Serum Testing for Evidence of Mild Traumatic Brain Injury - CAM 192

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 (Rajajee, 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, 2019).

Regulatory Status 
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).


  1. Measurement of blood, saliva and/or cerebrospinal fluid (CSF) biomarkers for the evaluation of mild traumatic brain injury, also known as concussion markers, including S100B, GFAP, and UCH-L1, is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY. This also includes proprietary panel tests and kits, including Banyan BTI™.

Traumatic brain injury (TBI) is a fairly common injury, with an incidence of 1.11 million and a prevalence of 2.35 million in the U.S. in 2016. 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. As many as 1 in 5 TBI patients have symptoms persisting past 1 month.

Accurate diagnosis of TBI is critical to effective management and intervention but can be challenging due to the nonspecific and variable presentation.  Tools available to objectively diagnose injury and prognosticate recovery are limited. Clinical assessment usually includes a neurological exam, followed by a computed tomography (CT) scan of the head to detect brain tissue damage that may require treatment. However, as most patients with mild TBI do not have detectable intracranial lesions, like epidural hematomas, on a CT scan, this assessment relies heavily on nonspecific symptoms that can vary widely and ignores the mechanistic heterogeneity of TBI.

Brain damage in TBIs is initially caused by external mechanical forces being transferred to intracranial contents, generating shearing and strain forces which stretch and damage axons, and can result in contusions, hematomas, cerebral edema and swelling. Common mechanisms include direct  impact, rapid acceleration/deceleration, penetrating injury, and blast waves. 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. 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.

Cell death and the initiation of local metabolic and inflammatory processes resulting from TBI results 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. Neurobiochemical marker levels in blood after TBI may reflect structural changes detected by neuroimaging. Simpler, sensitive, and specific tests that provide early, quantitative information about the extent of brain tissue damage, identifying and stratifying TBI, would allow rapid and tailored diagnosis of TBI, while minimizing the time, risk, and cost associated with current standards. No single ideal TBI biomarker exists. 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 and have been investigated both individually and in combination. 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.

S100 calcium-binding protein B (S100B)
S100B belongs to the calcium binding EF-hand protein group, and it has been associated with cytoskeleton structure, Ca2+ homeostasis, cell proliferation, protein phosphorylation and degradation. 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 patient and guidelines intended to reduce the need for CT scan using S100B levels in the blood for the initial management of mild TBI have been published. 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. The authors estimated CT scans would have been reduced by 32% with application of these guidelines. However, other investigators have failed to detect associations between S100B with CT abnormalities. 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, and its levels are also elevated in trauma, specifically orthopedic, without head injury. However, recent data highlight the inclusion of S100B in sets of markers that in combination could contribute to better diagnosis, monitoring, and treatment of CNS conditions.

Glial Fibrillary Acidic Protein (GFAP)
GFAPis a filament protein that maintains cell shape and structure, coordinates cells’ mobility and contributes to the transduction of molecular signals in astrocytes. It is released upon cellular disintegration and degradation of the astrocyte. Concentration of serum GFAP increases after neural trauma and TBI, either as the intact protein or as breakdown products. GFAP measurements have provided promising data on injury pathway indication, focal versus diffuse injuries, 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. Sensitivities have been reported between 67% and 100% while the specificities ranged from 0% and 89%. 

McMahon et al. (2015) performed a multicenter trial to evaluate GFAP and its breakdown product GFAP-BDP in the diagnosis of intracranial injury. They found that “GFAP-BDP demonstrated very good predictive ability (area under the curve=0.87) and demonstrated significant discrimination of injury severity (odds ratio, 1.45; 95% confidence interval, 1.29 – 1.64)”. The authors concluded that “use of GFAP-BDP yielded a net benefit above clinical screening alone and a net reduction in unnecessary scans by 12 – 30%.”

Ubiquitin C-terminal Hydrolase-L1 protein (UCH-L1)
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 axon’s integrity. UCH-L1 has been shown to increase after TBI in serum and CSF as well as correlate with TBI severity and abnormal CT findings. UCH-L1 has also been shown to be significantly elevated in serum among athletes after concussions. High prognostic value of poor outcome was found at both 3-months  and 6-months intervals. Two recent studies report the same sensitivity of 100% and specificities of 21% and 39%.

Clinical Utility and Validity
Welch et al. (2016) 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 for GFAP, 0.80 for UCH-L1, and 0.75 for S100B. Neither GFAP nor UCH-L1 curve values differed significantly from S100B. 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.” However, the authors note that further research is needed.

Wang et al. (2018) reported on the usage of TBI serum and CSF biomarkers as prognostic tools in the ED, neurointensive care unit, and out-of-hospital settings. In the case of mTBI, the researchers stated the similar biomarkers could aid in predicting any development of persistent post-concussive syndrome, including S100B, GFAP, and UCH-L1. Within 12 – 36 hours from TBI in neurointensive care units, it was found that serum levels of 100B correlate with patient outcomes, and S100B serum elvels > 0.7ng/mL correlate with 100% mortality. GFAP modestly correlates with poor outcomes, and “serum GFAP levels were also significantly higher in patients who died or had an unfavorable outcome and have predicted neurological outcome at 6 months.” It was also shown in other studies that GFAP and UCHL-1 proteins outperformed S100B in predicting poor outcomes, and the two together “predicate the recovery and unfavorable outcome by distinguishing patients with GOS [Glasgow Outcome Score] 1-3 from patients with GOS 4 – 5”.

Gan et al. (2019) evaluated TBI serum biomarkers for four clinical situations; “detecting concussion, predicting intracranial damage after mild TBI (mTBI), predicting delayed recovery after mTBI, and predicting adverse outcome after severe TBI (sTBI).” A total of 200 publications (61722 “observations”) were included. For concussion detection, 9 unique publications addressing 15 biomarkers and 946 observations were identified. Four panels (“copeptin, galectin-3, and MMP-9; GFAP and UCH-L1; 10 metabolites; and 17 metabolites”) were found to have areas under the curve (AUC) of over 0.9. For evaluation of necessity of CT scan after TBI, 56 publications, 24 biomarkers, and 23,316 observations were identified. S-100B (30 publications, 8464 observations) was found to have an AUC of 0.723 and GFAP/GFAP-BDP (16 publications, 2,040 observations) was found to have an AUC of 0.831. For evaluation of delayed recovery after mTBI, 44 publications, 29 biomarkers, and 13,291 observations were identified. S-100B (24 publications, 2,800 observations) had an AUC of 0.691; GFAP’s AUC was 0.716 (17 publications, 1959 observations). Finally, for evaluation of poor outcome after sTBI, S-100B (25 publications, 3,712 observations) was rated at AUC of 0.762, and GFAP (10 publications, 2,448 observations) was rated at AUC of 0.749. Neuron-specific enolase (9 publications, 911 observations) was rated at AUC of 0.715.

Banyan BTITM (Brain Trauma Indicator BTI) from Banyan Biomarkers, Inc. is a proprietary blood test available for clinical measurement of mild TBI. The Banyan BTI is an in vitro diagnostic chemiluminescent enzyme-linked immunosorbent assay (ELISA). The test consists of two kits which 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 cut-offs for UCH-L1 and GFAP are 327 pg/mL and 22 pg/mL respectively.

The Banyan BTI test was validated with a sample of 1,947 patients. Of these 1,947 patients, 120 had positive CT scans, and 117 of these 120 patients tested positive by Banyan BTI (97.5% sensitivity). Of the remaining 1,827 patients that tested negative, 666 tested negative by Banyan for a specificity of 36.5%. A total of 669 patients had negative Banyan results, so the negative predictive value was 99.6%.  

Another proprietary test for TBI has been designated as a “Breakthrough Device” by the U.S. Food and Drug Administration (FDA). The Tbit platform by BioDirection uses nanowires to detect specific protein molecules that are characteristic of TBI. This platform measures S100B and GFAP in the bloodstream. The manufacturer claimed a sensitivity of 100% and specificity of 41% on a sample of 100 patients. However, BioDirection includes a disclaimer saying that Tbit is not FDA-approved, not for use in diagnostic procedures, and only for research use (BioDirection, 2015). They claim, “The Tbit System is designed to measure the body’s response to trauma and provide a rapid point-of-care test result in less than 2 minutes from a single drop of blood, while current technology may run 3 – 4 hours or more and require serum testing in a central laboratory”.

In January 2021, Abbott Laboratories received FDA 510(K) clearance for the i-STAT™ Alinity™ handheld device, which would help evaluate mTBIs. It simultaneously measures UCH-L1 and GFAP in blood and produces results in 15 minutes once a plasma sample is inserted. It has a sensitivity of 95.8% and a > 99% negative predictive value. Abbott Laboratories states that this blood test’s availability “could help eliminate wait time in the emergency room and could reduce the number of unnecessary CT scans by up to 40%.” The company is also working on a whole blood test, and has received breakthrough designation to create a TBI test that runs “on its Alinity™ and ARCHITECT® core laboratory instruments”.

American College of Emergency Physicians (Jagoda et al., 2009) 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 (Level C).

Centers for Disease Control reaffirmed the 2008 ACEP recommendation in 2016. However, in 2018, the CDC remarked that “Health care professionals should not use biomarkers outside of a research setting for the diagnosis of children with mTBI”, noting that there is insufficient evidence to recommend any of the studied biomarkers for mTBI diagnosis in children. The CDC identified S100B, tau protein, autoantibodies against glutamate receptors and oxide metabolites, neuronal ubiquitin C-terminal hydrolase-L1, and glial fibrillary acidic protein biomarker levels as biomarkers that have been studied for concussion evaluation.

The Veterans Administration and Department of Defense 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:

a. Neuroimaging

b. 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

c. Electroencephalogram (EEG)”

Eastern Association for the Surgery of Trauma state 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 consensus statement from American College of Sports Medicine (ACSM), American Academy of Family Physicians (AAFP), American Academy of Orthopedic Surgeons (AAOS), American Medical Society for Sports Medicine (AMSSM), American Orthopedic Society for Sports Medicine (AOSSM), and the American Osteopathic Academy of Sports Medicine (AOASM) 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; Kochanek et al., 2019), and the American Academy of Neurology make no recommendation for or against any serum biomarkers of traumatic brain injury.

Concussion in Sport Group (CISG, 2017)
The Group states that fluid biomarkers are “important research tools” but need further validation and research to determine their clinical utility.

Brain Trauma Foundation (2014) 
The Foundation states that, although biomarkers are promising, there is not enough conclusive evidence to support their use.

American Academy of Pediatrics (AAP, 2018)
The AAP acknowledges that biomarkers such as “S100β, glial fibrillary acidic protein, neuron-specific enolase, τ, neurofilament light protein, amyloid β, brain-derived neurotrophic factor, creatine kinase and heart-type fatty acid binding protein, prolactin, cortisol, and albumin” have all been investigated in concussion evaluation, but none of these biomarkers have been used in clinical settings.

National Institute of Care and Excellence (NICE, 2019) 
The NICE guidelines regarding “assessment and early management of head injury in children, young people and adults” do not mention any serum biomarkers for evaluation of head injuries.

American Medical Society for Sports Medicine (2019)
The Society notes that fluid biomarkers (blood, saliva, and cerebrospinal fluid) in diagnosis of sports-related concussion is under active investigation, but states that overall evidence level is “low”. The Society writes that more studies are needed to determine their clinical utility. The Society also acknowledges the FDA approval of the “two-protein brain trauma indicator with glial fibrillary acidic protein and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), and clinical use of S100 calcium-binding protein b (s100b) in Europe”, but remark that neither of these tests have a role in diagnosis or management of a sports-related concussion.

Ontario Neurotrauma Foundation (ONF, 2018)
The ONF published this guideline titled “Guideline for Concussion/Mild Traumatic Brain Injury & Persistent Symptoms”, for adults, 3rd Edition in 2018. In it, they state that “Blood-based biomarkers are still considered investigational and therefore are not recommended for use in diagnosing/ assessing patients in the ED or PCP’s office”.

American Congress of Rehabilitation Medicine Brain Injury Interdisciplinary Special Interest Group Mild TBI Task Force (2020)
This task force published a synthesis of practice guidelines for “Management of Concussion and Mild Traumatic Brain Injury.” In it, they note that the Scandinavian Neurotrauma Committee guidelines recommend that “S100B values of <0.10 mg/L, if sampled within 6 hours of injury, can help rule out the need for CT in patients younger than 65 years with a Glasgow Coma Scale score of 14 or a Glasgow Coma Scale score of 15 with loss of consciousness or repeated vomiting”. However, they also remark that neither GFAP nor C-terminal hydrolase-L1 have been incorporated into any published clinical practice guidelines. Further, the task force notes that the biomarkers’ incremental value over established clinical decision rules (such as the Canadian CT head rule) is unknown.

The task force also states that “At present, there is no objective biomarker to determine mTBI resolution.”


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Coding Section






Unlisted molecular pathology procedure 



Unlisted chemistry procedure

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2018 Forward     


Annual review, no change to policy intent.


Annual review, no change to policy intent. Updating rationale and references. 


Annual review, updating policy verbiage to include saliva and CSF. No change to policy intent. Also updating background, rationale and references. 


Annual review, no change to policy intent. Rephrasing policy verbiage for clarity and updating coding. 


Updating next review date to line with Avalon. No other changes made. 


Corrected a typo in the coding section. No other changes was made. 


New Policy

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