vary widely from 5.4 to 27.1%. This retrospective study aimed to determine predictors for TGA recurrence. Methods: Cardiovascular risk profile and magnetic resonance imaging (MRI) of 340 hospitalized TGA patients between 2011 and 2020 were retrospectively analyzed. The median follow-up period amounted to 4.5 ± 2.7 years. Comparisons were made between TGA patients with and without subsequent recurrence. Results: TGA patients with subsequent recurrence were significantly younger (recurrent vs. single episode, 63.6 ± 8.6 years vs. 67.3 ± 10.5 years, p = 0.032) and showed a lower degree of cerebral microangiopathy compared to TGA patients without recurrence. The mean latency to recurrence was 3.0 years ± 2.1 years after the first episode. In a subgroup analysis, patients with at least five years of follow-up ( N = 160, median follow-up period 7.0 ± 1.4 years) had a recurrence rate of 11.3%. A 24.5% risk of subsequent TGA recurrence in the following five years was determined for TGA patients up to 70 years of age without microangiopathic changes on MRI (Fazekas' score 0). Conclusion: Younger TGA patients without significant microangiopathy do have an increased recurrence risk. In turn, pre-existing cerebrovascular pathology, in the form of chronic hypertension and cerebral microangiopathy, seems to counteract TGA recurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rogalewski, Beyer, Friedrich, Plümer, Zuhorn, Klingebiel, Woermann, Bien, Greeve and Schäbitz.)

Objective: Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear etiology for a period of <24 h. Several studies showed differences in vascular risk factors between TGA compared to transient ischemic attack (TIA) or healthy controls with varying results. This retrospective and cross-sectional study compares the cardiovascular risk profile of TGA patients with that of acute stroke patients. Methods: Cardiovascular risk profile and MR imaging of 277 TGA patients was retrospectively analyzed and compared to 216 acute ischemic stroke patients (26% TIA). Results: TGA patients were significantly younger and predominantly female compared to stroke patients. A total of 90.6% of TGA patients underwent MRI, and 53% of those showed hippocampal diffusion-weighted imaging (DWI) lesions. Scores for cerebral microangiopathy were lower in TGA patients compared to stroke patients. After statistical correction for age, TGA patients had higher systolic and diastolic blood pressure, higher cholesterol levels, lower HbA1c, as well as blood glucose levels, and lower CHA 2 DS 2 -VASc scores. Stroke patients initially displayed higher CRP levels than TIA and TGA patients. TGA patients without DWI lesions were older and showed higher CHA 2 DS 2 -VASc scores compared to TGA patients with DWI lesions. Conclusion: This study revealed significant differences between TGA and stroke patients in regard to the cardiovascular risk profile. Our main findings show a strong association between acute hypertensive peaks and TGA in patients not adapted to chronic hypertension, indicating a vascular cause of the disease., Competing Interests: CB receives research support from the Deutsche Forschungsgemeinschaft (German Research Council, Bonn, Germany) and Gerd-Altenhof-Stiftung (Deutsches Stiftungs-Zentrum, Essen, Germany). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rogalewski, Beyer, Friedrich, Plümer, Zuhorn, Greeve, Klingebiel, Woermann, Bien and Schäbitz.)

This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.

Embolic stroke of undetermined source (ESUS) represents a subpopulation of cryptogenic strokes defined by its embolic stroke pattern on imaging and if after a carefully performed diagnostic evaluation, a specific, well recognized cause of stroke has not been identified. This review article analyses the basics of the ESUS concept and provides an overview of the evidence from recent cohort studies. The definition, aetiology and diagnosis of ESUS are reassessed. Targeted diagnostics in ESUS patients can reduce the number of cryptogenic strokes by making a specific diagnosis., Competing Interests: RW: Honorare für eine Beratertätigkeit, Teilnahmegebühren für einen Kongress oder Fortbildungsveranstaltung, Reise- oder Übernachtungskosten mit Bezug zum Thema durch Medtronic, Boehringer Ingelheim, Daiichi, BMS, Pfizer, Bayer. Ferner Gelder und Sachmittelunterstützung der Deutschen Forschungsgesellschaft (DFG) und Medtronic. Gelder gehen auf ein Drittmittelkonto der Universität Leipzig.CWI: Honorare für Beratertätigkeit der Firma Medtronic. Teilnahmegebühren für einen Kongress oder Fortbildungsveranstaltung, Reise- oder Übernachtungskosten mit Bezug zum Thema durch Medtronic, St. Jude Medical, Abbott, Fa. Biotronik.WRS: Gelder und Sachmittelunterstützung mit Bezug zum Thema der Firma Böhringer-Ingelheim, Honorare für Vorträge und Advisory Boards Boehringer Ingelheim, Bayer, Daichi, Medtronic. Studienteilnahem RESPECT-ESUS., (Thieme. All rights reserved.)

Embolic stroke of unknown source (ESUS) is currently thought to represent a subpopulation of cryptogenic strokes defined by its embolic stroke pattern on imaging, and if after a carefully performed diagnostic evaluation, a specific, well-recognized cause of stroke has not been identified. The concept was primarily established to justify and enable the conduct of the ESUS trials, such as Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source (RESPECT-ESUS) and New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus aspirin to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS). With both studies having neutral results, the question arises if the ESUS concept is misleading or rather a gateway for a modern understanding of stroke etiology. This review will analyze the background of the ESUS concept, overview the results and the impact of the recent multicenter trials and cohort studies, and discuss the definition, etiology, and diagnosis of ESUS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose- The RE-SPECT ESUS trial (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) tested the hypothesis that dabigatran would be superior to aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. This exploratory subgroup analysis investigates the impact of age, renal function (both predefined), and dabigatran dose (post hoc) on the rates of recurrent stroke and major bleeding. Methods- RE-SPECT ESUS was a multicenter, randomized, double-blind trial of dabigatran 150 or 110 mg (for patients aged ≥75 years and/or with creatinine clearance 30 to <50 mL/minute) twice daily compared with aspirin 100 mg once daily. The primary outcome was recurrent stroke. Results- The trial, which enrolled 5390 patients from December 2014 to January 2018, did not demonstrate superiority of dabigatran versus aspirin for prevention of recurrent stroke in patients with embolic stroke of undetermined source. However, among the population qualifying for the lower dabigatran dose, the rate of recurrent stroke was reduced with dabigatran versus aspirin (7.4% versus 13.0%; hazard ratio, 0.57 [95% CI, 0.39-0.82]; interaction P =0.01). This was driven mainly by the subgroup aged ≥75 years (7.8% versus 12.4%; hazard ratio, 0.63 [95% CI, 0.43-0.94]; interaction P =0.10). Stroke rates tended to be lower with dabigatran versus aspirin with declining renal function. Risks for major bleeding were similar between treatments, irrespective of renal function, but with a trend for lower bleeding rates with dabigatran versus aspirin in older patients. Conclusions- In subgroup analyses of RE-SPECT ESUS, dabigatran reduced the rate of recurrent stroke compared with aspirin in patients qualifying for the lower dose of dabigatran. These results are hypothesis-generating. Aspirin remains the standard antithrombotic treatment for patients with embolic stroke of undetermined source. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

This expert opinion paper on atrial fibrillation detection after ischemic stroke includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. This paper was endorsed by the Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork. In patients with ischemic stroke, detection of atrial fibrillation should usually lead to a change in secondary stroke prevention, since oral anticoagulation is superior to antiplatelet drugs. The detection of previously undiagnosed atrial fibrillation can be improved in patients with ischemic stroke to optimize stroke prevention. This paper summarizes the present knowledge on atrial fibrillation detection after ischemic stroke. We propose an interdisciplinary standard for a "structured analysis of ECG monitoring" on the stroke unit as well as a staged diagnostic scheme for the detection of atrial fibrillation. Since the optimal duration and mode of ECG monitoring has not yet been finally established, this paper is intended to give advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on the expert opinion, reported case series and clinical experience. Therefore, this paper is not intended as a guideline.

Background and Purpose: Peripheral immune cell infiltration contributes to neural injury after ischemic stroke. However, in contrast to lymphocytes and neutrophils, the role of different monocyte/macrophage subsets remains to be clarified. Therefore, we evaluated the effects of selective and unselective monocyte/macrophage depletion and proinflammatory (M1-) and anti-inflammatory (M2-) macrophage transfer on the outcome after experimental cerebral ischemia., Methods: To assess short-term effects of monocytes/macrophages in acute ischemic stroke, mice underwent transient middle cerebral artery occlusion and received either clodronate liposomes for unselective macrophage depletion, MC-21-antibody for selective depletion of proinflammatory Ly-6C high monocytes, or proinflammatory (M1-) or anti-inflammatory (M2-) macrophage transfer. In addition, the impact of MC-21-antibody administration and M2-macrophage transfer on long-term neural recovery was investigated after photothrombotic stroke. Neurobehavioral tests were used to analyze functional outcomes, infarct volumes were determined, and immunohistochemical analyses were performed to characterize the postischemic inflammatory reaction., Results: Selective and unselective monocyte/macrophage depletion and M1- and M2-macrophage transfer did not influence tissue damage and neurobehavioral outcomes in the acute phase after middle cerebral artery occlusion. Beyond, selective depletion of Ly-6C high monocytes and M2-macrophage transfer did not have an impact on neural recovery after photothrombotic stroke., Conclusions: Targeting different monocyte/macrophage subsets has no impact on outcome after ischemic stroke in mice. Altogether, our study could not identify monocytes/macrophages as relevant therapeutic targets in acute ischemic stroke., (© 2017 American Heart Association, Inc.)

Background and Purpose: Bone marrow cell (BMC)-based therapies, either the transplantation of exogenous cells or stimulation of endogenous cells by growth factors like the granulocyte colony-stimulating factor (G-CSF), are considered a promising means of treating stroke. In contrast to large preclinical evidence, however, a recent clinical stroke trial on G-CSF was neutral. We, therefore, aimed to investigate possible synergistic effects of co-administration of G-CSF and BMCs after experimental stroke in mice to enhance the efficacy compared with single treatments., Methods: We used an animal model for experimental stroke as paradigm to study possible synergistic effects of co-administration of G-CSF and BMCs on the functional outcome and the pathophysiological mechanism., Results: G-CSF treatment alone led to an improved functional outcome, a reduced infarct volume, increased blood vessel stabilization, and decreased overall inflammation. Surprisingly, the combination of G-CSF and BMCs abrogated G-CSFs' beneficial effects and resulted in increased hemorrhagic infarct transformation, altered blood-brain barrier, excessive astrogliosis, and altered immune cell polarization. These increased rates of infarct bleeding were mainly mediated by elevated matrix metalloproteinase-9-mediated blood-brain barrier breakdown in G-CSF- and BMCs-treated animals combined with an increased number of dilated and thus likely more fragile vessels in the subacute phase after cerebral ischemia., Conclusions: Our results provide new insights into both BMC-based therapies and immune cell biology and help to understand potential adverse and unexpected side effects., (© 2016 American Heart Association, Inc.)

Background and Purpose: In spite of its high disease burden, there is no specific treatment for multi-infarct dementia. The preclinical evaluation of candidate drugs is limited because an appropriate animal model is lacking. Therefore, we aimed to evaluate whether a mouse model of recurrent photothrombotic stroke is suitable for the preclinical investigation of multi-infarct dementia., Methods: Recurrent photothrombotic cortical infarcts were induced in 25 adult C57BL/6 mice. Twenty-five sham-operated animals served as controls. The object recognition test and the Morris water maze test were performed >6 weeks to assess cognitive deficits. Afterward, histological analyses were performed to characterize histopathologic changes associated with recurrent photothrombotic infarcts., Results: After the first infarct, the object recognition test showed a trend toward an impaired formation of recognition memories (P=0.08), and the Morris Water Maze test revealed significantly impaired spatial learning and memory functions (P<0.05). After recurrent infarcts, the object recognition test showed significant recognition memory deficits (P<0.001) and the Morris water maze test demonstrated persisting spatial learning and memory deficits (P<0.05). Histological analyses revealed remote astrogliosis in the hippocampus., Conclusions: Our results show progressive cognitive deficits in a mouse model of recurrent photothrombotic stroke. The presented model resembles the clinical features of human multi-infarct dementia and enables the investigation of its pathophysiological mechanisms and the evaluation of treatment strategies., (© 2015 American Heart Association, Inc.)

Background and Purpose: Eligibility criteria are a key factor for the feasibility and validity of clinical trials. We aimed to develop an online tool to assess the potential effect of inclusion and exclusion criteria on the proportion of patients eligible for an acute stroke trial., Methods: We identified relevant inclusion and exclusion criteria of acute stroke trials. Based on these criteria and using a cohort of 1537 consecutive patients with acute ischemic stroke from 3 stroke centers, we developed a web portal feasibility platform for stroke studies (FePASS) to estimate proportions of eligible patients for acute stroke trials. We applied the FePASS resource to calculate the proportion of patients eligible for 4 recent stroke studies., Results: Sixty-one eligibility criteria were derived from 30 trials on acute ischemic stroke. FePASS, publicly available at http://fepass.uni-muenster.de, displays the proportion of patients in percent to assess the effect of varying values of relevant eligibility criteria, for example, age, symptom onset time, National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale, on this proportion. The proportion of eligible patients for 4 recent stroke studies ranged from 2.1% to 11.3%. Slight variations of the inclusion criteria could substantially increase the proportion of eligible patients., Conclusions: FePASS is an open access online resource to assess the effect of inclusion and exclusion criteria on the proportion of eligible patients for a stroke trial. FePASS can help to design stroke studies, optimize eligibility criteria, and to estimate the potential recruitment rate., (© 2014 American Heart Association, Inc.)

Interferon-β (IFN-β) stabilizes the blood-brain barrier (BBB) in vitro. Here we investigated the effect of serum from 15 IFN-β-1b-treated multiple sclerosis (MS) patients on the permeability read-outs of small solutes in an in vitro BBB model consisting of human brain microvascular endothelial cells in co-culture with rat astrocytes. The addition of sera from IFN-β-treated patients resulted in a significantly (p < 0.05) reduced permeability as compared with untreated patients. Our findings show that sera from IFN-β-1b-treated MS patients have a stabilizing effect on the in vitro BBB. We suggest an unknown potentially pro-inflammatory factor in the serum of MS patients that may lead to a BBB dysfunction and can be modulated by IFN-β.

Granulocyte-colony stimulating factor (G-CSF) is a hematopoietic growth factor that controls proliferation and differentiation of neural stem cells. Although recent studies have begun to explore G-CSF-related mechanisms of action in various disease models, little is known about its function in the healthy brain. In the present study, the effect of G-CSF deficiency on memory formation and motor skills was investigated. The impact of G-CSF deficiency on the structural integrity of the hippocampus was evaluated by analyzing the generation of doublecortin-expressing cells, the amount of bromodeoxyurine-labeled cells, the dendritic complexity in hippocampal neurons, the binding densities of NMDA and GABA(A) receptors and the induction of long-term potentiation (LTP). G-CSF deficiency caused a disruption in memory formation and in the development of motor skills. These impairments were associated with reduced ligand binding densities of NMDA receptors in hippocampal subfields CA3 and the dentate gyrus. The reduced excitation was potentiated by increased ligand binding densities of GABA(A) receptors resulting in a relative shift in favor of inhibition and impaired behavioral performance. These alterations were accompanied by impaired induction of LTP in the CA1 region. Moreover, G-CSF deficiency led to decreased dendritic complexity in hippocampal neurons in the dentate gyrus and the CA1 region. G-CSF deficiency also caused a reduction of neuronal precursor cells in the dentate gyrus. These findings confirm G-CSF as an essential neurotrophic factor, and point to a role in the proliferation, differentiation and functional integration of neural cells necessary for the structural and functional integrity of the hippocampal formation.

Patients with chronic kidney disease (CKD) have an increased risk for cardiovascular morbidity and mortality. Little attention has been paid to the problem of atrial fibrillation, although this arrhythmia is very frequent with a prevalence of 13 to 27% in patients on long-term hemodialysis. Because of the large number of pathophysiologic mechanisms involved, these patients have a high risk for both thromboembolic events and hemorrhagic complications. Stroke is a frequent complication in CKD: The US Renal Data System reports an incidence of 15.1% in hemodialysis patients compared with 9.6% in patients with other stages of CKD and 2.6% in a control cohort without CKD. The 2-yr mortality rates after stroke in these subgroups were 74, 55, and 28%, respectively. Although oral coumadin is the treatment of choice for atrial fibrillation, its use in patients with CKD is reported only in limited studies, all in hemodialysis patients, and is associated with a markedly increased rate of bleeding compared with patients without CKD. With regard to the high risk for stroke and the conflicting data about oral anticoagulation, an individualized stratification algorithm is presented based on relevant studies.