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1. Neurological outcome after minimally invasive coronary artery bypass surgery (NOMICS): An observational prospective cohort study.

Author

Björn Stessel, Kristof Nijs, Caroline Pelckmans, Jeroen Vandenbrande, Jean-Paul Ory, Alaaddin Yilmaz, Pascal Starinieri, Michiel Van Tornout, Nina De Klippel, and Paul Dendale

Subjects
Medicine, Science
Abstract

Background/objectivesEndoscopic coronary artery bypass grafting (Endo-CABG) is a minimally invasive CABG procedure with retrograde arterial perfusion. The main objective of this study is to assess neurocognitive outcome after Endo-CABG.Methods/designIn this prospective observational cohort study, patients were categorised into: Endo-CABG (n = 60), a comparative Percutaneous Coronary Intervention (PCI) group (n = 60) and a healthy volunteer group (n = 60). A clinical neurological examination was performed both pre- and postoperatively, delirium was assessed postoperatively. A battery of 6 neurocognitive tests, Quality of life (QoL) and the level of depressive feelings were measured at baseline and after 3 months. Patient Satisfaction after Endo-CABG was assessed at 3-month follow-up. Primary endpoints were incidence of postoperative cognitive dysfunction (POCD), stroke and delirium after Endo-CABG. Secondary endpoints were QOL, patient satisfaction and the incidence of depressive feelings after Endo-CABG.ResultsIn total, 1 patient after Endo-CABG (1.72%) and 1 patient after PCI (1.67%) suffered from stroke during the 3-month follow-up. POCD in a patient is defined as a Reliable Change Index ≤-1.645 or Z-score ≤-1.645 in at least two tests, and was found in respectively 5 and 6 patients 3 months after Endo-CABG and PCI. Total incidence of POCD/stroke was not different (PCI: n= 7 [15.9%]; Endo-CABG: n= 6 [13.0%], p = 0.732). ICU delirium after Endo-CABG was found in 5 (8.6%) patients. QoL increased significantly three months after Endo-CABG and was comparable with QoL level after PCI and in the control group. Patient satisfaction after Endo-CABG and PCI was comparable. At follow-up, the level of depressive feelings was decreased in all groups.ConclusionsThe incidence of poor neurocognitive outcome, including stroke, POCD and postoperative ICU delirium until three months after Endo-CABG is low and comparable with PCI.Trial registrationRegistered on ClinicalTrials.gov (NCT02979782).

Published
2020
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2. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Author

Götz Thomalla, Florent Boutitie, Henry Ma, Masatoshi Koga, Peter Ringleb, Lee H Schwamm, Ona Wu, Martin Bendszus, Christopher F Bladin, Bruce C V Campbell, Bastian Cheng, Leonid Churilov, Martin Ebinger, Matthias Endres, Jochen B Fiebach, Mayumi Fukuda-Doi, Manabu Inoue, Timothy J Kleinig, Lawrence L Latour, Robin Lemmens, Christopher R Levi, Didier Leys, Kaori Miwa, Carlos A Molina, Keith W Muir, Norbert Nighoghossian, Mark W Parsons, Salvador Pedraza, Peter D Schellinger, Stefan Schwab, Claus Z Simonsen, Shlee S Song, Vincent Thijs, Danilo Toni, Chung Y Hsu, Nils Wahlgren, Haruko Yamamoto, Nawaf Yassi, Sohei Yoshimura, Steven Warach, Werner Hacke, Kazunori Toyoda, Geoffrey A Donnan, Stephen M Davis, Christian Gerloff, Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L. Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bharath Cheripelli, Tae-Hee Cho, Chi-un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B. Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M. Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K. Mueller, Keith W. Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H. Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H. Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z. Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Keizo Yasui, Toshiro Yonehara, Shinichi Yoshimura, K. Aarnio, F. Alemseged, C. Anderson, T. Ang, M.L. Archer, J. Attia, P. Bailey, A. Balabanski, A. Barber, P.A. Barber, J. Bernhardt, A. Bivard, D. Blacker, C.F. Bladin, A. Brodtmann, D. Cadilhac, B.C.V. Campbell, L. Carey, S. Celestino, L. Chan, W.H. Chang, A. ChangI, C.H. Chen, C.-I. Chen, H.F. Chen, T.C. Chen, W.H. Chen, Y.Y. Chen, C.A. Cheng, E. Cheong, Y.W. Chiou, P.M. Choi, H.J. Chu, C.S. Chuang, T.C. Chung, L. Churilov, B. Clissold, A. Connelly, S. Coote, B. Coulton, E. Cowley, J. Cranefield, S. Curtze, C. D'Este, S.M. Davis, S. Day, P.M. Desmond, H.M. Dewey, C. Ding, G.A. Donnan, R. Drew, S. Eirola, D. Field, T. Frost, C. Garcia-Esperon, K. George, R. Gerraty, R. Grimley, Y.C. Guo, G. Hankey, J. Harvey, S.C. Ho, K. Hogan, D. Howells, P.M. Hsiao, C.H. Hsu, C.T. Hsu, C.-S. Hsu, J.P. Hsu, Y.D. Hsu, Y.T. Hsu, C.J. Hu, C.C. Huang, H.Y. Huang, M.Y. Huang, S.C. Huang, W.S. Huang, D. Jackson, J.S. Jeng, S.K. Jiang, L. Kaauwai, O. Kasari, J. King, T.J. Kleinig, M. Koivu, J. Kolbe, M. Krause, C.W. Kuan, W.L. Kung, C. Kyndt, C.L. Lau, A. Lee, C.Y. Lee, J.T. Lee, Y. Lee, Y.C. Lee, C. Levi, C.R. Levi, L.M. Lien, J.C. Lim, C.C. Lin, C.H. Lin, C.M. Lin, D. Lin, C.H. Liu, J. Liu, Y.C. Lo, P.S. Loh, E. Low, C.H. Lu, C.J. Lu, M.K. Lu, J. Ly, H. Ma, L. Macaulay, R. Macdonnell, E. Mackey, M. Macleod, J. Mahadevan, V. Maxwell, R. McCoy, A. McDonald, S. McModie, A. Meretoja, S. Mishra, P.J. Mitchell, F. Miteff, A. Moore, C. Muller, F. Ng, F.C. Ng, J-L. Ng, W. O'Brian, V. O'Collins, T.J. Oxley, M.W. Parsons, S. Patel, G.S. Peng, L. Pesavento, T. Phan, E. Rodrigues, Z. Ross, A. Sabet, M. Sallaberger, P. Salvaris, D. Shah, G. Sharma, G. Sibolt, M. Simpson, S. Singhal, B. Snow, N. Spratt, R. Stark, J. Sturm, M.C. Sun, Y. Sun, P.S. Sung, Y.F. Sung, M. Suzuki, M. Tan, S.C. Tang, T. Tatlisumak, V. Thijs, M. Tiainen, C.H. Tsai, C.K. Tsai, C.L. Tsai, H.T. Tsai, L.K. Tsai, C.H. Tseng, L.T. Tseng, J. Tsoleridis, H. Tu, H.T-H. Tu, W. Vallat, J. Virta, W.C. Wang, Y.T. Wang, M. Waters, L. Weir, T. Wijeratne, C. Williams, W. Wilson, A.A. Wong, K. Wong, T.Y. Wu, Y.H. Wu, B. Yan, F.C. Yang, Y.W. Yang, N. Yassi, H.L. Yeh, J.H. Yeh, S.J. Yeh, C.H. Yen, D. Young, C.L. Ysai, W.W. Zhang, H. Zhao, L. Zhao, Katharina Althaus-Knaurer, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A. Dixit, Geoffrey Donnan, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R. Lees, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Peter Schellinger, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Rüdiger von Kummer, Joanna Wardlaw, Rebecca A. Betensky, Gregoire Boulouis, Raphael A. Carandang, William A. Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L. Ford, John Hallenbeck, Gordon J. Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Michael H. Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H. Schwamm, Eric Searls, Shlee S. Song, Sidney Starkman, Albert J. Yoo, Ramin Zand, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Monash University [Melbourne], National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], University of Heidelberg, Medical Faculty, Massachusetts General Hospital [Boston], University of Melbourne, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Royal Adelaide Hospital [Adelaide Australia], National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Flanders Make [Leuven], Flanders Make, University of Newcastle [Australia] (UoN), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Vall d'Hebron University Hospital [Barcelona], University of Glasgow, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Girona Biomedical Research Institute [Girona, Spain] (IDIBGI), Ruhr-Universität Bochum [Bochum], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Aarhus University Hospital, Cedars-Sinai Medical Center, Florey Institute of Neuroscience and Mental Health [Melbourne, Victoria, Australia], Austin Health, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], China Medical University Hospital [Taichung], Karolinska Institutet [Stockholm], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Texas at Austin [Austin], Collaborators Evaluation of unknown Onset Stroke thrombolysis trials (EOS) investigators: Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Florent Boutitie, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bastian Cheng, Bharath Cheripelli, Tae-Hee Cho, Chi-Un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria Del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Martin Ebinger, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Matthias Endres, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Christian Gerloff, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Robin Lemmens, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-Cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K Mueller, Keith W Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Norbert Nighoghossian, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Peter Ringleb, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Vincent Thijs, Götz Thomalla, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Mayumi Fukuda-Doi, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Manabu Inoue, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Masatoshi Koga, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Kaori Miwa, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Kazunori Toyoda, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Haruko Yamamoto, Keizo Yasui, Toshiro Yonehara, Sohei Yoshimura, Shinichi Yoshimura, K Aarnio, F Alemseged, C Anderson, T Ang, M L Archer, J Attia, P Bailey, A Balabanski, A Barber, P A Barber, J Bernhardt, A Bivard, D Blacker, C F Bladin, A Brodtmann, D Cadilhac, B C V Campbell, L Carey, S Celestino, L Chan, W H Chang, A ChangI, C H Chen, C-I Chen, H F Chen, T C Chen, W H Chen, Y Y Chen, C A Cheng, E Cheong, Y W Chiou, P M Choi, H J Chu, C S Chuang, T C Chung, L Churilov, B Clissold, A Connelly, S Coote, B Coulton, E Cowley, J Cranefield, S Curtze, C D'Este, S M Davis, S Day, P M Desmond, H M Dewey, C Ding, G A Donnan, R Drew, S Eirola, D Field, T Frost, C Garcia-Esperon, K George, R Gerraty, R Grimley, Y C Guo, G Hankey, J Harvey, S C Ho, K Hogan, D Howells, P M Hsiao, C H Hsu, C T Hsu, C-S Hsu, J P Hsu, Y D Hsu, Y T Hsu, C J Hu, C C Huang, H Y Huang, M Y Huang, S C Huang, W S Huang, D Jackson, J S Jeng, S K Jiang, L Kaauwai, O Kasari, J King, T J Kleinig, M Koivu, J Kolbe, M Krause, C W Kuan, W L Kung, C Kyndt, C L Lau, A Lee, C Y Lee, J T Lee, Y Lee, Y C Lee, C Levi, C R Levi, L M Lien, J C Lim, C C Lin, C H Lin, C M Lin, D Lin, C H Liu, J Liu, Y C Lo, P S Loh, E Low, C H Lu, C J Lu, M K Lu, J Ly, H Ma, L Macaulay, R Macdonnell, E Mackey, M Macleod, J Mahadevan, V Maxwell, R McCoy, A McDonald, S McModie, A Meretoja, S Mishra, P J Mitchell, F Miteff, A Moore, C Muller, F Ng, F C Ng, J-L Ng, W O'Brian, V O'Collins, T J Oxley, M W Parsons, S Patel, G S Peng, L Pesavento, T Phan, E Rodrigues, Z Ross, A Sabet, M Sallaberger, P Salvaris, D Shah, G Sharma, G Sibolt, M Simpson, S Singhal, B Snow, N Spratt, R Stark, J Sturm, M C Sun, Y Sun, P S Sung, Y F Sung, M Suzuki, M Tan, S C Tang, T Tatlisumak, V Thijs, M Tiainen, C H Tsai, C K Tsai, C L Tsai, H T Tsai, L K Tsai, C H Tseng, L T Tseng, J Tsoleridis, H Tu, H T-H Tu, W Vallat, J Virta, W C Wang, Y T Wang, M Waters, L Weir, T Wijeratne, C Williams, W Wilson, A A Wong, K Wong, T Y Wu, Y H Wu, B Yan, F C Yang, Y W Yang, N Yassi, H L Yeh, J H Yeh, S J Yeh, C H Yen, D Young, C L Ysai, W W Zhang, H Zhao, L Zhao, Katharina Althaus-Knaurer, Martin Bendszus, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A Dixit, Geoffrey Donnan, Rainer Dziewas, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Werner Hacke, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R Lees, Didier Leys, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Catherine Oppenheim, Sven Poli, Peter Ringleb, Peter Schellinger, Stefan Schwab, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Danilo Toni, Roland Veltkamp, Rüdiger von Kummer, Nils Wahlgren, Joanna Wardlaw, Rebecca A Betensky, Gregoire Boulouis, Raphael A Carandang, William A Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L Ford, John Hallenbeck, Gordon J Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Arne Lauer, Michael H Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H Schwamm, Eric Searls, Shlee S Song, Sidney Starkman, Steven Warach, Ona Wu, Albert J Yoo, Ramin Zand, University of Newcastle [Callaghan, Australia] (UoN), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CarMeN, laboratoire, Yperzeele, Laetitia, Evaluation of Unknown Onset Stroke Thrombolysis trials (EOS) investigators, UCL - SSS/IONS - Institute of NeuroScience, UCL - (MGD) Service de neurologie, Supporting clinical sciences, UZB Other, Physical Medicine and Rehabilitation, Clinical sciences, Neuroprotection & Neuromodulation, Radiology and Nuclear Medicine, ANS - Neurovascular Disorders, Neurology, ACS - Atherosclerosis & ischemic syndromes, Graduate School, Center of Experimental and Molecular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Microcirculation

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Ischemic Stroke/*diagnostic imaging/*drug therapy, Tomography, X-Ray Computed/methods, Fibrinolytic Agents/adverse effects/*therapeutic use, 030204 cardiovascular system & hematology, Ischemic Stroke/diagnostic imaging, surgery, 0302 clinical medicine, Modified Rankin Scale, 030212 general & internal medicine, 10. No inequality, Infusions, Intravenous, Stroke, Tomography, Time-to-Treatment, General Medicine, Thrombolysis, X-Ray Computed/methods, Tissue Plasminogen Activator/adverse effects, 3. Good health, [SDV] Life Sciences [q-bio], Diffusion Magnetic Resonance Imaging/methods, Treatment Outcome, Meta-analysis, Tissue Plasminogen Activator, Intravenous, medicine.medical_specialty, Infusions, Intravenous thrombolysis, Neuroimaging, Neuroscience(all), Placebo, Tissue Plasminogen Activator/adverse effects/*therapeutic use, 03 medical and health sciences, Fibrinolytic Agents, Internal medicine, medicine, Humans, ddc:610, Ischemic Stroke, business.industry, neurology, Fibrinolytic Agents/adverse effects, Odds ratio, Recovery of Function, medicine.disease, Clinical research, Diffusion Magnetic Resonance Imaging, Human medicine, business, Tomography, X-Ray Computed, Fibrinolytic agent
Abstract

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Published
2020
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3. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2) : a randomised, double-blind, placebo-controlled, phase 3 trial

Author

Jennifer Graves, Adrian Pace, Maria Pia Sormani, Devon S. Conway, Bianca Weinstock-Guttman, Frederick E. Munschauer, Corey C. Ford, Vernon Rowe, Jana Lizrova Preiningerova, Shiv Saidha, Radek Ampapa, Jens Kuhle, Harold L. Moses, Claire S Riley, Tobias Derfuss, Lilyana Amezcua, Joshua Barton, Kottil Rammohan, Pierre Duquette, Thomas Leist, Alexander Rae-Grant, Evanthia Bernitsas, Myla D. Goldman, R. Talab, Jerry S. Wolinsky, Nina De Klippel, Guillermo Izquierdo Ayuso, Bridget Bagert, Virginia Devonshire, Mariko Kita, Hayrettin Tumani, Bhatia Perminder, Scott D. Newsome, Paul S. Giacomini, Frédéric Sedel, Jan Lycke, M. S. Freedman, Stewart Webb, Sanjay Yathiraj, Agata Klosek, Stephen Krieger, Edward Fox, Malgorzata Zajda, Eva Meluzinova, Valerie J Block, Lluís Ramió-Torrentà, John R. Corboy, Aaron E. Miller, Xavier Montalban, Mark A. Agius, Michelle L Apperson, Patricia K. Coyle, Giancarlo Comi, Jose Enrique Martinez Rodriguez, Daniela Rau, Derrick Robertson, Elias Hamp Birte, Douglas L. Arnold, Fred D. Lublin, Galina Vorobeychik, Benjamin Greenberg, Mathias Buttmann, Daniel Bandari, Ludivine Witkowski, Sharon G. Lynch, Victoria Fernandez Sanchez, Jonathan Calkwood, Maria Satori, Tania Kuempfel, Rana K. Zabad, J. Marc Girard, Bruce A.C. Cree, Ahmed T. Toosy, Don J. Mahad, Bruce A. Cohen, Jozef Koscielniak, Jonathan Carter, Daniel Selchen, Paul Friedemann, Sharon Stoll, Fryze Waldemar, Gerd Reifschneider, Mark S. Freedman, Gary Cutter, Franz Fazekas, Robert T. Naismith, Marta Vachova, Richard MacDonell, Mary Ann Picone, Gavin Giovannoni, Randall Trudell, Barbara Willekens, Orhan Aktas, Mark Marriott, Roger McKelvey, Bruce C.A. Cree, Christopher Severson, Rafael Arroyo Gonzalez, Kyle Smoot, Murat Terzi, Joanna Cooper, Lou Brundin, Hans-Peter Hartung, Piotr Sokolowski, Joe Guadagno, Stephen C. Reingold, Klaus Schmierer, Guy Laureys, Robert P. Lisak, Lawrence Samkoff, Carlo Pozzilli, Celia Oreja Guevara, Mitchel Freedman, Anthony T. Reder, and SPI2 investigative teams

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Biotin, Placebo, Severity of Illness Index, law.invention, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Internal medicine, Outcome Assessment, Health Care, Severity of illness, Aged, Disease Progression, Female, Humans, Middle Aged, Multiple Sclerosis, Chronic Progressive, Vitamin B Complex, Walking Speed, Clinical endpoint, Medicine, Expanded Disability Status Scale, business.industry, Multiple sclerosis, medicine.disease, Clinical trial, 030104 developmental biology, Cohort, Neurology (clinical), Human medicine, business, 030217 neurology & neurosurgery
Abstract

Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. Methods: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). Findings: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (

Published
2020

4. Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke : A multicentre, double-blind, randomised, placebo-controlled trial

Author

Peter D. Schellinger, Agnes Koves, Usman A. Khan, Didier Smadja, Gabriel Rodriguez Freitas, Ralf Lindert, Bill O'brien, Jaime Masjuan Vallejo, Aida Lago Martin, Cesar Minelli, Hassan Hosseini, Marine Wattez, Martin Grond, Claudio L. Bassetti, Konrad Rejdak, Marie-Laure Audoli-Inthavong, Luisa Rover, Pere Cardona, Kenneth Butcher, Gabriel R. de Freitas, Gyula Panczel, Tomas Segura Martin, Marianna Gottschal, Maurício André Gheller Friedrich, Hugues Chabriat, Alvaro Ximenez Carrillo, Laura Dorado, Jean-Philippe Neau, Joerg Berrouschot, D. G. Nabavi, Carla H.C. Moro, Nina De Klippel, Norbert Szegedi, Tomasz Berkowicz, Jesse Dawson, Andras Folyovich, Christian Denier, Jean-Louis Mas, Klaus Gröschel, Amit K Mistri, Thanh G. Phan, Timothy Kleinig, Aurore Sors, Dirk M. Hermann, Louise Shaw, Christine Roffe, Nikola Sprigg, Man Seok Park, Hans-Christoph Diener, Hassan Soda, Maite Martinez Zabaleta, Pietro Bassi, Luiz Carlos Porcello Marrone, Dylan Blacquiere, László Vécsei, Stephen N. Davis, Giuseppe Lembo, Rohan Grimley, Charlotte Cordonnier, Geert Vanhooren, Bernd Kallmuenzer, Peter Dioszeghy, Mikael Mazighi, Waldemar Brola, Francisco Moniche Alvarez, Yangha Hwang, Attila Valikovics, Waldemar Fryze, Philippe Desfontaines, Jaume Roquer Gonzalez, David Cohen, Zbigniew Bak, Csaba Ovary, Jae-Kwan Cha, Gisele Sampaio Silva, Carlos A. Molina, Rodrigo Bazan, Hee-Joon Bae, Rubens José Gagliardi, Geoffrey Cloud, Anna Członkowska, Attila Csanyi, Leonardo Barbarini, Sergi Amaro, Jong Sung Kim, Daniel Bereczki, Katharina Althaus, Robin Lemmens, Anetta Lasek-Bal, Theodore Wein, Piotr Sobolewski, Diederik Willem Dippel, Danilo Toni, Laszlo Szapary, Suzanne Ragab, Andrew Wong, Ute Marx, Estelle Lambert, Igor Sibon, Wim M. Mulleners, Ondrej Skoda, and Maciej Swiat

Subjects
0301 basic medicine, medicine.medical_specialty, business.industry, medicine.medical_treatment, Placebo-controlled study, Medizin, Placebo, law.invention, Clinical trial, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Randomized controlled trial, law, Modified Rankin Scale, Internal medicine, ischemic stroke, medicine, Clinical endpoint, Neurology (clinical), Stroke recovery, business, Adverse effect, 030217 neurology & neurosurgery
Abstract

Summary Background S44819, a selective GABAA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety Trial of Oral GABAA α5 antagonist S44819 after Recent ischemic Event (RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for enhancing clinical recovery of patients with ischaemic stroke. Methods RESTORE BRAIN was an international, randomised, double-blind, parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The study was done in specialised stroke units in 92 actively recruiting centres in 14 countries: ten were European countries (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were non-European countries (Australia, Brazil, Canada, and South Korea). Patients aged 18–85 years with acute ischaemic stroke involving cerebral cortex (National Institute of Health Stroke Scale [NIHSS] score 7–20) without previous disability were eligible for inclusion. Participants were randomly assigned to receive 150 mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment randomisation and allocation were centralised via the interactive web response system using computer-generated random sequences with a block size of 3. Blinding of treatment was achieved by identical appearance and taste of all sachets. Patients, investigators and individuals involved in the analysis of the trial were masked to group assignment. The primary endpoint was the modified Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift analysis (predefined main analysis) or by dichotomised analyses using 0–1 versus 2–6 and 0–2 versus 3–6 cutoffs (predefined secondary analysis). Secondary endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive Assessment (MoCA) scores, time needed to complete parts A and B of the Trail Making Test, and the Barthel index. Efficacy analyses were done on all patients who received at least one dose of treatment and had at least one mRS score taken after day 5 (specifically, on or after day 30). Safety was compared across treatment groups for all patients who received at least one dose of treatment. The study was registered at ClinicalTrials.gov , NCT02877615 . Findings Between Dec 19, 2016, and Nov 16, 2018, 585 patients were enrolled in the study. Of these, 197 (34%) were randomly assigned to receive 150 mg S44819 twice a day, 195 (33%) to receive 300 mg S44819 twice a day, and 193 (33%) to receive placebo twice a day. 189 (96%) of 197 patients in the 150 mg S44819 group, 188 (96%) of 195 patients in the 300 mg S44819 group, and 191 (99%) patients in the placebo group received at least one dose of treatment and had at least one mRS score taken after day 5, and were included in efficacy analyses. 195 (99%) of 197 patients in the 150 mg S44819 group, 194 (99%) of 195 patients in the 300 mg S44819 group, and 193 (100%) patients in the placebo group received at least one dose of treatment, and were included in safety analyses. The primary endpoint of mRS at day 90 did not differ between each of the two S44819 groups and the placebo group (OR 0·91 [95% CI 0·64–1·31]; p=0·80 for 150 mg S44819 compared with placebo and OR 1·17 [95% CI 0·81–1·67]; p=0·80 for 300 mg S44819 compared with placebo). Likewise, dichotomised mRS scores at day 90 (mRS 0–2 vs 3–6 or mRS 0–1 vs 2–6) did not differ between groups. Secondary endpoints did not reveal any significant group differences. The median NIHSS score at day 90 did not differ between groups (4 [IQR 2–8] in 150 mg S44819 group, 4 [2–7] in 300 mg S44819 group, and 4 [2–6] in placebo group), nor did the number of patients at day 90 with an NIHSS score of up to 5 (95 [61%] of 156 in 150 mg S44819 group, 106 [66%] of 161 in 300 mg S44819 group, and 104 [66%] of 157 in placebo group) versus more than 5 (61 [39%] in 150 mg S44819 group, 55 [34%] in 300 mg S44819 group, and 53 [34%] in placebo group). Likewise, the median MoCA score (22·0 [IQR 17·0–26·0] in 150 mg S44819 group, 23·0 [19·0–26·5] in 300 mg S44819 group, and 22·0 [17·0–26·0] in placebo group), time needed to complete parts A (50 s [IQR 42–68] in 150 mg S44819 group, 49 s [36–63] in 300 mg S44819 group, and 50 s [38–68] in placebo group) and B (107 s [81–144] in 150 mg S44819 group, 121 s [76–159] in 300 mg S44819 group, and 130 s [86–175] in placebo group) of the Trail Making Test, and the Barthel index (90 [IQR 60–100] in 150 mg S44819 group, 90 [70–100] in 300 mg S44819 group, and 90 [70–100] in placebo group) were similar in all groups. Number and type of adverse events were similar between the three groups. There were no drug-related adverse events and no drug-related deaths. Interpretation There was no evidence that S44819 improved clinical outcome in patients after ischaemic stroke, and thus S44819 cannot be recommended for stroke therapy. The concept of tonic inhibition after stroke should be re-evaluated in humans. Funding Servier.

Published
2020

5. Fluoxetine in progressive multiple sclerosis : the FLUOX-PMS trial

Author

Melissa Cambron, Jop Mostert, Marie D’Hooghe, Guy Nagels, Barbara Willekens, Jan Debruyne, Luc Algoed, Wim Verhagen, Raymond Hupperts, Dorothea Heersema, Jacques De Keyser, Liesbeth De Groot, Jan De Bruyne, Erwin Foselle, Daniel Guillaume, Henri Merckx, Ludo Vanopdenbosch, Mathieu Vokaer, Nina De Klippel, Dirk Nuytten, Ann Van Remoortel, Anoek Symons, Miguel D’haeseleer, Veronique Bissay, Annick Van Merhaegen-Wieleman, Michel Van Lint, Veronique Michiels, Patrick Haentjens, Bart Van Wijmeersch, Bart Tillemans, Wim Van Hecke, Gerald Hengstman, FLUOX-PMS Study Grp, Public Health Sciences, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Vriendenkring VUB, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience

Subjects
Oncology, medicine.medical_specialty, Clinical Neurology, Neuroprotection, Double blind, Multiple sclerosis, 03 medical and health sciences, DOUBLE-BLIND, 0302 clinical medicine, Clinical Trials, Phase II as Topic, Internal medicine, medicine, Humans, 030304 developmental biology, Progressive multiple sclerosis, 0303 health sciences, Fluoxetine, business.industry, neurology, Experimental autoimmune encephalomyelitis, fluoxetine, clinical trial, Multiple Sclerosis, Chronic Progressive, medicine.disease, Clinical trial, progressive multiple sclerosis, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, outcome, neuroprotection, Neurology (clinical), Human medicine, business, Axonal degeneration, 030217 neurology & neurosurgery, Selective Serotonin Reuptake Inhibitors, medicine.drug
Abstract

Background: Preclinical studies suggest that fluoxetine has neuroprotective properties that might reduce axonal degeneration in multiple sclerosis (MS). Objective: To determine whether fluoxetine slows accumulation of disability in progressive MS. Methods: In a double-blind multicenter phase 2 trial, patients with primary or secondary progressive MS were randomized to fluoxetine 40 mg/day or placebo for a period of 108 weeks. Clinical assessments were performed every 12 weeks by trained study nurses who visited the patients at their home. The primary outcome was the time to a 12-week confirmed 20% increase in the Timed 25 Foot Walk or 9-Hole Peg test. Secondary outcomes included the Hauser ambulation index, cognitive tests, fatigue, and brain magnetic resonance imaging (MRI). Results: In the efficacy analysis, 69 patients received fluoxetine and 68 patients received placebo. Using the log-rank test ( p = 0.258) and Cox regression analysis ( p = 0.253), we found no significant difference in the primary outcome between the two groups. Due to an unexpected slow rate of progression in the placebo group, there was insufficient statistical power to detect a potential benefit of fluoxetine. We found no differences between the two groups for secondary outcomes. Conclusion: The trial failed to demonstrate a neuroprotective effect of fluoxetine in patients with progressive MS.

Published
2019

6. No supportive evidence for TIA1 gene mutations in a European cohort of ALS-FTD spectrum patients

Author

Ellen Gelpi, Mathieu Vandenbulcke, Yalda Baradaran-Heravi, Alex Michotte, Alexandre de Mendonça, Elisa Bonomi, Peter Paul De Deyn, Peter Heutink, Bruno Bergmans, Matthew J. Fraidakis, Matthis Synofzik, Dirk Peeters, Eva Parobkova, Christine Van Broeckhoven, Patrick Santens, Peter De Jonghe, Radoslav Matej, Maria Rosário Almeida, Rik Vandenberghe, Hung Phuoc Nguyen, Pau Pastor, Alessandro Padovani, Gabriel Miltenberger-Miltenyi, Jan De Bleecker, Philip Van Damme, Sara Van Mossevelde, Isabel Santana, Ricard Rojas-García, Olivier Deryck, Julie van der Zee, Eric Salmon, Ana Verdelho, Christiana Willems, Nina De Klippel, Miquel Aguilar, Lubina Dillen, Alberto Lleó, Sergi Borrego-Écija, Sebastiaan Engelborghs, Sandro Sorbi, Jonathan Baets, Camilla Ferrari, Monica Diez-Fairen, Silvia Bagnoli, Barbara Borroni, Raquel Sánchez-Valle, Johan Goeman, Anne Sieben, Ignacio Illán-Gala, Patrick Cras, Panagiotis Alexopoulos, Janina Turon-Sans, Benedetta Nacmias, Adrian Ivanoiu, Irene Piaceri, Janine Diehl-Schmid, Jan Versijpt, Silvana Archettim, C. Ferreira, Frederico Simões do Couto, Jordi Clarimón, Dirk Nuytten, Javier Simón-Sánchez, Carlo Wilke, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, BELNEU Consortium1, EU EOD Consortium, Clinical sciences, Neurology, and Pathologic Biochemistry and Physiology

Subjects
0301 basic medicine, Oncology, Male, Aging, Geriatrics & Gerontology, Gene mutation, Frontotemporal dementia (FTD), AMYOTROPHIC-LATERAL-SCLEROSIS, Pathogenesis, Cohort Studies, 0302 clinical medicine, Gene Frequency, Medicine and Health Sciences, Missense mutation, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis, genetics [Frontotemporal Dementia], Medicine(all), General Neuroscience, ddc, genetics [Amyotrophic Lateral Sclerosis], genetics [European Continental Ancestry Group], Frontotemporal Dementia, Cohort, T cellerestricted intracellular antigen-1 gene (TIA1), Female, Life Sciences & Biomedicine, Cohort study, Frontotemporal dementia, medicine.medical_specialty, European Continental Ancestry Group, genetics [White People], Mutation, Missense, White People, 03 medical and health sciences, Internal medicine, mental disorders, medicine, Humans, ddc:610, genetics [T-Cell Intracellular Antigen-1], Biology, Allele frequency, T cell–restricted intracellular antigen-1 gene (TIA1), Science & Technology, business.industry, TIA1 protein, human, Amyotrophic Lateral Sclerosis, Neurosciences, TAR DNA-Binding protein 43 (TDP-43), FRONTOTEMPORAL DEMENTIA, medicine.disease, T-Cell Intracellular Antigen-1, 030104 developmental biology, Human medicine, Neurology (clinical), Neurosciences & Neurology, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Developmental Biology
Abstract

We evaluated the genetic contribution of the T cell-restricted intracellular antigen-1 gene (TIA1) in a European cohort of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Exonic resequencing of TIA1 in 1120 patients (693 FTD, 341 ALS, 86 FTD-ALS) and 1039 controls identified in total 5 rare heterozygous missense variants, affecting the TIA1 low-complexity domain (LCD). Only 1 missense variant, p.Met290Thr, identified in a familial FTD patient with disease onset at 64 years, was absent from controls yet received a combined annotation-dependent depletion score of 11.42. By contrast, 3 of the 4 variants also detected in unaffected controls, p.Val294Glu, p.Gln318Arg, and p.Ala381Thr, had combined annotation-dependent depletion scores greater than 20. Our findings in a large European patient-control series indicate that variants in TIA1 are not a common cause of ALS and FTD. The observation of recurring TIA1 missense variants in unaffected individuals lead us to conclude that the exact genetic contribution of TIA1 to ALS and FTD pathogenesis remains to be further elucidated. ispartof: NEUROBIOLOGY OF AGING vol:69 ispartof: location:United States status: published

Published
2018
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7. Clinical variability and onset age modifiers in an extended Belgian GRN founder family

Author

Eline Wauters, Sara Van Mossevelde, Kristel Sleegers, Julie van der Zee, Sebastiaan Engelborghs, Anne Sieben, Rik Vandenberghe, Stéphanie Philtjens, Marleen Van den Broeck, Karin Peeters, Ivy Cuijt, Wouter De Coster, Tim Van Langenhove, Patrick Santens, Adrian Ivanoiu, Patrick Cras, Jan L. De Bleecker, Jan Versijpt, Roeland Crols, Nina De Klippel, Jean-Jacques Martin, Peter P. De Deyn, Marc Cruts, Christine Van Broeckhoven, Johan Goeman, Dirk Nuytten, Mathieu Vandenbulcke, Alex Michotte, Eric Salmon, Olivier Deryck, Bruno Bergmans, Christiana Willems, Jean Delbeck, Neurology, Neuroprotection & Neuromodulation, Clinical sciences, Medicine and Pharmacy academic/administration, Belgian Neurology (BELNEU) Consortium, Wauters, Eline, Van Mossevelde, Sara, Sleegers, Kristel, van der Zee, Julie, Engelborghs, Sebastiaan, Sieben, Anne, Vandenberghe, Rik, PHILTJENS, Stephanie, Van den Broeck, Marleen, Peeters, Karin, Cuijt, Ivy, De Coster, Wouter, Van Langenhove, Tim, Santens, Patrick, Ivanoiu, Adrian, Cras, Patrick, De Bleecker, Jan L., Versijpt, Jan, Crols, Roeland, DE KLIPPEL, Nina, Martin, Jean-Jacques, De Deyn, Peter P., Cruts, Marc, and Van Broeckhoven, Christine

Subjects
0301 basic medicine, Clinical heterogeneity, Male, Aging, Geriatrics & Gerontology, Granulin, AMYOTROPHIC-LATERAL-SCLEROSIS, 0302 clinical medicine, Progranulins, Belgium, Loss of Function Mutation, Medicine and Health Sciences, Age of Onset, Exome, Genetics, Aged, 80 and over, Dimethylhydrazines, medicine.diagnostic_test, DEMENTIA, General Neuroscience, Frontotemporal lobar degeneration, Middle Aged, Pedigree, modifiers, ALZHEIMERS-DISEASE, Frontotemporal Dementia, Mutation (genetic algorithm), Intercellular Signaling Peptides and Proteins, Female, Life Sciences & Biomedicine, Frontotemporal dementia, GRN, Adult, Neuroscience(all), DIAGNOSTIC-CRITERIA, Clinical Neurology, PROGRANULIN LEVELS, MUTATION CARRIERS, Biology, Progressive supranuclear palsy, 03 medical and health sciences, medicine, Dementia, Humans, GRANULIN MUTATION CARRIERS, Genetic Association Studies, Genetic testing, Aged, FRONTOTEMPORAL LOBAR DEGENERATION, Science & Technology, Founder pedigree, HEXANUCLEOTIDE REPEAT, LINKAGE ANALYSIS, TARDBP MUTATIONS, Modifiers, Neurosciences, PROGRESSIVE SUPRANUCLEAR PALSY, medicine.disease, Ageing, 030104 developmental biology, TAU-GENE, Neurosciences & Neurology, Human medicine, Neurology (clinical), Geriatrics and Gerontology, Propionates, 030217 neurology & neurosurgery, Developmental Biology, Follow-Up Studies
Abstract

We previously reported a granulin (GRN) null mutation, originating from a common founder, in multiple Belgian families with frontotemporal dementia. Here, we used data of a 10-year follow-up study to describe in detail the clinical heterogeneity observed in this extended founder pedigree. We identified 85 patients and 40 unaffected mutation carriers, belonging to 29 branches of the founder pedigree. Most patients (74.4%) were diagnosed with frontotemporal dementia, while others had a clinical diagnosis of unspecified dementia, Alzheimer's dementia or Parkinson's disease. The observed clinical heterogeneity can guide clinical diagnosis, genetic testing, and counseling of mutation carriers. Onset of initial symptomatology is highly variable, ranging from age 45 to 80 years. Analysis of known modifiers, suggested effects of GRN rs5848, microtubule-associated protein tau H-1/H-2, and chromosome 9 open reading frame 72 G(4)C(2) repeat length on onset age but explained only a minor fraction of the variability. Contrary, the extended GRN founder family is a valuable source for identifying other onset age modifiers based on exome or genome sequences. These modifiers might be interesting targets for developing disease-modifying therapies. (C) 2018 The Authors. Published by Elsevier Inc. Belgian Science Policy Office Interuniversity Attraction Poles program; Flemish government initiated Methusalem excellence program; Flemish government initiated Impulse Program on Networks for Dementia Research; Queen Elisabeth Medical Foundation; Alzheimer Research Foundation; Research Foundation Flanders (FWO); Agency for Innovation by Science and Technology Flanders (IWT); University of Antwerp Research Fund; Belgium; IWT; FWO

Published
2017

8. Fluoxetine in progressive multiple sclerosis (FLUOX-PMS) : study protocol for a randomized controlled trial

Author

Erwin Fosselle, Jan Debruyne, Raymond Hupperts, Henri Merckx, Luc Algoed, Jop P. Mostert, Guy Laureys, Patrick Haentjens, Ludo Vanopdenbosch, Barbara Willekens, Annick Van Merhaegen-Wieleman, Dorothea Heersema, Wim Van Hecke, Gerald J D Hengstman, Wim Verhagen, Marie B. D'hooghe, Jacques De Keyser, Guy Nagels, Veronique Michiels, Bart Van Wijmeersch, Nina De Klippel, Melissa Cambron, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Neurowetenschappen, RS: CARIM - R2 - Cardiac function and failure, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Cardiologie, Surgery Specializations, Cognitive and Physiological Psychology, Neuroprotection & Neuromodulation, and Internal Medicine Specializations

Subjects
Male, Time Factors, Medicine (miscellaneous), Pharmacology, Neuropsychological Tests, ASTROCYTES, law.invention, Disability Evaluation, Study Protocol, DOUBLE-BLIND, Cognition, Randomized controlled trial, Belgium, Clinical Protocols, law, Clinical endpoint, Medicine and Health Sciences, Medicine, Pharmacology (medical), Netherlands, SEROTONIN, Brain, Middle Aged, Multiple Sclerosis, Chronic Progressive, trial, Magnetic Resonance Imaging, Neuroprotection, Clinical trial, RECEPTORS, Neuroprotective Agents, Treatment Outcome, Cerebral blood flow, Research Design, Disease Progression, Female, Primary progressive, Tomography, Optical Coherence, medicine.drug, Adult, Placebo, Multiple sclerosis, Clinical, Double-Blind Method, Fluoxetine, Humans, Aged, business.industry, medicine.disease, Radiography, Nerve Degeneration, Secondary progressive, Human medicine, business, Neuroscience
Abstract

Background Currently available disease-modifying treatments acting by modifying the immune response are ineffective in progressive multiple sclerosis (MS), which is caused by a widespread axonal degeneration. Mechanisms suspected to be involved in this widespread axonal degeneration are reduced axonal energy metabolism, axonal glutamate toxicity, and reduced cerebral blood flow. Fluoxetine might theoretically reduce axonal degeneration in MS because it stimulates energy metabolism through enhancing glycogenolysis, stimulates the production of brain-derived neurotrophic factor, and dilates cerebral arterioles. The current document presents the protocol of a clinical trial to test the hypothesis that fluoxetine slows down the progressive phase of MS. Methods/Design The FLUOX-PMS trial is a multi-center, randomized, controlled and double-blind clinical study. A total of 120 patients with the diagnosis of either secondary or primary progressive MS will be treated either by fluoxetine (40 mg daily) or placebo for a total period of 108 weeks. The primary endpoint is the time to confirmed disease progression defined as either at least a 20% increase in the timed 25-Foot Walk or at least a 20% increase in the 9-Hole Peg Test. Secondary endpoints include the Hauser ambulation index, cognitive changes, fatigue, magnetic resonance imaging of the brain, and in a small subgroup optical coherence tomography. Discussion The FLUOX-PMS trial will gives us information as to whether fluoxetine has neuroprotective effects in patients with progressive MS. Trial Registration Eudra-CT: 2011-003775-11

Published
2014

9. Tonic GABA-ergic modulation of striatal dopamine release studied by in vivo microdialysis in the freely moving rat

Author

Ilse Julia Smolders, Yvette Michotte, Guy Ebinger, Sophie Sarre, Nina De Klippel, Pharmaceutical Chemistry, Drug Analysis and Drug Information, and Vrije Universiteit Brussel

Subjects
Male, medicine.medical_specialty, Kainic acid, Dopamine, Microdialysis, Presynaptic Terminals, GABAB receptor, Feedback, chemistry.chemical_compound, Dopamine receptor D1, Phaclofen, Interneurons, Internal medicine, Excitatory Amino Acid Agonists, medicine, Animals, GABA-A Receptor Agonists, GABA-A Receptor Antagonists, Rats, Wistar, gamma-Aminobutyric Acid, Pharmacology, Kainic Acid, GABAA receptor, Chemistry, Dopaminergic, Homovanillic Acid, Bicuculline, Rats, Neostriatum, Substantia Nigra, Endocrinology, nervous system, GABA-B Receptor Agonists, 3,4-Dihydroxyphenylacetic Acid, Extracellular Space, GABA-B Receptor Antagonists, medicine.drug
Abstract

GABAA and GABAB receptor agonists and antagonists were administered locally in the striatum of intact and kainic acid lesioned rats. (+/-)-Baclofen, a GABAB receptor agonist, significantly decreased the level of extracellular dopamine in the striatum of intact rats. (+/-)-Phaclofen, a GABAB receptor antagonist, increased the level of extracellular dopamine in the striatum of intact rats and to a lesser extent in the striatum after kainic acid lesion. Pregnanolone (5 beta-pregnan-3 alpha-ol-20-one), a positive allosteric modulator of the GABAA receptor, significantly decreased the level of extracellular dopamine in intact rats. (-)-Bicuculline, a GABAB receptor antagonist, increased the level of extracellular dopamine in the striatum of intact rats, but failed to increase the level of extracellular dopamine after kainic acid lesion. The release of extracellular dopamine, due to infusion of phaclofen or bicuculline, was totally suppressed by tetrodotoxin. These results support a direct influence of GABA on the dopaminergic terminals via presynaptic GABAB receptors, while the effects via the GABAA receptor seem to be postsynaptic and mediated by striatal interneurons or the striatonigral feedback loop.

Published
1995
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10. Effect of M1- and M2-muscarinic drugs on striatal dopamine release and metabolism: an in vivo microdialysis study comparing normal and 6-hydroxydopamine-lesioned rats

Author

S. Sarre, Guy Ebinger, Nina De Klippel, and Yvette Michotte

Subjects
Atropine, Male, Agonist, medicine.medical_specialty, Microdialysis, medicine.drug_class, Dopamine, Striatum, Diamines, Rats, Sprague-Dawley, chemistry.chemical_compound, Reference Values, Internal medicine, medicine, Methoctramine, Animals, Oxidopamine, Neurotransmitter, Molecular Biology, General Neuroscience, Homovanillic acid, Homovanillic Acid, Pirenzepine, Receptors, Muscarinic, Corpus Striatum, Rats, Endocrinology, chemistry, 3,4-Dihydroxyphenylacetic Acid, Carbachol, Neurology (clinical), Developmental Biology, medicine.drug
Abstract

Microdialysis was used to study the effect of M1 and M2 selective agonists and antagonists on striatal dopamine release and metabolism. Microdialysis probes were implanted, under anesthesia, in the left and the right striatum of the normal rats and in the normal and denervated striatum of the nigral 6-hydroxydopamine-lesioned rats. Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined by liquid chromatography and electrochemical detection. The different drugs were infused through the dialysis probe during 40 min. Pirenzepine (5 microM), a selective M1 antagonist, produced a significant decrease in DA release in the normal and the 6-hydroxydopamine-lesioned rats, with no significant difference between both groups. Methoctramine, a selective M2 antagonist, produced a dose-dependent increase in DA release between 20 and 200 microM in the normal rats, with no significant effect on DOPAC and HVA. Infusing 75 microM methoctramine produced a significant increase in DA release with a more pronounced effect in the intact animals compared to the 6-hydroxydopamine-lesioned animals. The non-selective agonist carbachol produced a decrease in dopamine release after infusion of 50 microM (M2 effect) and an increase in dopamine release after infusion of 50 mM (M1 effect) in the normal rats. Infusing 50 microM carbachol in the denervated striatum, produced a slight increase in DA release. Our data suggest that presynaptic M1-muscarinic receptors enhance and M2-muscarinic receptors inhibit DA release in the striatum of the rat; and that 3 weeks after 6-hydroxydopamine lesioning there may be a normalisation of the number of M1-receptors with a loss of M2-receptors at the denervated side.

Published
1993
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11. Survey to evaluate diagnosis and management of headache in primary care: Headache Management Pattern programme

Author

João Sequeira Carlos, Nina De Klippel, and Jan-Peter Jansen

Subjects
Male, medicine.medical_specialty, Referral, Migraine Disorders, Triptans, Primary care, Chronic Migraine, Intervention (counseling), Surveys and Questionnaires, medicine, Humans, Medical history, Primary Health Care, business.industry, Anti-Inflammatory Agents, Non-Steroidal, General Medicine, medicine.disease, Europe, Migraine, Chronic Disease, Practice Guidelines as Topic, Physical therapy, Education, Medical, Continuing, Female, Differential diagnosis, business, medicine.drug
Abstract

The Headache Management Pattern (HMP) programme was designed to evaluate the current clinical situation regarding the diagnosis, treatment and referral of headache in a European primary care setting.A total of 705 GPs (from Germany, Portugal and Belgium), who regularly treated migraine patients, completed a questionnaire relating to four different case scenarios described in terms of symptoms, signs and medical history. Each GP completed clinical decision-trees which were created following IHS diagnostic criteria and published treatment guidelines.Of those questioned, 90% accurately diagnosed a new migraine case and 54% prescribed early intervention with a triptan. However, 23.7% prescribed an NSAID, despite a past history of failed headache relief, and 7.2% indicated that they would refer their patients to a specialist. In the case of a patient whose migraine was deteriorating, 55% of GPs counselled early intervention with a triptan. For chronic migraine sufferers, 42.6% of GPs chose to refer them to a specialist, whilst about one-third made appropriate adjustments to the patient's treatment. The final case, tension-type headache, proved the most difficult scenario to assess, with only 26% of those questioned reaching an adequate diagnosis. Between-country differences in clinical practice may result from local reimbursement policy, treatment guidelines, and different healthcare systems/facilities (e.g., access to specialised care)--all of which could influence the results obtained.A questionnaire such as the HMP programme inherently has limited depth, and the sampling procedure (GPs with triptan knowledge from three countries) needs to be considered when interpreting the results. Nevertheless, the survey provides important information relating to the management of headache in primary care, highlighting the need for both continuing medical education and also improved referral to specialist care.

Published
2008

12. Erratum to: A 2-year observational study of patients with relapsing-remitting multiple sclerosis converting to glatiramer acetate from other disease-modifying therapies: the COPTIMIZE trial

Author

Jette L. Frederiksen, Miguel A. Macías Islas, Astrid Edland, Tjalf Ziemssen, João Correia de Sá, Nina de Klippel, Adriana Carrá, Yossi Gilgun-Sherki, Klimentini E. Karageorgiou, Niall Tubridy, Olivier Heinzlef, Rafael H. Lander Delgado, Ovidiu Bajenaru, and Anne-Marie Landtblom

Subjects
Adult, Male, medicine.medical_specialty, Neurology, Internationality, Time Factors, Disease, Multiple Sclerosis, Relapsing-Remitting, Adjuvants, Immunologic, Internal medicine, Medicine, Humans, Longitudinal Studies, Prospective Studies, Glatiramer acetate, Neuroradiology, business.industry, Drug Substitution, Multiple sclerosis, Glatiramer Acetate, Middle Aged, medicine.disease, Treatment Outcome, Relapsing remitting, Observational study, Female, Neurology (clinical), Erratum, business, Peptides, medicine.drug
Abstract

Studies suggest that patients with relapsing-remitting multiple sclerosis (RRMS) who do not benefit from other disease-modifying treatments (DMTs) may benefit from converting to glatiramer acetate (GA). COPTIMIZE was a 24-month observational study designed to assess the disease course of patients converting to GA 20 mg daily from another DMT. Eligible patients had converted to GA and had received prior DMT for 3-6 months, depending on the reasons for conversion. Patients were assessed at baseline and at 6, 12, 18, and 24 months. In total, 672 patients from 148 centers worldwide were included in the analysis. Change of therapy to GA was prompted primarily by lack of efficacy (53.6 %) or intolerable adverse events (AEs; 44.8 %). Over a 24-month period, 72.7 % of patients were relapse free. Mean annual relapse rate decreased from 0.86 [95 % confidence interval (CI) 0.81-0.91] before the change to 0.32 (95 % CI 0.26-0.40; p0.0001) at last observation, while the progression of disability was halted, as the Kurtzke Expanded Disability Status Scale (EDSS) scores remained stable. Patients improved significantly (p0.05) on measures of fatigue, quality of life, depression, and cognition; mobility scores remained stable. The results indicate that changing RRMS patients to GA is associated with positive treatment outcomes.

Published
2014

13. Early outcome in acute ischemic stroke is not influenced by the prophylactic use of low-dose aspirin

Author

Luc Herroelen, Jacques De Keyser, Nina De Klippel, Gerontology, and University of Groningen

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Ischemia, Cerebral Hemorrhage/mortality/radiography, tomography, THERAPY, Aspirin/*administration & dosage, Brain Ischemia, Internal medicine, medicine.artery, Cause of Death, ischemic stroke, Medicine, Humans, Comparative Study, Antipyretic, cardiovascular diseases, Stroke, Cause of death, Endarterectomy, Aged, Cerebral Hemorrhage, Aspirin, business.industry, Vascular disease, ENDARTERECTOMY, medicine.disease, X-Ray Computed, Cerebrovascular Disorders, SEVERITY, Treatment Outcome, Neurology, Anesthesia, Middle cerebral artery, Cardiology, outcome, TRIAL, Female, Neurology (clinical), drug therapy/etiology/*prevention & control, business, Tomography, X-Ray Computed, Brain Ischemia/complications/*drug therapy/mortali, medicine.drug, Human
Abstract

Aspirin reduces the occurrence of ischemic strokes. In some prophylactic trials it was suggested that aspirin might also lessen stroke severity, and hence improve outcome in patients sustaining an ischemic stroke. We examined stroke severity (by using the Mathew scale) and early outcome (Barthel index and mortality on day 21) in 91 patients with an acute (

Published
1997

14. Survey to evaluate diagnosis and management of headache in primary care: Headache Management Pattern programme.

Author

Nina De Klippel, Jan-Peter Jansen, and João Sequeira Carlos

Subjects
*HEADACHE treatment, *MIGRAINE, *PRIMARY care, *SYMPTOMS, *HEALTH promotion, *HEALTH surveys, *PATIENTS
Abstract

ABSTRACTObjective:The Headache Management Pattern (HMP) programme was designed to evaluate the current clinical situation regarding the diagnosis, treatment and referral of headache in a European primary care setting.Design and methods:A total of 705 GPs (from Germany, Portugal and Belgium), who regularly treated migraine patients, completed a questionnaire relating to four different case scenarios described in terms of symptoms, signs and medical history. Each GP completed clinical decision-trees which were created following IHS diagnostic criteria and published treatment guidelines.Results:Of those questioned, 90 accurately diagnosed a new migraine case and 54 prescribed early intervention with a triptan. However, 23.7 prescribed an NSAID, despite a past history of failed headache relief, and 7.2 indicated that they would refer their patients to a specialist. In the case of a patient whose migraine was deteriorating, 55 of GPs counselled early intervention with a triptan. For chronic migraine sufferers, 42.6 of GPs chose to refer them to a specialist, whilst about one-third made appropriate adjustments to the patient's treatment. The final case, tension-type headache, proved the most difficult scenario to assess, with only 26 of those questioned reaching an adequate diagnosis. Between-country differences in clinical practice may result from local reimbursement policy, treatment guidelines, and different healthcare systems/facilities (e.g., access to specialised care) – all of which could influence the results obtained.Conclusions:A questionnaire such as the HMP programme inherently has limited depth, and the sampling procedure (GPs with triptan knowledge from three countries) needs to be considered when interpreting the results. Nevertheless, the survey provides important information relating to the management of headache in primary care, highlighting the need for both continuing medical education and also improved referral to specialist care. [ABSTRACT FROM AUTHOR]

Published
2008
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15. Organisation of inhospital acute stroke care and minimum criteria for stroke care units. Recommendations of the Belgian Stroke Council

Author

Vincent Thijs, Peeters, A., Dewindt, A., Hemelsoet, D., Nina De Klippel, Laloux, P., Redondo, P., Patrick Cras, Desfontaines, P., Raf Brouns, Sylvie De Raedt, Landegem, W., Vandermeeren, Y., Vanhooren, G., Internal Medicine Specializations, Neurology, Clinical sciences, and Neuroprotection & Neuromodulation

Subjects
education, stroke-unit, cardiovascular diseases, Human medicine, stroke care, health care economics and organizations, belgian stroke council
Abstract

There is ample evidence from randomized trials that for patients with stroke, stroke unit care is superior to care in general medical or neurological wards. This evidence, which has been adopted by international guidelines has to be implemented into daily stroke care. This consensus document prepared by the Belgian Stroke Council provides a set of minimum criteria to meet international standards for stroke care. It is intended to provide help in the creation of stroke units in centers who do not currently have one and to provide a benchmark for centres already having organised stroke care.

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