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Supplemental Digital Content is available in the text., Background and Purpose: Endovascular therapy is the standard of care in the treatment of acute ischemic stroke due to large-vessel occlusion. A direct association between the number of device passes and the occurrence of symptomatic intracranial hemorrhage (SICH) has been suggested. This study represents an in-depth investigation of the hypothesis that >3 retrieval attempts is associated with an increased rate of SICH in a large multicenter patient cohort. Methods: Two thousand six hundred eleven patients from the prospective German Stroke Registry were analyzed. Patients who received Endovascular therapy for acute large-vessel occlusion of the anterior circulation with known admission National Institutes of Health Stroke Scale and Alberta Stroke Program Early CT Score, final Thrombolysis in Cerebral Infarction, and number of retrieval passes were included. The primary outcome was defined as SICH. The secondary outcome was any type of radiologically confirmed intracranial hemorrhage within the first 24 hours. Multivariate mixed-effects models were used to adjust for cluster effects of the participating centers, as well as for confounders. Results: Five hundred ninety-three patients fulfilled the inclusion criteria. The median number of retrieval passes was 2 [interquartile range, 1–3]. SICH occurred in 26 cases (4.4%), whereas intracranial hemorrhage was identified by neuroimaging in 85 (14.3%) cases. More than 3 retrieval passes was the strongest predictor for SICH (odds ratio, 3.61 [95% CI, 1.38–9.42], P=0.0089) following adjustment for age, admission National Institutes of Health Stroke Scale, admission Alberta Stroke Program Early CT Score, and Thrombolysis in Cerebral Infarction, as well as time from symptom onset to flow restoration. Baseline Alberta Stroke Program Early CT Score of 8 to 9 (odds ratio, 0.26 [95% CI, 0.07–0.89], P=0.032) or 10 (odds ratio, 0.21 [95% CI, 0.06–0.78], P=0.020) were significant protective factors against the occurrence of SICH. Conclusions: More than 3 retrieval attempts is associated with a significant increase in SICH risk, regardless of patient age, baseline National Institutes of Health Stroke Scale, or procedure time. This should be considered when deciding whether to continue a procedure, especially in patients with large baseline infarctions. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356392.

Supplemental Digital Content is available in the text., Background and Purpose: Timely reperfusion is an important goal in treatment of eligible patients with acute ischemic stroke. However, during the coronavirus disease 2019 (COVID-19) pandemic, prehospital and in-hospital emergency procedures faced unprecedented challenges, which might have caused a decline in the number of acute reperfusion therapy applied and led to a worsening of key quality measures for this treatment during lockdown. Methods: This prospective multicenter cohort study used data from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry of patients with acute ischemic stroke treated with reperfusion therapies, that is, intravenous thrombolysis or endovascular therapy. We compared prehospital and in-hospital time-based performance measures (stroke-onset-to-admission, admission-to-treatment, admission-to-image, and image-to-treatment time) during the first 6 weeks after announcement of lockdown (lockdown period) with the same period in 2019 (reference period). Secondary outcomes included stroke severity (National Institutes of Health Stroke Scale) after 24 hours and occurrence of symptomatic intracranial hemorrhage (following the ECASS [European-Australasian Acute Stroke Study]-II criteria). Results: Across 20 stroke centers, 540 patients were treated with intravenous thrombolysis/endovascular therapy during lockdown period compared with 578 patients during reference period (−7% [95% CI, 5%–9%]). Performance measures did not change significantly during the lockdown period (2020/2019 minutes median: onset-to-admission 133/145; admission-to-treatment 51/48). Same was true for admission-to-image (20/19) and image-to-treatment (31/30) time in patients with available time of first image (n=871, 77.9%). Median National Institutes of Health Stroke Scale on admission (2020/2019: 11/11) and after 24 hours (2020/2019: 6/5) and percentage of symptomatic intracranial hemorrhage (2020/2019: 6.2/5.7) did not differ significantly between both periods. Conclusions: The COVID-19 pandemic lockdown resulted in a mild decline in the number of patients with stroke treated with acute reperfusion therapies. More importantly, the solid stability of key quality performance measures between the 2020 and 2019 period may indicate resilience of acute stroke care service during the lockdown, at least in well-established European stroke centers.

Background and Purpose: Tandem lesions in the anterior circulation account for up to 30% of all large vessel occlusion strokes. The optimal periprocedural approach in these lesions is still a matter of debate. Methods: Data from the German Stroke Registry—Endovascular Treatment between June 2015 and December 2019 were analyzed. The German Stroke Registry—Endovascular Treatment is an academic, independent, prospective, multicenter, observational registry study with 25 participating stroke centers from all over Germany enrolling consecutive mechanical thrombectomy patients. Tandem lesions were defined as a combination of a relevant extracranial internal carotid artery (ICA) pathology (ipsilateral stenosis >70% or occlusion) and concomitant intracranial large vessel occlusion. Successful reperfusion was defined as modified Thrombolysis in Cerebral Infarction score of 2b-3. The modified Rankin Scale score of 0 to 2 at 3 months indicated good outcome. The aim of this study was to investigate the safety and efficacy of different technical strategies in tandem lesions. Results: Out of 6635 patients, 874 (13.2%) presented with tandem lesions. Of these, 607 (69.5%) underwent acute treatment of the extracranial ICA. Acute treatment of the extracranial ICA lesion led to a higher probability of successful reperfusion (odds ratio, 40.63 [95% CI, 30.03–70.06]) compared with patients who did not undergo acute treatment of the extracranial ICA lesion and was associated with good clinical outcome (39.5% versus 29.3%, P P P =0.035) and intravenous thrombolysis (odds ratio, 10.58 [95% CI, 10.04–20.4]; P =0.033). Intracranial-first approach (n=227) compared with extracranial-first approach (n=267) resulted in a shorter time to flow restoration (53.5 versus 72.0 minutes, P P =0.24) without differences in periprocedural complications. Conclusions: In tandem lesions in the anterior circulation, acute treatment of the extracranial ICA lesion is associated with better clinical outcome and lower mortality. The intracranial-first approach might provide advantages.

Background: The optimal endovascular strategy for reperfusing distal medium-vessel occlusions (DMVO) remains unknown. This study evaluates angiographic and clinical outcomes of thrombectomy strategies in DMVO stroke of the posterior circulation. Methods: TOPMOST (Treatment for Primary Medium Vessel Occlusion Stroke) is an international, retrospective, multicenter, observational registry of patients treated for DMVO between January 2014 and June 2020. This study analyzed endovascularly treated isolated primary DMVO of the posterior cerebral artery in the P2 and P3 segment. Technical feasibility was evaluated with the first-pass effect defined as a modified Thrombolysis in Cerebral Infarction Scale score of 3. Rates of early neurological improvement and functional modified Rankin Scale scores at 90 days were compared. Safety was assessed by the occurrence of symptomatic intracranial hemorrhage and intervention-related serious adverse events. Results: A total of 141 patients met the inclusion criteria and were treated endovascularly for primary isolated DMVO in the P2 (84.4%, 119) or P3 segment (15.6%, 22) of the posterior cerebral artery. The median age was 75 (IQR, 62–81), and 45.4% (64) were female. The initial reperfusion strategy was aspiration only in 29% (41) and stent retriever in 71% (100), both achieving similar first-pass effect rates of 53.7% (22) and 44% (44; P =0.297), respectively. There were no significant differences in early neurological improvement (aspiration: 64.7% versus stent retriever: 52.2%; P =0.933) and modified Rankin Scale rates (modified Rankin Scale score 0–1, aspiration: 60.5% versus stent retriever 68.6%; P =0.4). In multivariable logistic regression analysis, the time from groin puncture to recanalization was associated with the first-pass effect (adjusted odds ratio, 0.97 [95% CI, 0.95–0.99]; P P Conclusions: Both first-pass aspiration and stent retriever thrombectomy for primary isolated posterior circulation DMVO seem to be safe and technically feasible leading to similar favorable rates of angiographic and clinical outcome.

Background and Purpose: This study evaluates the benefit of endovascular treatment (EVT) for patients with extensive baseline stroke compared with best medical treatment. Methods: This retrospective, multicenter study compares EVT and best medical treatment for computed tomography (CT)–based selection of patients with extensive baseline infarcts (Alberta Stroke Program Early CT Score ≤5) attributed to anterior circulation stroke. Patients were selected from the German Stroke Registry and 3 tertiary stroke centers. Primary functional end points were rates of good (modified Rankin Scale score of ≤3) and very poor outcome (modified Rankin Scale score of ≥5) at 90 days. Secondary safety end point was the occurrence of symptomatic intracerebral hemorrhage. Angiographic outcome was evaluated with the modified Thrombolysis in Cerebral Infarction Scale. Results: After 1:1 pair matching, a total of 248 patients were compared by treatment arm. Good functional outcome was observed in 27.4% in the EVT group, and in 25% in the best medical treatment group ( P =0.665). Advanced age (adjusted odds ratio, 1.08 [95% CI, 1.05–1.10], P P P =0.025) and symptomatic intracerebral hemorrhage (16.1% versus 5.6%, P =0.008) were significantly higher in the EVT group. The lowest rates of good functional outcome (≈15%) were observed in groups of failed and partial recanalization (modified Thrombolysis in Cerebral Infarction Scale score of 0/1–2a), whereas patients with complete recanalization (modified Thrombolysis in Cerebral Infarction Scale score of 3) with recanalization attempts ≤2 benefitted the most (modified Rankin Scale score of ≤3:42.3%, P =0.074) compared with best medical treatment. Conclusions: In daily clinical practice, EVT for CT–based selected patients with low Alberta Stroke Program Early CT Score anterior circulation stroke may not be beneficial and is associated with increased risk for hemorrhage and mortality, especially in the elderly. However, first- or second-pass complete recanalization seems to reveal a clinical benefit of EVT highlighting the vulnerability of the low Alberta Stroke Program Early CT Score subgroup. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03356392.

Background and Purpose— Stroke etiology drives thrombus composition. We thus hypothesized that endovascular treatment shows different efficacy in cardioembolic versus noncardioembolic large-vessel occlusions (LVOs). Methods— Procedural characteristics, grade of reperfusion, and functional outcome at discharge and 90 days were compared between patients with cardioembolic versus noncardioembolic LVO from the GSR-ET (German Stroke Registry–Endovascular Treatment; n=2589). To determine associations with functional outcome, adjusted odds ratios and 95% CIs were calculated using ordinal multivariable logistic regression models adjusting for potential baseline confounder variables. Results— Endovascular treatment of cardioembolic LVO had a higher rate of successful reperfusion (85.6% versus 81.0%; P =0.002) and a higher rate of complete reperfusion after a single thrombectomy pass (45.7% versus 38.1%; P Conclusions— These results provide evidence for higher efficacy of endovascular treatment in cardioembolic LVO compared with noncardioembolic LVO.

Background and Purpose— Endovascular treatment for large vessel occlusion in ischemic stroke has proven to be effective in large clinical trials. We aimed to provide real-world estimates of endovascular treatment reperfusion rates and functional outcome on a countrywide scale. Methods— Two thousand seven hundred ninety-four patients with large vessel occlusion were included into an investigator-initiated, industry-independent, prospective registry in 25 sites in Germany between June 2015 and April 2018. The primary outcome was the score on the modified Rankin Scale ranging from zero (no symptoms) to 6 (death) at 3 months. Secondary analyses included the prediction of a good outcome (modified Rankin Scale, 0–2). Dichotomized analyses of predictors were performed using logistic regression adjusted for potential confounders. Results— Median age was 75 years (interquartile range, 64–82); median National Institutes of Health Stroke Scale score was 15 (interquartile range, 10–19). Vessel occlusion was in the anterior circulation in 2265 patients (88%) and in the posterior circulation in 303 patients (12%). Intravenous alteplase before endovascular treatment was given in 1457 patients (56%). Successful reperfusion was achieved in 2143 subjects (83%). At 3 months, 854 patients (37%) showed a good outcome; mortality was 29%. There was no difference between anterior and posterior circulation occlusions ( P =0.27). Significant predictors for a good outcome were younger age (odds ratio [OR], 1.06; 95% CI, 1.05–1.07), no interhospital transfer (OR, 1.39; 95% CI, 1.03–1.88), lower stroke severity (OR, 1.10; 95% CI, 1.08–1.13), smaller infarct size (OR, 1.26; 95% CI, 1.15–1.39), alteplase use (OR, 1.49; 95% CI, 1.08–2.06), and reperfusion success (OR, 1.69; 95% CI, 1.45–1.96). Conclusions— High rates of favorable outcome can be achieved on a countrywide scale by endovascular treatment. Mortality appears to be greater in the daily routine than otherwise reported by authors of large randomized trials. There were no outcome differences between the anterior and posterior circulation. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT03356392.

Introduction: Endovascular thrombectomy(EVT) is considered standard of care for anterior circulation acute ischemic stroke(AIS) with large vessel occlusion(LVO). Young AIS-LVO patients have distinctly different underlying stroke mechanisms and etiologies. Methods: In this multicenter cohort study conducted from August 2014 to January 2020, we investigated the safety and effectiveness of EVT in young AIS-LVO patients aged≤50 years and evaluated associations between demographics, stroke etiology, neuroimaging factors and clinical outcomes, including functional outcomes, in-hospital mortality and symptomatic intracranial haemorrhage(sICH) in univariable and multivariable regression models. Results: 275 AIS-LVO patients from 10 tertiary centers in Germany, Sweden, Singapore and Taiwan were included. The more common TOAST subtypes included cardioembolism (82/275, 29.8%) and stroke of undetermined etiology (85/275, 30.9%). Arterial dissection was the most prevalent stroke etiology (42/195, 21.5%) and had the highest rate of good functional outcomes (29/42, 69.0%). Successful reperfusion was achieved in 85.1% (234/275). Excellent and good functional outcomes were achieved in 48.0% (132/275) and 66.0% (182/275) respectively. sICH occurred in 6.5% (18/275). National Institute of Health Stroke Scale (NIHSS) at presentation was inversely related with good functional outcomes (aOR0.92, 95% CI 0.88- 0.96 per point increase, p Conclusion: While differences in functional outcomes exist across varying stroke aetiologies, high rates of successful reperfusion and good outcomes are generally achieved in young AIS-LVO patients undergoing EVT.

Background and Purpose: Endovascular therapy is the standard of care in the treatment of acute ischemic stroke due to large-vessel occlusion. Often, more than one retrieval attempt is needed to achieve reperfusion. We aimed to quantify the influence of endovascular therapy on clinical outcome depending on the number of retrievals needed for successful reperfusion in a large multi-center cohort. Methods: For this observational cohort study, 2611 patients from the prospective German Stroke Registry included between June 2015 and April 2018 were analyzed. Patients who received endovascular therapy for acute anterior circulation stroke with known admission National Institutes of Health Stroke Scale score and Alberta Stroke Program Early CT Score, final Thrombolysis in Cerebral Infarction score, and number of retrievals were included. Successful reperfusion was defined as a Thrombolysis in Cerebral Infarction score of 2b or 3. The primary outcome was defined as functional independence (modified Rankin Scale score of 0–2) at day 90. Multivariate mixed-effects models were used to adjust for cluster effects of the participating centers and confounders. Results: The inclusion criteria were met by 1225 patients. The odds of good clinical outcome decreased with every retrieval attempt required for successful reperfusion: the first retrieval had the highest odds of good clinical outcome (adjusted odds ratio, 6.45 [95% CI, 4.0–10.4]), followed by the second attempt (adjusted odds ratio, 4.56 [95% CI, 2.7–7.7]), and finally the third (adjusted odds ratio, 3.16 [95% CI, 1.8–5.6]). Conclusions: Successful reperfusion within the first 3 retrieval attempts is associated with improved clinical outcome compared with patients without reperfusion. We conclude that at least 3 retrieval attempts should be performed in endovascular therapy of anterior circulation strokes. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03356392.

Background and Purpose— Emergent carotid artery stenting plus mechanical thrombectomy is an effective treatment for acute ischemic stroke patients with tandem occlusion of the anterior circulation. However, there is limited data supporting the safety of this approach in patients treated with prior intravenous thrombolysis (IVT). We aimed to investigate the safety of emergent carotid artery stenting-mechanical thrombectomy approach in stroke patient population treated with prior IVT. Methods— We assessed patients with acute ischemic stroke because of atherosclerotic tandem occlusion that were treated with emergent carotid artery stenting-mechanical thrombectomy approach from the multicenter observational Thrombectomy in Tandem Lesions registry. Patients were divided into 2 groups based on pretreatment IVT (IVT versus no-IVT). Intracerebral hemorrhages were classified according to the European Cooperative Acute Stroke Study II criteria. Results— Among 205 patients included in the present study, 125 (60%) received prior IVT. Time from symptoms onset-to-groin puncture was shorter (234±100 versus 256±234 minutes; P =0.002), and heparin use was less in the IVT group (14% versus 35%; P P =0.544), parenchymal hematoma type 1 to 2 (15% versus 18%; P =0.647), successful reperfusion (modified Thrombolysis in Cerebral Ischemia 2b–3), or 90-day favorable outcome (modified Rankin Scale score of 0–2 at 90 days). The 90-day all-cause mortality rate was significantly lower in the IVT group (8% versus 20%; P =0.017). After adjusting for covariates, IVT was not associated with symptomatic intracerebral hemorrhage or 90-day mortality. Conclusions— Emergent carotid artery stenting-mechanical thrombectomy approach was not associated with an increased risk of hemorrhagic complications in tandem occlusion patients who received IVT before the intervention.

Background and Purpose— Pretreatment lesion size on diffusion-weighted imaging (DWI) is a risk factor for symptomatic intracerebral hemorrhage (sICH) associated with thrombolytic treatment. Here, we investigated whether the Alberta Stroke Programme Early CT Score (ASPECTS) applied to DWI images (DWI-ASPECTS) predicts sICH risk accurately. Methods— In this retrospective multicenter study, prospectively collected data of 217 patients with anterior circulation stroke treated with intravenous or intraarterial thrombolysis within 6 hours after symptom onset were analyzed. Pretreatment DWI-ASPECTS scores were assessed by 2 independent investigators. For bleeding risk analysis, DWI-ASPECTS scores were either categorized into 0 to 7 (n=105) or 8 to 10 (n=112) or in 3 groups of similar sample size (DWI-ASPECTS 0 to 5 [n=69], 6 to 7 [n=70], and 8 to 10 [n=78]). Results— DWI-ASPECTS scores correlated well with the DWI lesion volume ( r =0.77, P P =0.004). sICH risk was 20.3%, 10%, and 2.6% in the 0 to 5, 6 to 7, and 8 to 10 DWI-ASPECTS groups, respectively. DWI-ASPECTS remained an independent prognostic factor for sICH after adjustment for clinical baseline variables (age, NIHSS, time to thrombolysis). Conclusions— DWI-ASPECTS predicts sICH risk after thrombolysis and may be helpful to contributing to quick sICH risk assessment before thrombolytic therapy.

Background and Purpose— Against the background of a relatively low rate of clinical events during carotid angioplasty and stenting (CAS) or carotid endarterectomy (CEA), diffusion-weighted imaging (DWI) is increasingly being used to compare the incidence of new ischemic lesions after both procedures. In addition, DWI may also provide a means of defining the role of different CAS techniques on this adverse outcome. Therefore, we performed a PubMed search and systematically analyzed all peer-reviewed studies published between January 1990 and June 2007 reporting on the occurrence of new DWI lesions after CAS or CEA. Summary of Review— In 32 studies comprising 1363 CAS and 754 CEA procedures, the incidence of any new DWI lesion was significantly higher after CAS (37%) than after CEA (10%) ( P P P P P Conclusions— New DWI lesions occur more frequently after CAS than after CEA. However, technical advances mainly in the field of endovascular therapy potentially reduce the incidence of these adverse ischemic events. In this scenario, DWI appears to be an ideal tool to compare and further improve both techniques.

Background and Purpose— The aim of the study was to evaluate whether leukoaraiosis (LA) is a risk factor for symptomatic intracerebral hemorrhage (sICH) in patients treated with thrombolysis for acute stroke. Methods— In this retrospective, multicenter analysis, we evaluated data from acute anterior circulation stroke patients (n=449; Results— The rate of sICH was significantly more frequent in patients with moderate to severe LA of the deep white matter (n=12 of 114; 10.5%) than in patients without relevant LA (n=13 of 335; 3.8%), corresponding to an odds ratio of 2.9 (95% CI, 1.29 to 6.59; P =0.015). In a logistic-regression analysis (including age, National Institutes of Health Stroke Scale score at presentation, and type of thrombolytic treatment), LA remained a significant independent risk factor (odds ratio, 2.9; P =0.03). Conclusions— LA of the deep white matter is an independent risk factor for sICH after thrombolytic treatment for acute stroke.

Background and Purpose— Diffusion-weighted imaging (DWI) may be a useful tool to evaluate the efficacy of cerebral protection devices in preventing thromboembolic complications during carotid angioplasty and stenting (CAS). The goals of this study were (1) to compare the frequency, number, and size of new DWI lesions after unprotected and protected CAS; and (2) to determine the clinical significance of these lesions. Methods— DWI was performed immediately before and within 48 hours after unprotected or protected CAS. Clinical outcome measures were stroke and death within 30 days. Results— The proportion of patients with any new ipsilateral DWI lesion (49% versus 67%; P P P Conclusions— The use of cerebral protection devices significantly reduces the incidence of new DWI lesions after CAS of which the majority are asymptomatic and less than 10 mm in diameter. The frequent occurrence of these lesions and their close correlation with the clinical outcome indicates that DWI could become a sensitive surrogate end point in future randomized trials of unprotected versus protected CAS.

Background and Purpose: —Delayed cell loss in neonates after cerebral hypoxic-ischemic injury (HII) is believed to be a major cause of cerebral palsy. In this study, we used radiolabeled annexin V, a marker of delayed cell loss (apoptosis), to image neonatal rabbits suffering from HII. Methods —Twenty-two neonatal New Zealand White rabbits had ligation of the right common carotid artery with reduction of inspired oxygen concentration to induce HII. Experimental animals (n=17) were exposed to hypoxia until an ipsilateral hemispheric decrease in the average diffusion coefficient occurred. After reversal of hypoxia and normalization of average diffusion coefficient values, experimental animals were injected with 99m Tc annexin V. Radionuclide images were recorded 2 hours later. Results —Experimental animals showed no MR evidence of blood-brain barrier breakdown or perfusion abnormalities after hypoxia. Annexin images demonstrated multifocal brain uptake in both hemispheres of experimental but not control animals. Histology of the brains from experimental animals demonstrated scattered pyknotic cortical and hippocampal neurons with cytoplasmic vacuolization of glial cells without evidence of apoptotic nuclei by terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL) staining. Double staining with markers of cell type and exogenous annexin V revealed that annexin V was localized in the cytoplasm of scattered neurons and astrocytes in experimental and, less commonly, control brains in the presence of an intact blood-brain barrier. Conclusions —Apoptosis may develop after HII even in brains that appear normal on diffusion-weighted and perfusion MR. These data suggest a role of radiolabeled annexin V screening of neonates at risk for the development of cerebral palsy.

Background and Purpose —Both early reperfusion and decompressive craniectomy have proved beneficial in the treatment of large space-occupying “malignant” hemispheric stroke. The aim of this study was to directly compare the benefit of reperfusion with that of craniectomy and to study the effects of combined treatment in a rat model of focal cerebral ischemia. Methods —Cerebral ischemia was introduced in 28 rats. Four groups were investigated: (1) no treatment, (2) decompressive craniectomy, (3) reperfusion, and (4) reperfusion and craniectomy as treatment at 1 hour after middle cerebral artery occlusion. Perfusion- and diffusion-weighted MRI were performed serially from 0.5 to 6 hours after middle cerebral artery occlusion. Results —The 6-hour DWI-derived hemispheric lesion volumes in the reperfusion group (10.2±3.9%), the craniectomy group (23.0±6.4%), and the combination group (21.8±12.4) were significantly smaller than that in the control group (44.1±5.4%) ( P Conclusions —Early reperfusion and craniectomy were shown to be effective in decreasing infarction volume by improving cerebral perfusion. Reperfusion remains the best therapy in malignant hemispheric stroke. Combined treatment yields no additional benefit compared with single treatment, probably because of early blood-brain barrier breakdown.

Background and Purpose —Recently, noninvasive MRI methods have been developed that are now capable of detecting and mapping regional hemodynamic responses to various stress tests, which involve the use of vasoactive substances such as acetazolamide or inhalation of carbon dioxide. The aim of this study was to assess regional cerebral blood oxygenation changes during breath holding at 1.5 T. Methods —In 6 healthy volunteers, T2*-weighted gradient echo images were acquired for a total dynamic scanning time of 10 minutes during alternating periods of breath holding and normal breathing at 40-second intervals after inspiration, at 30-second intervals after expiration, and at 18 seconds after expiration. To quantify the relative signal changes, 2.5-minute baseline image sampling with normal breathing was carried out. Results —Repeated challenges of breath holding of various durations induced an overall rise in blood oxygen level–dependent (BOLD) signal intensities. In general, BOLD signal intensity increases were greatest in gray matter and nonsignificant in white matter. Depending on the breath-holding duration and techniques, BOLD signal intensity increases of all activated pixels varied from 0.8% to 3.5%. Conclusions —The present study demonstrates that cerebral blood oxygenation changes during breath holding can be detected by means of fMRI at 1.5 T. The breath-holding test, a short and noninvasive method to study cerebral hemodynamics with fMRI, could become a useful alternative to the acetazolamide or CO 2 test.

Background and Purpose —During the past decade, transcranial Doppler sonography has widely been used to assess blood flow velocities in the basal intracranial arteries and cerebrovascular reactivity (CR) to various stimuli. Although numerous studies have shown a decline of cerebral blood flow velocity with age, the age dependency of CR, including cerebrovascular CO 2 reactivity, however, is controversial. Recently, we have reported a significant sex-related difference in CR, stressing the need to study the relation between normal aging and CR in both sexes separately. Methods —By means of transcranial Doppler sonography, CR was determined in 100 healthy, nonsmoking volunteers (age 20 to 70 years, 10 men and 10 women per decade). Results —In men, no change of CR with increasing age could be observed ( P =0.98). In contrast, CR in women declined significantly, with a step decrease from the 4th to the 5th decades (F=4.413; P P P Conclusions —There are no changes of CR during normal aging in men, whereas CR declines significantly from the 4th to the 5th decades in women. HRT in postmenopausal women appears to enhance CR.

Background and Purpose Cerebrovascular CO 2 reactivity can be assessed easily and reliably by transcranial Doppler sonography. The objectives of the present study were to evaluate sex differences in cerebral CO 2 reactivity and to specify the relation between CO 2 and cerebral blood flow velocity. Methods CO 2 reactivity of the circulation of both middle cerebral arteries was measured by bilateral transcranial Doppler sonography in 60 healthy volunteers (30 men, 30 women) aged 21 to 58 years. End-tidal carbon dioxide tensions (P etco 2 ) were elevated with the use of carbogene gas (95% O 2 , 5% CO 2 ). In each subject the mean blood flow velocity (V mean ) was plotted as a function of P etco 2 . Results The best-fit curves for the relation of V mean /P etco 2 were exponential functions, with the following basic equation: V mean (cm/s)= a e bx , where a is a theoretical quantity representing V mean at a P co 2 of 0 mm Hg, b is the relative slope of the curve (slope divided by the value of the function) corresponding to the definition of reactivity, and x is the P etco 2 (mm Hg). The mean value of b was 0.037±0.008 in women and 0.030±0.010 in men. ANOVA demonstrated a significant difference between men and women ( P Conclusions This study demonstrates a highly significant sex-related difference in CO 2 -induced cerebral vasomotor reactivity. The relation between altered carbon dioxide tensions and blood flow velocities of both middle cerebral arteries in 60 healthy volunteers was found to be exponential.

Background and Purpose— Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; ClinicalTrials.gov Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke. Methods— This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40 000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for. Results— Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 ( P =0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (n=42 of 256) in the EPO and 9.0% (n=24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; P =0.01) without any particular mechanism of death unexpected after stroke. Conclusions— Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.

Response: We appreciate the comments of Trinquart and Touze regarding our recently published article in which we summarized the immediate and long-term outcomes as well as the durability of intracranial stenting based on a systematic review of the literature.1 The authors criticize the statistical methods used to analyze the results. We perfectly agree with our colleagues that proper meta-analyses require procedures such as weighting, testing for heterogeneity as well as using random-effects or fixed-effects models. Today, these apparently complicated statistical procedures can easily be performed using widely available statistical software. In fact, we have used these methods extensively in previous own analyses.2 Although it is beyond doubt that meta-analyses are useful to guide our clinical decisions, it is more than questionable if the current …

Background and Purpose— Angioplasty and stenting is increasingly being used for the treatment of intracranial stenoses. Based on a literature search (01/1998 to 04/2008) we sought to determine the immediate and long-term outcomes, as well as the durability of this procedure. Summary of Review— We identified 31 studies dealing with 1177 procedures, which had mainly been performed in patients with a symptomatic (98%) intracranial high-grade stenosis (mean: 78±7%) at high technical success rates (median: 96%; interquartile range [IQR]: 90% to 100%). The periprocedural minor or major stroke and death rates ranged from 0% to 50% with a median of 7.7% (IQR: 4.4% to 14.3%). Periprocedural complications were significantly higher in the posterior versus the anterior circulation (12.1%, versus 6.6%, P P =0.47, OR: 1.15, CI:0.76 to 2.05). Restenosis >50% occurred more frequently after the use of a self-expandable stent (16/92; 17.4%, mean follow-up time: 5.4 months) than a balloon-mounted stent (61/443; 13.8%, mean follow-up time: 8.7 months; P Conclusions— Although intracranial stenting appears to be feasible, adverse events vary widely. Against the background of the results of this review yielding a high rate of restenoses and no clear impact of new stent devices on outcome, the widespread application of intracranial stenting outside the setting of randomized trials and in inexperienced centers currently does not seem to be justified.

Response: We thank Dr Zheng and colleagues for their interest in our recent review article and the author’s important remarks considering search strategies in meta-analyses. One main point of concern is the sole use of the Medline database for our literature search. In order to reach comprehensiveness of meta-analyses, Zheng et al strongly suggest the use of multiple databases, as well as the inclusion of “gray” literature such as dissertations. In this scenario, it would …

To the Editor: We examined the article by Schillinger et al,1 in which the authors describe the results of a multicenter registry investigating the potential effect of open- versus closed-cell design stents on periprocedural complications after carotid artery stenting (CAS). In contrast to a previously published study,2 they found no association between stent design and the 30-day combined rate of transient ischemic attack, stroke and death. Aside from the stent design (ie, open-cell versus closed-cell) the length of the stent might be an additional factor associated with outcome after CAS. While the length of a stenosis has already been identified as a …

Response: We thank Dr Cohen for his interest in our study and for his questions aiming at clarifying our data. Postprocedure strokes were considered minor if they increased the NIHSS by ≤3 at the end of 30 days. Justly, Dr Cohen raises the concern that clinically silent diffusion-weighted imaging lesions after carotid angioplasty and stenting (CAS) might have an impact on cognitive functions, which unquestionably deserves to be tested in large studies. On the other hand, current data from small studies indicate neither that CAS carries a high risk of cognitive decline nor that there is a clear association between the incidence of new diffusion-weighted imaging lesions and cognitive parameters. In fact, the effects of CEA and carotid PTA …