Traumatic brain injury (TBI) is characterized by pathologic injuries to the brain resulting from external forces or trauma. A broad range of sequela of varying clinical severity include focal contusions and hematomas, diffuse axonal injury, cerebral edema and swelling, and a cascade of molecular injury mechanisms (Hemphill, 2018).
Concussion refers to the trauma-induced alteration in mental status which may or may not involve loss of consciousness after a mild TBI (Evans & Whitlow, 2018).
Traumatic brain injury (TBI) is an expanding public health epidemic, with at least 2.8 million emergency department visits, hospitalizations, or deaths related to a TBI yearly (Wright, Kellermann, McGuire, Chen, & Popovic, 2013). Although approximately 75% of TBIs are mild, TBI can adversely affect a person’s quality of life in numerous ways, including cognitive functioning, emotional functioning, and physical effects (CDC, 2015). An estimated 5.3 million U.S. residents are living with TBI-related disabilities, including long-term cognitive and psychologic impairments (Selassie et al., 2008).
Accurate diagnosis of TBI is critical to effective management and intervention, but can be challenging due to the nonspecific and variable presentation, especially of mild TBI (Mondello et al., 2017). Tools available to objectively diagnose injury and predict recovery are limited (Mannix, Eisenberg, Berry, Meehan, & Hayes, 2014). Clinical assessment usually includes a neurological exam, often using one of several diagnostic tools developed to aid in concussion recognition, followed by a computed tomography or CT scan of the head to detect brain tissue damage that may require treatment (FDA, 2018). However, as most patients with mild TBI do not have detectable intracranial lesions on a CT scan, this assessment relies heavily on nonspecific symptoms that can vary widely (Strathmann, Schulte, Goerl, & Petron, 2014), and ignores the mechanistic heterogeneity of TBI (Maas et al., 2017).
Brain damage in TBIs is initially caused by external mechanical forces being transferred to intracranial contents, generating shearing and strain forces that stretch and damage axons, and can result in contusions, hematomas, cerebral edema and swelling (Blennow et al., 2016). Common mechanisms include direct impact, rapid acceleration/deceleration, penetrating injury, and blast waves (Hemphill, 2018). However, the pathophysiology of TBI is now understood to include not only the acute event, but also the resulting cascade of molecular injury mechanisms that are initiated at the time of initial trauma and continue for hours or days (Wang et al., 2018). The pathophysiology of even mild TBI is complex and may include both focal and diffuse injury patterns. Neuropathological changes found after mild TBI indicate mild multifocal axonal injury, including altered circuit dysfunction and traumatic axonal injury, together with activation of microglia (the resident innate immune cells of the central nervous system), chronic neuroinflammation, and microhemorrhages (Truettner, Bramlett, & Dietrich, 2018).
Cell death and the initiation of local metabolic and inflammatory processes resulting from TBI result in the release of a number of inflammatory mediators and damage-associated molecules that are able to cross a dysfunctional blood-brain barrier (Di Battista et al., 2015) or enter the circulation through the glymphatic pathway (Plog et al., 2015). Neurobiochemical marker levels in blood after TBI may reflect structural changes detected by neuroimaging (Mondello et al., 2017). Simpler, sensitive, and specific tests that provide early, quantitative information about the extent of brain tissue damage (Mondello, Akinyi, et al., 2012), identifying and stratifying TBI, would allow rapid and tailored diagnosis of TBI, while minimizing the time, risk, and cost associated with current standards (McMahon et al., 2015). No single ideal TBI biomarker exists (Halford et al., 2017). However, brain-specific markers of neuronal, glial, and axonal damage, identified in the peripheral blood, have shown potential clinical utility as diagnostic, prognostic, and monitoring adjuncts (Papa et al., 2015) and have been investigated both individually and in combination (Di Battista et al., 2015; Mondello, Jeromin, et al., 2012).
Acute-phase biomarkers, including S100 calcium-binding protein B (S100B), glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1), have shown potential for use in initial screening of patients presenting with head trauma, the vast majority of whom will have normal brain CT findings (Maas et al., 2017).
S100 calcium-binding protein B (S100B) belongs to the calcium binding EF-hand protein group, and has been associated with cytoskeleton structure, Ca2+ homeostasis, cell proliferation, protein phosphorylation and degradation (Chmielewska et al., 2018; Strathmann et al., 2014). S100B is expressed in the cytoplasm and the nucleus of astrocytes and is present in the bloodstream when the blood-brain barrier is disrupted. Several studies indicate that S100B measurement, either acutely or at several time points, can distinguish injured from non-injured patients (Strathmann et al., 2014) and guidelines intended to reduce the need for CT scans -- using S100B levels in the blood for the initial management of mild TBI -- have been published (Ingebrigtsen, Romner, & Kock-Jensen, 2000). These guidelines were recently validated in a large multicenter study where S100B was found to have a sensitivity of 97% and a specificity of 34% for the identification of intracranial hemorrhages confirmed by CT scans (Unden, Calcagnile, Unden, Reinstrup, & Bazarian, 2015). Although it has not been FDA-approved, in 2008 the American College of Emergency Physicians suggested that in mild TBI patients without significant extracranial injuries and a serum S100β of level less than 0.1μg/L measured within 4 h of injury, consideration could be given to not performing a CT (Jagoda et al., 2008). However, other investigators have failed to detect associations between S100B and CT abnormalities (Piazza et al., 2007). Additionally, it has limited utility in multiple trauma setting, as it is not brain-specific. S100B can be found in non-neural cells such as adipocytes, chondrocytes, and melanocytes (Papa et al., 2014), and its levels are also elevated in orthopedic trauma without head injury (Rothoerl & Woertgen, 2001). However, recent data highlight the inclusion of S100B in sets of markers, which in combination could contribute to better diagnosis, monitoring and treatment of CNS conditions (Chmielewska et al., 2018).
Glial Fibrillary Acidic Protein (GFAP) is a monomeric intermediate filament (structural) protein that maintains cell shape and structure, coordinates cells mobility and contributes to the transduction of molecular signals in astrocytes (Chmielewska et al., 2018). It is released upon cellular disintegration and degradation of the cytoskeleton (Mondello, Jeromin, et al., 2012). Concentration of serum GFAP increases after neural trauma (Vijayan, Lee, & Eng, 1990) and TBI (Nylen et al., 2006). GFAP measurements have provided promising data on injury pathway indication (Mondello, Jeromin, et al., 2012; Mondello et al., 2011), focal versus diffuse injuries (Mondello, Jeromin, et al., 2012), and prediction of morbidity and mortality (Strathmann et al., 2014). GFAP level was increased in patients with CT positive scans for intracranial lesions compared to CT negative scans after mild TBI (Lei et al., 2015). Sensitivities have been reported between 67% and 100%, while the specificities range from 0% and 89% (Mondello et al., 2017).
McMahon et al (2015) performed a multi-center trial to validate and characterize the use of GFAP breakdown products GFAP-BDP in the diagnosis of intracranial injury in a broad population of patients with a positive clinical screen for head injury. They found that "GFAP-BDP demonstrated very good predictive ability (AUC=0.87) and demonstrated significant discrimination of injury severity (odds ratio, 1.45; 95% confidence interval, 1.29-1.64). Use of GFAP-BDP yielded a net benefit above clinical screening alone and a net reduction in unnecessary scans by 12-30%. Used in conjunction with other clinical information, rapid measurement of GFAP-BDP is useful in establishing or excluding the diagnosis of radiographically apparent intracranial injury throughout the spectrum of TBI."
Ubiquitin C-terminal Hydrolase-L1 protein (UCH-L1) is a cytoplasmic enzyme highly enriched and specifically expressed in neurons, involved in the ubiquitinoylation of abnormal proteins destined for proteasomal degradation (Halford et al., 2017). It is also an important element of axonal transport and, by a strong interaction with cytoskeleton proteins, plays an important role in the axons' integrity (Chmielewska et al., 2018). UCH-L1 has been shown to increase after TBI, correlate with TBI severity and abnormal CT findings (Diaz-Arrastia et al., 2014). High prognostic value of poor outcome was found at both 3-month (Diaz-Arrastia et al., 2014) and 6-month intervals (Mondello, Akinyi, et al., 2012). Two recent studies report the same sensitivity of 100% and specificities of 21% and 39% (Mondello et al., 2017).
Welch et al (2016) conducted a multicenter prospective observational study that evaluated three serum biomarkers' (glial fibrillary acidic protein [GFAP], ubiquitin C-terminal hydrolase-L1 [UCH-L1] and S100B measured within 6 h of injury) ability to differentiate CT negative and CT positive findings. They found that "UCH-L1 was 100% sensitive and 39% specific at a cutoff value >40 pg/mL. To retain 100% sensitivity, GFAP was 0% specific (cutoff value 0 pg/mL) and S100B had a specificity of only 2% (cutoff value 30 pg/mL). All three biomarkers had similar values for areas under the receiver operator characteristic curve: 0.79 (95% confidence interval; 0.70–0.88) for GFAP, 0.80 (0.71–0.89) for UCH-L1, and 0.75 (0.65–0.85) for S100B. Neither GFAP nor UCH-L1 curve values differed significantly from S100B (p = 0.21 and p = 0.77, respectively). In our patient cohort, UCH-L1 outperformed GFAP and S100B when the goal was to reduce CT use without sacrificing sensitivity. UCH-L1 values <40 pg/mL could potentially have aided in eliminating 83 of the 215 negative CT scans."
Currently, Banyan BTITM (Brain Trauma Indicator BTI) from Banyan Biomarkers, Inc. is the only FDA-approved blood test available for clinical measurement of mTBI. The Banyan BTI is an in-vitro diagnostic chemiluminescent enzyme-linked immunosorbent assay (ELISA). The test consists of two kits that provide a semi-quantitative measurement of the concentrations of UCH-L1 and GFAP from serum collected within 12 hours of suspected head injury. Results from the test should be interpreted according to the table provided by the manufacturer. The test is claiming high sensitivity and high specificity in studies performed by the manufacturer (Banyan Biomarkers, Inc.).
On Feb 14, 2018 the U.S. Food and Drug Administration approved marketing of the first blood test, Banyan BTITM (Brain Trauma Indicator BTI) from Banyan Biomarkers, Inc., to evaluate mild traumatic brain injury (mTBI), commonly referred to as concussion, in adults. The test is approved to be used, along with other available clinical information, as an aid in the evaluation of patients 18 years of age and older with suspected traumatic brain injury (Glasgow Coma Scale score 13-15). A result from this test is associated with absence or presence of acute intracranial lesions visualized on a head CT (computed tomography) scan (FDA, 2018).
Measurement of the blood markers for the evaluation of mild traumatic brain injury also known as concussion markers, including S100B, GFAP, and UCH-L1, is considered INVESTIGATIONAL. This also includes proprietary panel tests and kits, including Banyan BTI™.
American College of Emergency Physicians (Jagoda et al., 2008) recommended in mild TBI patients without significant extracranial injuries and a serum S100β of level less than 0.1μg/L measured within 4 h of injury, consideration could be given to not performing a CT.
Centers for Disease Control (CDC, 2016) reaffirmed the 2008 ACEP recommendation in 2016.
The Veterans Administration and Department of Defense (VA/DoD, 2016) Practice Guideline for the Management of Concussion – mild Traumatic Brain Injury states that:
"Excluding patients with indicators for immediate referral, for patients identified by post-deployment screening or who present to care with symptoms or complaints potentially related to brain injury, we suggest against using the following tests to establish the diagnosis of mTBI or direct the care of patients with a history of mTBI:
- Serum biomarkers, including S100 calcium-binding protein B (S100-B), glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal esterase L1 (UCH-L1), neuron specific enolase (NSE), and α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid receptor (AMPAR) peptide
- Electroencephalogram (EEG)"
Eastern Association for the Surgery of Trauma (Barbosa et al., 2012) states that "Biochemical markers such as S-100, neuron-specific enolase, and serum tau should not be routinely used in the clinical management of patients with MTBI except in the context of a research protocol."
The American Association of Neuroscience Nurses/Association of Rehabilitation Nurses recommend:
- "After TBI, proteins are released into the bloodstream after crossing the blood-brain barrier, which can be detected by laboratory testing. Research surrounding biomarkers has focused on their correlation with CT findings and clinical outcomes.
- Some studies have shown that S-100B could reduce the number of CT scans performed on MTBI patients by as much as 30%, resulting in reduced health care costs. However, further validation needs to be performed before this can be universally accepted and FDA approval has not been given."
The consensus statement from American College of Sports Medicine (ACSM), American Academy of Family Physicians (AAFP), American Academy of Orthopaedic Surgeons (AAOS), American Medical Society for Sports Medicine (AMSSM), American Orthopaedic Society for Sports Medicine (AOSSM), and the American Osteopathic Academy of Sports Medicine (AOASM) (Herring et al., 2011) states that: "Investigation in the area of biomarkers (e.g., S-100 proteins, neuron specific enolase, tau protein) is inconclusive for identifying individuals with concussion and represents research that may one day be clinically applicable."
Guidelines from The Brain Trauma Foundation (Carney et al., 2016), and the American Academy of Neurology (Giza et al., 2013) make no recommendation for or against any serum biomarkers of traumatic brain injury.
- Barbosa, R. R., Jawa, R., Watters, J. M., Knight, J. C., Kerwin, A. J., Winston, E. S., . . . Rowell, S. E. (2012). Evaluation and management of mild traumatic brain injury: an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute Care Surg, 73(5 Suppl 4), S307-314. doi:10.1097/TA.0b013e3182701885
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- CDC. (2015). Report to Congress on Traumatic Brain Injury Epidemiology and Rehabilitation | Concussion | Traumatic Brain Injury | CDC Injury Center. Atlanta, GA: Centers for Disease Control and Prevention. Retrieved from https://www.cdc.gov/traumaticbraininjury/pubs/congress_epi_rehab.html.
- CDC. (2016). Updated Mild Traumatic Brain Injury Guideline for Adults | Concussion | Traumatic Brain Injury | CDC Injury Center. Retrieved from https://www.cdc.gov/traumaticbraininjury/mtbi_guideline.html.
- Chmielewska, N., Szyndler, J., Makowska, K., Wojtyna, D., Maciejak, P., & Plaznik, A. (2018). Looking for novel, brain-derived, peripheral biomarkers of neurological disorders. Neurol Neurochir Pol. doi:10.1016/j.pjnns.2018.02.002
- Di Battista, A. P., Buonora, J. E., Rhind, S. G., Hutchison, M. G., Baker, A. J., Rizoli, S. B., . . . Mueller, G. P. (2015). Blood Biomarkers in Moderate-To-Severe Traumatic Brain Injury: Potential Utility of a Multi-Marker Approach in Characterizing Outcome. Front Neurol, 6. doi:10.3389/fneur.2015.00110
- Diaz-Arrastia, R., Wang, K. K., Papa, L., Sorani, M. D., Yue, J. K., Puccio, A. M., . . . Vassar, M. J. (2014). Acute Biomarkers of Traumatic Brain Injury: Relationship between Plasma Levels of Ubiquitin C-Terminal Hydrolase-L1 and Glial Fibrillary Acidic Protein. In J Neurotrauma (Vol. 31, pp. 19-25).
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- FDA. (2018). FDA authorizes marketing of first blood test to aid in the evaluation of concussion in adults [Press release]. Retrieved from https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm596531.htm
- Giza, C. C., Kutcher, J. S., Ashwal, S., Barth, J., Getchius, T. S., Gioia, G. A., . . . Zafonte, R. (2013). Summary of evidence-based guideline update: evaluation and management of concussion in sports: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology, 80(24), 2250-2257. doi:10.1212/WNL.0b013e31828d57dd
- Halford, J., Shen, S., Itamura, K., Levine, J., Chong, A. C., Czerwieniec, G., . . . Wanner, I. B. (2017). New astroglial injury-defined biomarkers for neurotrauma assessment. J Cereb Blood Flow Metab, 37(10), 3278-3299. doi:10.1177/0271678x17724681
- Hemphill, J. C. (2018). Traumatic brain injury: Epidemiology, classification, and pathophysiology - UpToDate. In M. Aminoff (Ed.), UpToDate. Retrieved from https://www.uptodate.com/contents/traumatic-brain-injury-epidemiology-classification-and-pathophysiology?source=see_link.
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- Ingebrigtsen, T., Romner, B., & Kock-Jensen, C. (2000). Scandinavian guidelines for initial management of minimal, mild, and moderate head injuries. The Scandinavian Neurotrauma Committee.J Trauma, 48(4), 760-766.
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- Maas, A. I. R., Menon, D. K., Adelson, P. D., Andelic, N., Bell, M. J., Belli, A., . . . Yaffe, K. (2017). Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol, 16(12), 987-1048. doi:10.1016/s1474-4422(17)30371-x
- Mannix, R., Eisenberg, M., Berry, M., Meehan, W. P., 3rd, & Hayes, R. L. (2014). Serum biomarkers predict acute symptom burden in children after concussion: a preliminary study. J Neurotrauma, 31(11), 1072-1075. doi:10.1089/neu.2013.3265
- McMahon, P. J., Panczykowski, D. M., Yue, J. K., Puccio, A. M., Inoue, T., Sorani, M. D., . . . Vassar, M. J. (2015). Measurement of the Glial Fibrillary Acidic Protein and Its Breakdown Products GFAP-BDP Biomarker for the Detection of Traumatic Brain Injury Compared to Computed Tomography and Magnetic Resonance Imaging. In J Neurotrauma (Vol. 32, pp. 527-533).
- Mondello, S., Akinyi, L., Buki, A., Robicsek, S., Gabrielli, A., Tepas, J., . . . Wang, K. K. (2012). CLINICAL UTILITY OF SERUM LEVELS OF UBIQUITIN C-TERMINAL HYDROLASE AS A BIOMARKER FOR SEVERE TRAUMATIC BRAIN INJURY. Neurosurgery, 70(3), 666-675. doi:10.1227/NEU.0b013e318236a809
- Mondello, S., Jeromin, A., Buki, A., Bullock, R., Czeiter, E., Kovacs, N., . . . Hayes, R. L. (2012). Glial neuronal ratio: a novel index for differentiating injury type in patients with severe traumatic brain injury. J Neurotrauma, 29(6), 1096- 1104. doi:10.1089/neu.2011.2092
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- Vijayan, V. K., Lee, Y. L., & Eng, L. F. (1990). Increase in glial fibrillary acidic protein following neural trauma. Mol Chem Neuropathol, 13(1-2), 107-118.
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- Wright, D. W., Kellermann, A., McGuire, L. C., Chen, B., & Popovic, T. (2013). CDC Grand Rounds: Reducing Severe Traumatic Brain Injury in the United States. MMWR Morb Mortal Wkly Rep, 62(27), 549-552.
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History From 2018 Forward
Annual review, no change to policy intent. Rephrasing policy verbiage for clarity and updating coding.
Updating next review date to line up with Avalon. No other changes made.
Corrected a typo in the coding section. No other changes was made.