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Dear Sirs,
Cerebral microbleeds (CMB), detected as hypointense foci on blood-sensitive magnet resonance imaging (MRI), are a marker of cerebral small vessel disease [1]. Neuropathological examinations revealed that a subset of CMBs contain intact erythrocytes, indicating recent microhemorrhage [1]. In a prior observational study, new CMBs occurred in 4% of acute ischemic stroke (AIS) patients after receiving intravenous thrombolysis (IVT) with alteplase. New CMBs were associated with an increased risk for post-IVT intracerebral hemorrhage [2].
Here, we took the unique opportunity to assess the risk of IVT for the occurrence of new CMBs in AIS patients who had been randomly assigned to either alteplase (0.9 mg/kg) or placebo within the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke, ClinicalTrials.gov: NCT01525290)[3].
Eligible patients for this exploratory analysis had received two cerebral MRI examinations—one before and one after treatment (alteplase or placebo)—with the same field strength (i.e., 1.5 Tesla or 3 Tesla) and the same blood-sensitive MRI sequence (i.e., susceptibility weighted imaging (SWI) or T2*/gradient-recalled echo (GRE)). Parameters of the blood-sensitive MRI sequences varied according to center and manufacturer with slice thickness ranging from 1.5 to 7 mm, echo time (TE) from 11 to 51 ms, and repetition time (TR) from 460 to 2460 ms [4].
The CMBs were defined, according to consensus recommendations, as small (up to 10 mm in diameter), round or oval hypointense lesions with associated blooming seen on blood-sensitive MRI sequences [1]. The CMBs were rated by three raters (TBB, JV, LS) blinded to clinical information (with a very good inter-rater reliability as described previously [4]). New CMBs were categorized according to their distribution as lobar, deep (i.e., basal ganglia, thalamus) or infratentorial (i.e., brainstem, cerebellum) [4]. Newly appearing CMBs in the acute infarcted area, as seen on diffusion-weighted imaging, were not classified as new CMBs [2, 4].
Intracranial hemorrhage (ICH) was assessed on follow-up imaging 22 to 36 h after treatment.
The primary outcome was the proportion of patients with new CMBs on follow-up imaging (in the alteplase and placebo group). Secondary outcomes included symptomatic ICH according to the protocol of the Safe Implementation of Thrombolysis in Stroke–Monitoring Study (SITS-MOST) [5] and degree of disability, quantified on the modified Rankin Scale (mRS) 90 days after treatment (excellent outcome: mRS ≤ 1, severe dependency or death: mRS 4–6) [3].
Of 503 patients included in the WAKE-UP trial, 350 patients were available for final analysis (175 with alteplase, 175 with placebo; 129 patients were not sequentially examined on the same MRI scanners, image quality of the blood-sensitive MRI sequence was too poor for analysis in 24 patients). Patients included in the final analysis did not differ regarding age and sex compared to excluded patients (mean age: 64.7 [patients included, standard deviation [SD]: 11.8] vs. 66.3 [patients excluded, SD: 10.8], p = 0.15, t test; female: 120/350 [34.3%] vs. 58/153 [37.9%], p = 0.50, chi-squared test). However, there were fewer ICH in patients included in the final analysis (76/350 [22%] vs. 47/146 [32%]; p = 0.02, chi-squared test).
New CMBs occurred in four patients. Noteworthy, all patients with new CMBs had received alteplase resulting in a rate of 2.3% (4/175 patients; 95% confidence interval: 0.6–5.8%). Three patients had one new CMB and one patient had two new CMBs. Distribution of new CMBs was strictly lobar in all four patients (a pattern suggestive of underlying cerebral amyloid angiopathy [1, 6]) and preexisting CMBs were present in all patients with new CMBs. One patient with new CMBs had a severe stroke with an NIHSS score of 20 on admission. Any ICH occurred in two patients with new CMBs (hemorrhagic transformation of the infarcted brain tissue (HI2, Class 1b) in one patient and intracerebral hemorrhage within and beyond the infarcted brain tissue (PH2, Class 2) in the other patient [7]). One new CMB occurred contralateral to the hemorrhagic transformation (HI2, Class 1b) in one patient, two new CMBs occurred ipsilateral to the intracerebral hemorrhage (PH2, Class 2) in the other patient. Symptomatic ICH according to SITS-MOST occurred in one patient with new CMBs. Of note, of 76 patients with any ICH, 74 ICHs occurred in patients without new CMBs. At 90 days, one patient with new CMBs achieved an excellent functional outcome (mRS ≤ 1) and two patients with new CMBs had either died or had severe disability. Further details are shown in Table 1. Due to the small number of patients with new CMBs, no inferential statistical analysis was performed.
In this exploratory analysis of the randomized, placebo-controlled WAKE-UP trial, new CMBs occurred exclusively after receiving alteplase.
In the recently published THAWS trial (THrombolysis for Acute Wake-up and Unclear-onset Strokes With Alteplase at 0.6 mg/kg Trial [conducted in Japan]), new CMBs occurred in seven out of 113 AIS patients and were associated with poor neurological outcome [8]. In both study cohorts (WAKE-UP and THAWS) new CMBs occurred only in AIS patients receiving alteplase (as opposed to placebo).
The small number of outcomes, the lack of an inferential statistical analysis, a possible selection bias (ICH occurred more often in patients excluded from this analysis) as well as varying parameters of the blood-sensitive MRI sequences (e.g. slice thickness) in the different centers have to be taken into account when interpreting our findings. However, by comparing to placebo we were able to assess the effect of alteplase for the occurrence of new CMBs, thereby extending the knowledge of previous observational studies. Considering our results as well as the above-mentioned results from the THAWS trial, there is now accumulating evidence that alteplase contributes to the development of new CMBs in AIS patients. Although new CMBs occur rarely, our data call for further studies to determine if these new CMBs after receiving alteplase increase the risk of poor neurological outcome in AIS patients.
Abbreviations
- AIS:
-
Acute ischemic stroke
- CAA:
-
Cerebral amyloid angiopathy
- CMB:
-
Cerebral microbleed
- ICH:
-
Intracranial hemorrhage
- IVT:
-
Intravenous thrombolysis
- MRI:
-
Magnetic resonance imaging
- mRS:
-
Modified Rankin Scale
- NIHSS:
-
National Institutes of Health Stroke Scale
- SD:
-
Standard deviation
References
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Acknowledgement
The WAKE-UP Investigators are Amir Golsari, MD:Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Anna Alegiani, MD:Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Christoph Beck, MD:Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Chi-un Choe, MD:Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Dieke Voget, MD:Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany;Julia Hoppe, MD:Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Julian Schröder, MD:Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Michal Rozanski, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Alexander H. Nave, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Christian Wollboldt, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Isabelle van Sloten, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Jos Göhler, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Juliane Herm:Charité - Universitätsmedizin Berlin, Berlin, Germany; Jan Jungehülsing, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Janos Lückl, PhD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Jan M. Kröber, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Johannes Schurig:Charité - Universitätsmedizin Berlin, Berlin, Germany; Luzie Koehler, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Michael Knops:Charité - Universitätsmedizin Berlin, Berlin, Germany; Maria Roennefarth:Charité - Universitätsmedizin Berlin, Berlin, Germany; Nils Ipsen:Charité - Universitätsmedizin Berlin, Berlin, Germany; Peter Harmel, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Rouven Bathe-Peters:Charité - Universitätsmedizin Berlin, Berlin, Germany; Robert Fleischmann:Charité - Universitätsmedizin Berlin, Berlin, Germany; Ramanan Ganeshan:Charité - Universitätsmedizin Berlin, Berlin, Germany; Rohat Geran:Charité - Universitätsmedizin Berlin, Berlin, Germany; Simon Hellwig:Charité - Universitätsmedizin Berlin, Berlin, Germany; Sein Schmidt, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Serdar Tütüncü, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Thomas Krause, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Verena Gramse, MD:Charité - Universitätsmedizin Berlin, Berlin, Germany; Joachim Röther, MD:ASKLEPIOS Klinik Altona, Hamburg, Germany; Peter Michels, MD:ASKLEPIOS Klinik Altona, Hamburg, Germany; Dominik Michalski, MD:Universitätsklinikum Leipzig, Leipzig, Germany; Johann Pelz, MD:Universitätsklinikum Leipzig, Leipzig, Germany;Andreas Schulz, MD:Universitätsklinikum Leipzig, Leipzig, Germany; Carsten Hobohm, MD:Universitätsklinikum Leipzig, Leipzig, Germany; Christopher Weise, MD:Universitätsklinikum Leipzig, Leipzig, Germany; Gesa Weise, MD:Universitätsklinikum Leipzig, Leipzig, Germany; Johannes Orthgieß:Universitätsklinikum Leipzig, Leipzig, Germany; Katrin Pomrehn:Universitätsklinikum Leipzig, Leipzig, Germany; Mirko Wegscheider:Universitätsklinikum Leipzig, Leipzig, Germany; Anne K. Mueller, MD:Universitätsklinikum Leipzig, Leipzig, Germany; Michael Hennerici, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Martin Griebe, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Angelika Alonso, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Alexandra Filipov, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Annika Marzina, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Bettina Anders:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Christian Bähr:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Carolin Hoyer, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Christopher Schwarzbach, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Claudia Weber:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Eva Hornberger, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Hans-Werner Pledl, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Matti Klockziem:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Markus Stuermlinger, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Matthias Wittayer:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Marc Wolf, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Nadja Meyer:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Philipp Eisele, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Susanne Steinert:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Tamara Sauer, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Valentin Held, MD:Universitätsklinikum Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany; Peter Ringleb, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Simon Nagel, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Roland Veltkamp, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Sönke Schwarting, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Alexander Schwarz, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Christoph Gumbinger, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Christian Hametner, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Hemasse Amiri, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Jan Purrucker, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Mareva Ciatipis:Universitätsklinikum Heidelberg, Heidelberg, Germany; Oliver Menn, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Sibu Mundiyanapurath, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Simon Schieber, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Tobias Kessler, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Tilman Reiff, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Verena Panitz, MD:Universitätsklinikum Heidelberg, Heidelberg, Germany; Oliver Singer, MD:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Christian Foerch, MD:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Arne Lauer, MD:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Anika Männer:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Alexander Seiler, MD:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Damla Guerzoglu:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Jan H. Schäfer, MD:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Katharina Filipski, MD:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Matthias Lorenz:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Natalia Kurka, MD:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Pia Zeiner, MD:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Waltraud Pfeilschifter, MD:Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany; Rainer Dziewas, MD:Universitätsklinikum Münster, Münster, Germany; Jens Minnerup, MD:Universitätsklinikum Münster, Münster, Germany; Christian Albiker, MD:Universitätsklinikum Münster, Münster, Germany; Martin Ritter, MD:Universitätsklinikum Münster, Münster, Germany; Matthias Seidel, MD:Universitätsklinikum Münster, Münster, Germany; Ralf Dittrich, MD:Universitätsklinikum Münster, Münster, Germany; Bernd Kallmünzer, MD:Universitätsklinikum Erlangen, Erlangen, Germany; Tobias Bobinger, MD:Universitätsklinikum Erlangen, Erlangen, Germany; Dominik Madzar, MD:Universitätsklinikum Erlangen, Erlangen, Germany; David Stark, MD:Universitätsklinikum Erlangen, Erlangen, Germany; Jochen Sembill, MD:Universitätsklinikum Erlangen, Erlangen, Germany; Kosmas Macha, MD:Universitätsklinikum Erlangen, Erlangen, Germany; Klemens Winder, MD:Universitätsklinikum Erlangen, Erlangen, Germany; Lorenz Breuer, MD:Universitätsklinikum Erlangen, Erlangen, Germany; Martin Koehrmann, MD:Universitätsklinikum Erlangen, Erlangen, Germany; Maximilian Spruegel, MD:Universitätsklinikum Erlangen, Erlangen, Germany; Stefan Gerner, MD:Universitätsklinikum Erlangen, Erlangen, Germany; Sebastian Moeller:Universitätsklinikum Erlangen, Erlangen, Germany; Peter Kraft, MD:Universitätsklinikum Würzburg, Würzburg, Germany; Daniel Mackenrodt:Universitätsklinikum Würzburg, Würzburg, Germany; Christoph Kleinschnitz, MD:Universitätsklinikum Würzburg, Würzburg, Germany; Ahmed Elhfnawy:Universitätsklinikum Würzburg, Würzburg, Germany; Florian Heinen, MD:Universitätsklinikum Würzburg, Würzburg, Germany; Ignaz Gunreben, MD:Universitätsklinikum Würzburg, Würzburg, Germany; Sven Poli, MD:Universitätsklinikum Tübingen, Tübingen, Germany; Ulf Ziemann, MD:Universitätsklinikum Tübingen, Tübingen, Germany; Alexandra Gaenslen:Universitätsklinikum Tübingen, Tübingen, Germany; Dennis Schlak, MD:Universitätsklinikum Tübingen, Tübingen, Germany; Florian Haertig:Universitätsklinikum Tübingen, Tübingen, Germany; Francesca Russo:Universitätsklinikum Tübingen, Tübingen, Germany; Hardy Richter:Universitätsklinikum Tübingen, Tübingen, Germany; Matthias Ebner:Universitätsklinikum Tübingen, Tübingen, Germany; Martin Ribitsch, MD:Universitätsklinikum Tübingen, Tübingen, Germany; Martin Wolf, MD:Universitätsklinikum Tübingen, Tübingen, Germany; Christian Weimar, MD:Universitätsklinikum Essen, Essen, Germany; Vesna Zegarac, MD:Universitätsklinikum Essen, Essen, Germany; Hsin-Chieh Chen:Universitätsklinikum Essen, Essen, Germany; Katharina Althaus, MD:RKU-Universitäts- und Rehabilitationskliniken Ulm, Ulm, Germany; Hermann Neugebauer, MD:RKU-Universitäts- und Rehabilitationskliniken Ulm, Ulm, Germany; Eric Jüttler, MD:RKU-Universitäts- und Rehabilitationskliniken Ulm, Ulm, Germany; Julia Meier:RKU-Universitäts- und Rehabilitationskliniken Ulm, Ulm, Germany; Sebastian Stösser:RKU-Universitäts- und Rehabilitationskliniken Ulm, Ulm, Germany; Volker Puetz, MD:Universitätsklinikum Dresden, Dresden, Germany; Ulf Bodechtel, MD:Universitätsklinikum Dresden, Dresden, Germany; Claus. Z. Simonsen, PhD:Aarhus Universitetshospital, Aarhus, Denmark; Leif Ostergaard, PhD:Aarhus Universitetshospital, Aarhus, Denmark; Anette Møller, PhD:Aarhus Universitetshospital, Aarhus, Denmark; Dorte Damgaard, PhD:Aarhus Universitetshospital, Aarhus, Denmark; Kristina Hougaard Dupont, PhD:Aarhus Universitetshospital, Aarhus, Denmark; Marika Poulsen, MD:Aarhus Universitetshospital, Aarhus, Denmark; Niels Hjort, PhD:Aarhus Universitetshospital, Aarhus, Denmark; Noelia Ruiz de Morales, MD:Aarhus Universitetshospital, Aarhus, Denmark; Paul von Weitzel, PhD:Aarhus Universitetshospital, Aarhus, Denmark; Thomas Harbo, PhD:Aarhus Universitetshospital, Aarhus, Denmark; Jacob Marstrand, PhD:Bispebjerg Hospital, Copenhagen, Denmark; Andreas Hansen, MD:Bispebjerg Hospital, Copenhagen, Denmark; Hanne Christensen, PhD:Bispebjerg Hospital, Copenhagen, Denmark; Karen Aegidius, PhD:Bispebjerg Hospital, Copenhagen, Denmark; Lise Jeppesen, MD:Bispebjerg Hospital, Copenhagen, Denmark; Per Meden:Bispebjerg Hospital, Copenhagen, Denmark; Sverre Rosenbaum, PhD:Bispebjerg Hospital, Copenhagen, Denmark; Helle Iversen, MD:Glostrup Hospital, Glostrup, Denmark; Christina Back :Glostrup Hospital, Glostrup, Denmark; Jakob Hansen, PhD; Lene Michelsen, MD:Glostrup Hospital, Glostrup, Denmark; Thomas Truelsen, MD:Glostrup Hospital, Glostrup, Denmark; Boris Modrau, MD:Aalborg Sygehus, Syd, Aalborg, Denmark; Bo Kristensen:Aalborg Sygehus, Syd, Aalborg, Denmark; Karsten Vestergaard, MD:Aalborg Sygehus, Syd, Aalborg, Denmark; Lorenz Oppel, MD:Aalborg Sygehus, Syd, Aalborg, Denmark; Anke Wouters, PhD:UZ Leuven, Leuven, Belgium; Bart Swinnen, MD:UZ Leuven, Leuven, Belgium; Ide Smets:UZ Leuven, Leuven, Belgium; Jelle Demeestere:UZ Leuven, Leuven, Belgium; Laurens Dobbels:UZ Leuven, Leuven, Belgium; Raf Brouns, PhD:UZ Brussels, Brussels, Belgium; Ann De Smedt, PhD:UZ Brussels, Brussels, Belgium; Jacques DeKeyser:UZ Brussels, Brussels, Belgium; Laetita Yperzeele:UZ Brussels, Brussels, Belgium; Robbert-Jan Van Hooff, PhD:UZ Brussels, Brussels, Belgium; Andre Peeters, MD:UCL Saint Luc, Woluwe-Saint-Lambert, Belgium; Anne Dusart, MD:UCL Saint Luc, Woluwe-Saint-Lambert, Belgium; Ana Etexberria:UCL Saint Luc, Woluwe-Saint-Lambert, Belgium; Bernard Hanseeuw, PhD:UCL Saint Luc, Woluwe-Saint-Lambert, Belgium; Frederic London, MD:UCL Saint Luc, Woluwe-Saint-Lambert, Belgium; Jonathan Leempoel, MD:UCL Saint Luc, Woluwe-Saint-Lambert, Belgium; Katharina Hohenbichler:UCL Saint Luc, Woluwe-Saint-Lambert, Belgium; Nadia Younan, MD:UCL Saint Luc, Woluwe-Saint-Lambert, Belgium; Vicky Maqueda, MD:UCL Saint Luc, Woluwe-Saint-Lambert, Belgium; Patrice Laloux, PhD:UCL Mont Godinne, Yvoir, Belgium; Beatrijs De Coene, MD:UCL Mont Godinne, Yvoir, Belgium; Charlotte De Maeseneire, MD:UCL Mont Godinne, Yvoir, Belgium; Gaetane Turine:UCL Mont Godinne, Yvoir, Belgium; Yves Vandermeeren, PhD:UCL Mont Godinne, Yvoir, Belgium; Nina De Klippel, MD:Virga Jesse Hasselt, Hasselt, Belgium; Chris Willems, MD:Virga Jesse Hasselt, Hasselt, Belgium; Isabel de Hollander, MD:Virga Jesse Hasselt, Hasselt, Belgium; Peter Soors, MD:Virga Jesse Hasselt, Hasselt, Belgium; Sylvia Hermans, MD:Virga Jesse Hasselt, Hasselt, Belgium; Dimitri Hemelsoet, MD:UZ Ghent, Ghent, Belgium; Philippe Desfontaines, MD:Centre Hospitalier Chrétien, Liège, Belgium; Peter Vanacker, PhD:AZ Sint Lucas Brugge, Brugge, Belgium; Matthieu Rutgers, MD:Clinique de l'Europe, Brussels, Belgium; Charlotte Druart, MD:Clinique de l'Europe, Brussels, Belgium; Perrine Paindeville:Clinique de l'Europe, Brussels, Belgium; Dirk Peeters, MD:AZ Groeninge, Kortrijk, Belgium; Bart Bruneel, MD:AZ Groeninge, Kortrijk, Belgium; Evelien Vancaester, MD:AZ Groeninge, Kortrijk, Belgium; Frederik Vanhee, MD:AZ Groeninge, Kortrijk, Belgium; Guy Meersman, MD:AZ Groeninge, Kortrijk, Belgium; Paul Bourgeois, MD:AZ Groeninge, Kortrijk, Belgium; Patrick Vanderdonckt, MD:AZ Groeninge, Kortrijk, Belgium; Amandine Benoit, MD:Hôpital Neurologique, Lyon, France; Laurent Derex, MD:Hôpital Neurologique, Lyon, France; Laura Mechthouff, MD:Hôpital Neurologique, Lyon, France; Nadia Berhoune, MD:Hôpital Neurologique, Lyon, France; Thomas Ritzenthaler, PhD:Hôpital Neurologique, Lyon, France; Pierre Amarenco, MD:Hôpital Bichat Claude Bernard, Paris, France; Cristina Hobeanu, MD:Hôpital Bichat Claude Bernard, Paris, France; Elena Meseguer Gancedo, MD:Hôpital Bichat Claude Bernard, Paris, France; David Calvet, PhD:Centre Hospitalier Sainte-Anne, Paris, France; Alexandre Ladoux, MD:Centre Hospitalier Sainte-Anne, Paris, France; Alexandre Machet:Centre Hospitalier Sainte-Anne, Paris, France; Catherine Lamy, MD:Centre Hospitalier Sainte-Anne, Paris, France; Charles Mellerio, PhD:Centre Hospitalier Sainte-Anne, Paris, France; Catherine Oppenheim, PhD:Centre Hospitalier Sainte-Anne, Paris, France; Christine Rodriguez-Regent, MD:Centre Hospitalier Sainte-Anne, Paris, France; Eric Bodiguel, MD:Centre Hospitalier Sainte-Anne, Paris, France; Guillaume Turc, PhD:Centre Hospitalier Sainte-Anne, Paris, France; Julia Birchenall, MD:Centre Hospitalier Sainte-Anne, Paris, France; Laurence Legrand, MD:Centre Hospitalier Sainte-Anne, Paris, France; Ludovic Morin, MD:Centre Hospitalier Sainte-Anne, Paris, France; Myriam Edjali-Goujon, MD:Centre Hospitalier Sainte-Anne, Paris, France; Oliver Naggara, PhD:Centre Hospitalier Sainte-Anne, Paris, France; Soulliard Raphaelle:Centre Hospitalier Sainte-Anne, Paris, France; Sylvie Godon-Hardy, MD:Centre Hospitalier Sainte-Anne, Paris, France; Valérie Domigo, MD:Centre Hospitalier Sainte-Anne, Paris, France; Vincent Guiraud, MD:Centre Hospitalier Sainte-Anne, Paris, France; Yves Samson, PhD:Groupement Hospitalier Pitié Salpêtrière, Paris, France; Anne Leger, MD:Groupement Hospitalier Pitié Salpêtrière, Paris, France; Charlotte Rosso, PhD:Groupement Hospitalier Pitié Salpêtrière, Paris, France; Flore Baronnet-Chauvet, MD:Groupement Hospitalier Pitié Salpêtrière, Paris, France; Sophie Crozier, MD:Groupement Hospitalier Pitié Salpêtrière, Paris, France; Sandrine Deltour, MD:Groupement Hospitalier Pitié Salpêtrière, Paris, France; Marion Yger, MD:Groupement Hospitalier Pitié Salpêtrière, Paris, France; Igor Sibon, PhD:CHU de Bordeaux/Hôpital Pellegrin, Bordeaux, France; Pauline Renou, MD:CHU de Bordeaux/Hôpital Pellegrin, Bordeaux, France; Sharmilla Sagnier, MD:CHU de Bordeaux/Hôpital Pellegrin, Bordeaux, France; Mathieu Zuber, MD:Hôpital Paris Saint-Joseph, Paris, France; Ruben Tamazyan:Hôpital Paris Saint-Joseph, Paris, France; Gilles Rodier, MD:Centre Hospitalier de la Région d'Annecy, Metz-Tessy, France; Nathalie Morel, MD:Centre Hospitalier de la Région d'Annecy, Metz-Tessy, France; Sandra Felix:Centre Hospitalier de la Région d'Annecy, Metz-Tessy, France; Wilfried Vadot, MD:Centre Hospitalier de la Région d'Annecy, Metz-Tessy, France; Valerie Wolff, PhD:Hôpital Hautepierre, Strasbourg, France; Adriana Aniculaesei, MD:Hôpital Hautepierre, Strasbourg, France; Bertrand Yalo, MD:Hôpital Hautepierre, Strasbourg, France; Daniela Bindila:Hôpital Hautepierre, Strasbourg, France; Veronique Quenardelle, MD:Hôpital Hautepierre, Strasbourg, France; Karine Blanc-Lasserre, MD:Centre Hospitalier de Valence, Valence, France; Emmanuelle Landrault, MD:Centre Hospitalier de Valence, Valence, France; Ludovic Breynaert, MD:Centre Hospitalier de Valence, Valence, France; Serkan Cakmak, MD:Hôpital Nord Ouest – Villefranche sur Saône, Gleize, France; Stéphane Peysson, MD:Hôpital Nord Ouest – Villefranche sur Saône, Gleize, France; Alain Viguier, MD:Centre d'Investigation Clinique, Toulouse, France; Claire Lebely:Centre d'Investigation Clinique, Toulouse, France; Nicolas Raposo, MD:Centre d'Investigation Clinique, Toulouse, France; Anne-Evelyne Vallet, MD:Centre Hospitalier de Vienne, Vienne, France; Pauline Vallet, MD:Centre Hospitalier de Vienne, Vienne, France; Sébastian Brugirard, MD:Centre Hospitalier de Vienne, Vienne, France; Bharath Cheripelli:University of Glasgow, Glasgow, UK; Dheeraj Kalladka, MD:University of Glasgow, Glasgow, UK; Fiona Moreton, MD:University of Glasgow, Glasgow, UK; Krishna Dani, MD:University of Glasgow, Glasgow, UK; Salwa El Tawil, MD:University of Glasgow, Glasgow, UK; Sankaranarayanan Ramachandran, MD:University of Glasgow, Glasgow, UK; Xuya Huang, MD:University of Glasgow, Glasgow, UK; Elisabeth Warburton, MD:University of Cambridge, Cambridge, UK; Nicholas Evans, MD:University of Cambridge, Cambridge, UK; Richard Perry, MD:University College London, London, UK; Bhavni Patel, MD:St. George's Hospital London, London, UK; Geoffrey Cloud, MD:St. George's Hospital London, London, UK; Anthony Pereira, MD:St. George's Hospital London, London, UK; Barry Moynihan, MD:St. George's Hospital London, London, UK; Caroline Lovelock, MD:St. George's Hospital London, London, UK; Lillian Choy, MD:St. George's Hospital London, London, UK; Usman Khan, MD:St. George's Hospital London, London, UK; Christine Roffe, MD :North Staffordshire Hospital, Stafford, UK; Pippa Tyrell, MD:Salford Royal Hospital, Salford, UK; Craig Smith, MD:Salford Royal Hospital, Salford, UK; Anand Dixit, MD :Freeman Hospital, Newcastle upon Tyne, UK; Stephen Louw, MD:Freeman Hospital, Newcastle upon Tyne, UK; David Broughton, MD:James Cook University Hospital, Middlesbrough; Ashit Shetty, MD:Nottingham City Hospital, Nottingham, UK; Jason Appleton:Nottingham City Hospital, Nottingham, UK; Nikola Sprigg :Nottingham City Hospital, Nottingham, UK; Boris Raul Acosta, MD:Hospital Universitario Doctor Josep Trueta, Girona, Spain; Cecile van Eendenburg:Hospital Universitario Doctor Josep Trueta, Girona, Spain; Joaquin Serena Leal, PhD:Hospital Universitario Doctor Josep Trueta, Girona, Spain; Maria del Mar Castellanos Rodrigo:Hospital Universitario Doctor Josep Trueta, Girona, Spain; Mikel Terceno Izaga:Hospital Universitario Doctor Josep Trueta, Girona, Spain; Olga Belchí Guillamon:Hospital Universitario Doctor Josep Trueta, Girona, Spain; Juan Arenillas, PhD:Hospital Clínico Universitario de Valladolid, Valladolid, Spain; Ana Calleja, MD:Hospital Clínico Universitario de Valladolid, Valladolid, Spain; Elisa Cortijo, MD:Hospital Clínico Universitario de Valladolid, Valladolid, Spain; Patricia Mulero, MD:Hospital Clínico Universitario de Valladolid, Valladolid, Spain; Natalia Pérez de la Ossa, PhD:Trias i Pujol University Hospital, Barcelona, Spain; Alicia Garrido, MD:Trias i Pujol University Hospital, Barcelona, Spain; Alicia Martinez, MD:Trias i Pujol University Hospital, Barcelona, Spain; Carlos García Esperón, MD:Trias i Pujol University Hospital, Barcelona, Spain; Cristina Guerrero:Trias i Pujol University Hospital, Barcelona, Spain; David Carrera:Trias i Pujol University Hospital, Barcelona, Spain; Dolores Vilas, MD:Trias i Pujol University Hospital, Barcelona, Spain; Elena Lopez-cancio, PhD:Trias i Pujol University Hospital, Barcelona, Spain; Ernest Palomeras, MD:Trias i Pujol University Hospital, Barcelona, Spain; Giuseppe Lucente, MD:Trias i Pujol University Hospital, Barcelona, Spain; Meritxell Gomis, PhD:Trias i Pujol University Hospital, Barcelona, Spain;Irina Isern:Trias i Pujol University Hospital, Barcelona, Spain; Juan L. Becerra:Trias i Pujol University Hospital, Barcelona, Spain; Jose Hervas Vicente:Trias i Pujol University Hospital, Barcelona, Spain; Josep Sánchez, MD:Trias i Pujol University Hospital, Barcelona, Spain; Laura Dorado, PhD:Trias i Pujol University Hospital, Barcelona, Spain;Laia Grau:Trias i Pujol University Hospital, Barcelona, Spain; Lourdes Ispierto, MD:Trias i Pujol University Hospital, Barcelona, Spain; Luis Prats, MD:Trias i Pujol University Hospital, Barcelona, Spain; Miriam Almendrote, MD:Trias i Pujol University Hospital, Barcelona, Spain; María Hernández, PhD:Trias i Pujol University Hospital, Barcelona, Spain; Marta Jimenez, MD:Trias i Pujol University Hospital, Barcelona, Spain; Manuel Lozano Sánchez:Trias i Pujol University Hospital, Barcelona, Spain; Monica Millán Torne:Trias i Pujol University Hospital, Barcelona, Spain; Silvia Presas, MD:Trias i Pujol University Hospital, Barcelona, Spain; Xavier Ustrell, MD:Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain; Anna Pellisé, MD:Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain; Irene Navalpotro, MD:Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain; Alain Luna, MD:Hospital Universitario de Cruces de Baracaldo, Bilbao, Spain; Wouter Schonewille, MD:VCMO - Sint Antonius Ziekenhuis, Utrecht, Netherlands; Paul Nederkoorn, PhD:Academisch Medisch Centrum, Amsterdam, Netherlands; Charles Majoie, PhD:Academisch Medisch Centrum, Amsterdam, Netherlands; Lucie van den Berg:Academisch Medisch Centrum, Amsterdam, Netherlands; Sophie van den Berg:Academisch Medisch Centrum, Amsterdam, Netherlands; Thomas Zonneveld:Academisch Medisch Centrum, Amsterdam, Netherlands; Michel Remmers, MD:Amphia Ziekenhuis, Breda, Netherlands; Franz Fazekas, MD:Medizinische Universität Graz, Graz, Austria; Alexander Pichler, PhD:Medizinische Universität Graz, Graz, Austria; Simon Fandler, MD:Medizinische Universität Graz, Graz, Austria; Thomas Gattringer, PhD:Medizinische Universität Graz, Graz, Austria; Johannes Mutzenbach, MD:Christian-Doppler-Klinik, Paracelsus Medizinische Privatuniversität Salzburg, Salzburg, Austria; Jörg Weber, MD:Klinikum Klagenfurt am Wörthersee, Klagenfurth am Wörthersee, Austria; Elmar Höfner, MD:Klinikum Klagenfurt am Wörthersee, Klagenfurth am Wörthersee, Austria; Heinz Kohlfürst, MD:Klinikum Klagenfurt am Wörthersee, Klagenfurth am Wörthersee, Austria; Karin Weinstich, MD:Klinikum Klagenfurt am Wörthersee, Klagenfurth am Wörthersee, Austria; Lars Kellert, MD:Klinikum der Universität München, München, Germany;Anna Bayer-Karpinska, MD:Klinikum der Universität München, München, Germany; Christian Opherk, MD:Klinikum der Universität München, München, Germany; Frank Wollenweber, MD:Klinikum der Universität München, München, Germany; Matthias Klein, MD:Klinikum der Universität München, München, Germany; Tobias Neumann-Haefelin, MD:Klinikum Fulda, Fulda, Germany; Alexandra Pierskalla, MD:Klinikum Fulda, Fulda, Germany; Andreas Harloff, MD:Freiburger Universitätsklinik, Freiburg, Germany; Jürgen Bardutzky, MD:Freiburger Universitätsklinik, Freiburg, Germany; Florian Buggle, MD:Klinikum der Stadt Ludwigshafen am Rhein, Ludwigshafen am Rhein, Germany; Jörg von Schrader, MD:Klinikum der Stadt Ludwigshafen am Rhein, Ludwigshafen am Rhein, Germany; Rainer Kollmar, MD:Klinikum Darmstadt, Darmstadt, Germany; Josef Schill, MD:Klinikum Darmstadt, Darmstadt, Germany; Anna-Mareike Löbbe:Klinikum Darmstadt, Darmstadt, Germany; Thierry Moulin, PhD:Hôpital Jean Minjoz, Besançon, France; Benjamin Bouamra:Hôpital Jean Minjoz, Besançon, France; Louise Bonnet, MD:Hôpital Jean Minjoz, Besançon, France; Emmanuel Touzé, PhD:CHU de Caen, Caen, France; Anne-Laure Bonnet, MD:CHU de Caen, Caen, France; Julien Cogez, MD:CHU de Caen, Caen, France; Lin Li, MD:CHU de Caen, Caen, France; Sophie Guettier, MD:CHU de Caen, Caen, France; Arindam Kar, MD:Charing Cross Hospital London, London, UK; Aravinth Sivagnanaratham:Charing Cross Hospital London, London, UK; Olivia Geraghty, MD:Charing Cross Hospital London, London, UK;Urszula Bojaryn:Charing Cross Hospital London, London, UK; Arumugam Nallasivan, MD:Countess Of Chester Hospital, Chester, UK; Miguel Blanco Gonzales, MD:Hospital Clínico Universitario, Universidad de Santiago de Compostela, Santiago, Spain; Manuel Rodríguez-Yáñez, PhD:Hospital Clínico Universitario, Universidad de Santiago de Compostela, Santiago, Spain; Jose Tembl:Hospital Universitario y Politécnico de La Fe de Valencia, Valencia, Spain; David Gorriz:Hospital Universitario y Politécnico de La Fe de Valencia, Valencia, Spain; Stefan Oberndorfer, MD:Universitätsklinikum St. Pölten, St. Pölten, Austria; Elisabeth Prohaska, MD:Universitätsklinikum St. Pölten, St. Pölten, Austria. They are all site investigators. All the members are contributed to patient recruitment and on-site trial management.
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Open Access funding enabled and organized by Projekt DEAL. The WAKE-UP trial was funded by the European Union Seventh Framework Program.
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Dr. Braemswig is a participant in the Berlin Institute of Health-Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. Dr. Simonsen reports research grants from Novo Nordisk Foundation and Health Research Foundation of Central Denmark Region. Prof. Scheitz is participant in the BIH-Charité Advanced Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. Prof. Fiebach reports personal fees from Abbvie, AC Immune, Artemida, Bioclinica, Biogen, BMS, Brainomix, Cerevast, Daiichi-Sankyo, Eisai, Eli Lilly, Guerbet, Ionis Pharmaceuticals, Julius clinical, jung diagnostics, Merck, Nicolab, and Tau Rx, all outside the submitted work. Prof. Endres received funding from DFG under Germany´s Excellence Strategy – EXC-2049 – 390688087, BMBF, DZNE, DZHK, EU, Corona Foundation, and Fondation Leducq. Prof. Endres reports grants from Bayer and fees paid to the Charité from AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Amgen, GSK, Sanofi, Covidien, Novartis, Pfizer, all outside the submitted work. Prof. Lemmens is a senior clinical investigator of FWO Flanders. Dr. Schlemm is a participant in the Berlin Institute of Health-Charité Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health. Dr. Schlemm reports lecture fees from Daiichi Sankyo, outside of the submitted work. Prof. Nolte is participant of the BIH-Charité Clinical Fellow Program. Prof. Nolte reports lecture fees and/or consultancies from Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Pfizer, Alexion, Abbott and Gore & Ass., all outside the submitted work. All other authors declare that they have no conflict of interest.
Ethical approval
This is an exploratory analysis of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke, ClinicalTrials.gov: NCT01525290).[3] For each study site, the trial was approved by the national or local ethics committee or institutional review board, as described previously [3, 4]. Patients or their legal representatives provided written informed consent according to national and local regulations with an exception from explicit informed consent in emergency circumstances in some countries [3, 4].
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The WAKE UP Investigators are mentioned in the Acknowledgement section.
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Braemswig, T.B., Vynckier, J., Jensen, M. et al. New remote cerebral microbleeds in acute ischemic stroke: an analysis of the randomized, placebo-controlled WAKE-UP trial. J Neurol 269, 5660–5667 (2022). https://doi.org/10.1007/s00415-022-11175-y
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DOI: https://doi.org/10.1007/s00415-022-11175-y