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Investigators acknowledge the limitations of rodent or non-human primate stroke models, hundreds of putative neuroprotectants have been evaluated in preclinical models, but not one has entered the clinical realm. Initial studies focused on the neuron, but in recent years the focus has widened to also include other neural cells including astrocytes, pericytes and endothelial cells, which together form the neurovascular unit. Some new developments raise renewed hope for neuroprotection: the appearance of new compounds with multiple mechanisms of action, or the promulgation of new standards for a rigorous preclinical testing. At the bedside in the last 5 years, uric acid and nerinetide are the only compounds tested for clinical efficacy in randomised controlled trials (RCTs), where all patients had to receive reperfusion therapies, either intravenous thrombolysis and/or mechanical thrombectomy. In addition, otaplimastat, 3K3A-activated protein C (APC), intra-arterial verapamil and intra-arterial hypothermia were also assessed in combination with reperfusion therapy, but in RCTs that only included feasibility or safety outcomes. Some of these compounds yielded promising results which are discussed in this review. Altogether, a deeper knowledge of the mechanisms involved in the ischaemic death process at the neurovascular unit, an improved preselection and evaluation of drugs at the preclinical stage and the testing of putative neuroprotectants in enriched clinical studies of patients receiving reperfusion therapies, might prove more effective than in the past to reverse a dismal situation that has lasted already too long.

The authors utilize optical occlusion of penetrating blood vessels to induce cortical microinfarcts. Occlusion of even a single such vessel leads to behavioral dysfunction, whereas multiple, yet sparse, occlusions can induce substantial tissue damage. Excitotoxicity blockers ameliorate both effects. Microinfarctions are present in the aged and injured human brain. Their clinical relevance is controversial, with postulated sequelae ranging from cognitive sparing to vascular dementia. To address the consequences of microinfarcts, we used controlled optical methods to create occlusions of individual penetrating arterioles or venules in rat cortex. Single microinfarcts, targeted to encompass all or part of a cortical column, impaired performance in a macrovibrissa-based behavioral task. Furthermore, the targeting of multiple vessels resulted in tissue damage that coalesced across cortex, even though the intervening penetrating vessels were acutely patent. Post-occlusion administration of memantine, a glutamate receptor antagonist that reduces cognitive decline in Alzheimer's disease, ameliorated tissue damage and perceptual deficits. Collectively, these data imply that microinfarcts likely contribute to cognitive decline. Strategies that have received limited success in the treatment of ischemic injury, which include therapeutics against excitotoxicity, may be successful against the progressive nature of vascular dementia.

Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3–6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35–2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05–1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95–1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01–7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11–10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98–12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99–1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3–6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

Subclinical leaflet thrombosis of bioprosthetic aortic valves after transcatheter valve replacement (TAVR) and surgical aortic valve replacement (SAVR) has been found with CT imaging. The objective of this study was to report the prevalence of subclinical leaflet thrombosis in surgical and transcatheter aortic valves and the effect of novel oral anticoagulants (NOACs) on the subclinical leaflet thrombosis and subsequent valve haemodynamics and clinical outcomes on the basis of two registries of patients who had CT imaging done after TAVR or SAVR. Patients enrolled between Dec 22, 2014, and Jan 18, 2017, in the RESOLVE registry, and between June 2, 2014, and Sept 28, 2016, in the SAVORY registry, had CT imaging done with a dedicated four-dimensional volume-rendered imaging protocol at varying intervals after TAVR and SAVR. We defined subclinical leaflet thrombosis as the presence of reduced leaflet motion, along with corresponding hypoattenuating lesions shown with CT. We collected data for baseline demographics, antithrombotic therapy, and clinical outcomes. We analysed all CT scans, echocardiograms, and neurological events in a masked fashion. Of the 931 patients who had CT imaging done (657 [71%] in the RESOLVE registry and 274 [29%] in the SAVORY registry), 890 [96%] had interpretable CT scans (626 [70%] in the RESOLVE registry and 264 [30%] in the SAVORY registry). 106 (12%) of 890 patients had subclinical leaflet thrombosis, including five (4%) of 138 with thrombosis of surgical valves versus 101 (13%) of 752 with thrombosis of transcatheter valves (p=0·001). The median time from aortic valve replacement to CT for the entire cohort was 83 days (IQR 33–281). Subclinical leaflet thrombosis was less frequent among patients receiving anticoagulants (eight [4%] of 224) than among those receiving dual antiplatelet therapy (31 [15%] of 208; p<0·0001); NOACs were equally as effective as warfarin (three [3%] of 107 vs five [4%] of 117; p=0·72). Subclinical leaflet thrombosis resolved in 36 (100%) of 36 patients (warfarin 24 [67%]; NOACs 12 [33%]) receiving anticoagulants, whereas it persisted in 20 (91%) of 22 patients not receiving anticoagulants (p<0·0001). A greater proportion of patients with subclinical leaflet thrombosis had aortic valve gradients of more than 20 mm Hg and increases in aortic valve gradients of more than 10 mm Hg (12 [14%] of 88) than did those with normal leaflet motion (seven [1%] of 632; p<0·0001). Although stroke rates were not different between those with (4·12 strokes per 100 person-years) or without (1·92 strokes per 100 person-years) reduced leaflet motion (p=0·10), subclinical leaflet thrombosis was associated with increased rates of transient ischaemic attacks (TIAs; 4·18 TIAs per 100 person-years vs 0·60 TIAs per 100 person-years; p=0·0005) and all strokes or TIAs (7·85 vs 2·36 per 100 person-years; p=0·001). Subclinical leaflet thrombosis occurred frequently in bioprosthetic aortic valves, more commonly in transcatheter than in surgical valves. Anticoagulation (both NOACs and warfarin), but not dual antiplatelet therapy, was effective in prevention or treatment of subclinical leaflet thrombosis. Subclinical leaflet thrombosis was associated with increased rates of TIAs and strokes or TIAs. Despite excellent outcomes after TAVR with the new-generation valves, prevention and treatment of subclinical leaflet thrombosis might offer a potential opportunity for further improvement in valve haemodynamics and clinical outcomes. RESOLVE (Cedars-Sinai Heart Institute) and SAVORY (Rigshospitalet).

To increase the effective use of thrombolytics for acute stroke, the expertise of vascular neurologists must be disseminated more widely. We prospectively assessed whether telemedicine (real-time, two-way audio and video, and digital imaging and communications in medicine [DICOM] interpretation) or telephone was superior for decision making in acute telemedicine consultations. From January, 2004, to August, 2007, patients older than 18 years who presented with acute stroke symptoms at one of four remote spoke sites were randomly assigned, through a web-based, permuted blocks system, to telemedicine or telephone consultation to assess their suitability for treatment with thrombolytics, on the basis of standard criteria. The primary outcome measure was whether the decision to give thrombolytic treatment was correct, as determined by central adjudication. Secondary outcomes were the rate of thrombolytic use, 90-day functional outcomes (Barthel index [BI] and modified Rankin scale [mRS]), the incidence of intracerebral haemorrhages, and technical observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00283868. 234 patients were assessed prospectively. 111 patients were randomised to telemedicine, and 111 patients were randomised to telephone consultation; 207 completed the study. Mean National Institutes of Health stroke scale score at presentation was 9·5 (SD 8·1) points (11·4 [8·7] points in the telemedicine group versus 7·7 [7·0] points in the telephone group; p=0·002). One telemedicine consultation was aborted for technical reasons, although it was included in the analyses. Correct treatment decisions were made more often in the telemedicine group than in the telephone group (108 [98%] vs 91 [82%], odds ratio [OR] 10·9, 95% CI 2·7–44·6; p=0·0009). Intravenous thrombolytics were used at an overall rate of 25% (31 [28%] telemedicine vs 25 [23%] telephone, 1·3, 0·7–2·5; p=0·43). 90-day functional outcomes were not different for BI (95–100) (0·6, 0·4–1·1; p=0·13) or for mRS score (0·6, 0·3–1·1; p=0·09). There was no difference in mortality (1·6, 0·8–3·4; p=0·27) or rates of intracerebral haemorrhage after treatment with thrombolytics (2 [7%] telemedicine vs 2 [8%] telephone, 0·8, 0·1–6·3; p=1·0). However, there were more incomplete data in the telephone group than in the telemedicine group (12% vs 3%, 0·2, 0·1–0·3; p=0·0001). The authors of this trial report that stroke telemedicine consultations result in more accurate decision making compared with telephone consultations and can serve as a model for the effectiveness of telemedicine in other medical specialties. The more appropriate decisions, high rates of thrombolysis use, improved data collection, low rate of intracerebral haemorrhage, low technical complications, and favourable time requirements all support the efficacy of telemedicine for making treatment decisions, and might enable more practitioners to use this medium in daily stroke care. National Institute of Neurological Disorders and Stroke; California Institute of Telecommunications Technology; Department of Veterens' Affairs Research Division.

A highly interconnected network of arterioles overlies mammalian cortex to route blood to the cortical mantle. Here we test if this angioarchitecture can ensure that the supply of blood is redistributed after vascular occlusion. We use rodent parietal cortex as a model system and image the flow of red blood cells in individual microvessels. Changes in flow are quantified in response to photothrombotic occlusions to individual pial arterioles as well as to physical occlusions of the middle cerebral artery (MCA), the primary source of blood to this network. We observe that perfusion is rapidly reestablished at the first branch downstream from a photothrombotic occlusion through a reversal in flow in one vessel. More distal downstream arterioles also show reversals in flow. Further, occlusion of the MCA leads to reversals in flow through approximately half of the downstream but distant arterioles. Thus the cortical arteriolar network supports collateral flow that may mitigate the effects of vessel obstruction, as may occur secondary to neurovascular pathology.

Penetrating arterioles bridge the mesh of communicating arterioles on the surface of cortex with the subsurface microvascular bed that feeds the underlying neural tissue. We tested the conjecture that penetrating arterioles, which are positioned to regulate the delivery of blood, are loci of severe ischemia in the event of occlusion. Focal photothrombosis was used to occlude single penetrating arterioles in rat parietal cortex, and the resultant changes in flow of red blood cells were measured with two-photon laser-scanning microscopy in individual subsurface microvessels that surround the occlusion. We observed that the average flow of red blood cells nearly stalls adjacent to the occlusion and remains within 30% of its baseline value in vessels as far as 10 branch points downstream from the occlusion. Preservation of average flow emerges 350 μm away; this length scale is consistent with the spatial distribution of penetrating arterioles. We conclude that penetrating arterioles are a bottleneck in the supply of blood to neocortex, at least to superficial layers.

Randomised trials have shown that alteplase improves the odds of a good outcome when delivered within 4·5 h of acute ischaemic stroke. However, alteplase also increases the risk of intracerebral haemorrhage; we aimed to determine the proportional and absolute effects of alteplase on the risks of intracerebral haemorrhage, mortality, and functional impairment in different types of patients. We used individual patient data from the Stroke Thrombolysis Trialists' (STT) meta-analysis of randomised trials of alteplase versus placebo (or untreated control) in patients with acute ischaemic stroke. We prespecified assessment of three classifications of intracerebral haemorrhage: type 2 parenchymal haemorrhage within 7 days; Safe Implementation of Thrombolysis in Stroke Monitoring Study's (SITS-MOST) haemorrhage within 24–36 h (type 2 parenchymal haemorrhage with a deterioration of at least 4 points on National Institutes of Health Stroke Scale [NIHSS]); and fatal intracerebral haemorrhage within 7 days. We used logistic regression, stratified by trial, to model the log odds of intracerebral haemorrhage on allocation to alteplase, treatment delay, age, and stroke severity. We did exploratory analyses to assess mortality after intracerebral haemorrhage and examine the absolute risks of intracerebral haemorrhage in the context of functional outcome at 90–180 days. Data were available from 6756 participants in the nine trials of intravenous alteplase versus control. Alteplase increased the odds of type 2 parenchymal haemorrhage (occurring in 231 [6·8%] of 3391 patients allocated alteplase vs 44 [1·3%] of 3365 patients allocated control; odds ratio [OR] 5·55 [95% CI 4·01–7·70]; absolute excess 5·5% [4·6–6·4]); of SITS-MOST haemorrhage (124 [3·7%] of 3391 vs 19 [0·6%] of 3365; OR 6·67 [4·11–10·84]; absolute excess 3·1% [2·4–3·8]); and of fatal intracerebral haemorrhage (91 [2·7%] of 3391 vs 13 [0·4%] of 3365; OR 7·14 [3·98–12·79]; absolute excess 2·3% [1·7–2·9]). However defined, the proportional increase in intracerebral haemorrhage was similar irrespective of treatment delay, age, or baseline stroke severity, but the absolute excess risk of intracerebral haemorrhage increased with increasing stroke severity: for SITS-MOST intracerebral haemorrhage the absolute excess risk ranged from 1·5% (0·8–2·6%) for strokes with NIHSS 0–4 to 3·7% (2·1–6·3%) for NIHSS 22 or more (p=0·0101). For patients treated within 4·5 h, the absolute increase in the proportion (6·8% [4·0% to 9·5%]) achieving a modified Rankin Scale of 0 or 1 (excellent outcome) exceeded the absolute increase in risk of fatal intracerebral haemorrhage (2·2% [1·5% to 3·0%]) and the increased risk of any death within 90 days (0·9% [–1·4% to 3·2%]). Among patients given alteplase, the net outcome is predicted both by time to treatment (with faster time increasing the proportion achieving an excellent outcome) and stroke severity (with a more severe stroke increasing the absolute risk of intracerebral haemorrhage). Although, within 4·5 h of stroke, the probability of achieving an excellent outcome with alteplase treatment exceeds the risk of death, early treatment is especially important for patients with severe stroke. UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

Two phase 3 clinical trials (SAINT I and SAINT II) evaluated the free-radical–trapping agent NXY-059 for the treatment of acute ischemic stroke. The SAINT I trial, reported last year, suggested that NXY-059 might be effective. The authors now report the results of the SAINT II trial, which clearly shows that NXY-059 is not effective for ischemic stroke. The discrepancy in the findings of the two trials is best explained by chance false positive findings in the SAINT I trial. The authors report the results of the SAINT II trial, which clearly shows that the free-radical–trapping agent NXY-059 is not effective for ischemic stroke. Currently, thrombolysis with alteplase (tissue plasminogen activator [rt-PA]) is the only widely approved treatment for acute stroke, and it is underused. There is an urgent need for new therapies that are safer and can be offered to a higher percentage of patients. Cerebral tissue can be protected in animal models by a variety of agents that attenuate neuronal injury after ischemia, 1 but none of these putative neuroprotectants have been confirmed as an effective therapy in clinical trials. NXY-059, a free-radical–trapping agent, has been extensively tested in animal models of focal ischemic stroke and has been shown to improve functional recovery . . .

The principle “time is brain” has long guided acute stroke treatment, emphasizing that earlier intervention improves outcomes. While this dictum applies to current gold‐standard reperfusion therapies, its relevance to emerging regenerative approaches such as stem cell therapy remains to be established. A growing body of preclinical and clinical studies suggests that timing of cell delivery is a key determinant of graft survival, integration and therapeutic efficacy, largely through interactions with the evolving post‐stroke microenvironment. Here, we discuss how early transplantation may access salvageable tissue but faces a hostile inflammatory microenvironment, whereas transplantation at the subacute or chronic phase benefits from a more permissive milieu but by then much of the tissue has been irreversibly lost. We further suggest the optimal window also depends on cell type and mechanism of action: neuroprotective or immunomodulatory grafts may benefit from earlier delivery, while cells requiring long‐term survival and integration may perform better later. Thus, “time is brain” also applies to cell therapies, but it may require aligning graft delivery with the evolving post‐stroke microenvironment rather than the acute therapeutic window. Identifying biomarkers that track inflammatory changes, vascular remodeling and brain damage could personalize this “window of receptivity” and guide tailored future clinical trials. The concept that “time is brain” extends to stem cell therapy for stroke. Evidence across preclinical and clinical studies indicates that delivery timing shapes graft survival, integration, and efficacy by matching the evolving post‐stroke microenvironment. Biomarkers and imaging may personalize a receptive window and guide future cell therapy trials.