Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Discrepancy between post-treatment infarct volume and 90-day outcome in the ESCAPE randomized controlled trial.

BACKGROUND: Some patients with ischemic stroke have poor outcomes despite small infarcts after endovascular thrombectomy, while others with large infarcts sometimes fare better. AIMS: We explored factors associated with such discrepancies between post-treatment infarct volume (PIV) and functional outcome. METHODS: We identified patients with small PIV (volume ≤ 25th percentile) and large PIV (volume ≥ 75th percentile) on 24-48-h CT/MRI in the ESCAPE randomized-controlled trial. Demographics, comorbidities, baseline, and 24-48-h stroke severity (NIHSS), stroke location, treatment type, post-stroke complications, and other outcome scales like Barthel Index, and EQ-5D were compared between "discrepant cases" - those with 90-day modified Rankin Scale(mRS) ≤ 2 despite large PIV or mRS ≥ 3 despite small PIV - and "non-discrepant cases". Multi-variable logistic regression was used to identify pre-treatment and post-treatment factors associated with small-PIV/mRS ≥ 3 and large-PIV/mRS ≤ 2. Sensitivity analyses used different definitions of small/large PIV and good/poor outcome. RESULTS: Among 315 patients, median PIV was 21 mL; 27/79 (34.2%) patients with PIV ≤ 7 mL (25th percentile) had mRS ≥ 3; 12/80 (15.0%) with PIV ≥ 72 mL (75th percentile) had mRS ≤ 2. Discrepant cases did not differ by CT versus MRI-based PIV ascertainment, or right versus left-hemisphere involvement (p = 0.39, p = 0.81, respectively, for PIV ≤ 7 mL/mRS ≥ 3). Pre-treatment factors independently associated with small-PIV/mRS ≥ 3 included older age (p = 0.010), cancer, and vascular risk-factors; post-treatment factors included 48-h NIHSS (p = 0.007) and post-stroke complications (p = 0.026). Absence of vascular risk-factors (p = 0.004), CT-based lentiform nucleus sparing (p = 0.002), lower 24-hour NIHSS (p = 0.001), and absence of complications (p = 0.013) were associated with large-PIV/mRS ≤ 2. Sensitivity analyses yielded similar results. CONCLUSIONS: Discrepancies between functional ability and PIV are likely explained by differences in age, comorbidities, and post-stroke complications, emphasizing the need for high-quality post-thrombectomy stroke care. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01778335.

Defining reperfusion post endovascular therapy in ischemic stroke using MR-dynamic contrast enhanced perfusion.

OBJECTIVES: Cerebral blood flow (CBF) measurements after endovascular therapy (EVT) for acute ischemic stroke are important to distinguish early secondary injury related to persisting ischemia from that related to reperfusion when considering clinical response and infarct growth. METHODS: We compare reperfusion quantified by the modified Thrombolysis in Cerebral Infarction Score (mTICI) with perfusion measured by MRI dynamic contrast-enhanced perfusion within 5 h of EVT anterior circulation stroke. MR perfusion (rCBF, rCBV, rTmax, rT0) and mTICI scores were included in a predictive model for change in NIHSS at 24 h and diffusion-weighted imaging (DWI) lesion growth (acute to 24 h MRI) using a machine learning RRELIEFF feature selection coupled with a support vector regression. RESULTS: For all perfusion parameters, mean values within the acute infarct for the TICI-2b group (considered clinically good reperfusion) were not significantly different from those in the mTICI <2b (clinically poor reperfusion). However, there was a statistically significant difference in perfusion values within the acute infarct region of interest between the mTICI-3 group versus both mTICI-2b and <2b (p = 0.02). The features that made up the best predictive model for change in NIHSS and absolute DWI lesion volume change was rT0 within acute infarct ROI and admission CTA collaterals respectively. No other variables, including mTICI scores, were selected for these best models. The correlation coefficients (Root mean squared error) for the cross-validation were 0.47 (13.7) and 0.51 (5.7) for change in NIHSS and absolute DWI lesion volume change. CONCLUSION: MR perfusion following EVT provides accurate physiological approach to understanding the relationship of CBF, clinical outcome, and DWI growth. ADVANCES IN KNOWLEDGE: MR perfusion CBF acquired is a robust, objective reperfusion measurement providing following recanalization of the target occlusion which is critical to distinguish potential therapeutic harm from the failed technical success of EVT as well as improve the responsiveness of clinical trial outcomes to disease modification.

Outcome of intracranial flow diversion according to the antiplatelet regimen used: a systematic review and meta-analysis.

BACKGROUND: Thromboembolic complications are not uncommon in patients undergoing neurointerventional procedures. The use of flow diverting stents is associated with higher risks of these complications despite current dual antiplatelet regimens. OBJECTIVE: To explore contemporary evidence on the safety of emerging dual antiplatelet regimens in flow diverting stenting procedures. METHODS: We performed a systematic review and meta-analysis to identify relevant articles in electronic databases, and relevant references. Studies reporting the complications and mortality of flow diverting stenting procedures using acetyl salicylic acid (ASA) + ticagrelor or ASA + prasugrel compared with ASA + clopidogrel were included. RESULTS: Of 452 potentially relevant studies, we identified 49 studies (2526 patients) which reported the safety of ticagrelor or prasugrel for pooled analysis, and five studies (1005 patients) for meta-analysis. The pooled overall mortality in all studies was 2.14%, ischemic complications 6.89%, and hemorrhagic complications 3.68%. The use of ticagrelor or prasugrel was associated with a lower risk of mortality compared with clopidogrel (RR=4.57, 95% CI 1.23 to 16.99; p=0.02). Considering ischemic events, ASA + clopidogrel was as safe as ASA + prasugrel (RR=0.55, 95% CI 0.11 to 2.74; p=0.47) and ASA + ticagrelor (RR=0.74, 95% CI 0.32 to 1.74; p=0.49). ASA +ticagrelor was not associated with a higher risk of hemorrhagic complications (RR=0.92, 95% CI 0.27 to 3.16; p=0.89). CONCLUSIONS: Evidence suggests that dual antiplatelet regimens including ticagrelor or prasugrel are safe for patients undergoing flow diversion procedures. Regimens using ticagrelor were associated with better survival than those using clopidogrel in the included studies.

Acute ischemic stroke with tandem lesions: technical endovascular management and clinical outcomes from the ESCAPE trial.

BACKGROUND: Tandem occlusions of the extracranial carotid and intracranial carotid or middle cerebral artery have a particularly poor prognosis without treatment. Several management strategies have been used with no clear consensus recommendations. We examined subjects with tandem occlusions enrolled in the ESCAPE trial and their outcomes. METHODS: Data are from the ESCAPE trial. Additional data were sought on interventions for each subject. RESULTS: There were 54 (17%) subjects with tandem extracranial and intracranial occlusions. Patients in the endovascular treatment arm (n=30) were more likely to be younger (median age 66 years, p<0.01), male (66.7%, p=0.03), diabetic, and without atrial fibrillation. Subjects with tandem occlusions were more likely to have intracranial internal carotid artery occlusions than M1 occlusions (p<0.01). Of the 30 intervention-arm subjects, 17 (57%) underwent emergency endovascular treatment of the extracranial disease, 10 subjects before and seven subjects after intracranial thrombectomy. Of the remaining 13 subjects, only four required staged carotid revascularization due to persistent severe carotid stenosis; four had cervical pseudo-occlusions with no residual stenosis after large distal carotid thrombus burden aspiration/retrieval. Outcomes were similar between subjects with and without tandem lesions. The use of antithrombotic agents after acute carotid artery stenting was variable but no symptomatic intracerebral hemorrhage was seen in subjects who underwent emergency endovascular treatment of extracranial carotid artery. CONCLUSIONS: Tandem occlusions occurred in one-sixth of patients and were treated highly variably within the ESCAPE trial. While outcomes were similar, the best method to treat the carotid artery in patients with tandem occlusion awaits further randomized data. TRIAL REGISTRATION NUMBER: NCT01778335.

Imaging department organization in a stroke center and workflow processes in acute stroke.

The imaging department is an integral part of the stroke management task force and plays a critical role. Accurate and timely interpretation of images obtained in the emergency department and involvement in decision-making has contributed immensely in stroke care. In fact, the treatment paradigm has changed considerably after the recent positive endovascular clinical trials; and so is the hospital workflow and treatment site. As a result, the imaging department has become the site of maximum activity during an acute stroke protocol. Time management, teamwork and standardized institutional protocols contribute to improve functional outcome. In this review article, we emphasize the critical role an Imaging department's organization plays in a stroke center and the workflow involved in management of acute stroke.

Vessel Patency at 24 Hours and Its Relationship With Clinical Outcomes and Infarct Volume in REVASCAT Trial (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset).

BACKGROUND AND PURPOSE: Higher rates of target vessel patency at 24 hours were noted in the thrombectomy group compared with control group in recent randomized trials. As a prespecified secondary end point, we aimed to assess 24-hour revascularization rates by treatment groups and occlusion site as they related to clinical outcome and 24-hour infarct volume in REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset). METHODS: Independent core laboratory adjudicated vessel status according to modified arterial occlusive lesion classification at 24 hours on computed tomographic/magnetic resonance (94.2%/5.8%) angiography and 24-hour infarct volume on computed tomography were studied (95/103 patients in the thrombectomy group versus 94/103 in the control group, respectively). Complete revascularization was defined as modified arterial occlusive lesion grade 3. Its effect on clinical outcome was analyzed by ordinal logistic regression. RESULTS: Complete revascularization was achieved in 70.5% of the solitaire group and in 22.3% of the control group (P<0.001). Significant differences in complete revascularization rates were found for terminus internal carotid artery, M1, and tandem occlusions (all P<0.001) but not for M2 occlusions. In the thrombectomy group, 2 out of 63 patients (3.1%) with modified Thrombolysis in Cerebral Infarction 2b/3 after thrombectomy showed arterial reocclusion (modified arterial occlusive lesion grade 0/1) at 24 hours. Complete revascularization was associated with improved outcome in both thrombectomy (adjusted odds ratio, 4.5; 95% confidence interval, 1.9-10.9) and control groups (adjusted odds ratio, 2.7; 95% confidence interval, 1.0-6.7). Revascularization (modified arterial occlusive lesion grade 2/3) was associated with smaller infarct volumes in either treatment arm. CONCLUSIONS: Complete revascularization at 24 hours is a powerful predictor of favorable clinical outcome, whereas revascularization of any type results in reduced infarct volume in both thrombectomy and control groups. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379.

Rapid delayed growth of ruptured supraclinoid blister aneurysm after successful flow diverting stent treatment.

A 62-year-old woman presented with a subarachnoid hemorrhage secondary to a ruptured right supraclinoid internal carotid artery blister aneurysm. She was treated in an emergent fashion with two flow diverting pipeline embolization devices (PED) deployed in a telescoping fashion. CT angiography performed for unrelated reasons at 7 months showed successful treatment of the aneurysm without evidence of residual aneurysm. However, a follow-up digital subtraction angiogram performed at 9 months showed a large aneurysm in a modified position compared with the original aneurysm. This is the first case of rapid regrowth of a supraclinoid blister aneurysm after successful treatment with a PED, and demonstrates the need for close follow-up for similar aneurysms treated with this novel device.

Infarct in a New Territory After Treatment Administration in the ESCAPE Randomized Controlled Trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times).

BACKGROUND AND PURPOSE: Infarct in a new previously unaffected territory (INT) is a potential complication of endovascular treatment. We applied a recently proposed methodology to identify and classify INTs in the ESCAPE randomized controlled trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times). METHODS: The core laboratory identified INTs on 24-hour follow-up imaging, blinded to treatment allocation, after assessing all baseline imaging. INTs were classified into 3 types (I-III) and 2 subtypes (A/B) based on size and if catheter manipulation was likely performed across the vessel territory ostium. Logistic regression was used to understand the effect of multiple a priori identified variables on INT occurrence. Ordinal logistic regression was used to analyze the effect of INTs on modified Rankin Scale shift at 90 days. RESULTS: From 308 patients included, 14 INTs (4.5% overall; 2.8% on follow-up noncontrast computed tomography, 11.7% on follow-up magnetic resonance imaging) were identified (5.0% in endovascular treatment arm versus 4.0% in control arm [P=0.7]). The use of intravenous alteplase was associated with a 68% reduction in the odds of INT occurrence (3.0% with versus 9.1% without; odds ratio, 0.32; 95% confidence interval, 0.11-0.96; adjusted for age, sex, and treatment type). No other variables were associated with INTs. INT occurrence was associated with reduced probability of good clinical outcome (common odds ratio, 0.25; 95% confidence interval, 0.09-0.74; adjusted for age, type of treatment, and follow-up scan). CONCLUSIONS: INTs are uncommon, detected more frequently on follow-up magnetic resonance imaging, and affect clinical outcome. In experienced centers, endovascular treatment is likely not causal, whereas intravenous alteplase may be therapeutic. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01778335.

Rapid delayed growth of ruptured supraclinoid blister aneurysm after successful flow diverting stent treatment.

A 62-year-old woman presented with a subarachnoid hemorrhage secondary to a ruptured right supraclinoid internal carotid artery blister aneurysm. She was treated in an emergent fashion with two flow diverting pipeline embolization devices (PED) deployed in a telescoping fashion. CT angiography performed for unrelated reasons at 7 months showed successful treatment of the aneurysm without evidence of residual aneurysm. However, a follow-up digital subtraction angiogram performed at 9 months showed a large aneurysm in a modified position compared with the original aneurysm. This is the first case of rapid regrowth of a supraclinoid blister aneurysm after successful treatment with a PED, and demonstrates the need for close follow-up for similar aneurysms treated with this novel device.

Multiphase CT angiography increases detection of anterior circulation intracranial occlusion.

OBJECTIVE: To evaluate whether the use of multiphase CT angiography (CTA) improves interrater agreement for intracranial occlusion detection between stroke neurology trainees and an expert neuroradiologist. METHODS: A neuroradiologist and 2 stroke neurology fellows independently reviewed 100 prospectively collected single-phase and multiphase CTA scans from acute ischemic stroke patients with mild symptoms (NIH Stroke Scale score ≤5). The presence and location of a vascular occlusion(s) were documented. Interrater agreement single- and multiphase CTA was quantified using unweighted κ statistics. We assessed for any occlusions, anterior vs posterior occlusions, and pial vessel asymmetry. RESULTS: Using multiphase CTA, the neuroradiologist detected 50 scans with anterior circulation occlusions and 15 scans with posterior circulation occlusions. Median reading time was 2 minutes per scan. Median reading time for the neurologists was 3 minutes per multiphase CTA scan. Interrater agreement was fair between the 2 neurologists and neuroradiologist when using single-phase CTA (κ = 0.45 and 0.32). Agreement improved minimally when stratified by anterior vs posterior circulation. When using multiphase CTA, agreement was high for detection of occlusion or asymmetry of pial vessels in the anterior circulation (κ = 0.80 and 0.84). CONCLUSIONS: Multiphase CTA improves diagnostic accuracy in minor ischemic stroke for detection of anterior circulation intracranial occlusion. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that multiphase CTA, compared to single-phase CTA, improves the interrater agreement between stroke neurology trainees and an expert neuroradiologist for detecting anterior circulation intracranial vascular occlusion in patients with minor acute ischemic strokes.

History, Evolution, and Importance of Emergency Endovascular Treatment of Acute Ischemic Stroke.

More than 800,000 people in North America suffer a stroke each year, with ischemic stroke making up the majority of these cases. The outcomes of ischemic stroke range from complete functional and cognitive recovery to severe disability and death; outcome is strongly associated with timely reperfusion treatment. Historically, ischemic stroke has been treated with intravenous thrombolytic agents with moderate success. However, five recently published positive trials have established the efficacy of endovascular treatment in acute ischemic stroke. In this review, we will discuss the history of stroke treatments moving from various intravenous thrombolytic drugs to intra-arterial thrombolysis, early mechanical thrombectomy devices, and finally modern endovascular devices. Early endovascular therapy failures, recent successes, and implications for current ischemic stroke management and future research directions are discussed.

Intra-Arterial Therapy and Post-Treatment Infarct Volumes: Insights From the ESCAPE Randomized Controlled Trial.

BACKGROUND AND PURPOSE: The goal of reperfusion therapy in acute ischemic stroke is to limit brain infarction. The objective of this study was to investigate whether the beneficial effect of endovascular treatment on functional outcome could be explained by a reduction in post-treatment infarct volume. METHODS: The Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial was a multicenter randomized open-label trial with blinded outcome evaluation. Among 315 enrolled subjects (endovascular treatment n=165; control n=150), 314 subject's infarct volumes at 24 to 48 hours on magnetic resonance imaging (n=254) or computed tomography (n=60) were measured. Post-treatment infarct volumes were compared by treatment assignment and recanalization/reperfusion status. Appropriate statistical models were used to assess relationship between baseline clinical and imaging variables, post-treatment infarct volume, and functional status at 90 days (modified Rankin Scale). RESULTS: Median post-treatment infarct volume in all subjects was 21 mL (interquartile range =65 mL), in the intervention arm, 15.5 mL (interquartile range =41.5 mL), and in the control arm, 33.5 mL (interquartile range =84 mL; P<0.01). Baseline National Institute of Health Stroke Scale (P<0.01), site of occlusion (P<0.01), baseline noncontrast computed tomographic scan Alberta Stroke Program Early CT score (ASPECTS) (P<0.01), and recanalization (P<0.01) were independently associated with post-treatment infarct volume, whereas age, sex, treatment type, intravenous alteplase, and time from onset to randomization were not (P>0.05). Post-treatment infarct volume (P<0.01) and delta National Institute of Health Stroke Scale (P<0.01) were independently associated with 90-day modified Rankin Scale, whereas laterality (left versus right) was not. CONCLUSIONS: These results support the primary results of the ESCAPE trial and show that the biological underpinning of the success of endovascular therapy is a reduction in infarct volume. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01778335.

Childhood autism in India: A case-control study using tract-based spatial statistics analysis.

CONTEXT: Autism is a serious behavioral disorder among young children that now occurs at epidemic rates in developing countries like India. We have used tract-based spatial statistics (TBSS) of diffusion tensor imaging (DTI) measures to investigate the microstructure of primary neurocircuitry involved in autistic spectral disorders as compared to the typically developed children. OBJECTIVE: To evaluate the various white matter tracts in Indian autistic children as compared to the controls using TBSS. MATERIALS AND METHODS: Prospective, case-control, voxel-based, whole-brain DTI analysis using TBSS was performed. The study included 19 autistic children (mean age 8.7 years ± 3.84, 16 males and 3 females) and 34 controls (mean age 12.38 ± 3.76, all males). Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) values were used as outcome variables. RESULTS: Compared to the control group, TBSS demonstrated multiple areas of markedly reduced FA involving multiple long white matter tracts, entire corpus callosum, bilateral posterior thalami, and bilateral optic tracts (OTs). Notably, there were no voxels where FA was significantly increased in the autism group. Increased RD was also noted in these regions, suggesting underlying myelination defect. The MD was elevated in many of the projections and association fibers and notably in the OTs. There were no significant changes in the AD in these regions, indicating no significant axonal injury. There was no significant correlation between the FA values and Childhood Autism Rating Scale. CONCLUSION: This is a first of a kind study evaluating DTI findings in autistic children in India. In our study, DTI has shown a significant fault with the underlying intricate brain wiring system in autism. OT abnormality is a novel finding and needs further research.

Diffusion tensor imaging in evaluation of posterior fossa tumors in children on a 3T MRI scanner.

CONTEXT: Primary intracranial tumors in children are commonly located in the posterior fossa. Conventional MRI offers limited information regarding the histopathological type of tumor which is essential for better patient management. AIMS: The purpose of the study was to evaluate the usefulness of advanced MR imaging techniques like diffusion tensor imaging (DTI) in distinguishing the various histopathological types of posterior fossa tumors in children. SETTINGS AND DESIGN: DTI was performed on a 3T MRI scanner in 34 untreated children found to have posterior fossa lesions. MATERIALS AND METHODS: Using third party software, various DTI parameters [apparent diffusion coefficient (ADC), fractional anisotropy (FA), radial diffusivity, planar index, spherical index, and linear index] were calculated for the lesion. STATISTICAL ANALYSIS USED: Data were subjected to statistical analysis [analysis of variance (ANOVA)] using SPSS 15.0 software. RESULTS: We observed significant correlation (P < 0.01) between ADC mean and maximum, followed by radial diffusivity (RD) with the histopathological types of the lesions. Rest of the DTI parameters did not show any significant correlation in our study. CONCLUSIONS: The results of our study support the hypothesis that most cellular tumors and those with greater nuclear area like medulloblastoma would have the lowest ADC values, as compared to less cellular tumors like pilocytic astrocytoma.