There are approximately 69 million traumatic brain injuries (TBI) in the world every year.1 It is the leading cause of death and long-term disability among all trauma related injuries.1 Accidental falls, motor vehicle accidents, being hit with or against an object, and physical violence are the most common causes of TBI.2 Contrary to popular belief, sports-related concussions are not the most frequent cause— these account for only 3% of all TBIs.2 The evaluation of these patients comes with many challenges for caretakers in the emergency department including the lack of simple, rapid, and objective tools to evaluate these patients. Subjective symptoms, neurologic assessment, and computerized tomography (CT) of the head are the main sources of information to determine the diagnosis and course of action.3
The neurologic assessment may become difficult due to confounding factors, such as baseline conditions, as well as concomitant drugs and alcohol use.4,5 Most of the symptoms (headache, dizziness, confusion) are not sensitive or specific for TBI.4,5 The Glasgow Coma Score (GCS) is commonly used for evaluation and classification of severity of TBI.6 Depending on the GCS score, TBIs are classified in mild, moderate, and severe, GCS 13–15, 9–12, and 3–8, respectively.7 The head CT is usually performed without contrast.6 The standard clinical interview and CT do not have a high sensitivity for mild traumatic brain injury (mTBI)8 — commonly referred to as concussion. Moreover, the diagnosis of mTBI might be missed in over 50% of cases.9 Importantly, overutilization of CT scans has not provided better patient outcomes. Most mTBI patients presenting to the emergency department will receive a CT scan, however, less than 10% of these scans will demonstrate any findings related to trauma.7 This overutilization of CTs provides unnecessary radiation exposure to patients, prolongs patient stays, and decreases scanner availability.7,10 Furthermore, wide gaps and variability in both patient education and follow-up upon discharge exist. Disease state information provided at discharge has been estimated between 19% to 72% with only 22% to 58% of patients receiving any type of follow-up care.11
Clinical decision rules (CDR) such as the Canadian CT Head Rule (CCHR) and the New Orleans Criteria (NOC) National Emergency X-Radiography Utilization Study II have been created to mitigate some of these challenges. However, the implementation of these rules and guidelines has not been standardized and globally accepted. Interestingly, surveys have shown, for various reasons, that clinicians do not always feel comfortable using clinical decision rules.13,14
A promising approach to significantly improve TBI evaluation and treatment in ED settings lies within utilization of blood-based biomarkers—specifically those originating from the brain. Brain biomarkers detected in biofluid are representative of the complex array of pathophysiological processes that occur following brain injury. A complete, broad comprehension of these processes is imperative for further development of therapies. Fortunately, the scientific advancements presented within the last decade have dramatically increased this level of understanding.15
Currently, the pathophysiological processes in TBI depicted by brain biomarkers include injury to the dendrites, neuronal cell body, myelin, synapses, and astroglia16-19 due to direct injury, vascular stretch and/or neuroinflammation.20,21 The biomarkers reach the peripheral blood via various mechanisms including disruption of the blood–brain barrier and via the glymphatic system.22
Many brain biomarkers have been investigated as an objective tool to aid the assessment of patients with suspected traumatic brain injury.15 Characteristics of the ideal blood-based biomarker candidate(s) include measurability in the peripheral blood and ability to capture TBI severity. In addition, these brain proteins should be highly brain specific and correlate with TBI prognosis.15 A wide variety of brain markers of neuronal and astrocytic/glial origin have been assessed as potential candidates. In the last decade, the S100β protein was included in some evaluation protocols for mTBI patients in Nordic and other European countries.23 However, due to the low specificity of this protein as a brain biomarker,15 its implementation has been limited as this protein is also present in adipocytes, musculoskeletal cells, and melanocytes.15
As research has progressed, two promising acute biomarkers, Glial Fibrillar Acid Protein (GFAP) and C-terminal Ubiquitin L1 Hydrolase (UCH-L1), have been identified and U.S. Food and Drug Administration (FDA) cleared in the evaluation of mTBI patients. GFAP is a glial protein, part of the cytoskeleton of astrocytes and is present in the gray and white matter of the brain.24 It supports the cell and blood brain barrier.24 UCH-L1 is a specific protein in the cytoplasm of neurons, constituting up to 2% of total brain proteins.24 A portion of this protein is also found in axons, which highlights its importance in signal transport and neuronal metabolism in the brain.24
UCH-L1 and GFAP levels are measurable in peripheral blood within the first hour after trauma.12 UCH-L1 levels elevate immediately following injury, whereas GFAP levels tend to peak several hours later.12 Both values decrease over time, however, GFAP values can remain elevated beyond seventy-two hours.13 The difference in origin and the kinetics of these two proteins underscore the importance of measuring both in mTBI patients after acute injury. Of note, Papa et al. showed that GFAP and UCH-L1 elevations may detect intracranial lesions.12 This study also highlighted how UCH-L1 performed best in the first hours after the trauma.12 Both plasma and GFAP and UCH-L1 have demonstrated the ability to predict incomplete recovery after injury.24
Furthermore, plasma GFAP concentrations showed discrimination between CT negative and MRI (magnetic resonance imaging) positive vs. MRI negative scans when the samples were collected within 24 hours after injury.26 A “Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK- TBI)” publication demonstrated that GFAP outperformed S100β in its ability to predict intracranial lesions in a CT scan across all severities of TBI.27 Notably, 73% and 56% of mTBI, GCS 15, with a negative CT still had incomplete recovery at 2 weeks and 6 months after the injury, respectively.28 A CT Scan model studied by Zimmer, et al, showed a reduction in the amount of CT scans compared to S100β.29
These biomarkers have been cleared for clinical use in the United States by the FDA as well as in other regulatory agencies around the world as an aid in ruling out intracranial lesions in mTBI, GCS 13–15, in patients 18 or older who are evaluated within 12 hours from injury by Banyan, 2018,30 Abbott Point of Care, 2021,31 and Abbott Core Diagnostics, 2023.32 Currently, several European countries are reviewing incorporating these blood tests into their local guidelines. In 2022, the French Society for Emergency Medicine (SFMU) updated the “Management of Adult Patients with Mild Traumatic Brain Injury” to include the role of biomarkers in the assessment and management of ED patients with mild TBI.33 To reduce the number of CT scans, these professional practice recommendations advise running a blood test combining UCH-L1 and GFAP within 12 hours following mTBI for adult patients with intermediate risk.33 Furthermore, the National Academies of Science, Engineering, and Medicine has favorably reviewed these blood tests and published its Proceedings of a Workshop this year.34 According to this report, GFAP and UCH-L1 “… are useful in the ED setting in predicting normal CT scans and, if widely implemented, may be able to reduce use of cranial CT.”34
Implementation of these biomarkers into clinical practice will not only provide objective information to physicians when it matters most but also lays the groundwork for potential use of blood-based biomarkers in diagnosis of TBI,35 monitoring of patient recovery, and development of treatments for these patients.34 Clinical utilization of these brain biomarkers has the potential to transform what is currently the standard approach for TBI in acute care settings and helps both clinicians and patients alike.
References
1. Dewan MC, Rattani A, Gupta S, et al. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2018;130(4):1-18. doi:10.3171/2017.10.JNS17352.
2. Faul M, Xu L, Wald MM, Coronado VG. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006. National Center for Injury Prevention and Control. Published online 2002.
3. Jagoda AS, Bazarian JJ, Bruns JJ Jr, et al. Clinical policy: neuroimaging and decision making in adult mild traumatic brain injury in the acute setting. Ann Emerg Med. 2008;52(6):714-748. doi:10.1016/j.annemergmed.2008.08.021.
4. Kelly DF. Alcohol and head injury: an issue revisited. J Neurotrauma. 1995;12(5):883-890. doi:10.1089/neu.1995.12.883.
5. Biberthaler P, Mussack T, Wiedemann E, et al. Elevated serum levels of S-100B reflect the extent of brain injury in alcohol intoxicated patients after mild head trauma. Shock. 2001;16(2):97-101. doi:10.1097/00024382-200116020-00002.
6. Vella MA, Crandall ML, Patel MB. Acute Management of Traumatic Brain Injury. Surg Clin North Am. 2017;97(5):1015-1030. doi:10.1016/j.suc.2017.06.003.
7. Korley FK, Kelen GD, Jones CM, Diaz-Arrastia R. Emergency department evaluation of traumatic brain injury in the United States, 2009–2010. J Head Trauma Rehabil. 2016;31:379-387. doi:10.1097/HTR.0000000000000187.
8. Yuh EL, Mukherjee P, Lingsma HF, et al. Magnetic resonance imaging improves 3-month outcome prediction in mild traumatic brain injury. Ann Neurol. 2013;73(2):224-35. doi:10.1002/ana.23783.
9. Powell JM, Ferraro JV, Dikmen SS, Temkin NR, Bell KR. Accuracy of mild traumatic brain injury diagnosis. Arch Phys Med Rehabil. 2008;89(8):1550-1555. doi:10.1016/j.apmr.2007.12.035.
10. Su YS, Schuster JM, Smith DH, Stein SC. Cost-Effectiveness of Biomarker Screening for Traumatic Brain Injury. J Neurotrauma. 2019;36(13):2083-2091. doi:10.1089/neu.2018.6020.
11. Seabury SA, Gaudette É, Goldman DP, et al. Assessment of Follow-up Care After Emergency Department Presentation for Mild Traumatic Brain Injury and Concussion: Results From the TRACK-TBI Study. JAMA Netw Open. 2018;1(1):e180210. doi:10.1001/jamanetworkopen.2018.0210.
12. Papa L, Brophy GM, Welch RD, et al. Time Course and Diagnostic Accuracy of Glial and Neuronal Blood Biomarkers GFAP and UCH-L1 in a Large Cohort of Trauma Patients With and Without Mild Traumatic Brain Injury. JAMA Neurol. 2016;73(5):551-560. doi:10.1001/jamaneurol.2016.0039.
13. Papa L, Ladde JG, O'Brien JF, et al. Evaluation of Glial and Neuronal Blood Biomarkers Compared With Clinical Decision Rules in Assessing the Need for Computed Tomography in Patients With Mild Traumatic Brain Injury. JAMA Netw Open. 2022;1;5(3):e221302. doi:10.1001/jamanetworkopen.2022.
14. Richardson S, Dauber-Decker KL, McGinn T, Barnaby DP, Cattamanchi A, Pekmezaris R. Barriers to the Use of Clinical Decision Support for the Evaluation of Pulmonary Embolism: Qualitative Interview Study. JMIR Hum Factors. 2021;8(3):e25046. Published 2021 Aug 4. doi:10.2196/25046.
15. Wang KK, Yang Z, Zhu T, et al. An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn. 2018;18(2):165-180. doi:10.1080/14737159.2018.1428089.
16. Zhang Z, Moghieb A, Wang KKW. Acute, Subacute and chronic Biomarkers for CNS injury In: Wang KK, Zhang Z, Kobeissy FH, eds. Biomarkers of Brain Injury and Neurological Disorders. CRC Press; 2014:1-25.
17. Wang KK, Moghieb A, Yang Z, Zhang Z. Systems biomarkers as acute diagnostics and chronic monitoring tools for traumatic brain injury. SPIE Defense, Security, and Sensing. 87230O–87230O–15; 2013.
18. Mondello S, Muller U, Jeromin A, Streeter J, Hayes RL, Wang KK. Blood-based diagnostics of traumatic brain injuries. Expert Rev Mol Diagn. 2011;11(1):65-78. doi:10.1586/erm.10.104.
19. Zetterberg H, Blennow K. Fluid biomarkers for mild traumatic brain injury and related conditions. Nat Rev Neurol. 2016;12(10):563-574. doi:10.1038/nrneurol.2016.127.
20. Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery. 2014;75 Suppl 4(0 4):S24-S33. doi:10.1227/NEU.0000000000000505.
21. Sharp DJ, Scott G, Leech R. Network dysfunction after traumatic brain injury. Nat Rev Neurol. 2014;10(3):156-166. doi:10.1038/nrneurol.2014.15.
22. Plog BA, Dashnaw ML, Hitomi E, et al. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J Neurosci. 2015;35(2):518-526. doi:10.1523/JNEUROSCI.3742-14.2015.
23. Undén J, Ingebrigtsen T, Romner B; Scandinavian Neurotrauma Committee (SNC). Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update. BMC Med. 2013;25;11:50. doi:10.1186/1741-7015-11-50.
24. Wang KKW, Kobeissy FH, Shakkour Z, Tyndall JA. Thorough overview of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein as tandem biomarkers recently cleared by US Food and Drug Administration for the evaluation of intracranial injuries among patients with traumatic brain injury. Acute Med Surg. 2021;19;8(1):e622. doi:10.1002/ams2.622.
25. Korley FK, Jain S, Sun X, 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 cohort study. Lancet Neurol. 2022;21(9):803-813. doi:10.1016/S1474-4422(22)00256-3.
26. Yue JK, Yuh EL, Korley FK, et al. Association between plasma GFAP concentrations and MRI abnormalities in patients with CT-negative traumatic brain injury in the TRACK-TBI cohort: a prospective multicentre study. Lancet Neurol. 2019;18(10):953-961. doi:10.1016/S1474-4422(19)30282-0.
27. Okonkwo DO, Puffer RC, Puccio AM, et al. Point-of-Care Platform Blood Biomarker Testing of Glial Fibrillary Acidic Protein versus S100 Calcium-Binding Protein B for Prediction of Traumatic Brain Injuries: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study. J Neurotrauma. 2020;37(23):2460-2467. doi:10.1089/neu.2020.7140.
28. Madhok DY, Rodriguez RM, Barber J, et al. Outcomes in Patients With Mild Traumatic Brain Injury Without Acute Intracranial Traumatic Injury. JAMA Netw Open. 2022;5(8):e2223245. doi:10.1001/jamanetworkopen.2022.23245.
29. Zimmer L, McDade C, Beyhaghi H, et al. Cost-Effectiveness of Blood-Based Brain Biomarkers for Screening Adults with Mild Traumatic Brain Injury in the French Health Care Setting. J Neurotrauma. 2023;40(7-8):706-719. doi:10.1089/neu.2022.0270.
30. FDA authorizes marketing of first blood test to aid in the evaluation of concussion in adults. U.S. Food and Drug Administration. Published February 13, 2018. Accessed June 7, 2023. https://www.fda.gov/news-events/press-announcements/fda-authorizes-marketing-first-blood-test-aid-evaluation-concussion-adults.
31. 501(k) Premarket Notification. US Food and Drug Administration. Decision Date Jan 8, 2021. 501(k) No K201778. Accessed on May 31, 2023. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K201778.
32. 501(k) Premarket Notification. US Food and Drug Administration. Decision Date Mar 2, 2023. 501(k) No K223602. Accessed on May 31, 2023. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K223602.
33. Gil-Jardiné C, Payen JF, Bernard R. Professional Practice Recommendations: Management of Adult Patients with Mild Traumatic Brain Injury. French Society for Emergency Medicine. Published online 2022:1-32.
34. Forum on Traumatic Brain Injury, Board on Health Sciences Policy, Health and Medicine Division, National Academies of Sciences, Engineering, and Medicine. Biomarkers for traumatic brain injury: Proceedings of a workshop. Snair M, Matney C, Bowman K, eds. Published online 2023. doi:10.17226/26932.
35. Bazarian JJ, Biberthaler P, Welch RD, et al. Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study. Lancet Neurol. 2018;17(9):782-789. doi:10.1016/S1474-4422(18)30231-X.
