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Traumatic brain injury – integrated approaches

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Traumatic brain injury (TBI) is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force.1 It varies in severity from mild TBI (which includes concussion) to moderate and severe TBI. Severe TBI carries a high mortality rate, estimated at 3040% in observational studies on unselected populations.2 Survivors experience a substantial burden of physical, psychiatric, emotional, and cognitive disabilities, which disrupt the life of individuals and families, and pose huge costs to society. Such disabilities are not restricted to more severe cases, but also occur frequently after moderate or mild TBI. TBI is a growing public health problem of substantial proportions. Over 50 million TBIs occur internationally each year.3 The epidemiology of TBI is changing: in high income countries (HIC), TBI incidence is rising in the elderly, while in low and middle income countries (LMIC), the burden of TBI from road traffic incidents is increasing. Across all ages, TBI represents 30 to 40% of all-injury related deaths, and neurological injury is expected to remain the most important cause of disability from neurological disease (2–3 times higher than that for Alzheimer disease or cerebrovascular disorders) till 2030.4 TBI costs the international economy approximately US $400 billion annually (which, given an estimated Standardized Gross World Product (SGWP) of $73·7 trillion5 , represents approximately 0·5% of the entire annual global output. The wide variations in clinical manifestations of TBI are attributable to the complexity of the brain, and to the pattern and extent of damage, which depends on type, intensity, direction and duration of the external forces that cause TBI. In traffic related injuries, acceleration-deceleration forces can result in immediate shearing of connecting nerve fibres, or trigger progressive loss of connectivity over time. Forces generated by a fall or blow to the head more often cause bruises (contusions). Individuals may react very differently to similar injury forces. Conceptually, it is important to distinguish between the primary damage, inflicted at the time of injury, and secondary damage, which evolves over hours, days, weeks, or months, or even over a lifetime in some cases. Secondary damage is substantially driven by host responses to the primary injury. As a bruised ankle may swell following injury, so may the brain. The difference is that the brain is contained within the rigid skull, and any swelling results in increased pressure within the skull. This increased pressure, in turn, can lead to life threatening shifts of brain structures or make it more difficult for blood to flow through the brain, resulting in ischaemia and deprivation of oxygen to the brain. TBI is best viewed as a collection of different disease processes (figure 1), with different clinical patterns and outcomes, each requiring different approaches to diagnosis and management. TBI may also impose a long-term risk for neurodegenerative disorders6,7, stroke8,9, Parkinsonism10,11,12 , epilepsy13 and an increased long-term mortality rate14,15 compared to the general population. These risks also occur in milder forms of TBI, especially after repetitive injuries. This accumulating knowledge makes it clear that TBI is not a single event, but can be a chronic and often progressive disease with long-term consequences (see Patient Testimony, which illustrates a continuing process of coping and adaptation – even following an ostensibly good recovery). Clinical progress has not kept pace with the rising global burden of TBI and recognition of the prolonged effects of injury. The most recent major breakthrough in clinical management was the introduction of Computerized Tomography (CT) scanning into routine care – now more than 40 years ago. However, since then, outcome after TBI has seen no major improvement in HICs with developed trauma systems. This lack of progress is caused by many factors, both political and clinical. Public and political awareness of the magnitude of the problem caused by TBI—including the clinical impact on patients, families, and society, and public health burden and costs to society—is low. In addition, there has been insufficient clinical recognition of the complex heterogeneity of TBI, in terms of disease type, outcome, and prognosis. Treatment approaches provide insufficient recognition of specific needs of individual patients, and disconnects exist along the chain of trauma care, especially between acuteand post-acute care. Clinical research has, until recently, mainly focussed on more severe TBI, but the vast majority (70 to 90%) of patients suffer from mild TBI. Though the individual impact of mild TBI is less, the category as a whole makes the largest contribution to the global burden of disability, and structured follow-up and timely intervention in this group could deliver substantial gains in public health and societal costs.16 We believe that a strategic global collaboration is required at several levels. First, policy makers and funders need to support an integrated effort by the entire neurotrauma community to identify best practices for systems of care and management, including approaches to TBI prevention. Second, our research strategies need to better characterize TBI through the disease course, and incorporate emerging research paradigms and tools into clinical studies. While the need for increased research funding is undeniable, these organizational improvements are essential to maximize the benefit of developing global research collaborations, and achieve the best possible returns on research funding. Finally, we need an intensive knowledge transfer exercise to implement the outputs of these efforts into clinical practice. Such implementation requires that we inform and involve health policy makers, health care professionals, and the general public, regarding the magnitude of the problem, the extent of (and gaps in) our current knowledge, and emerging advances. The overall aims of this Commission are to set out directions for improvements in clinical care and to establish research priorities. We aim to provide a foundation for implementation of policy measures that minimize the risk of TBI and maximize chances of recovery when it does happen. This manuscript represents the efforts of a consortium of leading health-care professionals with expertise in epidemiology, health economics, diagnosis, treatment, outcome assessment, biology, and ethics, all of whom are involved in the International Initiative for Traumatic Brain Injury Research (InTBIR) studies, with input provided by other collaborating specialists and, crucially, by patients.

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Traumatic brain injury – integrated
approaches to improving clinical care and
research

,Andrew I.R. Maas, MD1$; David K. Menon, MD2$; P. David Adelson, MD1;
Nada Andelic, MD4; Michael J. Bell, MD5; Antonio Belli, MD6; Peter Bragge,
PhD7 ; Alexandra Brazinova, MD8; Andras Buki, MD9; Randall M. Chesnut,
MD10; Giuseppe Citerio, MD11,12; Mark Coburn, MD13; D. Jamie Cooper, MD14;
A. Tamara Crowder, PhD15; Endre Czeiter, MD9; Marek Czosnyka, PhD16;
Ramon Diaz-Arrastia, MD17; Jens P. Dreier, MD18; Ann-Christine Duhaime,
MD19; Ari Ercole, MD2; Thomas A. van Essen, MD20,21; Valery L. Feigin, MD22;
Guoyi Gao, MD23; Joseph Giacino, PhD24; Laura E. Gonzalez-Lara, PhD25;
Russell L. Gruen, MD26; Deepak Gupta, MD27; Jed A. Hartings, PhD28; Sean Hill,
PhD29; Ji-yao Jiang23, MD; Naomi Ketharanathan MD30; Erwin J.O. Kompanje,
MD31; Linda Lanyon, PhD32; Steven Laureys, MD33; Fiona Lecky, MD34; Harvey
Levin, PhD35; Hester F. Lingsma, PhD36; Marc Maegele, MD37; Marek Majdan,
PhD8; Geoffrey Manley, MD38; Jill Marsteller, PhD39; Luciana Mascia, MD40;
Charles McFadyen, BMBCh2; Stefania Mondello, MD41; Virginia Newcombe,
MD2; Aarno Palotie, MD42,43,44; Paul M. Parizel, MD45; Wilco Peul, MD20;
Suzanne Polinder, PhD36; Louis Puybasset, MD46; Todd E. Rasmussen,
MD15,47,48; Rolf Rossaint, MD13; Peter Smielewski, PhD16; Jeannette Söderberg,
PhD32; Simon Stanworth, MD49; Murray B. Stein, MD50; Nicole von
Steinbüchel, PhD51; William Stewart, MBChB52; Ewout W. Steyerberg36,53,
PhD; Nino Stocchetti, MD54; Anneliese Synnot, MPH55,56; Braden Te Ao22, PhD;
Dick Tibboel30, MD; Alice Theadom, PhD22; Walter Videtta, MD57; Kevin K.W.
Wang, PhD58; W. Huw Williams, PhD59; Lindsay Wilson, PhD60; Kristine Yaffe,
MD61; for the InTBIR# Participants and Investigators*

$
First and second author have equally contributed to the manuscript
#
: International Traumatic Brain Injury Research (InTBIR) Initiative
*Listed at the end of the manuscript




1
Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, Arizona




© 2017. This manuscript version is made available under the Elsevier user license
http://www.elsevier.com/open-access/userlicense/1.0/

,1
Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium
2
Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK


4
Division of Clinical Neuroscience, Department of Physical Medicine and Rehabilitation, Oslo University
Hospital and University of Oslo, Oslo, Norway
5
University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
6
NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham, UK
7
BehaviourWorks Australia, Monash Sustainable Development Institute, Monash University, Victoria, Australia
8
Department of Public Health, Faculty of Health Sciences and Social Work, Trnava University, Trnava, Slovakia.
9
Department of Neurosurgery, University of Pecs and MTA-PTE Clinical Neuroscience MR Research Group and
Janos Szentagothai Research Centre, University of Pecs, Hungarian Brain Research Program, Pecs, Hungary
10
Departments of Neurological Surgery, Orthopaedics and Sports Medicine University of Washington,
Harborview Medical Center, Seattle, WA, USA
11
School of Medicine and Surgery, Università Milano Bicocca, Milano, Italy
12
NeuroIntensive Care, Azienda Ospedaliera San Gerardo di Monza, Monza, Italy
13
Department of Anaesthesiology, University Hospital RWTH Aachen, Aachen, Germany
14
School of Public Health & PM, Monash University and The Alfred Hospital, Melbourne, Victoria, Australia
15
US Combat Casualty Care Research Program, Fort Detrick, MD, USA
16
Brain Physics Lab, Division of Neurosurgery, Dept of Clinical Neurosciences, University of Cambridge,
Addenbrooke’s Hospital, Cambridge, UK
17
Department of Neurology and Center for Brain Injury and Repair, University of Pennsylvania Perelman School
of Medicine, Philadelphia, USA,
18
Centrum für Schlaganfallforschung, Charité – Universitätsmedizin Berlin, Berlin, Germany
19
Department of Neurosurgery, Harvard Medical School, Boston, Massachusetts, USA
20
Dept. of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands
21
Dept. of Neurosurgery, Medical Center Haaglanden, The Hague, The Netherlands
22
National Institute for Stroke and Applied Neurosciences, Faculty of Health and Environmental Studies,
Auckland University of Technology, Auckland, New Zealand
23
Department of Neurosurgery, Shanghai Renji hospital, Shanghai Jiaotong University/school of medicine,
Shanghai, China
24
Department of Physical Medicine and Rehabilitation, Harvard Medical School and Spaulding Rehabilitation
Hospital, Charlestown, Massachusetts, USA
25
The Brain and Mind Institute, Western University, London, Ontario, Canada
26
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; and Monash University,
Australia
27
Department of Neurosurgery, Neurosciences Centre & JPN Apex trauma centre, All India Institute of Medical
Sciences, New Delhi-110029, India.
28
Department of Neurosurgery, University of Cincinnati, Cincinnati, Ohio, United States
29
Blue Brain Project, EPFL, Geneva, Switzerland CH-1202
30
Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center, Sophia Children’s Hospital,
Rotterdam, The Netherlands
31
Department of Intensive Care, Erasmus MC University Medical Center Rotterdam, the Netherlands
32
Karolinska Institutet, INCF International Neuroinformatics Coordinating Facility, Stockholm, Sweden
33
Cyclotron Research Center , University of Liège, Liège, Belgium
34
Centre for Urgent and Emergency Care Research (CURE), Health Services Research Section, School of Health
and Related Research (ScHARR), University of Sheffield, Sheffield ,UK
35
Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas, USA
36
Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
37
Cologne-Merheim Medical Center (CMMC), Department of Traumatology, Orthopedic Surgery and

, Sportmedicine, Witten/Herdecke University, Cologne, Germany
38
Department of Neurological Surgery, University of California, San Francisco, California, USA
39
Johns Hopkins School of Medicine, Baltimore, Maryland, USA
40
Department of medical and surgical Science and Biotechnologies, Sapienza University of Rome, Rome, Italy 41
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Italy
42
Analytic and Translational Genetics Unit, Department of Medicine; Psychiatric & Neurodevelopmental
Genetics Unit, Department of Psychiatry; Department of Neurology, Massachusetts General Hospital, Boston,
MA, USA


43
Program in Medical and Population Genetics; The Stanley Center for Psychiatric Research, The Broad
Institute of MIT and Harvard, Cambridge, MA, USA
44
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
45
Department of Radiology, Antwerp University Hospital and University of Antwerp, Edegem, Belgium
46
Department of Anesthesiology and Critical Care, Pitié -Salpêtrière Teaching Hospital, Assistance Publique,
Hôpitaux de Paris and University Pierre et Marie Curie, Paris, France
47
Uniformed Services University, Bethesda, MD, USA
48
Walter Reed Department of Surgery Bethesda, MD, USA
49
NHS Blood and Transplant Level 2, John Radcliffe Hospital, Oxford, UK
50
Department of Psychiatry and Department of Family Medicine and Public Health, UCSD School of Medicine,
La Jolla California, USA
51
Institute of Medical Psychology and Medical Sociology, Universitätsmedizin Göttingen, Göttingen, Germany 52
Department of Neuropathology, Queen Elizabeth University Hospital and University of Glasgow, Glasgow, UK
53
Dept of medical statistics and bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
54
Department of Pathophysiology and Transplantation, Milan University, and Neuroscience ICU, Fondazione
IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
55
Australian & New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine,
Monash University, Australia
56
Centre for Health Communication and Participation, School of Psychology and Public Health, La Trobe
University, Melbourne, Australia
57
Hospital Nacional Professor Alejandro Posadas, Illia y Marconi El Palomar, Buenos Aires, Argentina
58
Department of Psychiatry, University of Florida, Gainesville, Florida, USA
59
Centre for Clinical Neuropsychology Research, Department of Psychology, University of Exeter, UK
60
Division of Psychology, University of Stirling, Stirling, UK
61
Divisions of Psychiatry, Neurology and Epidemiology, UCSF School of Medicine, San Francisco, California, USA

Corresponding authors:

Andrew I.R. Maas, MD
Department of Neurosurgery, Antwerp University Hospital / University of Antwerp
Wilrijkstraat 10
2650 Edegem – Belgium Phone:
+ 32 3 821 46 32
E-mail:

David K. Menon, MD
Division of Anaesthesia, University of Cambridge
Box 93, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK.
Telephone +44 1223 217889; Fax: +44 1223 217887
E-mail:

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