Serum Markers in Quantification of TBI

As neurosurgeons, we take care of patients with traumatic injuries of  the most complex and important organ, the brain. However, the tools available to assess the extent of the traumatic brain injury (TBI) and predict outcomes stand in stark contrast to the life-course-altering impact a TBI can have on an individual and his family. Just imagine a cardiologist ordering a CT scan of the heart to figure out how well it is working; unimaginable, but this is exactly what we are doing for our patients with TBI.

Research effort to lessen or cure traumatic brain injury is hampered by significant heterogeneity of the study patient population. Biomarkers may offer a therapeutic or curative option for TBI. Bio-fluid-based biomarkers, and in this discussion, serum-based biomarkers, represent a potential tool to diminish the noise associated with the plethora of clinical presentations and quantitatively define the extent of injury. We may learn that the population appears heterogeneous, but when focusing on the brain injury, outcomes and treatment responses can become more reliably predicted.

The first published study regarding serum biomarkers in TBI was published in 1993, discussing protein 14-3-2 as well as total myelin protein. In 1995, Ingebrigtsen et al. published a series of patients with head injury who had serum levels of S-100 drawn at admission and 12 hours later with findings suggestive that this biomarker could potentially provide both diagnostic and prognostic information, even after minor TBI without radiographic abnormality. Since that time, several biomarkers have been developed, each bringing attention to injury of a specific element of the nervous system, including neuronal cell bodies, dendrites, axons, synapses, astroglia and microglia.

Several blood biomarkers are being studied; however, some stand out regarding current clinical applications. These include GFAP, S100B, NF-L and UCH-L1. S100B is the most studied protein present in CNS astrocytes. This is present in the blood within one hour and peaks <6 hours. It does not have high specificity to the brain; however, due to its sensitivity, there is an opportunity to use this as a screening tool prior to undergoing a CT head/radiation. It also contributes to the prediction of poor outcomes as well as the presence of ongoing secondary injury. Because of this, some recommend this as a reasonable option for serial testing in the ICU setting to monitor recovery and/or development of secondary brain injury.

Glial fibrillary acidic protein (GFAP) is a protein expressed in glial cells. It is an FDA-approved blood test to assess for neurologic injury and point of care (POC) technology is available for use in the ED and possibly in the pre-hospital setting in the future. GFAP has both sensitivity and specificity for brain injury and correlates with both presentation GCS scores and CT findings. Thus, it is a good test to triage for scanning. Levels also predict death and unfavorable outcomes.

Neurofilament proteins (NF) are proteins exclusively found in neurons. NF-L is a known biomarker that can correlate with diffusion tensor imaging (DTI) as a measure of axonal injury and outcomes. This biomarker can also provide insight about patients prone to further neurologic decline. Of note, day-of-injury levels can predict incomplete recovery; this is promising for minor TBI and/or concussion.

Ubiquitin C-terminal hydrolase-L1 (UCH – L1) is of neuronal origin within the cytoplasm. This is detectable within one hour and peaks at eight hours. CENTER-TBI has shown that it adds to the prognostication ability when integrated with IMPACT and CRASH scores. It is also expressed in the testis, ovaries and kidneys, and thus has lower specificity; however, when combined with GFAP, the sensitivity, and specificity for brain injury is greatly improved. In addition to GFAP, it also can prognosticate death and poor outcomes.

Biomarkers can play many roles in the care of our TBI patients, including pre-hospital evaluation, screening for imaging necessity and determining the severity of an injury. Once a brain injury is established, biomarkers can also provide longitudinal information on recovery,  either in the ICUs during acute illness or later during rehabilitation. Prognostic information can also be provided by these biomarkers, which, when discussed in the appropriate context, can help providers and families make treatment decisions.