- Open Access
Rehabilitation and outcomes after complicated vs uncomplicated mild TBI: results from the CENTER-TBI study
BMC Health Services Research volume 22, Article number: 1536 (2022)
Despite existing guidelines for managing mild traumatic brain injury (mTBI), evidence-based treatments are still scarce and large-scale studies on the provision and impact of specific rehabilitation services are needed. This study aimed to describe the provision of rehabilitation to patients after complicated and uncomplicated mTBI and investigate factors associated with functional outcome, symptom burden, and TBI-specific health-related quality of life (HRQOL) up to six months after injury.
Patients (n = 1379) with mTBI from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study who reported whether they received rehabilitation services during the first six months post-injury and who participated in outcome assessments were included. Functional outcome was measured with the Glasgow Outcome Scale – Extended (GOSE), symptom burden with the Rivermead Post Concussion Symptoms Questionnaire (RPQ), and HRQOL with the Quality of Life after Brain Injury – Overall Scale (QOLIBRI-OS). We examined whether transition of care (TOC) pathways, receiving rehabilitation services, sociodemographic (incl. geographic), premorbid, and injury-related factors were associated with outcomes using regression models. For easy comparison, we estimated ordinal regression models for all outcomes where the scores were classified based on quantiles.
Overall, 43% of patients with complicated and 20% with uncomplicated mTBI reported receiving rehabilitation services, primarily in physical and cognitive domains. Patients with complicated mTBI had lower functional level, higher symptom burden, and lower HRQOL compared to uncomplicated mTBI. Rehabilitation services at three or six months and a higher number of TOC were associated with unfavorable outcomes in all models, in addition to pre-morbid psychiatric problems. Being male and having more than 13 years of education was associated with more favorable outcomes. Sustaining major trauma was associated with unfavorable GOSE outcome, whereas living in Southern and Eastern European regions was associated with lower HRQOL.
Patients with complicated mTBI reported more unfavorable outcomes and received rehabilitation services more frequently. Receiving rehabilitation services and higher number of care transitions were indicators of injury severity and associated with unfavorable outcomes. The findings should be interpreted carefully and validated in future studies as we applied a novel analytic approach.
A high number of patients experience prolonged symptoms, disabilities, and diminished health-related quality of life (HRQOL) after mild traumatic brain injury (mTBI) [1, 2]. In the first six months after injury, patients with complicated mTBI (presence of intracranial injury on computed tomography, CT) report higher symptom burden, poorer functional outcomes and lower HRQOL than those with uncomplicated injury [1, 3,4,5]. A subgroup of patients with mTBI and extra-cranial injuries also report more symptoms and functional deficits . These patients tend to have longer acute hospital stays and several different care pathways  and are often in need of regular follow-up and provision of acute and post-acute rehabilitation services . Substantial geographical variation exists in the organization and provision of acute and post-acute rehabilitation services, which influences outcomes of TBI and challenges comparison of results across studies .
Although several guidelines exist on how to manage prolonged symptoms after mTBI, evidence-based treatments are lacking, leading to a risk of inadequate rehabilitation or no rehabilitation at all. In general, there are several challenges in the context of mTBI rehabilitation research, including relatively small sample sizes, and heterogeneity in clinical characteristics, interventions, and outcome measures . A recent systematic review on specialized rehabilitation after mTBI highlighted a need for studies with a larger age range, applying sensitive outcome measures focusing on aspects influenced by mTBI, and assessment at an early stage to identify those with an increased risk of long-term symptoms in need of rehabilitation .
This study will use the large patient sample of adults and elderly from the Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI) study  to investigate rehabilitation services provided after mTBI and factors associated with global functioning, symptom burden, and TBI-specific HRQOL six months after injury.
The specific objectives are to
Describe transition of care (TOC) pathways and rehabilitation provision to patients after complicated and uncomplicated mTBI in the first six months after the injury.
Investigate the association between sociodemographic (incl. geographic), premorbid, and injury-related factors, rehabilitation and transitions of care and functional outcome, symptom burden, and TBI-specific HRQOL six months after complicated and uncomplicated mTBI.
Based on the literature, we assume that patients with mTBI, in general, are provided few rehabilitation services. However, we expect that patients with complicated mTBI receive more rehabilitation services than those with uncomplicated mTBI. We also hypothesize that provision of services will be related to the severity of brain injury and overall injury severity, regardless of functional level and symptom burden.
Study design and participants
Participants were recruited between December 19, 2014 and December 17, 2017 within CENTER-TBI, a multicenter, prospective observational longitudinal cohort study conducted in Europe and Israel. The trial was registered at ClinicalTrials.gov on 06.08.2014 (#NCT02210221, https://clinicaltrials.gov/ct2/show/NCT02210221). The core study covered all spectrums of TBI severity (i.e., mild, moderate, and severe) and included N = 4509 patients from 65 centers. Included patients had a clinical diagnosis of TBI, an indication for CT scan, and presented to a medical center within 24 h post-injury. Individuals with severe pre-existing neurological disorders were excluded from the core study. First, all patients were evaluated in the emergency room (ER). Then, depending on patients’ needs, three clinical care pathways were differentiated: ER (patients seen in the ER and then discharged), admission to a hospital ward (ADM), or to an intensive care unit (ICU). Further details on the main descriptive findings of CENTER-TBI can be found elsewhere .
In the present study, we included N = 1379 individuals aged 16 years and above who had sustained a mTBI based on baseline Glasgow Coma Scale (GCS)  values (i.e., 13–15). All participants completed the outcome instruments and provided information on receiving rehabilitation services or not within the first six months after injury.
The CENTER-TBI study (EC grant 602,150) was conducted in accordance with all relevant laws of the European Union (EU) and all relevant laws of the countries where the recruiting sites were located. Informed consent was obtained from the patients and/or the legal representative/next of kin, according to the local regulations for all participants recruited in the Core Dataset of CENTER-TBI and documented in the electronic case report form (e-CRF). For the full list of sites, ethical committees, and ethical approval details, see the official CENTER-TBI website (https://www.center-tbi.eu/project/ethical-approval).
Data and instruments
Sociodemographic, premorbid, and injury-related data (independent variables)
Sociodemographic and injury-related data were collected at the time of study enrollment. Data comprised the following variables: sex (female or male), age (continuous and dichotomized at median value), education (continuous, i.e., in years, and dichotomized at median value), living situation (living alone or not alone), work participation (employed, unemployed, and others, i.e., retired, studying, or homemaker).
The geographical region was determined based on the country of the participating sites using the EU Vocabularies classification (EuroVoc) . Austria, Belgium, France, Germany, the Netherlands, and the United Kingdom were grouped into Western European countries; Italy and Spain into Southern region; Denmark, Finland, Latvia, Lithuania, Norway, and Sweden into Northern region; Hungary, Romania, and Serbia represented Eastern Europe. Southern and Eastern European regions were collapsed into one group due to the small number of participants. Because we were mainly interested in assessing rehabilitation and outcomes across Europe, we limited the analyses to European countries.
The premorbid somatic health status (healthy, mild systemic disease, severe systemic disease, and severe systemic disease with constant threat to life) was determined based on the classification of the American Society of Anesthesiologists Physical Status Classification System . Due to a low number of cases, both severe groups were collapsed into one (i.e., severe systematic disease). Premorbid psychological problems were self-reported by the participants (yes/no).
Injury-related data included injury mechanism (road traffic accident, fall, and others), clinical care pathways (ER, ADM, and ICU), the most frequent TOC pathways (ER, ICU, neurological hospital ward [WN], other ward [WO], rehabilitation [RE], home [HO], nursing home [NS]), number of TOC, TBI severity as measured by the GCS with additional classification based on information on the presence of any intracranial abnormalities on the first CT scan (uncomplicated mTBI: GCS ≥ 13 and no abnormalities on the CT scan; complicated mTBI: GCS ≥ 13 and visible abnormalities on the CT scan), brain injury severity assessed by the Abbreviated Injury Scale  (AIS; Brain injury AIS, score ≥ 3 considered as severe intracranial injury), and extracranial injury severity as measured by the Injury Severity Score (ISS) . The ISS ranges from 0 (no trauma) to 75 (not survivable), and a score > 15 is considered as major overall trauma .
The information on rehabilitation was based on the self-reported rehabilitation services received within the first six months (i.e., either at three or six months) after TBI and distinguished between no rehabilitation (0) and any kind of rehabilitation including in- and out-patient services (1). Additionally, we summarized information on TOC reporting all transitions including information on discharge to a rehabilitation unit.
The number of rehabilitation services provided was determined by summation of the self-reported information on rehabilitation provision received in various domains (i.e., occupational therapy, physiotherapy, cognitive rehabilitation, speech therapy, and psychological services). Since multiple answers were allowed, we aggregated this information by distinguishing between three groups: no help provided, help provided at least for one domain, and at least for two domains.
The timing of rehabilitation was defined as: early rehabilitation (within one to three months after injury) and late rehabilitation (later than three months after injury).
Outcome instruments (dependent variables)
The functional recovery status of the participants was assessed using the Glasgow Outcome Scale – Extended (GOSE) . The GOSE is a clinician-reported outcome instrument evaluating functional recovery after TBI on an eight-point scale (1: dead, 2: vegetative state, 3/4: lower/upper severe disability, 5/6: lower/upper moderate disability, 7/8: lower/upper good recovery). Additionally, information can be obtained from the patients or their proxies using the questionnaire version—GOSE-Q . In the present study, missing information on the GOSE was centrally replaced by values substituted from the GOSE-Q or clinical ratings to avoid data loss. Since the GOSE-Q is not able to differentiate between vegetative state and lower severe disability, GOSE levels 2 and 3 were collapsed into one category (2 or 3). The missing values at six-months outcome assessments were imputed using a multi-state model .
The symptom burden was quantified using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) . The RPQ is a patient-reported outcome measure (PROM) using a five-point Likert scale (from 0: not experienced at all to 4: a severe problem) to evaluate 16 post-concussion symptoms during the past 24 h compared with the condition before the accident: headache, dizziness, nausea and/or vomiting, noise sensitivity, sleep disturbance, fatigue, irritability, depression, frustration, forgetfulness and poor memory, poor concentration, slow thinking, blurred vision, light sensitivity, double vision, and restlessness. As advised by King et al. , all scores of 1 (indicating that the problem was the same as before the injury) were removed. The RPQ total score ranges from 0 to 64.
The TBI-related HRQOL was measured by the Quality of Life after Brain Injury—Overall Scale (QOLIBRI-OS) . The QOLIBRI-OS is a short PROM assessing physical condition, cognition, emotions, daily life and autonomy, social relationships, and current and future prospects. The six items are rated on a five-point Likert scale (from 0: not at all to 4: very). The transformed total score ranges from 0 to 100.
Descriptive analyses were carried out to summarize the characteristics of the patients. We report mean, standard deviation, median, and range for continuous data and absolute and relative frequencies for categorical data. Mann–Whitney U tests for continuous data and Chi-square tests for categorical data were applied for comparative analyses.
The number of missing values in independent variables varied from < 1% (premorbid somatic health status) to 15% (education). Missing data – assumed as missing at random (MAR) – were imputed using multivariate imputation by chained equations (MICE).
Three independent regression models were applied to estimate the associations between sociodemographic (incl. geographic), premorbid, and injury-related factors and respective outcomes (functional recovery status, symptom burden, and TBI-specific HRQOL). We also performed regression analyses in the subsample of the patients with more severe overall trauma (i.e., ISS > 15) to receive a more accurate picture of the influence of the factors on the outcomes in this subsample.
To allow for easy comparison of the results from the regression analyses, we estimated ordinal regression models for all outcomes grouping the scores based on quantiles (i.e., 25%, 50%, and 75%). This classification resulted in three categories for the GOSE since the 75% quantile represented the maximum of the scale: GOSE ≤ 6 (up to moderate recovery), GOSE = 7 (average good recovery), and GOSE 8 = (full recovery). The quantiles for the RPQ resulted in the following four categories: RPQ = 0 (no symptom burden), 0 < RPQ ≤ 6 (low average symptom burden), 6 < RPQ ≤ 16 (high average symptom burden), and RPQ > 16 (high symptom burden). The QOLIBRI-OS had the following four groups: QOLIBRI-OS ≤ 58 (low HRQOL), 58 < QOLIBRI-OS ≤ 75 (low average HRQOL), 75 < QOLIBRI-OS ≤ 83 (high average HRQOL), and QOLIBRI-OS > 83 (high HRQOL).
Since the main goal was to find associations between the outcomes and the chosen factors, we did not focus on the validation of the regression models and did not report the goodness of model fit.
All analyses were performed with the R version 4.0.2  using the packages table 1  for descriptive analyses and mice  for the imputation of the missing values. The significance level was set at 5%.
The total sample comprised of 1379 participants (62.9% males, 96% White) with an average age of 52 ± 19 years (Mdn = 54, range 16–93). For more details, see the sample attrition plot in Fig. 1.
The distribution of uncomplicated and complicated mTBI was equal (51% and 49%, respectively). Injuries were predominantly caused by falls (47.2%) followed by road traffic accidents (39.3%). At six months after TBI, most individuals (72.9%) showed good recovery (GOSE: 7–8).
The uncomplicated and complicated mTBI group comparisons revealed significant differences regarding age, years of education, employment status, and injury- and rehabilitation-related factors (see Table 1).
Transition of care (TOC) pathways
Overall, most of the patients were discharged from the ER back home (26.8%), of whom the majority had sustained an uncomplicated mTBI (85.2%). The average number of TOC differed significantly between the mTBI groups averaging 2 ± 1 in the uncomplicated mTBI group and 3 ± 1 in the complicated mTBI group (W = 89.28, p < 0.001). Admission to an inpatient rehabilitation facility at least once during the TOC pathways amounted to 9% of the total sample and 24% for those who reported receiving any kind of rehabilitation during the first half year after TBI. For visualization of the most frequent TOC pathways (n > 20), see Fig. 2. Additional visualization of the TOC pathways of the patients with major trauma is provided in Additional file 1 – Figure A1.
Rehabilitation and provided professional help after mTBI
Rehabilitation services were more frequently provided to patients with complicated mTBI compared to uncomplicated mTBI (42.6% vs. 20.0%). Among those who received any kind of rehabilitation services within six months after mTBI (n = 439), 87.9% were treated within the first three months after TBI.
Professional help was provided primarily in physical and cognitive domains. Physical therapy ranked first (76.1%), followed by occupational therapy (27.6%), and cognitive rehabilitation (26.4%). Most of those who received rehabilitation (45.1%) received professional help in more than one domain. The trend was similar between the mTBI groups, with individuals receiving professional help less frequent after uncomplicated mTBI (see Fig. 3). For details on the subsample with major trauma, see Additional file 1 – Figure A2.
Regression analyses results
Functional recovery (GOSE)
Higher probability of better functional recovery was associated with the following factors: being male (compared to being female: OR = 1.86, CI95%:1.48–2.34), having more than 13 years of education (compared to having less than 13 years of education: OR = 1.38, CI95%:1.09–1.76), being retired, student, or homemaker (collapsed into one category called “other” compared to being employed: OR = 1.45, CI95%:1.13–1.86), and sustaining a fall (compared to road traffic accident: OR = 1.60, CI95%:1.25–2.04). In contrast, the following factors showed lower probability of a better recovery compared to respective reference groups: having premorbid psychological problems (OR = 0.65, CI95%:0.47–0.90), sustaining a complicated mTBI (OR = 0.67, CI95%:0.51–0.89), having a higher number of TOC (OR = 0.76, CI95%:0.67–0.86), being discharged to another facility (OR = 0.33, CI95%:0.11–0.99) or being discharged to a rehabilitation facility (OR = 0.59, CI95%:0.36–0.97). In addition, sustaining major trauma (OR = 0.70, CI95%:0.52–0.95) and receiving rehabilitation (OR = 0.40, CI95%:0.31– 0.52) was associated with lower probability of a more favorable recovery. For an overview, see Fig. 4; for more details on regression analyses results, see Additional file 2 – Table A1.
Symptom burden (RPQ)
The probability of a lower symptom burden was associated with the following factors: being male (OR = 0.52, CI95%:0.42–0.65), having more than 13 years of education (OR = 0.77, CI95%:0.61–0.98), being retired, student/school going, or homemaker (collapsed into one category called “other”; OR = 0.74, CI95%:0.59–0.94), and sustaining a fall (OR = 0.66, CI95%:0.53–0.83). The following factors were associated with probability of a higher symptom burden: having a severe premorbid health condition (OR = 1.47, CI95%:1.01–2.16), premorbid psychological problems (OR = 2.27, CI95%:1.66–3.10), a higher number of TOC (OR = 1.13, CI95%:1.01–1.26), and receiving rehabilitation (OR = 2.30, CI95%:1.81– 2.92). For an overview, see Fig. 5; for more details on regression analyses results, see Additional file 2 – Table A2.
The probability of better HRQOL was associated with the following factors: being male (OR = 1.32, CI95%:1.07–1.63) and having more than 13 years of education (OR = 1.36, CI95%:1.09–1.70).
In contrast, the following factors showed a lower probability of a higher HRQOL: being unemployed (OR = 0.36, CI95%:0.23–0.58), living in Southern or Eastern Europe (OR = 0.51, CI95%:0.40–0.66), having a mild (OR = 0.77, CI95%:0.60–0.97) or severe health condition prior to TBI (OR = 0.37, CI95%:0.25–0.55), suffering from psychological problems before TBI (OR = 0.40, CI95%:0.29–0.56), having a higher number of TOC (OR = 0.87, CI95%:0.78–0.97), and receiving rehabilitation (OR = 0.46, CI95%:0.36– 0.59). For an overview, see Fig. 6; for more details on regression analyses results, see Additional file 2 – Table A3.
Additional analyses in the subsample of the patients with major trauma were carried out for the functional recovery status only as the ISS in the main analyses was associated with lower probability of a better functional outcome. However, the sub-analyses did not find other important associations of interest. For further details, see Additional file 2 – Table A4.
This is the first European study to describe the provision of rehabilitation to patients with complicated and uncomplicated mTBI. Further, to investigate the association between TOC pathways, rehabilitation, sociodemographic (incl. geographic), premorbid, and injury-related factors and functional outcome, symptom burden and TBI-specific HRQL up to 6 months after injury.
Approximately one third of patients with mTBI were discharged from the ER directly to home. The vast majority of these sustained an uncomplicated mTBI. In those admitted to the hospital, the final discharge destination was home as well, and there were few transitions of care to inpatient rehabilitation. Consistent with our first hypothesis, only one fifth of patients with uncomplicated mTBI received rehabilitation services in the first six months after injury. However, for patients with complicated mTBI, the number of care transitions was significantly higher and more complex, showing that 43% received rehabilitation services. The rehabilitation services were primarily provided within the first three months (i.e., acute and sub-acute phase); thus, we could not use this variable in the advanced modeling. The importance of early rehabilitation is, however, assessed in other studies where it has been highlighted that targeted early intervention programs for patients with mTBI might be cost-effective .
Physiotherapy was the most frequent service delivered in both patient groups, in line with previous studies [7, 8]. This finding might be related to the fact that physical therapy is the most available service across countries.
The second most frequent services were occupational therapy and cognitive rehabilitation, most frequently delivered to patients with complicated mTBI. In contrast, psychological services were provided to less than one-fourth of the total sample and represented one of the services with the lowest coverage in this study, along with speech therapy. A previous study on all TBI severity levels also reported under-provision of these services .
Most of the included cases showed good recovery (GOSE) with low symptom burden (RPQ) and non-impaired HRQOL (QOLIBRI-OS) at 6 months after injury. Nonetheless, we found significantly reduced functional level, higher symptom burden and lower quality of life in complicated mTBI compared to uncomplicated cases. This is in line with previous studies that consider complicated mTBI as a more severe brain injury than uncomplicated mTBI [1, 2, 4]. Indeed, Scandinavian guidelines for initial management of minimal, mild, and moderate TBI  recommend that patients with mTBI (GCS 13–15) who have intracranial findings on CT-scans should be managed as patients with moderate TBI. This further highlights the large heterogeneity within the mTBI spectrum.
We found that a higher number of TOC and receiving rehabilitation services was associated with a lower probability of better outcomes. As mentioned previously, higher numbers of TOC and rehabilitation were more frequent in patients with complicated mTBI. Thus, in line with previous studies [6, 29, 30], rehabilitation services provided in this study could be interpreted as an indicator of injury severity.
In addition, sustaining injury due to a fall and more severe injury, as measured by lower GCS score, higher ISS, presence of extracranial injuries and longer acute and rehabilitation hospitalization has previously been found to predict poorer outcomes after TBI [31, 32]. Thus, this finding is unlikely to reflect the effectiveness of rehabilitation services, but rather the nature of the injury. Moreover, poorer outcomes were associated with premorbid somatic and psychological problems. Pre-existing conditions are known to negatively influence outcomes after mTBI [33, 34]. While sustaining a mTBI may exacerbate underlying health conditions, it is also possible that the additive effects of a TBI and existing somatic or psychological problems further complicate the recovery process.
Male gender and higher education was associated with a higher probability of better outcomes, in line with other studies [33,34,35]. These findings may indicate that individuals at risk of developing incomplete recovery after mTBI, such as females and those with lower education should be offered regular follow-up programs.
Interestingly, in the modeling of HRQOL, we found that residency in Southern/Eastern Europe versus Western Europe was associated with a lower probability of better HRQOL. Whether this finding is due to differences in TBI care across the geographical regions is unclear and the result should be interpreted with caution. Previous reports from this project, however, have highlighted substantial variations in TBI care  across Europe that might influence patient outcomes. The results showing a negative association between the Southern/Eastern region and HRQOL are in contrast with a recent health inequalities analysis in Europe that showed the worst health outcomes for participants from the UK (Western Europe) and best outcomes for participants from Italy (Southern Europe) . Analyses based on data obtained from general population samples using the QOLIBRI-OS showed the highest HRQOL reported by Dutch individuals (Western Europe) followed by Italian participants, while respondents from the UK displayed the lowest HRQOL .
A previous CENTER-TBI study found that living in Central and Eastern Europe was a significant negative predictor of access to rehabilitation in the first 12 months after TBI . This may reflect the different organization of health care systems in Europe including funding, coverage of rehabilitation services, and referral policies leading to fragmented rehabilitation provision, and serving as important access barriers to rehabilitation after TBI. Future studies are needed to better understand these barriers and their influence on rehabilitation outcomes including HRQOL.
Strengths and limitations
The present study’s strengths are its large sample size and the high number of participating European countries, which together render a robust overview of mTBI and rehabilitation provision. However, a substantial proportion of trauma centers involved in this study are from urban areas in North-Western Europe. Therefore, the generalizability of findings to other regions is limited.
Further, more than half of patients that received rehabilitation did not provide detailed information on the type of rehabilitation services. In addition, we do not know if rehabilitation services provided in this study were targeted to consequences of TBI or extracranial injuries. Participants were asked to “indicate any help in specific areas that you have been given because of your injury”. Physiotherapy, as the most provided service in this study, is often given due to extracranial injuries.
To avoid loss of statistical power, we imputed missing predictor values using the MICE approach. However, to date, there is no consensus on the goodness-of-fit pooling procedure (e.g., Nagelkerke R2) for ordinal logistic regressions with multiply imputed data. Therefore, we relied on the significance of predictors to derive conclusions about the influence of selected factors on outcomes after traumatic brain injury. Our statistical approach allows easy comparisons between differently scaled outcomes, although grouping outcome values by quantiles may result in a loss of information. A methodological extension to assess goodness of fit in ordinal regression models using multiply imputed data would allow a more accurate assessment of model fit.
Patients with complicated mTBI reported lower functional recovery, higher symptom burden, and lower HRQOL and were more frequently offered rehabilitation services. Received rehabilitation services and higher numbers of care transition pathways as an indicator of injury severity were associated with lower probability of better outcomes in this study. These findings, however, should be interpreted carefully and validated in future studies as we used a novel regression analysis approach for easy comparisons between differently scaled outcome measurements.
Availability of data and materials
All relevant data are available upon request from CENTER-TBI, and the authors are not legally allowed to share it publicly. The authors confirm that they received no special access privileges to the data. CENTER-TBI is committed to data sharing and in particular to responsible further use of the data. Hereto, we have a data sharing statement in place: https://www.center-tbi.eu/data/sharing. The CENTER-TBI Management Committee, in collaboration with the General Assembly, established the Data Sharing policy, and Publication and Authorship Guidelines to assure correct and appropriate use of the data as the dataset is hugely complex and requires help of experts from the Data Curation Team or Bio- Statistical Team for correct use. This means that we encourage researchers to contact the CENTER-TBI team for any research plans and the Data Curation Team for any help in appropriate use of the data, including sharing of scripts. Requests for data access can be submitted online: https://www.center-tbi.eu/data. The complete Manual for data access is also available online: https://www.center-tbi.eu/files/SOP-Manual-DAPR-2402020.pdf.
Admission to a hospital ward
Abbreviated Injury Scale
Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury
Electronic Case Report Form
Glasgow Coma Scale
Glasgow Outcome Scale – Extended
Health-Related Quality of Life
Intensive Care Unit
Injury Severity Score
Missing At Random
Multivariate Imputation by Chained Equations
Mild Traumatic Brain Injury
Patient Reported Outcome Measure
Quality of Life After Brain Injury – Overall Scale
Rivermead Post-Concussion Symptoms Questionnaire
Traumatic Brain Injury
Transition of Care
Neurological Hospital Ward
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We gratefully thank all CENTER-TBI participants and investigators. We are immensely grateful to our patients for helping us in our efforts to improve care and outcomes after TBI.
The CENTER-TBI participants and investigators
Cecilia Åkerlund18, Krisztina Amrein19, Nada Andelic1,3, Lasse Andreassen20, Audny Anke21, Anna Antoni22, Gérard Audibert23, Philippe Azouvi14,15, Maria Luisa Azzolini24, Ronald Bartels25, Pál Barzó26, Romuald Beauvais27, Ronny Beer28, Bo-Michael Bellander29, Antonio Belli30, Habib Benali31, Maurizio Berardino32, Luigi Beretta24, Morten Blaabjerg33, Peter Bragge34, Alexandra Brazinova35, Vibeke Brinck36, Joanne Brooker37, Camilla Brorsson38, Andras Buki39, Monika Bullinger40, Manuel Cabeleira41, Alessio Caccioppola42, Emiliana Calappi 42, Maria Rosa Calvi24, Peter Cameron43, Guillermo Carbayo Lozano44, Marco Carbonara42, Simona Cavallo32, Giorgio Chevallard45, Arturo Chieregato45, Giuseppe Citerio46, 47, Hans Clusmann48, Mark Coburn49, Jonathan Coles50, Jamie D. Cooper52, Marta Correia52, Amra Čović2, Nicola Curry53, Endre Czeiter39, Marek Czosnyka41, Claire Dahyot-Fizelier54, Paul Dark55, Helen Dawes16,17, Véronique De Keyser56, Vincent Degos31, Francesco Della Corte57, Hugo den Boogert25, Bart Depreitere58, Đula Đilvesi 59, Abhishek Dixit60, Emma Donoghue37, Jens Dreier61, Guy-Loup Dulière62, Ari Ercole60, Patrick Esser17, Erzsébet Ezer63, Martin Fabricius64, Valery L. Feigin65, Kelly Foks66, Shirin Frisvold67, Alex Furmanov68, Pablo Gagliardo69, Damien Galanaud31, Dashiell Gantner43, Guoyi Gao70, Pradeep George71, Alexandre Ghuysen72, Lelde Giga73, Ben Glocker74, Jagoš Golubovic59, Pedro A. Gomez75, Johannes Gratz76, Benjamin Gravesteijn77, Francesca Grossi57, Russell L. Gruen78, Deepak Gupta79, Juanita A. Haagsma77, Iain Haitsma80, Raimund Helbok28, Eirik Helseth7,8, Lindsay Horton 81, Jilske Huijben77, Peter J. Hutchinson82, Bram Jacobs83, Stefan Jankowski84, Mike Jarrett36, Ji-yao Jiang71, Faye Johnson85, Kelly Jones65, Mladen Karan59, Angelos G. Kolias82, Erwin Kompanje86, Daniel Kondziella64, Evgenios Kornaropoulos60, Lars-Owe Koskinen87, Noémi Kovács88, Ana Kowark89, Alfonso Lagares75, Linda Lanyon71, Steven Laureys90, Fiona Lecky91, 92, Didier Ledoux90, Rolf Lefering93, Valerie Legrand94, Aurelie Lejeune95, Leon Levi96, Roger Lightfoot97, Hester Lingsma77, Andrew I.R. Maas56, Ana M. Castaño-León62, Marc Maegele98, Marek Majdan35, Alex Manara99, Geoffrey Manley100, Costanza Martino101, Hugues Maréchal62, Julia Mattern102, Catherine McMahon103, Béla Melegh104, David Menon60, Tomas Menovsky56, Ana Mikolic77, Benoit Misset90, Visakh Muraleedharan71, Lynnette Murray43, Ancuta Negru105, David Nelson18, Virginia Newcombe60, Daan Nieboer77, József Nyirádi19, Otesile Olubukola91, Matej Oresic106, Fabrizio Ortolano42, Aarno Palotie107, 108, 109, Paul M. Parizel110, Jean-François Payen111, Natascha Perera27, Vincent Perlbarg31, Paolo Persona112, Wilco Peul113, Anna Piippo-Karjalainen114, Matti Pirinen107, Dana Pisica77, Horia Ples105, Suzanne Polinder77, Inigo Pomposo44, Jussi P. Posti 12,13, Louis Puybasset115, Andreea Radoi 116, Arminas Ragauskas117, Rahul Raj114, Malinka Rambadagalla118, Isabel Retel Helmrich77, Jonathan Rhodes119, Sylvia Richardson120, Sophie Richter60, Samuli Ripatti107, Saulius Rocka117, Cecilie Roe1,3,8, Olav Roise121,122, Jonathan Rosand123, Jeffrey V. Rosenfeld124, Christina Rosenlund125, Guy Rosenthal68, Rolf Rossaint89, Sandra Rossi112, Daniel Rueckert74 Martin Rusnák126, Juan Sahuquillo116, Oliver Sakowitz102, 127, Renan Sanchez-Porras127, Janos Sandor128, Nadine Schäfer93, Silke Schmidt129, Herbert Schoechl130, Guus Schoonman131, Rico Frederik Schou132, Elisabeth Schwendenwein22, Charlie Sewalt77, Ranjit D. Singh113, Toril Skandsen133, 134, Peter Smielewski41, Abayomi Sorinola135, Emmanuel Stamatakis60, Simon Stanworth53, Robert Stevens136, William Stewart137, Ewout W. Steyerberg77, 138, Nino Stocchetti139, Nina Sundström140, Riikka Takala141, Viktória Tamás135, Tomas Tamosuitis142, Mark Steven Taylor35, Braden Te Ao65, Olli Tenovuo12,13, Alice Theadom65, Matt Thomas99, Dick Tibboel143, Marjolein Timmers86, Christos Tolias144, Tony Trapani43, Cristina Maria Tudora105, Andreas Unterberg102, Peter Vajkoczy 145, Shirley Vallance43, Egils Valeinis73, Zoltán Vámos63, Mathieu van der Jagt146, Gregory Van der Steen56, Joukje van der Naalt83, Jeroen T.J.M. van Dijck 113, Inge A. M. van Erp113, Thomas A. van Essen113, Wim Van Hecke147, Caroline van Heugten148, Dominique Van Praag149, Ernest van Veen77, Thijs Vande Vyvere147, Roel P. J. van Wijk113, Alessia Vargiolu47, Emmanuel Vega95, Kimberley Velt77, Jan Verheyden147, Paul M. Vespa150, Anne Vik133, 151, Rimantas Vilcinis142, Victor Volovici80, Nicole von Steinbüchel2, Daphne Voormolen77, Petar Vulekovic59, Kevin K.W. Wang152, Daniel Whitehouse60, Eveline Wiegers77, Guy Williams60, Lindsay Wilson81, Stefan Winzeck60, Stefan Wolf153, Zhihui Yang123, Peter Ylén154, Alexander Younsi102, Frederick A. Zeiler60,155, Veronika Zelinkova35, Agate Ziverte73, Tommaso Zoerle42
18 Department of Physiology and Pharmacology, Section of Perioperative Medicine and Intensive Care, Karolinska Institutet, Stockholm, Sweden
19 János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
20 Department of Neurosurgery, University Hospital Northern Norway, Tromso, Norway
21 Department of Physical Medicine and Rehabilitation, University Hospital Northern Norway, Tromso, Norway
22 Trauma Surgery, Medical University Vienna, Vienna, Austria
23 Department of Anesthesiology & Intensive Care, University Hospital Nancy, Nancy, France
24 Department of Anesthesiology & Intensive Care, S Raffaele University Hospital, Milan, Italy
25 Department of Neurosurgery, Radboud University Medical Center, Nijmegen, The Netherlands
26 Department of Neurosurgery, University of Szeged, Szeged, Hungary
27 International Projects Management, ARTTIC, Munchen, Germany
28 Department of Neurology, Neurological Intensive Care Unit, Medical University of Innsbruck, Innsbruck, Austria
29 Department of Neurosurgery & Anesthesia & intensive care medicine, Karolinska University Hospital, Stockholm, Sweden
30 NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham, UK
31 Anesthesie-Réanimation, Assistance Publique – Hopitaux de Paris, Paris, France
32 Department of Anesthesia & ICU, AOU Città della Salute e della Scienza di Torino - Orthopedic and Trauma Center, Torino, Italy
33 Department of Neurology, Odense University Hospital, Odense, Denmark
34 BehaviourWorks Australia, Monash Sustainability Institute, Monash University, Victoria, Australia
35 Department of Public Health, Faculty of Health Sciences and Social Work, Trnava University, Trnava, Slovakia
36 Quesgen Systems Inc., Burlingame, California, USA
37 Australian & New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
38 Department of Surgery and Perioperative Science, Umeå University, Umeå, Sweden.
39 Department of Neurosurgery, Medical School, University of Pécs, Hungary and Neurotrauma Research Group, János Szentágothai Research Centre, University of Pécs, Hungary
40 Department of Medical Psychology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
41 Brain Physics Lab, Division of Neurosurgery, Dept of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
42 Neuro ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
43 ANZIC Research Centre, Monash University, Department of Epidemiology and Preventive Medicine, Melbourne, Victoria, Australia
44 Department of Neurosurgery, Hospital of Cruces, Bilbao, Spain
45 NeuroIntensive Care, Niguarda Hospital, Milan, Italy
46 School of Medicine and Surgery, Università Milano Bicocca, Milano, Italy
47 NeuroIntensive Care, ASST di Monza, Monza, Italy
48 Department of Neurosurgery, Medical Faculty RWTH Aachen University, Aachen, Germany.
49 Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany
50 Department of Anesthesia & Neurointensive Care, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.
52 School of Public Health & PM, Monash University and The Alfred Hospital, Melbourne, Victoria, Australia
52 Radiology/MRI department, MRC Cognition and Brain Sciences Unit, Cambridge, UK
53 Oxford University Hospitals NHS Trust, Oxford, UK
54 Intensive Care Unit, CHU Poitiers, Potiers, France
55 University of Manchester NIHR Biomedical Research Centre, Critical Care Directorate, Salford Royal Hospital NHS Foundation Trust, Salford, UK
56 Department of Neurosurgery, Antwerp University Hospital and University of Antwerp, Edegem, Belgium
57 Department of Anesthesia & Intensive Care, Maggiore Della Carità Hospital, Novara, Italy
58 Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium
59 Department of Neurosurgery, Clinical centre of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
60 Division of Anaesthesia, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
61 Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
62 Intensive Care Unit, CHR Citadelle, Liège, Belgium
63 Department of Anaesthesiology and Intensive Therapy, University of Pécs, Pécs, Hungary
64 Departments of Neurology, Clinical Neurophysiology and Neuroanesthesiology, Region Hovedstaden Rigshospitalet, Copenhagen, Denmark
65 National Institute for Stroke and Applied Neurosciences, Faculty of Health and Environmental Studies, Auckland University of Technology, Auckland, New Zealand
66 Department of Neurology, Erasmus MC, Rotterdam, the Netherlands
67 Department of Anesthesiology and Intensive care, University Hospital Northern Norway, Tromso, Norway
68 Department of Neurosurgery, Hadassah-hebrew University Medical center, Jerusalem, Israel
69 Fundación Instituto Valenciano de Neurorrehabilitación (FIVAN), Valencia, Spain
70 Department of Neurosurgery, Shanghai Renji hospital, Shanghai Jiaotong University/school of medicine, Shanghai, China
71 Karolinska Institutet, INCF International Neuroinformatics Coordinating Facility, Stockholm, Sweden
72 Emergency Department, CHU, Liège, Belgium
73 Neurosurgery clinic, Pauls Stradins Clinical University Hospital, Riga, Latvia
74 Department of Computing, Imperial College London, London, UK
75 Department of Neurosurgery, Hospital Universitario 12 de Octubre, Madrid, Spain
76 Department of Anesthesia, Critical Care and Pain Medicine, Medical University of Vienna, Austria
77 Department of Public Health, Erasmus Medical Center-University Medical Center, Rotterdam, The Netherlands
78 College of Health and Medicine, Australian National University, Canberra, Australia
79 Department of Neurosurgery, Neurosciences Centre & JPN Apex trauma centre, All India Institute of Medical Sciences, New Delhi-110029, India
80 Department of Neurosurgery, Erasmus MC, Rotterdam, the Netherlands
81 Division of Psychology, University of Stirling, Stirling, UK
82 Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital & University of Cambridge, Cambridge, UK.
83 Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
84 Neurointensive Care , Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
85 Salford Royal Hospital NHS Foundation Trust Acute Research Delivery Team, Salford, UK
86 Department of Intensive Care and Department of Ethics and Philosophy of Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
87 Department of Clinical Neuroscience, Neurosurgery, Umeå University, Umeå, Sweden.
88 Hungarian Brain Research Program - Grant No. KTIA_13_NAP-A-II/8, University of Pécs, Pécs, Hungary
89 Department of Anaesthesiology, University Hospital of Aachen, Aachen, Germany
90 Cyclotron Research Center , University of Liège, Liège, Belgium
91 Centre for Urgent and Emergency Care Research (CURE), Health Services Research Section, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
92 Emergency Department, Salford Royal Hospital, Salford UK
93 Institute of Research in Operative Medicine (IFOM), Witten/Herdecke University, Cologne, Germany
94 VP Global Project Management CNS, ICON, Paris, France
95 Department of Anesthesiology-Intensive Care, Lille University Hospital, Lille, France
96 Department of Neurosurgery, Rambam Medical Center, Haifa, Israel
97 Department of Anesthesiology & Intensive Care, University Hospitals Southhampton NHS Trust, Southhampton, UK
98 Cologne-Merheim Medical Center (CMMC), Department of Traumatology, Orthopedic Surgery and Sportmedicine, Witten/Herdecke University, Cologne, Germany
99 Intensive Care Unit, Southmead Hospital, Bristol, Bristol, UK
100 Department of Neurological Surgery, University of California, San Francisco, California, USA
101 Department of Anesthesia & Intensive Care,M. Bufalini Hospital, Cesena, Italy
102 Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany
103 Department of Neurosurgery, The Walton centre NHS Foundation Trust, Liverpool, UK
104 Department of Medical Genetics, University of Pécs, Pécs, Hungary
105 Department of Neurosurgery, Emergency County Hospital Timisoara , Timisoara, Romania
106 School of Medical Sciences, Örebro University, Örebro, Sweden.
107 Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
108 Analytic and Translational Genetics Unit, Department of Medicine; Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
109 Program in Medical and Population Genetics; The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
110 Department of Radiology, University of Antwerp, Edegem, Belgium
111 Department of Anesthesiology & Intensive Care, University Hospital of Grenoble, Grenoble, France
112 Department of Anesthesia & Intensive Care, Azienda Ospedaliera Università di Padova, Padova, Italy
113 Dept. of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands and Dept. of Neurosurgery, Medical Center Haaglanden, The Hague, The Netherlands
114 Department of Neurosurgery, Helsinki University Central Hospital
115 Department of Anesthesiology and Critical Care, Pitié -Salpêtrière Teaching Hospital, Assistance Publique, Hôpitaux de Paris and University Pierre et Marie Curie, Paris, France
116 Neurotraumatology and Neurosurgery Research Unit (UNINN), Vall d'Hebron Research Institute, Barcelona, Spain
117 Department of Neurosurgery, Kaunas University of technology and Vilnius University, Vilnius, Lithuania
118 Department of Neurosurgery, Rezekne Hospital, Latvia
119 Department of Anaesthesia, Critical Care & Pain Medicine NHS Lothian & University of Edinburg, Edinburgh, UK
120 Director, MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK
121 Division of Orthopedics, Oslo University Hospital, Oslo, Norway
122 Institue of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
123 Broad Institute, Cambridge MA Harvard Medical School, Boston MA, Massachusetts General Hospital, Boston MA, USA
124 National Trauma Research Institute, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia
125 Department of Neurosurgery, Odense University Hospital, Odense, Denmark
126 International Neurotrauma Research Organisation, Vienna, Austria
127 Klinik für Neurochirurgie, Klinikum Ludwigsburg, Ludwigsburg, Germany
128 Division of Biostatistics and Epidemiology, Department of Preventive Medicine, University of Debrecen, Debrecen, Hungary
129 Department Health and Prevention, University Greifswald, Greifswald, Germany
130 Department of Anaesthesiology and Intensive Care, AUVA Trauma Hospital, Salzburg, Austria
131 Department of Neurology, Elisabeth-TweeSteden Ziekenhuis, Tilburg, the Netherlands
132 Department of Neuroanesthesia and Neurointensive Care, Odense University Hospital, Odense, Denmark
133 Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, NTNU, Trondheim, Norway
134 Department of Physical Medicine and Rehabilitation, St.Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
135 Department of Neurosurgery, University of Pécs, Pécs, Hungary
136 Division of Neuroscience Critical Care, John Hopkins University School of Medicine, Baltimore, USA
137 Department of Neuropathology, Queen Elizabeth University Hospital and University of Glasgow, Glasgow, UK
138 Dept. of Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
139 Department of Pathophysiology and Transplantation, Milan University, and Neuroscience ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
140 Department of Radiation Sciences, Biomedical Engineering, Umeå University, Umeå, Sweden.
141 Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital and University of Turku, Turku, Finland
142 Department of Neurosurgery, Kaunas University of Health Sciences, Kaunas, Lithuania
143 Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands
144 Department of Neurosurgery, Kings college London, London, UK
145 Neurologie, Neurochirurgie und Psychiatrie, Charité – Universitätsmedizin Berlin, Berlin, Germany
146 Department of Intensive Care Adults, Erasmus MC– University Medical Center Rotterdam, Rotterdam, the Netherlands.
147 icoMetrix NV, Leuven, Belgium
148 Movement Science Group, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK
149 Psychology Department, Antwerp University Hospital, Edegem, Belgium
150 Director of Neurocritical Care, University of California, Los Angeles, USA
151 Department of Neurosurgery, St.Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
152 Department of Emergency Medicine, University of Florida, Gainesville, Florida, USA
153 Department of Neurosurgery, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
154 VTT Technical Research Centre, Tampere, Finland.
155 Section of Neurosurgery, Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
CENTER-TBI was supported by the European Union 7th Framework programme (EC grant 602150). Additional funding was obtained from the Hannelore Kohl Stiftung (Germany), from OneMind (USA), and from Integra LifeSciences Corporation (USA). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Ethics approval and consent to participate
The CENTER-TBI study (EC grant 602150) was conducted in accordance with all relevant laws of the European Union (EU) and all relevant laws of the countries where the recruiting sites were located. Informed consent was obtained from the patients and/or the legal representative/next of kin, according to the local regulations for all participants recruited in the Core Dataset of CENTER-TBI and documented in the electronic case report form (e-CRF). For the full list of sites, ethical committees, and ethical approval details, see Additional file 4 or the official CENTER-TBI website (https://www.center-tbi.eu/project/ethical-approval). The trial was registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT0221022.
Consent for publication
OT has received funding from consultancy for NeuroTraumaSciences Ltd. and from Sigrid Juselius Foundation. The other authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Additional file 1.
Patients with major trauma.
Additional file 2.
Results of regression analyses.
Additional file 3.
The CENTER-TBI participants and investigators.
Additional file 4.
Sites, ethical committees, and ethical approval.
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Howe, E.I., Zeldovich, M., Andelic, N. et al. Rehabilitation and outcomes after complicated vs uncomplicated mild TBI: results from the CENTER-TBI study. BMC Health Serv Res 22, 1536 (2022). https://doi.org/10.1186/s12913-022-08908-0
- Mild TBI