ORCID Profile
0000-0001-6973-8677
Current Organisations
Austin Health
,
James Cook University
,
Royal Melbourne Hospital
,
University of Melbourne
,
University of Sydney
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2022
DOI: 10.1161/STROKEAHA.121.036670
Abstract: Emerging data suggest tissue within the infarct lesion is not homogenously damaged following ischemic stroke but has a gradient of injury. Using blood-brain-barrier (BBB) disruption as a marker of tissue injury, we tested whether therapeutic reperfusion improves clinical outcome by reducing the severity of tissue injury within the infarct in patients with ischemic stroke. In a pooled analysis of patients treated for anterior circulation large vessel occlusion in the EXTEND-IA TNK (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke) and EXTEND-IA part-2 (Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke) trials, post-treatment BBB permeability at 24 hours was calculated based on the extent of T1-brightening by extravascular gadolinium on T2* perfusion-weighted imaging and measured within the diffusion-weighted-imaging lesion. First, to determine the clinical significance of BBB disruption as a marker of severity of tissue injury, we examined the association between post-treatment BBB permeability and functional outcome. Second, we performed an exploratory (reperfusion, BBB permeability, functional outcome) mediation analysis to estimate the proportion of the reperfusion-outcome relationship that is mediated by change in BBB permeability. In the 238 patients analyzed, an increased BBB permeability measured within the infarct at 24 hours was associated with a reduced likelihood of favorable outcome (90-day modified Rankin Scale score of ≤2) after adjusting for age, baseline National Institutes of Health Stroke Scale, premorbid modified Rankin Scale, infarct topography, laterality, thrombolytic agent, sex, parenchymal hematoma, and follow-up infarct volume (adjusted odds ratio, 0.86 [95% CI, 0.75–0.98] P =0.023). Mediation analysis suggested reducing the severity of tissue injury (as estimated by BBB permeability) accounts for 18.2% of the association between reperfusion and favorable outcome, as indicated by a reduction in the regression coefficient of reperfusion after addition of BBB permeability as a covariate. In patients with ischemic stroke, reduced severity of tissue injury within the infarct, as determined by assessing the integrity of the BBB, is independently associated with improved functional outcome. In addition to reducing diffusion-weighted imaging-defined infarct volume, reperfusion may also improve clinical outcome by reducing tissue injury severity within the infarct.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2021
DOI: 10.1161/STR.52.SUPPL_1.P335
Abstract: Background: Blood Brain Barrier (BBB) disruption is central to vasogenic edema development after ischemia in preclinical studies. We investigated the relationship between BBB disruption and cerebral edema in patients receiving reperfusion therapies for anterior circulation large vessel occlusion. Methods: In a post-hoc pooled analysis of the Tenecteplase versus Alteplase before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK) part 1 and 2 multicenter RCTs, the DWI lesion on 24h post-treatment MRI and peri-infarct salvaged penumbra derived from pre-treatment CT-Perfusion (CTP) were segmented and registered to 24h MR Perfusion. A validated permeability measure (percentage of measured cerebral blood volume lost due to T1 effect from gadolinium leakage across the BBB) was calculated for each ROI. The association between post-treatment BBB disruption in the infarct and cerebral edema assessed on a trichotomized ordinal scale of negligible ( mm midline shift), mild (≥1 to mm) or severe (≥5mm) was analyzed using ordinal logistic regression. Results: Of 220 patients analyzed, median (IQR) BBB disruption was 2.36(1.4-4.1)% in the infarct, 1.61(1.0-2.6)% in salvaged penumbra and 0.98(0.7-1.5)% in normal brain (p .001). There were 119 (54.1%) patients with negligible, 90 (40.8%) mild and 11 (5.0%) severe cerebral edema at 24h. In multivariable analysis, infarct BBB disruption was associated with increased cerebral edema (cOR=1.11 per%, 95%CI 1.02-1.21 =0.012, adjusted for age, admission NIHSS and reperfusion (mTICI2b/3 or % reperfusion on early CTP 2h post-lysis). Infarct BBB disruption correlated with follow-up infarct volume (rho=0.37 .001), and was associated with parenchymal hematoma (aOR=1.18, 95%CI 1.00-1.40 =0.048) and worse outcome assessed on 90-day modified Rankin Scale (cOR=1.16 per%, 95%CI 1.08-1.26 .001, adjusted for age, admission NIHSS and reperfusion). Conclusions: BBB disruption after reperfusion treatment extends beyond the infarct lesion, and is associated with cerebral edema development, hemorrhagic transformation and poor outcome. Further studies to evaluate BBB integrity as an imaging biomarker and potential therapeutic target in malignant cerebral edema after ischemic stroke are needed.
Publisher: Elsevier BV
Date: 06-2022
Publisher: Elsevier BV
Date: 09-2009
Publisher: Elsevier BV
Date: 03-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2018
DOI: 10.1161/STROKEAHA.118.021631
Abstract: Impaired microvascular reperfusion despite complete recanalization (no-reflow) represents a potential therapeutic target to improve outcomes after recanalization therapies. Although well documented in animal models, this phenomenon has not been demonstrated clinically. We investigated whether transcranial Doppler can detect acute microvascular changes postrecanalization as a biomarker of the no-reflow phenomenon in stroke patients. Consecutive patients with recanalized (Thrombolysis in Cerebral Infarction grade IIb/III) acute middle cerebral artery occlusion by thrombectomy at a Comprehensive Stroke Centre with a high-volume neurovascular laboratory were retrospectively identified. Sonographic measures of middle cerebral artery territory microvascular resistance (pulsatility index and resistive index) on days 1 to 3 follow-up transcranial Doppler were compared between patients and age/gender-matched controls. In 53 patients, middle cerebral artery pulsatility index was significantly more likely to be asymmetrically increased on interside comparison (27.9% versus 4.9% P =0.007) and abnormally elevated beyond normal reference ranges (46.7% versus 22.0% P =0.016) in the symptomatic hemisphere. Middle cerebral artery pulsatility index elevation was associated with less hemorrhagic infarction (9.5% versus 45.8% P =0.009) but worse functional outcome irrespective of infarct volume as assessed on 90-day modified Rankin Scale (score of ≤1, 18.2% versus 58.1% P =0.035). Elevated microvascular resistance within the ischemic territory is commonly present after successful recanalization as measured by pulsatility index on transcranial Doppler and may be a readily available and clinically relevant biomarker of the no-reflow phenomenon.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2020
DOI: 10.1161/STROKEAHA.120.031467
Abstract: Severity-based assessment tools may assist in prehospital triage of patients to comprehensive stroke centers (CSCs) for endovascular thrombectomy (EVT), but criticisms regarding diagnostic inaccuracy have not been adequately addressed. This study aimed to quantify the benefits and disadvantages of severity-based triage in a large real-world paramedic validation of the Ambulance Clinical Triage for Acute Stroke Treatment (ACT-FAST) algorithm. Ambulance Victoria paramedics assessed the prehospital ACT-FAST algorithm in patients with suspected stroke from November 2017 to July 2019 following an 8-minute training video. All patients were transported to the nearest stroke center as per current guidelines. ACT-FAST diagnostic accuracy was compared with hospital imaging for the presence of large vessel occlusion (LVO) and need for CSC-level care (LVO, intracranial hemorrhage, and tumor). Patient-level time saving to EVT was modeled using a validated Google Maps algorithm. Disadvantages of CSC bypass examined potential thrombolysis delays in non-LVO infarcts, proportion of patients with false-negative EVT, and CSC overburdening. Of 517 prehospital assessments, 168/517 (32.5%) were ACT-FAST positive and 132/517 (25.5%) had LVO. ACT-FAST sensitivity and specificity for LVO was 75.8% and 81.8%, respectively. Positive predictive value was 58.8% for LVO and 80.0% when intracranial hemorrhage and tumor (CSC-level care) were included. Within the metropolitan region, 29/55 (52.7%) of ACT-FAST-positive patients requiring EVT underwent a secondary interhospital transfer. Prehospital bypass with avoidance of secondary transfers was modeled to save 52 minutes (95% CI, 40.0–61.5) to EVT commencement. ACT-FAST was false-positive in 8 patients receiving thrombolysis (8.1% of 99 non-LVO infarcts) and false-negative in 4 patients with EVT requiring secondary transfer (5.4% of 74 EVT cases). CSC bypass was estimated to over-triage 1.1 patients-per-CSC-per-week in our region. The overall benefits of an ACT-FAST algorithm bypass strategy in expediting EVT and avoiding secondary transfers are estimated to substantially outweigh the disadvantages of potentially delayed thrombolysis and over-triage, with only a small proportion of EVT patients missed.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2021
DOI: 10.1161/STROKEAHA.120.033246
Abstract: Whether reperfusion into infarcted tissue exacerbates cerebral edema has treatment implications in patients presenting with extensive irreversible injury. We investigated the effects of endovascular thrombectomy and reperfusion on cerebral edema in patients presenting with radiological evidence of large hemispheric infarction at baseline. In a systematic review and in idual patient-level meta-analysis of 7 randomized controlled trials comparing thrombectomy versus medical therapy in anterior circulation ischemic stroke published between January 1, 2010, and May 31, 2017 (Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration), we analyzed the association between thrombectomy and reperfusion with maximal midline shift (MLS) on follow-up imaging as a measure of the space-occupying effect of cerebral edema in patients with large hemispheric infarction on pretreatment imaging, defined as diffusion-magnetic resonance imaging or computed tomography (CT)-perfusion ischemic core 80 to 300 mL or noncontrast CT-Alberta Stroke Program Early CT Score ≤5. Risk of bias was assessed using the Cochrane tool. Among 1764 patients, 177 presented with large hemispheric infarction. Thrombectomy and reperfusion were associated with functional improvement (thrombectomy common odds ratio =2.30 [95% CI, 1.32–4.00] reperfusion common odds ratio =4.73 [95% CI, 1.66–13.52]) but not MLS (thrombectomy β=−0.27 [95% CI, −1.52 to 0.98] reperfusion β=−0.78 [95% CI, −3.07 to 1.50]) when adjusting for age, National Institutes of Health Stroke Score, glucose, and time-to-follow-up imaging. In an exploratory analysis of patients presenting with core volume mL or CT-Alberta Stroke Program Early CT Score ≤3 (n=76), thrombectomy was associated with greater MLS after adjusting for age and National Institutes of Health Stroke Score (β=2.76 [95% CI, 0.33–5.20]) but not functional improvement (odds ratio, 1.71 [95% CI, 0.24–12.08]). In patients presenting with large hemispheric infarction, thrombectomy and reperfusion were not associated with MLS, except in the subgroup with very large core volume ( mL) in whom thrombectomy was associated with increased MLS due to space-occupying ischemic edema. Mitigating cerebral edema-mediated secondary injury in patients with very large infarcts may further improve outcomes after reperfusion therapies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-02-2022
DOI: 10.1212/WNL.0000000000013210
Abstract: The relevance of impaired microvascular tissue-level reperfusion despite complete upstream macrovascular angiographic reperfusion (no-reflow) in human stroke remains controversial. We investigated the prevalence and clinical-radiologic features of this phenomenon and its associations with outcomes in 3 international randomized controlled thrombectomy trials with prespecified follow-up perfusion imaging. In a pooled analysis of the Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial (EXTEND-IA ClinicalTrials.gov NCT01492725), Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK NCT02388061), and Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke (EXTEND-IA TNK Part 2 NCT03340493) trials, patients undergoing thrombectomy with final angiographic expanded Treatment in Cerebral Infarction score of 2c to 3 score for anterior circulation large vessel occlusion and 24-hour follow-up CT or MRI perfusion imaging were included. No-reflow was defined as regions of visually demonstrable persistent hypoperfusion on relative cerebral blood volume or flow maps within the infarct and verified quantitatively by % asymmetry compared to a mirror homolog in the absence of carotid stenosis or reocclusion. Regions of no-reflow were identified in 33 of 130 patients (25.3%), encompassed a median of 60.2% (interquartile range 47.8%–70.7%) of the infarct volume, and involved both subcortical (n = 26 of 33, 78.8%) and cortical (n = 10 of 33, 30.3%) regions. Patients with no-reflow had a median 25.2% (interquartile range 16.4%–32.2%, p 0.00001) relative cerebral blood volume interside reduction and 19.1% (interquartile range 3.9%–28.3%, p = 0.00011) relative cerebral blood flow reduction but similar mean transit time (median −3.3%, interquartile range −11.9% to 24.4%, p = 0.24) within the infarcted region. Baseline characteristics were similar between patients with and those without no-reflow. The presence of no-reflow was associated with hemorrhagic transformation (adjusted odds ratio [aOR] 1.79, 95% confidence interval [CI] 2.32–15.57, p = 0.0002), greater infarct growth (β = 11.00, 95% CI 5.22–16.78, p = 0.00027), reduced NIH Stroke Scale score improvement at 24 hours (β = −4.06, 95% CI 6.78–1.34, p = 0.004) and being dependent or dead at 90 days as assessed by the modified Rankin Scale (aOR 3.72, 95% CI 1.35–10.20, p = 0.011) in multivariable analysis. Cerebral no-reflow in humans is common, can be detected by its characteristic perfusion imaging profile using readily available sequences in the clinical setting, and is associated with posttreatment complications and being dependent or dead. Further studies evaluating the role of no-reflow in secondary injury after angiographic reperfusion are warranted. This study provides Class II evidence that cerebral no-reflow on CT/MRI perfusion imaging at 24 hours is associated with posttreatment complications and poor 3-month functional outcome.
Publisher: Springer Science and Business Media LLC
Date: 06-02-2017
Publisher: SAGE Publications
Date: 29-08-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2017
DOI: 10.1161/STROKEAHA.117.017235
Abstract: Interhospital transfer is a critical component in the treatment of acute anterior circulation large vessel occlusive stroke transferred for mechanical thrombectomy. Real-world data for benchmarking and theoretical modeling are limited. We sought to characterize transfer workflow from primary stroke center (PSC) to comprehensive stroke center after the publication of positive thrombectomy trials. Consecutive patients transferred from 3 high-volume PSCs to a single comprehensive stroke center between January 2015 and August 2016 were included in a retrospective study. Factors associated with key time metrics were analyzed with emphasis on PSC intrahospital workflow. Sixty-seven patients were identified. Median age was 74 years (interquartile range [IQR], 63.5–78) and National Institutes of Health Stroke Scale 17 (IQR, 12–21). Median transfer time measured by PSC-door-to-comprehensive stroke center-door was 128 minutes (IQR, 107–164), of which 82.8% was spent at PSCs (door-in-door-out [DIDO] 106 minutes IQR, 86–143). The lengthiest component of DIDO was computed-tomography-to-retrieval-request (median 59.5 minutes IQR, 44–83). The 37.3% had DIDO exceeding 120 minutes. DIDO times differed significantly between PSCs ( P =0.01). In multivariate analyses, rerecruiting the initial ambulance crew for transfer ( P .01) and presentation during working hours ( P =0.04) were associated with shorter DIDO times. In a metropolitan hub-and-spoke network, PSC-door-to-comprehensive stroke center-door and DIDO times are long even in high-volume PSCs. Improving PSC workflow represents a major opportunity to expedite mechanical thrombectomy and improve patient outcomes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2017
Publisher: American Medical Association (AMA)
Date: 07-04-2020
Publisher: Massachusetts Medical Society
Date: 06-04-2023
Publisher: Elsevier BV
Date: 07-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2022
DOI: 10.1161/STROKEAHA.120.034019
Abstract: The National Institutes of Health Stroke Scale (NIHSS) underestimates clinical severity in posterior circulation stroke and patients presenting with low NIHSS may be considered ineligible for reperfusion therapies. This study aimed to develop a modified version of the NIHSS, the Posterior NIHSS (POST-NIHSS), to improve NIHSS prognostic accuracy for posterior circulation stroke patients with mild-moderate symptoms. Clinical data of consecutive posterior circulation stroke patients with mild-moderate symptoms (NIHSS ), who were conservatively managed, were retrospectively analyzed from the Basilar Artery Treatment and Management registry. Clinical features were assessed within 24 hours of symptom onset dysphagia was assessed by a speech therapist within 48 hours of symptom onset. Random forest classification algorithm and constrained optimization were used to develop the POST-NIHSS in the derivation cohort. The POST-NIHSS was then validated in a prospective cohort. Poor outcome was defined as modified Rankin Scale score ≥3 at 3 months. We included 202 patients (mean [SD] age 63 [14] years, median NIHSS 3 [interquartile range, 1–5]) in the derivation cohort and 65 patients (mean [SD] age 63 [16] years, median NIHSS 2 [interquartile range, 1–4]) in the validation cohort. In the derivation cohort, age, NIHSS, abnormal cough, dysphagia and gait/truncal ataxia were ranked as the most important predictors of functional outcome. POST-NIHSS was calculated by adding 5 points for abnormal cough, 4 points for dysphagia, and 3 points for gait/truncal ataxia to the baseline NIHSS. In receiver operating characteristic analysis adjusted for age, POST-NIHSS area under receiver operating characteristic curve was 0.80 (95% CI, 0.73–0.87) versus NIHSS area under receiver operating characteristic curve, 0.73 (95% CI, 0.64–0.83), P =0.03. In the validation cohort, POST-NIHSS area under receiver operating characteristic curve was 0.82 (95% CI, 0.69–0.94) versus NIHSS area under receiver operating characteristic curve 0.73 (95% CI, 0.58–0.87), P =0.04. POST-NIHSS showed higher prognostic accuracy than NIHSS and may be useful to identify posterior circulation stroke patients with NIHSS at higher risk of poor outcome.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.JSTROKECEREBROVASDIS.2016.01.036
Abstract: Correct identification of symptomatic high-grade internal carotid artery stenosis from low-grade or total chronic occlusion is critical for patient selection for urgent carotid endarterectomy. Carotid pseudo-occlusion is a flow-related artifact on noninvasive imaging that can lead to an incorrect diagnosis of total internal carotid artery occlusion, thereby denying an eligible patient for appropriate surgical treatment. We present an 82-year-old man with a symptomatic critical internal carotid artery, which was detected on time-resolved 4-dimensional computed-tomography angiography, whereas single-phase computed-tomography angiography, magnetic resonance angiography, and Doppler ultrasonography suggested apparent occlusion. To our understanding, the use of 4-dimensional computed-tomography angiography to identify carotid pseudo-occlusion has not been previously reported.
Publisher: Wiley
Date: 07-07-2016
DOI: 10.1111/JON.12375
Abstract: Differentiation between true acute tandem occlusion involving the extracranial internal carotid artery (ICA) from pseudotandem occlusion with a patent extracranial ICA has important prognostic and therapeutic implications. We explored the utility of perfusion-derived 4-dimensional CT angiogram (4D-CTA) in identifying carotid pseudo-occlusion in a single-center pilot study. Acute stroke patients with delayed antegrade ICA flow on 4D-CTA despite an apparent tandem occlusion on conventional single-phase CTA were prospectively identified over a 2.5-year period (2013-2015). Eight patients were identified. Delayed antegrade intracranial flow from the apparently occluded ICA was detected up to 50 seconds after contrast administration on 4D-CTA. The distal intracranial ICA was the most common site of true occlusion. Reconstruction of the 4D-CTA images required an additional processing time of 2-3 minutes. 4D-CTA is a novel noninvasive technique that can identify carotid pseudo-occlusion in the acute stroke setting. Our preliminary findings suggest that 4D-CTA can be easily incorporated into an existing acute stroke neuroimaging protocol.
Publisher: Springer Science and Business Media LLC
Date: 06-07-2019
DOI: 10.1007/S11910-019-0970-7
Abstract: Urgent reperfusion treatment with intravenous thrombolysis or mechanical thrombectomy reduces disability after ischaemic stroke. Imaging plays an important role in identifying patients who benefit, particularly in extended time windows. However, the role of post-treatment neuroimaging is less well established. We review recent advances in neuroimaging after reperfusion treatment and provide a practical guide to the options and management implications. Post-treatment imaging is critical to identify patients with reperfusion-related haemorrhage and oedema requiring intervention. It also can guide the timing and intensity of antithrombotic medication. The degree of reperfusion on post-thrombectomy angiography and infarct volume and topography using CT or MRI carry important prognostic significance. Perfusion-weighted MRI and permeability analysis may help detect persistent perfusion abnormalities post-treatment and predict haemorrhagic complications. Post-treatment neuroimaging provides clinically relevant information to identify complications, assess prognosis and perform quality assurance after acute ischaemic stroke. Recent advances in neuroimaging represent a potential avenue to explore post-reperfusion pathophysiology and uncover therapeutic targets for secondary ischaemic and haemorrhagic injury.
Publisher: SAGE Publications
Date: 17-07-2019
Abstract: Administration of intravenous idarucizumab to reverse dabigatran anticoagulation prior to thrombolysis for patients with acute ischemic stroke has been previously described, but not in the prehospital setting. The speed and predictability of idarucizumab reversal is well suited to prehospital treatment in a mobile stroke unit and allows patients with recent dabigatran intake to access reperfusion therapy. To describe feasibility of prehospital idarucizumab administration prior to thrombolysis on the Melbourne mobile stroke unit. The Melbourne mobile stroke unit is a specialized stroke ambulance servicing central metropolitan Melbourne, Australia and provides prehospital assessment, scanning and treatment with an integrated CT scanner and multidisciplinary stroke team. All cases were identified through the mobile stroke unit treatment registry since launch in November 2017. Of a total of n = 20 thrombolysis cases in the first 4 months of operation, three patients (15%) received intravenous idarucizumab 5 g for dabigatran reversal prior to thrombolysis. Mean time between idarucizumab administration and thrombolysis was approximately 10 minutes. Two of the three patients were shown to have large vessel occlusion on CTA in the mobile stroke unit and proceeded to endovascular thrombectomy. At 24 hours, only one patient had a small amount of asymptomatic petechial hemorrhage on follow-up imaging. All patients demonstrated substantial neurological recovery and were discharged to inpatient rehabilitation. Rapid treatment with prehospital administration of idarucizumab prior to thrombolysis using a mobile stroke unit is feasible and facilitates hyperacute treatment.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2016
DOI: 10.1161/STROKEAHA.116.013021
Abstract: The use of thrombolysis in acute minor ischemic stroke (MIS) remains controversial. We sought to determine the safety and efficacy of intravenous tissue-type plasminogen activator (IV-tPA) in acute MIS patients with demonstrable penumbra on computed tomographic perfusion study. Consecutive MIS patients with National Institutes of Health Stroke Scale ≤3 were identified from a prospective single tertiary-center database over a 4.5-year period (2011–2015). Cases with demonstrable penumbra were analyzed according to treatment received: IV-tPA versus standard stroke-unit care without thrombolysis. Seventy-three patients of 195 acute MIS admissions had a demonstrable penumbra (34 IV-tPA versus 39 standard stroke-unit care). Overall median National Institutes of Health Stroke Scale and premorbid modified Rankin Scale were 2 and 0, respectively. Median age was 73.2 (interquartile range, 67.3–82.8) years. There were no differences in baseline demographics, risk factors, stroke localization and cause, rates of vascular occlusion (38.2% versus 38.5% P =1.000), or mean penumbral volume (41.3 versus 25.1 mL P =0.150 IV-tPA versus standard stroke-unit care) between groups. There were no symptomatic intracerebral hemorrhages in either group. Patients treated with IV-tPA were more likely to have an excellent functional outcome at discharge (88.2% versus 53.9% P =0.002) and 90 days (91.2% versus 71.8% P =0.042). Ordinal analysis demonstrated a favorable shift in modified Rankin Scale with IV-tPA both at discharge (odds ratio, 5.23 95% confidence interval, 1.83–12.20) and 90 days (odds ratio, 4.35 95% confidence interval, 1.77–11.36). In selected MIS patients with demonstrable penumbra on computed tomographic perfusion, IV-tPA is safe and associated with significant improvement in functional outcome at discharge and 90 days.
Publisher: BMJ
Date: 06-01-2016
Publisher: SAGE Publications
Date: 17-05-2021
DOI: 10.1177/0271678X211017696
Abstract: The relationship between reperfusion and edema is unclear, with experimental and clinical data yielding conflicting results. We investigated whether the extent of salvageable and irreversibly-injured tissue at baseline influenced the effect of therapeutic reperfusion on cerebral edema. In a pooled analysis of 415 patients with anterior circulation large vessel occlusion from the Tenecteplase-versus-Alteplase-before-Endovascular-Therapy-for-Ischemic-Stroke (EXTEND-IA TNK) part 1 and 2 trials, associations between core and mismatch volume on pre-treatment CT-Perfusion with cerebral edema at 24-hours, and their interactions with reperfusion were tested. Core volume was associated with increased edema (p 0.001) with no significant interaction with reperfusion (p = 0.82). In comparison, a significant interaction between reperfusion and mismatch volume (p = 0.03) was observed: Mismatch volume was associated with increased edema in the absence of reperfusion (p = 0.009) but not with reperfusion (p = 0.27). When mismatch volume was dichotomized at the median (102 ml), reperfusion was associated with reduced edema in patients with large mismatch volume (p 0.001) but not with smaller mismatch volume (p = 0.35). The effect of reperfusion on edema may be variable and dependent on the physiological state of the cerebral tissue. In patients with small to moderate ischemic core volume, the benefit of reperfusion in reducing edema is related to penumbral salvage.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2022
DOI: 10.1161/STROKEAHA.121.037073
Abstract: Cerebral edema after large hemispheric infarction is associated with poor functional outcome and mortality. Net water uptake (NWU) quantifies the degree of hypoattenuation on unenhanced-computed tomography (CT) and is increasingly used to measure cerebral edema in stroke research. Hemorrhagic transformation and parenchymal contrast staining after thrombectomy may confound NWU measurements. We investigated the correlation of NWU measured postthrombectomy with volumetric markers of cerebral edema and association with functional outcomes. In a pooled in idual patient level analysis of patients presenting with anterior circulation large hemispheric infarction (core 80–300 mL or Alberta Stroke Program Early CT Score ≤5) in the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke trials) data set, cerebral edema was defined as the volumetric expansion of the ischemic hemisphere expressed as a ratio to the contralateral hemisphere(rHV). NWU and midline-shift were compared with rHV as the reference standard on 24-hour follow-up CT, adjusted for hemorrhagic transformation and the use of thrombectomy. Association between edema markers and day 90 functional outcomes (modified Rankin Scale) was assessed using ordinal logistic regression. Overall (n=144), there was no correlation between NWU and rHV (r s =0.055, P =0.51). In sub-group analyses, a weak correlation between NWU with rHV was observed after excluding patients with any degree of hemorrhagic transformation (r s =0.211, P =0.015), which further improved after excluding thrombectomy patients (r s =0.453, P =0.001). Midline-shift correlated strongly with rHV in all sub-group analyses (r s .753, P =0.001). Functional outcome at 90 days was negatively associated with rHV (adjusted common odds ratio, 0.46 [95% CI, 0.32–0.65] P .001) and midline-shift (adjusted common odds ratio, 0.85 [95% CI, 0.78–0.92] P .001) but not NWU (adjusted common odds ratio, 1.00 [95% CI, 0.97–1.03] P =0.84), adjusted for age, baseline National Institutes of Health Stroke Scale, and thrombectomy. Prognostic performance of NWU improved after excluding patients with hemorrhagic transformation and thrombectomy (adjusted odds ratio, 0.90 [95% CI, 0.80–1.02] P =0.10). NWU correlated poorly with conventional markers of cerebral edema and was not associated with clinical outcome in the presence of hemorrhagic transformation and thrombectomy. Measuring NWU postthrombectomy requires validation before implementation into clinical research. At present, the use of NWU should be limited to baseline CT, or follow-up CT only in patients without hemorrhagic transformation or treatment with thrombectomy.
Publisher: SAGE Publications
Date: 08-06-2023
DOI: 10.1177/17474930231180434
Abstract: The no-reflow phenomenon refers to the absence of microvascular reperfusion despite macrovascular reperfusion. The aim of this analysis was to summarize the available clinical evidence on no-reflow in patients with acute ischemic stroke. A systematic literature review and a meta-analysis of clinical data on definition, rates, and impact of the no-reflow phenomenon after reperfusion therapy was carried out. A predefined research strategy was formulated according to the Population, Intervention, Comparison, and Outcome (PICO) model and was used to screen for articles in PubMed, MEDLINE, and Embase up to 8 September 2022. Whenever possible, quantitative data were summarized using a random-effects model. Thirteen studies with a total of 719 patients were included in the final analysis. Most studies (n = 10/13) used variations of the Thrombolysis in Cerebral Infarction scale to evaluate macrovascular reperfusion, whereas microvascular reperfusion and no-reflow were mostly assessed on perfusion maps (n = 9/13). In one-third of stroke patients with successful macrovascular reperfusion (29%, 95% confidence interval (CI), 21–37%), the no-reflow phenomenon was observed. Pooled analysis showed that no-reflow was consistently associated with reduced rates of functional independence (odds ratio (OR), 0.21, 95% CI, 0.15–0.31). The definition of no-reflow varied substantially across studies, but it appears to be a common phenomenon. Some of the no-reflow cases may simply represent remaining vessel occlusions, and it remains unclear whether no-reflow is an epiphenomenon of the infarcted parenchyma or causes infarction. Future studies should focus on standardizing the definition of no-reflow with more consistent definitions of successful macrovascular reperfusion and experimental set-ups that could detect the causality of the observed findings.
Publisher: S. Karger AG
Date: 2020
DOI: 10.1159/000505847
Abstract: b i Aim: /i /b To evaluate the degree of variability in microstructural injury within and adjacent to regions identified as infarcted tissue using diffusion tensor imaging (DTI). b i Methods: /i /b In this prospective longitudinal study, 18 patients presenting within 12 h of anterior circulation acute ischemic stroke who underwent CT perfusion (CTP) at baseline followed by fluid-attenuated inversion recovery (FLAIR) and DTI 1-month were analyzed. Four regions of interest (ROI) corresponding to the severity of hypoperfusion on CTP within and beyond the radiological infarct lesion defined on FLAIR were segmented. Fractional anisotropy (FA) and mean diffusivity (MD) were quantified for each ROI and compared to a mirror homologue in the contralateral hemisphere. Ipsilateral to contralateral FA and MD ratios were compared across ROIs. b i Results: /i /b Lower FA and higher MD values were observed within both the infarct lesion and the peri-infarct tissue compared with their homologous contralateral brain regions (all comparisons i /i ≤ 0.01). No difference was observed in FA and MD between remote nonhypoperfused tissue and its contralateral homologous region (FA i /i = 0.42, MD i /i ≥ 0.99). The magnitude of asymmetry (ipsilateral/contralateral ratios) of FA and MD was greater with increasing severity of hypoperfusion in a dose-response pattern. Asymmetry greatest in the area of infarction with severe hypoperfusion, followed by infarction with moderate hypoperfusion, the peri-infarct hypoperfused tissue, and lastly the remote nonhypoperfused normal tissue (median on clustered quantile regression i /i ≤ 0.01). b i Conclusion: /i /b A gradient of microstructural injury corresponding to the severity of ischemic insult is present within and beyond conventionally defined infarct boundaries. The traditional dichotomized notion of infarcted versus noninfarcted tissue widely adopted in clinical research and in practice warrants reexamination.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-07-2019
Publisher: SAGE Publications
Date: 19-06-2023
DOI: 10.1177/17474930231182018
Abstract: Following reperfusion treatment in ischemic stroke, computed tomography (CT) imaging at 24 h is widely used to assess radiological outcomes. Even without visible hyperattenuation, occult angiographic contrast may persist in the brain and confound Hounsfield unit-based imaging metrics, such as net water uptake (NWU). We aimed to assess the presence and factors associated with retained contrast post-thrombectomy on 24-h imaging using dual-energy CT (DECT), and its impact on the accuracy of NWU as a measure of cerebral edema. Consecutive patients with anterior circulation large vessel occlusion who had post-thrombectomy DECT performed 24-h post-treatment from two thrombectomy stroke centers were retrospectively studied. NWU was calculated by interside comparison of HUs of the infarct lesion and its mirror homolog. Retained contrast was quantified by the difference in NWU values with and without adjustment for iodine. Patients with visible hyperdensities from hemorrhagic transformation or visible contrast retention and bilateral infarcts were excluded. Cerebral edema was measured by relative hemispheric volume (rHV) and midline shift (MLS). Of 125 patients analyzed (median age 71 (IQR = 61–80), baseline National Institutes of Health Stroke Scale (NIHSS) 16 (IQR = 9.75–21)), reperfusion (defined as extended-Thrombolysis-In-Cerebral-Infarction 2b–3) was achieved in 113 patients (90.4%). Iodine-subtracted NWU was significantly higher than unadjusted NWU (17.1% vs 10.8%, p 0.001). In multivariable median regression analysis, increased age (p = 0.024), number of passes (p = 0.006), final infarct volume (p = 0.023), and study site (p = 0.021) were independently associated with amount of retained contrast. Iodine-subtracted NWU correlated with rHV (rho = 0.154, p = 0.043) and MLS (rho = 0.165, p = 0.033) but unadjusted NWU did not (rHV rho = –0.035, p = 0.35 MLS rho = 0.035, p = 0.347). Angiographic iodine contrast is retained in brain parenchyma 24-h post-thrombectomy, even without visually obvious hyperdensities on CT, and significantly affects NWU measurements. Adjustment for retained iodine using DECT is required for accurate NWU measurements post-thrombectomy. Future quantitative studies analyzing CT after thrombectomy should consider occult contrast retention.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-01-2023
Publisher: Wiley
Date: 17-01-2023
DOI: 10.1002/ANA.26587
Abstract: Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship. In a pooled, patient‐level analysis of the EXTEND‐IA trials and SELECT study, we used a mediation analysis framework to quantify infarct growth and cerebral edema (midline shift) mediation effect on successful reperfusion (modified Treatment in Cerebral Ischemia ≥ 2b) association with functional outcome (modified Rankin Scale distribution). Furthermore, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift. A total 542 of 665 (81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful versus unsuccessful reperfusion. Median infarct growth was 12.3ml (interquartile range [IQR] = 1.8–48.4), and median midline shift was 0mm (IQR = 0–2.2). Of 249 (37%) demonstrating a midline shift of ≥1mm, median shift was 2.75mm (IQR = 1.89–4.21). Successful reperfusion was associated with reductions in both predefined mediators, infarct growth (β = −1.19, 95% confidence interval [CI] = −1.51 to −0.88, p 0.001) and midline shift (adjusted odds ratio = 0.36, 95% CI = 0.23–0.57, p 0.001). Successful reperfusion association with improved functional outcome (adjusted common odds ratio [acOR] = 2.68, 95% CI = 1.86–3.88, p 0.001) became insignificant (acOR = 1.39, 95% CI = 0.95–2.04, p = 0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect, respectively. Analysis considering an alternative hypothesis demonstrated consistent results. In this mediation analysis from a pooled, patient‐level cohort, a significant proportion (~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect, and identify novel therapeutic targets to further enhance reperfusion benefits. ANN NEUROL 2023 :793–804
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2019
DOI: 10.1161/STROKEAHA.118.023361
Abstract: The benefit of endovascular therapy in extended time windows has been demonstrated in patients with anterior circulation large vessel occlusion ischemic stroke and favorable imaging profile. We evaluated whether collaterals and thrombus burden influence the associations between revascularization, time-to-treatment, and outcome in endovascular therapy-treated patients with basilar artery occlusion. We retrospectively analyzed clinical and imaging data of consecutive endovascular therapy-treated patients with basilar artery occlusion included in the multicenter Basilar Artery Treatment and Management Collaboration. The BATMAN (Basilar Artery on Computed Tomography Angiography score, which evaluates thrombus burden and collaterals) and the PC-CS (Posterior Circulation Collateral score, which evaluates collaterals) were assessed on computed tomography angiography, blinded to clinical outcome. Good outcome was defined as modified Rankin Scale score of ≤3 within 3 months revascularization (successful reperfusion) as modified Thrombolysis in Cerebral Infarction 2b–3 (or TIMI [Thrombolysis in Myocardial Infarction] 2–3 in the BASICS [Basilar Artery International Cooperation Study] registry). We included 172 patients with basilar artery occlusion treated with endovascular therapy (124 with mechanical thrombectomy): mean (SD) age 65 (13) years, median National Institutes of Health Stroke Scale 22 (interquartile range 12–30), 64 (37%) treated hours. Revascularization (achieved in 79% of patients) was associated with good outcome ( P =0.003). The use of new generation thrombectomy devices was associated with good outcome ( P =0.03). In patients who achieved revascularization, 29/46 (63%) of patients with a favorable BATMAN score and 26/51 (51%) with favorable PC-CS had good outcomes. In logistic regression analysis (adjusted for age, National Institutes of Health Stroke Scale, and time-to-treatment ≤6/ hours), revascularization was associated with good outcome in patients with favorable BATMAN score (odds ratio, 15.8 95% CI, 1.4–175 P =0.02) or PC-CS (odds ratio, 9.4 95% CI, 1.4–64 P =0.02). In patients who achieved revascularization, early (time-to-treatment ≤6 hours) but not late treatment was associated with improved outcome in patients with unfavorable BATMAN score (18/52 [35%] odds ratio, 15 95% CI, 1.9–124 P =0.01) or PC-CS (16/44 [36%] odds ratio, 5.5 95% CI, 1.4–21 P =0.01). Revascularization is associated with good outcome in patients with basilar artery occlusion with good collaterals and less extensive occlusion, even hours after onset.
Publisher: Springer Science and Business Media LLC
Date: 20-02-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2022
DOI: 10.1161/STROKEAHA.121.036104
Abstract: Factors contributing to cerebral edema in the post-hyperacute period of ischemic stroke (first 24–72 hours) are poorly understood. Blood-brain barrier (BBB) disruption and postischemic hyperperfusion reflect microvascular dysfunction and are associated with hemorrhagic transformation. We investigated the relationships between BBB integrity, cerebral blood flow, and space-occupying cerebral edema in patients who received acute reperfusion therapy. We performed a pooled analysis of patients treated for anterior circulation large vessel occlusion in the EXTEND-IA TNK and EXTEND-IA TNK part 2 trials who had MRI with dynamic susceptibility contrast-enhanced perfusion-weighted imaging 24 hours after treatment. We investigated the associations between BBB disruption and cerebral blood flow within the infarct with cerebral edema assessed using 2 metrics: first midline shift (MLS) trichotomized as an ordinal scale of negligible ( mm), mild (≥1 to mm), or severe (≥5 mm), and second relative hemispheric volume (rHV), defined as the ratio of the 3-dimensional volume of the ischemic hemisphere relative to the contralateral hemisphere. Of 238 patients analyzed, 133 (55.9%) had negligible, 93 (39.1%) mild, and 12 (5.0%) severe MLS at 24 hours. The associated median rHV was 1.01 (IQR, 1.00–1.028), 1.03 (IQR, 1.01–1.077), and 1.15 (IQR, 1.08–1.22), respectively. MLS and rHV were associated with poor functional outcome at 90 days ( P .002). Increased BBB permeability was independently associated with more edema after adjusting for age, occlusion location, reperfusion, parenchymal hematoma, and thrombolytic agent used (MLS cOR, 1.12 [95% CI, 1.03–1.20], P =0.005 rHV β, 0.39 [95% CI, 0.24–0.55], P .0001), as was reduced cerebral blood flow (MLS cOR, 0.25 [95% CI, 0.10–0.58], P =0.001 rHV β, −2.95 [95% CI, −4.61 to −11.29], P =0.0006). In subgroup analysis of patients with successful reperfusion (extended Treatment in Cerebral Ischemia 2b-3, n=200), reduced cerebral blood flow remained significantly associated with edema (MLS cOR, 0.37 [95% CI, 0.14–0.98], P =0.045 rHV β, −2.59 [95% CI, −4.32 to −0.86], P =0.004). BBB disruption and persistent hypoperfusion in the infarct after reperfusion treatment is associated with space-occupying cerebral edema. Further studies evaluating microvascular dysfunction during the post-hyperacute period as biomarkers of poststroke edema and potential therapeutic targets are warranted.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-03-2021
DOI: 10.1212/WNL.0000000000011520
Abstract: To investigate the efficacy of tenecteplase (TNK), a genetically modified variant of alteplase with greater fibrin specificity and longer half-life than alteplase, prior to endovascular thrombectomy (EVT) in patients with basilar artery occlusion (BAO). To determine whether TNK is associated with better reperfusion rates than alteplase prior to EVT in BAO, clinical and procedural data of consecutive patients with BAO from the Basilar Artery Treatment and Management (BATMAN) registry and the Tenecteplase vs Alteplase before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK) trial were retrospectively analyzed. Reperfusion % or absence of retrievable thrombus at the time of the initial angiogram was evaluated. We included 110 patients with BAO treated with IV thrombolysis prior to EVT (mean age 69 [SD 14] years median NIH Stroke Scale score 16 [interquartile range (IQR) 7–32]). Nineteen patients were thrombolysed with TNK (0.25 mg/kg or 0.40 mg/kg) and 91 with alteplase (0.9 mg/kg). Reperfusion % occurred in 26% (n = 5/19) of patients thrombolysed with TNK vs 7% (n = 6/91) thrombolysed with alteplase (risk ratio 4.0, 95% confidence interval 1.3–12 p = 0.02), despite shorter thrombolysis to arterial puncture time in the TNK-treated patients (48 [IQR 40–71] minutes) vs alteplase-treated patients (110 [IQR 51–185] minutes p = 0.004). No difference in symptomatic intracranial hemorrhage was observed (0/19 [0%] TNK, 1/91 [1%] alteplase p = 0.9). TNK may be associated with an increased rate of reperfusion in comparison with alteplase before EVT in BAO. Randomized controlled trials to compare TNK with alteplase in patients with BAO are warranted. NCT02388061 and NCT03340493. This study provides Class III evidence that TNK leads to higher reperfusion rates in comparison with alteplase prior to EVT in patients with BAO.
Publisher: BMJ
Date: 04-2022
DOI: 10.1136/BMJOPEN-2021-056573
Abstract: Mobile stroke units (MSUs) equipped with a CT scanner are increasingly being used to assess and treat stroke patients’ prehospital with thrombolysis and transfer them to the most appropriate hospital for ongoing stroke care and thrombectomy when indicated. The effect of MSUs in both reducing the time to reperfusion treatment and improving patient outcomes is now established. There is now an opportunity to improve the efficacy of treatment provided by the MSU. Tenecteplase is a potent plasminogen activator, which may have benefits over the standard of care stroke lytic alteplase. Specifically, in the MSU environment tenecteplase presents practical benefits since it is given as a single bolus and does not require an infusion over an hour like alteplase. In this trial, we seek to investigate if tenecteplase, given to patients with acute ischaemic stroke as diagnosed on the MSU, improves the rate of early reperfusion. TASTE-A is a prospective, randomised, open-label, blinded endpoint (PROBE) phase II trial of patients who had an ischaemic stroke assessed in an MSU within 4.5 hours of symptom onset. The primary endpoint is early reperfusion measured by the post-lysis volume of the CT perfusion lesion performed immediately after hospital arrival. The study was approved by the Royal Melbourne Hospital Human Ethics committee. The findings will be published in peer-reviewed journals, presented at academic conferences and disseminated among consumer and healthcare professional audiences. NCT04071613 .
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-03-2022
DOI: 10.1212/WNL.0000000000013302
Abstract: Detailed study of tenecteplase (TNK) in patients older than 80 years is limited. The objective of our study was to assess the safety and efficacy of TNK at 0.25 and 0.40 mg/kg doses in patients older than 80 years with large vessel occlusion. We performed a pooled analysis of the EXTEND-IA TNK randomized controlled trials (n = 502). Patients were adults presenting with ischemic stroke due to occlusion of the intracranial internal carotid, middle cerebral, or basilar artery presenting within 4.5 hours of symptom onset. We compared the treatment effect of TNK 0.25 mg/kg, TNK 0.40 mg/kg, and alteplase 0.90 mg/kg, stratifying for patient age ( years). Outcomes evaluated include 90-day modified Rankin Scale (mRS) score, all-cause mortality, and symptomatic ICH. Treatment effect was adjusted for baseline NIH Stroke Score, age, and time from symptom onset to puncture via mixed effects proportional odds and logistic regression models. In patients years (n = 137), TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs 4, adjusted common odds ratio (acOR) 2.70, 95% CI 1.23–5.94) and reduced mortality (acOR 0.34, 95% CI 0.13–0.91) vs 0.40 mg/kg. TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs 4, acOR 2.28, 95% CI 1.03–5.05) vs alteplase. No difference in 90-day mRS or mortality was detected between alteplase and TNK 0.40 mg/kg. Symptomatic ICH was observed in 4 patients treated with TNK 0.40 mg/kg, 1 patient treated with alteplase, and 0 patients treated with TNK 0.25 mg/kg. In patients ≤80 years, no differences in 90-day mRS, mortality, or symptomatic ICH were observed among TNK 0.25 mg/kg, alteplase, and TNK 0.40 mg/kg. TNK 0.25 mg/kg was associated with improved 90-day mRS and lower mortality in patients older than 80 years. No differences among the doses were observed in younger patients. NCT02388061, NCT03340493. This study provides Class II evidence that tenecteplase 0.25 mg/kg given before endovascular therapy in patients years old with large vessel occlusion stroke is associated with better functional outcomes at 90 days and reduced mortality when compared to tenecteplase 0.40 mg/kg or alteplase 0.90 mg/kg.
No related grants have been discovered for Felix Ng.