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Background: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions., Summary: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced., (© 2021 S. Karger AG, Basel.)

Background: Diffusion magnetic resonance imaging (MRI) is the current-state-of-the-art technique to clinically investigate acute (0-24 h) ischemic stroke tissue. However, reduced apparent diffusion coefficient (ADC)-considered a marker of tissue damage-was observed to reverse spontaneously during the subacute stroke phase (24-72 h) which means that low ADC cannot be used to reflect the damaged tissue after 24 h in experimental and clinical studies. One reason for the change in ADC is that ADC values drop with cytotoxic edema (acute phase) and rise when vasogenic edema begins (subacute phase). Recently, combined 1 H- and 23 Na-MRI was proposed as a more accurate approach to improve delineation between reversible (penumbra) and irreversible ischemic injury (core). The aim of this study was to investigate the effects of reperfusion on the ADC and the sodium MRI signal after experimental ischemic stroke in rats in well-defined areas of different viability levels of the cerebral lesion, i.e. core and penumbra as defined via perfusion and histology. Transient middle cerebral artery occlusion was induced in male rats by using the intraluminal filament technique. MRI sodium, perfusion and diffusion measurement was recorded before reperfusion, shortly after reperfusion and 24 h after reperfusion. The animals were reperfused after 90 min of ischemia., Results: Sodium signal in core did not change before reperfusion, increased after reperfusion while sodium signal in penumbra was significantly reduced before reperfusion, but showed no changes after reperfusion compared to control. The ADC was significantly decreased in core tissue at all three time points compared to contralateral side. This decrease recovered above commonly applied viability thresholds in the core after 24 h., Conclusions: Reduced sodium-MRI signal in conjunction with reduced ADC can serve as a viability marker for penumbra detection and complement hydrogen diffusion- and perfusion-MRI in order to facilitate time-independent assessment of tissue fate and cellular bioenergetics failure in stroke patients.

Background and Purpose: The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large data set from preclinical studies, to examine the effects of early versus late administration of intravenous recombinant tissue-type plasminogen activator., Methods: We collected data from 26 individual studies from 9 international centers (13 researchers; 716 animals) that compared recombinant tissue-type plasminogen activator with controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3 hours) versus late (≥3 hours) drug administration. Final infarct volumes, assessed by histology or magnetic resonance imaging, were compared in each study, and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested., Results: When compared with saline controls, early recombinant tissue-type plasminogen activator administration was associated with a significant benefit (absolute difference, -6.63 mm(3); 95% confidence interval, -9.08 to -4.17; I(2)=76%), whereas late recombinant tissue-type plasminogen activator treatment showed a deleterious effect (+5.06 mm(3); 95% confidence interval, +2.78 to +7.34; I(2)=42%; Pint<0.00001). Results remained unchanged after subgroup analyses., Conclusions: Our results provide the basis needed for the design of future preclinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multicenter trial would require 123 animals per group instead of 40 for a single-center trial., (© 2016 American Heart Association, Inc.)

Background and Purpose: Intracerebral hemorrhage (ICH) is the most adverse event of thrombolysis in ischemic stroke. Cerebral amyloid angiopathy increases the risk for spontaneous lobar ICH. Although thrombolysis may be performed in cerebral amyloid angiopathy-affected patients, there is still little knowledge available on the risk for secondary ICH., Methods: We investigated the effect of recombinant tissue-type plasminogen activator on experimental ischemic stroke in APP23 transgenic mice (n=18) and wild-type littermates (n=15). Focal ischemic stroke was induced in 26-month-old mice by temporal middle cerebral artery occlusion (filament model), followed by treatment with 10 mg/kg recombinant tissue-type plasminogen activator. Twenty-four hours later, a functional score was assessed and the mice were euthanized for histological analysis. ICH was classified as grades 1 to 3 depending on severity., Results: The groups did not differ regarding mortality (P=0.67) and functional deficit (P=0.18). Compared with wild-type mice, the APP23 genotype was associated with a higher appearance for ICH in the infarct area (P=0.05). ICH severity grades 2 and 3 correlated significantly with infarct size (P=0.004 and 0.008, respectively)., Conclusions: The APP23 genotype was not associated with increased mortality or worse functional outcome. Our results suggest an increased risk for ICH in the cerebral amyloid angiopathy-affected brain; however, no ICH was observed outside the ischemic area., (© 2014 American Heart Association, Inc.)

This study characterizes a new model of thromboembolic stroke of the middle cerebral artery in C57 black/6J mice, thus offering an opportunity to use the model for studying ischemic stroke in transgenic mice. Thromboembolic stroke was induced by local injection of either 1.5 or 3.0 UI of thrombin directly into the right MCA of C57 black/6J mice. Cerebral blood flow (CBF) velocity was measured continuously by laser Doppler flowmetry, which allowed documentation of both MCA occlusion and of spontaneous recanalization. After 24 h, all animals were euthanized. Cryosections were cut at 400-μm intervals and silver stained with the high-contrast method for volumetric assessment of infarct size. Interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), caspase-3 and hsp 70 protein levels were investigated by immunofluorescence. Thrombin injection resulted in clot formation in all animals. Cortical infarction occurred in 63% of the mice while 37% had a spontaneous MCA recanalization during the first 20 min following thrombin injection. In cases of successful MCA occlusion with consequent infarction, the clot was stable up to 2 h after formation. Subsequently, 20% recanalized spontaneously. Infarctions were restricted to the cortex with a mean lesion volume of 36 ± 5 for 1.5 UI and 56 ± 8 for 3.0 UI thrombin. Protein levels of IL-6, TNF-α, caspase-3, and hsp 70 were significantly increased after MCAO. The results demonstrate that the mouse thromboembolic stroke model produces cortical infarctions of consistent size in C57 black/6J mice, which is dependent upon the amount of thrombin used for clot formation. Spontaneous MCA recanalization occurs after 2 h of ischemia in 20% of mice. Thus, the thromboembolic model is an applicable stroke model for C57 black/6J mice, which mimics many of the features of human stroke, including spontaneous recanalization. However, strain differences between Swiss and C57 black/6J mice must be taken into account when using the model.

Background: A recent study suggests that patients with persistent occlusion of the middle cerebral artery (MCA) following treatment with recombinant tissue plasminogen activator (rt-PA) have better outcomes than patients with MCA occlusion not receiving rt-PA. We performed a study to elucidate possible mechanisms of this finding in a new model of thromboembolic stroke closely mimicking human pathophysiology., Methods: Thromboembolic stroke was induced by local injection of thrombin directly into the right MCA of C57 black/6J mice. Rt-PA was administered 20 and 40 min after clot formation. The efficiency of rt-PA to induce thrombolysis was measured by laser Doppler. After 24 h, all animals were euthanized and interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase (MMP)-9, Caspase-3, hsp 32 and hsp 70 protein levels were investigated by immunofluorescence. Presence of hemorrhage was verified and infarct volume was measured using histology., Results: Thrombin injection resulted in clot formation giving rise to cortical brain infarction. Early rt-PA treatment starting at 20 min after the clot formation resulted in 100% recanalization. However, rt-PA-induced thrombolysis dissolved the clot in only 38% of the animals when administered 40 min after clot formation. Protein levels of IL-6, TNF-α, MMP-9, Caspase-3, hsp 32 and hsp 70 were increased after MCAO, whereas treatment with rt-PA attenuated the expressions of inflammatory markers in those animals where the thrombolysis was successful. In addition, the infarct size was significantly reduced with rt-PA treatment compared to non-treated MCAO, regardless of whether MCA thrombolysis was successful., Conclusions: The present study demonstrates a clear correlation of the protein expression of inflammatory mediators, apoptosis and stress genes with the recanalization data after rt-PA treatment. In this model rt-PA treatment decreases the infarct size regardless of whether vessel recanalization is successful.

Intima-media thickness (IMT) provides a surrogate end point of cardiovascular outcomes in clinical trials evaluating the efficacy of cardiovascular risk factor modification. Carotid artery plaque further adds to the cardiovascular risk assessment. It is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. The scientific basis for use of IMT in clinical trials and practice includes ultrasound physics, technical and disease-related principles as well as best practice on the performance, interpretation and documentation of study results. Comparison of IMT results obtained from epidemiological and interventional studies around the world relies on harmonization on approaches to carotid image acquisition and analysis. This updated consensus document delineates further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT. Standardized methods will foster homogenous data collection and analysis, improve the power of randomized clinical trials incorporating IMT and plaque measurements and facilitate the merging of large databases for meta-analyses. IMT results are applied to individual patients as an integrated assessment of cardiovascular risk factors. However, this document recommends against serial monitoring in individual patients., (Copyright © 2012 S. Karger AG, Basel.)

Purpose: To estimate changes in the (23)Na density and in the (23)Na relaxation time T(2) * in the anatomically small murine brain after stroke., Materials and Methods: Three-dimensional acquisition weighted chemical shift imaging at a resolution of 0.6 × 0.6 × 1.2 mm(3) was used for sodium imaging and relaxation parameter mapping. In vivo measurements of the mouse brain (n = 4) were performed 24 hours after stroke, induced by microinjection of purified murine thrombin into the right middle cerebral artery. The measurement time was 14 minutes in one mouse and 65 minutes in the other three. An exponential fit estimation of the free induction decay was calculated for each voxel enabling the reconstruction of locally resolved relaxation parameter maps., Results: The infarcted areas showed an increase in sodium density between 160% and 250%, while the T(2) * relaxation time increased by 5%-72% compared to unaffected contralateral brain tissue., Conclusion: (23)Na chemical shift imaging at a resolution of 0.6 × 0.6 × 1.2 mm(3) enabled sodium imaging of the anatomical small mouse brain and the acquired data allowed calculating relaxation parameter maps and hence a more exact evaluation of sodium signal changes after stroke., (Copyright © 2011 Wiley-Liss, Inc.)

Two clinical trials have used ultrasound to improve tPA thrombolysis in patients with acute ischemic stroke. The Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic tPA (CLOTBUST) trial reported accelerated recanalisation of the middle cerebral artery (MCA) in patients with symptoms of MCA infarction, which were monitored with 2-MHz transcranial Doppler. In CLOTBUST, there was no increased bleeding as evidenced by cranial computed tomography. The Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia (TRUMBI) trial, which employed magnetic resonance imaging (MRI) before and after tPA thrombolysis, was discontinued prematurely because of an increased number of secondary hemorrhages, possibly related to the use of low frequency 300-kHz ultrasound. The purpose of our work is to help identify possible mechanisms of intracerebral hemorrhage resulting from sonothrombolysis by applying a simulation tool that estimates the pressure levels in the human brain that are produced with different sonothrombolysis devices. A simulation software based on a finite difference time domain (FDTD) three-dimensional (3D) scheme was developed to predict acoustic pressures in the brain. This tool numerically models the wave propagation through the skull and reproduces both ultrasound protocols of CLOTBUST and TRUMBI for analysis of the distribution of acoustic pressure in the brain during stroke treatment. For the simulated TRUMBI trial, we analyzed both a "high" and "low" hypothesis according to published parameters (for high and low amplitude excitations). For these hypotheses, the mean peak rarefactional pressures in the brain were 0.26 +/- 0.2 MPa (high hypothesis) and 0.06 +/- 0.05 MPa (low hypothesis), with maximal local values as high as 1.2 MPa (high hypothesis) and 0.27 MPa (low hypothesis) for configurations modelled in this study. The peak rarefactional pressure was thus higher than the inertial acoustic cavitation threshold in the presence of a standing wave in large areas of the brain, even outside the targeted clot. For the simulated CLOTBUST trial, the maximum peak negative pressure was less than 0.07 MPa. This simulated pressure is below the threshold for both inertial and stable acoustic cavitation but likewise lower than any acoustic pressure that has been reported as sufficient for effective sonothrombolysis. Simulating the pressure field of ultrasound protocols for clinical trials of sonothrombolysis may help explain mechanisms of adverse effects. Such simulations could prove useful in the initial design and optimization of future protocols for this promising therapy of ischemic stroke.

Improved treatment of acute ischemic stroke with ultrasound and microbubbles in combination with thrombolytic drugs shows great promise, but the optimal techniques, indications, and contraindications have not yet been well defined. Moreover, details such as microbubble dosage, delivery, required thrombolytic drug dosage, and optimal ultrasound characteristics all remain uncertain. Recent results suggest that ultrasound and microbubbles may be effective in clot lysis of ischemic stroke without additional thrombolytic drugs. Moreover, targeting thrombus with specific immunobubbles may improve the efficacy of sonothrombolysis. Safety remains a major concern in the further development of ultrasound-enhanced thrombolysis and extensive animal work is required to define the most promising methods to translate into human application., (Copyright 2009 S. Karger AG, Basel.)

The general indication for the use of ultrasound contrast agents in neurosonologic applications is an insufficient signal-to-noise ratio when investigating the cerebral macro- and microcirculation. Clinical problems that are often encountered in native sonography are 'no flow, slow flow and low flow' phenomena. In these cases, ultrasound contrast agents are used to differentiate between vessel occlusion and insufficient insonation conditions, as well as for the detection of very slow blood flow velocities and low flow volumes. Echo-contrast agents significantly increase the success rate of transcranial color duplex examinations of patients with acute cerebrovascular disease. Ultrasound contrast imaging also allows assessment of the cerebral microcirculation. There are a number of techniques available for performing perfusion studies. These generally utilize high mechanical index imaging, since until recently lower acoustic outputs were unable to detect microbubbles in the brain. New-generation microbubbles in combination with very sensitive contrast-specific ultrasound techniques now enable real-time visualization of stroke. Moreover, destruction sequences with assessment of microbubble replenishment using real-time, low mechanical index imaging are now available. This article reviews of state-of-the-art contrast-specific imaging techniques for ultrasound evaluation of acute stroke patients., (Copyright 2009 S. Karger AG, Basel.)

Background and Purpose: Fever after stroke is a strong predictor for a negative outcome with infections as the most common cause. The aim of this pilot study was to evaluate the effects of prophylactic antibiotic therapy on the incidence and height of fever after acute ischemic stroke., Methods: This is a randomized, controlled study of antibiotic prophylaxis in patients with ischemic stroke enrolled within 24 hours from clinical onset who presented bedridden (modified Rankin score >3) with no significant infection. Interventions included prophylactic mezlocillin plus sulbactam (3 x 2 g/1 g for 4 days) or conventional management. Over 10 days, body temperature was continuously monitored, and the presence of infection was daily assessed. Primary end points were incidence and height of fever; secondary end points included rate of infection and clinical outcome., Results: Sixty patients were included (mean, 75 years; median National Institutes of Health Stroke Scale score, 16). Over the first 3 days, patients in the intervention group showed lower mean body temperatures as well as lower daily peak temperatures (P<0.05). Throughout the observation period, 15 of 30 patients in the intervention group but 27 of 30 patients in the conventionally treated group developed an infection (P<0.05). Mean interval until the diagnosis of infection was 5.1 days in the intervention group and 3.3 days in the control group (P<0.05). Clinical outcome was more favorable in patients with prophylactic therapy (P=0.01)., Conclusions: In patients with acute severe stroke, prophylactic administration of mezlocillin plus sulbactam over 4 days decreases body temperature, lowers the rate of infection, and may be associated with a better clinical outcome.

The field of neurovascular ultrasound is expanding rapidly with exciting new applications. While ultrasound contrast agents were initially used to overcome insufficient transcranial bone windows for identification of the basal cerebral arteries, new-generation microbubbles in combination with very sensitive contrast-specific ultrasound techniques now enable real-time visualization of stroke. This article will provide a review of recent and emerging developments in ultrasound technology and contrast-specific imaging techniques for evaluation of acute stroke patients., (Copyright 2008 S. Karger AG, Basel.)

Stroke poses a massive burden of disease, yet we have few effective therapies. The paucity of therapeutic options stands contrary to intensive research efforts. The failure of these past investments demands a thorough re-examination of the pathophysiology of ischaemic brain injury. Several critical areas hold the key to overcoming the translational roadblock: (1) vascular occlusion: current recanalization strategies have limited effectiveness and may have serious side effects; (2) complexity of stroke pathobiology: therapy must acknowledge the 'Janus-faced' nature of many stroke targets and must identify endogenous neuroprotective and repair mechanisms; (3) inflammation and brain-immune-system interaction: inflammation contributes to lesion expansion, but is also instrumental in lesion containment and repair; stroke outcome is modulated by the interaction of the injured brain with the immune system; (4) regeneration: the potential of the brain for reorganization, plasticity and repair after injury is much greater than previously thought; (5) confounding factors, long-term outcome and predictive modelling. These 5 areas are linked on all levels and therefore need to be tackled by an integrative approach and innovative therapeutic strategies.

We report a traumatic pseudoaneurysm of the internal carotid artery bifurcation and subclavian artery with recurrent strokes events in a 19-year-old man. He was admitted with an acute left hemiparesis. His history revealed a similar episode 1 year and a major car accident 3 years previously. Contrast enhanced MR angiography confirmed colour Doppler sonographic findings of a carotid and subclavian artery pseudoaneurysm presumably resulting from seat-belt trauma. The pseudoaneurysm, containing thrombus, was thought to be the source of artery-to-artery embolism.

Abstract: Combined 2-MHz ultrasound (US) and second-generation, sulfur hexafluoride microbubbles (MB) treatment (US+MB) was performed in a permanent middle cerebral artery (MCA) occlusion model in rats to evaluate possible effects on the ischemic cascade. We used 16 Wistar rats and the MCA occlusion model for stroke induction. Glutamate, pyruvate, lactate and glycerol levels were measured by intracerebral microdialysis before and after stroke induction and after US+MB application (n = 8) for 20 h. After 24 h, brain infarct volume, apoptosis and IL-6 and TNF-alpha levels were evaluated. The infarct volume was significantly reduced (p < 0.05) in the US+MB-treated group compared with control animals. In additional, glutamate levels were significantly lower in US+MB-treated animals, and these animals showed a higher rate of apoptotic cell death in the infarcted area. The levels of IL-6 and TNF-alpha concentrations were not different in both groups, and there was no apoptotic cell death outside the infarction in animals treated with US+MB. The results demonstrate that US+MB with second generation microbubbles does not have a harmful effect on ischemic stroke in an MCA occlusion model of the rat. (E-mail: fatar@neuro.ma.uni-heidelberg.de) [Copyright &y& Elsevier]