Perfusion Changes in Acute Stroke Treated with Theophylline as an Add-on to Thrombolysis:A Randomized Clinical Trial Subgroup Analysis

PURPOSE: Theophylline has been suggested to have a neuroprotective effect in ischemic stroke; however, results from animal stroke models and clinical trials in humans are controversial. The aim of this study was to assess the effect of theophylline on the cerebral perfusion with multiparametric magnetic resonance imaging (MRI). METHODS: The relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative mean transit time (rMTT) in the infarct core, penumbra, and unaffected tissue were measured using multi-parametric MRI at baseline and 3‑h follow-up in patients treated with theophylline or placebo as an add-on to thrombolytic therapy. RESULTS: No significant differences in mean rCBF, rCBV, and rMTT was found in the penumbra and unaffected tissue between the theophylline group and the control group between baseline and 3‑h follow-up. In the infarct core, mean rCBV increased on average by 0.05 in the theophylline group and decreased by 0.14 in the control group (p < 0.04). Mean rCBF and mean rMTT in the infarct core were similar between the two treatment groups. CONCLUSION: The results indicate that theophylline does not change the perfusion in potentially salvageable penumbral tissue but only affects the rCBV in the infarct core. In contrast to the penumbra, the infarct core is unlikely to be salvageable, which might explain why theophylline failed in clinical trials. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s00062-021-01029-x) contains supplementary material, which is available to authorized users

Stroke with unknown time of symptom onset: baseline clinical and magnetic resonance imaging data of the first thousand patients in WAKE-UP (efficacy and safety of mri-based thrombolysis in wake-up stroke: a randomized, doubleblind, placebo-controlled trial)

Background and Purpose—We describe clinical and magnetic resonance imaging (MRI) characteristics of stroke patients with unknown time of symptom onset potentially eligible for thrombolysis from a large prospective cohort. Methods—We analyzed baseline data from WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial), an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. MRI judgment included assessment of the mismatch between visibility of the acute ischemic lesion on diffusion-weighted imaging and fluid-attenuated inversion recovery. Results—Of 1005 patients included, diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was present in 479 patients (48.0%). Patients with daytime-unwitnessed stroke (n=138, 13.7%) had a shorter delay between symptom recognition and hospital arrival (1.5 versus 1.8 hours; P=0.002), a higher National Institutes of Stroke Scale score on admission (8 versus 6; P&lt;0.001), and more often aphasia (72.5% versus 34.0%; P&lt;0.001) when compared with stroke patients waking up from nighttime sleep. Frequency of diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was comparable between both groups (43.7% versus 48.7%; P=0.30). Conclusions—Almost half of the patients with unknown time of symptom onset stroke otherwise eligible for thrombolysis had MRI findings making them likely to be within a time window for safe and effective thrombolysis. Patients with daytime onset unwitnessed stroke differ from wake-up stroke patients with regards to clinical characteristics but are comparable in terms of MRI characteristics of lesion age. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01525290. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-005906-32

Clinical characteristics of unknown symptom onset stroke patients with and without diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch

Background: Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) mismatch was suggested to identify stroke patients with unknown time of symptom onset likely to be within the time window for thrombolysis. Aims: We aimed to study clinical characteristics associated with DWI-FLAIR mismatch in patients with unknown onset stroke. Methods: We analyzed baseline MRI and clinical data from patients with acute ischemic stroke proven by DWI from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. Clinical characteristics were compared between patients with and without DWI-FLAIR mismatch. Results: Of 699 patients included, 418 (59.8%) presented with DWI-FLAIR mismatch. A shorter delay between last seen well and symptom recognition (p = 0.0063), a shorter delay between symptom recognition and arrival at hospital (p = 0.0025), and history of atrial fibrillation (p = 0.19) were predictors of DWI-FLAIR mismatch in multivariate analysis. All other characteristics were comparable between groups. Conclusions: There are only minor differences in measured clinical characteristics between unknown symptom onset stroke patients with and without DWI-FLAIR mismatch. DWI-FLAIR mismatch as an indicator of stroke onset within 4.5 h shows no relevant association with commonly collected clinical characteristics of stroke patients

Effect of informed consent on patient characteristics in a stroke thrombolysis trial

Objective: To determine whether the manner of consent, i.e., informed consent by patients themselves or informed consent by proxy, affects clinical characteristics of samples of acute stroke patients enrolled in clinical trials. Methods: We analyzed the manner of obtaining informed consent in the first 1,005 patients from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset running in 6 European countries. Patients providing informed consent by themselves were compared with patients enrolled by proxy consent. Baseline clinical measures were compared between groups. Results: In 359 (35.7%) patients, informed consent was by proxy. Patients with proxy consent were older (median 71 vs 66 years, p &lt; 0.0001) and had a higher frequency of arterial hypertension (58.2% vs 43.4%, p &lt; 0.0001). They showed higher scores on the NIH Stroke Scale (median 11 vs 5, p &lt; 0.0001) and more frequently aphasia (73.7% vs 20.0%, p &lt; 0.0001). The rate of proxy consent varied among countries (p &lt; 0.0001), ranging from 77.1% in Spain to 1.2% in Denmark. Conclusions: Patients recruited by proxy consent were older, had more severe strokes, and had higher prevalence of aphasia than those with capacity to give personal consent. Variations in the manner of consent across countries may influence trial results. Clinicaltrials.gov and Clinicaltrialsregister.eu identifiers: NCT01525290 (clinicaltrials.gov); 2011-005906-32 (clinicaltrialsregister.eu)

Stroke Lesion Segmentation in FLAIR MRI Datasets Using Customized Markov Random Fields

Robust and reliable stroke lesion segmentation is a crucial step toward employing lesion volume as an independent endpoint for randomized trials. The aim of this work was to develop and evaluate a novel method to segment sub-acute ischemic stroke lesions from fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) datasets. After preprocessing of the datasets, a Bayesian technique based on Gabor textures extracted from the FLAIR signal intensities is utilized to generate a first estimate of the lesion segmentation. Using this initial segmentation, a customized voxel-level Markov random field model based on intensity as well as Gabor texture features is employed to refine the stroke lesion segmentation. The proposed method was developed and evaluated based on 151 multi-center datasets from three different databases using a leave-one-patient-out validation approach. The comparison of the automatically segmented stroke lesions with manual ground truth segmentation revealed an average Dice coefficient of 0.582, which is in the upper range of previously presented lesion segmentation methods using multi-modal MRI datasets. Furthermore, the results obtained by the proposed technique are superior compared to the results obtained by two methods based on convolutional neural networks and three phase level-sets, respectively, which performed best in the ISLES 2015 challenge using multi-modal imaging datasets. The results of the quantitative evaluation suggest that the proposed method leads to robust lesion segmentation results using FLAIR MRI datasets only as a follow-up sequence

Clinical and Imaging Characteristics in Patients with SARS-CoV-2 Infection and Acute Intracranial Hemorrhage

Background and purpose: Intracranial hemorrhage has been observed in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19), but the clinical, imaging, and pathophysiological features of intracranial bleeding during COVID-19 infection remain poorly characterized. This study describes clinical and imaging characteristics of patients with COVID-19 infection who presented with intracranial bleeding in a European multicenter cohort. Methods: This is a multicenter retrospective, observational case series including 18 consecutive patients with COVID-19 infection and intracranial hemorrhage. Data were collected from February to May 2020 at five designated European special care centers for COVID-19. The diagnosis of COVID-19 was based on laboratory-confirmed diagnosis of SARS-CoV-2. Intracranial bleeding was diagnosed on computed tomography (CT) of the brain within one month of the date of COVID-19 diagnosis. The clinical, laboratory, radiologic, and pathologic findings, therapy and outcomes in COVID-19 patients presenting with intracranial bleeding were analyzed. Results: Eighteen patients had evidence of acute intracranial bleeding within 11 days (IQR 9-29) of admission. Six patients had parenchymal hemorrhage (33.3%), 11 had subarachnoid hemorrhage (SAH) (61.1%), and one patient had subdural hemorrhage (5.6%). Three patients presented with intraventricular hemorrhage (IVH) (16.7%). Conclusion: This study represents the largest case series of patients with intracranial hemorrhage diagnosed with COVID-19 based on key European countries with geospatial hotspots of SARS-CoV-2. Isolated SAH along the convexity may be a predominant bleeding manifestation and may occur in a late temporal course of severe COVID-19

A Prospective Multicenter Registry on Feasibility, Safety, and Outcome of Endovascular Recanalization in Childhood Stroke (Save ChildS Pro).

Rationale: Early evidence for the benefit of mechanical thrombectomy (MT) in pediatric patients with intracranial large vessel occlusion has been shown in previous retrospective cohorts. Higher-level evidence is needed to overcome the limitations of these studies such as the lack of a control group and the retrospective design. Randomized trials will very likely not be feasible, and several open questions remain, for example, the impact of arteriopathic etiologies or a possible lower age limit for MT. Save ChildS Pro therefore aims to demonstrate the safety and effectiveness of MT in pediatric patients compared to the best medical management and intravenous thrombolysis. Design: Save ChildS Pro is designed as a worldwide multicenter prospective registry comparing the safety and effectiveness of MT to the best medical care alone in the treatment of pediatric arterial ischemic stroke (AIS). It will include pediatric patients (<18 years) with symptomatic acute intracranial arterial occlusion who underwent either MT or best medical treatment including intravenous thrombolysis. Outcomes: The primary endpoint of Save ChildS Pro is the modified Rankin Scale score at 90 days post-stroke. Secondary endpoints will comprise the decrease of the Pediatric National Institutes of Health Stroke Scale score from admission to discharge and rate of complications. Discussion: Save ChildS Pro aims to provide high-level evidence for MT for pediatric patients with AIS, thereby improving functional outcome and quality of life and reducing the individual, societal, and economic burden of death and disability resulting from pediatric stroke. Clinical Trial Registration: Save ChildS Pro is registered at the German Clinical Trials Registry (DRKS; identifier: DRKS00018960)

Treatment Methods and Early Neurologic Improvement After Endovascular Treatment of Tandem Occlusions in Acute Ischemic Stroke

Background and Purpose: A tandem occlusion of the intracranial circulation and the extracranial carotid artery (ICA) occurs in 10–20% of all strokes based on large vessel occlusion (LVO). The optimal treatment strategy for those patients is unknown. We report our management strategy and the outcome in these patients in a large single-center cohort.Materials and Methods: We retrospectively identified and analyzed all patients treated by Mechanical Thrombectomy (MT) for an intracranial LVO associated with an occlusion of the extracranial ICA between April 2009 and May 2016 (163/1,645, 9.9%). The following data was collected: Recanalization rate, occurrence of symptomatic intracranial hemorrhage (sICH), clinical result according to the early neurological improvement (ENI, NIHSS score improvement of ≥8 points after 24 h or NIHSS score of 0 or 1 after 3 days) and functional outcome and mortality during long term follow up. Secondary endpoints were the patency of the internal carotid artery at 24 h. Patient demographics and anti-aggregation regimen were recorded as co-variables.Results: 163/1,645 (9.9%) MT patients had a tandem occlusion. All thrombectomy procedures were performed with stent retrievers. PTA with or without additional placement of a stent was performed in 149 vs. 14 patients. The overall rate of TICI IIB/III recanalization was 91.4%. An early neurological improvement was found in 79 of 163 patients (48.4%), 51% (76/149) in the stent group and 21% (3/14) in the non stent group. 120/163 patients (73.6%) had a long term favorable outcome (mRS 0–2). The ICA re-occlusion rate at 24 h was 5.4% (8/149) in the stent group and 42% (6/14) in the non stent group. The rate of symptomatic hemorrhage was 4.9%.The regression analysis showed that only younger age (p = 0.002) and shorter recanalization times (p = 0.017) were associated with good outcome.Conclusion: Stent-PTA of the ICA in addition to MT with a stent retriever was safe and effective in tandem occlusion of the anterior brain circulation. PTA and MT without stenting in tandem lesions showed a higher early re-occlusion rate and lower rate of early neurological improvement. The technical approach should aim for the fastest possible recanalization of the intracranial vessels, either with stenting first or last

Major central nervous system complications after allogeneic stem cell transplantation: A large retrospective study on 888 consecutive adult patients.

AbstractObjectivesMajor complications affecting the central nervous system (CNS) present a challenge after allogeneic stem cell transplantation (allo‐SCT).MethodsIncidence, risk factors, and outcome were retrospectively analyzed in 888 patients in a monocentric study.ResultsCumulative incidence (CI) of major CNS complications at 1 year was 14.8% (95%CI 12.3%‐17.2%). Median follow‐up is 11 months. CNS complications were documented in 132 patients: in 36 cases, classified metabolic; 26, drug‐related neurotoxicity (14 attributed to cyclosporine A, 4 to antilymphocyte globulin); 11, cerebrovascular (ischemic n = 8, bleeding n = 3); 9, infections; 9, psychiatric; and 9, malignant. The cause of CNS symptoms remained unclear for 37 patients (28%). Multivariate analysis demonstrated an association of CNS complication with patient age (P < .001). The estimated OS of patients with any CNS complication was significantly lower than in patients without neurological complications (P < .001), and the CI of non‐relapse mortality (NRM) was higher for patients with CNS complication (P < .001). A significant negative impact on survival can only be demonstrated for metabolic CNS complications and CNS infections (NRM, P < .0001 and P = .0003, respectively), and relapse (P < .0001).ConclusionCNS complications after allo‐SCT are frequent events with a major contribution to morbidity and mortality. In particular, the situations of unclear neurological complications need to be clarified by intensive research