Research considerations for prospective studies of patients with coma and disorders of consciousness
Authors: Tinti Lorenzo , Lawson Thomas , Molteni Erika , Kondziella Daniel , Rass Verena , Sharshar Tarek , Bodien Yelena G , Giacino Joseph T , Mayer Stephan A , Amiri Moshgan , Muehlschlegel Susanne , Venkatasubba Rao Chethan P , Vespa Paul M , Menon David K , Citerio Giuseppe , Helbok Raimund , McNett Molly ,   The Curing Coma Campaign Collaborators, Agarwal Sachin , Aiyagari Venkatesh , Akbari Yama , Albertson Asher , Alexander Sheila , Alexandrov Anne , Alkhachroum Ayham , Al-Mufti Fawaz , Amiri Moshagan , Appavu Brian , Gebrewold Meron Awraris , Ayounb Marc , Badenes Rafael , Bader Mary Kay , Badjiata Neeraj , Balu Ram , Barlow Brooke , Barra Megan , Beekman Rachel , Beghi Ettore , Beqiri Erta , Berlin Tracey , Bilotta Federico , Bleck Thomas , Bodien Yelena , Boerwinkle Varina , Boly Melanie , Bonnel Alexandra , Brazzi Luca , Brown Emery , Bulic Sebina , Caceres Eder , Caceres Adrian , Cafiero Tullio , Carroll Elizabeth , Cediel Emilio G , Chou Sherry , Citerio Giuseppe , Claassen Jan , Condie Chad , Conti Alfredo , Cosmas Katie , Costa Paolo , Creutzfeldt Claire , Dangayach Neha , Dauri Mario , Debicki Derek , DeGeorgia Michael , Der-Nigoghossian Caroline , Desai Masoom , Dhar Rajat , Diringer Michael , Durr Emily , Edlow Brian , Ercole Ari , Estraneo Anna , Falcone Guido , Farrokh Salia , Ferguson Adam , Fernandez-Espejo Davinia , Fink Ericka , Fins Joseph , Foreman Brandon , Franchi Federico , Frontera Jennifer , Ganesan Rishi , Gaspard Nicolas , Ghavam Ahmeneh , Giacino Joseph , Gibbons Christie , Gilmore Emily , Glustein Chavie , Gosseries Olivia , Green Theresa , Greer David , Guanci Mary , Gupta Deepak , Hahn Cecil , Hakimi Ryan , Hammond Flora , Hanley Daniel F , Hartings Jed , Hassan Ahmed , Helbok Raimund , Hemphill Claude , Da Cunha Arthur Henrique Galvão Bruno , Hinson Holly , Hirsch Karen , Hocker Sarah , Hu Peter , Hu Xiao , Human Theresa , Hwang David , Illes Judy , Jaffa Matthew , James Michael L , Janas Anna , Johnson Susan , Jones Morgan , Jox Ralf J , Kalanuria Atul , Keller Emanuela , Kennedy Lori , Kennelly Megan , Keogh Maggie , Kim Jenn , Kim Keri , Kirsch Hannah , Kirschen Matthew , Ko Nerissa , Kondziella Daniel , Kreitzer Natalie , Kromm Julie , Kumar Abhay , Kurtz Pedro , Laureys Steven , Lawson Thomas , Lejeune Nicolas , Lewis Ariane , Liang John , Ling Geoffrey , Livesay Sarah , Luppi Andrea , MacDonald Jennifer , Maddux Craig , Mahanes Dea , Mainali Shraddha , Maldonado Nelson , Ribeiro Rennan Martins , Mascia Luciana , Massimini Marcello , Mathur Rohan , Mayer Stephan , McCredie Victoria , McNett Molly , Mejia-Mantilla Jorge , Mendoza Michael , Menon David , Meyfroidt Geert , Mijangos Julio , Moberg Dick , Moheet Asma , Molteni Erika , Montalenti Elisa , Monti Martin , Morrison Chris , Muehlschlegel Susanne , Munar Marina , Murtaugh Brooke , Naccache Lionel , Nagayama Masao , Nairon Emerson , Nakagawa Thomas , Naldi Andrea , Narenthiran Ganesalingam , Natarajan Girija , Nemetsky Esther , Newcombe Virginia , Nielsen Niklas , Niznick Naomi , Noronha-Falcão Filipa , Nyquist Paul , Olson DaiWai , Othman Marwan , Owen Adrian , Padayachy Llewellyn , Pajoumand Mehrnaz , Park Soojin , Pergakis Melissa , Perry Heidi , Polizzotto Len , Pouratian Nader , Spivack Marilyn Price , Prisco Lara , Provencio Javier , Puglises Francesco , Puybasset Louis , Rao Chethan , Rasmussen Lindsay , Rass Verena , Rasulo Frank , Ray Bappaditya , Ricci Zaccaria , Richardson Risa , Shinotsuka Cassia Righy , Robba Chiara , Robertson Courtney , Rohaut Benjamin , Rolston John , Romagnoli Stefano , Rosanova Mario , Rosenthal Eric , Rowe Shaun , Rubin Michael , Russell Mary Beth , Silva Gisele Sampaio , Sanz Leandro , Sarasso Simone , Sarwal Aarti , Schiff Nicolas , Schnakers Caroline , Seder David , Shah Vishank Arun , Shapiro-Rosenbaubm Amy , Shapshak Angela , Sharma Kartavya , Sharma Kumar Ajay , Sharshar Tarek , Shutter Lori , Sitt Jacobo , Slomine Beth , Smetana Keaton , Smielewski Peter , Smith Wade , Stamatakis Emmanuel , Steinberg Alexis , Stevens Robert , Suarez Jose , Sung Gene , Sussman Bethany , Taran Shaurya , Mazzeo Anna Teresa , Thibaut Aurore , Thompson David , Threlkeld Zachary , Tinti Lorenzo , Toker Daniel , Torbey Michel , Tosto Jenna , Trevick Stephen , Tsaousi Georgia , Turgeon Alexis , Udy Andrew , Varelas Panos , Vespa Paul , Videtta Walter , Voss Henning , Vox Ford , Wagner Amy , Wahlster Sarah , Wainwright Mark , Whyte John , Witherspoon Briana , Yakhkind Aleksandra (Sasha) , Yeager Susan , Young Michael , Zafar Sahar , Zafonte Ross , Zahuranec Darin , Zammit Chris , Zhang Bei , Ziai Wendy , Zimmerman Lara , Zink Elizabeth 
Published: January 2024

Abstract
Disorders of consciousness are neurological conditions characterized by impaired arousal and awareness of self and environment. Behavioural responses are absent or are present but fluctuate. Disorders of consciousness are commonly encountered as a consequence of both acute and chronic brain injuries, yet reliable epidemiological estimates would require inclusive, operational definitions of the concept, as well as wider knowledge dissemination among involved professionals. Whereas several manifestations have been described, including coma, vegetative state/unresponsive wakefulness syndrome and minimally conscious state, a comprehensive neurobiological definition for disorders of consciousness is still lacking. The scientific literature is primarily observational, and studies-specific aetiologies lead to disorders of consciousness. Despite advances in these disease-related forms, there remains uncertainty about whether disorders of consciousness are a disease-agnostic unitary entity with a common mechanism, prognosis or treatment response paradigm. Our knowledge of disorders of consciousness has also been hampered by heterogeneity of study designs, variables, and outcomes, leading to results that are not comparable for evidence synthesis. The different backgrounds of professionals caring for patients with disorders of consciousness and the different goals at different stages of care could partly explain this variability. The Prospective Studies working group of the Neurocritical Care Society Curing Coma Campaign was established to create a platform for observational studies and future clinical trials on disorders of consciousness and coma across the continuum of care. In this narrative review, the author panel presents limitations of prior observational clinical research and outlines practical considerations for future investigations. A narrative review format was selected to ensure that the full breadth of study design considerations could be addressed and to facilitate a future consensus-based statement (e.g. via a modified Delphi) and series of recommendations. The panel convened weekly online meetings from October 2021 to December 2022. Research considerations addressed the nosographic status of disorders of consciousness, case ascertainment and verification, selection of dependent variables, choice of covariates and measurement and analysis of outcomes and covariates, aiming to promote more homogeneous designs and practices in future observational studies. The goal of this review is to inform a broad community of professionals with different backgrounds and clinical interests to address the methodological challenges imposed by the transition of care from acute to chronic stages and to streamline data gathering for patients with disorders of consciousness. A coordinated effort will be a key to allow reliable observational data synthesis and epidemiological estimates and ultimately inform condition-modifying clinical trials.