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Background: Outcome data regarding the administration of tenecteplase (TNK) to acute ischemic stroke (AIS) patients presenting in the extended time window are limited. Objectives: We aimed to assess the current evidence regarding the efficacy and safety of TNK at a dose of 0.25 mg/kg for AIS treatment in the extended time window. Design: A systematic review and meta-analysis was conducted including all available randomized-controlled clinical trials (RCTs) that compared TNK 0.25 mg/kg versus no thrombolysis in AIS patients presenting in the extended time window (>4.5 h after last-seen-well or witnessed onset). Data sources and methods: Eligible studies were identified by searching Medline, Scopus, and international conference abstracts. The predefined efficacy outcomes of interest were 3-month excellent functional outcome [defined as the modified Rankin Scale (mRS) score ⩽1; primary outcome], 3-month good functional outcome (mRS ⩽ 2), 3-month reduced disability (⩾1-point reduction across all mRS scores). We determined symptomatic intracranial hemorrhage (sICH), any ICH and 3-month mortality as safety endpoints. A random-effects model was used to calculate risk ratios (RRs) and common odds ratios (cORs) with corresponding 95% confidence intervals (CIs). Results: Three RCTs were included comprising 556 patients treated with TNK versus 560 controls. TNK 0.25 mg/kg was associated with a higher likelihood of 3-month excellent functional outcome compared to controls (RR = 1.17; 95% CI = 1.01–1.36; I 2 = 0%), whereas there was no difference regarding good functional outcome (RR = 1.05; 95% CI = 0.94–1.17; I 2 = 0%) and reduced disability (adjusted cOR = 1.14; 95% CI = 0.92–1.40; I 2 = 0%) at 3 months. The risks of sICH (RR = 1.67; 95% CI = 0.70–4.00; I 2 = 0%), any ICH (RR = 1.08; 95% CI = 0.90–1.29; I 2 = 0%) and 3-month mortality (RR = 1.10; 95% CI = 0.81–1.49; I 2 = 0%) were similar between the groups. Conclusion: Based on data from three RCTs showing increased efficacy and a favorable safety profile of TNK in the treatment of AIS in the extended time window, continuing efforts of ongoing RCTs in the field are clearly supported. Trial registration: PROSPERO registration ID: CRD42023448707. [ABSTRACT FROM AUTHOR]

Background: Mechanical thrombectomy (MT) has become increasingly common in recent years, as studies have shown that it can be an effective treatment for acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). However, the efficacy of MT in the extended time window (6 to 24 h) is still uncertain. Our study aims to evaluate the outcomes of MT in the extended time window for AIS patients. Methods: We reviewed data on AIS patients who received MT beyond six hours of stroke onset from 2015 to 2022. The patients' occlusions were in the internal carotid artery (ICA), middle cerebral artery (MCA), or posterior circulation. Our evaluation included the modified Rankin scale (mRS) and 90-day mortality rates, as well as complications, such as symptomatic intracranial hemorrhage (sICH). Results: Thirty-one patients were included in this study, with a mean age of 75.6 ± 15.1 years, of whom 54.8% were male. The median NIHSS score at presentation was 17. Successful recanalization (TICI 2b to 3) was achieved in 90.3% of patients and the rate of sICH was 6.4%. No difference was observed between the two age groups. The younger age group (<80 years old) showed a better clinical outcome (mRS 0–2; p < 0.05, Fisher's exact test) compared with the older age group. The overall mortality rate was 6.4%. Conclusion: Our study shows that (MT) can be performed effectively and safely within an extended time window, resulting in satisfactory functional outcomes, particularly in the younger age group. [ABSTRACT FROM AUTHOR]

Background and Purpose: The effect of noncontrast CT (NCCT) on the eligibility for endovascular therapy (EVT) in an extended time window remains to be elucidated. We sought to assess the efficacy and safety of NCCT in comparison with CT perfusion (CTP) in selecting patients with acute ischemic stroke (AIS) for EVT 6‐24 hours after onset. Methods: PubMed, Embase, and Cochrane libraries were searched from inception to August 31, 2022, to identify all studies reporting 90‐day outcomes of EVT in patients with AIS in an extended time window. A meta‐analysis was performed for the pooled risk ratio (RR) with 95% confidence interval (CI) using a random‐effects model. The primary outcome used to assess efficacy was good functional independence, defined as a modified Rankin Scale score of 0‐2 at 90 days. Secondary outcomes included successful reperfusion, symptomatic intracranial hemorrhage (sICH), and mortality at 90 days. Results: We included four nonrandomized studies with a total of 2685 patients. The outcomes of good functional independence at 90 days (RR = 0.98; 95% CI: 0.88‐1.07; I2 = 0%; p =.62), successful reperfusion (RR = 0.98; 95% CI: 0.93‐1.03; I2 = 50.5%; p =.11), sICH (RR = 1.11; 95% CI: 0.55‐2.21; I2 = 49.4%; p =.12), or mortality at 90 days (RR = 1.18; 95% CI: 0.99‐1.40; I2 = 0%; p =.42) did not differ significantly between the two groups. Conclusions: These findings suggest that NCCT is as effective as CTP in selecting patients for EVT in an extended time window. [ABSTRACT FROM AUTHOR]

Mechanical thrombectomy (MT) is recommended in patients with anterior large vessel occlusion from 6 to 24 hours after stroke onset in selected patients with baseline ischemia defined by Alberta stroke program early CT score (ASPECTS) ≥ 6. Recent studies have shown that carefully selected patients with lower ASPECTS 3-5 and even with ASPECTS 0-2 could benefit from MT. A 45-year-old patient was admitted to our emergency department 14 hours after the stroke onset. The neurological assessment revealed severe dysarthria, gaze palsy to the right, and severe left arm and leg palsy. His National Institutes of Health Stroke Scale (NIHSS) score was 10. The emergent brain CT scan showed large right middle cerebral artery territory infarction with right internal carotid artery and right M2 segment occlusion on CT angiography. The ASPECTS was 2. CT perfusion showed a good core/penumbra mismatch ratio in temporal/peri-insular parts and basal ganglia. The MT was performed 14 hours after the stroke onset with a TICI 2b score. The treatment was complicated by the progression of severe brain edema and brain herniation which required emergent decompressive craniectomy. The patient was discharged to the neurorehabilitation center after 26 hospital days with an NIHSS 10. On the last outpatient visit, after three months, the patient scored 5 on NIHHS and 3 on the 3-month Modified Rankin Score. Our patient was successfully treated by MT despite a low ASPECTS and extended time window. Further randomized control trials are necessary to define which subgroup of these patients can benefit from MT. [ABSTRACT FROM AUTHOR]

Background: Standard-dose intravenous alteplase for acute ischemic stroke (AIS) in the unknown or extended time window beyond 4.5 h after symptom onset is both effective and safe for certain patients who were selected based on multimodal neuroimaging. However, uncertainty exists regarding the potential benefit of using low-dose alteplase among the Asian population outside the 4.5-h time window. Methods: Consecutive AIS patients who received intravenous alteplase between 4.5 and 9 h after symptom onset or with an unknown time of onset guided by multimodal computed tomography (CT) imaging were identified from our prospectivelymaintained database. The primary outcome was excellent functional recovery, defined as having amodified Rankin scale (mRS) score of 0-1 at 90 days. Secondary outcomes included functional independence (an mRS score of 0-2 at 90 days), earlymajor neurologic improvement (ENI), early neurologic deterioration (END), any intracranial hemorrhage (ICH), symptomatic ICH (sICH), and 90-day mortality. Propensity score matching (PSM) and multivariable logistic regression models were used to adjust for confounding factors and compare the clinical outcomes between the low- and standard-dose groups. Results: From June 2019 to June 2022, a total of 206 patients were included in the final analysis, of which 143 were treated with low-dose alteplase and 63 were treated with standard-dose alteplase. After accounting for confounding factors, we observed that there were no statistically significant differences between the standard- and low-dose groups with respect to excellent functional recovery [adjusted odds ratio = 1.22 (aOR), 95% confidence interval (CI): 0.62-2.39; adjusted rate difference (aRD) = 4.6%, and 95% CI: -11.2 to 20.3%]. Patients of both groups had similar rates of functional independence, ENI, END, any ICH, sICH, and 90-daymortality. In the subgroup analysis, patients aged ≥70 years were more likely to achieve excellent functional recovery when receiving standard-dose rather than low-dose alteplase. Conclusion: The effectiveness of low-dose alteplase might be comparable to that of standard-dose alteplase in AIS patients aged <70 years with favorable perfusion-imaging profiles in the unknown or extended time window but not in those aged 70 years. Furthermore, low-dose alteplase did not significantly reduce the risk of sICH compared to standard-dose alteplase. [ABSTRACT FROM AUTHOR]

Background and Purpose: Endovascular thrombectomy (EVT) has benefits in selected patients 6–24 h after stroke onset. However, the response to EVT >24 h after stroke onset is still unclear. We compared the early response to EVT in patients with different time windows. Methods: Patients who underwent EVT in an emergency setting were enrolled and categorized according to when EVT was performed: within 6 (early), 6–24 (late), and >24 h (very late) after stroke onset. Early neurological improvement (ENI) and deterioration (END) were defined as improvement and worsening, respectively, of National Institutes of Health Stroke Scale (NIHSS) score by ≥4 points after EVT. The three groups' clinical characteristics and response to EVT were compared. We also investigated factors associated with ENI and END. Results: During study period, 274 patients underwent EVT (109 early, 104 late, and 61 very late). Patients who underwent EVT very late were younger (p = 0.007), had smaller ischemic cores, and had lower initial NIHSS scores (8 ± 5) than those who underwent EVT early (14 ± 6) and late (13 ± 7; p < 0.001). Stroke mechanisms also differed according to the time window (p < 0.001): cardioembolism was more common after early EVT, whereas large-artery atherosclerosis was more prevalent among patients who underwent EVT very late. ENI was significantly more common after early (60.6%) and late EVT (51.0%) than after very late EVT (29.5%; p = 0.001); however, rates of END did not differ (11.0%, 13.5%, and 4.9%, respectively). ENI was independently associated with male, higher NIHSS score, and early and late EVT. END was associated with failure of recanalization. Conclusions: ENI was more observed and associated with early and late EVT. Highly selected patients receiving very late EVT may not benefit from ENI but may still have a chance to prevent END. The occurrence of END was associated not with time window but with failure of recanalization. [ABSTRACT FROM AUTHOR]

For advanced territorial ischemia numerous retrospective and prospective studies have shown a positive effect of mechanical thrombectomy (MT) compared to best medicinal treatment alone. For patients with minor stroke (NIHSS < 6) there is currently a lack of evidence for MT. Appropriate study protocols must differentiate between patients with large vessel occlusion with disproportionately mild symptoms and more distal vascular occlusion and therefore correspondingly fewer clinical symptoms. The role of intravenous lysis treatment before MT as bridging lysis also currently retains its general recommendation, as large studies could not show a uniform noninferiority of MT alone. In addition, the use of intra-arterial lysis after successful MT offers a promising approach, which still needs to be evaluated. Novel aspiration catheters and stent-retrievers as well as competing thrombectomy techniques can be compared by the first pass effect, the successful recanalization with only one attempt at thrombectomy. Contact aspiration and stent-retriever thrombectomy under aspiration are equivalent and established thrombectomy procedures. For the latter, several detailed maneuver tactics are described for improvement of thrombectomy success. Also, in retrospective studies the combination with a balloon-guided catheter promises a further improvement of recanalization results. In the case of failure of supra-aortic vessel probing with inguinal access, radial access and direct carotid puncture are alternative access routes. Recent studies on ICA stenting with tandem occlusions showed a benefit of stents without an increased risk for symptomatic intracranial hemorrhage. The retrograde approach, to first treat the intracranial vessel occlusion and then the carotid stenosis, seems to be advantageous. [ABSTRACT FROM AUTHOR]

Based on recent trials regarding the early time window, omitting intravenous thrombolysis (IVT) before endovascular thrombectomy (EVT) in eligible patients seems unjustified. Whether this also concerns the extended time window, 4.5 to 9 h from last seen well, is yet unclear. All consecutive patients treated with IVT, EVT, or IVT plus EVT in the extended time window at Helsinki University Hospital (HUS) between 1/2021 and 12/2022 were compared with matched controls treated in the early time window between 1/2016 and 12/2020. Regression analysis was applied on functional outcome at 90 days, evaluated on modified Rankin Scale (mRS), and on the occurrence of symptomatic intracerebral hemorrhage (sICH), adjusted for potential confounders. Altogether 134 patients and 134 matching controls were included. Functional outcomes did not significantly differ between the extended versus early time window. Among patients with IVT plus EVT, the adjusted odds ratio (aOR) for a favorable outcome shift on mRS was 1.15, 95% confidence interval (CI) 0.54–2.43. Although sICH occurred more frequently (2.2% versus 3.0%) in the extended time window, regression analysis did not show a significant difference, aOR 0.96, 95% CI 0.14–6.87. We found no significant differences in the functional or safety outcomes between the extended versus early time window among patients with either IVT, EVT, or IVT plus EVT. There were no signals indicating, that IVT or EVT should be avoided in eligible patients in the extended time window which aligns with the current clinical treatment guidelines of HUS. • There is lack of data on thrombolysis before thrombectomy in the late time window. • Functional outcomes did not significantly differ in the late vs. early time window. • Rates of symptomatic intracranial hemorrhage were low in both time windows. • We found no signals showing thrombolysis should be omitted in eligible patients. [ABSTRACT FROM AUTHOR]

Background: The data regarding patients eligible for endovascular thrombectomy (EVT), especially in the developing world is lacking. Objective: To determine the proportion of patients with acute ischemic stroke (AIS) who are eligible for EVT in the 0-24-h time window. Materials and Methods: We performed a retrospective cohort study using prospectively collected AIS data between July 2017 and September 2019. Demographic, clinical, and management information were analyzed. EVT eligibility was explored using the following criteria: National Institutes of Health Stroke Scale (NIHSS) score ≥6, presence of anterior circulation large-vessel occlusion (ACLVO), Alberta stroke program early Computerized Tomography score (ASPECTS) ≥6, baseline modified Rankin Scale (mRS) score 0–2, and within 24 h of time last seen well (TLSW). EVT-eligible patients were further evaluated for in-hospital course and outcomes. Results: In the study period of 27 months, there were 221 patients with AIS who presented within 24 h. The mean age of the patients was 54.4 (16.0) years and 66.1% (146) were males. A majority (61.5% [136/221]) arrived within 6 h of TLSW. Of these, 81.6% (111/136) presented in the time window for thrombolysis (0–4.5 h). The patients with NIHSS ≥6 and ACLVO constituted 41.2% (91/221) of the patients. AIS eligible for EVT constituted 19.5% (43/221) of the patients. Conclusion: In our study, the proportion of AIS eligible for endovascular thrombectomy was comparable to the developed world. These data predict a large potential for the late-window EVT in India. [ABSTRACT FROM AUTHOR]

Abstract Background Current guidelines limit thrombolytic treatment of stroke to those patients who present within 4.5 h to minimize the risk of hemorrhagic complications. Risk of hemorrhage increases with increasing blood-brain barrier (BBB) disruption. This study aimed to determine, in a cohort of patients presenting outside of an IV-tPA treatment window, whether disruption of the BBB is time dependent, and what proportion of patients could be safely treated. Methods We analyzed untreated stroke patients, seen between 2011 and 2015, who had MRI studies in the time window of 4 to 24 h from symptoms onset. Permeability of the BBB was measured within the ischemic tissue using an application of dynamic susceptibility contrast imaging. Patients were dichotomized into two groups based on a 20% threshold of BBB disruption and compared using logistic regression. Results Of the 222 patients included in the final analysis, over half, 129 (58%), had preserved BBB integrity below the 20% threshold. There was no relationship between time imaged after symptom onset and the amount of BBB disruption (p = 0.138) across the population; BBB disruption varied widely. Conclusions Estimating BBB integrity may help to expand the treatment window for stroke patients by identifying those individuals for whom thrombolytic therapy can be considered.

OBJECTIVE: The objective of this study was to determine the proportion of stroke patients presenting in an extended time window who have a thrombolytic treatment target. BACKGROUND: Patients presenting up to 24 h after stroke onset have been found to have penumbral tissue on multimodal imaging. Stroke patients presenting in this extended time window without a large vessel occlusion (LVO) may benefit from reperfusion therapy using thrombolysis. METHODS: Patients seen at our institutions from 2011 through 2015 were reviewed to identify those who presented >4 h and 1.2. Patients with a mismatch presented earlier (P = 0.012), were more likely to be female (P = 0.03), and had higher National Institutes of Health Stroke Scale (P < 0.001). CONCLUSIONS: Almost half of the patients presenting 4–24 h from LSN had a target for thrombolysis in our study. Multimodal imaging may be able to expand the population of treatable stroke patients given the results of recent clinical trials.

Introduction: After positive findings in clinical trials the time window for endovascular thrombectomy (EVT) for patients with an acute ischemic stroke has been expanded up to 24 h from symptom onset or last seen well (LSW). We aimed to compare EVT patients' characteristics and outcomes in the early versus extended time window and to compare outcomes with the DAWN and DEFUSE 3 trial results., Patients and Methods: Consecutive EVT patients from 16 mostly European comprehensive stroke centers from the EVA-TRISP cohort were included. We compared rates of 90-day good functional outcomes (Modified Rankin Scale 0-2), symptomatic intracranial hemorrhage (sICH), and 90-day mortality between patients treated in the early (<6 h after onset or LSW) versus extended (6-24 h after onset or LSW) time windows., Results: We included 9313 patients, of which 6876 were treated in the early and 2437 in the extended time window. National Institutes of Health Stroke Scale (NIHSS) score at presentation was lower in patients treated in the extended time window (median 13 [IQR 7-18] vs 15 [IQR 9-19], p  < 0.001). The percentage of patients with good functional outcome was slightly lower in the extended time window (37.4% vs 42.2%, p  < 0.001). However, rates of successful recanalization, sICH, and mortality were similar. Good functional outcome rates after EVT were slightly lower for patients in the extended window in the EVA-TRISP cohort as compared to DAWN and DEFUSE 3., Discussion and Conclusion: According to this large multicenter cohort study reflecting daily clinical practice, EVT use in the extended time window appears safe and effective., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ivana Berisavac: speaker honoraria from Medtronic. Visnja Padjen: speaker honoraria from Medtronic and Boehringer Ingelheim. Ronen R. Leker: received speaker honoraria from IscemaView, Boehringer Ingelheim, Pfizer, Jansen, Biogen, Medtronic and Abott and advisory board honoraria from Jansen and Filterlex. Andrea Zini: has received funding for speaker honoraria and consulting fees from Boehringer Ingelheim, Astra Zeneca, Daiichi Sankyo, CSL Behring, for scientific advisory board from Bayer, Astra Zeneca. Mirjam R. Heldner: reports grants from Swiss National Science Foundation, SITEM Research Support Funds and Swiss Heart Foundation, not directly related to this manuscript. Christian H Nolte: has received honoraria for lectures or speaker’s bureau from Alexion, AstraZeneca, BMS, Novartis and Pfizer. The other authors report nothing to disclose.

Background: rt-PA for ischemic stroke in the unknown or extended time window beyond the first 4. 5 h after symptom onset is safe and effective for certain patients after selection by multimodal neuroimaging. However, the evidence for this approach comes mainly from patients with anterior circulation stroke (ACS), while the data on posterior circulation stroke (PCS) are scarce.Methods: Ischemic stroke patients treated with IV-thrombolysis in the unknown or extended time window between January 2011 and May 2019 were identified from an institutional registry. The patients were categorized into PCS or ACS based on clinico-radiological findings. We analyzed the hemorrhagic complications, clinical and imaging efficacy outcomes, and mortality rates by comparing the PCS and ACS patient groups. Adjusted outcome analyses were performed after propensity score matching for the relevant factors.Results: Of the 182 patients included, 38 (20.9%) had PCS and 144 (79.1%) had ACS. Symptomatic acute large vessel occlusion (LVO) was present in 123 patients on admission [27 (22.0%) PCS and 96 (78.0%) ACS]. The score on the National Institutes of Health Stroke Scale (NIHSS), the time from last seen normal, and the door-to-needle times were similar in PCS and ACS. In patients with LVO, the NIHSS score was lower [8 (5–15) vs. 14 (9–18), p = 0.005], and infarction visible on follow-up imaging was less common [70.4 vs. 87.5%; aRD, −18.9% (−39.8 to −2.2%)] in the PCS patient group. There was a trend toward a lower risk for intracranial hemorrhage (ICH) following intravenous thrombolysis in PCS vs. ACS, without reaching a statistical significance [5.3 vs. 16.9%; aRD, −10.4% (−20.4 to 4.0%)]. The incidence of symptomatic ICH [according to the ECASS III criteria: 2.6 vs. 3.5%; aRD, −2.9% (−10.3 to 9.2%)], efficacy outcomes, and mortality rates were similar in PCS and ACS patients.Conclusions: In this real-world clinical cohort, the safety and the efficacy of rt-PA for ischemic stroke in the unknown or extended time window did not show relevant differences between PCS and ACS, with a trend toward less hemorrhagic complications in PCS. The findings reconfirm the clinician in the usage of rt-PA beyond the first 4.5 h also in selected patients with PCS.

Background: rt-PA for ischemic stroke in the unknown or extended time window beyond the first 4. 5 h after symptom onset is safe and effective for certain patients after selection by multimodal neuroimaging. However, the evidence for this approach comes mainly from patients with anterior circulation stroke (ACS), while the data on posterior circulation stroke (PCS) are scarce. Methods: Ischemic stroke patients treated with IV-thrombolysis in the unknown or extended time window between January 2011 and May 2019 were identified from an institutional registry. The patients were categorized into PCS or ACS based on clinico-radiological findings. We analyzed the hemorrhagic complications, clinical and imaging efficacy outcomes, and mortality rates by comparing the PCS and ACS patient groups. Adjusted outcome analyses were performed after propensity score matching for the relevant factors. Results: Of the 182 patients included, 38 (20.9%) had PCS and 144 (79.1%) had ACS. Symptomatic acute large vessel occlusion (LVO) was present in 123 patients on admission [27 (22.0%) PCS and 96 (78.0%) ACS]. The score on the National Institutes of Health Stroke Scale (NIHSS), the time from last seen normal, and the door-to-needle times were similar in PCS and ACS. In patients with LVO, the NIHSS score was lower [8 (5–15) vs. 14 (9–18), p = 0.005], and infarction visible on follow-up imaging was less common [70.4 vs. 87.5%; aRD, −18.9% (−39.8 to −2.2%)] in the PCS patient group. There was a trend toward a lower risk for intracranial hemorrhage (ICH) following intravenous thrombolysis in PCS vs. ACS, without reaching a statistical significance [5.3 vs. 16.9%; aRD, −10.4% (−20.4 to 4.0%)]. The incidence of symptomatic ICH [according to the ECASS III criteria: 2.6 vs. 3.5%; aRD, −2.9% (−10.3 to 9.2%)], efficacy outcomes, and mortality rates were similar in PCS and ACS patients. Conclusions: In this real-world clinical cohort, the safety and the efficacy of rt-PA for ischemic stroke in the unknown or extended time window did not show relevant differences between PCS and ACS, with a trend toward less hemorrhagic complications in PCS. The findings reconfirm the clinician in the usage of rt-PA beyond the first 4.5 h also in selected patients with PCS. [ABSTRACT FROM AUTHOR]

Background: Endovascular treatment of acute ischemic stroke with large-vessel occlusion is the standard of care now. Initially restricted to 6 h after onset, the treatment can now be offered to selected patients up to 24 h based on clinical and imaging criteria. Objective: Perfusion imaging can help in identifying patients who may benefit from endovascular treatment in the extended time window. Manual analysis of perfusion images is time and skill intensive. Rapid processing of perfusion and diffusion (RAPID) is an automated image analysis system that analyzes perfusion maps. We report our initial experience of using this system in selection of patients for endovascular stroke treatment. Methods: All patients who presented with acute stroke underwent baseline imaging with computed tomography (CT) and CT angiogram or magnetic resonance imaging (MRI) and MR angiogram. Patients presenting between 6 and 24 h after onset underwent perfusion imaging, which was analyzed by RAPID. The results were used to select the patients who then underwent mechanical thrombectomy. Results: RAPID results identifying ischemic core and hypoperfused tissue were available within 5 min in each of the three cases. At 3 months, all patients showed improvement in the modified Rankin Scale. Conclusion: In extended time windows, RAPID provides a fast and reliable estimate of salvageable brain tissue to help select patients for endovascular treatment.

Purpose: New guidelines recommend thrombectomy up to 24 h in selected patients; however, the workload and benefit of extending time window are not known. We conducted a prospective single-centre study to determine the caseload, imaging and interventional need of extended time window. Methods: All consecutive ischemic stroke patients within 24 h from onset in an 11-month period were included. Thrombectomy eligibility in the 0–6 h time window was based on current guidelines; in the 6–24 h time window, it was based on a combination of DEFUSE 3 and DAWN study criteria using MRI to identify target mismatch. Clinical outcome in treated patients was assessed at 3 months. Results: Within 24 h of onset, 437 patients were admitted. In the 0–6 h time window, 238 patients (54.5%) arrived of whom 221 (92.9%) underwent CTA or MRA, 82 (34.5%) had large vessel occlusion (LVO), 30 (12.6%) had thrombectomy and 11 (36.6%) became independent (mRS ≤ 2). In the extended 6–24 h time window, 199 patients (45.5%) arrived of whom 127 (63.8%) underwent CTA or MRA, 44 (22.1%) had LVO, 8 (4%) had thrombectomy and 4 (50%) became independent. Conclusion: Extending the time window from 6 to 24 h results in a 26.7% increase in patients receiving thrombectomy and a 36.4% increase of independent clinical outcome in treated patients at the price of a significantly increased burden of clinical and imaging screening due to the similar caseload but a smaller proportion of treatment eligible patients in the extended as compared with the standard time window. [ABSTRACT FROM AUTHOR]

Background: Penumbral brain tissue identified with multimodal imaging can be salvaged with reperfusion in an extended time window. The risk of severe hemorrhagic complications after reperfusion therapy increases with worsening disruption of the blood-brain barrier (BBB). The relationship between penumbral tissue and BBB disruption has not been previously studied.Methods: Stroke patients presenting in an extended time window without a large vessel occlusion who underwent diffusion-perfusion MRI within 24 h of last-seen-normal were included. The volume of penumbral tissue was calculated using mismatch on MRI. Mean permeability derangement (MPD) of the BBB was measured within the ischemic lesion. A target profile (TP) for treatment was defined based on the EXTEND trial.Results: 222 patients were included with a median age of 73 and 55% women. The median NIHSS was 6, the mean core volume was 14 ml, the mean ischemic volume was 47 mL and the mean mismatch volume was 33 mL. Higher MPD was significantly associated with less mismatch volume (p = 0.001). A target profile was associated with lower MPD (OR 0.97; CI 0.96:0.99; p < 0.001). Of the 105 patients who had a TP, 31 (30%) had a MPD > 20% suggesting an increased risk of hemorrhage. Thus, 33% (74/222) of patients had a favorable profile for benefit and safety.Conclusions: Patients presenting in an extended time window with a favorable penumbral profile for treatment have less severe BBB disruption. Up to a third of patients who currently go untreated could be considered for enrollment in a clinical trial of thrombolysis in an extended time window.

Background: Penumbral brain tissue identified with multimodal imaging can be salvaged with reperfusion in an extended time window. The risk of severe hemorrhagic complications after reperfusion therapy increases with worsening disruption of the blood-brain barrier (BBB). The relationship between penumbral tissue and BBB disruption has not been previously studied. Methods: Stroke patients presenting in an extended time window without a large vessel occlusion who underwent diffusion-perfusion MRI within 24 h of last-seen-normal were included. The volume of penumbral tissue was calculated using mismatch on MRI. Mean permeability derangement (MPD) of the BBB was measured within the ischemic lesion. A target profile (TP) for treatment was defined based on the EXTEND trial. Results: 222 patients were included with a median age of 73 and 55% women. The median NIHSS was 6, the mean core volume was 14 ml, the mean ischemic volume was 47 mL and the mean mismatch volume was 33 mL. Higher MPD was significantly associated with less mismatch volume (p = 0.001). A target profile was associated with lower MPD (OR 0.97; CI 0.96:0.99; p < 0.001). Of the 105 patients who had a TP, 31 (30%) had a MPD > 20% suggesting an increased risk of hemorrhage. Thus, 33% (74/222) of patients had a favorable profile for benefit and safety. Conclusions: Patients presenting in an extended time window with a favorable penumbral profile for treatment have less severe BBB disruption. Up to a third of patients who currently go untreated could be considered for enrollment in a clinical trial of thrombolysis in an extended time window. [ABSTRACT FROM AUTHOR]

Background: Current guidelines limit thrombolytic treatment of stroke to those patients who present within 4.5 h to minimize the risk of hemorrhagic complications. Risk of hemorrhage increases with increasing blood-brain barrier (BBB) disruption. This study aimed to determine, in a cohort of patients presenting outside of an IV-tPA treatment window, whether disruption of the BBB is time dependent, and what proportion of patients could be safely treated.Methods: We analyzed untreated stroke patients, seen between 2011 and 2015, who had MRI studies in the time window of 4 to 24 h from symptoms onset. Permeability of the BBB was measured within the ischemic tissue using an application of dynamic susceptibility contrast imaging. Patients were dichotomized into two groups based on a 20% threshold of BBB disruption and compared using logistic regression.Results: Of the 222 patients included in the final analysis, over half, 129 (58%), had preserved BBB integrity below the 20% threshold. There was no relationship between time imaged after symptom onset and the amount of BBB disruption (p = 0.138) across the population; BBB disruption varied widely.Conclusions: Estimating BBB integrity may help to expand the treatment window for stroke patients by identifying those individuals for whom thrombolytic therapy can be considered. [ABSTRACT FROM AUTHOR]

Background and purpose: Acute ischemic stroke treatment with intravenous thrombolysis (IVT) is restricted to a time window of 4.5 h after known or presumed onset. Recently, magnetic resonance imaging‐guided treatment decision‐making in wake‐up stroke (WUS) was shown to be effective. The aim of this study was to determine the safety and outcome of IVT in patients with a time window beyond 4.5 h selected by computed tomography perfusion (CTP) imaging. Methods: We analyzed all consecutive patients last seen well beyond 4.5 h after stroke onset treated with IVT based on CTP between January 2015 and October 2018. CTP was visually assessed to estimate the mismatch between cerebral blood flow and cerebral blood volume maps. Early infarct signs were documented according to Alberta Stroke Program Early CT Score (ASPECTS). Safety data were obtained for mortality and symptomatic intracerebral hemorrhage (sICH). Follow‐up was assessed with the modified Rankin Scale (mRS). Results: A total of 70 patients fulfilled the inclusion criteria (mean age ± SD 77.6 ± 11.5 years, 50.0% female). Median National Institutes of Health Stroke Scale score on admission was 8.0 [interquartile range (IQR), 4–14]. The most frequent reasons for an extended time window were WUS (60.0%) and delayed hospital admission (27.1%). Median time from last seen well to IVT was 11.4 h. Median ASPECTS was 10 (IQR, 9–10) and CTP mismatch 90% (IQR, 80%–100%). A total of 24 patients (34.3%) underwent additional mechanical thrombectomy. sICH occurred in four patients (5.7%). At follow‐up, 49.3% had an mRS score of 0–2 and 22.4% had an mRS score of 0–1. Conclusions: In patients presenting in an extended time window beyond 4.5 h, IVT treatment with decision‐making based on CTP might be a safe procedure. Further evaluation in clinical trials is needed. [ABSTRACT FROM AUTHOR]

Background: Endovascular treatment of acute ischemic stroke with large-vessel occlusion is the standard of care now. Initially restricted to 6 h after onset, the treatment can now be offered to selected patients up to 24 h based on clinical and imaging criteria. Objective: Perfusion imaging can help in identifying patients who may benefit from endovascular treatment in the extended time window. Manual analysis of perfusion images is time and skill intensive. Rapid processing of perfusion and diffusion (RAPID) is an automated image analysis system that analyzes perfusion maps. We report our initial experience of using this system in selection of patients for endovascular stroke treatment. Methods: All patients who presented with acute stroke underwent baseline imaging with computed tomography (CT) and CT angiogram or magnetic resonance imaging (MRI) and MR angiogram. Patients presenting between 6 and 24 h after onset underwent perfusion imaging, which was analyzed by RAPID. The results were used to select the patients who then underwent mechanical thrombectomy. Results: RAPID results identifying ischemic core and hypoperfused tissue were available within 5 min in each of the three cases. At 3 months, all patients showed improvement in the modified Rankin Scale. Conclusion: In extended time windows, RAPID provides a fast and reliable estimate of salvageable brain tissue to help select patients for endovascular treatment. [ABSTRACT FROM AUTHOR]

Background: Mechanical thrombectomy (MT) has become increasingly common in recent years, as studies have shown that it can be an effective treatment for acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). However, the efficacy of MT in the extended time window (6 to 24 h) is still uncertain. Our study aims to evaluate the outcomes of MT in the extended time window for AIS patients., Methods: We reviewed data on AIS patients who received MT beyond six hours of stroke onset from 2015 to 2022. The patients' occlusions were in the internal carotid artery (ICA), middle cerebral artery (MCA), or posterior circulation. Our evaluation included the modified Rankin scale (mRS) and 90-day mortality rates, as well as complications, such as symptomatic intracranial hemorrhage (sICH)., Results: Thirty-one patients were included in this study, with a mean age of 75.6 ± 15.1 years, of whom 54.8% were male. The median NIHSS score at presentation was 17. Successful recanalization (TICI 2b to 3) was achieved in 90.3% of patients and the rate of sICH was 6.4%. No difference was observed between the two age groups. The younger age group (<80 years old) showed a better clinical outcome (mRS 0-2; p < 0.05, Fisher's exact test) compared with the older age group. The overall mortality rate was 6.4%., Conclusion: Our study shows that (MT) can be performed effectively and safely within an extended time window, resulting in satisfactory functional outcomes, particularly in the younger age group., Competing Interests: The authors declare no conflicts of interest.

The cerebral collateral circulation is an increasingly important consideration in the management of acute ischemic stroke and is a key determinant of outcomes. Growing evidence has demonstrated that better collaterals can predict the rate of infarct progression, degree of recanalization, the likelihood of hemorrhagic transformation and various therapeutic opportunities. Collaterals can also identify those unlikely to respond to reperfusion therapies, helping to optimize resources. More randomized trials are needed to evaluate the risks and benefits of endovascular reperfusion with consideration of collateral status. This reviews our current understanding of the pathophysiologic mechanisms, effect on outcomes and strategies for improvement of the collateral system., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Standard-dose intravenous alteplase for acute ischemic stroke (AIS) in the unknown or extended time window beyond 4.5 h after symptom onset is both effective and safe for certain patients who were selected based on multimodal neuroimaging. However, uncertainty exists regarding the potential benefit of using low-dose alteplase among the Asian population outside the 4.5-h time window., Methods: Consecutive AIS patients who received intravenous alteplase between 4.5 and 9 h after symptom onset or with an unknown time of onset guided by multimodal computed tomography (CT) imaging were identified from our prospectively maintained database. The primary outcome was excellent functional recovery, defined as having a modified Rankin scale (mRS) score of 0-1 at 90 days. Secondary outcomes included functional independence (an mRS score of 0-2 at 90 days), early major neurologic improvement (ENI), early neurologic deterioration (END), any intracranial hemorrhage (ICH), symptomatic ICH (sICH), and 90-day mortality. Propensity score matching (PSM) and multivariable logistic regression models were used to adjust for confounding factors and compare the clinical outcomes between the low- and standard-dose groups., Results: From June 2019 to June 2022, a total of 206 patients were included in the final analysis, of which 143 were treated with low-dose alteplase and 63 were treated with standard-dose alteplase. After accounting for confounding factors, we observed that there were no statistically significant differences between the standard- and low-dose groups with respect to excellent functional recovery [adjusted odds ratio = 1.22 (aOR), 95% confidence interval (CI): 0.62-2.39; adjusted rate difference (aRD) = 4.6%, and 95% CI: -11.2 to 20.3%]. Patients of both groups had similar rates of functional independence, ENI, END, any ICH, sICH, and 90-day mortality. In the subgroup analysis, patients aged ≥70 years were more likely to achieve excellent functional recovery when receiving standard-dose rather than low-dose alteplase., Conclusion: The effectiveness of low-dose alteplase might be comparable to that of standard-dose alteplase in AIS patients aged <70 years with favorable perfusion-imaging profiles in the unknown or extended time window but not in those aged ≥70 years. Furthermore, low-dose alteplase did not significantly reduce the risk of sICH compared to standard-dose alteplase., 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 © 2023 Wang, Ji and Fang.)

Within the last year, four randomised-controlled clinical trials (RCTs) have been published comparing intravenous thrombolysis (IVT) with tenecteplase and alteplase in acute ischaemic stroke (AIS) patients with a non-inferiority design for three of them. An expedited recommendation process was initiated by the European Stroke Organisation (ESO) and conducted according to ESO standard operating procedure based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. We identified three relevant Population, Intervention, Comparator, Outcome (PICO) questions, performed systematic reviews of the literature and meta-analyses, assessed the quality of the available evidence, and wrote evidence-based recommendations. Expert consensus statements were provided if insufficient evidence was available to provide recommendations based on the GRADE approach. For patients with AIS of <4.5 h duration who are eligible for IVT, tenecteplase 0.25 mg/kg can be used as a safe and effective alternative to alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS of <4.5 h duration who are eligible for IVT, we recommend against using tenecteplase at a dose of 0.40 mg/kg (low evidence, strong recommendation). For patients with AIS of <4.5 h duration with prehospital management with a mobile stroke unit who are eligible for IVT, we suggest tenecteplase 0.25 mg/kg over alteplase 0.90 mg/kg (low evidence, weak recommendation). For patients with large vessel occlusion (LVO) AIS of <4.5 h duration who are eligible for IVT, we recommend tenecteplase 0.25 mg/kg over alteplase 0.9 mg/kg (moderate evidence, strong recommendation). For patients with AIS on awakening from sleep or AIS of unknown onset who are selected with non-contrast CT, we recommend against IVT with tenecteplase 0.25 mg/kg (low evidence, strong recommendation). Expert consensus statements are also provided. Tenecteplase 0.25 mg/kg may be favoured over alteplase 0.9 mg/kg for patients with AIS of <4.5 h duration in view of comparable safety and efficacy data and easier administration. For patients with LVO AIS of <4.5 h duration who are IVT-eligible, IVT with tenecteplase 0.25 mg/kg is preferable over skipping IVT before MT, even in the setting of a direct admission to a thrombectomy-capable centre. IVT with tenecteplase 0.25 mg/kg may be a reasonable alternative to alteplase 0.9 mg/kg for patients with AIS on awakening from sleep or AIS of unknown onset and who are IVT-eligible after selection with advanced imaging., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Intellectual and financial disclosures of the module working group members are presented in Supplemental Table., (© European Stroke Organisation 2023.)

Background: Perfusion computed tomography (PCT) has emerged as alternative to magnetic resonance imaging (MRI) for assessment of patients clinically qualifying for off-label thrombolysis within 4.5 to 9 hours after onset of ischemic stroke. However, disadvantage of PCT is its often limited anatomic coverage with only 2 or 3 slices when using a 4- to 64-section scanner. Our purpose was therefore to evaluate the value of 2- and 3-slice perfusion compared to whole-brain perfusion.Methods: One hundred twenty-five patients undergoing MRI beyond 4.5 hours after symptom onset with supratentorial perfusion deficit were selected retrospectively. Accordingly to PCT slice positioning, 2 or 3 slices of the whole-brain perfusion weighted imaging data set were depicted. Volumes of infarct (using cerebral blood volume) and penumbra (using time-to-peak and cerebral blood volume) were calculated, and results were compared with 2- and 3-slice-derived volumes, respectively.Results: Whole-brain imaging revealed a mismatch of more than 20% in 68.8% of patients (defined as 100%). Two-slice imaging detected a perfusion deficit in 72% and a mismatch in 48.8% (sensitivity = 70.9%). Three-slice imaging detected a perfusion deficit in 76% and a mismatch in 50.4% (sensitivity = 73.3%). Although there was no significant difference between 2- and 3-slice imaging (P > .23), both techniques revealed significantly less patients with mismatch compared to whole-brain coverage (P < .01).Conclusions: Two- and 3-slice imaging like obtained with PCT on most installed CT systems to assess perfusion deficits with subsequent mismatch calculation in acute stroke outside the 4.5-hour time window is significantly inferior to whole-brain coverage and, hence, has to be considered as a less-than-ideal solution. [ABSTRACT FROM AUTHOR]

What is known and objective Cerebral systemic thrombolysis (i.v. thrombolysis) with tissue-type plasminogen activator (rt- PA) is the only proven medical therapy for ischaemic stroke. The use of i.v. thrombolysis up to 4·5 h from stroke onset was approved in certain countries in 2008, but its safety and efficacy have not been fully determined to date. Objective: To assess the long-term outcome and complication rate of i.v. thrombolysis performed in the extended 'time window'. Methods The study included 403 ischaemic stroke patients consecutively treated with i.v. thrombolysis from 2006 to 2012 at three comprehensive stroke centres in Poland. The long-term outcome and the haemorrhagic complications' ( HC) rate were compared between subgroups of patients treated within 3 vs. 3-4·5 h from stroke onset. Results and discussion About 132 (32·75%) patients were treated between 3 and 4·5 h from stroke onset. Neurological deficits tended to be more severe in patients treated ≤3 than in those treated 3-4·5 h (National Institutes of Health Stroke Scale, NIHSS 12 vs.10 points; P = 0·053); however, the ratio of patients with a favourable outcome ( mRS 0-2 points) and mortality did not differ between the two groups (53·9 vs. 58·3, P = 0·39 and 17·7 vs. 21·2, P = 0·39, respectively). The rate of HC also did not differ between the two groups (18·8% vs. 15·1%, P = 0·46). What is new and conclusion The efficacy of i.v. thrombolysis routinely performed in an extended 'time window' is not reduced when compared to procedures performed within 3 h from symptom onset. [ABSTRACT FROM AUTHOR]

Objective: To investigate the efficacy and safety of extending thrombolytic time window of recombinant tissue-type plasminogen activator(rt PA) in the therapy of acute ischemic stroke by multimode MRI. Methods: 68 patients were divided into rt PA group(group A) with intravenous injection of rt PA(0.9 mg/kg) and normal drugs and routine group(group B) with normal drugs. Each group was divided into two subgroups depending on the onset time. Head CT/multimode MR and NIHSS/MRS were assessed before and after treatment. The incidence of adverse reactions were recorded. Results: The NIHSS scores at each time point after treatment were significantly lower in two subgroups of group A than those of group B(P<0.05). The NIHSS score of less than 4.5h onset group was evidently lower than that of 4.5-6h group in group A(P<0.05). The percentage of better outcome patients was higher in group A than that in group B(P<0.05). Group A had higher risk of symptomatic intracranial hemorrhage than group B. Conclusions: Intravenous thrombolytic therapy for acute ischemic stroke extended time window by multimode MRI was safety and efficacy, which had better long-term results than routine therapy, but with higher risk of symptomatic intracranial hemorrhage. [ABSTRACT FROM AUTHOR]

Several clinical trials have demonstrated that advanced neuroimaging can select patients for recanalization therapy in an extended time window. The favorable functional outcomes and safety profile of these studies have led to the incorporation of neuroimaging in endovascular treatment guidelines, and most recently, also extended to decision making on thrombolysis. Two randomized clinical trials have demonstrated that patients who are not amenable to endovascular thrombectomy within 4.5 hours from symptoms discovery or beyond 4.5 hours from the last-known-well time may also be safely treated with intravenous thrombolysis and have a clinical benefit above the risk of safety concerns. With the growing aging population, increased stroke incidence in the young, and the impact of evolving medical practice, healthcare and stroke systems of care need to adapt continuously to provide evidence-based care efficiently. Therefore, understanding and incorporating appropriate screening strategies is critical for the prompt recognition of potentially eligible patients for extended-window intravenous thrombolysis. Here we review the clinical trial evidence for thrombolysis for acute ischemic stroke in the extended time window and provide a review of new enrolling clinical trials that include thrombolysis intervention beyond the 4.5 hour window. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to determine the proportion of stroke patients presenting in an extended time window who have a thrombolytic treatment target., Background: Patients presenting up to 24 h after stroke onset have been found to have penumbral tissue on multimodal imaging. Stroke patients presenting in this extended time window without a large vessel occlusion (LVO) may benefit from reperfusion therapy using thrombolysis., Methods: Patients seen at our institutions from 2011 through 2015 were reviewed to identify those who presented >4 h and <24 h from last seen normal (LSN) and did not receive acute treatment. Magnetic resonance imaging (MRI) scans were used to dichotomize patients using a diffusion-perfusion mismatch ratio of 1.2., Results: During the study period, 3469 patients were evaluated by our stroke service, with 893 seen 4-24 h from LSN who were not treated. MRI was performed with diffusion and perfusion imaging in 439 patients, of whom 26 were excluded due to hemorrhage and 37 were excluded due to LVO. This left 376 patients who potentially could have been treated with thrombolysis in an extended time window and were included in the analysis. Of these, 156 (42%) demonstrated a mismatch ratio >1.2. Patients with a mismatch presented earlier ( P = 0.012), were more likely to be female ( P = 0.03), and had higher National Institutes of Health Stroke Scale ( P < 0.001)., Conclusions: Almost half of the patients presenting 4-24 h from LSN had a target for thrombolysis in our study. Multimodal imaging may be able to expand the population of treatable stroke patients given the results of recent clinical trials., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Brain Circulation.)

Introduction: Despite the increasing national adoption of automated computed tomography perfusion (CTP) to select thrombectomy patients 6 hours after last known well, reliability issues have been anecdotally reported. Unreliable diagnostic tests add time and confusion to a process that requires efficiency. Our study aims to critically assess an automated CTP program in a contemporary cohort of patients presenting with large vessel occlusion (LVO) in the extended time window by evaluating the rate of unreliable automated CTP maps and whether this influences clinical outcomes.Methods: A retrospective review of consecutive thrombectomy candidates undergoing CTP imaging in the extended time window was performed. All automated CTP maps using RAPID software (iSchemaView, Menlo Park, CA) were assessed for reliability. Clinical outcomes were compared between patients with and without reliable RAPID reports.Results: Ninety-nine consecutive thrombectomy candidates underwent automated CTP imaging from February 2017 to December 2018. Of these, 78 (79%) had LVO determined by CT angiographyand were included in the study population. Automated CTP maps were unreliable in 13% of cases as a result of motion artifact (n = 3) and contrast bolus flow issues (n = 7). Heart failure was more frequent in patients with unreliable studies. Clinical outcomes did not significantly differ between patients with and without unreliable studies.Conclusions: Thirteen percent of CTP maps generated by automated software were unreliable, with an increased frequency among patients with heart failure. Given the rate of unreliable automated CTP maps, further studies are warranted to not only establish the true necessity of currently available CTP software, but also more reliable methods to select patients for thrombectomy presenting in the extended time window. [ABSTRACT FROM AUTHOR]