Quantitative Signal Intensity in Fluid-Attenuated Inversion Recovery and Treatment Effect in the WAKE-UP Trial
Authors: Cheng Bastian , Boutitie Florent , Nickel Alina , Wouters Anke , Cho Tae-Hee , Ebinger Martin , Endres Matthias , Fiebach Jochen B. , Fiehler Jens , Galinovic Ivana , Puig Josep , Thijs Vincent , Lemmens Robin , Muir Keith W. , Nighoghossian Norbert , Pedraza Salvador , Simonsen Claus Z. , Gerloff Christian , Thomalla Götz ,   on behalf of the WAKE-UP Investigators*, Golsari Amir , Alegiani Anna , Beck Christoph , Choe Chi-un , Voget Dieke , Hoppe Julia , Schröder Julian , Rozanski Michal , Nave Alexander H. , Wollboldt Christian , van Sloten Isabelle , Göhler Jos , Herm Juliane , Jungehülsing Jan , Lückl Janos , Kröber Jan M. , Schurig Johannes , Koehler Luzie , Schlemm Ludwig , Knops Michael , Roennefarth Maria , Ipsen Nils , Harmel Peter , Bathe-Peters Rouven , Fleischmann Robert , Ganeshan Ramanan , Geran Rohat , Hellwig Simon , Schmidt Sein , Tütüncü Serdar , Krause Thomas , Gramse Verena , Röther Joachim , Michels Peter , Michalski Dominik , Pelz Johann , Schulz Andreas , Hobohm Carsten , Weise Christopher , Weise Gesa , Orthgieß Johannes , Pomrehn Katrin , Wegscheider Mirko , Mueller Anne K. , Hennerici Michael , Griebe Martin , Alonso Angelika , Filipov Alexandra , Marzina Annika , Anders Bettina , Bähr Christian , Hoyer Carolin , Schwarzbach Christopher , Weber Claudia , Hornberger Eva , Pledl Hans-Werner , Klockziem Matti , Stuermlinger Markus , Wittayer Matthias , Wolf Marc , Meyer Nadja , Eisele Philipp , Steinert Susanne , Sauer Tamara , Held Valentin , Ringleb Peter , Nagel Simon , Veltkamp Roland , Schwarting Sönke , Schwarz Alexander , Gumbinger Christoph , Hametner Christian , Amiri Hemasse , Purrucker Jan , Ciatipis Mareva , Menn Oliver , Mundiyanapurath Sibu , Schieber Simon , Kessler Tobias , Reiff Tilman , Panitz Verena , Singer Oliver , Foerch Christian , Lauer Arne , Männer Anika , Seiler Alexander , Guerzoglu Damla , Schäfer Jan H. , Filipski Katharina , Lorenz Matthias , Kurka Natalia , Zeiner Pia , Pfeilschifter Waltraud , Dziewas Rainer , Minnerup Jens , Albiker Christian , Ritter Martin , Seidel Matthias , Dittrich Ralf , Kallmünzer Bernd , Bobinger Tobias , Madzar Dominik , Stark David , Sembill Jochen , Macha Kosmas , Winder Klemens , Breuer Lorenz , Koehrmann Martin , Spruegel Maximilian , Gerner Stefan , Kraft Peter , Mackenrodt Daniel , Kleinschnitz Christoph , Elhfnawy Ahmed , Heinen Florian , Gunreben Ignaz , Poli Sven , Ziemann Ulf , Gaenslen Alexandra , Schlak Dennis , Haertig Florian , Russo Francesca , Richter Hardy , Ebner Matthias , Ribitsch Martin , Wolf Martin , Weimar Christian , Zegarac Vesna , Chen Hsin-Chieh , Althaus Katharina , Neugebauer Hermann , Jüttler Eric , Meier Julia , Stösser Sebastian , Puetz Volker , Bodechtel Ulf , Ostergaard Leif , Møller Anette , Damgaard Dorte , Dupont Kristina Hougaard , Poulsen Marika , Hjort Niels , de Morales Noelia Ruiz , von Weitzel Paul , Harbo Thomas , Marstrand Jacob , Hansen Andreas , Christensen Hanne , Aegidius Karen , Jeppesen Lise , Meden Per , Rosenbaum Sverre , Iversen Helle , Hansen Jakob , Michelsen Lene , Truelsen Thomas , Modrau Boris , Vestergaard Karsten , Oppel Lorenz , Sygehus Aalborg , Aalborg Syd , Swinnen Bart , Smets Ide , Demeestere Jelle , Dobbels Laurens , Brouns Raf , De Smedt Ann , DeKeyser Jacques , Yperzeele Laetita , Van Hooff Robbert- Jan , Peeters Andre , Dusart Anne , Etexberria Ana , Hanseeuw Bernard , London Frederic , Leempoel Jonathan , Hohenbichler Katharina , Younan Nadia , Maqueda Vicky , Laloux Patrice , De Coene Beatrijs , De Maeseneire Charlotte , Turine Gaetane , Vandermeeren Yves , De Klippel Nina , Willems Chris , de Hollander Isabel , Soors Peter , Hermans Sylvia , Hemelsoet Dimitri , Desfontaines Philippe , Vanacker Peter , Rutgers Matthieu , Druart Charlotte , Peeters Dirk , Bruneel Bart , Vancaester Evelien , Vanhee Frederik , Meersman Guy , Bourgeois Paul , Vanderdonckt Patrick , Benoit Amandine , Derex Laurent , Mechthouff Laura , Berhoune Nadia , Ritzenthaler Thomas , Amarenco Pierre , Hobeanu Cristina , Gancedo Elena Meseguer , Calvet David , Ladoux Alexandre , Machet Alexandre , Lamy Catherine , Mellerio Charles , Oppenheim Catherine , Rodriguez-Regent Christine , Bodiguel Eric , Turc Guillaume , Birchenall Julia , Legrand Laurence , Morin Ludovic , Edjali-Goujon Myriam , Naggara Oliver , Raphaelle Soulliard , Godon-Hardy Sylvie , Domigo Valérie , Guiraud Vincent , Samson Yves , Leger Anne , Rosso Charlotte , Baronnet-Chauvet Flore , Crozier Sophie , Deltour Sandrine , Yger Marion , Sibon Igor , Renou Pauline , Sagnier Sharmilla , Zuber Mathieu , Tamazyan Ruben , Rodier Gilles , Morel Nathalie , Felix Sandra , Vadot Wilfried , Wolff Valerie , Aniculaesei Adriana , Yalo Bertrand , Bindila Daniela , Quenardelle Veronique , Blanc-Lasserre Karine , Landrault Emmanuelle , Breynaert Ludovic , Cakmak Serkan , Peysson Stéphane , Viguier Alain , Lebely Claire , Raposo Nicolas , Vallet Anne-Evelyne , Vallet Pauline , Brugirard Sébastian , Cheripelli Bharath , Kalladka Dheeraj , Moreton Fiona , Dani Krishna , Tawil Salwa El , Ramachandran Sankaranarayanan , Huang Xuya , Warburton Elisabeth , Evans Nicholas , Perry Richard , Patel Bhavni , Cloud Geoffrey , Pereira Anthony , Moynihan Barry , Lovelock Caroline , Choy Lillian , Khan Usman , Roffe Christine , Tyrell Pippa , Smith Craig , Dixit Anand , Louw Stephen , Broughton David , Shetty Ashit , Appleton Jason , Sprigg Nikola , Acosta Boris Raul , van Eendenburg Cecile , Leal Joaquin Serena , Mar Castellanos Rodrigo Maria del , Izaga Mikel Terceno , Guillamon Olga Belchí , Arenillas Juan , Calleja Ana , Cortijo Elisa , Mulero Patricia , de la Ossa Natalia Pérez , Garrido Alicia , Martinez Alicia , Esperón Carlos García , Guerrero Cristina , Carrera David , Vilas Dolores , Lopez-cancio Elena , Palomeras Ernest , Lucente Giuseppe , Gomis Meritxell , Isern Irina , Becerra Juan L. , Vicente Jose Hervas , Sánchez Josep , Dorado Laura , Grau Laia , Ispierto Lourdes , Prats Luis , Almendrote Miriam , Hernández María , Jimenez Marta , Sánchez Manuel Lozano , Torne Monica Millán , Presas Silvia , Ustrell Xavier , Pellisé Anna , Navalpotro Irene , Luna Alain , Schonewille Wouter , Nederkoorn Paul , Majoie Charles , van den Berg Lucie , van den Berg Sophie , Zonneveld Thomas , Remmers Michel , Fazekas Franz , Pichler Alexander , Fandler Simon , Gattringer Thomas , Mutzenbach Johannes , Weber Jörg , Höfner Elmar , Kohlfürst Heinz , Weinstich Karin , Kellert Lars , Bayer-Karpinska Anna , Opherk Christian , Wollenweber Frank , Klein Matthias , Neumann- Haefelin Tobias , Pierskalla Alexandra , Harloff Andreas , Bardutzky Jürgen , Buggle Florian , von Schrader Jörg , Kollmar Rainer , Schill Josef , Löbbe Anna-Mareike , Moulin Thierry , Bouamra Benjamin , Bonnet Louise , Touzé Emmanuel , Bonnet Anne-Laure , Touze Emmanuel , Cogez Julien , Li Lin , Guettier Sophie , Kar Arindam , Sivagnanaratham Aravinth , Geraghty Olivia , Bojaryn Urszula , Nallasivan Arumugam , Gonzales Miguel Blanco , Rodríguez-Yáñez Manuel , Tembl Jose , Gorriz David , Oberndorfer Stefan , Prohaska Elisabeth 
Published: October 2019

Background and Purpose—
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.