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  • Boutitie, Florent  (16)
  • Lemmens, Robin  (16)
  • Wouters, Anke  (16)
  • 1
    Online Resource
    Online Resource
    Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data
    Elsevier BV ; 2020
    In:  The Lancet Vol. 396, No. 10262 ( 2020-11), p. 1574-1584
    Details
    In: The Lancet, Elsevier BV, Vol. 396, No. 10262 ( 2020-11), p. 1574-1584
    Type of Medium: Online Resource
    ISSN: 0140-6736
    URL: Article
    DOI: 10.1016/S0140-6736(20)32163-2
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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    SSG: 5,21
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  • 2
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    Diffusion-Weighted Imaging and Fluid-Attenuated Inversion Recovery Quantification to Predict Diffusion-Weighted Imaging-Fluid-Attenuated Inversion Recovery Mismatch Status in Ischemic Stroke With Unknown Onset
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Stroke Vol. 53, No. 5 ( 2022-05), p. 1665-1673
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 53, No. 5 ( 2022-05), p. 1665-1673
    Abstract: Visual rating of diffusion-weighted imaging (DWI)–fluid-attenuated inversion recovery (FLAIR) mismatch can be challenging. We evaluated quantification of DWI and FLAIR to predict DWI-FLAIR mismatch status in ischemic stroke. Methods: In screened patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-Up Stroke), we retrospectively studied relative DWI (rDWI SI) and FLAIR signal intensity (rFLAIR SI). We defined the optimal mean rFLAIR SI and interquartile range of the rDWI SI in the DWI lesion to predict DWI-FLAIR mismatch status. We investigated agreement between each quantitative parameter and the DWI-FLAIR mismatch and the association between both quantitative parameters. We evaluated the predictive value of the quantitative parameters for excellent functional outcome by logistic regression, adjusted for DWI lesion volume, treatment, age, and National Institutes of Health Stroke Scale score. Results: In the rFLAIR and rDWI SI analysis, 213/369 and 241/421 subjects respectively had a DWI-FLAIR mismatch. A mean rFLAIR SI cutoff of 1.09 and interquartile range rDWI SI cutoff of 0.47 were optimal to predict the DWI-FLAIR mismatch with a sensitivity and specificity of 77% (95% CI, 71%–83%) and 67% (95% CI, 59%–74%), and 76% (95% CI, 70%–81%) and 72% (95% CI, 65%–79%), respectively. For both quantitative parameters, agreement with the DWI-FLAIR mismatch was fair (73%, κ=0.44 [95% CI, 0.35–0.54] for rFLAIR and 74%, κ=0.48 [95% CI, 0.39–0.56] for rDWI). Both quantitative parameters correlated moderately (Pearson R=0.54 [95% CI, 0.46–0.61]; P 〈 0.001, n=367). The interquartile range rDWI SI (n=188), but not the mean rFLAIR SI (n=172), was an independent predictor of excellent functional outcome (odds ratio, 0.67 per 0.1 unit increase of interquartile range rDWI SI, 95% CI, 0.51–0.89, P =0.01). Conclusions: Agreement between the quantitative and qualitative approach may be insufficient to advocate DWI or FLAIR quantification as alternative for visual rating.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.121.036871
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467823-8
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  • 3
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    Quantitative Signal Intensity in Fluid-Attenuated Inversion Recovery and Treatment Effect in the WAKE-UP Trial
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Stroke Vol. 51, No. 1 ( 2020-01), p. 209-215
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. 1 ( 2020-01), p. 209-215
    Abstract: Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (fluid-attenuated inversion recovery relative signal intensity [FLAIR-rSI]) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke Trial), intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of diffusion weighted imaging fluid-attenuated inversion recovery mismatch, that is, in those with no marked fluid-attenuated inversion recovery hyperintensity in the region of the acute diffusion weighted imaging lesion. In this post hoc analysis, we investigated whether quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods— FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analyzed by binary logistic regression using different end points, that is, favorable outcome defined as mRS score of 0 to 1, independent outcome defined as mRS score of 0 to 2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for National Institutes of Health Stroke Scale at symptom onset and stroke lesion volume. Results— FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD, 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS score of 0 to 1 ( P =0.169) and shift analysis ( P =0.086) but reached significance for mRS score of 0 to 2 ( P =0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical end points with increasing FLAIR-rSI. Conclusions— In patients in whom no marked parenchymal fluid-attenuated inversion recovery hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of diffusion weighted imaging lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.119.027390
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 4
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    Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Stroke Vol. 52, No. 7 ( 2021-07), p. 2338-2346
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 52, No. 7 ( 2021-07), p. 2338-2346
    Abstract: We aimed to investigate fluid-attenuated inversion recovery changes in the penumbra. Methods: We determined core and perfusion lesions in subjects from the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke) and AXIS 2 trial (Granulocyte Colony-Stimulating Factor in Patients With Acute Ischemic Stroke) with perfusion- and diffusion-weighted imaging at baseline. Only subjects with a mismatch volume 〉 15 mL and ratio 〉 1.2 were included. We created voxel-based relative fluid-attenuated inversion recovery signal intensity (rFLAIR SI) maps at baseline and follow-up. We studied rFLAIR SI in 2 regions of interest: baseline penumbra (baseline perfusion lesion−[core lesion+voxels with apparent diffusion coefficient 〈 620 10 −6 mm 2 /s]) and noninfarcted penumbra (baseline perfusion lesion−follow-up fluid-attenuated inversion recovery lesion) at 24 hours (WAKE-UP) or 30 days (AXIS 2). We analyzed the association between rFLAIR SI and severity of hypoperfusion, defined as time to maximum of the residue function. Results: In the baseline penumbra, rFLAIR SI was elevated (ratio, 1.04; P =1.7×10 − 13 ; n=126) and correlated with severity of hypoperfusion (Pearson r, 0.03; P 〈 1.0×10 − 4 ; n=126). In WAKE-UP, imaging at 24 hours revealed a further increase of rFLAIR SI in the noninfarcted penumbra (ratio, 1.05 at 24 hours versus 1.03 at baseline; P =7.1×10 −3 ; n=43). In AXIS 2, imaging at 30 days identified reversibility of the rFLAIR SI (ratio, 1.02 at 30 days versus 1.04 at baseline; P =1.5×10 −3 ; n=26) since it was no longer different from 1 (ratio, 1.01 at 30 days; P =0.099; n=26). Conclusions: Penumbral rFLAIR SI increases appear early after stroke onset, correlate with severity of hypoperfusion, further increase at 24 hours, and are reversible by 30 days. Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT01525290. URL: https://clinicaltrials.gov ; Unique identifier: NCT00927836.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.120.033071
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 5
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    Hyperintense acute reperfusion marker associated with hemorrhagic transformation in the WAKE-UP trial
    SAGE Publications ; 2021
    In:  European Stroke Journal Vol. 6, No. 2 ( 2021-06), p. 128-133
    Details
    In: European Stroke Journal, SAGE Publications, Vol. 6, No. 2 ( 2021-06), p. 128-133
    Abstract: Hyperintense acute reperfusion marker (HARM) is an indicator of early disruption of the blood-brain-barrier. Our aim was to investigate the incidence of HARM in patients with a diffusion weighted imaging (DWI) - fluid attenuated inversion recovery (FLAIR) mismatch and determine the association between this marker and hemorrhagic complications as well as clinical outcome. Patients and Methods We included patients from the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial who underwent baseline perfusion weighted imaging (PWI). HARM was defined as a hyperintense signal in the cerebrospinal fluid space on FLAIR imaging at 24 h after baseline imaging. We compared baseline characteristics in patients with and without HARM and investigated the association between HARM and any hemorrhagic transformation (HT) and parenchymal hematoma (PH) in a multivariate logistic regression. We also explored HARM as an independent predictor of poor outcome, defined as a modified Rankin Scale of 3–6 at 90 days. Results HARM was present in 14 of 223 (6%) patients with a DWI-FLAIR mismatch and baseline characteristics were similar in patients with vs without HARM. HARM showed an independent relationship with any HT (OR 6.67; 95%CI 1.72–26.58) and any PH (OR 6.92; 95%CI 1.34–29.49). The rate of HARM was similar in patients with good and poor outcome (5%, p = 0.90). Conclusion In the WAKE-UP trial, the incidence of HARM was only 6% at 24 h. An association was present between HARM and hemorrhagic complications, but no relationship with functional outcome was observed.
    Type of Medium: Online Resource
    ISSN: 2396-9873 , 2396-9881
    URL: Article
    DOI: 10.1177/23969873211007686
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
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  • 6
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    Estimating nocturnal stroke onset times by magnetic resonance imaging in the WAKE-UP trial
    SAGE Publications ; 2022
    In:  International Journal of Stroke Vol. 17, No. 3 ( 2022-03), p. 323-330
    Details
    In: International Journal of Stroke, SAGE Publications, Vol. 17, No. 3 ( 2022-03), p. 323-330
    Abstract: Fluid-attenuated inversion recovery (FLAIR) sequences have gained a role to guide treatment of patients with unknown time of stroke symptom onset. Evolution of signal intensities in FLAIR is associated with time since stroke onset with continuous linear increases. Aims Estimating symptom onset during night-sleep in patients from the WAKE-UP trial based on relative signal intensities FLAIR (FLAIR-rSI) from acute stroke lesions an independent dataset (PRE-FLAIR study). Methods FLAIR-rSI was quantified in stroke lesions in PRE-FLAIR and WAKE-UP. The PRE-FLAIR study was a multicenter observational trial establishing FLAIR as a surrogate parameter for time since stroke onset. WAKE-UP was a randomized controlled trial that revealed a benefit for alteplase in patients selected based on a DWI-FLAIR mismatch. Stroke onset times were recorded in PRE-FLAIR and used to fit a linear regression model with FLAIR-rSI, adjusted for patient age and lesion volume. The model was applied to FLAIR-rSI of stroke lesions to estimate onset times in those patients enrolled in WAKE-UP who had symptom onset during night-sleep. Results FLAIR-rSI was quantified in 399 patients from PRE-FLAIR. Linear regression indicated a significant association of age ( p = 0.001), lesion volume ( p = 0.005) and FLAIR-rSI ( p  〈  0.001) with time since symptom onset (adjusted R 2  = 0.179). In 813 patients from WAKE-UP, distribution of times of last seen well, symptom recognition and MRI examination were recorded. Median times of last seen well were 1 h before midnight (IQR 2.4 h) and symptom recognition 7 h after midnight (IRQ 2.2 h). Based on the FLAIR-rSI profiles, we estimated median stroke onset 6.1 h after midnight (IQR 2.7 h). Conclusion Nocturnal strokes during night-sleep may predominantly occur during the early morning hours. Our results are in line with evidence of characteristic diurnal patterns of cardiovascular events.
    Type of Medium: Online Resource
    ISSN: 1747-4930 , 1747-4949
    URL: Article
    DOI: 10.1177/17474930211059608
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
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  • 7
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    Early effect of thrombolysis on structural brain network organisation after anterior‐circulation stroke in the randomized WAKE‐UP trial
    Wiley ; 2022
    In:  Human Brain Mapping Vol. 43, No. 16 ( 2022-11), p. 5053-5065
    Details
    In: Human Brain Mapping, Wiley, Vol. 43, No. 16 ( 2022-11), p. 5053-5065
    Abstract: The symptoms of acute ischemic stroke can be attributed to disruption of the brain network architecture. Systemic thrombolysis is an effective treatment that preserves structural connectivity in the first days after the event. Its effect on the evolution of global network organisation is, however, not well understood. We present a secondary analysis of 269 patients from the randomized WAKE‐UP trial, comparing 127 imaging‐selected patients treated with alteplase with 142 controls who received placebo. We used indirect network mapping to quantify the impact of ischemic lesions on structural brain network organisation in terms of both global parameters of segregation and integration, and local disruption of individual connections. Network damage was estimated before randomization and again 22 to 36 h after administration of either alteplase or placebo. Evolution of structural network organisation was characterised by a loss in integration and gain in segregation, and this trajectory was attenuated by the administration of alteplase. Preserved brain network organization was associated with excellent functional outcome. Furthermore, the protective effect of alteplase was spatio‐topologically nonuniform, concentrating on a subnetwork of high centrality supported in the salvageable white matter surrounding the ischemic cores. This interplay between the location of the lesion, the pathophysiology of the ischemic penumbra, and the spatial embedding of the brain network explains the observed potential of thrombolysis to attenuate topological network damage early after stroke. Our findings might, in the future, lead to new brain network‐informed imaging biomarkers and improved prognostication in ischemic stroke.
    Type of Medium: Online Resource
    ISSN: 1065-9471 , 1097-0193
    URL: Issue
    URL: Article
    DOI: 10.1002/hbm.v43.16
    DOI: 10.1002/hbm.26073
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 8
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    Different Mismatch Concepts for Magnetic Resonance Imaging–Guided Thrombolysis in Unknown Onset Stroke
    Wiley ; 2020
    In:  Annals of Neurology Vol. 87, No. 6 ( 2020-06), p. 931-938
    Details
    In: Annals of Neurology, Wiley, Vol. 87, No. 6 ( 2020-06), p. 931-938
    Abstract: To explore the prevalence of the perfusion‐weighted imaging (PWI)–diffusion‐weighted imaging (DWI) mismatch and response to intravenous thrombolysis in the WAKE‐UP trial. Methods We performed a prespecified post hoc analysis of ischemic stroke patients screened for DWI–fluid‐attenuated inversion recovery (FLAIR) mismatch in WAKE‐UP who underwent PWI. We defined PWI‐DWI mismatch as ischemic core volume  〈  70ml, mismatch volume  〉  10ml, and mismatch ratio  〉  1.2. Primary efficacy end point was a modified Rankin Scale score of 0–1 at 90 days, adjusted for age and symptom severity. Results Of 1,362 magnetic resonance imaging–screened patients, 431 underwent PWI. Of these, 57 (13%) had a double mismatch, 151 (35%) only a DWI‐FLAIR mismatch, and 54 (13%) only a PWI‐DWI mismatch. DWI‐FLAIR mismatch was more prevalent than PWI‐DWI mismatch (48%, 95% confidence interval [CI] = 43–53% vs 26%, 95% CI = 22–30%; p   〈  0.0001). Screening for either one of the mismatch profiles resulted in a yield of 61% (95% CI = 56–65%). Prevalence of PWI‐DWI mismatch was similar in patients with (27%) or without (24%) DWI‐FLAIR mismatch ( p = 0.52). In an exploratory analysis in the small subgroup of 208 randomized patients with PWI, PWI‐DWI mismatch status did not modify the treatment response ( p for interaction = 0.73). Interpretation Evaluating both the DWI‐FLAIR and PWI‐DWI mismatch patterns in patients with unknown time of stroke onset will result in the highest yield of thrombolysis treatment. The treatment benefit of alteplase in patients with a DWI‐FLAIR mismatch seems to be driven not merely by the presence of a PWI‐DWI mismatch, although this analysis was underpowered. ANN NEUROL 2020;87:931–938
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    URL: Article
    DOI: 10.1002/ana.v87.6
    DOI: 10.1002/ana.25730
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2037912-2
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  • 9
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    Safety and efficacy of intravenous thrombolysis in stroke patients on prior antiplatelet therapy in the WAKE-UP trial
    Springer Science and Business Media LLC ; 2020
    In:  Neurological Research and Practice Vol. 2, No. 1 ( 2020-12)
    Details
    In: Neurological Research and Practice, Springer Science and Business Media LLC, Vol. 2, No. 1 ( 2020-12)
    Abstract: One quarter to one third of patients eligible for systemic thrombolysis are on antiplatelet therapy at presentation. In this study, we aimed to assess the safety and efficacy of intravenous thrombolysis in stroke patients on prescribed antiplatelet therapy in the WAKE-UP trial. Methods WAKE-UP was a multicenter, randomized, double-blind, placebo-controlled clinical trial to study the efficacy and safety of MRI-guided intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time. The medication history of all patients randomized in the WAKE-UP trial was documented. The primary safety outcome was any sign of hemorrhagic transformation on follow-up MRI. The primary efficacy outcome was favorable functional outcome defined by a score of 0–1 on the modified Rankin scale at 90 days after stroke, adjusted for age and baseline stroke severity. Logistic regression models were fitted to study the association of prior antiplatelet treatment with outcome and treatment effect of intravenous alteplase. Results Of 503 randomized patients, 164 (32.6%) were on antiplatelet treatment. Patients on antiplatelet treatment were older (70.3 vs. 62.8 years, p   〈   0.001), and more frequently had a history of hypertension, atrial fibrillation, diabetes, hypercholesterolemia, and previous stroke or transient ischaemic attack. Rates of symptomatic intracranial hemorrhage and hemorrhagic transformation on follow-up imaging did not differ between patients with and without antiplatelet treatment. Patients on prior antiplatelet treatment were less likely to achieve a favorable outcome (37.3% vs. 52.6%, p  = 0.014), but there was no interaction of prior antiplatelet treatment with intravenous alteplase concerning favorable outcome ( p  = 0.355). Intravenous alteplase was associated with higher rates of favorable outcome in patients on prior antiplatelet treatment with an adjusted odds ratio of 2.106 (95% CI 1.047–4.236). Conclusions Treatment benefit of intravenous alteplase and rates of post-treatment hemorrhagic transformation were not modified by prior antiplatelet intake among MRI-selected patients with unknown onset stroke. Worse functional outcome in patients on antiplatelets may result from a higher load of cardiovascular co-morbidities in these patients.
    Type of Medium: Online Resource
    ISSN: 2524-3489
    URL: Article
    DOI: 10.1186/s42466-020-00087-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 10
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    Preserved structural connectivity mediates the clinical effect of thrombolysis in patients with anterior-circulation stroke
    Springer Science and Business Media LLC ; 2021
    In:  Nature Communications Vol. 12, No. 1 ( 2021-05-10)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-05-10)
    Abstract: Thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke aims to restore compromised blood flow and prevent further neuronal damage. Despite the proven clinical efficacy of this treatment, little is known about the short-term effects of systemic thrombolysis on structural brain connectivity. In this secondary analysis of the WAKE-UP trial, we used MRI-derived measures of infarct size and estimated structural network disruption to establish that thrombolysis is associated not only with less infarct growth, but also with reduced loss of large-scale connectivity between grey-matter areas after stroke. In a causal mediation analysis, infarct growth mediated a non-significant 8.3% (CI 95% [−8.0, 32.6]%) of the clinical effect of thrombolysis on functional outcome. The proportion mediated jointly through infarct growth and change of structural connectivity, especially in the border zone around the infarct core, however, was as high as 33.4% (CI 95% [8.8, 77.4]%). Preservation of structural connectivity is thus an important determinant of treatment success and favourable functional outcome in addition to lesion volume. It might, in the future, serve as an imaging endpoint in clinical trials or as a target for therapeutic interventions.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-021-22786-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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