A Systematic Review of Clinical Outcome Trajectories from 3 to 12 Months Following Mild or Moderate Traumatic Brain Injury

Abstract

Our objective was to determine the extent to which clinical outcomes at 3 months predict the 6- to 12-month trajectory in people presenting with mild or moderate traumatic brain injury (TBI). We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searched MEDLINE, EMBASE, EBSCO, and the Web of Science Citation Index from 2005 until May 2025. All observational or interventional study designs that reported clinical outcomes in patients at 3 months, and at a later time point, following mild or moderate TBI were eligible for inclusion. Two authors independently selected and extracted data. Risk of bias was assessed using the Downs and Black checklist. Thirty studies (29 observational, 1 interventional) involving 7993 patients (7781 with mild TBI [mTBI]) met the inclusion criteria. Study quality was variable, and heterogeneity in study inclusion criteria and outcome reporting precluded meta-analyses and identification of patient and injury predictors of post 3-month outcome trajectory. Vulnerable populations—including older adults, those with pre-existing cognitive impairment, psychiatric illness, or intoxication—were frequently excluded. Analysis of the four most commonly reported outcome measures (Rivermead Post-Concussion Symptoms Questionnaire, Extended Glasgow Outcome Scale, Short Form 36 Health Survey, and Quality of Life after Brain Injury)–revealed symptom and functional improvement over time, particularly from hospital discharge to 3 months post-injury. However, substantial problems persist thereafter with 21–65% of patients continuing to experience symptoms or impairment, depending on cohort and outcome measure. The small number of patients with moderate TBI precluded comparison of outcomes to patients with mTBI. To improve clinical care, research, and patient experience, future targeted studies should identify factors determining the post-TBI outcome trajectory.

Keywords

mild and moderate TBI outcomes at 3 months and beyond RPQ and GOSE

Background

Traumatic brain injury (TBI) is an alteration of brain function or other evidence of brain pathology due to an external force. It is a major global cause of disability and mortality with over 50 million new cases annually.¹ Existing research and clinical guidelines in acute care heavily focus on the initial clinical identification and treatment of life-threatening injuries in patients with severe TBI.² However, over 95% of patients present with an initial Glasgow Coma Scale (GCS) >8 and are conventionally defined as having mild (GCS 13–15) or moderate TBI (GCS 9–12).^2–4 Only around 1% of patients with mild TBI (mTBI) have life-threatening injuries, and most patients are discharged directly from the emergency department without further follow-up or treatment.⁵ However, there is growing evidence that many patients with mTBI may have significant ongoing functional impairment and disability within the first year of injury.⁵ Furthermore, health care services may not currently adequately address problems that persist after mild and moderate injuries.

Limited evidence exists on how outcomes evolve in the first year following injury and how early outcomes (at 3 months) predict longer-term outcomes. Two previous reviews only included three and five studies, respectively, that assessed functional and other outcomes at 3 months following mTBI.^6,7 The 2014 review by Carroll et al.⁶ focussing mainly on cognitive function post mTBI found early post-discharge cognitive deficits on a variety of instruments. However, there was conflicting evidence of persistence beyond 3 months post-injury. The 2022 review of mTBI in older adults (>60 years) by Hulme et al.⁷ suggested that at least one-third had not fully recovered functional outcomes at 6 months post-injury. Outcomes for people who have sustained moderate TBI are not well represented in research, as their outcomes are often assessed in combination with people who have sustained severe TBI for the prediction of outcomes at single time points.⁸ In order to understand gaps in service provision for people who have sustained mild and moderate TBI, a better understanding of the post-acute evolution of clinical outcomes is required. In addition, there is increasing awareness that outcomes beyond the first 3–6 months after TBI are important.

Our systematic review therefore aimed to: 1.

describe clinical outcomes following mild and moderate TBI at 3 months post-injury.

assess the relationship between clinical outcomes at 3 months and outcomes at 6–12 months post-injury.

Methods

A systematic review was undertaken in accordance with the general principles recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42021264931).^9,10

Eligibility criteria

All observational or interventional study designs focusing on TBI were eligible for inclusion. The study population of interest consisted of people presenting to the emergency department or similar acute hospital setting with an initial GCS of 9–15, aged 16 or over who sustained head injury with associated signs/symptoms of TBI (defined as injury to the brain or alteration of brain function due to an external force). Although there are a wide number of scales that have been developed to assess disability, impairment, and function, as well as quality-of-life measures following TBI, the following commonly used and validated measures were included: Glasgow Outcome Scale (GOS) and Extended Glasgow Outcome Scale (GOSE), Rivermead Post-Concussion Symptoms Questionnaire (RPQ), Short Form 36 Health Survey (SF-36) and Short Form 12 Health Survey (SF-12), EuroQol-5 Dimension (EQ-5D), and the Quality of Life after Brain Injury (QOLIBRI) questionnaire. These include the major “outcome” Common Data Elements recommended by the International Traumatic Brain Injury Research Initiative supported by the European Community (EC) and U.S. National Institutes of Health (NIH).¹¹ While most of the aforementioned assess quality of life and ability to function, the RPQ was devised to gauge the severity of post-concussion symptoms. The range of symptoms assessed in the RPQ encompasses physical (e.g., headache, fatigue), emotional (e.g., feeling irritable or depressed), and cognitive (e.g., difficulty concentrating, forgetfulness) domains of post-TBI lived experience. The patient is asked to rate the degree to which each of the 16 symptoms is more of a problem compared with before the injury, using values from 0 to 4 (0 = no symptom, 1 = no worse than before injury, 2/3/4 = new or worse mild/moderate/severe post-injury symptom). Symptom scores of 1 are not included in the total score. The RPQ total score ranges from 0 to 64. All outcomes had to be assessed at 3 months and later time points at or within 12 months of injury to evaluate how impairment persisted and developed. We excluded case reports, narrative reviews, editorials and opinions, nonhuman/biological studies, abstracts or conference presentations with insufficient detail for data extraction, and studies not reporting outcomes of interest. Non-English language studies were also excluded.

Data sources and searches

To reflect the implementation of international TBI guidelines (such as the first NiCE head injury guideline),^2,12—which, since 2005, have led to more liberal computed tomography (CT) imaging and to recommendations for treatment pathways for patients with mTBI—we included publications from January 1, 2005, to May 2025. We searched the following electronic databases: MEDLINE (Ovid), EMBASE (Ovid), Cumulative Index to Nursing and Allied Health Literature (EBSCO), and Web of Science Core Collection Social Sciences Citation Index (Clarivate Analytics). Searches were supplemented by hand searching the reference lists of all relevant studies including existing systematic reviews assessing outcomes following TBI,^5,13–16 forward citation searching of relevant articles, and undertaking targeted searches of the World Wide Web using the Google search engine. Further details on the search strategy can be found in Supplementary Data S1.

All identified citations from the electronic searches and other resources were imported into and managed using the EndNote bibliographic software (version 21; Clarivate Analytics, Philadelphia, PA).

Study selection

Three reviewers (C.M., T.S., and M.T.) independently completed title and abstract screening. Full reports of studies potentially meeting the inclusion criteria were retrieved and examined independently by four reviewers (C.M., F.L., T.S., and M.T.). Retrieved full reports that did not meet the inclusion criteria were excluded with documented reasons. Any disagreements were resolved through discussion or arbitration by a topic expert (F.L.) and included by consensus.

Data extraction and quality assessment

For eligible studies, data relating to study design (e.g., study details, sample size, population characteristics, presence of injuries on CT imaging, follow-up), methodological quality, and outcomes (e.g., functional outcome measures, predictive factors assessed and association with outcomes) were extracted by one reviewer (C.M.) into a standardized data extraction form and independently checked for accuracy by a second reviewer (T.S. or M.T.). Any discrepancies were resolved through discussion, or if this was unsuccessful, wider group opinion was sought (F.L.).

The methodological quality of each included study was assessed using the Downs and Black checklist¹⁷ for randomized and nonrandomized studies. The checklist consists of 27 items across five domains: study quality, external validity, study bias, confounding and selection bias, and power of the study. Twenty-six items were answered either yes (assigned a score of 1) or no/unable to determine (assigned a score of 0), and one item was scored yes (2), partially (1), or no (0), resulting in a maximum of 28. Methodological quality was classified as “excellent” if studies had a score of 26 or higher, “good” if scores ranged between 20 and 25, “fair” if they ranged between 15 and 19, and “poor” if the score was 14 or lower.¹⁷

Data synthesis and analysis

Due to significant levels of heterogeneity between studies (study design, participants, inclusion criteria, outcome measurements) and variable reporting of items, a meta-analysis was not considered feasible. As a result, a pre-specified narrative synthesis approach was undertaken, with data being summarized in tables with accompanying narrative summaries that included a description of study characteristics, the included variables, and effect estimates, where applicable.¹⁰

Patient and Public Involvement and Engagement

Our authorship includes a scientific commentator and TBI Researcher—with lived experience as a TBI Survivor (J.P.)—who critically reviewed the article drafts and approved the final version for submission.

Ethics statement

The published PROSPERO protocol for secondary analysis of anonymized data from eligible published studies¹⁰ does not require separate ethical review. All included studies had appropriate ethical review.

Results

Study flow

Figure 1 summarizes the process of identifying and selecting relevant literature. A total of 1561 unique records underwent title and abstract screening, and the full texts of 94 articles were further assessed. Of these, 30 studies met the review eligibility criteria.^18–47 The majority of the articles were excluded primarily for not having usable or relevant outcome data or an inappropriate study population. A full list of excluded studies with reasons for exclusion is provided in Supplementary Data S2.

FIG. 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram.

Study and patient characteristics

Study characteristics are summarized in Supplementary Data S3. The 30 included studies comprised 29 longitudinal cohort studies and 1 pilot randomized controlled trial.^18–47 Three articles reported separate RPQ outcomes from the same cohort study^23,24,39 and were appraised independently; therefore, the 30 articles describe 28 separate cohorts. Nine studies were conducted in Europe (including the UK), 13 in the United States, 3 studies (5 publications) in Australia or New Zealand, 1 study in Indonesia, 1 study in Tunisia, and 1 study in Taiwan. Six studies were conducted on patients enrolled in the NIH-funded Transforming Research and Clinical Knowledge in Traumatic Brain Injury program; however, these studies differed, with sometimes overlapping patient cohorts and/or reported different outcomes, so were assessed separately.^{27–30,38,40} The included studies encompassed 7993 unique patients of whom 179 (2.2%) patients had moderate TBI (presenting GCS 9–12), 33 patients had either mild (presenting GCS 13–15) or moderate TBI³⁵ (0.4%), and 7781 patients had mTBI. All studies solely included patients who had presented to the hospital emergency department of—or were transferred into—a specialist neuroscience or high-level trauma center within 48 h of injury and were invited for post-discharge follow-up. The mTBI cohort studies exhibited considerable heterogeneity in inclusion criteria as regard to age at presentation, duration of any loss of consciousness, and post-traumatic amnesia. Exclusion criteria were even more heterogeneous as regard to the presence of intoxication at presentation, any past history of substance addiction, neurodegenerative or psychiatric conditions, previous TBI, having indications for CT brain scan, CT findings, and the ability to speak the local language, consent to, and engage with follow-up (Supplementary Data S4).

Quality assessment

A detailed assessment of the quality of each included study can be found in Supplementary Data S3, Supplementary Table S4. In general, 20 studies^{19–27,31–36,39,43–46} were rated as poor quality, and 10 studies^{18,28–30,37,38,40–42,47} were rated as fair using the Downs and Black checklist.¹⁷ Table 1 presents the overall score for each study. Studies tended to score poorly on measures demonstrating internal and external cohort representativeness, sufficient power to detect meaningful differences, and adjustment for confounders in analyses of outcome.

Table 1.

Quality Assessment of Included Studies

Study	Overall score	Rating ^a
Al Fauzi et al.¹⁸	15	Fair
Candrian et al.¹⁹	13	Poor
Carroll et al.²⁰	12	Poor
Chakroun et al.²¹	12	Poor
Chiang et al.²²	12	Poor
Heitger et al.^23,24,39	10,10,14	Poor
Karaliute et al.²⁵	12	Poor
Kraus et al.²⁶	13	Poor
Madhok et al.²⁷	13	Poor
McCrea et al.²⁸	15	Fair
McMahon et al.²⁹	15	Fair
Nelson et al.³⁰	16	Fair
Richey et al.³¹	14	Poor
Roe et al.³²	10	Poor
Sandhaug et al.³³	10	Poor
Sigurdardottir et al.³⁴	9	Poor
Thompson et al.³⁵	9	Poor
Voormolen et al.³⁷	17	Fair
Verberne et al.³⁶	13	Poor
Yue et al.³⁸	16	Fair
Machamer et al.⁴⁰	18	Fair
Keatley et al.⁴¹	16	Fair
Hume et al.⁴²	15	Fair
Norrie et al.⁴³	13	Poor
Roy et al.⁴⁴	13	Poor
Martha et al.⁴⁵	13	Poor
Miller et al.⁴⁶	13	Poor
Thuss et al.⁴⁷	19	Fair

Methodological quality was classified as “excellent” if studies had a score of 26 or higher, “good” if scores ranged between 20 and 25, “fair” if they ranged between 15 and 19, and “poor” if the score was 14 or lower.¹⁷

Effect on outcomes

Table 2 presents the 12 outcomes meeting the inclusion criteria that were reported across the included studies. The Rivermead Post-Concussion Symptoms Questionnaire and GOS or GOSE were the most frequently reported outcome measures, and these two outcomes, alongside the Short Form-36 Health Survey and Quality of Life after Brain Injury outcome measures, were reported in three or more studies, constituting both clinical evaluation and patient-reported outcomes. Heterogeneity of study design and limited reporting of study information prevented meta-analysis.

Table 2.

Outcomes Assessed

Outcome assessed	Number of studies	Total patients
Rivermead post-concussion symptoms questionnaire	15	5570
Glasgow outcome scale	13	4155^a
Short form-36 health survey	5	1433
Quality of life after brain injury	3	1265
Functional independence measure/functional status examination	2	74
Checklist of post-concussion syndromes	1	100
Barthel index	1	16
EuroQol-5 dimension 5 level survey	1	182
Acute concussion evaluation	1	260
World health organization quality of life scale	1	40
Depression, anxiety and stress scale	1	40
Fatigue severity scale	1	159

Three thousand six hundred and twenty-four unique patients after accounting for the overlap of TRACK-TBI cohorts.^27,29,38

TRACK-TBI, Transforming Research and Clinical Knowledge in Traumatic Brain Injury.

Rivermead Post-Concussion Symptoms Questionnaire

Fifteen studies reported the RPQ as an outcome, and the findings are summarized in Table 3. Table 3 demonstrates that the studies identified usually reported mean or median RPQ scores, sometimes with standard deviations or interquartile ranges (IQRs). In addition, the questionnaire results are also reported as percentages of the study cohort with any, >1, or >2 new symptoms (scores of 2 or more), or the mean/median number of symptoms (scores of 2 or more) being experienced. The two largest studies Kraus et al. (N = 2005) and Machamer et al. (N = 1563) reported mean RPQs of 7.3 and 14.2 at 3 months and 3.6 and 12.9 at 6 months, respectively. The inclusion criteria in the study by Kraus et al. were limited to patients aged 16–64 and with symptoms indicating the presence of mTBI, while Machamer et al.⁴⁰ included all patients aged over 17, and all patients who underwent CT head imaging. The higher RPQ scores—indicating a higher symptom burden—reported by Machamer et al.¹⁹ may reflect these differences. One study solely assessed 13 emotional or cognitive RPQ symptom elements.

Table 3.

Studies Reporting Outcomes for the Rivermead Post-Concussion Symptoms Questionnaire

Study	Total patients	Discharge/Early outcome	3 months	6 months	1 year	2 years
Candrian et al.¹⁹	35	Mean score 15.51 (SD 8)	Mean 8.97 (SD 10.6)		Mean 6.69 (SD 9.5)
Carroll et al.²⁰	61	Mean score 1432% >2 new post-injury symptoms	Mean 10.828% > 2 new post-injury symptoms	Mean 10.823% >2 new post-injury symptoms	Mean 10.818% >2 new post-injury symptoms	Mean 10.922% >2 new post-injury symptoms
Chakroun-Walha et al.²¹	130	54.6% >3 new post-injury symptoms	N = 91, 22% >3 new post-injury symptoms	N = 56, 21.4% >3 new post-injury symptoms
Heitger et al.^23,24 (3 articles with the same population)	37	Mean 19.81 (SD 11.72)91% any new post-injury symptom	Mean 9.81 (SD 9.89)59% any new post-injury symptom	Mean 10.24 (SD 10.65)52% any new post-injury symptom	Mean 10.13 (SD 11.9)51% any new post-injury symptom
Karaliute et al.²⁵	318	50% 159/318 symptomsMean 6.4 (SD 10.9)	25.5% 83/326 symptomsMean 9.8 (SD 10.9)		19.1% 54/282 symptomsMean 5.1 (SD 8.1)
Kraus et al.²⁶	2005		Mean 7.3	Mean 3.6
Richey et al.³¹	447	>1 symptom132/259 (51%) <6511/74 (14.9%) 65+	>1 symptom120/239 (50.2%) <6524/66 (36.4%) 65+	>1 symptom107/221 (48.4%) <65 11/59 (18.6%) 65+
Roe et al.³²	52		Any new symptom 38 (73%)	Any new symptom 26 (50%)	Any new symptom 22 (42%)
Sigurdardottir et al.²⁷	74		mTBI = 40Mean 20.8 (SD 18.3)Moderate TBI = 34Mean 17 (SD 15.4)		mTBI = 33Mean 15.9 (SD 16.9)Moderate TBI = 33 Mean 15.6 (SD 16.2)
Machamer et al.⁴⁰	1593	N = 1593Mean 18.4 (SD 14.9)Median 15IQR (6–28)Number of symptoms:Mean 6.8 (SD 4.8)Median 6IQR (3–11)	N = 1480Mean 14.2 (SD 14.8)Median 9IQR (3–11)Number of symptoms:Mean 5.2 (SD 4.9)Median 4IQR (1–9)	N = 1397Mean 12.9 (SD 14.6)Median 8IQR (0–20.5)Number of symptoms:Mean 4.9 (SD 4.9)Median 3IQR (0–8)	N = 1292Mean 12.2 (SD 14.2)Median 6IQR (0–20)Number of symptoms:Mean 4.6 (SD 4.8)Median 3IQR (0–8)
Keatley et al.⁴¹	253	Mean 14.2 (SD 10.04)	Mean 12.34 (SD 12.59)	Mean 11.01 (SD 12.91)
Norrie et al.⁴³	159	Fatigue item mean 2.09 (SD 1.24)	Fatigue item mean 1.03 (SD 1.05)	Fatigue item mean 0.96 (SD 1.05)
Roy et al.⁴⁴	217	217169 no depressive symptoms48 depressive symptoms	No depressive symptomsMean 8.2 (SD 8.7)Depressive symptomsMean 30.7 (SD 15.2)	No depressive symptomsMean 6.3 (SD 8)Depressive symptomsMean 32.3 (SD 14.6)
Martha et al.⁴⁵	18	11 older adults (55 and over)Mean 25.1 ± 8.17 younger adultsMean 21.4 ± 9.1	11 older adults (55 and over)Mean 18.0 ± 7.17 younger adultsMean 14.6 ± 4.8	11 older adults (55 and over)Mean 17.1 ± 3.67 younger adultsMean 12.6 ± 3.5
Miller et al.⁴⁶	171	Mean 17.96 (SD 13.40)	Mean 11.73 (SD 15.75)	Mean 10.68 (SD 14.48)

IQR, interquartile range; mTBI, mild traumatic brain injury; SD, standard deviation.

Table 3 illustrates considerable variation in RPQ outcomes with the highest mean RPQ score at 3 months (30.7) reported in Roy et al.⁴⁴ for a subgroup (n = 49) of mTBI patients who met criteria for CT head imaging and who had depressive symptoms. The reported RPQ increased at 6 months (32.3) in these patients and is 10-fold greater than the mean 6-month RPQ score in Kraus et al.²⁶ Whereas the majority of included studies (12 out of 15) reported 6-month outcomes, the minority reported 12 months outcomes (7 out of 15) with 3-fold variation in the mean RPQ score^25,27 (5.1–15.9). One smaller study reported a 24-month mean RPQ of 10.9.²⁰ The prevalence of new symptoms at 3 months ranged from were 22% with >3 new symptoms²¹ to 73% with >1 new symptom.³²

Across studies, the largest reductions in symptom burden were reported between discharge/early outcomes and 3 months. Small reductions and even increases were reported in RPQ scores among 3 months, 6 months, and 1 year.^32,41 This indicated that patients with post-concussion symptoms at 3 months were likely to continue to be symptomatic at later time points, ranging from 21% to 52% prevalence in those followed up.^21–23

Glasgow Outcome Scale Extended/Glasgow Outcome Scale

Fourteen studies reported the GOSE or GOS as an outcome, and the findings are summarized in Table 4. The two largest studies were Nelson et al. (N = 1154) and Voormolen et al. (N = 1104). In a cohort of mTBI patients who met criteria for CT head imaging, Nelson et al. reported that 64% of patients had a GOSE <8 at 3 months, 60% at 6 months, and 53% at 1 year. Voormolen et al. reported that in a cohort of mTBI patients who underwent CT imaging in those with no intracranial injuries, 23% had a GOSE <7 at 3 months, 16% had GOSE <7 at 6 months compared to 41% GOSE <7 at 3 months, and 35% GOSE <7 at 6 months in those with injuries identified on imaging.

Table 4.

Studies Reporting Outcomes for the Glasgow Outcome Scale Extended

Study	Total patients	Discharge/Early outcome	3 months	6 months	1 year	2 years
Al Fauzi et al.¹⁸	3216 control16 intervention	Control mean 2.5^a (SD 0.5)Intervention mean 3^a (SD 0.5)	Control mean 3^a (SD 0)Intervention mean 3^a (SD 0.4)	Control mean 3.5^a (SD 0.5)Intervention mean 3.5^a (SD 0.5)
Carroll et al.²⁰	61		Mean 7.325% GOSE <8	Mean 7.530% GOSE <8	Mean 7.429% GOSE <8	Mean 7.428% GOSE <8
Chiang et al.²²	10018 moderate recovery (initial GOSE mean < 7)82 fine recovery (initial GOSE mean ≥ 7)	MeanModerate recovery 6.8Fine recovery 7.6	MeanModerate recovery 7Fine recovery 8		MeanModerate recovery 7.7Fine recovery 8
Madhok et al.²⁷	271 total		N = 211 GOSE <8 127/211 (60.2%)	N = 185 GOSE <8 121/185 (65.4%)
McCrea et al.²⁸	93 moderate TBI	41% GOSE > 3	N = 8469% GOSE > 3	N = 7571% GOSE > 3	N = 7275% GOSE > 3
McMahon et al.²⁹	348		N = 348Mean 6.9 (SD 1.1)	N = 305Mean 6.9 (SD 1.0)	N = 199Mean 7.1 (SD 1.0)
Nelson et al.³⁰	1154	N = 975 87%GOSE <8	64% GOSE <8	60% GOSE <8	N = 76853% GOSE <8
Richey et al.³¹	447	GOSE <8Age < 65160/258 (65.1%)Age 65 + 26/76 (34.2%)	GOSE <8Age < 65146/240 (60.8%)Age 65 + 20/69 (29%)	GOSE <8Age < 65131/225 (58.2%)Age 65 + 14/66 (21.2%)
Sandhaug et al.³³	20		Mean 5 (SD 1)		Mean 6 (SD 2)	Mean 6 (SD 2)
Thompson et al.³⁵	33 youngerOlder age group 65+ (n = 15)		Younger mean 6.9 (SD 1.4)Older mean 5.1 (SD 2.3)	Younger mean 7.3 (SD 1.4)Older mean 5.2 (SD 2.4)	Younger mean 7.3 (SD 1.5)Older mean 4.6 (SD 0.1)
Voormolen et al.³⁷	1104		Uncomplicated mTBI GOSE <7 23%Mean 7.2 (SD 1.1)Complicated mTBI GOSE <7 41%Mean 6.5 (SD 1.4)	Uncomplicated mTBI GOSE <7 16%Mean 7.3 (SD 1.1)Complicated mTBI GOSE <7 35%Mean 6.7 (SD 1.3)
Yue et al.³⁸	260		GOSE <780 (30.8%)	GOSE <780 (30.8%)
Roy et al.⁴⁴	217		GOSE = 8No depressive symptoms84 (49.4%)Depressive symptoms1 (3.2%)	N = 181 GOSE = 8No depressive symptoms89 (60.1%)Depressive symptoms2 (6.9%)
Thuss et al.⁴⁷	154		GOSE <889 (58%)Predicted by baseline factors of living situation, intracranial injury HADS-D (Hospital Anxiety and Depression Scale) and HISC (Head Injury Symptoms Checklist) at baseline in multivariable model of demographic, comorbid and injury factors in multivariate model	GOSE <869 (47%)No significant predictors in multivariate model28 of 89 with 3 month GOSE <8 improved11 of 66 with 3 month GOSE = 8 deteriorated

Out of maximum 5 on Glasgow Outcome Scale (not Extended Glasgow Outcome Scale where range is 1–8 with the additional differentiation of upper and lower levels for GOS 3–5).

GOSE, Extended Glasgow Outcome Scale; mTBI, mild traumatic brain injury; SD, standard deviation; TBI, traumatic brain injury.

The lowest mean score at 3 months (GOS = 3 equivalent to GOSE 3–4) was reported by Al Fauzi et al. in 32 patients with moderate TBI recruited in Tunisia, which increased to 3.5 at 6 months. A mean GOSE of 8 at 3 months was reported for a subpopulation of mTBI patients identified as having a good recovery trajectory in Chiang et al., which contrasted with a mean GOSE of 7 at 3 months in patients who had initial functional impairment. All studies identified that a proportion of patients had some functional impairment at 6 or 12 months as indicated by a GOSE <8.

Short Form-36 Health Survey

Five studies reported outcomes for the SF-36 (Table 5). Four studies reported outcomes for the physical and mental component summaries (PCS, MCS), and one study reported outcomes for the vitality section. The largest study, Voormolen et al. (N = 1104), found mTBI patients with injuries identified on CT imaging to have lower mean PCS and MCS scores at 3 and 6 months post-injury than patients without injuries identified on CT.

Table 5.

Studies Reporting Outcomes for Short Form-36 Health Survey

Study	Total patients	Discharge/Early outcome	3 months	6 months	1 year
Chiang et al.²²	100	PCSUnder average QoL and worsening (n = 14) mean = 40Under average QoL and improving (n = 35) mean = 40Fine QoL and slight worsening (n = 51) mean = 59MCSPersistently under average QoL (n = 11) mean = 33Persistently fine QoL (n = 89) mean = 52	PCSUnder average QoL and worsening (n = 14) mean = 39Under average QoL and improving (n = 35) mean = 42Fine QoL and slight worsening (n = 51) mean = 59MCSPersistently under average QoL (n = 11) mean = 32Persistently fine QoL (n = 89) mean = 52		PCSUnder average QoL and worsening (n = 14) mean = 32Under average QoL and improving (n = 35) mean = 49Fine QoL and slight worsening (n = 51) mean = 58MCSPersistently under average QoL (n = 11) mean = 31Persistently fine QoL (n = 89) mean = 52
Heitger et al.³⁹	3737 controls	PCS mean 44MCS mean 43PCS mean 58MCS 55	PCS mean 56MCS mean 49PCS mean 58MCS mean 55	PCS mean 56MCS mean 51PCS mean 58MCS mean 55
Thompson et al.³⁵	33Older age group 65+(n = 15)	PCSYounger mean 43.6 (SD 12.2)Older mean 34 (SD 15.2)MCSYounger mean 47.6 (SD 10.1)Older mean 47.1 (SD 15.1)	PCSYounger mean 41.7 (SD 10.1)Older mean 32.8 (SD 9.3)MCSYounger mean 48.8 (SD 6.5)Older mean 51.8 (SD 9.7)	PCSYounger mean 51.1 (SD 9.2)Older mean 36.3 (SD 10.9)MCSYounger mean 49.9 (SD 6.5)Older mean 55 (SD 7.2)	PCSYounger mean 50.5 (SD 11.7)Older mean 33.3 (SD 9.7)MCSYounger mean 49.1 (SD 7)Older mean 56 (SD 9.3)
Voormolen et al.³⁷	1104		Uncomplicated mTBIPCS <40 = 24%Mean 47.4 (SD 10.6)MCS <40 = 22%Mean 48.2 (SD 10.9)Complicated mTBIPCS <40 = 29%Mean 45.6 (SD 10.2)MCS <40 = 30%Mean 46 (SD 12.1)	Uncomplicated mTBIPCS <40 = 21%Mean 48.6 (SD 10.4)MCS <40 = 21%Mean 48.6 (SD 11.1)Complicated mTBIPCS <40 = 22%Mean 47.6 (SD 10)MCS <40 = 28%Mean 47.2 (SD 12)
Norrie et al.⁴³	159	SF36 VitalityMean 46.6 (SD 24.7)	SF 36 VitalityMean 60.2 (SD 19.7)	SF 36 VitalityMean 62.1 (SD 20.2)

PCS, SF36 Physical Component Summary; MCS, SF36 Mental Component Summary; QoL, quality of life; SD, standard deviation.

Quality of Life after Brain Injury Scale

Three studies reported outcomes for the QOLIBRI (Table 6). Chiang et al. presented mean scores on the 1–5 scale across the six domains, while the other two studies converted these scores to a 1–100 scale. Chiang et al. identified two different recovery pathways in a cohort of 100 patients. Patients with impaired quality of life at 3 months continued to have impairment at 6 months; however, by 12 months, the difference in symptom burden between the two groups had resolved.

Table 6.

Studies Reporting Outcomes for Quality of Life Brain After Injury Scale

Study	Total patients	Discharge/Early outcome	3 months	6 months	1 year	2 years
Carroll et al.²⁰	61	Mean = 75	Mean = 80	Mean = 80	Mean = 81	Mean = 82
Chiang et al.²²	10041 poor QoL baseline59 fine QoL baseline	Poor mean 2.3Fine mean 3.5	Poor mean 2.5Fine mean 3.5		Poor mean 3.5Fine mean 3.7
Voormolen et al.³⁷	1104		Uncomplicated mTBI<60 = 19%Mean 74.8 (SD 16.5)Complicated mTBI<60 = 26%Mean 70.8 (SD 17.5)	Uncomplicated mTBI<60 = 19%Mean 75.2 (SD 17.2)Complicated mTBI<60 = 21%Mean 72.3 (SD 17.2)

QoL, quality of life; mTBI, mild traumatic brain injury; SD, standard deviation.

Other outcomes

Eight other outcomes were reported in either one or two of the included studies (Table 2). Of these, only the Checklist of Post-Concussion Syndromes (N = 100), EuroQol-5 Dimension 5 Level Survey (N = 182), Acute Concussion Evaluation Score (N = 260), and Fatigue Severity Scale (N = 159) were reported for 100 or more patients.

Predictive factors

Fourteen studies identified factors which may be associated with clinical outcomes at 3 months and later time points (Table 7).^{22–25,27,29,33–35,37,38,43,45,46} By stratifying patients by CT findings, two of the larger studies Voormolen et al. (N = 1104) and McMahon et al. (n = 348) found that patients with injuries identified on CT imaging had statistically significantly worse clinical outcomes and a higher symptom burden at 3 months compared to patients without injuries identified on imaging. However, the differences in reported outcomes between those with injuries and without injuries identified on CT imaging narrowed and even resolved for some outcome measures at later time points. Five studies reported multivariable models.^{24,25,27,34,38} Psychiatric history/symptoms were identified as independently associated with 3-month and longer-term outcomes in three of these studies. Other factors identified in single studies as independently associated with outcomes—particularly GOSE—included: initial injury severity (reflected by GCS or CT findings), ethnicity, years in education, duration of post-traumatic amnesia, history of previous migraines, female sex, and social deprivation. Three studies stratified outcome analysis by age.^33,35,45 These suggest that although older adults may not have greater impaired function or high symptom burden than younger adults, the nature of their symptoms and impairment differed.

Table 7.

Factors Assessed for Impact on Outcomes at or Later Than 3 Months Post Sustaining Moderate or Mild Traumatic Brain Injury

Risk factor	Number of studies	Number of studies assessing the effect of variable on outcome trajectory or at single/multiple time points			Studies predictive of outcome at multiple time points
Risk factor	Number of studies	Randomized allocation	Univariable analysis (N)	Multivariable analysis (N)	Studies predictive of outcome at multiple time points
Age	10^{22,24,27,31,35,38,41,45–47}		8^{22,27,31,35,41,45–47}	4^22,24,38,46	4^22,35,45,46
Sex	7^{22,27,32,38,41,46,47}		6^{22,27,32,41,46,47}	3^38,46,47	3^41,46,47
Educational attainment/years in education	7^{22,24,27,38,41,46,47}		5^{22,27,41,46,47}	5^{22,24,27,38,46}	1^22,27,41,46*
Initial GCS	5^{24,27,38,46,47}		4^27,38,46,47	3^24,38,46	1⁴⁶
CT findings	5^{29,30,37,38,47}		4^29,30,37,47	2^38,47	2^30,37*
Psych disease	4^27,38,41,47		3^27,41,47	2^27,38	3^27,38,41
LOC	3^27,41,46		3^27,41,46	1⁴⁶	1^41,46
Post-traumatic amnesia	3^27,41,46		1^27,41,46	1⁴⁶	1⁴⁶
Intoxicated when injured	3^27,32,41		3^27,32,41
Race	3^27,41,46		3^27,41,46	2^27,46	3^27,41,46
Ethnicity	2^27,46		2^27,46	2^27,46	1²⁷
Living alone	2^32,47		2^32,47
Married/Partnered	2^22,41		2^22,41
Employment	2^22,41		2^22,41	1²²	1²²*
Injury mechanism	2^27,46		2^27,46	2^27,46	2^27,46
Had CT imaging	1⁴⁶		1⁴⁶	1⁴⁶	1⁴⁶
Anticoagulant	1²⁷		1²⁷
Cardiovascular disease	1³⁸			1³⁸
GI disease	1³⁸			1³⁸
Respiratory disease	1³⁸			1³⁸
Comorbidities	1^22,47		1^22,47
Headache/Migraine	1³⁸			1³⁸	1³⁸
Prior concussions	1⁴¹		1⁴¹
Work-related injury	1⁴¹		1⁴¹
Altered mental state	1⁴¹		1⁴¹
Toxicology screen	1²⁷		1²⁷	1²⁷
Hypotension	1²⁷		1²⁷
Hypoxia	1²⁷		1²⁷
AIS	1³²		1³²
Household income	1^22,46		2^22,46	1⁴⁶	1⁴⁶
Deprivation index	1⁴⁶		1⁴⁶	1⁴⁶	1⁴⁶
Health insurance	1⁴⁶		1⁴⁶	1⁴⁶	1⁴⁶
Injury-related litigation	1⁴⁶		1⁴⁶	1⁴⁶	1⁴⁶
Early motor function (eye movement + arm function)	1²³			1²³	1²³
IC P3NOGO amplitudes	1¹⁹		1¹⁹		1¹⁹

*Statistically significant association in this study.

AIS, acute ischemic stroke; CT, computed tomography; GI, gastrointestinal; GCS, Glasgow Coma Scale; LOC, loss of consciousness.

Trajectory of outcomes over time

Across studies reporting the RPQ, GOSE, SF-36, and QOLIBRI, the majority showed evidence of improvement over time: RPQ 15/15 studies, GOSE 12/14 studies, SF-36 5/5, and QOLIBRI 3/3 studies. Two studies recorded worsening RPQ symptom burden, one study worsening of the SF36 PCS and one worsening of GOSE over time in 13–23% of patients.^22,32,41,47 The largest reported improvements occurred between early assessments (while in hospital or at discharge) and outcomes measured at 3 months. Across all four outcome measures, significant persistent symptom burden, impairment of function, or of quality of life was reported at 6 and 12 months. Notably, between 20% and 50% of patients were reported to have post-concussion symptoms at 6 and 12 months.^{23–25,31,39} Over half of patients were reported to have GOSE less than 8, and around one-third patients were reported to have GOSE less than 7 at these time points.^30,31,37 Voormolen et al. found that over 20% of patients had impairment that affected daily quality of life as measured by SF-36 and QOLIBRI at 6 months. No single study conducted a multivariable analysis predicting outcome trajectory beyond 3 months (Table 7). Two of the smaller studies (<200 patients) conducted multilevel multivariable models with time of follow-up as predictor,^22,46 identifying demographics (age, gender) and social determinants of health (employment and insurance status/area deprivation) as significant. Three larger studies modelled change over time and characterized trajectories by age³¹ (not predictive), CT findings³⁷ (not predictive), and extent of depressive symptoms⁴⁴ (predictive of poorer PCS recovery) in univariable analyses.

Discussion

Summary

We conducted a systematic review characterizing the trajectory of clinical outcomes following mild and moderate TBI. Whereas previous reviews have estimated the prevalence of symptom burden at single time points, identifying factors associated with increased impairment or characterized the early trajectory of recovery (within 3 months of injury),^5,14–16 we included a specific focus on the change in outcome between 3 months and later time points. Across four commonly reported outcome measures (RPQ, GOSE, SF-36, and QOLIBRI), we have found that disease burden reduced over time, particularly from discharge to 3 months post-injury. However, a significant proportion of patients (between 22% and 70% depending on cohort and outcome measure) had symptoms or impairment at 3 months with little resolution (21–65% with symptoms or impairment) and worsening for some at 6 and 12 months follow-up.

Strengths and limitations

Our systematic review reports a search strategy encompassing four electronic databases, and we found 30 studies with 28 separate cohorts that met the inclusion criteria. Our review includes all relevant AMSTAR systematic review checklist quality domains apart from a formal assessment of the risk of publication bias (item 10) of included studies.⁴⁸ However, the nature of our research question (assessing prevalence of symptom burden trajectory) and the noninterventional nature of the majority of the studies included make our review less susceptible to publication bias.

Our review is limited by the nature of the studies identified, which met the inclusion criteria. Outcomes for only 179 patients solely with moderate TBI could be identified across the included studies compared to 7781 patients with mTBI, which prevents any meaningful comparison of the trajectory of recovery between these two groups. Differences in outcome measures used in different studies and how the same outcome was reported prevented meta-analysis and affected the accuracy with which recovery trajectories could be described. The majority (20/30) of included studies were found to have poor quality using our quality assessment tool, which again weakens the strength of conclusions that can be drawn from our narrative synthesis—most studies did not report a sampling strategy or screening log, limiting assessment of internal validity versus eligible individuals with moderate or mTBI presenting to the emergency department. One study reported that about 8% of patients with mTBI consented to enrollment in the ED, while a second study in older adults reported 72%. Neither study reported the characteristics of those not enrolled.²¹ The supplementary data extraction Table 3 reflects follow-up rates at 3 months as a proportion of those initially consenting, and 6- and/or 12-month follow-up rates as a proportion of the 3-month cohort. Both rates are generally high (generally over 50%, with many at or close to 100%); however, some studies only included patients with at least one or complete follow-up across time points.^20,37,38 Furthermore, many studies excluded vulnerable populations who frequently present with TBI such as those with pre-existing dementia,^{14,18,19,22,35,45,47} older adults,^{18,19,22,23,26} people with previous psychiatric illness,^{20,34,42,46,47}intoxicated at the time of injury and/or history of substance abuse,^{22–24,34,39,42,43,47} or patients with injuries on a CT brain scan.^{19,22–24,27,39,41,43} These exclusions limit the external validity of findings; many studies attempted to compensate for this by enrolling people with extracranial injuries or uninjured—as “control” cohorts^{19,20,22,24,26,30,39,40,42,45}—nevertheless, the heterogeneity of study inclusion criteria within the definitions of mild and moderate TBI is notable. Consistent, well-matched controls allow more reliable attribution of PCS symptoms (such as headache) to TBI versus other conditions that occur in the non-TBI population (such as a viral infection or mental health problems). However, identifying controls is difficult if not impossible for vulnerable TBI populations such as those with pre-injury dementia or intoxication who sustain TBI through ground-level falls. Given the significant disease burden,¹ prognostic studies including these vulnerable populations—even without controls—are still of value.

A further limitation concerns the reporting of outcomes. While dichotomizing an ordinal scale like the GOSE can facilitate outcome analysis (Table 4), it can also lead to a significant loss of information as a GOSE of 7 (“good recovery” with minor persisting problems) represents a vastly different clinical reality than a GOSE of 5 or 6 (moderate disability). By grouping these patients, the true spectrum of disability is obscured. This common practice of binary reporting prevents a nuanced understanding of functional recovery trajectories, which should be addressed in future research.¹

Although 12 outcome measures were assessed across included studies, only 4 outcomes were assessed in over 1000 patients (RPQ, GOSE, SF-36, and QOLIBRI). Therefore, our description of the recovery trajectory is characterized best by these outcome measures. An aim of our study was to assess how outcomes at 3 months impacted on later outcomes and identify factors which affected this trajectory. Although some studies identified risk factors for outcomes measured at single time points, no study identified factors that affected the trajectory in multivariable models. However, Voormolen et al.³⁷ stratified recovery trajectory by presence of injuries identified on CT imaging, Thompson et al.³⁵ and Richey et al.³¹ stratified recovery trajectory by age group, and Roy et al.⁴⁴ compared recovery with and without depressive symptoms. One study, Chiang et al.,²² was able to identify worse recovery trajectories in a group of patients with a high early symptom burden in a small cohort of patients. Overall, the limited exploration of factors affecting recovery trajectory reported in the included studies prevents the identification of different recovery trajectories being characterized for different patient subgroups.

Comparison to previous literature

As highlighted by Voormolen et al.,⁴⁹ measures of prevalence of post-concussion symptoms and functional outcomes can vary widely when different classification methods is used. Our review found considerable variation in the prevalence of impairment estimated at the same time points, both with the same outcome measures and with different measures. Using the RPQ, up to 52% of patients were estimated to have one or more new post-concussion symptoms at 3 and 6 months,^21,23 with mean 3- and 6-month RPQ scores varying 10-fold between studies (with different inclusion criteria and subgroups). Mean scores RPQ scores in 7 cohorts with 12-month follow-up varied threefold with the range of mean scores encompassing that recorded by other large studies.⁵⁰ An estimated 29–64% of patients had a GOSE <8 at 3 months and 21–65.4% at 6 months.^27,31

Our review found a similar prevalence of post-concussion symptoms following mTBI to that reported by Cancelliere et al.⁵ (31.3%) at 3–6 months post-injury. As in previous studies, our review found CT findings and pre-morbid psychiatric history to be predictors of worse recovery.^8,15,16 However, our systematic review is unique in identifying the trajectory of recovery after 3-months of injury across a diverse range of outcome measures. The only other review that assessed the trajectory of recovery focused on the period immediately following injury to 4–6 weeks post-injury.¹⁴ Although not the primary focus of our review, we found a similar magnitude of recovery to McCrae et al.¹⁴ during this early period.

Implications

When clinically assessing patients with persistent impairment at 3 months following mild and moderate TBI, it is important to be able to advise them of their likely recovery trajectory. Our review highlights that symptoms and impairments at 3 months, as measured using RPQ, GOSE, SF-36, and QOLIBRI, are likely to persist at 6–12 months. However, there is limited evidence to identify which patients are likely to have such persistent symptoms, and it seems possible that at 3 months, symptom-free patients could subsequently deteriorate, given the findings of this review. Research like that conducted by Chiang et al.²² aimed at identifying patient subgroups based on early symptom burden with different recovery trajectories in the first year following TBI is needed to provide patients with individualized advice regarding their prognosis.

Moreover, the prevalence of patients who have persisting impairment at 3 months and later time points varied widely based on different analyses of the RPQ (mean, median scores/numbers of symptoms, and percentages with number of symptoms above varying cutoff)⁴⁷ and differing summaries of other outcome measures used. Although efforts are being made to ensure common data elements are collected in TBI studies, there is a need to standardize which outcomes are used to assess symptom burden and thresholds used to identify persisting post-concussion symptoms.¹¹ Differences in reporting between studies even using the same outcome measure prevented meta-analysis. The need to be able to provide patients with individualized prognoses following TBI and measure outcomes that best reflect the impact of TBI on patients are research priorities identified in the James Lind Alliance research priority setting exercise for concussion.⁵¹ Future research needs to address this challenge while minimizing post-TBI losses to follow up.⁵² The heterogeneity identified in 3–12 month outcomes of so-called mTBI speaks to the need for a more nuanced multidimensional disease characterization that may provide more clarity in providing patients with a prognosis. To this end, a recent proposal recommends moving away from the mild/moderate dichotomization of TBI to a more granular assessment based on the initial GCS score (e.g., 13, 14).^52–54

Conclusion

A significant proportion of patients were found to have symptoms or impairment following mild and moderate TBI across different studies at 3 months following injury. Most of these patients had persisting impairment at 6 and 12 months following injury. There was limited evidence available to identify factors that affect the recovery trajectory and frequent exclusion of vulnerable subgroups. Studies were heterogeneous in inclusion criteria, reported multiple outcome measures, and used different thresholds to classify persisting symptoms, which led to wide variation in estimates of symptom burden. Standardized reporting of outcome measures is needed as part of common data elements to enable future research to identify factors predicting the outcome trajectory at 3 months after TBI.

Transparency, Rigor, and Reproducibility Summary

We conducted this systematic review according to the protocol published on PROSPERO from https://www.crd.york.ac.uk/PROSPERO/view/CRD42021264931. The search strategies and results are summarized in the main text PRISMA diagram and tables in the article with further detail (search strategies and data extraction tables) in Supplementary Material and list of citations plus excluded studies.

Authors’ Contributions

A.M., L.W., and F.L. conceived the study and approved part funding from the CENTER TBI Work Package 17. C.M., F.L., R.W., A.P., and L.W. developed their review protocol subsequently published on PROSPERO, taking account of TBI, lived experience (J.P.), specialist neurorehabilitation (R.S.), and wider emergency care (T.S., M.T.) perspectives. A.P. and R.W. developed the database search strategies and conducted the electronic searches, importing citations into the review reference software. C.M., M.T., and T.L. independently screened citation titles and abstracts for relevance. C.M., M.T., T.L., and F.L. independently assessed full texts of studies potentially meeting the inclusion criteria, extracting outcome data, and conducting quality assessments of included studies. C.M. and F.L. tabulated the reported outcomes from included studies, conducted a narrative synthesis of outcomes, and drafted the article. All authors reviewed and provided comments on the article and approved the final draft for submission.

Supplemental Material

sj-docx-1-nrt-10.1177_08977151261459960 — Supplemental material for A Systematic Review of Clinical Outcome Trajectories from 3 to 12 Months Following Mild or Moderate Traumatic Brain Injury

Supplemental material, sj-docx-1-nrt-10.1177_08977151261459960 for A Systematic Review of Clinical Outcome Trajectories from 3 to 12 Months Following Mild or Moderate Traumatic Brain Injury by Carl Marincowitz, Fiona Lecky, Abdullah Pandor, Ruth Wong, Thomas Shanahan, Michael Tonkins, Rajiv Singh, James Piercy, Andrew Maas, and Lindsay Wilson

Supplemental Material

sj-docx-2-nrt-10.1177_08977151261459960 — Supplemental material for A Systematic Review of Clinical Outcome Trajectories from 3 to 12 Months Following Mild or Moderate Traumatic Brain Injury

Supplemental material, sj-docx-2-nrt-10.1177_08977151261459960 for A Systematic Review of Clinical Outcome Trajectories from 3 to 12 Months Following Mild or Moderate Traumatic Brain Injury by Carl Marincowitz, Fiona Lecky, Abdullah Pandor, Ruth Wong, Thomas Shanahan, Michael Tonkins, Rajiv Singh, James Piercy, Andrew Maas, and Lindsay Wilson

Supplemental Material

sj-docx-3-nrt-10.1177_08977151261459960 — Supplemental material for A Systematic Review of Clinical Outcome Trajectories from 3 to 12 Months Following Mild or Moderate Traumatic Brain Injury

Supplemental material, sj-docx-3-nrt-10.1177_08977151261459960 for A Systematic Review of Clinical Outcome Trajectories from 3 to 12 Months Following Mild or Moderate Traumatic Brain Injury by Carl Marincowitz, Fiona Lecky, Abdullah Pandor, Ruth Wong, Thomas Shanahan, Michael Tonkins, Rajiv Singh, James Piercy, Andrew Maas, and Lindsay Wilson

Supplemental Material

sj-docx-4-nrt-10.1177_08977151261459960 — Supplemental material for A Systematic Review of Clinical Outcome Trajectories from 3 to 12 Months Following Mild or Moderate Traumatic Brain Injury

Supplemental material, sj-docx-4-nrt-10.1177_08977151261459960 for A Systematic Review of Clinical Outcome Trajectories from 3 to 12 Months Following Mild or Moderate Traumatic Brain Injury by Carl Marincowitz, Fiona Lecky, Abdullah Pandor, Ruth Wong, Thomas Shanahan, Michael Tonkins, Rajiv Singh, James Piercy, Andrew Maas, and Lindsay Wilson

Footnotes

Acknowledgments

The authors acknowledge assistance in article preparation from Joanne Palfreyman, CURE Administrator, University of Sheffield.

Author Disclosure Statement

The authors have no conflicts of interest to declare.

Funding Information

The study was part funded by the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury European Union’s 7th Framework Program (EC Grant 602150). F.L. is part funded by the United Kingdom TBI REPORTER infrastructure Grant (UKRI). This review was part funded by the Collaborative European NeuroTrauma Effectiveness Research Grant EU FP7 Grant 602150. The funder had no role in the conduct of this study.

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