During the management of concussions, we are always looking for more objective tests that can help diagnose mild traumatic brain injuries (mTBI) and help guide the treatment of these patients. One of the current cutting-edge technologies that has gained some traction in the media in the past few years is using blood biomarkers and laboratory testing in managing concussions. It is an up-and-coming and ever-changing space in concussion research. In this blog, we will discuss whether or not laboratory findings should be routinely used to diagnose and manage acute and persistent concussions.
Three main topics regarding the use of blood biomarkers will be discussed (1):
The theory behind using blood tests for concussion testing is that if there is an injury to the neuronal structures of the brain and/or the blood-brain barrier, we should start to see brain-specific proteins in the systemic circulation that are generally absent. While that is an excellent theory, it turns out that it is not as specific to neurological disorders as we would like.
Currently, there is no accurate concussion laboratory test because there are no reliable blood markers that are both specific and sensitive to mild traumatic brain injury. There are a few blood markers of interest in research settings, but more work needs to be done before they are readily available clinically. There are a handful of blood biomarkers that are showing promise, but they still cannot outperform our clinical tests, such as a complete neurological exam and comparison to baseline testing values; therefore, they have little clinical utility.
The current blood markers that have shown some promise include:
S100B is a calcium-binding protein found in astrocytes, glial cells, adipose tissue, cardiac cells, and skeletal muscles. Because of its abundance in glial cells, the theory is that elevated blood levels of S100B may suggest increased intracranial damage and the presence of a concussion.
However, in a study conducted by Geyer et al. (2009), S100B levels were unable to distinguish between children who had a mild head injury with no symptoms and those who had a head injury and concussion symptoms. Furthermore, S100B levels have been shown to be increased in ice hockey players, marathon runners, boxers, and basketball players who did not sustain a head injury, which suggests that exercise alone may also increase S100B levels (1).
While S100B may not be able to diagnose a concussion, it is promising in its ability to rule out more severe intracranial injuries, such as intracranial hemorrhage or skull fracture. Castellani et al. (2009) showed that normal S100B levels predicted the absence of intracranial injury and skull fracture with 100 percent accuracy in adolescents who sustained a head injury.
Adult data also showed that S100B could accurately rule out intracranial injury, which can reduce the need for unnecessary brain imaging in uncomplicated cases. A recent meta-analysis showed that at its threshold of 0.1 μg/L, S100B had a sensitivity of 91% and a specificity of 30%, meaning that it is quite good at ruling out a concussion but not good at confirming that a concussion is present (4).
Therefore, S100B has some promise as an immediate post-concussion assessment tool in its ability to rule out more severe injury. Still, it is not specific enough for generalized use in clinical care.
NSE is an enzyme found in neuronal cytoplasm, smooth muscle cells, adipose cells, red blood cells, and platelets.
In the aforementioned study by Geyer et al. (2009), NSE levels were also unable to distinguish between children who had a mild head injury with no symptoms and those who had a head injury and concussion symptoms.
Furthermore, NSE could not detect the presence or absence of intracranial injury in this population and would have missed 25% of intracranial injuries (6).
Additionally, a systematic review on the prognostic value of NSE for the prediction of prolonged concussion symptoms after mTBI found no association in 9 of the 10 studies included. Only one study found a positive value, and it was only at the 2-week time period. NSE was non-predictive at later time points (7).
GFAP is a filament protein found in astrocytes. Laboratory testing has shown some promise in accurately diagnosing concussion and/or intracranial injury.
There was a significant difference in GFAP levels in concussed collegiate athletes during the acute phase compared to their pre-season baseline levels. However, this difference peaked at 24h post-injury and returned to baseline levels within a week (9). Interestingly, GFAP levels were also higher in athletes who sustained loss of consciousness or post-traumatic amnesia, suggesting that GFAP may also track acute injury severity.
Unfortunately, GFAP levels immediately after injury were not predictive of PCS burden; therefore, they may be more useful as a concussion screening tool than a management tool (10).
GFAP has also shown promise in its ability to rule out more serious intracranial injury after mTBI, showing 71% sensitivity and 71% specificity in detecting more severe brain injury after a head impact.
UCH-L1 is one of the most abundant proteins in the brain, making up 1-5% of total neuronal protein.
Similar to GFAP, UCH-L1 is elevated in collegiate athletes in the first 24 hours post-concussion compared to their pre-season baseline levels (9). There have been varying reports on the utility of this finding because studies have also shown elevated levels of UCH-L1 in non-concussion orthopedic injuries, which may mean that it is more injury-sensitive than concussion-sensitive (10).
NFL is part of the intermediate filament proteins found abundantly in the axons of neurons.
In a recent meta-analysis, NFL was found to be significantly elevated in patients who have sustained a head injury or concussion compared to control subjects (11). Subgroup testing showed that patients suffering from sports-related mTBI had the highest levels of serum NFL. Still, there was no association found in head injuries alone or military veterans who sustained an mTBI.
Other studies in athletes who sustained a sports-related concussion showed that NFL levels remained elevated in PCS patients up to 5 years after the initial injury in those that are still symptomatic compared to control subjects, showing its possible usefulness in both acute and chronic concussions (17).
This begs the question of whether NFL is useful as an mTBI marker generally or if there is something more specific to sports injuries that leads to the higher levels seen in the research. More research is needed to determine the accuracy of its use in different patient populations.
Tau is one of the microtubule-associated proteins within the structure of axons. It has received considerable media attention due to the link between hyperphosphorylated tau, the formation of perivascular neurofibrillary tangles, and their correlation with chronic traumatic encephalopathy (CTE).
In acute concussions, however, Tau does not seem to be a valuable biomarker to diagnose concussions, as all athletes, regardless of whether they have sustained a concussion, have increased tau concentrations compared to control subjects. There is some evidence that tau levels may be a prognostic factor, as the athletes who had sustained an mTBI and had the highest tau levels took the longest to return to sport (12).
There is gaining traction for the use of inflammatory biomarkers for the diagnosis of concussion, but the specificity of the markers is still up for debate.
Nitta et al. (2019) found that there was a significant elevation of IL-6 and IL-1RA after mTBI compared to pre-injury levels and control subjects in high school football players. IL-6 levels at 6 hours post-injury were also predictive of the length of symptom recovery. However, IL-6 is not specific to concussion and is elevated in many different injury conditions, so it is likely more helpful as a prognosis tool than ruling concussions in or out.
Other inflammatory markers of interest include fibroblast growth factor 21 (FGF21) and monocyte chemoattractant protein 1 (MCP-1), which are related to an increase in the number and severity of symptoms post-mTBI (14). Again, research into the sensitivity and specificity of these inflammatory molecules is still ongoing.
The first and only blood test that the FDA has approved for use in mTBI is the combination use of GFAP and UCH-L1, but not for the diagnosis of concussion, but rather screening for the presence of intracranial hemorrhage.
While the approval of this test made its rounds on news outlets as a concussion test, that is not accurate reporting. There remains to be an FDA-approved test for the diagnosis of concussion in the absence of intracranial hemorrhage. The combination of GFAP and UCH-L1 is only 70% accurate in diagnosing concussions, which is still well below the 94% accuracy of the SCAT symptom score.
So, while technically, there is a blood test that the FDA has approved for use in the clinical post-concussion assessment, it is not specific to diagnosing concussion but instead ruling out more severe conditions as a means of decreasing the amount of unnecessary imaging.
https://www.fda.gov/news-events/press-announcements/fda-authorizes-marketing-first-blood-test-aid-evaluation-concussion-adults
When a patient’s concussion symptoms become chronic, it can be challenging to determine what the exact driver of their ongoing symptoms is because of the symptom overlap between the various physiologic systems. Therefore, using a battery of standard laboratory tests to rule out other common conditions that could be contributing to their persistent symptom burden may be warranted.
For example, a complete blood count to rule out conditions such as anemia in younger female athletes that are prone to anemia would be indicated if your patient is presenting with symptoms of both anemia and concussion, such as persistent headaches, chronic fatigue, difficulty concentrating, irritability, etc.
Other panels that may be worth running in certain populations include laboratory tests of blood glucose levels, thyroid hormone levels, and a basic metabolic panel.
Furthermore, because of the associated autonomic dysfunction that is found in a subset of patients with PCS and the possibility of damage to the pituitary gland and stalk during the initial injury, running blood tests to check pituitary hormone and downstream sex steroid levels may also be warranted if they are not responding to a physical rehabilitation program.
https://pubmed.ncbi.nlm.nih.gov/36788181/
Below is a table of some of the common symptoms that are associated with pituitary dysfunction (15, 16):
| Acute corticotroph deficiency | weakness, fatigue, nausea, dizziness, vomiting, hypoglycemia, hypotension |
| Chronic corticotroph deficiency | pallor, weight loss, anorexia, tiredness, hypoglycemia |
| Thyrotropin deficiency | weight gain, constipation, tiredness, dry skin, hair loss, cold intolerance, slow mental processes, hoarseness, bradycardia |
| Gonadotropin deficiency |
|
| Growth Hormone deficiency (adults) | decreased quality of life, fatigue, increased visceral fat mass, decreased muscle strength and mass, premature atherosclerosis |
| Prolactin deficiency (woman) | inability to breastfeed |
| Antidiuretic Hormone deficiency | nocturia, polyuria, polydipsia |
These dysfunctions are most common in more severe head injuries, such as those that sustained a basal skull fracture, intracranial hemorrhage, cortical contusions, diffuse axonal injury, and those who experienced post-traumatic seizures. Other risk factors include older patients and those who sustained a car accident after sustaining a primary concussion (15,16).
To read more about how concussions can affect the autonomic nervous system, please see our previous blog post: What Flavor/Subtype of Concussion Does Your Patient Have? Autonomic Type Deep-Dive.
In conclusion, having a readily available blood test to aid in the diagnosis and management of concussions is something that has the potential to improve our management of mild traumatic brain injuries significantly. Unfortunately, there is just not good enough research to conclude that any currently available testing is sensitive or specific enough to be used over our already existing methods of diagnosis. It is an area of ongoing research and something the entire concussion healthcare community will keep a close eye on over the coming years as research continues to press further into the concussion biomarker space.
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