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Three Part Question

In [patients who present with mild traumatic brain injury to an Emergency Department] can we [predict those at high risk of persisting post-concussion symptoms?] This may include [clinical features and emerging technologies eg MRI, biomarkers.]

Clinical Scenario

Emergency physician clinical gestalt has been found to be overly optimistic regarding the incidence of PPCS; a recent study found while complete recovery was expected in over 90% of patients ~50% developed PPCS. A systematic review concluded that no available models adequately predict outcome after mTBI; many failing due to poor methodology. Subsequently, UPFRONT generated a prediction model which depends on psychological assessment at two weeks (the high number of patients precludes this in the NHS), and is not able to stratify
patients on ED assessment. NICE Guidelines note there is an urgent need for a decision rule that risk stratifies patients at high-risk for PPCS early after presentation.

There are a number of candidates to improve prediction – these include clinical features, premorbid factors and newer technologies including biomarkers and MRI. Current best models have found that clinical features ~2 weeks after injury are most predictive. However, there is some evidence that biomarkers within the ED visit and/or early MRI may help with earlier risk stratification. This search has focused on the key literature to show the current status of this area.

Search Strategy

Search terms included: mild traumatic brain injury, concussion, outcome, post concussion syndrome, prediction, biomarkers, proteomics, MRI, neuroimaging

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
A Mikolic et al. 2021 Europe including UK centres.	GCS 13 to 15	Cohort Study	External validation of the main five previously developed mild TBI outcome predictive models	None of the currently available prognostic models for early prediction of GOSE and PPCS have both good calibration and discrimination in persons with mild TBI.
N Temkin et al. 2022 USA	Predominantly mild TBI but does include ~200 patients with moderate-to-severe.	Prospective Cohort Study	3 month symptom burden (Rivermead post-concussion score)	TBI severity not related to symptom burden. Two-week symptom load was significantly related to 3 month symptom burden	Mixed population. Did not assess factors prior to the 2 weeks. Did not assess functional status
van der Naalt et al 2017 Netherlands	Level 1 trauma centres GCS 13 to 15	Observational cohort study	Functional outcome at 6 months (Glasgow Outcome Score Extended)	Psychological factors measured 2 weeks after injury (ie, emotional distress and maladaptive coping experienced early after injury) in combination with pre-injury mental health problems, education, and age are important predictors for recovery at 6 months following mTBI.	Did not stand up to being externally validated in the Mikolic study above. Large loss of patients at 2 weeks (which is where the model was built) ?biased sample. Loss to follow-up at six months.
Richter et al 2021 Europe including UK centres.	GCS 13 to 15	Cohort study	Functional outcome at 6 months (Glasgow Outcome Score Extended)	Advanced MRI reveals potential neuroanatomical substrates of mTBI in white matter and is most strongly associated with odds of recovery if performed within 72 hours, although future validation is required.	Small number (n = 81) Requires external validation.
Yuh EL, et al. 2013 USA	GCS 13 to 15 Level 1 Trauma centers	Cohort study	Functional outcome at 3 months (Glasgow Outcome Score Extended)	The addition of early CT and MRI markers to a prognostic model based on previously known demographic, clinical, and socioeconomic predictors resulted in a >2-fold increase in the explained variance in 3-month GOS-E.	Small numbers (135) Needs external validation.
Palacios et al 2022 USA	GCS 13 to 15 Level 1 Trauma centers	Cohort study	Functional outcome at 6 months (Glasgow Outcome Score Extended)	Abnormal imaging parameters measured 2 weeks after injury were associated with 6 month outcome.	N = 391 Associations only – no formal prognostic model developed.
Yue et al 2019 USA	Mild TBI (GCS 13 to 15) CT negative	Cohort study	Lesion presence on MRI	GFAP levels within 24 hours of TBI predict lesions on MRI that are not visible on CT. AUC 0·777 (95% CI 0·726-0·829)
Czeiter et al 2020 Europe including UK centres.	TBI who required a CT head	Cohort Study	Injury Severity	Serum biomarkers (S100 calcium-binding protein B (S100B), neuron specific enolase (NSE), glial fibrillary acidic protein (GFAP), Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), neurofilament light polypeptide (NFL) and total(t)-tau) obtained within 24 hours of injury scale with clinical severity. Also validated findings of the Yue study above for biomarkers to predict MRI findings.	Mixed population
Whitehouse et al. 2022 Europe including UK centres.	TBI who required a CT head	Cohort Study	Presence of abnormalities on CT	Biomarker concentration within 24 hours of TBI is primarily related to severity of injury and intracranial disease burden, rather than pathoanatomical type of injury. Biomarkers were elevated in isolated skull fractures	Not looking at prediction but shows biomarkers scale with injury severity defined by lesion extent.
Kulbe at al 2022 USA	GCS 13 to 15 Level 1 Trauma centers Needed a head CT	Cohort Study	Probable PTSD (PCL-5 >32_ 6 months post injury.	Inverse association between PTSD and (log)GFAP (adjusted OR = 0.85, 95% CI 0.77-0.95 per log unit increase	Association – not a usable clinical model Needs external validation.
Siman et al 2020 USA	Adults and children Normal head CT if performed Mild TBI (GCS 13 to 15)	Cohort Study	30 and 90 day performance in the Standardized Assessment of Concussion (SAC) and the Rivermead Post-Concussion Symptom Questionnaire (RPCSQ).	Blood level of SNTF on the day of a CT-negative mTBI strongly discriminates a subset of injury cases and is prognostic for persistent impairments in cognitive and sensory-motor function.	Single Site Single biomarker Small numbers for a prognostic study (n = 95 after TBI) Mixed adult/child population – could there be an age effect with SNTF like there is with NFL?
Papa et al 2019 USA	Sports concussion	Cohort Study	Cognitive function pre and post football season	Select miRNAs were associated with baseline concussion assessments at the beginning of the season and with neurocognitive changes from pre to post-season in collegiate football players.	Not ED based Potential repetitive TBI rather than single event
Hossain et al. 2019 Finland	GCS 13 to 15 CT head required	Cohort Study	GOSE and Rivermead Post Concussion Score at 6 months	The early levels of GFAP and NF-L are significantly correlated with the outcome in patients with mTBI. The level of NF-L within 24 h from arrival has a significant predictive value in mTBI also in a multi-variate model.	Small patient numbers (107)
Helmrich et al 2022 Europe including UK centres.	TBI who required a CT head	Cohort Study	GOSE	High acute biomarker levels were associated with poor outcome. biomarkers improved the prognostic value in addition to demographic, clinical, and radiological characteristics for the prediction of 6-month GOSE.	Only looking at functional recovery (GOSE) with no analysis of other health related outcomes.
Korley et al 2022 USA	TBI who required a CT head	Cohort Study	GOSE	Both GFAP and UCHL-1 showed prognostic value for predicting death and unfavourable outcome but not for predicting incomplete recovery. Biomarkers improved the prediction for death and unfavourable outcome in moderate and severe when added to the IMPACT prediction model.	Only sampling two biomarkers. Use of GOSE as only outcome metric.
Hossain et al 2020 Finland	GCS 13 to 15 CT head required	Cohort Study	GOSE and Rivermead Post Concussion Score at 6 months	levels of T-tau significantly correlated with ordinal GOSE score.	Small patient numbers (105)

Comment(s)

There is a need to be able to predict which patients are at high risk of ongoing symptoms. This will help triage those patients who need into follow-up (a finite resource so only high risk can be referred), who may benefit from early intervention and better design clinical trials by facilitating trial enrichment. The current evidence does have prediction models suitable for clinical use. It also does not include patients who have not required a CT brain. However, the data shows promise for future improved prediction modeling.

Clinical Bottom Line

There is emerging evidence of improved outcome prediction in TBI utilising emerging technology including MRI and blood-based biomarkers, however, more work is needed before these can be utilised in a clinical setting.

References

1. A Mikolic et al. Prediction of global functional outcome and post-concussive symptoms after mild TBI. J Neurotrauma. 2021;38(2);196-209.
2. N Temkin et al. Risk factors for high symptom burden 3 months after TBI and implications for clinical trial design: a TRACK-TBI study. J Neurotrauma 2022, Online ahead of print
3. van der Naalt et al Early predictors of outcome after mTBI (UPFRONT). Lancet Neurology. 2017;16(7):532-540.
4. Richter et al Neuroanatomical Substrates and Symptoms Associated With Magnetic Resonance Imaging of Patients With Mild Traumatic Brain Injury JAMA Network Open 2021;4(3):e210994.
5. Yuh EL, et al. Magnetic resonance imaging improves 3-month outcome prediction in mild traumatic brain injury. Annals of Neurology 2013;73(2):224-235.
6. Palacios et al Diffusion tensor imaging reveals elevated diffusivity of white matter microstructure that is independently associated with long-term outcome after mTBI J Neurotrauma 2022, Online ahead of print
7. Yue et al Association between plasma GFAP concentrations and MRI abnormalities in patients with CT-negative TBI. Lancet Neurology 2019;18(10):953-961
8. Czeiter et al Blood biomarkers on admission in acute TBI. EBioMedicine 2020;56:102785
9. Whitehouse et al Relationship of admission blood proteomic biomarkers to lesion type and lesion burden. EBioMedicine 2022;75:103777
10. Kulbe at al Association of day-of-injury GFAP and six month PTSD in patients with mild TBI. Neuropsychopharmacology 2022, Online ahead of print
11. Siman et al Serum SNTF, a surrogate marker of axonal injury is prognostic for lasting brain dysfunction in mild TBI treated in the ED Frontiers in Neurology 2020;11:249
12. Papa et al Elevations in MicroRNA Biomarkers in Serum Are Associated with Measures of Concussion, Neurocognitive Function, and Subconcussive Trauma over a Single National Collegiate Athletic Association Division J Neurotrauma 2019;436(8):1343-1351
13. Hossain et al Early levels of GFAP and NFL in predicting outcome of mild TBI. J Neurotrauma 2019;36(10):1551-1560.
14. Helmrich et al Incremental prognostic value of acute serum biomarkers for functional outcome after traumatic brain injury (CENTER-TBI): an observational cohort study. Lancet Neurology 2022;21(9):792-802
15. Korley et al. Prognostic value of day-of-injury plasma GFAP and UCH-L1 concentrations for predicting functional recovery after traumatic brain injury in patients from the US TRACK-TBI cohort: an observational cohor Lancet Neurology 2022;21(9):803-813
16. Hossain et al Admission Levels of Total Tau and beta-Amyloid Isoforms 1-40 and 1-42 in Predicting the Outcome of Mild Traumatic Brain Injury Frontiers in Neurology 2020;11:325