Response by Bivard et al to letter regarding article, "Impact of Computed Tomography Perfusion Imaging on the Response to Tenecteplase in Ischemic Stroke: Analysis of 2 Randomized Controlled Trials"

No abstract available

Perfusion Computed Tomography in Traumatic Brain Injury

Introduction: Almost 50 years ago, computed tomography (CT) revolutionized the management of traumatic brain injury (TBI) by imagining intracranial hematomas. This allowed prompt and accurate selection of patients who would benefit from surgical evacuation. Since then, unenhanced CT has been the gold standard imaging modality for patients with acute TBI. Today, multidetector CT can track intravenous contrasts flowing through brain creating maps that depict the speed and the amount of blood at capillary level. This imaging modality takes the name of perfusion CT. Perfusion CT is routinely used during the hyperacute phase of patients suffering from stroke to diagnose areas of penumbra (poorly perfused but still viable brain tissue) that may benefit from revascularization. Here, we summarize the current status of the research on the role of perfusion CT in patients suffering from TBI

Modafinil treatment modulates functional connectivity in stroke survivors with severe fatigue

Post-stroke fatigue has a significant impact on stroke survivors’ mental and physical well-being. Our recent clinical trial showed significant reduction of post-stroke fatigue with modafinil treatment, however functional connectivity changes in response to modafinil have not yet been explored in stroke survivors with post-stroke fatigue. Twenty-eight participants (multidimensional fatigue inventory-20 ≥ 60) had MRI scans at baseline, and during modafinil and placebo treatment. Resting-state functional MRI data were obtained, and independent component analysis was used to extract functional networks. Resting-state functional connectivity (rsFC) was examined between baseline, modafinil and placebo treatment using permutation testing with threshold-free cluster enhancement. Overall twenty-eight participants (mean age: 6 +/-2 14.3, mean baseline MFI-20: 72.3 +/-9.24) were included. During modafinil treatment, increased rsFC was observed in the right hippocampus (p = 0.004, 11 voxels) compared to placebo. This coincided with lower rsFC in the left frontoparietal (inferior parietal lobule, p = 0.023, 13 voxels), somatosensory (primary somatosensory cortex; p = 0.009, 32 voxels) and mesolimbic network (temporal pole, p = 0.016, 35 voxels). In conclusion, modafinil treatment induces significant changes in rsFC in post-stroke fatigue. This modulation of rsFC may relate to a reduction of post-stroke fatigue; however, the relationship between sensory processing, neurotransmitter expression and fatigue requires further exploration

Risk factors of hemorrhagic transformation in acute ischaemic stroke : A systematic review and meta-analysis

Background: Hemorrhagic transformation (HT) following reperfusion therapies for acute ischaemic stroke often predicts a poor prognosis. This systematic review and meta-analysis aims to identify risk factors for HT, and how these vary with hyperacute treatment [intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT)]. Methods: Electronic databases PubMed and EMBASE were used to search relevant studies. Pooled odds ratio (OR) with 95% confidence interval (CI) were estimated. Results: A total of 120 studies were included. Atrial fibrillation and NIHSS score were common predictors for any intracerebral hemorrhage (ICH) after reperfusion therapies (both IVT and EVT), while a hyperdense artery sign (OR = 2.605, 95% CI 1.212–5.599, I2 = 0.0%) and number of thrombectomy passes (OR = 1.151, 95% CI 1.041–1.272, I2 = 54.3%) were predictors of any ICH after IVT and EVT, respectively. Common predictors for symptomatic ICH (sICH) after reperfusion therapies were age and serum glucose level. Atrial fibrillation (OR = 3.867, 95% CI 1.970–7.591, I2 = 29.1%), NIHSS score (OR = 1.082, 95% CI 1.060–1.105, I2 = 54.5%) and onset-to-treatment time (OR = 1.003, 95% CI 1.001–1.005, I2 = 0.0%) were predictors of sICH after IVT. Alberta Stroke Program Early CT score (ASPECTS) (OR = 0.686, 95% CI 0.565–0.833, I2 =77.6%) and number of thrombectomy passes (OR = 1.374, 95% CI 1.012–1.866, I2 = 86.4%) were predictors of sICH after EVT. Conclusion: Several predictors of ICH were identified, which varied by treatment type. Studies based on larger and multi-center data sets should be prioritized to confirm the results. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=268927, identifier: CRD42021268927

Growth Hormone Deficiency Is Frequent After Recent Stroke

Introduction: The incidence of pituitary dysfunction after severe ischemic stroke is unknown, however given the increasing attention to pituitary dysfunction after neurological injuries such as traumatic brain injury, this may represent a novel area of research in stroke.Methods: We perform an arginine and human growth hormone releasing hormone challenge on ischemic stroke patients within a week of symptom onset.Results: Over the study period, 13 patients were successfully tested within a week of stroke (baseline NIHSS 10, range 7–16). Overall, 9(69%) patients had a poor response, with 7(54%) of these patients meeting the criteria for had human growth hormone deficiency. Other measures of pituitary function were within normal ranges.Conclusion: After major ischemic stroke, low GH levels are common and may play a role in stroke recovery

Does variability in automated perfusion software outputs for acute ischemic stroke matter? Reanalysis of EXTEND perfusion imaging

Aims We reprocessed the Extending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) perfusion imaging with a different automated software with the aim of comparing mismatch eligibility and outcomes. Methods EXTEND baseline perfusion imaging data were reprocessed using autoMIStar software to identify patients who were eligible based on the same target mismatch criteria as per the original trial. Results From the 225 patients fulfilling RAPID-based mismatch criteria randomized in the EXTEND study, 196 (87%) patients met the revised mismatch criteria. Most common reasons for not meeting revised criteria were core >70 ml (n = 9), and no perfusion lesion/lack of penumbral tissue (n = 20). The revised perfusion lesion volumes were significantly smaller compared to the original RAPID volumes (median 68 ml IQR 34-102 ml vs. 42 ml 16-92 ml, p = 0.036). Of the patients who met the revised mismatch criteria, 40% receiving alteplase had modified Rankin Scale (mRS) 0-1 at 3-month compared to 28% with placebo (Adjusted Odds Ratio (OR) = 2.23, CI 1.08-4.58, p = 0.028). In contrast, in the original mismatch cohort, 35% receiving alteplase had mRS 0-1 at 3-month compared to 30% with placebo (adjusted OR = 1.88, p = 0.056). Conclusions These data reinforce the benefit of alteplase in the later time window, and suggest that differences in automated perfusion imaging software outputs may be clinically relevant.Peer reviewe

Thrombolysis implementation intervention and clinical outcome : a secondary analysis of a cluster randomized trial

Background: Multiple studies have attempted to increase the rate of intravenous thrombolysis for ischemic stroke using interventions to promote adherence to guidelines. Still, many of them did not measure individual-level impact. This study aimed to make a posthoc comparison of the clinical outcomes of patients in the "Thrombolysis ImPlementation in Stroke (TIPS)"study, which aimed to improve rates of intravenous thrombolysis in Australia. Methods: A posthoc analysis was conducted using individual-level patient data. Excellent (Three-month post treatment modified Rankin Score 0-2) and poor clinical outcome (Three-month post treatment modified Rankin Score 5-6) and post treatment parenchymal haematoma were the three main outcomes, and a mixed logistic regression model was used to assess the difference between the intervention and control groups. Results: There was a non-significant higher odds of having an excellent clinical outcome of 57% (odds ratio: 1.57; 95% CI: 0.73-3.39) and 33% (odds ratio: 1.33; 95% CI: 0.73-2.44) during the active-And post-intervention period respectively, for the intervention compared to the control group. A non-significant lower odds of having a poor clinical outcome was also found in the intervention, relative to control group of 4% (odds ratio: 0.96; 95% CI: 0.56-2.07) and higher odds of having poor outcome of 44% (odds ratio: 1.44 95% CI: 0.61-3.41) during both active and post-intervention period respectively. Similarly, a non-significant lower odds of parenchymal haematoma was also found for the intervention group during the both active-(odds ratio: 0.53; 95% CI: 0.21-1.32) and post-intervention period (odds ratio: 0.96; 95% CI: 0.36-2.52). Conclusion: The TIPS multi-component implementation approach was not effective in reducing the odds of post-Treatment severe disability at 90 days, or post-thrombolysis hemorrhage

Impact of computed tomography perfusion imaging on the response to tenecteplase in ischemic stroke: analysis of two randomized controlled trials

Background: We pooled 2 clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke, 1 that demonstrated superiority of tenecteplase and the other that showed no difference between the treatments in patient clinical outcomes. We tested the hypotheses that reperfusion therapy with tenecteplase would be superior to alteplase in improving functional outcomes in the group of patients with target mismatch as identified with advanced imaging. Methods: We investigated whether tenecteplase-treated patients had a different 24-hour reduction in the National Institutes of Health Stroke Scale and a favorable odds ratio of a modified Rankin scale score of 0 to 1 versus 2 to 6 compared with alteplase-treated patients using linear regression to generate odds ratios. Imaging outcomes included rates of vessel recanalization and infarct growth at 24 hours and occurrence of large parenchymal hematoma. Baseline computed tomography perfusion was analyzed to assess whether patients met the target mismatch criteria (absolute mismatch volume >15 mL, mismatch ratio >1.8, baseline ischemic core <70 mL, and volume of severely hypoperfused tissue <100 mL). Patients meeting target mismatch criteria were analyzed as a subgroup to identify whether they had different treatment responses from the pooled group. Results: Of 146 pooled patients, 71 received alteplase and 75 received tenecteplase. Tenecteplase-treated patients had greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 7; alteplase, 2; P=0.018) and less parenchymal hematoma (2 of 75 versus 10 of 71; P=0.02). The pooled group did not show improved patient outcomes when treated with tenecteplase (modified Rankin scale score 0–1: odds ratio, 1.77; 95% confidence interval, 0.89–3.51; P=0.102) compared with alteplase therapy. However, in patients with target mismatch (33 tenecteplase, 35 alteplase), treatment with tenecteplase was associated with greater early clinical improvement (median National Institutes of Health Stroke Scale score change: tenecteplase, 6; alteplase, 1; P<0.001) and better late independent recovery (modified Rankin scale score 0–1: odds ratio, 2.33; 95% confidence interval, 1.13–5.94; P=0.032) than those treated with alteplase. Conclusions: Tenecteplase may offer an improved efficacy and safety profile compared with alteplase, benefits possibly exaggerated in patients with baseline computed tomography perfusion–defined target mismatch. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01472926. URL: https://www.anzctr.org.au. Unique identifier: ACTRN12608000466347

Comparing mismatch strategies for patients being considered for ischemic stroke tenecteplase trials

Background: Currently there are multiple variations of imaging-based patient selection mismatch methods in ischemic stroke. In the present study, we sought to compare the two most common mismatch methods and identify if there were different effects on the outcome of a randomized clinical trial depending on the mismatch method used. Aims: Investigate the effect of clinical and imaging-based mismatch criteria on patient outcomes of a pooled cohort from randomized trials of intravenous tenecteplase versus alteplase. Methods: Baseline clinical and imaging scores were used to categorize patients as meeting either the DAWN mismatch (baseline NIHSS ≥ 10, and age cut-offs for ischemic core volume) or DEFUSE 2 mismatch criteria (mismatch volume > 15 mL, mismatch ratio > 1.8 and ischemic core < 70 mL). We then investigated whether tenecteplase-treated patients had favorable odds of less disability (on modified Rankin scale, mRS) compared to those treated with alteplase, for clinical and imaging mismatch, respectively. Results: From 146 pooled patients, 71 received alteplase and 75 received tenecteplase. The overall pooled group did not show improved patient outcomes when treated with tenecteplase (mRS 0-1 OR 1.77, 95% CI 0.89–3.51, p = 0.102) compared with alteplase. A total of 39 (27%) patients met both clinical and imaging mismatch criteria, 25 (17%) patients met only imaging criteria, 36 (25%) met only clinical mismatch criteria and, finally, 46 (31%) did not meet either of imaging or mismatch criteria. Patients treated with tenecteplase had more favorable outcomes when they met either imaging mismatch (mRS 0–1, OR 2.33, 95% CI 1.13–5.94, p = 0.032) or clinical mismatch criteria (mRS 0–1, OR 2.15, 95% CI 1.142, 8.732, p = 0.027) but with differing proportions. Conclusion: Target mismatch selection was more inclusive and exhibited in a larger treatment effect between tenecteplase and alteplase

Thrombolysis implementation intervention and clinical outcome: A secondary analysis of a cluster randomized trial

Background: Multiple studies have attempted to increase the rate of intravenous thrombolysis for ischemic stroke using interventions to promote adherence to guidelines. Still, many of them did not measure individual-level impact. This study aimed to make a posthoc comparison of the clinical outcomes of patients in the "Thrombolysis ImPlementation in Stroke (TIPS)" study, which aimed to improve rates of intravenous thrombolysis in Australia. Methods: A posthoc analysis was conducted using individual-level patient data. Excellent (Three-month post treatment modified Rankin Score 0-2) and poor clinical outcome (Three-month post treatment modified Rankin Score 5-6) and post treatment parenchymal haematoma were the three main outcomes, and a mixed logistic regression model was used to assess the difference between the intervention and control groups. Results: There was a non-significant higher odds of having an excellent clinical outcome of 57% (odds ratio: 1.57; 95% CI: 0.73-3.39) and 33% (odds ratio: 1.33; 95% CI: 0.73-2.44) during the active-and post-intervention period respectively, for the intervention compared to the control group. A non-significant lower odds of having a poor clinical outcome was also found in the intervention, relative to control group of 4% (odds ratio: 0.96; 95% CI: 0.56- 2.07) and higher odds of having poor outcome of 44% (odds ratio: 1.44 95% CI: 0.61-3.41) during both active and post-intervention period respectively. Similarly, a non-significant lower odds of parenchymal haematoma was also found for the intervention group during the both active- (odds ratio: 0.53; 95% CI: 0.21-1.32) and post-intervention period (odds ratio: 0.96; 95% CI: 0.36-2.52). Conclusion: The TIPS multi-component implementation approach was not effective in reducing the odds of posttreatment severe disability at 90 days, or post-thrombolysis hemorrhage.This study was funded by the National Health and Medical Research Council (NHMRC) partnership grant (569328), part-funded by an NHMRC Practitioner Fellowship (1043913) and NHMRC Translating Research Into Practice fellowship, and included partnership grant contribution funding from Boehringer Ingelheim, in-kind support from Agency for Clinical Innovation Stroke Care Network/Stroke Services New South Wales (NSW), Stroke Foundation and NSW Cardiovascular Research Network-National Heart Foundation, with a cash contribution from the Victorian Stroke Clinical Network and infrastructure funding from the Hunter Medical Research Institute and The University of Newcastle