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Tenecteplase for thrombolysis in a 4.5-to-24-hour window did not improve disability outcomes at 90 days in patients with ischemic stroke who had been chosen on the basis of imaging. Most patients had endovascular thrombectomy.

In patients with ischemic stroke and a proximal cerebral arterial occlusion and salvageable tissue on imaging, alteplase followed by thrombectomy with a stent retriever was more effective than alteplase alone in improving reperfusion, neurologic recovery, and functional outcome. The results of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trial, 1 which showed reduced disability among patients with ischemic stroke who were treated with endovascular thrombectomy in addition to standard care, represent an advance in stroke care. The MR CLEAN study followed several trials that had neutral findings with respect to the use of endovascular thrombectomy. 2 – 4 In the largest of these trials, the Interventional Management of Stroke 3 (IMS-3) study, investigators compared the administration of 0.9 mg of alteplase per kilogram of body weight to a bridging strategy of . . .

BackgroundRevascularization after endovascular therapy for acute ischemic stroke is measured by the Thrombolysis In Cerebral Infarction (TICI) scale, yet variability exists in scale definitions. We examined the degree of reperfusion with the expanded TICI (eTICI) scale and association with outcomes in the HERMES collaboration of recent endovascular trials.MethodsThe HERMES Imaging Core, blind to all other data, evaluated angiography after endovascular therapy in HERMES. A battery of TICI scores (mTICI, TICI, TICI2C) was used to define reperfusion of the initial target occlusion defined by non-invasive imaging and conventional angiography.ResultsAngiography of 801 subjects was available, including 797 defined by non-invasive imaging (154 internal carotid artery (ICA), 583 M1, 60 M2) and 748 by conventional angiography (195 ICA, 459 M1, 94 M2). Among 729 subjects in whom the reperfusion grade could be established, using eTICI (3=100%, 2C=90–99%, 2b67=67–89%, 2b50=50–66%) of the conventional angiography target occlusion, there were 63 eTICI 3 (9%), 166 eTICI 2c (23%), 218 eTICI 2b67 (30%), 103 eTICI 2b50 (14%), 100 eTICI 2a (14%), 19 eTICI 1 (3%), and 60 eTICI 0 (8%). Modified Rankin Scale shift analyses from baseline to 90 days showed that increasing TICI grades were linked with better outcomes, with significant distinctions between TICI 0/1 versus 2a (p=0.028), 2a versus 2b50 (p=0.017), and 2b50 versus 2b67 (p=0.014).ConclusionsThe benefit of endovascular therapy in HERMES was strongly associated with increasing degrees of reperfusion defined by eTICI. The eTICI metric identified meaningful distinctions in clinical outcomes and may be used in future studies and routine practice.

Whether infarct size modifies intra-arterial treatment effect is not certain, particularly in patients with large infarcts. We examined the effect of the baseline Alberta Stroke Program Early CT Score (ASPECTS) on the safety and efficacy of intra-arterial treatment in a subgroup analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN). MR CLEAN was a randomised, controlled, open-label, phase 3 trial of intra-arterial treatment in patients (aged ≥18 years from the Netherlands) with proximal arterial occlusion of the anterior circulation, given intra-arterial treatment within 6 h of stroke onset. The primary outcome was 90 day modified Rankin Scale (mRS) score. We estimated the intra-arterial treatment effect for all patients in MR CLEAN who had ASPECTS graded by using multivariable ordinal logistic regression analysis (a proportional odds model) to calculate the adjusted common odds ratio for a shift towards a better functional outcome according to the mRS for intra-arterial treatment and usual care than for usual care alone. We entered an interaction term into the model to test for interaction with prespecified ASPECTS subgroups: 0–4 (large infarct) versus 5–7 (moderate infarct) versus 8–10 (small infarct). MR CLEAN is registered with the Netherlands Trial Registry, number NTR1804, and the ISRCTN Registry, number ISRCTN10888758. 496 patients—232 (47%) in the intra-arterial treatment and usual care group and 264 (53%) in the usual care alone group—were included in the analysis. We noted no significant difference in intra-arterial treatment effect between the ASPECTS subgroups according to 90 day ordinal mRS (adjusted common odds ratio interaction term relative to ASPECTS 8–10: ASPECTS 0–4: 0·79 [95% CI 0·20–3·19], p=0·740; and ASPECTS 5–7: 1·02 [0·44–2·35], p=0·966). Intra-arterial treatment did not cause a significant increase in the proportion of patients with at least one serious adverse event in any of the ASPECTS subgroups (ASPECTS 0–4: eight [73%] of 11 patients in treatment and usual care group vs 11 [58%] of 19 in usual care alone group, p=0·42; ASPECTS 5–7: 32 [59%] of 54 vs 19 [49%] of 39, p=0·31; ASPECTS 8–10: 70 [42%] of 167 vs 82 [40%] of 206; p=0·68). For death within 7 days or within 30 days and hemicraniectomy, the differences between the intra-arterial treatment and usual care versus usual care alone groups were not significant by ASPECTS subgroups. A significantly higher proportion of patients had recurrent ischaemic stroke in the intra-arterial treatment plus usual care group than in the usual care alone group in the ASPECTS 8–10 subgroup (eight [5%] vs one [<1%]; p=0·007). Contrary to findings from previous studies suggesting that only patients with non-contrast CT ASPECTS of more than 7 benefit from intra-arterial treatment, data from this study suggest that patients with ASPECTS 5–7 should be treated. Further evidence is needed for patients with ASPECTS 0–4, for whom treatment might yield only marginal absolute benefit. Dutch Heart Foundation, AngioCare, Medtronic/Covidien/EV3, Medac/Lamepro, Penumbra, Stryker, and Top Medical.

Thrombolytic therapy is not consistently effective in patients with acute ischemic stroke. In this phase 2 study, transcranial Doppler ultrasonography that was aimed at residual obstruction in the middle cerebral artery during thrombolytic therapy with tissue plasminogen activator resulted in improved recanalization of the artery. Ultrasonic enhancement of thrombolysis may be due to improved transport of the drug to the thrombus. A larger trial will be needed to investigate the effects of this approach on neurologic recovery. In this study, transcranial Doppler ultrasonography during thrombolytic therapy with tissue plasminogen activator resulted in improved recanalization of the artery and a trend toward improved neurologic outcomes. Half of patients who have had ischemic stroke remain moderately or severely disabled despite treatment with intravenous tissue plasminogen activator (t-PA). 1 Major reasons for incomplete recovery include a severe initial ischemic insult and slow and incomplete thrombolysis. 2 , 3 Successful thrombolysis depends on the delivery of t-PA to the thrombus through residual blood flow around the arterial obstruction. 4 , 5 In experimental models, ultrasound has been shown to facilitate the activity of fibrinolytic agents within minutes of its exposure to a thrombus and to blood that contains t-PA. 2 , 4 – 9 The mechanisms of ultrasound-enhanced thrombolysis include improved drug transport, reversible alteration of . . .

Background Fetal growth restriction (FGR) is a serious obstetric condition for which there is currently no treatment. The EVERREST Prospective Study has been designed to characterise the natural history of pregnancies affected by severe early onset FGR and establish a well phenotyped bio-bank. The findings will provide up-to-date information for clinicians and patients and inform the design and conduct of the EVERREST Clinical Trial: a phase I/IIa trial to assess the safety and efficacy of maternal vascular endothelial growth factor (VEGF) gene therapy in severe early onset FGR. Data and samples from the EVERREST Prospective Study will be used to identify ultrasound and/or biochemical markers of prognosis in pregnancies with an estimated fetal weight (EFW) <3rd centile between 20+0 and 26+6 weeks of gestation. Methods This is a 6 year European multicentre prospective cohort study, recruiting women with a singleton pregnancy where the EFW is <3rd centile for gestational age and <600 g at 20+0 to 26+6 weeks of gestation. Detailed data are collected on: maternal history; antenatal, peripartum, and postnatal maternal complications; health economic impact; psychological impact; neonatal condition, progress and complications; and infant growth and neurodevelopment to 2 years of corrected age in surviving infants. Standardised longitudinal ultrasound measurements are performed, including: fetal biometry; uterine artery, umbilical artery, middle cerebral artery, and ductus venosus Doppler velocimetry; and uterine artery and umbilical vein volume blood flow. Samples of maternal blood and urine, amniotic fluid (if amniocentesis performed), placenta, umbilical cord blood, and placental bed (if caesarean delivery performed) are collected for bio-banking. An initial analysis of maternal blood samples at enrolment is planned to identify biochemical markers that are predictors for fetal or neonatal death. Discussion The findings of the EVERREST Prospective Study will support the development of a novel therapy for severe early onset FGR by describing in detail the natural history of the disease and by identifying women whose pregnancies have the poorest outcomes, in whom a therapy might be most advantageous. The findings will also enable better counselling of couples with affected pregnancies, and provide a valuable resource for future research into the causes of FGR. Trial registration NCT02097667 registered 31 st October 2013.

ObjectivesWe tested whether FLAIR vascular hyperintensities (FVH)–DWI mismatch could identify candidates for thrombectomy most likely to benefit from revascularization.MethodsWe retrospectively reviewed 100 patients with proximal MCA occlusion from 18 stroke centers randomized in the IV-thrombolysis plus mechanical thrombectomy arm of the THRACE trial (2010–2015). We tested the associations between successful revascularization on digital subtraction angiography (modified Thrombolysis in Cerebral Infarction 2b/3) and 3-month favorable outcome (modified Rankin Scale score ≤ 2), stratified on FVH–DWI mismatch status, with secondary analyses adjusted on National Institutes of Health Stroke Scale (NIHSS) and DWI lesion volume.ResultsFVH–DWI mismatch was present in 79% of patients, with a similar prevalence at 1.5 T (80%) and 3 T (78%). Successful revascularization (74%) was more frequent in patients with FVH–DWI mismatch (63/79, 80%) than in patients without (11/21, 52%), p = 0.01. The OR of favorable outcome for revascularization were 15.05 (95% CI 3.12–72.61, p < 0.001) in patients with FVH–DWI mismatch and 0.83 (95% CI 0.15–4.64, p = 0.84) in patients without FVH–DWI mismatch (p = 0.011 for interaction). Similar results were observed after adjustment for NIHSS (OR = 12.73 [95% CI 2.69–60.41, p = 0.001] and 0.96 [95% CI 0.15–6.30, p = 0.96]) or for DWI volume (OR = 12.37 [95% CI 2.76–55.44, p = 0.001] and 0.91 [95% CI 0.16–5.33, p = 0.92]) in patients with and without FVH–DWI mismatch, respectively.ConclusionsThe FVH–DWI mismatch identifies patients likeliest to benefit from revascularization, irrespective of initial DWI lesion volume and clinical stroke severity, and could serve as a useful surrogate marker for penumbral evaluation.Key Points• The FVH–DWI mismatch, defined by FLAIR vascular hyperintensities (FVH) located beyond the boundaries of the DWI lesion, is associated with large penumbra.• Among stroke patients with proximal middle cerebral artery occlusion referred for thrombectomy, those with FVH–DWI mismatch are most likely to benefit from revascularization.• FVH–DWI mismatch provides an alternative to PWI–DWI mismatch in order to select patients who are candidates for thrombectomy.

To compare the clinical outcomes among various infarct patterns and to investigate the associations between the morphological parameters of contralateral middle cerebral artery (cMCA) M segment and infarct patterns in ischemic stroke attributed to large vessel occlusion (LVO) in M segment caused by intracranial atherosclerotic disease (ICAD). Patients with stroke attributed to M -ICAD-LVO were enrolled. The infarct patterns were categorized into artery-to-artery embolism (AAE), large infarct, borderzone infarct (BZI), and perforating artery infarction (PAI). The morphological parameters of cMCA-M segment included proximal and distal diameter, arc, and chord length. The tortuosity index of cMCA-M segment was calculated by (arc length/chord length - 1) × 100%. A total of 171 participants were enrolled. Compared to AAE, the risk of poor outcome increased in BZI (odds ratio [OR] = 5.51, 95% confidence interval [CI] = 1.71-17.78, p = 0.004) and large infarct (OR = 10.92, 95% CI = 2.01-59.27, p = 0.006) and was comparable in PAI. The tortuosity index (OR = 2.85, 95% CI = 1.13-7.18, p = 0.026) and arc length (OR = 2.47, 95% CI = 1.02-5.97, p = 0.045) significantly increased in BZI than other three patterns. Participants other than BZI were categorized into large infarct (n = 32) and non-large-infarct (n = 46) groups, and the proximal diameter (OR = 0.22, 95% CI = 0.07-0.72, p = 0.012), arc length (OR = 0.88, 95% CI = 0.78-0.98, p = 0.018), and chord length (OR = 0.87, 95% CI = 0.77-0.995, p = 0.042) were associated with large infarct. For patients with M -ICAD-LVO, large infarct and BZI had poorer outcomes than PAI and AAE. The cMCA-M segment with elevated tortuosity and arc length was associated with BZI, whereas a thin and short M segment was correlated with large infarct in patients with a less tortuous cMCA trunk.

BackgroundThe Careggi Collateral Score (CCS) (qualitative–quantitative evaluation) was developed from a single-centre cohort as an angiographic score to describe both the extension and effectiveness of the pial collateral circulation in stroke patients with occlusion of the anterior circulation. We aimed to examine the association between CCS (quantitative evaluation) and 3-month modified Rankin Scale (mRS) score in a large multi-center cohort of patients receiving thrombectomy for stroke with occlusion of middle cerebral artery (MCA).MethodsWe conducted a study on prospectively collected data from 1284 patients enrolled in the Italian Registry of Endovascular Treatment in Acute Stroke. According to the extension of the retrograde reperfusion in the cortical anterior cerebral artery (ACA)-MCA territories, CCS ranges from 0 (absence of retrograde filling) to 4 (visualization of collaterals until the alar segment of the MCA).ResultsUsing CCS of 4 as reference, CCS grades were associated in the direction of unfavourable outcome on 3-month mRS shift (0 to 6); significant difference was found between CCS of 0 and CCS of 1 and between CCS of 3 and CCS of 4. CCS ≥ 3 was the optimal cut-off for predicting 3-month excellent outcome, while CCS ≥ 1 was the optimal cut-off for predicting 3-month survival. CCS of 0 and CCS < 3 were associated in the direction of unfavourable recanalization on TICI shift (0 to 3) compared with CCS ≥ 1 and CCS ≥ 3, respectively. Compared with CCS ≥ 3 as reference, CCS of 0 and CCS 1 to 2 were associated in the direction of unfavourable recanalization on TICI shift. There was no evidence of heterogeneity of effects of successful recanalization and procedure time ≤ 60 min on 3-month mRS shift across CCS categories.ConclusionThe CCS could provide a future advantage for improving the prognosis in patients receiving thrombectomy for stroke with M1 or M1–M2 segment of the MCA occlusion.

Cognitive paradigms induce changes in cerebral blood flow (CBF) associated with increased metabolic demand, namely neurovascular coupling (NVC). We tested the hypothesis that the effect of complexity and duration of cognitive paradigms will either enhance or inhibit the NVC response. Bilateral CBF velocity (CBFV) in the middle cerebral arteries (MCAs) via transcranial Doppler ultrasound (TCD), blood pressure (BP), electrocardiogram (ECG) and end-tidal CO 2 (EtCO 2 ) of 16 healthy participants (aged 21–71 years) were simultaneously recorded at rest and during randomized paradigms of different complexities (naming words beginning with P-,R-,V- words and serial subtractions of 100–2,100–7,1000–17), and durations (5s, 30s and 60s). CBFV responses were population mean normalized from a 30-s baseline period prior to task initiation. A significant increase in bilateral CBFV response was observed at the start of all paradigms and provided a similar pattern in most responses, irrespective of complexity or duration. Although significant inter-hemispherical differences were found during performance of R-word and all serial subtraction paradigms, no lateralisation was observed in more complex naming word tasks. Also, the effect of duration was manifested at late stages of 100–7, but not for other paradigms. CBFV responses could not distinguish different levels of complexity or duration with a single presentation of the cognitive paradigm. Further studies of the ordinal scalability of the NVC response are needed with more advanced modelling techniques, or different types of neural stimulation.