Introducing the Concept of Sanctuary Sites in Ischemic Stroke.

BACKGROUND: The topography of arterial territories has been defined using digital maps of supratentorial infarcts. Regions with a high probability of infarction (Pi) exist in the deep compartment due to a paucity of collaterals. However, less attention has been given to regions with a low Pi. METHODS: Using published digital maps, patients with cortical stroke and documented vessel occlusion were included. Infarcts from T2-weighted magnetic resonance images were segmented and registered onto a standard brain template (Montreal Neurological Institute 152). Segmented magnetic resonance images were averaged to yield the Pi at a voxel level. The overall Pi for the combined arterial territories was calculated to ensure that Pi was in the range of 0 to 1. Sanctuary sites were identified as regions with Pi <0.1. RESULTS: There were 154 patients (63% men; median age, 69 years; and interquartile range, 57-78 years). The magnetic resonance imaging scan used for segmentation was performed at a median interval of 35 (interquartile range, 3-66) days after stroke onset. Sanctuary sites were present in the frontal (gyrus rectus, the paracentral lobule, and orbitofrontal and precentral gyrus), parietal (postcentral, supramarginal, and angular gyrus, superior and inferior parietal lobule, and precuneus and posterior cingulate), and occipital cortex (cuneus, middle, and superior occipital gyrus). CONCLUSIONS: We propose that following vessel occlusion, there are cortical regions with a low Pi, which we termed sanctuary sites. The anatomic basis for this observation is the compensatory capacity of leptomeningeal collaterals.

Assessing the diagnostic accuracy of CT perfusion: a systematic review.

Background and purpose: Computed tomography perfusion (CTP) has successfully extended the time window for reperfusion therapies in ischemic stroke. However, the published perfusion parameters and thresholds vary between studies. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines, we conducted a systematic review to investigate the accuracy of parameters and thresholds for identifying core and penumbra in adult stroke patients. Methods: We searched Medline, Embase, the Cochrane Library, and reference lists of manuscripts up to April 2022 using the following terms "computed tomography perfusion," "stroke," "infarct," and "penumbra." Studies were included if they reported perfusion thresholds and undertook co-registration of CTP to reference standards. The quality of studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool and Standards for Reporting of Diagnostic Accuracy (STARD) guidelines. Results: A total of 24 studies were included. A meta-analysis could not be performed due to insufficient data and significant heterogeneity in the study design. When reported, the mean age was 70.2 years (SD+/-3.69), and the median NIHSS on admission was 15 (IQR 13-17). The perfusion parameter identified for the core was relative cerebral blood flow (rCBF), with a median threshold of <30% (IQR 30, 40%). However, later studies reported lower thresholds in the early time window with rapid reperfusion (median 25%, IQR 20, 30%). A total of 15 studies defined a single threshold for all brain regions irrespective of collaterals and the gray and white matter. Conclusion: A single threshold and parameter may not always accurately differentiate penumbra from core and oligemia. Further refinement of parameters is needed in the current era of reperfusion therapy.

Corrigendum: Phase I trial outcome of amnion cell therapy in patients with ischemic stroke (I-ACT).

[This corrects the article DOI: 10.3389/fnins.2023.1153231.].

Phase I trial outcome of amnion cell therapy in patients with ischemic stroke (I-ACT).

Background: We proposed a Phase I dose escalation trial to assess the safety of allogeneic human amniotic epithelial cells (hAECs) in stroke patients with a view to informing the design for a Phase II trial. Methods: The design is based on 3 + 3 dose escalation design with additional components for measuring MR signal of efficacy as well as the effect of hAECs (2-8 × 106/kg, i.v.) on preventing immunosuppression after stroke. Results: Eight patients (six males) were recruited within 24 h of ischemic stroke onset and were infused with hAECs. We were able to increase the dose of hAECs to 8 × 106 cells/kg (2 × 106/kg, n = 3; 4 × 106/kg, n = 3; 8 × 106/kg, n = 2). The mean age is 68.0 ± 10.9 (mean ± SD). The frequencies of hypertension and hyperlipidemia were 87.5%, diabetes was 37.5%, atrial fibrillation was 50%, ischemic heart disease was 37.5% and ever-smoker was 25%. Overall, baseline NIHSS was 7.5 ± 3.1, 7.8 ± 7.2 at 24 h, and 4.9 ± 5.4 at 1 week (n = 8). The modified Rankin scale at 90 days was 2.1 ± 1.2. Supplemental oxygen was given in five patients during hAEC infusion. Using pre-defined criteria, two serious adverse events occurred. One patient developed recurrent stroke and another developed pulmonary embolism whilst in rehabilitation. For the last four patients, infusion of hAECs was split across separate infusions on subsequent days to reduce the risk for fluid overload. Conclusion: Our Phase I trial demonstrates that a maximal dose of 2 × 106/kg hAECs given intravenously each day over 2 days (a total of 4 × 106/kg) is safe and optimal for use in a Phase II trial. Clinical trial registration: ClinicalTrials.gov, identifier ACTRN12618000076279P.

Clinical Outcomes and Patient Safety of Nasogastric Tube in Acute Stroke Patients.

Nasogastric tube (NGT) is often used in stroke patients who are dysphagic (deglutition disorders) or have decreased conscious state. This method of feeding is assumed to have minimal complications. The aim of this study is to analyze complications associated with NGT and variables associated with mortality. Retrospective analysis of 250 acute stroke patients requiring NGT feeding between 2003 and 2020. There were 250 patients (median age 76 (IQR 68-83), 56.4% males, median time to NGT 1 day (IQR 0-3). Discussion with family prior to insertion of NGT recorded in 46 (18.4%). There were 123 cases (49.2%) of aspiration pneumonia. There were 188 (75.2%) NGT associated complications: 67 patients (26.8%) had failed insertion, 31 required multiple attempts, 129 patients (51.6%) pulled out NGT, 107 patients (42.8%) had NGT placed in wrong positions and require reinsertion, 20 cases in the lung, 5 pneumothorax cases, 97 in the gastro oesophageal junction or hiatus hernias, 1 case of oesophageal ulceration, 37 coiled, kinked or resistance. 78 cases the tips were not seen on chest X-ray (CXR), gastrointestinal bleeding in 9 cases, epistaxis in 6 cases), 96 patients (38.4%) required restrain. There were 91 death (36.4%) with 73 patients occurring during hospital admission and a further 18 died within 6 months. Death was more frequent in those age > 60 (72 of 216 patients versus 1 of 33 patients, p < 0.01). The median National Institute of Health Stroke Score/NIHSS of those with aspiration pneumonia was higher than those without (19.5 versus 15, p < 0.01). Decision tree analysis first split at age (≤ 59 versus > 59, p = 0.03), NIHSS (≤ 16 or > 16, p = 0.02), post-stroke pneumonia (p = 0.04) and multiple NGT insertion (p = 0.01). The area under the ROC curve was for this model was 0.75 (95% CI 0.69-0.80). Complications were common among patients with NGT complications. These findings may be used to inform discussions with families regarding NGT.

Topographic Evolution of Anterior Cerebral Artery Infarction and Its Impact on Motor Impairment.

INTRODUCTION: Motor deficit is common following anterior cerebral artery (ACA) stroke. This study aimed to determine the impact on the motor outcome, given the location of descending corticofugal fiber tracts (from the primary motor cortex [M1], dorsal and ventral premotor area [PMdv], and supplementary motor area [SMA]) and the regional variations in collateral support of the ACA territory. METHODS: Patients with ACA vessel occlusion were included. Disruption to corticofugal fibers was inferred by overlap of tracts with a lesion on computed tomography perfusion at the onset and on magnetic resonance imaging (MRI) poststroke. The motor outcome was defined by dichotomized and combined National Institute of Health Stroke Scale (NIHSS) sub-scores for the arm and leg. Multivariate hierarchical partitioning was used to analyze the proportional contribution of the corticofugal fibers to the motor outcome. RESULTS: Forty-seven patients with a median age of 77.5 (interquartile range 68.0-84.5) years were studied. At the stroke onset, 96% of patients showed evidence of motor deficit on the NIHSS, and the proportional contribution of the corticofugal fibers to motor deficit was M1-33%, SMA-33%, and PMdv-33%. By day 7, motor deficit was present in <50% of patients and contribution of M1 fiber tracts to the motor deficit was reduced (M1-10.2%, SMA-61.0%, PMdv-28.8%). We confirmed our findings using publicly available high-resolution templates created from Human Connectome Project data. This also showed a reduction in involvement of M1 fiber tracts on initial perfusion imaging (33%) compared to MRI at a median time of 7 days poststroke (11%). CONCLUSION: Improvements in the motor outcome seen in ACA stroke may be due to the relative sparing of M1 fiber tracts from infarction. This may occur as a consequence of the posterior location of M1 fiber tracts and the evolving topography of ACA stroke due to the compensatory capacity of leptomeningeal anastomoses.

Anterior Cerebral Artery Stroke: Role of Collateral Systems on Infarct Topography.

Background and Purpose: The circle of Willis (CoW) and leptomeningeal anastomoses play an important role in transforming infarct topography following middle cerebral artery occlusion. Their role in infarct topography following anterior cerebral artery occlusion is not well understood. The aim of this study was to evaluate the role of the CoW and leptomeningeal anastomoses in modifying regional variation in infarct topography following occlusion of the anterior cerebral artery and its branches. Methods: Perfusion and magnetic resonance imaging of patients with anterior cerebral artery stroke and evidence of vessel occlusion were segmented and manually registered to standard brain template for voxel-wise comparison. Next, a computer model of the cerebral arteries was formulated as network of nodes connected by cylindrical pipes. The experiments included occlusion of successive branches of the anterior cerebral artery while the configurations of the CoW were varied. Results: Forty-seven patients with a median age of 77.5 years (interquartile range, 68.0­84.5 years) were studied. The regions with the highest probabilities of infarction were the superior frontal gyrus (probability =0.26) and anterior cingulate gyrus (probability =0.24). The regions around the posterior cingulate gyrus (probability =0.08), paracentral lobule (probability =0.05), precuneus and superior parietal lobule (probability =0.03) had a low probability of infarction. Following occlusions distal to the anterior communicating artery, the computer model demonstrated an increase in flow (>30%) in neighboring cortical arteries with leptomeningeal anastomoses. Conclusions: Traditionally the CoW has been regarded as the primary collateral system. However, our computer model shows that the CoW is only helpful in redirecting flow following proximal vessel occlusions (pre-anterior communicating artery). More important are leptomeningeal anastomoses, which play an essential role in distal vessel occlusions, influencing motor outcome by modifying the posterolateral extent of infarct topography.

Stroke Severity, and Not Cerebral Infarct Location, Increases the Risk of Infection.

Infection is a leading cause of death in patients with stroke; however, the impact of cerebral infarct size or location on infectious outcome is unclear. To examine the effect of infarct size on post-stroke infection, we utilised the intraluminal middle-cerebral artery occlusion (MCAO) mouse model of ischemic stroke and adjusted the duration of arterial occlusion. At 1 day following stroke onset, the proportion of mice with infection was significantly greater in mice that had larger infarct sizes. Additionally, the presence of lung infection in these mice with severe strokes extended past 2 days, suggestive of long-term immune impairment. At the acute phase, our data demonstrated an inverse relationship between infarct volume and the number of circulating leukocytes, indicating the elevated risk of infection in more severe stroke is associated with reduced cellularity in peripheral blood, owing predominately to markedly decreased lymphocyte numbers. In addition, the stroke-induced reduction of lymphocyte-to-neutrophil ratio was also evident in the lung of all post-stroke animals. To investigate the effect of infarct location on post-stroke infection, we additionally performed a photothrombotic (PT) model of stroke and using an innovative systematic approach of analysis, we found the location of cerebral infarct does not impact on the susceptibility of post-stroke infection, confirming the greater role of infarct volume over infarct location in the susceptibility to infection. Our experimental findings were validated in a clinical setting and reinforced that stroke severity, and not infarct location, influences the risk of infection after stroke.

Refining the ischemic penumbra with topography.

It has been 40 years since the ischemic penumbra was first conceptualized through work on animal models. The topography of penumbra has been portrayed as an infarcted core surrounded by penumbral tissue and an extreme rim of oligemic tissue. This picture has been used in many review articles and textbooks before the advent of modern imaging. In this paper, we review our understanding of the topography of the ischemic penumbra from the initial experimental animal models to current developments with neuroimaging which have helped to further define the temporal and spatial evolution of the penumbra and refine our knowledge. The concept of the penumbra has been successfully applied in clinical trials of endovascular therapies with a time window as long as 24 h from onset. Further, there are reports of "good" outcome even in patients with a large ischemic core. This latter observation of good outcome despite having a large core requires an understanding of the topography of the penumbra and the function of the infarcted regions. It is proposed that future research in this area takes departure from a time-dependent approach to a more individualized tissue and location-based approach.